Characterizing the oligomers distribution along the aggregation pathway of amyloid Aß1-40 by NMR.

This study delves into the early aggregation process of the Aß1-40 amyloid peptide, elucidating the associated oligomers distribution. Motivated by the acknowledged role of small oligomers in the neurotoxic damage linked to Alzheimer's disease, we present an experimental protocol for preparing 26-O-acyl isoAß1-40, a modified Aß1-40 peptide facilitating rapid isomerization to the native amide form at neutral pH. This ensures seed-free solutions, minimizing experimental variability. Additionally, we demonstrate the efficacy of coupling NMR diffusion ordered spectroscopy (DOSY) with the Inverse Laplace Transform (ILT) reconstruction method, for effective characterization of early aggregation processes. This innovative approach efficiently maps oligomers distributions across a wide spectrum of initial peptide concentrations offering unique insights into the evolution of oligomers relative populations. As a proof of concept, we demonstrate the efficacy of our approach assessing the impact of Epigallocathechin gallate, a known remodeling agent of amyloid fibrils, on the oligomeric distributions of aggregated Aß1-40. The DOSY-ILT proposed approach stands as a robust and discriminating asset, providing a powerful strategy for rapidly gaining insight into potential inhibitors' impact on the aggregation process.

AXL receptor as an emerging molecular target in colorectal cancer.

AXL receptor tyrosine kinase (AXL) is a receptor tyrosine kinase whose aberrant expression has recently been associated with colorectal cancer (CRC), contributing to tumor growth, epithelial-mesenchymal transition (EMT), increased invasiveness, metastatic spreading, and the development of drug resistance. In this review we summarize preclinical data, the majority of which are limited to recent years, convincingly linking the AXL receptor to CRC. These findings support the value of targeting AXL with molecules in drug discovery, offering novel and advanced therapeutic or diagnostic tools for CRC management.

Molecular Characterization of the Recombinant Ig1 Axl Receptor Domain: An Intriguing Bait for Screening in Drug Discovery.

Axl receptor tyrosine kinase and its ligand Gas6 regulate several biological processes and are involved in both the onset and progression of tumor malignancies and autoimmune diseases. Based on its key role in these settings, Axl is considered a promising target for the development of molecules with therapeutic and diagnostic purposes. In this paper, we describe the molecular characterization of the recombinant Ig1 domain of Axl (Ig1 Axl) and its biochemical properties. For the first time, an exhaustive spectroscopic characterization of the recombinant protein through circular dichroism and fluorescence studies is also reported, as well as a binding analysis to its natural ligand Gas6, paving the way for the use of recombinant Ig1 Axl as a bait in drug discovery screening procedures aimed at the identification of novel and specific binders targeting the Axl receptor.

Structure-Based Design of Peptides Targeting VEGF/VEGFRs.

Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) play a main role in the regulation of angiogenesis and lymphangiogenesis. Furthermore, they are implicated in the onset of several diseases such as rheumatoid arthritis, degenerative eye conditions, tumor growth, ulcers and ischemia. Therefore, molecules able to target the VEGF and its receptors are of great pharmaceutical interest. Several types of molecules have been reported so far. In this review, we focus on the structure-based design of peptides mimicking VEGF/VEGFR binding epitopes. The binding interface of the complex has been dissected and the different regions challenged for peptide design. All these trials furnished a better understanding of the molecular recognition process and provide us with a wealth of molecules that could be optimized to be exploited for pharmaceutical applications.

Designing Novel Strategies for Improving Old Legumes: An Overview from Common Vetch.

Common vetch (Vicia sativa L.) is a grain legume used in animal feeding, rich in protein content, fatty acid, and mineral composition that makes for a very adequate component to enrich feedstuff. In addition, relevant pharmacological properties have been reported in humans. The common vetch, similar to other legumes, can fix atmospheric nitrogen, a crucial feature for sustainable agricultural systems. These properties enhance the use of vetch as a cover crop and its sowing in intercropping systems. Moreover, several studies have recently pointed out the potential of vetch in the phytoremediation of contaminated soils. These characteristics make vetch a relevant crop, which different potential improvements target. Varieties with different yields, flowering times, shattering resistance, nutritional composition, rhizobacteria associations, drought tolerance, nitrogen fixation capacity, and other agronomic-relevant traits have been identified when different vetch accessions are compared. Recently, the analysis of genomic and transcriptomic data has allowed the development of different molecular markers to be used for assisted breeding purposes, promoting crop improvement. Here, we review the potential of using the variability of V. sativa genetic resources and new biotechnological and molecular tools for selecting varieties with improved traits to be used in sustainable agriculture systems.

