PhysiPKPD: A pharmacokinetics and pharmacodynamics module for PhysiCell.

Unlabelled: Pharmacokinetics and pharmacodynamics (PKPD) are key considerations in any study of molecular therapies. It is thus imperative to factor their effects into any model of biological tissue involving such therapies. Furthermore, creating a standardized and flexible framework will benefit the community by increasing access to such modules and enhancing their communicability.

Multiscale Model of Antiviral Timing, Potency, and Heterogeneity Effects on an Epithelial Tissue Patch Infected by SARS-CoV-2.

We extend our established agent-based multiscale computational model of infection of lung tissue by SARS-CoV-2 to include pharmacokinetic and pharmacodynamic models of remdesivir. We model remdesivir treatment for COVID-19; however, our methods are general to other viral infections and antiviral therapies. We investigate the effects of drug potency, drug dosing frequency, treatment initiation delay, antiviral half-life, and variability in cellular uptake and metabolism of remdesivir and its active metabolite on treatment outcomes in a simulated patch of infected epithelial tissue.

Persistence as an Optimal Hedging Strategy.

Bacteria invest in a slow-growing subpopulation, called persisters, to ensure survival in the face of uncertainty. This hedging strategy is remarkably similar to financial hedging, where diversifying an investment portfolio protects against economic uncertainty. We provide a new, to our knowledge, theoretical foundation for understanding cellular hedging by unifying the study of biological population dynamics and the mathematics of financial risk management through optimal control theory.

Trends of mutation accumulation across global SARS-CoV-2 genomes: Implications for the evolution of the novel coronavirus.

To understand SARS-CoV-2 microevolution, this study explored the genome-wide frequency, gene-wise distribution, and molecular nature of all point-mutations detected across its 71,703 RNA-genomes deposited in GISAID till 21 August 2020. Globally, nsp1/nsp2 and orf7a/orf3a were the most mutation-ridden non-structural and structural genes respectively. Phylogeny of 4618 spatiotemporally-representative genomes revealed that entities belonging to the early lineages are mostly spread over Asian countries, including India, whereas the recently-derived lineages are more globally distributed.

Aerobic microbial communities in the sediments of a marine oxygen minimum zone.

The ecology of aerobic microorganisms is never explored in marine oxygen minimum zone (OMZ) sediments. Here we reveal aerobic bacterial communities along ∼3 m sediment-horizons of the eastern Arabian Sea OMZ. Sulfide-containing sediment-cores retrieved from 530 mbsl (meters beneath the sea-level) and 580 mbsl were explored at 15-30 cm intervals, using metagenomics, pure-culture-isolation, genomics and metatranscriptomics.

Iterative community-driven development of a SARS-CoV-2 tissue simulator.

The 2019 novel coronavirus, SARS-CoV-2, is a pathogen of critical significance to international public health. Knowledge of the interplay between molecular-scale virus-receptor interactions, single-cell viral replication, intracellular-scale viral transport, and emergent tissue-scale viral propagation is limited. Moreover, little is known about immune system-virus-tissue interactions and how these can result in low-level (asymptomatic) infections in some cases and acute respiratory distress syndrome (ARDS) in others, particularly with respect to presentation in different age groups or pre-existing inflammatory risk factors.

Administration of Defective Virus Inhibits Dengue Transmission into Mosquitoes.

The host-vector shuttle and the bottleneck in dengue transmission is a significant aspect with regard to the study of dengue outbreaks. As mosquitoes require 100-1000 times more virus to become infected than human, the transmission of dengue virus from human to mosquito is a vulnerability that can be targeted to improve disease control. In order to capture the heterogeneity in the infectiousness of an infected patient population towards the mosquito population, we calibrate a population of host-to-vector virus transmission models based on an experimentally quantified infected fraction of a mosquito population.

Designing combination therapies using multiple optimal controls.

Strategic management of populations of interacting biological species routinely requires interventions combining multiple treatments or therapies. This is important in key research areas such as ecology, epidemiology, wound healing and oncology. Despite the well developed theory and techniques for determining single optimal controls, there is limited practical guidance supporting implementation of combination therapies.

Microbiome and ecology of a hot spring-microbialite system on the Trans-Himalayan Plateau.

Little is known about life in the boron-rich hot springs of Trans-Himalayas. Here, we explore the geomicrobiology of a 4438-m-high spring which emanates ~70 °C-water from a boratic microbialite called Shivlinga. Due to low atmospheric pressure, the vent-water is close to boiling point so can entropically destabilize biomacromolecular systems.

