Transferrin: From Inorganic Biochemistry to Medicine

Transferrin is one of the key proteins of iron metabolism in mammalians. It is responsible for the transfer of the essential iron(III) ions through the biological fluids from absorption to storage and utilization sites. Moreover, transferrin is involved in the metabolism of other metal ions that are either trace or toxic elements. In recent years the crystal structure of transferrin has been solved at high resolution. This has allowed an extensive reinterpretation of the many spectroscopic studies carried out on this protein in the last decade as well as the elucidation of some interesting structure-function relationships. We review here recent progresses in transferrin biochemistry, particular focus being given to those aspects that are relevant from a medical point of view

The Interaction of the Antitumor Complexes Na[trans-RuCl4 (DMSO)(Im)] and Na[trans-RuCl4(DMSO)(Ind)] With Apotransferrin: a Spectroscopic Study

The interaction of two antitumor ruthenium(III) complexes,-Na[trans-RuCl4(DMSO)(Im)] and Na[trans-RuCl4(DMSO)(Ind)]- with human serum apotransferrin (apoTf) was investigated through a number of spectroscopic techniques such as UV-Vis absorption, CD and 1H NMR spectroscopy. Interestingly, the hydrolysis profiles of these complexes in a physiological buffer are markedly affected by the presence, in solution, of apoTf suggesting the occurrence of a specific interaction of their respective hydrolysis products with the protein. The formation of stable adducts with apotransferrin has been demonstrated by CD spectroscopy, and additional information obtained through 1H NMR of the hyperfine shifted signals. The bound ruthenium(III) species may be detached from these adducts by addition of excess citrate at low pH. The behavior of the investigated ruthenium(III) complexes with apoTf is compared with that of the recently described and strictly related ru-im and ru-ind antitumour complexes, and discussed in the frame of general strategies of drug targeting

Elastocapillary network model of inhalation

The seemingly simple process of inhalation relies on a complex interplay between muscular contraction in the thorax, elasto-capillary interactions in individual lung branches, propagation of air between different connected branches, and overall air flow into the lungs. These processes occur over considerably different length and time scales; consequently, linking them to the biomechanical properties of the lungs, and quantifying how they together control the spatiotemporal features of inhalation, remains a challenge. We address this challenge by developing a computational model of the lungs as a hierarchical, branched network of connected liquid-lined flexible cylinders coupled to a viscoelastic thoracic cavity. Each branch opens at a rate and a pressure that is determined by input biomechanical parameters, enabling us to test the influence of changes in the mechanical properties of lung tissues and secretions on inhalation dynamics. By summing the dynamics of all the branches, we quantify the evolution of overall lung pressure and volume during inhalation, reproducing the shape of measured breathing curves. Using this model, we demonstrate how changes in lung muscle contraction, mucus viscosity and surface tension, and airway wall stiffness---characteristic of many respiratory diseases, including those arising from COVID-19, cystic fibrosis, chronic obstructive pulmonary disease, asthma, and emphysema---drastically alter inhaled lung capacity and breathing duration. Our work therefore helps to identify the key factors that control breathing dynamics, and provides a way to quantify how disease-induced changes in these factors lead to respiratory distress.Comment: In pres

Caracterização e diferenciação de espécies florestais por meio da análise de imagens de sementes: uma nova abordagem metodológica