A Chemical Strategy for the Preparation of Multimodified Peptide Imaging Probes.

Multimodality probes appear of great interest for innovative imaging applications in disease diagnosis. Herein, we present a chemical strategy enabling site-specific double-modification and cyclization of a peptide probe exploiting native chemical ligation (NCL) and thiol-maleimide addition. The synthetic strategy is straightforward and of general applicability for the development of double-labeled peptide multimodality probes.

Participação democrática como instrumento de controle social da gestão pública / Democratic participation as an instrument of social control of public management

No Brasil, a partir do processo de redemocratização, diversos rearranjos políticos e sociais ocorreram, sendo os mais notáveis a mudança política estatal, a descentralização do poder e a mobilização dos grupos em desvantagem na busca do atendimento de suas demandas. Neste particular, persiste uma tensão explícita entre os movimentos sociais e a representação política, característica típica das democracias liberais, especialmente no caso brasileiro, isto porque a participação ativa do cidadão é o mecanismo pelo qual se estabelece o controle social, ou seja, o processo de regulação do Estado pelos civis, o qual busca considerar os interesses dos indivíduos nas decisões públicas. Este estudo visa compreender os mecanismos estabelecidos entre sociedade e Estado por meio da análise das motivações da participação civil nos espaços políticos. Ao fim, conclui que, nas democracias contemporâneas, a participação ativa do sujeito social e o controle social exercido pelos arranjos coletivos ­ face à força política que respalda a resistência e o consenso nos territórios de entendimento ­ tendem a assegurar os direitos básicos e a justiça social, razão pela qual se reconhece a relevância dos espaços de participação como referência para o consubstanciamento da democracia ativa

In Brazil, from the redemocratization process, several political and social rearrangements occurred, the most notable being the state political change, the decentralization of power and the mobilization of disadvantaged groups in the search for meeting their demands. In this particular, an explicit tension persists between social movements and political representation, a typical characteristic of liberal democracies, especially in the Brazilian case, this because the active participation of the citizen is the mechanism by which social control is established, that is, the process of regulation of the State by civilians, which seeks to consider the interests of individuals in public decisions. This study aims to understand the mechanisms established between society and the State, analyzing the motivations of civil participation in political spaces, concluding that in contemporary democracies, the active participation of the social subject and the social control exercised by collective arrangements - in the face of the political force that supports resistance and consensus in territories of understanding ­ tend to ensure basic rights and social justice, which is why the relevance of spaces for participation is recognized as a reference for the substantiation of active democracy

Switching the N-Capping Region from all-L to all-D Amino Acids in a VEGF Mimetic Helical Peptide.

The N-capping region of an α-helix is a short N-terminal amino acid stretch that contributes to nucleate and stabilize the helical structure. In the VEGF mimetic helical peptide QK, the N-capping region was previously demonstrated to be a key factor of QK helical folding. In this paper, we explored the effect of the chiral inversion of the N-capping sequence on QK folding, performing conformational analysis in solution by circular dichroism and NMR spectroscopy. The effect of such a modification on QK stability in serum and the proliferative effect were also evaluated.

Adapting Agriculture to Climate Change: A Synopsis of Coordinated National Crop Wild Relative Seed Collecting Programs across Five Continents.

