Hidden Markov Models

Hidden Markov Models (HMMs), although known for decades, have made a big career nowadays and are still in state of development. This book presents theoretical issues and a variety of HMMs applications in speech recognition and synthesis, medicine, neurosciences, computational biology, bioinformatics, seismology, environment protection and engineering. I hope that the reader will find this book useful and helpful for their own research

Aerospace medicine and biology: A continuing bibliography with indexes (supplement 405)

This bibliography lists 225 reports, articles and other documents introduced into the NASA Scientific and Technical Information System during Sep. 1995. Subject coverage includes: aerospace medicine and physiology, life support systems and man/system technology, protective clothing, exobiology and extraterrestrial life, planetary biology, and flight crew behavior and performance

The Evolution of Drug Resistant Mycobacterium Tuberculosis

Mycobacterium tuberculosis (Mtb) poses a global health catastrophe that has been compounded by the emergence of highly drug resistant Mtb strains. We used whole genome sequencing (WGS) to directly compare the accumulation of mutations in Mtb isolated from cynomolgus macaques with active, latent and early reactivation disease. Based on the distribution of single nucleotide polymorphisms (SNPs) observed, we calculated the mutation rates for these disease states. Our data suggest that during latency, Mtb acquires a similar number of chromosomal mutations as would be expected to emerge in a logarithmically growing culture over the same period of time despite reduced bacterial replication during latent infection. The pattern of polymorphisms suggests that the mutational burden in vivo is due to oxidative DNA damage. We next sought to determine why some strains of Mtb are preferentially associated with high-level drug resistance. We demonstrate that Mtb strains from the East Asian lineage acquire drug resistances in vitro more quickly than Mtb strains from the Euro-American lineage. Their higher drug resistance rate in vitro reflects a higher basal mutation. Moreover, the in vitro mutation rate correlates well with the bacterial mutation rate in humans as determined by whole genome sequencing of clinical isolates. Finally, using an agent-based model, we show that the observed differences in mutation rate predict a significantly higher probability of multi-drug resistance in patients infected with East Asian lineage strains of Mtb. Lastly, we sought to determine the mechanisms Mtb uses to proofread nascently polymerized DNA. Through fluctuation analysis of deletion mutants of two potential $polIII\epsilon$ homologs, we demonstrate that neither is responsible for the maintenance of DNA replication fidelity. To explore the possibility that one of these homologs, Rv3711c, participates in an unknown redundant pathway, we used transposon capture and sequence (TraCS) to identify genes conditionally essential in an Rv3711c deletion mutant. Our analysis suggests that while Rv3711c does not participate in proofreading, it may act in an alternative novel DNA repair pathway. Taken together, our fluctuation analysis and TraCS data suggest that mycobacteria do not use canonical methods of proofreading to maintain genomic fidelity

Multiscale Modeling of T Cells in Mycobacterium Tuberculosis Infection

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (Mtb), is one of the deadliest infectious diseases in the world and remains a significant global health burden. Central to the immune response against Mtb are T cells, a type of adaptive immune cell that can kill infected cells, secrete cytokines to activate other immune cells, and orchestrate the broader immune response. Over the past few decades, experimental studies have significantly furthered our understanding of T-cell biology and function during Mtb infection. However, these findings have yet to translate to a clinically effective TB vaccine. As a complementary approach to experimental studies, systems biology and computational modeling can provide context to T-cell function by describing T-cell interactions with other immune cells across multiple scales. In this thesis we utilize a systems biology approach to characterize T-cell behavior, function, and movement across multiple physiological and temporal scales during Mtb infection. In addition, we develop a whole-host model of the immune response to Mtb. Following infection with Mtb, the immune response leads to the development of multiple lung granulomas – organized structures composed of immune cells that surround bacteria. Using a previously developed agent-based model of granuloma formation and function, we explore the role of T cells within the granuloma and predict that T-cell exhaustion, a type of T-cell dysfunction, is prevented from occurring by the physical structure of the granuloma. Next, we develop a novel whole lung model that tracks the formation of multiple granulomas. Using this model, we predict that a special type of T-cell, called a multi-functional CD8+ T cell, is key in preventing dissemination events - when bacteria escape one granuloma and seed the formation of a new one elsewhere in the lung. We also present a model of T-cell priming, proliferation, and differentiation within the lymph nodes and blood following TB vaccination and illustrate that non-human primates and humans respond similarly when receiving TB vaccination. We mathematically link the whole lung model and lymph node and blood model to create a whole-host model of the immune response following Mtb infection. We show that this model can capture various aspects of human and non-human primate TB disease and predict that biomarkers in the blood may only faithfully represent events in the lung at early time points after infection. Using this model, we predict that resident memory T cells are important mediators of protection against reinfection with Mtb and additionally predict the lifespan of these crucial cells in humans. Finally, we develop a protocol for calibrating mathematical and computational models to experimental datasets. Overall, this dissertation builds on our knowledge of the various roles T cells play in responding to Mtb infection, presents a set of computational models for evaluating the T-cell response to either infection or vaccination, and identifies mechanisms that control different outcomes across multiple scales following Mtb infection, reinfection, or vaccination.PHDBioinformaticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/167940/1/louisjos_1.pd

2019 EURēCA Abstract Book

Listing of student participant abstracts

Antioxidant and DPPH-Scavenging Activities of Compounds and Ethanolic Extract of the Leaf and Twigs of Caesalpinia bonduc L. Roxb.

Antioxidant effects of ethanolic extract of Caesalpinia bonduc and its isolated bioactive compounds were evaluated in vitro. The compounds included two new cassanediterpenes, 1α,7α-diacetoxy-5α,6β-dihydroxyl-cass-14(15)-epoxy-16,12-olide (1)and 12α-ethoxyl-1α,14β-diacetoxy-2α,5α-dihydroxyl cass-13(15)-en-16,12-olide(2); and others, bonducellin (3), 7,4’-dihydroxy-3,11-dehydrohomoisoflavanone (4), daucosterol (5), luteolin (6), quercetin-3-methyl ether (7) and kaempferol-3-O-α-L-rhamnopyranosyl-(1Ç2)-β-D-xylopyranoside (8). The antioxidant properties of the extract and compounds were assessed by the measurement of the total phenolic content, ascorbic acid content, total antioxidant capacity and 1-1-diphenyl-2-picryl hydrazyl (DPPH) and hydrogen peroxide radicals scavenging activities.Compounds 3, 6, 7 and ethanolic extract had DPPH scavenging activities with IC50 values of 186, 75, 17 and 102 μg/ml respectively when compared to vitamin C with 15 μg/ml. On the other hand, no significant results were obtained for hydrogen peroxide radical. In addition, compound 7 has the highest phenolic content of 0.81±0.01 mg/ml of gallic acid equivalent while compound 8 showed the highest total antioxidant capacity with 254.31±3.54 and 199.82±2.78 μg/ml gallic and ascorbic acid equivalent respectively. Compound 4 and ethanolic extract showed a high ascorbic acid content of 2.26±0.01 and 6.78±0.03 mg/ml respectively.The results obtained showed the antioxidant activity of the ethanolic extract of C. bonduc and deduced that this activity was mediated by its isolated bioactive compounds