Early treatment gains for antibiotic administration and within human host time series data.

As technological improvements continue to infiltrate and impact medical practice, it has become possible to non-invasively collect dense physiological time series data from individual patients in real time. These advances continue to improve physicians' ability to detect and to treat infections early. One important benefit of early detection and treatment of nascent infections is that it leads to earlier resolution.

A pilot study of the noninvasive assessment of the lung microbiota as a potential tool for the early diagnosis of ventilator-associated pneumonia.

Background: Ventilator-associated pneumonia (VAP) remains a common complication in critically ill surgical patients, and its diagnosis remains problematic. Exhaled breath contains aerosolized droplets that reflect the lung microbiota. We hypothesized that exhaled breath condensate fluid (EBCF) in hygroscopic condenser humidifier/heat and moisture exchanger (HCH/HME) filters would contain bacterial DNA that qualitatively and quantitatively correlate with pathogens isolated from quantitative BAL samples obtained for clinical suspicion of pneumonia.

Non-invasive detection of pulmonary pathogens in ventilator-circuit filters by PCR.

Ventilator associated pneumonia is a common and costly complication in critically ill and injured surgical patients. The diagnosis of pneumonia remains problematic and non-specific. Using clinical criteria, a diagnosis of pneumonia is typically not made until an infection is well established.

A low dimensional dynamical model of the initial pulmonary innate response to infection.

In order to gain a deeper understanding of the onset and progression of pulmonary infections we present and analyze a low dimensional, phenomenological model of infection and the innate immune response in the lungs. Because pulmonary innate immunity has features unique to itself, general mathematical models of the immune system may not be appropriate. The differential equations model that we propose is based on current knowledge of the biology of pulmonary innate immunity and accurately reproduces known features of the initial phase of the dynamics of pulmonary innate system as exhibited in recent experiments.

Simultaneous on-chip DC dielectrophoretic cell separation and quantitative separation performance characterization.

Through integration of a MOSFET-based microfluidic Coulter counter with a dc-dielectrophoretic cell sorter, we demonstrate simultaneous on-chip cell separation and sizing with three different samples including 1) binary mixtures of polystyrene beads, 2) yeast cells of continuous size distribution, and 3) mixtures of 4T1 tumor cells and murine bone marrow cells. For cells with continuous size distribution, it is found that the receiver operator characteristic analysis is an ideal method to characterize the separation performance. The characterization results indicate that dc-DEP separation performance degrades as the sorting throughput (cell sorting rate) increases, which provides insights into the design and operation of size-based microfluidic cell separation.

Clustering in cell cycle dynamics with general response/signaling feedback.

Motivated by experimental and theoretical work on autonomous oscillations in yeast, we analyze ordinary differential equations models of large populations of cells with cell-cycle dependent feedback. We assume a particular type of feedback that we call responsive/signaling (RS), but do not specify a functional form of the feedback. We study the dynamics and emergent behavior of solutions, particularly temporal clustering and stability of clustered solutions.

Measurement of the volume growth rate of single budding yeast with the MOSFET-based microfluidic Coulter counter.

We report on measurements of the volume growth rate of ten individual budding yeast cells using a recently developed MOSFET-based microfluidic Coulter counter. The MOSFET-based microfluidic Coulter counter is very sensitive, provides signals that are immune from the baseline drift, and can work with cell culture media of complex composition. These desirable features allow us to directly measure the volume growth rate of single cells of Saccharomyces cerevisiae LYH3865 strain budding yeast in YNB culture media over a whole cell cycle.

An Analysis of Quantitative PCR Reliability Through Replicates Using the C Method.

There is considerable interest in quantitatively measuring nucleic acids from single cells to small populations. The most commonly employed laboratory method is the real-time polymerase chain reaction (PCR) analyzed with the crossing point or crossing threshold (C(t)) method. Utilizing a multiwell plate reader we have performed hundreds of replicate reactions at each of a set of initial conditions whose initial number of copies span a concentration range of ten orders of magnitude.

ODE, RDE and SDE models of cell cycle dynamics and clustering in yeast.

Biologists have long observed periodic-like oxygen consumption oscillations in yeast populations under certain conditions, and several unsatisfactory explanations for this phenomenon have been proposed. These ‘autonomous oscillations’ have often appeared with periods that are nearly integer divisors of the calculated doubling time of the culture. We hypothesize that these oscillations could be caused by a form of cell cycle synchronization that we call clustering.

Periodic fermentor yield and enhanced product enrichment from autonomous oscillations.

Four decades of work have clearly established the existence of autonomous oscillations in budding yeast culture across a range of operational parameters and in a few strains. Autonomous oscillations impact substrate conversion to biomass and products. Relatively little work has been done to quantify yield in this case.

Reliable cell disruption in yeast.

We report the results of an optical assay to determine the degree of cell wall disruption in yeast. The results indicate that cell wall disruption with glass beads yields reproducible results that can be modelled with an integral measure of time to failure that implies a decreasing failure rate. It is shown that a standard protocol results in only 60% disruption, with a relatively large coefficient of variation.

Molecular seismology: an inverse problem in nanobiology.

The density profile of an elastic fiber like DNA will change in space and time as ligands associate with it. This observation affords a new direction in single molecule studies provided that density profiles can be measured in space and time. In fact, this is precisely the objective of seismology, where the mathematics of inverse problems have been employed with success.

Structure theorems and the dynamics of nitrogen catabolite repression in yeast.

By using current biological understanding, a conceptually simple, but mathematically complex, model is proposed for the dynamics of the gene circuit responsible for regulating nitrogen catabolite repression (NCR) in yeast. A variety of mathematical "structure" theorems are described that allow one to determine the asymptotic dynamics of complicated systems under very weak hypotheses. It is shown that these theorems apply to several subcircuits of the full NCR circuit, most importantly to the URE2-GLN3 subcircuit that is independent of the other constituents but governs the switching behavior of the full NCR circuit under changes in nitrogen source.

Connecting the dots between genes, biochemistry, and disease susceptibility: systems biology modeling in human genetics.

Understanding how DNA sequence variations impact human health through a hierarchy of biochemical and physiological systems is expected to improve the diagnosis, prevention, and treatment of common, complex human diseases. We have previously developed a hierarchical dynamic systems approach based on Petri nets for generating biochemical network models that are consistent with genetic models of disease susceptibility. This modeling approach uses an evolutionary computation approach called grammatical evolution as a search strategy for optimal Petri net models.

Pharmacokinetics of O6-benzylguanine (NSC637037) and its metabolite, 8-oxo-O6-benzylguanine.

O6-Benzylguanine and its metabolite, 8-oxo-O6-benzylguanine, are equally potent inhibitors of the DNA repair enzyme, O6-alkylguanine-DNA alkyltransferase. Pharmacokinetic values are derived from cancer patients participating in a phase I trial (10 or 20 mg/m2 of O6-benzylguanine in a single bolus dose or 10 to 120 mg/m2 as a 60-min constant infusion). A two-compartment model fits the plasma concentration versus time profile of O6-benzylguanine.