The Adapting Agriculture to Climate Change Project set out to improve the diversity, quantity, and accessibility of germplasm collections of crop wild relatives (CWR). Between 2013 and 2018, partners in 25 countries, heirs to the globetrotting legacy of Nikolai Vavilov, undertook seed collecting expeditions targeting CWR of 28 crops of global significance for agriculture. Here, we describe the implementation of the 25 national collecting programs and present the key results. A total of 4587 unique seed samples from at least 355 CWR taxa were collected, conserved ex situ, safety duplicated in national and international genebanks, and made available through the Multilateral System (MLS) of the International Treaty on Plant Genetic Resources for Food and Agriculture (Plant Treaty). Collections of CWR were made for all 28 targeted crops. Potato and eggplant were the most collected genepools, although the greatest number of primary genepool collections were made for rice. Overall, alfalfa, Bambara groundnut, grass pea and wheat were the genepools for which targets were best achieved. Several of the newly collected samples have already been used in pre-breeding programs to adapt crops to future challenges.

Towards the Development, Maintenance and Standardized Phenotypic Characterization of Single-Seed-Descent Genetic Resources for Chickpea.

Here we present the approach used to develop the INCREASE "Intelligent Chickpea" Collections, from analysis of the information on the life history and population structure of chickpea germplasm, the availability of genomic and genetic resources, the identification of key phenotypic traits and methodologies to characterize chickpea. We present two phenotypic protocols within H2O20 Project INCREASE to characterize, develop, and maintain chickpea single-seed-descent (SSD) line collections. Such protocols and related genetic resource data from the project will be available for the legume community to apply the standardized approaches to develop Chickpea Intelligent Collections further or for multiplication/seed-increase purposes. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Characterization of chickpea seeds for seed-trait descriptors Basic Protocol 2: Characterization of chickpea lines for plant-trait descriptors specific for primary seed increase.

Structural characterization of the thermal unfolding pathway of human VEGFR1 D2 domain.

Folding stability is a crucial feature of protein evolution and is essential for protein functions. Thus, the comprehension of protein folding mechanisms represents an important complement to protein structure and function, crucial to determine the structural basis of protein misfolding. In this context, thermal unfolding studies represent a useful tool to get a molecular description of the conformational transitions governing the folding/unfolding equilibrium of a given protein. Here, we report the thermal folding/unfolding pathway of VEGFR1D2, a member of the immunoglobulin superfamily by means of a high-resolution thermodynamic approach that combines differential scanning calorimetry with atomic-level unfolding monitored by NMR. We show how VEGFR1D2 folding is driven by an oxidatively induced disulfide pairing: the key event in the achievement of its functional structure is the formation of a small hydrophobic core that surrounds a disulfide bridge. Such a 'folding nucleus' induces the cooperative transition to the properly folded conformation supporting the hypothesis that a disulfide bond can act as a folding nucleus that eases the folding process.

[Community Therapy and psychic distress in the family system: an approach based on the new paradigm of science]. / Terapia Comunitária e sofrimento psíquico no sistema familiar: um enfoque baseado no novo paradigma da ciência.

The scope of this study was to analyze the behavior patterns adopted by family members dealing with individuals in psychological distress within the scope of the relationships established in the family system, after participating in Community Therapy sessions. It was based on research with a qualitative approach using the research-action-intervention method. The intervention used centered around twelve Community Therapy sessions. Ten family members of people in psychological distress monitored by a Psychosocial Care Center took part in the study. Field notebook records, videos obtained with the tapes of the Community Therapy sessions, the interview material and Community Therapy itself were used as the empirical material production technique. The study revealed that the family members' understanding of psychological distress could be transformed as they attributed new meanings and performed fundamental actions to balanced living in the family. Community Therapy was seen as a practice that facilitated changes in the lives of its participants, as it contributed to generate social and individual interactions that stimulated family members to rethink concepts and to create spaces of coexistence and human and respectful care that permeated the family unit.

