Biology subjects

Mathur, S.

Publications and source records attributed to Mathur, S..

34 records · Page 2Linked to original sources

bioRxiv2024

The phase separation landscape of genome-wide genetic perturbations

Biomolecular organization is central to cell function. While phase separation is a key mechanism orchestrating this organization, we lack a comprehensive view of genes that can globally influence this process in vivo. To identify such genes, we combined functional genomics and synthetic biology. We developed a bioorthogonal system that can identify changes in the intracellular milieu that globally tune phase separation. We measured in vivo phase diagrams of a synthetic system across >25 million cells in 2,888 yeast knockouts, and identified 68 genes whose deletion alters the phase boundaries of the synthetic system, an unexpected result given the systems bioorthogonal design. Genes involved in TORC1 signaling and metabolism, particularly carbohydrate-, amino acid- and nucleotide synthesis were enriched. The mutants that changed phase separation also showed high pleiotropy, suggesting that phase separation interrelates with many aspects of biology. Highlights- A synthetic protein system reveals the genetic and environmental tunability of protein phase separation - Genetic knockouts affecting phase separation are highly pleiotropic - Carbohydrate, amino acid, and nucleotide metabolism contribute to modulating phase separation potential - Protein phase separation is a globally tunable property of the intracellular environment O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/620319v1_ufig1.gif" ALT="Figure 1"> View larger version (81K): org.highwire.dtl.DTLVardef@4b8403org.highwire.dtl.DTLVardef@1c80503org.highwire.dtl.DTLVardef@c10bf2org.highwire.dtl.DTLVardef@1f76c71_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Modulation of photosystem II heterogeneity and stomatal functioning contribute to sustaining photochemistry and photoprotection in mangroves exposed to a cold wave

Cold waves restrict the distribution of mangroves. This study examined the contribution of PSII heterogeneity and stomatal functioning to sustaining photochemistry and photoprotection in mangroves during a cold wave. We exposed eight populations of Kandelia obovata (cold-tolerant) and, Bruguiera gymnorhiza (cold-susceptible) from different latitudes to 27/20{degrees}C (favorable) and 10/3{degrees}C (chilling; simulated cold wave) day and night temperatures. Multiple trait responses imply that cold waves affected K. obovata the least. Significant changes in chlorophyll fluorescence transients (photosystem II [PSII]) with a slight decrease in the redox status of P700 (photosystem I [PSI]) imply a greater impact of a cold wave on PSII. During the cold wave, photochemical efficiency of PSII, efficiency of the water-splitting complex, light absorptance, stomatal pore area, cyclic electron flow, nonphotochemical quenching, and number of active PSII and PSII QB reducing centers decreased, while light transmittance, night respiration, and inactive PSII QB nonreducing, PSII{beta}, and {gamma} centers increased in both species. The population of K. obovata from the coldest latitudinal site (Fujian, China) was least affected by cold wave due to local evolutionary adaptations. Modulation of PSII heterogeneity and stomatal functioning is important to sustaining photochemistry and photoprotection in mangroves to cope with cold waves. HighlightsPSII heterogeneity and stomatal functioning support mangroves to cope with cold waves. Local evolutionary adaptations promote the cold tolerance of mangrove populations.

plant biology↗

bioRxiv2024

Salmonella Typhimurium infection inhibits macrophage IFNbeta signaling in a TLR4-dependent manner

Type I Interferons (IFNs) generally have a protective role during viral infections, but their function during bacterial infections is dependent on the bacterial species. Legionella pneumophila, Shigella sonnei and Mycobacterium tuberculosis can inhibit type I IFN signaling. Here we examined the role of type I IFN, specifically IFN{beta}, in the context of Salmonella enterica serovar Typhimurium (STm) macrophage infections and the capacity of STm to inhibit type I IFN signaling. We demonstrate that IFN{beta} has no effect on the intracellular growth of STm in infected bone marrow derived macrophages (BMDMs) derived from C57BL/6 mice. STm infection inhibits IFN{beta} signaling but not IFN{gamma} signaling in a murine macrophage cell line. We show that this inhibition is independent of the type III and type VI secretion systems expressed by STm and is also independent of bacterial phagocytosis. The inhibition is Toll-like receptor 4 (TLR4)-dependent as the TLR4 ligand, lipopolysaccharide (LPS), alone is sufficient to inhibit IFN{beta}-mediated signaling and STm-infected, TLR4-deficient BMDMs do not exhibit inhibited IFN{beta} signaling. In summary, we show that macrophages exposed to STm have reduced IFN{beta} signaling via crosstalk with TLR4 signaling, and that IFN{beta} signaling does not affect cell autonomous host defense against STm.