Biometric seed analysis can be used to characterize and differentiate forest species. However, forest species are generally studied using manual methods such as measurements with a digital caliper, which provides a limited amount of information on plant morphological characteristics, whereas agronomic species are analyzed using expensive and often inaccessible equipment. Thus, the objective of the present study was to demonstrate that seed image analysis and processing tools can help characterize and differentiate Brazilian forest species. For this purpose, the seeds of 155 forest species belonging to 42 families were photographed and analyzed to extract data on their morphometric descriptors using a new methodological approach. A total of 18 characteristics were assessed, namely eight dimensions, four shape characteristics, and six color characteristics. A set of approximately 1.827 million data was extracted from 101,521 seed images. Digital image processing efficiently characterized the studied seeds and the obtained characteristics allowed us to differentiate between species, including those belonging to the same botanical family and genus. Therefore, seed image analysis using the proposed methodology can be used to characterize, differentiate, and automatedly identify forest species in Brazil.A análise biométrica de sementes contribui para a caracterização e diferenciação de espécies florestais. Entretanto, os estudos com espécies nativas geralmente utilizam métodos manuais como o paquímetro digital, o qual extrai uma quantidade limitada de características, enquanto espécies agronômicas dispõem de equipamentos caros e pouco acessíveis. Assim, o objetivo deste trabalho é demonstrar que ferramentas de análise e processamento de imagens de sementes podem auxiliar na caracterização e diferenciação de espécies nativas brasileiras. Para isso, sementes de 155 espécies nativas, distribuídas em 42 famílias botânicas foram fotografadas e analisadas para extração de descritores morfométricos por meio de uma nova abordagem metodológica. Um total de 18 características foram geradas, sendo oito para dimensões, quatro para formato, e seis para cor. Um conjunto de aproximadamente 1,827 milhões de dados foram obtidos a partir 101.521 imagens de sementes. O processamento digital de imagens foi eficiente para a caracterização das sementes nativas, e as características utilizadas permitiram diferenciar as espécies, inclusive àquelas que estão contidas na mesma família botânica e gênero. Portanto, a análise de imagens de sementes pela metodologia proposta contribui para a caracterização, diferenciação e automatização na identificação de espécies florestais nativas do Brasil

Elastometry of Complex Fluid Pendant Capsules

Oil/water interfaces are ubiquitous in nature. Opposing polarities at these interfaces attract surface-active molecules, which can seed complex viscoelastic or even solid interfacial structure. Biorelevant proteins such as hydrophobin, polymers such as PNIPAM, and the asphaltenes in crude oil (CRO) are examples of some systems where such layers can occur. When a pendant drop of CRO is aged in brine, it can form an interfacial elastic membrane of asphaltenes so stiff that it wrinkles and crumples upon retraction. Most of the work studying CRO/brine interfaces focuses on the viscoelastic liquid regime, leaving a wide range of fully solidified, elastic interfaces largely unexplored. In this work, we quantitatively measure elasticity in all phases of drop retraction. In early retraction, the interface shows a fluid viscoelasticity measurable using a Gibbs isotherm or dilatational rheology. Further retraction causes a phase transition to a 2D elastic solid with nonisotropic, nonhomogeneous surface stresses. In this regime, we use new techniques in the elastic membrane theory to fit for the elasticities of these solid capsules. These elastic measurements can help us develop a deeper understanding not only of CRO interfaces but also of the myriad fluid systems with solid interfacial layers.</p

BIOACTIVE COMPOUNDS IN DIASPORES OF Astronium urundeuva (M.Allemão) Engl. FOR QUALITY MAINTENANCE DURING STORAGE

The success of seed production and marketing depends on ideal conditions for storage. Some forest species have seed conservation problems due to the high incidence of fungi that reduce physiological quality. Thus, the objective was to evaluate the effectiveness of the application of bioactive compounds in diaspores of Astronium urundeuva (M.Allemão) Engl. (Anacardiaceae) to maintain physiological quality and reduce the incidence of fungi during storage. For this, two factorial trials were set up: (i) application of four essential oils (cinnamon, clove, orange and melaleuca) at five concentrations (0.00, 1.25, 2.50, 3.75 and 5.0 mL.kg-1); and (ii) five plant extracts (clove, cinnamon, quina, garlic and lemongrass) at five concentrations (0%, 25%, 50%, 75% and 100%). Diaspores were evaluated at 0, 30, 60, 90, 120, 150 and 180 days for germination, seed vigor and fungal incidence. The essential oils of clove (4.6 mL.kg-1) and melaleuca (3.7 mL.kg-1) and plant extracts of clove (71%) and lemongrass (73%) can be applied to maintain physiological quality and reduce the incidence of fungi during the storage of A. urundeuva diaspores. In addition to these, the essential oils of cinnamon (3.8 mL.kg-1) and orange (4.0 mL.kg-1) and plant extracts of cinnamon (72%) and quina (74%) can be used as an alternative to synthetic fungicide. Therefore, the application of products based on natural bioactive compounds is an alternative to the use of chemicals in sanitary control during the storage of A. urundeuva seeds

Viabilidade de sementes de erva-mate oriundas de polinização controlada.