O presente estudo buscou analisar os comportamentos adotados por familiares que lidam com entes em sofrimento psíquico, no âmbito das relações estabelecidas no sistema familiar, depois de participarem de rodas de Terapia Comunitária. Pesquisa de abordagem qualitativa que utilizou o método da pesquisa-ação-intervenção. A intervenção utilizada foram doze rodas de Terapia Comunitária. Fizeram parte do estudo dez familiares de pessoas em sofrimento psíquico acompanhadas em um Centro de Atenção Psicossocial. Como técnicas de produção do material empírico foram utilizados os registros do caderno de campo, os vídeos obtidos com a gravação das rodas de Terapia Comunitária, o material das entrevistas e a própria Terapia Comunitária. O estudo revelou que a compreensão dos familiares acerca do sofrimento psíquico pôde ser transformada na medida que atribuíam novos significados e realizavam ações fundamentais ao convívio equilibrado na família. A Terapia Comunitária pôde ser elucidada como uma prática que facilitou mudanças na vida de seus participantes, pois contribuiu para gerar interações sociais e individuais que estimularam os familiares a repensarem conceitos e a criarem espaços de convivência e cuidado humanos e respeitosos que se difundiram para o sistema familiar.

Terapia Comunitária e sofrimento psíquico no sistema familiar: um enfoque baseado no novo paradigma da ciência / Community Therapy and psychic distress in the family system: an approach based on the new paradigm of science

Resumo O presente estudo buscou analisar os comportamentos adotados por familiares que lidam com entes em sofrimento psíquico, no âmbito das relações estabelecidas no sistema familiar, depois de participarem de rodas de Terapia Comunitária. Pesquisa de abordagem qualitativa que utilizou o método da pesquisa-ação-intervenção. A intervenção utilizada foram doze rodas de Terapia Comunitária. Fizeram parte do estudo dez familiares de pessoas em sofrimento psíquico acompanhadas em um Centro de Atenção Psicossocial. Como técnicas de produção do material empírico foram utilizados os registros do caderno de campo, os vídeos obtidos com a gravação das rodas de Terapia Comunitária, o material das entrevistas e a própria Terapia Comunitária. O estudo revelou que a compreensão dos familiares acerca do sofrimento psíquico pôde ser transformada na medida que atribuíam novos significados e realizavam ações fundamentais ao convívio equilibrado na família. A Terapia Comunitária pôde ser elucidada como uma prática que facilitou mudanças na vida de seus participantes, pois contribuiu para gerar interações sociais e individuais que estimularam os familiares a repensarem conceitos e a criarem espaços de convivência e cuidado humanos e respeitosos que se difundiram para o sistema familiar.

Abstract The scope of this study was to analyze the behavior patterns adopted by family members dealing with individuals in psychological distress within the scope of the relationships established in the family system, after participating in Community Therapy sessions. It was based on research with a qualitative approach using the research-action-intervention method. The intervention used centered around twelve Community Therapy sessions. Ten family members of people in psychological distress monitored by a Psychosocial Care Center took part in the study. Field notebook records, videos obtained with the tapes of the Community Therapy sessions, the interview material and Community Therapy itself were used as the empirical material production technique. The study revealed that the family members' understanding of psychological distress could be transformed as they attributed new meanings and performed fundamental actions to balanced living in the family. Community Therapy was seen as a practice that facilitated changes in the lives of its participants, as it contributed to generate social and individual interactions that stimulated family members to rethink concepts and to create spaces of coexistence and human and respectful care that permeated the family unit.

Probing the helical stability in a VEGF-mimetic peptide.

The analysis of the forces governing helix formation and stability in peptides and proteins has attracted considerable interest in order to shed light on folding mechanism. We analyzed the role of hydrophobic interaction, steric hindrance and chain length on i, i + 3 position in QK peptide, a VEGF mimetic helical peptide. We focused on position 10 of QK, occupied by a leucine, as previous studies highlighted the key role of the Leu7-Leu10 interaction in modulating the helix formation and inducing an unusual thermodynamic stability. Leu10 has been replaced by hydrophobic amino acids with different side-chain length, hydrophobicity and steric hindrance. Ten peptides were, hence, synthesized and analyzed combining circular dichroism, calorimetry and NMR spectroscopy. We found that helical content and thermal stability of peptide QK changed when Leu10 was replaced. Interestingly, we observed that the changes in the helical content and thermal stability were not always correlated and they depend on the type of interaction (strength and geometry) that could be established between Leu7 and the residue in position 10.

Radiomics-based machine learning differentiates "ground-glass" opacities due to COVID-19 from acute non-COVID-19 lung disease.