microbiology↗

bioRxiv2023

OprF functions as a latch to direct Outer Membrane Vesicle release in Pseudomonas aeruginosa.

Bacterial Outer Membrane Vesicles (OMVs) contribute to virulence, competition, immune avoidance and communication. This has led to great interest in how they are formed. To date, investigation has focused almost exclusively on what controls the initiation of OMV biogenesis. Regardless of the mechanism of initiation, all species face a similar challenge before an OMV can be released: How does the OM detach from the underlying peptidoglycan (PG) in regions that will ultimately bulge and then vesiculate? The OmpA family of OM proteins (OprF in P. aeruginosa) is widely conserved and unusually abundant in OMVs across species considering their major role in PG attachment. OmpA homologs also have the interesting ability to adopt both PG-bound (two-domain) and PG-released (one-domain) conformations. Using targeted deletion of the PG-binding domain we showed that loss of cell wall association, and not general membrane destabilization, is responsible for hypervesiculation in OprF-modified strains. We therefore propose that OprF functions as a latch, capable of releasing PG in regions destined to become OMVs. To test this hypothesis, we developed a protocol to assess OprF conformation in live cells and purified OMVs. While >90% of OprF proteins exist in the two-domain conformation in the OM of cells, we show that the majority of OprF in OMVs is present in the one-domain conformation. With this work, we take some of the first steps in characterizing late-stage OMV biogenesis and identify a family of proteins whose critical role can be explained by their unique ability to fold into two distinct conformations. SignificanceVesicular transport is now recognized to operate in all domains of life. However, the study of OMV biogenesis has been challenging because genetic screens failed to identify proteins analogous to those involved in eukaryotic vesicular transport. With this work we identify the first protein whose direct action can both define the location and govern the mechanism of OMV release. Our latch model is consistent with previous observations linking OmpA family proteins to OMV biogenesis, but further describes a physical mechanism that has broad implications for vesicle production and function across species. The work presented here advances our understanding of a fundamental virulence-associated process in bacteria, while underscoring stark differences in how transport vesicles are formed in prokaryotes versus eukaryotes.

microbiology↗

bioRxiv2023

Strong environmental memory revealed by experimental evolution in static and fluctuating environments

Evolution in a static environment, such as a laboratory setting with constant and uniform conditions, often proceeds via large-effect beneficial mutations that may become maladaptive in other environments. Conversely, natural settings require populations to endure environmental fluctuations. A sensible assumption is that the fitness of a lineage in a fluctuating environment is the time-average of its fitness over the sequence of static conditions it encounters. However, transitions between conditions may pose entirely new challenges, which could cause deviations from this time-average. To test this, we tracked hundreds of thousands of barcoded yeast lineages evolving in static and fluctuating conditions and subsequently isolated 900 mutants for pooled fitness assays in 15 environments. We find that fitness in fluctuating environments indeed often deviates from the expectation based on static components, leading to fitness non-additivity. Moreover, closer examination reveals that fitness in one component of a fluctuating environment is often strongly influenced by the previous component. We show that this environmental memory is especially common for mutants with high variance in fitness across tested environments, even if the components of the focal fluctuating environment are excluded from this variance. We employ a simple mathematical model and whole-genome sequencing to propose mechanisms underlying this effect, including lag time evolution and sensing mutations. Our results demonstrate that environmental fluctuations have large impacts on fitness and suggest that variance in static environments can explain these impacts.

evolutionary biology↗

bioRxiv2022

A chromosome-scale assembly of Brassica carinata (BBCC) accession HC20 containing resistance to multiple pathogens and an early generation assessment of introgressions into B. juncea (AABB)

