Identification of Driver Epistatic Gene Pairs Combining Germline and Somatic Mutations in Cancer.

Cancer arises from the complex interplay of various factors. Traditionally, the identification of driver genes focuses primarily on the analysis of somatic mutations. We describe a new method for the detection of driver gene pairs based on an epistasis analysis that considers both germline and somatic variations. Specifically, the identification of significantly mutated gene pairs entails the calculation of a contingency table, wherein one of the co-mutated genes can exhibit a germline variant. By adopting this approach, it is possible to select gene pairs in which the individual genes do not exhibit significant associations with cancer. Finally, a survival analysis is used to select clinically relevant gene pairs. To test the efficacy of the new algorithm, we analyzed the colon adenocarcinoma (COAD) and lung adenocarcinoma (LUAD) samples available at The Cancer Genome Atlas (TCGA). In the analysis of the COAD and LUAD samples, we identify epistatic gene pairs significantly mutated in tumor tissue with respect to normal tissue. We believe that further analysis of the gene pairs detected by our method will unveil new biological insights, enhancing a better description of the cancer mechanism.

Exploring molecular evolution of Rubisco in C3 and CAM Orchidaceae and Bromeliaceae.

BACKGROUND: The CO2-concentrating mechanism associated to Crassulacean acid metabolism (CAM) alters the catalytic context for Rubisco by increasing CO2 availability and provides an advantage in particular ecological conditions. We hypothesized about the existence of molecular changes linked to these particular adaptations in CAM Rubisco. We investigated molecular evolution of the Rubisco large (L-) subunit in 78 orchids and 144 bromeliads with C3 and CAM photosynthetic pathways. The sequence analyses were complemented with measurements of Rubisco kinetics in some species with contrasting photosynthetic mechanism and differing in the L-subunit sequence. RESULTS: We identified potential positively selected sites and residues with signatures of co-adaptation. The implementation of a decision tree model related Rubisco specific variable sites to the leaf carbon isotopic composition of the species. Differences in the Rubisco catalytic traits found among C3 orchids and between strong CAM and C3 bromeliads suggested Rubisco had evolved in response to differing CO2 concentration. CONCLUSIONS: The results revealed that the variability in the Rubisco L-subunit sequence in orchids and bromeliads is composed of coevolving sites under potential positive adaptive signal. The sequence variability was related to δ13C in orchids and bromeliads, however it could not be linked to the variability found in the kinetic properties of the studied species.

The acetabulum as an adult age marker and the new IDADE2 (the IDADE2 web page).

OBJECTIVE: In 2006, an age estimation method was proposed utilizing Bayesian inference to interpret age-progressive changes in the acetabulum. This was accompanied by the IDADE2 software to facilitate calculations. However, the MS-DOS operating system on which the software was based became obsolete. The main goal of this article is to present the new IDADE2, which incorporates web-based facilities. MATERIALS AND METHODS: The original IDADE2 has been re-written in R and presented as a web page. As in the original, this web page uses Bayesian inference to estimate age of unidentified individuals. The materials used to create the reference datasets of this web page include acetabular scores from documented skeletal samples from Spain (n = 24♀ and 52♂), Portugal (n = 317♀ and 294♂), and the US (n = 370♀ and 456♂). RESULTS: The IDADE2 website has eight sections. Six of these are informative to guide the user. The other two (Option 1 and Option 2) are dedicated to estimating age at death. Option 1 allows users to estimate the age of individual(s) in their test sample based on our reference data of acetabular scores. Option 2 allows users to estimate age from the acetabulum with their own reference and test collections or-if the users prefer-another age marker and method of choice. DISCUSSION: The IDADE2 website is applicable both to forensic anthropological casework on single individuals and to bioarchaeological analyses of large skeletal samples. This website is easy to use and freely accessible, responding to previous critiques and incorporating method advancements.

Comparison of a shortened isosorbide dinitrate-potentiated head-up tilt testing with the conventional protocol: tolerance and diagnostic accuracy.

BACKGROUND: The head-up tilt test (HUT) is widely used to investigate unexplained syncope; however, in clinical practice, it is long and sometimes not well tolerated. OBJECTIVES: To compare the sensitivity, specificity, accuracy, and patients' tolerance of a conventional and shortened HUT. METHODS: Patients with a history of vasovagal syndrome (VVS) were randomized to a conventional HUT (group I) consisting of 20-minute passive tilt followed by 25 minutes after administration of sublingual isosorbide dinitrate (ISDN), or a shortened HUT (group II) where ISDN was given immediately after tilt and observed for 25 minutes. The control group consisted of age- and gender-matched subjects without VVS symptoms. A specific questionnaire to evaluate tolerance was applied. RESULTS: Sixty patients (29 ± 10 years, 82% female) were included. In group I, 22/30 patients had a positive HUT compared to 21/30 in group II (73% vs 70%, P = 0.77). There was also no difference in the accuracy between the two protocols (63% vs 73%, P = 0.24). The time to positivity was shorter in group II (13.2 minutes vs 30 minutes, P < 0.001). Within the control group (n = 60), the frequency of false-positives was 47% and 23% for the conventional and shortened HUT, respectively (P = 0.058). After conventional HUT, 65.2% subjects reported that the test was too long compared to 25% subjects after the shortened HUT (P = 0.002). CONCLUSION: In this study, the HUT without passive phase was not inferior to the conventional HUT regarding sensitivity, specificity, and accuracy. Furthermore, the shortened ISDN-potentiated protocol allowed faster diagnosis and was better tolerated.

A novel in situ passive heating method for evaluating whole-tree responses to daytime warming in remote environments.

BACKGROUND: Many significant ecosystems, including important non-forest woody ecosystems such as the Cerrado (Brazilian savannah), are under threat from climate change, yet our understanding of how increasing temperatures will impact native vegetation remains limited. Temperature manipulation experiments are important tools for investigating such impacts, but are often constrained by access to power supply and limited to low-stature species, juvenile individuals, or heating of target organs, perhaps not fully revealing how entire or mature individuals and ecosystems will react to higher temperatures. RESULTS: We present a novel, modified open top chamber design for in situ passive heating of whole individuals up to 2.5 m tall (but easily expandable) in remote field environments with strong solar irradiance. We built multiple whole-tree heating structures (WTHSs) in an area of Cerrado around native woody species Davilla elliptica and Erythroxylum suberosum to test the design and its effects on air temperature and humidity, while also studying the physiological responses of E. suberosum to short-term heating. The WTHSs raised internal air temperature by approximately 2.5 °C above ambient during the daytime. This increased to 3.4 °C between 09:00 and 17:00 local time when thermal impact was greatest, and during which time mean internal temperatures corresponded closely with maximum ambient temperatures. Heating was consistent over time and across WTHSs of variable size and shape, and they had minimal effect on humidity. E. suberosum showed no detectable response of photosynthesis or respiration to short-term experimental heating, but some indication of acclimation to natural temperature changes. CONCLUSIONS: Our WTHSs produced a consistent and reproducible level of daytime heating in line with mid-range climate predictions for the Cerrado biome by the end of the century. The whole-tree in situ passive heating design is flexible, low-cost, simple to build using commonly available materials, and minimises negative impacts associated with passive chambers. It could be employed to investigate the high temperature responses of many understudied species in a range of complex non-forest environments with sufficient solar irradiance, providing new and important insights into the possible impacts of our changing climate.

Incidence and characteristics of transient St-segment elevation during transseptal puncture.

PURPOSE: Delineate retrospectively and prospectively the incidence and characteristics of transient ST-segment elevation during transseptal puncture. METHODS: The study retrospectively evaluated 307 patients from January 1, 2015, to December 31, 2017, and prospectively evaluated 231 patients from January 1, 2018, to July 31, 2019. RESULTS: The presence of ST-segment elevation was significantly higher in the prospective sample than in the retrospective sample (5.2% vs. 1.3%, p < 0.05). Between the two groups, there was no significant difference in age, sex, comorbidities, left atrial volume index, and the etiology of atrial fibrillation among patients with ST-segment alteration. In all patients, the ST-segment elevation was observed in the inferior wall derivations, except for one patient with ST elevation in lead I, AVL, V1-V4 during the septal puncture, associated with sinus bradycardia and reversed hypotension with intravenous fluids. Comparative analysis of the systolic and diastolic arterial pressure and the minimum heart rate during the phenomenon demonstrated more severity in the retrospectively evaluated population than in the prospective population. There was a significant association between the occurrence of ST-segment elevation > 2 mm and the presence of symptoms. In these patients, coronary angiography showed no alterations. Atropine was administered to one patient who presented with junctional bradycardia after the puncture. This medication reversed the situation. CONCLUSION: ST-segment elevation is a short-term phenomenon that can occur during transseptal catheterization without clinically evident symptoms. The catheter ablation procedure can be safely concluded despite the occurrence of the phenomenon.

Flexible structural protein alignment by a sequence of local transformations.

MOTIVATION: Throughout evolution, homologous proteins have common regions that stay semi-rigid relative to each other and other parts that vary in a more noticeable way. In order to compare the increasing number of structures in the PDB, flexible geometrical alignments are needed, that are reliable and easy to use. RESULTS: We present a protein structure alignment method whose main feature is the ability to consider different rigid transformations at different sites, allowing for deformations beyond a global rigid transformation. The performance of the method is comparable with that of the best ones from 10 aligners tested, regarding both the quality of the alignments with respect to hand curated ones, and the classification ability. An analysis of some structure pairs from the literature that need to be matched in a flexible fashion are shown. The use of a series of local transformations can be exported to other classifiers, and a future golden protein similarity measure could benefit from it. AVAILABILITY: A public server for the program is available at http://dmi.uib.es/ProtDeform/. SUPPLEMENTARY INFORMATION: All data used, results and examples are available at http://dmi.uib.es/people/jairo/bio/ProtDeform.

[Oral anticoagulation in patients with atrial fibrillation: from guidelines to bedside]. / Anticoagulação oral em pacientes com fibrilação atrial: das diretrizes à prática clínica.

OBJECTIVE: Although oral anticoagulation has proved beneficial for patients with atrial fibrillation (AF) and embolic risk factors, it is still underused. The objective of this study was to evaluate the adequacy of anticoagulation therapy in patients with AF followed in a private clinic specialized in cardiology, in accordance with the American and European societies of cardiology guidelines/2006 and with the Brazilian Guidelines/2003. METHODS: Between November 2005 and August 2006, we evaluated 7,486 electrocardiograms and selected 53 patients with AF and complete chart records. Clinical characteristics, including embolic risk factor, echocardiographic data and medical treatment were reviewed. RESULTS: Among the 53 patients (68+/-16 years; 29 men), 25 (48%) had hypertension, 20 (38%) heart failure and 3 (6%) diabetes. Among the 15 patients with high embolic risk, 13 (86%) were on oral anticoagulation. In accordance with the American and European guidelines: 32 (60%) patients were Class I, 17 (32%) Class IIa, 1 (2%) Class IIb and 3 (6%) Class III. Treatment was adequate in 21 (66%) Class I patients and 13 (76%) Class IIa. In these, anticoagulation therapy was used in 7/19 (37%) patients > 75 years compared to 22/30 (73%) younger. Among the 3 patients within Class III, 1 was incorrectly on OAC. According to Brazilian guidelines, 33 (62%) were on correctly indicated antithrombotic therapy. There was no difference in the appropriate prescription of oral anticoagulants, comparing the international and Brazilian guidelines (55% vs. 55%). CONCLUSION: According to recent guidelines, anticoagulant therapy has been adequately prescribed for the majority of AF patients, although this is still far from ideal, especially in a cardiology clinic. It is even more critical in the group of older patients.

Positively selected amino acid replacements within the RuBisCO enzyme of oak trees are associated with ecological adaptations.

Phylogenetic analysis by maximum likelihood (PAML) has become the standard approach to study positive selection at the molecular level, but other methods may provide complementary ways to identify amino acid replacements associated with particular conditions. Here, we compare results of the decision tree (DT) model method with ones of PAML using the key photosynthetic enzyme RuBisCO as a model system to study molecular adaptation to particular ecological conditions in oaks (Quercus). We sequenced the chloroplast rbcL gene encoding RuBisCO large subunit in 158 Quercus species, covering about a third of the global genus diversity. It has been hypothesized that RuBisCO has evolved differentially depending on the environmental conditions and leaf traits governing internal gas diffusion patterns. Here, we show, using PAML, that amino acid replacements at the residue positions 95, 145, 251, 262 and 328 of the RuBisCO large subunit have been the subject of positive selection along particular Quercus lineages associated with the leaf traits and climate characteristics. In parallel, the DT model identified amino acid replacements at sites 95, 219, 262 and 328 being associated with the leaf traits and climate characteristics, exhibiting partial overlap with the results obtained using PAML.

Correction: Positively selected amino acid replacements within the RuBisCO enzyme of oak trees are associated with ecological adaptations.

[This corrects the article DOI: 10.1371/journal.pone.0183970.].

Incidência de lesões esofágicas em pacientes submetidos a ablação de fibrilação atrial com cateter circular multipolar (PVAC-GOLD®) / Incidence of esophageal lesions in patients undergoing ablation for atrial fibrillation with multipolar pulmonary vein ablation catheter (PVAC-GOLD®)

Lesões do esôfago são descritas como complicação da ablação por radiofrequência da fibrilação atrial. Os trabalhos que avaliaram a formação das lesões esofágicas em ablações de fibrilação atrial tiveram como padrão de fonte de energia a radiofrequência em modo unipolar, utilizando o cateter irrigado. Atualmente está disponível o cateter circular multipolar (PVAC-GOLD®), que utiliza ciclos de aplicação de energia em fases (Duty-Cycled Phased RF). Este trabalho tem como objetivo avaliar a ocorrência de lesão esofágica em pacientes submetidos a ablação de fibrilação atrial utilizando-se o cateter PVAC-GOLD®. Método: Entre agosto de 2014 e agosto de 2017, foram incluídos pacientes submetidos a ablação de fibrilação atrial sintomática com uso do cateter PVAC-GOLD®. Por meio da realização de endoscopia digestiva alta no pós-operatório, buscou-se determinar a ocorrência de lesão esofágica térmica associada ao procedimento. Resultados: O estudo incluiu um total de 117 pacientes (74% com fibrilação atrial paroxística), com média de idade de 54,8 anos, e predominantemente do sexo masculino. Destes, apenas 2 apresentaram lesões esofágicas térmicas diagnosticadas por meio da endoscopia digestiva alta. Conclusão: A lesão esofágica parece ser um achado incomum em pacientes submetidos a isolamento elétrico das veias pulmonares com o cateter circular multipolar (PVAC-GOLD®)

Esophageal lesions are described as a complication after ablation for atrial fibrillation. The studies evaluating the development of esophageal lesions in ablation due to atrial fibrillation had unipolar mode radiofrequency energy source using an irrigated catheter. A multipolar pulmonary vein ablation catheter (PVAC-GOLD®) is currently available, which uses phase-in cycles of energy (Duty-Cycled Phased RF). This study aims to evaluate the occurrence of esophageal lesions in patients undergoing ablations due to atrial fibrillation using the PVAC-GOLD® catheter. Method: Between August 2014 and August 2017, patients undergoing ablation due to symptomatic atrial fibrillation with the use of the PVAC-GOLD® catheter were included in the study. Upper digestive endoscopy was performed in the postoperative period to determine the presence of thermal esophageal lesions associated to the procedure. Results: A total of 117 patients, with mean age of 54.8 years, predominantly males, were included in the study. Of these patients, only 2 presented thermal esophageal lesions diagnosed by endoscopy. Conclusion: Esophageal lesion seems to be an unusual finding in patients undergoing electrical isolation of the pulmonary veins using the multipolar pulmonary vein ablation catheter (PVAC-GOLD®)

The significance of the ProtDeform score for structure prediction and alignment.

BACKGROUND: When a researcher uses a program to align two proteins and gets a score, one of her main concerns is how often the program gives a similar score to pairs that are or are not in the same fold. This issue was analysed in detail recently for the program TM-align with its associated TM-score. It was shown that because the TM-score is length independent, it allows a P-value and a hit probability to be defined depending only on the score. Also, it was found that the TM-scores of gapless alignments closely follow an Extreme Value Distribution (EVD). The program ProtDeform for structural protein alignment was developed recently and is characterised by the ability to propose different transformations of different protein regions. Our goal is to analyse its associated score to allow a researcher to have objective reasons to prefer one aligner over another, and carry out a better interpretation of the output. RESULTS: The study on the ProtDeform score reveals that it is length independent in a wider score range than TM-scores and that PD-scores of gapless (random) alignments also approximately follow an EVD. On the CASP8 predictions, PD-scores and TM-scores, with respect to native structures, are highly correlated (0.95), and show that around a fifth of the predictions have a quality as low as 99.5% of the random scores. Using the Gold Standard benchmark, ProtDeform has lower probabilities of error than TM-align both at a similar speed. The analysis is extended to homology discrimination showing that, again, ProtDeform offers higher hit probabilities than TM-align. Finally, we suggest using three different P-values according to the three different contexts: Gapless alignments, optimised alignments for fold discrimination and that for superfamily discrimination. In conclusion, PD-scores are at the very least as valuable for prediction scoring as TM-scores, and on the protein classification problem, even more reliable.

On the ancestral compatibility of two phylogenetic trees with nested taxa.

Compatibility of phylogenetic trees is the most important concept underlying widely-used methods for assessing the agreement of different phylogenetic trees with overlapping taxa and combining them into common supertrees to reveal the tree of life. The notion of ancestral compatibility of phylogenetic trees with nested taxa was recently introduced. In this paper we analyze in detail the meaning of this compatibility from the points of view of the local structure of the trees, of the existence of embeddings into a common supertree, and of the joint properties of their cluster representations. Our analysis leads to a very simple polynomial-time algorithm for testing this compatibility, which we have implemented and is freely available for download from the BioPerl collection of Perl modules for computational biology.

Anticoagulação oral em pacientes com fibrilação atrial: das diretrizes à prática clínica / Oral anticoagulation in patients with atrial fibrillation: from guidelines to bedside

OBJETIVO: Apesar da anticoagulação oral (ACO) ter benefício comprovado em pacientes com fibrilação atrial (FA) e fatores de risco embólico, ela vem sendo subutilizada. O objetivo desse estudo foi avaliar a adequação da terapêutica anticoagulante em pacientes com FA acompanhados em clínica especializada em cardiologia, privada, de acordo com as diretrizes das sociedades americana e europeia de cardiologia de 2006 e a diretriz da Sociedade Brasileira de Cardiologia (SBC) de 2003. MÉTODOS: No período de novembro/2005 a agosto/2006 foram avaliados 7.486 eletrocardiogramas e selecionados 53 pts com laudo de FA e informações claras relatadas em prontuário sobre fatores de risco embólico e terapêutica de ACO. RESULTADOS: Dentre os 53 pacientes incluídos (68±16 anos; 29 homens - 55 por cento), 25 (48 por cento) tinham HAS, 20 (38 por cento) insuficiência cardíaca e 3 (6 por cento) DM. Dentre os 15 pacientes com alto risco embólico, 13 (86 por cento) estavam em uso de ACO. De acordo com a recomendação das diretrizes americana e europeia: 32 (60 por cento) pacientes tinham indicação Classe I, 17 (32 por cento) Classe IIa, 1 (2 por cento) Classe IIb e 3 (6 por cento) Classe III. Estavam adequadamente tratados 21 (66 por cento) pacientes da Classe I e 13 (76 por cento) pacientes Classe IIa. Nesse subgrupo, 7/19 (37 por cento) pacientes com idade >75 anos estavam sendo anticoagulados, comparado a 22/30 (73 por cento) daqueles com idade inferior (p=0,016). Dentre os três pacientes com indicação Classe III, um estava incorretamente com prescrição de anticoagulante. Pela diretriz da SBC, 33 (62 por cento) recebiam terapêutica antitrombótica adequada. Não houve diferença na utilização correta de ACO, comparando-se a diretriz brasileira e diretrizes americana e europeia (55 por cento vs. 55 por cento). CONCLUSÃO: A terapêutica anticoagulante está sendo prescrita adequadamente na maioria dos pacientes com FA, embora esse índice ainda esteja muito aquém ...

OBJECTIVE: Although oral anticoagulation has proved beneficial for patients with atrial fibrillation (AF) and embolic risk factors, it is still underused. The objective of this study was to evaluate the adequacy of anticoagulation therapy in patients with AF followed in a private clinic specialized in cardiology, in accordance with the American and European societies of cardiology guidelines/2006 and with the Brazilian Guidelines/2003. METHODS: Between November 2005 and August 2006, we evaluated 7,486 electrocardiograms and selected 53 patients with AF and complete chart records. Clinical characteristics, including embolic risk factor, echocardiographic data and medical treatment were reviewed. RESULTS: Among the 53 patients (68±16 years; 29 men), 25 (48 percent) had hypertension, 20 (38 percent) heart failure and 3 (6 percent) diabetes. Among the 15 patients with high embolic risk, 13 (86 percent) were on oral anticoagulation. In accordance with the American and European guidelines: 32 (60 percent) patients were Class I, 17 (32 percent) Class IIa, 1 (2 percent) Class IIb and 3 (6 percent) Class III. Treatment was adequate in 21 (66 percent) Class I patients and 13 (76 percent) Class IIa. In these, anticoagulation therapy was used in 7/19 (37 percent) patients > 75 years compared to 22/30 (73 percent) younger. Among the 3 patients within Class III, 1 was incorrectly on OAC. According to Brazilian guidelines, 33 (62 percent) were on correctly indicated antithrombotic therapy. There was no difference in the appropriate prescription of oral anticoagulants, comparing the international and Brazilian guidelines (55 percent vs. 55 percent). CONCLUSION: According to recent guidelines, anticoagulant therapy has been adequately prescribed for the majority of AF patients, although this is still far from ideal, especially in a cardiology clinic. It is even more critical in the group of older patients.

Respuesta inmunitaria inducida por vacuna antiaftosa oleosa en bovinos de areas tropicales de Colombia / Immune response induced by oil-adjuvanted foot-and-mouth disease vaccine in cattle in tropical areas of Colombia

La respuesta inmunitaria inducida por vacuna de tipo oleoso contra la fiebre aftosa fue evaluada por la determinacion de los titulos de anticuerpos sericos neutralizantes a los 2, 4, 6, 7, 9, 12 15 y 18 meses siguientes a la aplicacion de 1 y 2 dosis de vacuna en grupos de vacas, novillas y terneras bajo condiciones diversas de manejo y con antecedentes de vacunacion periodica realizada con vacuna hidroxido-saponinada. Se aplicaron 6000 dosis de vacuna oleosa preparadas por el Centro Panamericano de Fiebre Aftosa (Rio de Janeiro, Brasil) con las cepas viralesA27-Cundinamarca/75-8046 y O1-Campos/Brasil. Cuatro predios de diferentes regiones tropicales fueron selecionados para la aplicacionde 3000 dosis iniciales seguidas de una segunda aplicacion a los 6 y 12 meses. En cada etapa de sangria se tomaron 430 muestras de sueros. Las vacas y novillas mostraron titulos altos de anticuerpos a los 2 meses despues de la primera vacunacion frente a los dos tipos de virus O y A. A los 4 y 6 meses se observo una disminucion de los titulos, con una diferencia no superior a 1 log en relacion conlos titulos obtenidos inicialmente a 2 meses. Igualmente, esta diferencia no fue mayor de 1,5 log con relacion al valor obtenido finalmente a los 12 meses. Fue evidente la obtencion de titulos superiores y mas persistentes durante 12 meses despues de la aplicacion de una segunda dosis de vacuna oleosa. Con base en los resultados obtenidos se sugiere un minimo de tres vacunaciones con intervalos de 6 meses en los bovinos menores de 18 meses, seguidos de vacunacion anual. En el caso de bovinos de 18 a 36 meses, se sugiere la aplicacion de la segunda dosis a los 6 meses para continuar con vacunacion anual. Las poblaciones de bovinos adultos con antecedentes de inmunizacion periodica cada 4 meses con vacuna de tipo hidroxido saponinada podrian recibir una dosis cada año.