Computational study of parameter sensitivity in DevR regulated gene expression.

The DevRS two-component system plays a pivotal role in signal transmission and downstream gene regulation in Mycobacterium tuberculosis. Under the hypoxic condition, phosphorylated DevR interacts with multiple binding sites at the promoter region of the target genes. In the present work, we carried out a detailed computational analysis to figure out the sensitivity of the kinetic parameters.

A population of bang-bang switches of defective interfering particles makes within-host dynamics of dengue virus controllable.

The titre of virus in a dengue patient and the duration of this viraemia has a profound effect on whether or not a mosquito will become infected when it feeds on the patient and this, in turn, is a key driver of the magnitude of a dengue outbreak. The assessment of the heterogeneity of viral dynamics in dengue-infected patients and its precise treatment are still uncertain. Infection onset, patient physiology and immune response are thought to play major roles in the development of the viral load.

In silico modeling of phosphorylation dependent and independent c-Myc degradation.

Background: c-Myc plays an important role in cell proliferation, cell growth and in differentiation, making it a key regulator for carcinogenesis and pluripotency. Tight control of c-myc turnover is required by ubiquitin-mediated degradation. This is achieved in the system by two F-box proteins Skp2 and FBXW7.

Optimal control of acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is a blood cancer affecting haematopoietic stem cells. AML is routinely treated with chemotherapy, and so it is of great interest to develop optimal chemotherapy treatment strategies. In this work, we incorporate an immune response into a stem cell model of AML, since we find that previous models lacking an immune response are inappropriate for deriving optimal control strategies.

Enhanced carbon-sulfur cycling in the sediments of Arabian Sea oxygen minimum zone center.

Biogeochemistry of oxygen minimum zone (OMZ) sediments, which are characterized by high input of labile organic matter, have crucial bearings on the benthic biota, gas and metal fluxes across the sediment-water interface, and carbon-sulfur cycling. Here we couple pore-fluid chemistry and comprehensive microbial diversity data to reveal the sedimentary carbon-sulfur cycle across a water-depth transect covering the entire thickness of eastern Arabian Sea OMZ, off the west coast of India. Geochemical data show remarkable increase in average total organic carbon content and aerial sulfate reduction rate (J) in the sediments of the OMZ center coupled with shallowing of sulfate methane transition zone and hydrogen sulfide and ammonium build-up.

Deciphering Parameter Sensitivity in the BvgAS Signal Transduction.

To understand the switching of different phenotypic phases of Bordetella pertussis, we propose an optimized mathematical framework for signal transduction through BvgAS two-component system. The response of the network output to the sensory input has been demonstrated in steady state. An analysis in terms of local sensitivity amplification characterizes the nature of the molecular switch.

Effect of dielectric interface on charge aggregation in the voltage-gated K(+) ion channel.

Background: There is experimental evidence of many cases of stable macromolecular conformations with charged amino-acids facing lipid, an arrangement thought to be energetically unfavourable.

Methods And Objectives: Employing classical electrostatics, we show that, this is not necessarily the case and studied the physical basis of the specific role of proximity of charges to the dielectric interface between two different environments. We illustrate how self and induced energies due to the dielectric medium polarization, on either side of the interface, contribute differentially to the stability of a pair of charges and hence the mutual conformation of the S3b-S4 α-helix pair of the voltage-gated K(+) channel.

Electrostatic interaction between dipoles and side chains in the voltage sensor domain of K(+) channel.

Background: It is well known that α-helices of protein, possessing equal and opposite charged ends, behaves like a macrodipole, but the relative importance of such macrodipoles to the aggregation of a pair of helix in the voltage sensor domain (VSD) of K+ ion channel, has not been assessed. In the VSD, importance has been given primarily to the helically arranged Arginine residues of helix, but the role of the charged residues of S3b is less focused.

Method And Objective: Applying electrostatic theory, we have studied the interaction between the charges of S3b-S4 α-helix pair of KvAP through virtual mutagenesis.

Role of terminal dipole charges in aggregation of α-helix pair in the voltage gated K(+) channel.

The voltage sensor domain (VSD) of the potassium ion channel KvAP is comprised of four (S1-S4) α-helix proteins, which are encompassed by several charged residues. Apart from these charges, each peptide α-helix having two inherent equal and opposite terminal dipolar charges behave like a macrodipole. The activity of voltage gated ion channel is electrostatic, where all the charges (charged residues and dipolar terminal charges) interact with each other and with the transmembrane potential.