Brassica carinata (BBCC) commonly referred to as Ethiopian mustard is a natural allotetraploid containing the genomes of Brassica nigra (BB) and Brassica oleracea (CC). It is an oilseed crop endemic to the Northeastern regions of Africa. Although it is grown in a limited manner, B. carinata is of value as it is resistant/highly tolerant to most of the pathogens affecting cultivated Brassica species of the Us triangle that are grown worldwide as oilseed and vegetable crops. We report a chromosome-scale genome assembly of B. carinata accession HC20 using long-read Oxford Nanopore and Illumina sequencing and BioNano optical maps. The assembly has a scaffold N50 of ~39.8 Mb and covers ~1.11 Gb of the genome. We compared the available long-read genome assemblies of the six species of the Us triangle and found a highly conserved gene number and collinearity suggesting that B. juncea (AABB), B. napus (AACC), and B. carinata are strict allopolyploids. We cataloged the nucleotide-binding and leucine-rich repeat immune receptor (NLR) repertoire of B. carinata resulting in the identification of 465 NLRs. We investigated the extent and nature of early generation genomic interactions between the subgenomes of B. carinata and B. juncea in interspecific crosses between the two species. We found that C chromosome additions are well tolerated, with homoeologous exchanges occurring between the A and C genomes. Based on the genomic interactions, we propose strategies to utilize the interspecific crosses for transferring disease resistance from B. carinata to B. juncea and other Brassica species.

plant biology↗

bioRxiv2022

Detectability of runs of homozygosity is influenced by analysis parameters as well as population-specific demographic history

Wild populations are increasingly threatened by human-mediated climate change and land use changes. As populations decline, the probability of inbreeding increases, along with the potential for negative effects on individual fitness. Detecting and characterizing runs of homozygosity (ROHs) is a popular strategy for assessing the extent of individual inbreeding present in a population and can also shed light on the genetic mechanisms contributing to inbreeding depression. Here, we analyze simulated and empirical data sets to demonstrate the downstream effects of program selection and long-term demographic history on ROH inference. We also apply a sensitivity analysis to evaluate the effects of various parameter values on ROH-calling results and demonstrate its utility for parameter value selection. We show that ROH inferences can be biased when sequencing depth and the distribution of ROH length is not interpreted in light of demographic history as well as program-specific tendencies. This is particularly important for the management of endangered species, as underestimating inbreeding signals in the genome can substantially undermining conservation initiatives. Based on our observations, we suggest using a combination of ROH detection tools and ROH length-specific inferences to generate robust population inferences regarding inbreeding history. We outline these recommendations for ROH estimation at multiple levels of sequencing effort typical of conservation genomics studies.

evolutionary biology↗

bioRxiv2022

Genetic mechanisms and biological processes underlying host response to ophidiomycosis (Snake Fungal Disease) inferred from tissue-specific transcriptome analyses.

There is growing concern about infectious diseases in wildlife species caused by pathogenic fungi. Detailed knowledge exists about host pathology and the molecular mechanisms underlying host physiological response to some fungal diseases affecting amphibians and bats but is lacking for others with potentially significant impacts on large groups of animals. One such disease is ophidiomycosis (Snake Fungal Disease; SFD) which is caused by the fungus Ophidiomyces ophidiicola and impacts diverse species of snakes. Despite this potential, the biological mechanisms and molecular changes occurring during infection are unknown for any snake species. To gain this information, we performed a controlled experimental infection of captive Prairie rattlesnakes (Crotalus viridis) with O. ophidiicola at different temperatures. We then generated liver, kidney, and skin transcriptomes from control and infected snakes to assess tissue specific genetic responses to infection. Given previous SFD histopathological studies and the fact that snakes are ectotherms, we expected highest fungal activity on skin and a significant impact of temperature on host response. In contrast, we found that most of the differential gene expression was restricted to internal tissues and fungal-infected snakes showed transcriptome profiles indicative of long-term inflammation of specific tissues. Infected snakes at the lower temperature had the most pronounced overall host functional response whereas, infected snakes at the higher temperature had overall expression profiles similar to control snakes possibly indicating recovery from the disease. Overall, our results suggest SFD is a systemic disease with a chronic host response, unlike acute response shown by amphibians to Batrachochytrium dendrobatidis infections. Our analysis also generated a list of candidate protein coding genes that potentially mediate SFD response in snakes, providing tools for future comparative and evolutionary studies into variable species susceptibility to ophidiomycosis. Author summaryOphidiomycosis (Snake Fungal Disease; SFD) is an infectious fungal disease in snakes that has been documented in more than 40 species over the past 20 years. Though many snake species seem vulnerable to SFD, little is known about how snake physiology changes in response to infection with the causative fungus, Ophidiomyces ophidiicola. Here we report results from the first experimental transcriptomic study of SFD in a snake host. Our goals were to identify genes with a putative role in host response, use this information to understand what biological changes occur in different tissues in snakes when infected with O. ophidiicola, and determine if temperature has an impact in these ectothermic animals. We conclude that SFD is a systemic disease with a chronic inflammation leading to deterioration of internal organs and that these physiological impacts are more pronounced at low rather than high temperatures. These results contrast with fungal infections in amphibians where hosts show an acute response mostly restricted to skin. Our list of candidate genes carry utility in potentially diagnosing genetic susceptibility to SFD in snake species of conservation concern.

