Age and Vasodilator Response to Different Hyperemic Agents: Adenosine versus Contrast Medium.

Background: Age-related remodelling has the potential to affect the microvascular response to hyperemic stimuli. However, its precise effects on the vasodilatory response to adenosine and contrast medium, as well as its influence on fractional flow reserve (FFR) and contrast fractional flow reserve (cFFR), have not been previously investigated. We investigate the impact of age on these indices. Methods: We extrapolated data from the post-revascularization optimization and physiological evaluation of intermediate lesions using fractional flow reserve (PROPHET-FFR) and The Multi-center Evaluation of the Accuracy of the Contrast MEdium INduced Pd/Pa RaTiO in Predicting (MEMENTO) studies. Only lesions with a relevant vasodilatory response to adenosine and contrast medium were considered of interest. A total of 2080 patients, accounting for 2294 pressure recordings were available for analysis. The cohort was stratified into three age terciles. Age-dependent correlations with FFR, cFFR, distal pressure/aortic pressure (Pd/Pa) and instantaneous wave-free ratio (iFR) were calculated. The vasodilatory response was calculated in 1619 lesions (with both FFR and cFFR) as the difference between resting and hyperaemic pressure ratios and correlated with aging. The prevalence of FFR-cFFR discordance was assessed. Results: Age correlated positively to FFR (r = 0.062, p = 0.006), but not with cFFR (r = 0.024, p = 0.298), Pd/Pa (r = -0.015, p = 0.481) and iFR (r = -0.026, p = 0.648). The hyperemic response to adenosine (r = -0.102, p ≤ 0.0001) and to contrast medium (r = -0.076, p = 0.0023) showed a negative correlation with age. When adjusted for potential confounders, adenosine induced hyperaemia was negatively associated with age (p = 0.04 vs p = 0.08 for cFFR). Discordance decreased across age terciles (14.64% vs 12.72% vs 10.12%, p = 0.032). Conclusions: As compared to adenosine, contrast induced hyperaemia appeared to be less affected by age. cFFR may be considered a more stable and reproducible tool to assess epicardial stenosis in elderly patients. Clinical Trial Registration: PROPHET-FFR STUDY, Clinicaltrials.gov (NCT05056662).

The Immunopeptidomics Ontology (ImPO).

The adaptive immune response plays a vital role in eliminating infected and aberrant cells from the body. This process hinges on the presentation of short peptides by major histocompatibility complex Class I molecules on the cell surface. Immunopeptidomics, the study of peptides displayed on cells, delves into the wide variety of these peptides. Understanding the mechanisms behind antigen processing and presentation is crucial for effectively evaluating cancer immunotherapies. As an emerging domain, immunopeptidomics currently lacks standardization-there is neither an established terminology nor formally defined semantics-a critical concern considering the complexity, heterogeneity, and growing volume of data involved in immunopeptidomics studies. Additionally, there is a disconnection between how the proteomics community delivers the information about antigen presentation and its uptake by the clinical genomics community. Considering the significant relevance of immunopeptidomics in cancer, this shortcoming must be addressed to bridge the gap between research and clinical practice. In this work, we detail the development of the ImmunoPeptidomics Ontology, ImPO, the first effort at standardizing the terminology and semantics in the domain. ImPO aims to encapsulate and systematize data generated by immunopeptidomics experimental processes and bioinformatics analysis. ImPO establishes cross-references to 24 relevant ontologies, including the National Cancer Institute Thesaurus, Mondo Disease Ontology, Logical Observation Identifier Names and Codes and Experimental Factor Ontology. Although ImPO was developed using expert knowledge to characterize a large and representative data collection, it may be readily used to encode other datasets within the domain. Ultimately, ImPO facilitates data integration and analysis, enabling querying, inference and knowledge generation and importantly bridging the gap between the clinical proteomics and genomics communities. As the field of immunogenomics uses protein-level immunopeptidomics data, we expect ImPO to play a key role in supporting a rich and standardized description of the large-scale data that emerging high-throughput technologies are expected to bring in the near future. Ontology URL: https://zenodo.org/record/10237571 Project GitHub: https://github.com/liseda-lab/ImPO/blob/main/ImPO.owl.

PrOgnosis in Pulmonary Embolism (PoPE): 30-Day mortality risk score based on five admission parameters.

INTRODUCTION AND OBJECTIVE: Several scoring systems have been developed for risk stratification in patients with acute pulmonary embolism (PE). The Pulmonary Embolism Severity Index (PESI) and its simplified version (sPESI) are among the most used, however the high number of variables hinder its application. Our aim was to derive an easy-to-perform score based on simple parameters obtained at admission to predict 30-day mortality in acute PE patients. METHODS: Retrospective study in 1115 patients with acute PE from two institutions (derivation cohort n=835, validation cohort n=280). The primary endpoint was all-cause mortality at 30 days. Statistically and clinically relevant variables were selected for multivariable Cox regression analysis. We derived and validated a multivariable risk score model and compared to other established scores. RESULTS: The primary endpoint occurred in 207 patients (18.6%). Our model included five variables weighted as follows: modified shock index ≥1.1 (hazard ratio [HR] 2.57, 1.68-3.92, p<0.001), active cancer (HR 2.27, 1.45-3.56, p<0.001), altered mental state (HR 3.82, 2.50-5.83, p<0.001), serum lactate concentration ≥2.50 mmol/L (HR 5.01, 3.25-7.72, p<0.001), and age ≥80 years (HR 1.95, 1.26-3.03, p=0.003). The prognostic ability was superior to other scores (area under curve [AUC] 0.83 [0.79-0.87] vs 0.72 [0.67-0.79] in PESI and 0.70 [0.62-0.75] in sPESI, p<0.001) and its performance in the validation cohort was deemed good (73 events in 280 patients, 26.1%, AUC=0.76, 0.71-0.82, p<0.0001) and superior to other scores (p<0.05). CONCLUSIONS: The PoPE score (https://tinyurl.com/ybsnka8s) is an easy tool with superior performance to predict early mortality in patients admitted for PE with non-high-risk PE.

Age-related changes in the coronary microcirculation influencing the diagnostic performance of invasive pressure-based indices and long-term patient prognosis.

OBJECTIVES: Investigate age-related changes in coronary microvascular function, its effect on hyperemic and non-hyperemic indices of stenosis relevance, and its prognostic implications. BACKGROUND: Evidence assessing the effect of age on fractional flow reserve (FFR), resting mean distal intracoronary pressure/mean aortic pressure (Pd/Pa), and microcirculatory function remains scarce. METHODS: This is a post hoc study of a large prospective international registry (NCT03690713) including 1134 patients (1326 vessels) with coronary stenoses interrogated with pressure and flow guidewires. Age-dependent correlations with functional indices were analyzed. Prevalences of FFR, resting Pd/Pa, and coronary flow reserve (CFR) classification agreement were assessed. At 5 years follow-up, the relation between resting Pd/Pa, CFR, and their age-dependent implications on FFR-guided percutaneous coronary intervention (PCI) deferral (deferred if FFR > 0.80) were investigated using vessel-oriented composite outcomes (VOCO) composed of death, myocardial infarction, and repeated revascularization. RESULTS: Age correlated positively with FFR (r = 0.08, 95% confidence interval [CI]: 0.03 to 0.13, p = 0.005), but not with resting Pd/Pa (r = -0.03, 95% CI:-0.09 to 0.02, p = 0.242). CFR correlated negatively with age (r = -0.15, 95% CI: -0.21 to -0.10, p < 0.001) due to a significant decrease in maximal hyperemic flow in older patients. Patients over 60 years of age with FFR-guided deferred-PCI abnormal resting Pd/Pa or abnormal CFR had increased risk of VOCO (hazard ratio [HR]: 2.10, 95% CI: 1.15 to 4.36, p = 0.048; HR: 2.46, 95% CI:1.23 to 4.96, p = 0.011; respectively). CONLUSIONS: Aging is associated with decrease in microcirculatory vasodilation, as assessed with adenosine-based methods like CFR. In patients older than 60 years in whom PCI is deferred according to FFR > 0.80, CFR and resting Pd/Pa have an incremental value in predicting future vessel-oriented patient outcomes.

Ontologies and Knowledge Graphs in Oncology Research.

The complexity of cancer research stems from leaning on several biomedical disciplines for relevant sources of data, many of which are complex in their own right. A holistic view of cancer-which is critical for precision medicine approaches-hinges on integrating a variety of heterogeneous data sources under a cohesive knowledge model, a role which biomedical ontologies can fill. This study reviews the application of ontologies and knowledge graphs in cancer research. In total, our review encompasses 141 published works, which we categorized under 14 hierarchical categories according to their usage of ontologies and knowledge graphs. We also review the most commonly used ontologies and newly developed ones. Our review highlights the growing traction of ontologies in biomedical research in general, and cancer research in particular. Ontologies enable data accessibility, interoperability and integration, support data analysis, facilitate data interpretation and data mining, and more recently, with the emergence of the knowledge graph paradigm, support the application of Artificial Intelligence methods to unlock new knowledge from a holistic view of the available large volumes of heterogeneous data.

Age and functional relevance of coronary stenosis: a post hoc analysis of the ADVISE II trial.

BACKGROUND: The influence of age-dependent changes on fractional flow reserve (FFR) or instantaneous wave-free ratio (iFR) and the response to pharmacological hyperaemia has not been investigated. AIMS: We investigated the impact of age on these indices. METHODS: This is a post hoc analysis of the ADVISE II trial, including a total of 690 pressure recordings (in 591 patients). Age-dependent correlations with FFR and iFR were calculated and adjusted for stenosis severity. Patients were stratified into three age terciles. The hyperaemic response to adenosine, calculated as the difference between resting and hyperaemic pressure ratios, and the prevalence of FFR-iFR discordance were assessed. RESULTS: Age correlated positively with FFR (r=0.08, 95% CI: 0.01 to 0.15, p=0.015), but not with iFR (r=-0.03, 95% CI: -0.11 to 0.04, p=0.411). The hyperaemic response to adenosine decreased with patient age (0.12±0.07, 0.11±0.06, 0.09±0.05, for the 1st [33-58 years], 2nd [59-69 years] and 3rd [70-94 years] age tertiles, respectively, p<0.001) and showed significant correlation with age (r=-0.14, 95% CI: -0.21 to -0.06, p<0.001). The proportion of patients with FFR ≤0.80+iFR >0.89 discordance doubled in the first age tercile (14.1% vs 7.1% vs 7.0%, p=0.005). CONCLUSIONS: The hyperaemic response of the microcirculation to adenosine administration is age dependent. FFR values increase with patient age, while iFR values remain constant across the age spectrum. These findings contribute to explaining differences observed in functional stenosis classification with hyperaemic and non-hyperaemic coronary indices.

Hybrid panel of biomarkers can be useful in the diagnosis of pleural and peritoneal effusions.

BACKGROUND: In clinical practice, pleural and peritoneal effusions are usual diagnosis. We evaluated the performance of a hybrid panel of biomarkers in the diagnosis of the main diseases affecting pleura and/or peritoneum. METHODS: Samples of pleural/ peritoneal fluid from 120 patients were evaluated for: CEA (carcinoembryonic antigen), VEGF-A (vascular endothelial growth factor A), PD-L1/B7-H1 (programmed death-ligand 1), NGAL (neutrophil gelatinase-associated lipocalin), TREM-1 (triggering receptor expressed in myeloid cells type-1) and IFNγ (gamma-interferon) by Luminex®; CALP (Calprotectin) by ELISA, and ADA (adenosine deaminase) by enzymatic deamination. RESULTS: For malignant effusion (ME) diagnosis, CEA and NGAL presented superior performance than VEGF-A, PD-L1 and CALP. A CEA-NGAL association showed good sensitivity (86.6%) and accuracy (79.2%). For non-tuberculous infectious effusion (NTBIE), NGAL presented the best performance with sensitivity (75.0%), specificity (62.0%) and accuracy (65.0%) higher than TREM-1 and CALP; however, when associated, although with good sensitivity, there was important decrease in specificity. For tuberculous pleural effusion (TPE), IFNy-ADA presented excellent sensitivity (100%), specificity (87.6%), NPV (100%) and accuracies (~90%). CONCLUSIONS: CEA, NGAL, ADA and IFNy were useful in discriminating ME and TPE. However, for NTBIE diagnosis, the hybrid panel did not demonstrate advantages over the classic parameters.

Performance of the UroVysion® FISH assay for the diagnosis of malignant effusions using two cutoff strategies.

The cytological examination of cavity fluids has limited sensitivity in the diagnosis of malignancy. Aneuploidy, which is commonly observed in neoplastic cells, could potentially be used as an ancillary diagnostic tool. To evaluate the detection of aneuploid cells in cavitary effusion samples using the fluorescence in situ hybridization (FISH) assay UroVysion® with some adaptations and two different cutoff strategies. Seventy samples of pleural or peritoneal fluid with positive (n = 40), negative (n = 15), or suspicious (n = 15) oncotic cytology were subjected to FISH assay with the multitarget UroVysion® kit, which is composed of probes that hybridize to the centromeric region of chromosomes 3, 7, and 17 and to the locus 9p21. FISH performance was evaluated using two different cutoffs: (1) the manufacturer's cutoff (M-FISH) and 2) a proposed cutoff (P-FISH). Using M-FISH, the diagnostic sensitivity was 57.1%, specificity 87.5%, and accuracy 60.0%; with P-FISH, the sensitivity was 87.3%, specificity 71.4%, and accuracy 85.7%. When combined with cytology, the sensitivity, specificity, and accuracy were 88.0%, 83.3%, and 87.8%, respectively. Malignant cells presented a predominance of chromosomal gains. The UroVysion® test using the P-FISH cutoff was effective in demonstrating aneuploid cells in all malignant effusions, confirming the diagnosis of malignancy even in cases with suspicious cytology.

Tackling the challenges of matching biomedical ontologies.

BACKGROUND: Biomedical ontologies pose several challenges to ontology matching due both to the complexity of the biomedical domain and to the characteristics of the ontologies themselves. The biomedical tracks in the Ontology Matching Evaluation Initiative (OAEI) have spurred the development of matching systems able to tackle these challenges, and benchmarked their general performance. In this study, we dissect the strategies employed by matching systems to tackle the challenges of matching biomedical ontologies and gauge the impact of the challenges themselves on matching performance, using the AgreementMakerLight (AML) system as the platform for this study. RESULTS: We demonstrate that the linear complexity of the hash-based searching strategy implemented by most state-of-the-art ontology matching systems is essential for matching large biomedical ontologies efficiently. We show that accounting for all lexical annotations (e.g., labels and synonyms) in biomedical ontologies leads to a substantial improvement in F-measure over using only the primary name, and that accounting for the reliability of different types of annotations generally also leads to a marked improvement. Finally, we show that cross-references are a reliable source of information and that, when using biomedical ontologies as background knowledge, it is generally more reliable to use them as mediators than to perform lexical expansion. CONCLUSIONS: We anticipate that translating traditional matching algorithms to the hash-based searching paradigm will be a critical direction for the future development of the field. Improving the evaluation carried out in the biomedical tracks of the OAEI will also be important, as without proper reference alignments there is only so much that can be ascertained about matching systems or strategies. Nevertheless, it is clear that, to tackle the various challenges posed by biomedical ontologies, ontology matching systems must be able to efficiently combine multiple strategies into a mature matching approach.

The measurement of serum osmolality and its application to clinical practice and laboratory: literature review / A medida da osmolalidade sérica e sua aplicação na prática clínica e laboratorial: revisão da literatura

ABSTRACT Introduction: Serum osmolality is an essential laboratory parameter to understand several clinical disorders such as electrolyte disturbances, exogenous intoxication and hydration status. Objective: This study aims to update knowledge about the osmolality examination through research papers published to date. Materials and methods: The survey was conducted on PubMed database. It highlights main concepts, both historical and physiological aspects, and the clinical applications of the serum osmolality test. In addition, an extensive survey of formulas for the serum osmolality calculation was conducted. Discussion: The measurement of serum osmolality is relevant in changes in intracellular and extracellular balance, as a trusted and valuable indicator of solute concentration in the blood. The mathematical equations for serum osmolality calculation acquire relevance in health services where serum is not available, and situations in which calculation of the osmolal gap is necessary, but the variability of the formulas is a significant bias. Conclusion: The measurement of serum osmolality is useful in cases of dehydration, sodium and potassium disorders, glucose alteration, exogenous poisoning, adrenal insufficiency, neurological injury, physical exercise and others.

RESUMO Introdução: A osmolalidade sérica constitui um parâmetro laboratorial importante para compreensão de diversas desordens clínicas, como os distúrbios eletrolíticos, as intoxicações exógenas e o status de hidratação. Objetivo: Este trabalho visa atualizar os conhecimentos acerca do exame de osmolalidade por meio da pesquisa de artigos científicos publicados até a presente data. Materiais e métodos: A pesquisa foi realizada no banco de dados do PubMed. Este artigo de atualização aborda os principais conceitos, aspectos históricos, aspectos fisiológicos e aplicações clínicas do exame de osmolalidade sérica. Foi também realizado um levantamento das diferentes fórmulas propostas para o cálculo da osmolalidade sérica. Discussão: A medida da osmolalidade sérica é pertinente nas alterações do equilíbrio intra e extracelular, sendo um bom indicador para avaliar as concentrações de solutos no sangue. As fórmulas matemáticas para o cálculo da osmolalidade sérica são úteis quando a medida laboratorial não está disponível, bem como nas situações em que o cálculo do gap osmolal se faz necessário, mas a variabilidade das fórmulas é um viés significativo. Conclusão: A medida da osmolalidade sérica é útil na avaliação de diversas condições clínicas, como na desidratação, nos distúrbios dos íons sódio e potássio, nas disglicemias, nas intoxicações exógenas, na insuficiência adrenal, nas lesões neurológicas, nos exercícios físicos, entre outras.

Auto-organização e autonomia: princípios básicos na caracterização de saúde mental / Self-organization and autonomy: basic principles in the characterization of mental health

Introdução: Se na tradição ocidental vigora a abordagem mecanicista, de inspiração cartesiana, onde a doença é isolada analiticamente e tratada, na tradição oriental a relação saúde-doença é, há milênios, concebida como uma desarmonia biopsicossocial de um indivíduo inserido num meio e dotado de rica subjetividade. Em documento de 2001, a Organização Mundial de Saúde faz menção a uma abordagem médica sistêmica, integrada, tal qual os chineses praticam há muito tempo. Pensando nessa mudança de paradigma, entendemos haver, em nossa cultura, certa carência de ferramentas epistemológicas capazes de lidar com essa complexidade. Objetivo: Contrapor as perspectivas orientais (chinesa, em particular) no trato com a saúde (a mental, em específico), com a tradição ocidental de práticas médicas. Método: Estudo de abordagem qualitativa mediante revisão bibliográfica e análise interpretativa, estabelecendo-se comparação entre os dois tipos de prática médicas. Resultados: Nesse sentido, foram explorados os princípios da teoria da auto-organização, sugerindo que tal abordagem epistemológica poderia ser de extrema valia no que concerne à elaboração de um novo olhar sobre as relações médico/paciente e saúde/doença (AU).

Introduction: If in the Western tradition the Cartesian-inspired mechanistic approach, where disease is analytically isolated and treated, in the Eastern tradition the health-disease relationship has been conceived for millennia as a biopsychosocial disharmony of an individual inserted in a medium and gifted of rich subjectivity. In a 2001 document, the World Health Organization mentions a systemic, integrated medical approach, as the Chinese have long practiced. Thinking of this paradigm shift, we understand that there is in our culture a certain lack of epistemological tools capable of dealing with this complexity. Objective: To oppose the Eastern (Chinese, in particular) perspectives of treatment with health (the mental, in particular), with the Western tradition of medical practices. Methodology: Study of qualitative approach through bibliographic review and interpretative analysis, establishing a comparison between the two types of medical practice. Results: In this sense, the principles of the theory of self-organization were explored, suggesting that such an epistemological approach could be of extreme value in the elaboration of a new look on the doctor / patient and health / illness relationships (AU).

Naturalismo e ciência cognitiva: por uma abordagem sistêmica / Naturalism and cognitive science: a systematic approach

Ao avaliarmos o papel desempenhado pela filosofia dentro do quadro geral dos saberes constituídos, procuraremos determinar no presente artigo o sentido da idéia de que a ciência cognitiva veio ocupar o papel que sempre coube à epistemologia. Investigando as relações entre a filosofia e a ciência cognitiva, avaliaremos criticamente a proposta do filósofo brasileiro Marcos Barbosa de Oliveira, de que a ciência cognitiva deveria dividir-se entre ciência cognitiva natural e cultural. Ao nos posicionarmos contra essa proposta, argumentaremos que dividir a ciência cognitiva em dois domínios traria mais problemas que soluções aos estudos referentes à mente, pois entendemos que a integração entre os saberes, os esforços para a constituição de um patamar teórico-conceitual comum, bem como o intercâmbio de idéias, uma das principais propostas da ciência cognitiva, não deveriam ser abandonados em virtude do temor de que a ciência cognitiva estaria tratando como naturais aspectos da cognição que seriam culturais. Por fim, procuraremos apontar para a direção de uma perspectiva sistêmica, em que as especificidades entre os saberes não seriam tão nítidas como comumente são compreendidas e investigadas

Linguagem, natureza humana e cognição: Wittgenstein e o problema mente-corpo / Language, human nature and cognition: Wittgenstein and the mind-body problem

O percurso argumentativo do presente trabalho, resultante de pesquisa teórica, parte da concepção de filosofia para Wittgenstein Num segundo momento, argumentaremos que, no que tange ao plano mental, tanto a tradição cartesiana quanto a empirista assenta-se numa dicotomia entre o “interno” e o “externo”, algo terminantemente recusado por Wittgenstein, pois tais assimetrias conduzem inevitavelmente ao solipsismo. Ao expormos a ideia de natureza humana em Wittgenstein, observaremos que, para o filósofo, não faz o menor sentido separar a mente do corpo, o interno do externo, pois o ser humano constitui-se numa unidade psicofísica “jogada” no fluxo da vida, no plano da linguagem e da ação. Nas considerações finais, especularemos acerca da possibilidade de máquinas virem a expressarem comportamento inteligente. Neste sentido, entendemos que, para Wittgenstein, comportar-se como humano seria algo que vai muito além de realizar com propriedade certos procedimentos lógicos, tais como fazem os computadores atuais. Em suma, comportar-se ou agir como humano é ser capaz de expressar sentimentos, vontades genuínas, receios e anseios, bem como estar suscetível a sentir prazeres e dores, e isto, a rigor, pensamos ser um horizonte ainda distante de ser contemplado por máquinas.

Molecular profiling of the human nasal epithelium: A proteomics approach.

A comprehensive proteomic profiling of nasal epithelium (NE) is described. This study relies on simple subcellular fractionation used to obtain soluble- and membrane-enriched fractions followed by 2-dimensional liquid chromatography (2D-LC) separation and tandem mass spectrometry (MS/MS). The cells were collected using a brushing technique applied on NE of clinically evaluated volunteers. Subsequently, the soluble- and the membrane-protein enriched fractions were prepared and analyzed in parallel using 2D-LC-MS/MS. In a set of 1482 identified proteins, 947 (63.9%) proteins were found to be associated to membrane fraction. Grand average hydropathy value index (GRAVY) analysis, the transmembrane protein mapping and annotations of primary location deposited in the Human Protein Reference Database (HPRD) confirmed an enrichment of hydrophobic proteins on this dataset. Ingenuity Pathway Analysis (IPA) of soluble fraction revealed an enrichment of molecular and cellular functions associated with cell death, protein folding and drug metabolism while in membrane fraction showed an enrichment of functions associated with molecular transport, protein trafficking and cell-to-cell signaling and interaction. The IPA showed similar enrichment of functions associated with cellular growth and proliferation in both soluble and membrane subproteomes. This finding was in agreement with protein content analysis using exponentially modified protein abundance index (emPAI). A comparison of our data with previously published studies focusing on respiratory tract epithelium revealed similarities related to identification of proteins associated with physical barrier function and immunological defence. In summary, we extended the NE molecular profile by identifying and characterizing proteins associated to pivotal functions of a respiratory epithelium, including the control of fluid volume and ionic composition at the airways' surface, physical barrier maintenance, detoxification and immunological defence. The extent of similarities supports the applicability of a less invasive analysis of NE to assess prognosis and treatment response of lung diseases such as asthma, cystic fibrosis and chronic obstructive pulmonary disease.

Serum proteomics signature of cystic fibrosis patients: a complementary 2-DE and LC-MS/MS approach.

Complementary 2D-PAGE and 'shotgun' LC-MS/MS approaches were combined to identify medium and low-abundant proteins in sera of Cystic Fibrosis (CF) patients (mild or severe pulmonary disease) in comparison with healthy CF-carrier and non-CF carrier individuals aiming to gain deeper insights into the pathogenesis of this multifactorial genetic disease. 78 differentially expressed spots were identified from 2D-PAGE proteome profiling yielding 28 identifications and postulating the existence of post-translation modifications (PTM). The 'shotgun' approach highlighted altered levels of proteins actively involved in CF: abnormal tissue/airway remodeling, protease/antiprotease imbalance, innate immune dysfunction, chronic inflammation, nutritional imbalance and Pseudomonas aeruginosa colonization. Members of the apolipoproteins family (VDBP, ApoA-I, and ApoB) presented gradually lower expression from non-CF to CF-carrier individuals and from those to CF patients, results validated by an independent assay. The multifunctional enzyme NDKB was identified only in the CF group and independently validated by WB. Its functions account for ion sensor in epithelial cells, pancreatic secretion, neutrophil-mediated inflammation and energy production, highlighting its physiological significance in the context of CF. Complementary proteomics-based approaches are reliable tools to reveal pathways and circulating proteins actively involved in a heterogeneous disease such as CF.

Representações mentais e ciência cognitiva: dependência excessiva e problemas / Mental representations and cognitive science: excessive dependency and problems

Sendo as noções de representação e computação centrais no arcabouço teórico-conceitual e nas efetivas reproduções e simulações em Ciência Cognitiva, pretendemos, no presente ensaio teórico, discutir especialmente os problemas concernentes à noção de representação no que tange às simulações e/ou reproduções do pensamento nos artifícios da inteligência artificial e das redes conexionistas. Neste sentido, enfatizaremos em nossas reflexões o que julgamos ser o principal problema no que se refere à implementação de propriedades "inteligentes" em artifícios não biológicos, a saber, o problema da estrutura, ou problema dos frame, que consiste no problema de como desenvolver e sustentar um modelo interno do mundo, de modo que se possa implementar tarefas triviais, tais como atravessar uma rua movimentada sem ser atropelado ou fritar um ovo eficientemente, por exemplo.

Enzyme classification with peptide programs: a comparative study.

BACKGROUND: Efficient and accurate prediction of protein function from sequence is one of the standing problems in Biology. The generalised use of sequence alignments for inferring function promotes the propagation of errors, and there are limits to its applicability. Several machine learning methods have been applied to predict protein function, but they lose much of the information encoded by protein sequences because they need to transform them to obtain data of fixed length. RESULTS: We have developed a machine learning methodology, called peptide programs (PPs), to deal directly with protein sequences and compared its performance with that of Support Vector Machines (SVMs) and BLAST in detailed enzyme classification tasks. Overall, the PPs and SVMs had a similar performance in terms of Matthews Correlation Coefficient, but the PPs had generally a higher precision. BLAST performed globally better than both methodologies, but the PPs had better results than BLAST and SVMs for the smaller datasets. CONCLUSION: The higher precision of the PPs in comparison to the SVMs suggests that dealing with sequences is advantageous for detailed protein classification, as precision is essential to avoid annotation errors. The fact that the PPs performed better than BLAST for the smaller datasets demonstrates the potential of the methodology, but the drop in performance observed for the larger datasets indicates that further development is required.Possible strategies to address this issue include partitioning the datasets into smaller subsets and training individual PPs for each subset, or training several PPs for each dataset and combining them using a bagging strategy.

Dynamic modularity in protein interaction networks predicts breast cancer outcome.

Changes in the biochemical wiring of oncogenic cells drives phenotypic transformations that directly affect disease outcome. Here we examine the dynamic structure of the human protein interaction network (interactome) to determine whether changes in the organization of the interactome can be used to predict patient outcome. An analysis of hub proteins identified intermodular hub proteins that are co-expressed with their interacting partners in a tissue-restricted manner and intramodular hub proteins that are co-expressed with their interacting partners in all or most tissues. Substantial differences in biochemical structure were observed between the two types of hubs. Signaling domains were found more often in intermodular hub proteins, which were also more frequently associated with oncogenesis. Analysis of two breast cancer patient cohorts revealed that altered modularity of the human interactome may be useful as an indicator of breast cancer prognosis.