: BioNetGen is an open-source software package for rule-based modeling of complex biochemical systems. Version 2.2 of the software introduces numerous new features for both model specification and ...simulation. Here, we report on these additions, discussing how they facilitate the construction, simulation and analysis of larger and more complex models than previously possible.
Stable BioNetGen releases (Linux, Mac OS/X and Windows), with documentation, are available at http://bionetgen.org Source code is available at http://github.com/RuleWorld/bionetgen CONTACT: bionetgen.help@gmail.comSupplementary information: Supplementary data are available at Bioinformatics online.
Tyrosine kinase inhibitors (TKIs) are widely used to treat solid tumors but can be cardiotoxic. The molecular basis for this toxicity and its relationship to therapeutic mechanisms remain unclear; we ...therefore undertook a systems-level analysis of human cardiomyocytes (CMs) exposed to four TKIs. CMs differentiated from human induced pluripotent stem cells (hiPSCs) were exposed to sunitinib, sorafenib, lapatinib, or erlotinib, and responses were assessed by functional assays, microscopy, RNA sequencing, and mass spectrometry (GEO: GSE114686; PRIDE: PXD012043). TKIs have diverse effects on hiPSC-CMs distinct from inhibition of tyrosine-kinase-mediated signal transduction; cardiac metabolism is particularly sensitive. Following sorafenib treatment, oxidative phosphorylation is downregulated, resulting in a profound defect in mitochondrial energetics. Cells adapt by upregulating aerobic glycolysis. Adaptation makes cells less acutely sensitive to sorafenib but may have long-term negative consequences. Thus, CMs exhibit adaptive responses to anti-cancer drugs conceptually similar to those previously shown in tumors to mediate drug resistance.
•Signatures of tyrosine kinase inhibitors (TKIs) in iPSC-derived cardiomyocytes•Cellular metabolism is among the processes most commonly affected by TKI drugs•Sorafenib represses mitochondrial electron transport and disrupts energetics•Induction of glycolysis is an adaptive response that reduces sorafenib toxicity
Anti-cancer drugs can have adverse effects on normal organs, most problematically the heart. Wang et al. study the responses of cardiac cells to one class of targeted anti-cancer drugs (tyrosine kinase inhibitors) and find that they commonly disrupt metabolism. Sorafenib, for example, interferes with energy production in the mitochondria of heart cells, causing cells to rely on glucose as an energy source, a shift that has been observed in heart disease.
Signaling via the Akt/mammalian target of rapamycin pathway influences CD4(+) T cell differentiation; low levels favor regulatory T cell induction and high levels favor Th induction. Although the ...lipid phosphatase phosphatase and tensin homolog (PTEN) suppresses Akt activity, the control of PTEN activity is poorly studied in T cells. In this study, we identify multiple mechanisms that regulate PTEN expression. During Th induction, PTEN function is suppressed via lower mRNA levels, lower protein levels, and an increase in C-terminal phosphorylation. Conversely, during regulatory T cell induction, PTEN function is maintained through the stabilization of PTEN mRNA transcription and sustained protein levels. We demonstrate that differential Akt/mammalian target of rapamycin signaling regulates PTEN transcription via the FoxO1 transcription factor. A mathematical model that includes multiple modes of PTEN regulation recapitulates our experimental findings and demonstrates how several feedback loops determine differentiation outcomes. Collectively, this work provides novel mechanistic insights into how differential regulation of PTEN controls alternate CD4(+) T cell fate outcomes.