pathology↗

bioRxiv2021

Transcriptional regulation of HSFA7 and post-transcriptional modulation of HSFB4a by miRNA4200 govern general and varietal thermotolerance in tomato

Heat shock factors (HSFs) are at the core of heat stress (HS) response in plants. However, the contribution of HSFs governing the inherent thermotolerance mechanism in tomato from sub-tropical hot climates is poorly understood. With the above aim, comparative expression profiles of the HSF family in a HS tolerant (CLN1621L) and a sensitive cultivar (CA4) of tomato under HS revealed cultivar-biased regulation of an activator (HSFA7a) and repressor (HSFB4a) class HSF. Functional characterization of HSFA7a that was strongly up-regulated in the tolerant cultivar by VIGS-based silencing and overexpression established it as a positive regulator of HS-tolerance. While knock-down and overexpression analyses of HSFB4a that was down-regulated in CLN1621L in HS, showed it as a negative regulator of thermotolerance. Promoter:GUS reporter assays and promoter sequence analyses suggest heat-mediated transcriptional control of both the HSF genes in the contrasting cultivars. Moreover, we show HSFB4a is also regulated post-transcriptionally by microRNA Sly-miR4200 using degradome, short-tandem-target-mimic of Sly-miR4200 and transient in-planta Sly-miR4200-effector:HSFB4a-reporter assays. This miRNA is induced several folds upon HS in the tolerant variety thereby reducing HSFB4a levels. We thus propose that the alleviation of HSFB4a repressor governs thermotolerance in the tolerant cultivar by regulating downstream heat stress responsive genes.

molecular biology↗

bioRxiv2021

Associations between lower limb isometric torque, isokinetic torque, and explosive force with phases of reactive stepping in young, healthy adults

Reactive stepping is one of the only strategies that can lead to successful stabilization following a large challenge to balance. Improving function of specific muscles associated with reactive stepping may improve features of reactive balance control. Accordingly, this study aimed to determine the relationship between lower limb muscle strength and explosive force with force plate-derived timing measures of reactive stepping. Nineteen young, healthy adults (27.6 {+/-} 3.0 years of age; 10 women: 9 men) responded to 6 perturbations (~13-15% of body weight) using an anterior lean-and-release system (causing a forward fall), where they were instructed to recover balance in as few steps as possible. Foot-off, swing, and restabilization times were estimated from force plates. Peak isokinetic torque, isometric torque, and explosive force of the knee extensors/flexors and plantar/dorsiflexors were measured using isokinetic dynamometry. Correlations were run based on a priori hypotheses and corrected for the number of comparisons (Bonferroni) for each variable. Knee extensor explosive force was negatively correlated with swing time (r = -0.582, p = 0.009). Knee flexor peak isometric torque also showed a negative association with restabilization time (r = -0.459, p = 0.048), however this was not statistically significant after correcting for multiple comparisons. There was no significant relationship between foot-off time and knee or plantar flexor explosive force (p > 0.025). These findings suggest that there may be utility to identifying specific aspects of reactive step timing when studying the relationship between muscle strength and reactive balance control. Exercise training aimed at improving falls risk should consider targeting specific aspects of muscle strength depending on specific deficits in reactive stepping.