Ground-glass opacities (GGOs) are a non-specific high-resolution computed tomography (HRCT) finding tipically observed in early Coronavirus disesase 19 (COVID-19) pneumonia. However, GGOs are also seen in other acute lung diseases, thus making challenging the differential diagnosis. To this aim, we investigated the performance of a radiomics-based machine learning method to discriminate GGOs due to COVID-19 from those due to other acute lung diseases. Two sets of patients were included: a first set of 28 patients (COVID) diagnosed with COVID-19 infection confirmed by real-time polymerase chain reaction (RT-PCR) between March and April 2020 having (a) baseline HRCT at hospital admission and (b) predominant GGOs pattern on HRCT; a second set of 30 patients (nCOVID) showing (a) predominant GGOs pattern on HRCT performed between August 2019 and April 2020 and (b) availability of final diagnosis. Two readers independently segmented GGOs on HRCTs using a semi-automated approach, and radiomics features were extracted using a standard open source software (PyRadiomics). Partial least square (PLS) regression was used as the multivariate machine-learning algorithm. A leave-one-out nested cross-validation was implemented. PLS ß-weights of radiomics features, including the 5% features with the largest ß-weights in magnitude (top 5%), were obtained. The diagnostic performance of the radiomics model was assessed through receiver operating characteristic (ROC) analysis. The Youden's test assessed sensitivity and specificity of the classification. A null hypothesis probability threshold of 5% was chosen (p < 0.05). The predictive model delivered an AUC of 0.868 (Youden's index = 0.68, sensitivity = 93%, specificity 75%, p = 4.2 × 10-7). Of the seven features included in the top 5% features, five were texture-related. A radiomics-based machine learning signature showed the potential to accurately differentiate GGOs due to COVID-19 pneumonia from those due to other acute lung diseases. Most of the discriminant radiomics features were texture-related. This approach may assist clinician to adopt the appropriate management early, while improving the triage of patients.

The INCREASE project: Intelligent Collections of food-legume genetic resources for European agrofood systems.

Food legumes are crucial for all agriculture-related societal challenges, including climate change mitigation, agrobiodiversity conservation, sustainable agriculture, food security and human health. The transition to plant-based diets, largely based on food legumes, could present major opportunities for adaptation and mitigation, generating significant co-benefits for human health. The characterization, maintenance and exploitation of food-legume genetic resources, to date largely unexploited, form the core development of both sustainable agriculture and a healthy food system. INCREASE will implement, on chickpea (Cicer arietinum), common bean (Phaseolus vulgaris), lentil (Lens culinaris) and lupin (Lupinus albus and L. mutabilis), a new approach to conserve, manage and characterize genetic resources. Intelligent Collections, consisting of nested core collections composed of single-seed descent-purified accessions (i.e., inbred lines), will be developed, exploiting germplasm available both from genebanks and on-farm and subjected to different levels of genotypic and phenotypic characterization. Phenotyping and gene discovery activities will meet, via a participatory approach, the needs of various actors, including breeders, scientists, farmers and agri-food and non-food industries, exploiting also the power of massive metabolomics and transcriptomics and of artificial intelligence and smart tools. Moreover, INCREASE will test, with a citizen science experiment, an innovative system of conservation and use of genetic resources based on a decentralized approach for data management and dynamic conservation. By promoting the use of food legumes, improving their quality, adaptation and yield and boosting the competitiveness of the agriculture and food sector, the INCREASE strategy will have a major impact on economy and society and represents a case study of integrative and participatory approaches towards conservation and exploitation of crop genetic resources.

Exploiting Protein N-Terminus for Site-Specific Bioconjugation.

Although a plethora of chemistries have been developed to selectively decorate protein molecules, novel strategies continue to be reported with the final aim of improving selectivity and mildness of the reaction conditions, preserve protein integrity, and fulfill all the increasing requirements of the modern applications of protein conjugates. The targeting of the protein N-terminal alpha-amine group appears a convenient solution to the issue, emerging as a useful and unique reactive site universally present in each protein molecule. Herein, we provide an updated overview of the methodologies developed until today to afford the selective modification of proteins through the targeting of the N-terminal alpha-amine. Chemical and enzymatic strategies enabling the selective labeling of the protein N-terminal alpha-amine group are described.

Condition-dependent male copulatory courtship and its benefits for females.

Postcopulatory sexual selection has shaped the ornaments used during copulatory courtship. However, we know relatively little about whether these courtship ornaments are costly to produce or whether they provide indirect benefits to females. We used the mealworm beetle, Tenebrio molitor, to explore this. We challenged males using an entomopathogenic fungus and compared their courtship (frequency of leg and antennal contacts to the female), copulation duration, number of eggs laid, and hatching rate against control males. Infected males copulated for longer yet they reduced their leg and antennal contacts compared to control males. However, there was no obvious relation between infection, copulation duration, and courtship with egg production and hatching success. In general, our results indicate that the ornaments used during postcopulatory courtship are condition-dependent. Moreover, such condition dependence cannot be linked to male fitness.

Metabolic and conformational stabilization of a VEGF-mimetic beta-hairpin peptide by click-chemistry.

HPLW is a Vascular Endothelial Growth Factor (VEGF)-mimicking beta-hairpin peptide endowed of proangiogenic effect and showing valuable biomedical application in the proangiogenic therapy. However, the translational potential of HPLW is limited by its low metabolic stability, which would shorten the in vivo efficacy of the molecule. Here, we developed a peptide analog of HPLW, named HPLW2, that retains the structural and biological properties of the original peptide but features an impressive resistance to degradation by human serum proteases. HPLW2 was obtained by covalently modifying the chemical structure of the peptide with molecular tools known to impart protease resistance. Notably, the peptide was cyclized by installing an interstrand triazole bridge through Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reaction. HPLW2 appears as a novel and promising drug candidate with potential biomedical application in the proangiogenic therapy as a low molecular weight drug, alternative to the use of VEGF. Our work points out the utility of the interstrand triazole bridge as effective chemical platform for the conformational and metabolic stabilization of beta-hairpin bioactive peptides.

Common Vetch, Valuable Germplasm for Resilient Agriculture: Genetic Characterization and Spanish Core Collection Development.

Common vetch (Vicia sativa L.) is a legume used for animal feed because of its high protein content and great capacity for nitrogen fixation, making this crop relevant in sustainable agriculture. The Spanish vetch collection, conserved at the Spanish Plant Genetic Resources Center (CRF), is one of the largest collections of this species worldwide, including landraces, wild relatives mainly collected in Spain, and commercial cultivars, but also accessions of international origin. The analysis of the genetic diversity of this material, whose genome has not been sequenced yet, and the assembly of a representative collection could play a pivotal role in conserving and exploiting these genetic resources in breeding programs mainly in those focused on consequences and demands of climate change. In this work, a set of 14 simple sequence repeat (SSR) reference alleles for genetic diversity analysis of the CRF vetch collection has been developed, used for genotyping more than 545 common vetch accessions from all over the world and validated. All the tested markers were polymorphic for the analyzed accessions. Overall, at least 86 different loci were identified with 2-11 alleles per locus with an average of 6.1 alleles per locus. Also, the analyses of the generated SSR database support that most of these SSR markers are transferable across closely related species of Vicia genus. Analysis of molecular variance revealed that wild relatives have a higher genetic diversity than landraces. However, cultivars have similar diversity than landraces, indicating that genetic variability has been barely lost due to the breeding of this legume. Low differences of genetic variations between Spanish and non-Spanish accessions have been observed, suggesting a high degree of diversity within Spanish genotypes, which provide 95% of the total genetic variation, so we have focused our efforts on characterizing genotypes of Spanish origin that were further studied using storage protein profiles. Based on SSR, seed protein profiles, and agromorphological and passport data, a vetch core collection (VCC) containing 47 V. sativa accessions of Spanish origin has been established. In this collection, the characterization has been expanded using ISSR markers, and it has been reevaluated with new agromorphological data, including drought tolerance characters. This VCC presents a minimum loss of genetic diversity concerning the total collection and constitutes an invaluable material that can be used in future breeding programs for direct use in a resilient agricultural system.