Neutrophils play a central role in eliminating bacterial pathogens, but may also contribute to end-organ damage in sepsis. Interleukin-8 (IL-8), a key modulator of neutrophil function, signals ...through neutrophil specific surface receptors CXCR-1 and CXCR-2. In this study a mechanistic computational model was used to evaluate and deploy an extracorporeal sepsis treatment which modulates CXCR-1/2 levels. First, a simplified mechanistic computational model of IL-8 mediated activation of CXCR-1/2 receptors was developed, containing 16 ODEs and 43 parameters. Receptor level dynamics and systemic parameters were coupled with multiple neutrophil phenotypes to generate dynamic populations of activated neutrophils which reduce pathogen load, and/or primed neutrophils which cause adverse tissue damage when misdirected. The mathematical model was calibrated using experimental data from baboons administered a two-hour infusion of E coli and followed for a maximum of 28 days. Ensembles of parameters were generated using a Bayesian parallel tempering approach to produce model fits that could recreate experimental outcomes. Stepwise logistic regression identified seven model parameters as key determinants of mortality. Sensitivity analysis showed that parameters controlling the level of killer cell neutrophils affected the overall systemic damage of individuals. To evaluate rescue strategies and provide probabilistic predictions of their impact on mortality, time of onset, duration, and capture efficacy of an extracorporeal device that modulated neutrophil phenotype were explored. Our findings suggest that interventions aiming to modulate phenotypic composition are time sensitive. When introduced between 3-6 hours of infection for a 72 hour duration, the survivor population increased from 31% to 40-80%. Treatment efficacy quickly diminishes if not introduced within 15 hours of infection. Significant harm is possible with treatment durations ranging from 5-24 hours, which may reduce survival to 13%. In severe sepsis, an extracorporeal treatment which modulates CXCR-1/2 levels has therapeutic potential, but also potential for harm. Further development of the computational model will help guide optimal device development and determine which patient populations should be targeted by treatment.
High speed back-to-back transmission of NRZ data at 12.5 Gbit/s was achieved over a repeaterless optical network without the use of forward error correction or optical clock recovery using a hybrid ...integrated silicon photonics optical interconnect. The interconnect comprises an electroabsorption modulator based on dilute nitride multiple quantum well material on GaAs substrate optically coupled to large core silicon waveguide using passive alignment and flip-chip bonding.
We present a design methodology for hybrid lasers to realise mode-hop free operation by controlling the cavity mode spacing. In this study, a compact hybrid photonic crystal laser (H-PhCL) was ...employed which allowed a reduction of the Fabry–Perot length of the laser cavity and eliminated the need for an active mode stabilisation mechanism in order to realise mode-hop free operation. The H-PhCL was formed by butt-coupling a reflective semiconductor optical amplifier (RSOA) with a two-dimensional silicon (Si) photonic crystal (PhC) cavity. Continuous stable single frequency operation with >40 dB side-mode suppression ratio (SMSR) of the laser was achieved for gain currents of up to 100 mA, i.e., up to four times the threshold current. The shorter length of the laser cavity enabled single frequency operation due to the selection of a single longitudinal mode by the PhC narrowband reflector. Various longitudinal mode spacing regimes were studied to explain the mode-hop free characteristics of the H-PhCL. The proposed hybrid laser design methodologies can be adapted to eliminate mode-hopping in laser wavelength.
The authors present results on the performance of a hybrid external cavity photonic crystal laser-comprising semiconductor optical amplifier, and a 2D photonic crystal cavity fabricated in ...low-temperature amorphous silicon. The authors demonstrate that lithographic control over amorphous silicon photonic crystal cavity-resonant wavelengths is possible, and that single-mode lasing at optical telecommunications wavelengths is possible on an amorphous silicon platform.
Despite considerable investment into potential therapeutic approaches for Alzheimer's disease (AD), currently approved treatment options are limited. Predictive modeling using quantitative systems ...pharmacology (QSP) can be used to guide the design of clinical trials in AD. This study developed a QSP model representing amyloid beta (Aβ) pathophysiology in AD. The model included mechanisms of Aβ monomer production and aggregation to form insoluble fibrils and plaques; the transport of soluble species between the compartments of brain, cerebrospinal fluid (CSF), and plasma; and the pharmacokinetics, transport, and binding of monoclonal antibodies to targets in the three compartments. Ordinary differential equations were used to describe these processes quantitatively. The model components were calibrated to data from the literature and internal studies, including quantitative data supporting the underlying AD biology and clinical data from clinical trials for anti‐Aβ monoclonal antibodies (mAbs) aducanumab, crenezumab, gantenerumab, and solanezumab. The model was developed for an apolipoprotein E (APOE) ɛ4 allele carrier and tested for an APOE ɛ4 noncarrier. Results indicate that the model is consistent with data on clinical Aβ accumulation in untreated individuals and those treated with monoclonal antibodies, capturing increases in Aβ load accurately. This model may be used to investigate additional AD mechanisms and their impact on biomarkers, as well as predict Aβ load at different dose levels for mAbs with known targets and binding affinities. This model may facilitate the design of scientifically enriched and efficient clinical trials by enabling a priori prediction of biomarker dynamics in the brain and CSF.
Abstract
Background
COVID-19 pneumonia is associated with the development of acute respiratory distress syndrome (ARDS) displaying some typical histological features. These include diffuse alveolar ...damage with extensive pulmonary coagulation activation. This results in fibrin deposition in the microvasculature, leading to the formation of hyaline membranes in the air sacs. Well-conducted clinical trials have found that nebulised heparin limits pulmonary fibrin deposition, attenuates progression of ARDS, hastens recovery and is safe in non-COVID ARDS. Unfractionated heparin also inactivates the SARS-CoV-2 virus and prevents entry into mammalian cells. Nebulisation of heparin may therefore limit fibrin-mediated lung injury and inhibit pulmonary infection by SARS-CoV-2. Based on these findings, we designed the CHARTER-Ireland Study, a phase 1b/2a randomised controlled study of nebulised heparin in patients requiring advanced respiratory support for COVID-19 pneumonia.
Methods
This is a multi-centre, phase 1b/IIa, randomised, parallel-group, open-label study. The study will randomise 40 SARs-CoV-2-positive patients receiving advanced respiratory support in a critical care area. Randomisation will be via 1:1 allocation to usual care plus nebulised unfractionated heparin 6 hourly to day 10 while receiving advanced respiratory support or usual care only. The study aims to evaluate whether unfractionated heparin will decrease the procoagulant response associated with ARDS up to day 10. The study will also assess safety and tolerability of nebulised heparin as defined by number of severe adverse events; oxygen index and respiratory oxygenation index of intubated and unintubated, respectively; ventilatory ratio; and plasma concentration of interleukin (IL)-1β, IL6, IL-8, IL-10 and soluble tumour necrosis factor receptor 1, C-reactive protein, procalcitonin, ferritin, fibrinogen and lactate dehydrogenase as well as the ratios of IL-1β/IL-10 and IL-6/IL-10. These parameters will be assessed on days 1, 3, 5 and 10; time to separation from advanced respiratory support, time to discharge from the intensive care unit and number tracheostomised to day 28; and survival to days 28 and 60 and to hospital discharge, censored at day 60. Some clinical outcome data from our study will be included in the international meta-trials, CHARTER and INHALE-HEP.
Discussion
This trial aims to provide evidence of potential therapeutic benefit while establishing safety of nebulised heparin in the management of ARDS associated with SARs-CoV-2 infection.
Trial registration
ClinicalTrials.gov
NCT04511923
. Registered on 13 August 2020.
Protocol version 8, 22/12/2021
Protocol identifier: NUIG-2020-003
EudraCT registration number: 2020-003349-12 9 October 2020
Low levels of genetic variation at traditional molecular markers have hampered genetic research within the family Acipenseridae. In an effort to develop a large set of polymorphic genetic markers, ...172 clones were sequenced from three subgenomic libraries of shovelnose sturgeon Scaphirhynchus platorynchus; the libraries were enriched for two dinucleotide and one tetranucleotide microsatellite motifs (CA, GA, and TAGA). Primers were designed for 113 of the sequences and tested against shovelnose sturgeon, pallid sturgeon S. albus, white sturgeon Acipenser transmontanus, lake sturgeon A. fulvescens, and green sturgeon A. medirostris. Of the 113 primer sets tested, 96% amplified in one or more species (58 dimeric and 50 tetrameric). In Scaphirhynchus species, 93% of all loci amplified, and 76% were polymorphic. Within the individual Acipenser species, 65–80% of loci amplified, with 42–58% being polymorphic. Polymorphic systems for Scaphirhynchus species predominately displayed simple, disomic banding patterns, while those for Acipenser species typically displayed banding patterns characteristic of tetraploid or higher polyploid levels. These new microsatellite loci provide a group of genetic markers that are detectable with noninvasive sampling and that should prove useful in the preservation of threatened and endangered sturgeon species worldwide.
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