EpiphaNet: An Interactive Tool to Support Biomedical Discoveries

Background. EpiphaNet (http://epiphanet.uth.tmc.edu) is an interactive knowledge discovery system, which enables researchers to explore visually sets of relations extracted from MEDLINE using a combination of language processing techniques. In this paper, we discuss the theoretical and methodological foundations of the system, and evaluate the utility of the models that underlie it for literature‐based discovery. In addition, we present a summary of results drawn from a qualitative analysis of over six hours of interaction with the system by basic medical scientists. Results: The system is able to simulate open and closed discovery, and is shown to generate associations that are both surprising and interesting within the area of expertise of the researchers concerned. Conclusions: EpiphaNet provides an interactive visual representation of associations between concepts, which is derived from distributional statistics drawn from across the spectrum of biomedical citations in MEDLINE. This tool is available online, providing biomedical scientists with the opportunity to identify and explore associations of interest to them

Systems Biology Approaches to Discerning Striated Muscle Pathologies

The human muscular system represents nearly 75% of the body mass and encompasses two major muscle forms- striated and smooth. Striated muscle, composed broadly of myofibers, accompanying membrane systems, cytoskeletal networks together with the metabolic and regulatory machinery, have revealed complexities in composition, structure and function. A disruption to any component within this complex system of interactions lead to disorders of the muscle, typically characterized by muscle fiber loss, reduced motor output and in some cases death. Advent of high-throughput technologies coupled with elegant approaches to deciphering data using bioinformatics and systems biology, are providing new venues for detailed exploration of mammalian muscle. This dissertation describes the use of publicly available high-throughput data, in conjunction with co-expression network methodologies developed for a comprehensive, interpretable systems-level perspective on mechanisms underlying associated muscle pathologies. This study begins with the exploration of the temporal transcriptional response of skeletal muscle to Botulinum Neurotoxin-A (Botox ®) over a 1-year period, in the framework of muscle physiology. Next, utilizing co-expression network analysis, putative markers associated with recovery of muscle trophicity are identified, furthermore providing an unbiased validation of the response documented earlier. These studies represent the first attempt at categorically assessing the whole-transcriptomic changes associated with BoNT-A treatment in muscle. The latter half of this research focuses on discerning patho-mechanisms of human diseases affecting muscle. Particularly, co-expression network statistics are leveraged to identify dysregulated pathways and biomarkers of disease progression, underlying duchenne muscular dystrophy. Next, a quantitative framework integrating transcriptional, protein interaction, and drug-target data is developed to extract functional similarities and mechanisms amongst 20 diseases affecting the muscle. Lastly, an approach to differential co-expression analysis using signed and weighted co-expression networks is described. This approach is subsequently utilized to assess and identify differential mechanisms underlying ischemic and idiopathic dilated cardiomyopathy. The analysis and results from the aforementioned studies have enabled a deeper understanding of the complex interactions underlying muscle pathologies; providing opportunities for drug development and personalized medicine

Co-expression Network Approach Reveals Functional Similarities among Diseases Affecting Human Skeletal Muscle