Com base na autoecologia das espécies, este estudo tem como hipótese, que cruzamento não endogâmicos produzem sementes com maior percentual de embriões viáveis. Desta maneira, objetivouse avaliar a viabilidade de sementes de erva-mate oriundas de polinização controlada. Para tanto, galhos de duas fêmeas e um macho, não aparentados, foram isolados com sacos de tecido não tramado (TNT), preso com arame fino e enrolado algodão hidrofóbico, para evitar o anelamento dos galhos e entrada de insetos e água. Após a antese, flores masculinas foram coletadas e friccionadas nas flores femininas, até observação de presença de pólen. Os galhos permaneceram fechados até a coleta dos frutos, que foram coletados com coloração vermelho escuro e foram, posteriormente, beneficiados. Foram coletados frutos dos galhos onde ocorreu polinização aberta, obtendo-se famílias. Para análise das sementes, foi utilizado o teste do tetrazólio, sendo determinada a viabilidade e o estágio de desenvolvimento embrionário das sementes (globular, coração, pós-coração, torpedo ou maduro). Na polinização controlada, a fêmea 1 apresentou 75% de sementes viáveis e 73% apresentaram o embrião no estágio coração, e 46% de sementes viáveis e 59% no estágio coração na polinização aberta; a fêmea 2 apresentou 29% de sementes viáveis, 49% coração e 17% pós coração na polinização controlada e 11% de sementes viáveis, 16% coração e 12% pós coração na polinização aberta. Os resultados preliminares indicam o aceite da hipótese, pois as sementes de erva-mate oriundas de polinização controlada apresentaram maior viabilidade.Resumo

DNA methylation-based classification of central nervous system tumours.

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology

<i>MYCN</i> amplification drives an aggressive form of spinal ependymoma

Spinal ependymal tumors form a histologically and molecularly heterogeneous group of tumors with generally good prognosis. However, their treatment can be challenging if infiltration of the spinal cord or dissemination throughout the central nervous system (CNS) occurs and, in these cases, clinical outcome remains poor. Here, we describe a new and relatively rare subgroup of spinal ependymal tumors identified using DNA methylation profiling that is distinct from other molecular subgroups of ependymoma. Copy number variation plots derived from DNA methylation arrays showed MYCN amplification as a characteristic genetic alteration in all cases of our cohort (n = 13), which was subsequently validated using fluorescence in situ hybridization. The histological diagnosis was anaplastic ependymoma (WHO Grade III) in ten cases and classic ependymoma (WHO Grade II) in three cases. Histological re-evaluation in five primary tumors and seven relapses showed characteristic histological features of ependymoma, namely pseudorosettes, GFAP- and EMA positivity. Electron microscopy revealed cilia, complex intercellular junctions and intermediate filaments in a representative sample. Taking these findings into account, we suggest to designate this molecular subgroup spinal ependymoma with MYCN amplification, SP-EPN-MYCN. SP-EPN-MYCN tumors showed distinct growth patterns with intradural, extramedullary localization mostly within the thoracic and cervical spine, diffuse leptomeningeal spread throughout the whole CNS and infiltrative invasion of the spinal cord. Dissemination was observed in 100% of cases. Despite high-intensity treatment, SP-EPN-MYCN showed significantly worse median progression free survival (PFS) (17 months) and median overall survival (OS) (87 months) than all other previously described molecular spinal ependymoma subgroups. OS and PFS were similar to supratentorial ependymoma with RELA-fusion (ST-EPN-RELA) and posterior fossa ependymoma A (PF-EPN-A), further highlighting the aggressiveness of this distinct new subgroup. We, therefore, propose to establish SP-EPN-MYCN as a new molecular subgroup in ependymoma and advocate for testing newly diagnosed spinal ependymal tumors for MYCN amplification

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe