An optimized strategy to measure protein stability highlights differences between cold and hot unfolded states

Macromolecular crowding ought to stabilize folded forms of proteins, through an excluded volume effect. This explanation has been questioned and observed effects attributed to weak interactions with other cell components. Here we show conclusively that protein stability is affected by volume exclusion and that the effect is more pronounced when the crowder's size is closer to that of the protein under study. Accurate evaluation of the volume exclusion effect is made possible by the choice of yeast frataxin, a protein that undergoes cold denaturation above zero degrees, because the unfolded form at low temperature is more expanded than the corresponding one at high temperature. To achieve optimum sensitivity to changes in stability we introduce an empirical parameter derived from the stability curve. The large effect of PEG 20 on cold denaturation can be explained by a change in water activity, according to Privalov's interpretation of cold denaturation

Toward Understanding the Molecular Bases of Stretch Activation: A Structural Comparison Of The Two Troponin C Isoforms Of Lethocerus

Muscles are usually activated by calcium binding to the calcium sensory protein troponin-C, which is one of the three components of the troponin complex. However, in cardiac and insect flight muscle activation is also produced by mechanical stress. Little is known about the molecular bases of this calcium-independent activation. In Lethocerus, a giant water bug often used as a model system because of its large muscle fibers, there are two troponin-C isoforms, called F1 and F2, that have distinct roles in activating the muscle. It has been suggested that this can be explained either by differences in structural features or by differences in the interactions with other proteins. Here we have compared the structural and dynamic properties of the two proteins and shown how they differ. We have also mapped the interactions of the F2 isoform with peptides spanning the sequence of its natural partner, troponin-I. Our data have allowed us to build a model of the troponin complex and may eventually help in understanding the specialized function of the F1 and F2 isoforms and the molecular mechanism of stretch activation

Towards Understanding the Molecular Bases of Stretch Activation: A Structural comparison of the Two Troponin C Isoforms of Lethocerus.

Muscles are usually activated by calcium binding to the calcium sensory protein troponin-C, which is one of the three components of the troponin complex. However, in cardiac and insect flight muscle activation is also produced by mechanical stress. Little is known about the molecular bases of this calcium-independent activation. In Lethocerus, a giant water bug often used as a model system because of its large muscle fibers, there are two troponin-C isoforms, called F1 and F2, that have distinct roles in activating the muscle. It has been suggested that this can be explained either by differences in structural features or by differences in the interactions with other proteins. Here we have compared the structural and dynamic properties of the two proteins and shown how they differ. We have also mapped the interactions of the F2 isoform with peptides spanning the sequence of its natural partner, troponin-I. Our data have allowed us to build a model of the troponin complex and may eventually help in understanding the specialized function of the F1 and F2 isoforms and the molecular mechanism of stretch activation

Introdução à nanotecnologia.

BREVE HISTÓRICO SOBRE A NANOTECNOLOGIA E NANOCIÊNCIA A possibilidade de se manipular e controlar coisas ?muito pequenas? foi vislumbrada há mais de seis décadas pelo físico norte-americano Richard Feynman (ganhador do prêmio Nobel de Física em 1985), em sua seminal palestra ministrada durante o encontro da Sociedade Americana de Física em Pasadena, Estados Unidos. Nessa palestra, Feynman conjecturou que não haveria limites físicos para, por exemplo, se escrever na cabeça de um alfinete, sugerindo que ?havia muito espaço lá embaixo?.1 Apesar da manipulação da matéria na escala atômica ou nanométrica já existir, sua comprovação experimental esbarrava na necessidade do desenvolvimento de técnicas avançadas de microscopia que permitissem a visualização e a manipulação de átomos e moléculas e seus arranjos. Em 1974 o professor Norio Taniguchi associou o conceito "nano" à tecnologia, época em que já havia se tornado possível a obtenção de materiais na escala nanométrica, devido principalmente à evolução dos microscópios eletrônicos.2 De fato, um dos feitos mais importantes para o desenvolvimento da nanociência foi a invenção, em 1981, do microscópio de tunelamento por varredura (STM, do inglês scanning tunneling microscope) pelos cientistas Gerd Binning e Heinrich Rohrer na IBM de Zurich, Suíça. A descoberta permitiu o imageamento bidimensional de superfícies condutoras com resolução atômica, e ambos os pesquisadores foram agraciados com o prêmio Nobel de Física em 1986 pela importante descoberta.1 Alguns anos depois, Binning e colaboradores desenvolveram o microscópio de força atômica (AFM, do inglês atomic force microscope), que não demandava utilização de corrente elétrica no imageamento e possibilitava varrer qualquer tipo de superfície, fosse ela condutora elétrica ou não.3 Desde então, muito se tem avançado no desenvolvimento de técnicas e tecnologias empregadas na formação e caracterização de diversos tipos de nanoestruturas, bem como em investigações sobre muitas de suas interessantes propriedades e potenciais aplicações, em áreas diversas como eletroeletrônica, medicina, agricultura e pecuária e meio ambiente. Nesse contexto, dois termos são conhecidos e vêm sendo cada vez mais difundidos em nosso cotidiano: a nanociência e a nanotecnologia. Enquanto a nanociência diz respeito ao estudo e conhecimento dos fenômenos que envolvem a manipulação, seja no desenho, controle e modificação dos materiais nas diferentes escalas (atômica, molecular e macromolecular), estando relacionada às diversas áreas do conhecimento (engenharia, física, química, biologia, eletrônica, computação, medicina), a nanotecnologia diz respeito à produção, caracterização e aplicação dos nanomateriais nas mais diferentes áreas.4,5 Sendo assim, nanociência e nanotecnologia objetivam a compreensão, o controle e aplicação da matéria na escala nanométric

Quality of Living Perceived of the Young People of the Vale do Sinos / RS/Brazil

The objective of this study was to identify the Quality of Life level of young people from Vale do Sinos / RS. The methodology was observational, descriptive and transversal. The sample had 391 young people. The data collection instruments were the WHOQOL-Bref and a socioeconomic questionnaire. Resulting in a total average score of 52.37 points, the highest for the Social Relations Domain and the lowest for the Environment. When compared to the variables "Sex", "Income" and "Age", the one with the highest statistically significant association among the domains was "Income", followed by "Sex" and "Age". It was concluded that the QoL of young people is smaller when compared with other studies, being relevant investments in public policies

The Chemical Probes Portal: an expert review-based public resource to empower chemical probe assessment, selection and use.

We describe the Chemical Probes Portal (https://www.chemicalprobes.org/), an expert review-based public resource to empower chemical probe assessment, selection and use. Chemical probes are high-quality small-molecule reagents, often inhibitors, that are important for exploring protein function and biological mechanisms, and for validating targets for drug discovery. The publication, dissemination and use of chemical probes provide an important means to accelerate the functional annotation of proteins, the study of proteins in cell biology, physiology, and disease pathology, and to inform and enable subsequent pioneering drug discovery and development efforts. However, the widespread use of small-molecule compounds that are claimed as chemical probes but are lacking sufficient quality, especially being inadequately selective for the desired target or even broadly promiscuous in behaviour, has resulted in many erroneous conclusions in the biomedical literature. The Chemical Probes Portal was established as a public resource to aid the selection and best-practice use of chemical probes in basic and translational biomedical research. We describe the background, principles and content of the Portal and its technical development, as well as examples of its applications and use. The Chemical Probes Portal is a community resource and we therefore describe how researchers can be involved in its content and development

canSAR: update to the cancer translational research and drug discovery knowledgebase.

canSAR (https://cansar.ai) is the largest public cancer drug discovery and translational research knowledgebase. Now hosted in its new home at MD Anderson Cancer Center, canSAR integrates billions of experimental measurements from across molecular profiling, pharmacology, chemistry, structural and systems biology. Moreover, canSAR applies a unique suite of machine learning algorithms designed to inform drug discovery. Here, we describe the latest updates to the knowledgebase, including a focus on significant novel data. These include canSAR's ligandability assessment of AlphaFold; mapping of fragment-based screening data; and new chemical bioactivity data for novel targets. We also describe enhancements to the data and interface

NMR backbone assignments of the tyrosine kinase domain of human fibroblast growth factor receptor 3 in apo state and in complex with inhibitor PD173074

Fibroblast growth factors receptors (FGFR) are transmembrane protein tyrosine kinases involved in many cellular process, including growth, differentiation and angiogenesis. Dysregulation of FGFR enzymatic activity is associated with developmental disorders and cancers; therefore FGFRs have become attractive targets for drug discovery, with a number of agents in late-stage clinical trials. Here, we present the backbone resonance assignments of FGFR3 tyrosine kinase domain in the ligand-free form and in complex with the canonical FGFR kinase inhibitor PD173074. Analysis of chemical shift changes upon inhibitor binding highlights a characteristic pattern of allosteric network perturbations that is of relevance for future drug discovery activities aimed at development of conformationally-selective FGFR inhibitors