TesisLa sangre encontrada en la escena del crimen se ha constituido como elemento esencial en el esclarecimiento de investigaciones judiciales. Por tal razón los autores de los diferentes delitos tratan de eliminar dicha evidencia, lavando las prendas u objetos manchados. Existe una prueba llamada "Luminol", esta se realiza con el reactivo Bluestar Forensic Free, porque tiene la función de revelar sangre oculta después del lavado. Para determinar si la calidad de la tela y el tiempo de exposición del producto de limpieza, alteran la reacción químioluminiscete, en telas con manchas de sangre lavadas, planteando objetivos específicos: Determinar si la dilución de los productos de limpieza afectan la reacción de quimioluminiscencia de Bluestar Forensic Free sobre manchas sanguíneas de interés forense; Determinar si el tiempo de exposición en el lavado con los productos de limpieza afectan la reacción del reactivo de revelado (Biuestar Forensic Free) sobre las telas con mancha de sangre; Determinar si la dilución de los productos de limpieza y el tiempo de exposición por calidad de tela, inhiben la reacción de químiolumiscencia {Biuestar Forensic Free) sobre manchas sanguíneas de interés forense. El presente trabajo de investigación se desarrolló en el Laboratorio de Microbiología Ambiental de la EFP de Biología - Facultad de Ciencias Biológicas de la Universidad Nacional San Cristóbal de Huamanga y Laboratorio de Biología Forense de la Policía Nacional Ayacucho- Perú. El tipo de investigación: Básico experimental, usando el método: Fase pre- Analítica: Preparación de telas, Obtención de la sangre, Preparación de telas con manchas de sangre, el patrón y blanco, Preparar los patrones positivo y negativo, Preparación de las diluciones de los productos de limpieza. Fase Analítica: Lavado de las telas con mancha de sangre cada 4 horas, Enjuague de los trozos de tela remojados, Revelado, Fotografías. Fase Post Analítica: Valoración de la quimioluminiscencia, Análisis estadístico (ANVA) Con arreglo factorial axbxc. Considerando el nivel de confianza, P value > 0.05. Obteniendo como resultado valores positivos de 250 a 225, valores intermedios de 224 a 221 y negativos de 200 a 196. Concluyendo: Se evaluaron la reacción de "Biuestar Forensic Free" si detecta manchas sanguíneas de interés forense. Las diluciones (0/400; 20/400; 40/400; 60/400; 80/400; 1 00/400) de los productos de limpieza afectaron la reacción de quimioluminiscencia de Bluestar Forensic Free sobre manchas sanguíneas de interés forense. El tiempo (0; 4; 8; 12; 16; 20) horas de exposición en el lavado con los productos de limpieza afectaron la reacción del Bluestar Forensic Free, sobre las telas con mancha de sangre. La dilución de los productos de limpieza y el tiempo de exposición en cada tipo de tela, no inhiben la reacción de quimioluminiscencia del Bluestar Forensic Free sobre manchas sanguíneas de interés forense. Palabra

Co-expression Network Approach Reveals Functional Similarities among Diseases Affecting Human Skeletal Muscle

Diseases affecting skeletal muscle exhibit considerable heterogeneity in intensity, etiology, phenotypic manifestation and gene expression. Systems biology approaches using network theory, allows for a holistic understanding of functional similarities amongst diseases. Here we propose a co-expression based, network theoretic approach to extract functional similarities from 20 heterogeneous diseases comprising of dystrophinopathies, inflammatory myopathies, neuromuscular, and muscle metabolic diseases. Utilizing this framework we identified seven closely associated disease clusters with 20 disease pairs exhibiting significant correlation (p < 0.05). Mapping the diseases onto a human protein-protein interaction network enabled the inference of a common program of regulation underlying more than half the muscle diseases considered here and referred to as the “protein signature.” Enrichment analysis of 17 protein modules identified as part of this signature revealed a statistically non-random dysregulation of muscle bioenergetic pathways and calcium homeostasis. Further, analysis of mechanistic similarities of less explored significant disease associations [such as between amyotrophic lateral sclerosis (ALS) and cerebral palsy (CP)] using a proposed “functional module” framework revealed adaptation of the calcium signaling machinery. Integrating drug-gene information into the quantitative framework highlighted the presence of therapeutic opportunities through drug repurposing for diseases affecting the skeletal muscle

The Janus face of proliferating plasmablasts in dengue and COVID-19 infections.

INTRODUCTION: B cells play an integral role in the immune response to both dengue fever and COVID-19. Prior scRNAseq analyses of peripheral plasmablasts in COVID-19 have revealed a heterogeneous population with distinct cell subsets associated with proliferation; prior studies in patients with dengue fever have likewise shown the presence of proliferative pre-plasmablasts in the circulation. These findings may have implications for disease severity. In this study, we sought to gain a mechanistic understanding of the intracellular processes in naive and memory B cells that are associated with and may lead to an expanded proliferative plasmablast population in the circulation. METHODS: We analyzed age-controlled (pediatric and adult), peripheral blood mononuclear cell scRNAseq datasets from patients infected with either dengue (primary or secondary) or COVID-19 (non-severe or severe) from previously published studies. Our preliminary analysis showed that pediatric patients with dengue and adults with COVID-19 had an expanded proliferative plasmablast (p-PB) population. By contrast, neither the adults with dengue nor the children with COVID-19 in our dataset had p-PBs. We used this distinctive preliminary signature to guide our analyses design and expanded our analyses to naive and memory B cells. RESULTS: In age/disease conditions with and without p-PBs, we found differences in cell sensing and activation, including via the B cell receptor and downstream signal transduction. Likewise, inflammation was mediated differently: relative to groups without p-PBs, those with p-PBs had increased expression of interferon response and S100 genes (particularly severe COVID-19). Furthermore, several transcription factors at the nexus of activation, inflammation, and cell fate decisions were expressed differently in groups with and without p-PBs. DISCUSSION: We used dengue and COVID-19 infections in adult and pediatric patients (focusing on naive B, memory B, and plasmablast cells) as a model to better understand the mechanisms that may give rise to p-PB populations in the circulation. Our results indicate that a more pro-inflammatory state in naive and memory B cells correlated with - and could influence the generation of- proliferating plasmablasts. Further exploration of these mechanisms will have implications for immune memory, vaccine development, and post-viral autoimmune syndromes

Plasmin Cascade Mediates Thrombotic Events in SARS-CoV-2 Infection via Complement and Platelet-Activating Systems

Objective: Recently emerged beta-coronavirus SARS-CoV-2, has resulted in the current pandemic designated COVID-19. COVID-19 manifests as severe illness exhibiting systemic inflammatory response syndrome, acute respiratory distress syndrome (ARDS), thrombotic events, and shock, exacerbated further by co-morbidities and age. Recent clinical evidence suggests that the development of ARDS and subsequent pulmonary failure result from a complex interplay between cell types (endothelial, epithelial and immune) within the lung promoting inflammatory infiltration and a pro-coagulative state. How the complex molecular events mediated by SARS-CoV-2 in infected lung epithelial cells lead to thrombosis and pulmonary failure, is yet to be fully understood. Methods: We address these questions here, using publicly available transcriptomic data in the context of lung epithelia affected by SARS-CoV-2 and other respiratory infections, in vitro. We then extend our results to the understanding of in vivo lung, using a publicly available COVID-19 lung transcriptomic study. Results and Conclusions: Our analysis indicates that there exists a complex interplay between the fibrinolytic system particularly plasmin, and the complement and platelet-activating systems upon SARS-CoV-2 infection, with a potential for therapeutic intervention

Single-rooted pyramidal molars: A rare case report

Anatomical variations of the first primary molars are very rare. Anatomic variation in root canal configuration, especially in multi-rooted teeth such as primary molars, makes the diagnosis and successful root canal therapy challenging. Thorough knowledge of root canal morphology and anatomical variations of primary teeth can help a pediatric dentist in successful root canal treatment. These deviations are also one of the major causes for endodontic treatment failure owing to inadequate cleaning, shaping, and sealing of root canal system. In addition, periodontally, fused roots are more prone to tooth destruction. The main purpose of the article is to present a very rare case of primary first molars with an unusual morphology as a single root called pyramidal molar. Various etiological factors are discussed briefly, and emphasis is placed on endodontic and periodontal aspects of these root canal aberrations

Modular and mechanistic changes across stages of colorectal cancer.

BackgroundWhile mechanisms contributing to the progression and metastasis of colorectal cancer (CRC) are well studied, cancer stage-specific mechanisms have been less comprehensively explored. This is the focus of this manuscript.MethodsUsing previously published data for CRC (Gene Expression Omnibus ID GSE21510), we identified differentially expressed genes (DEGs) across four stages of the disease. We then generated unweighted and weighted correlation networks for each of the stages. Communities within these networks were detected using the Louvain algorithm and topologically and functionally compared across stages using the normalized mutual information (NMI) metric and pathway enrichment analysis, respectively. We also used Short Time-series Expression Miner (STEM) algorithm to detect potential biomarkers having a role in CRC.ResultsSixteen Thousand Sixty Two DEGs were identified between various stages (p-value ≤ 0.05). Comparing communities of different stages revealed that neighboring stages were more similar to each other than non-neighboring stages, at both topological and functional levels. A functional analysis of 24 cancer-related pathways indicated that several signaling pathways were enriched across all stages. However, the stage-unique networks were distinctly enriched only for a subset of these 24 pathways (e.g., MAPK signaling pathway in stages I-III and Notch signaling pathway in stages III and IV). We identified potential biomarkers, including HOXB8 and WNT2 with increasing, and MTUS1 and SFRP2 with decreasing trends from stages I to IV. Extracting subnetworks of 10 cancer-relevant genes and their interacting first neighbors (162 genes in total) revealed that the connectivity patterns for these genes were different across stages. For example, BRAF and CDK4, members of the Ser/Thr kinase, up-regulated in cancer, displayed changing connectivity patterns from stages I to IV.ConclusionsHere, we report molecular and modular networks for various stages of CRC, providing a pseudo-temporal view of the mechanistic changes associated with the disease. Our analysis highlighted similarities at both functional and topological levels, across stages. We further identified stage-specific mechanisms and biomarkers potentially contributing to the progression of CRC