Intermittency as metastability: a predictive approach to evolution in disordered environments

Many systems across the sciences evolve through a combination of multiplicative growth and diffusive transport. In the presence of disorder, these systems tend to form localized structures which alternate between long periods of relative stasis and short bursts of activity. This behaviour, known as intermittency in physics and punctuated equilibrium in evolutionary theory, is difficult to forecast; in particular there is no general principle to locate the regions where the system will settle, how long it will stay there, or where it will jump next. Here I introduce a predictive theory of linear intermittency that closes these gaps. I show that any positive linear system can be mapped onto a generalization of the "maximal entropy random walk", a Markov process on graphs with non-local transition rates. This construction reveals the localization islands as local minima of an effective potential, and intermittent jumps as barrier crossings in that potential. My results unify the concepts of intermittency in linear systems and Markovian metastability, and provide a generally applicable method to reduce, and predict, the dynamics of disordered linear systems. Applications span physics, evolutionary dynamics and epidemiology.Comment: Extension of arXiv:1912.0589

On the Use of Coarse-Grained Thermodynamic Landscapes to Efficiently Estimate Folding Kinetics for RNA Molecules

Thesis advisor: Peter CloteRNA folding pathways play an important role in various biological processes, such as 1) the conformational switch in spliced leader RNA from Leptomonas collosoma, which controls transsplicing of a portion of the 5’ exon, and 2) riboswitches–portions of the 5’ untranslated region of mRNA that regulate genes by allostery. Since RNA folding pathways are determined by the thermodynamic landscape, we have developed a number of novel algorithms—including FFTbor and FFTbor2D—which efficiently compute the coarse-grained energy landscape for a given RNA sequence. These energy landscapes can then be used to produce a model for RNA folding kinetics that can compute both the mean first passage time (MFPT) and equilibrium time in a deterministic and efficient manner, using a new software package we call Hermes. The speed of the software provided within Hermes—namely FFTmfpt and FFTeq—present what we believe to be the first suite of kinetic analysis tools for RNA sequences that are suitable for high throughput usage, something we believe to be of interest in the field of synthetic design.Thesis (PhD) — Boston College, 2015.Submitted to: Boston College. Graduate School of Arts and Sciences.Discipline: Biology

CMOS system for high throughput fluorescence lifetime sensing using time correlated single photon counting

Fluorescence lifetime sensing using time correlated single photon counting (TCSPC) is a key analytical tool for molecular and cell biology research, medical diagnosis and pharmacological development. However, commercially available TCSPC equipment is bulky, expensive and power hungry, typically requiring iterative software post-processing to calculate the fluorescence lifetime. Furthermore, the technique is restrictively slow due to a low photon throughput limit which is necessary to avoid distortions caused by TCSPC pile-up. An investigation into CMOS compatible multimodule architectures to miniaturise the standard TCSPC set up, allow an increase in photon throughput by overcoming the TCSPC pile-up limit, and provide fluorescence lifetime calculations in real-time is presented. The investigation verifies the operation of the architectures and leads to the selection of optimal parameters for the number of detectors and timing channels required to overcome the TCSPC pile-up limit by at least an order of magnitude. The parameters are used to implement a low power miniaturised sensor in a 130 nm CMOS process, combining single photon detection, multiple channel timing and embedded pre-processing of the fluorescence lifetime, all within a silicon area of < 2 mm2. Single photon detection is achieved using an array of single photon avalanche diodes (SPADs) arranged in a digital silicon photomultiplier (SiPM) architecture with a 10 % fill-factor and a compressed 250 ps output pulse, which provides a photon throughput of > 700 MHz. An array of time-interleaved time-to-digital converters (TI-TDCs) with 50 ps resolution and no processing dead-time records up to eight photon events during each excitation period, significantly reducing the effect of TCSPC pile-up. The TCSPC data is then processed using an embedded centre-of-mass method (CMM) pre-calculation to produce single exponential fluorescence lifetime estimations in real-time. The combination of high photon throughput and real-time calculation enables advances in applications such as fluorescence lifetime imaging microscopy (FLIM) and time domain fluorescence lifetime activated cell sorting. To demonstrate this, the device is validated in practical bulk sample fluorescence lifetime, FLIM and simulated flow based experiments. Photon throughputs in excess of the excitation frequency are demonstrated for a range of organic and inorganic fluorophores for minimal error in lifetime calculation by CMM (< 5 %)

Gastrointestinal viruses and beyond: antiviral development and molecular epidemiology

With over 27 viral families known to infect humans, viral pathogens impose a significant global public health and economic burden. Despite this, only a small fraction of human viruses possess antiviral treatments or vaccines. Whilst antiviral development efforts are crucial to the host-pathogen arms race, so too is the molecular surveillance of these viruses to identify prevalent and virulent strains for vaccine development. This thesis begins, in chapter four, with the development of broad-spectrum non-nucleoside inhibitor compounds using a complex-based pharmacophore and virtual screening approach. This virtual screen identified one compound, NCS-013, which demonstrated broad-spectrum inhibition of the transcriptional activity of human norovirus and feline calicivirus from the Caliciviridae, Zika virus and hepatitis C virus from the Flaviviridae and hepatitis A virus from the Picornaviridae. The second half of the thesis focuses on molecular epidemiology of norovirus and adenovirus, two of the leading causes of viral gastroenteritis worldwide. In chapter five, we observed an interesting dynamic of GII.4 Sydney 2012 [P16] co-dominance in clinical samples throughout the study period. We also enhanced our sewage surveillance capabilities through the addition of partial ORF1 sequencing enabling the identification of recombinant strains. The role of non-group F adenoviruses in gastroenteritis although often reported, remains an area of controversy. In chapter six, we analysed sewage to complement clinical samples and better understand the diversity of adenovirus within the population, including from healthy individuals. In summary, this thesis approached the problem of viral pathogens from both the angle of antiviral development and through understanding of population-level molecular epidemiology, which can contribute to future vaccine development efforts

1995 BRAC Commission

JCSG - MED 12 &amp; 13 Economic Analysis - Medical Facilities, NCR; Comprehensive Study of Military Health Service System. Box 123, L-050