neuroscience↗

bioRxiv2021

A conserved HSF:miR169:NF-YA loop involved in tomato and Arabidopsis heat stress tolerance

Regulatory feedbacks are at the basis of different stress and developmental networks in plants. Here, we report that tomato and Arabidopsis plants improve their heat stress tolerance through Heat stress transcription factor (HSF)-mediated transcriptional regulation of MIR169 and post-transcriptional regulation of NF-YA transcription factors. We show that HSFs recognize tomato and Arabidopsis MIR169 promoters using yeast-one-hybrid/ChIP-qPCR. Silencing tomato HSFs using virus-induced-gene-silencing (VIGS) reduce Sly-MIR169 levels and enhance Sly-NF-YA9/A10 target expression. Further, tomato transgenic plants overexpressing Sly-MIR169 and Sly-NF-YA9/A10-VIGS knock-down tomato plants as well as Arabidopsis plants overexpressing At-MIR169d and At-nf-ya2 mutants showed a link with increased heat tolerance. In contrast, Arabidopsis plants overexpressing At-NF-YA2, or those expressing a non-cleavable At-NF-YA2 form (miR169-resistant At-NF-YA2) as well as plants inhibited for At-miRNA169d regulation (miR169d mimic plants) were more sensitive to heat stress, highlighting NF-YA as negative regulator of heat tolerance. Furthermore, post-transcriptional cleavage of NF-YA by elevated miR169 levels result in alleviating the repression of heat stress effectors HSFA7a/b in tomato and Arabidopsis revealing a retroactive control of HSFs by the miR169:NF-YA node. Hence, a regulatory feedback loop involving HSFs, miR169s and NF-YAs plays a critical role in the regulation of heat stress response in tomato and Arabidopsis plants.

genomics↗

bioRxiv2020

The effect of perturbation magnitude on lower limb muscle activity during reactive stepping using functional data analysis

This study aimed to determine the effect of perturbation magnitude on stance and stepping limb muscle activation during reactive stepping using functional data analysis. Nineteen healthy, young adults responded to 6 small and 6 large perturbations using an anterior lean-and-release system, evoking a single reactive step. Muscle activity from surface electromyography was compared between the two conditions for medial gastrocnemius, biceps femoris, tibialis anterior, and vastus lateralis of the stance and stepping limb using functional data analysis. Stance limb medial gastrocnemius and biceps femoris activation increased in the large compared to small perturbation condition immediately prior to foot-off and at foot contact. In the stepping limb, significant increases in medial gastrocnemius, biceps femoris, and tibialis anterior activity occurred immediately prior to foot-off during the large perturbations. Similar to the stance limb, medial gastrocnemius and biceps femoris activity significantly increased during and following foot contact in the large, compared to small, perturbation condition. Lastly, vastus lateralis activity significantly increased for large, compared to small, perturbations during foot-off and immediately following foot contact. These findings highlight lower limb muscle activity modulation associated with perturbation magnitude throughout reactive stepping and the additional benefit of implementing functional data analysis to study reactive balance control.

neuroscience↗

bioRxiv2020

Test-retest reliability of force plate-derived measures of reactive stepping

BackgroundCharacterizing reactive stepping is important to describe the responses effectiveness. Measures of reactive stepping related to step initiation, execution, and termination phases have been frequently reported to characterize reactive balance control. However, the test-retest reliability of these measures are unknown. Research questionsWhat is the between- and within-session test-retest reliability of various force plate-derived measures of reactive stepping? MethodsNineteen young, healthy adults responded to 6 small (~8-10% of body weight) and 6 large perturbations (~13-15% of body weight) using an anterior lean-and-release system. Tests were conducted on two visits separated by at least two days. Participants were instructed to recover balance in as few steps as possible. Step onset, foot-off, swing, and restabilization times were extracted from force plates. Relative test-retest reliability was determined through intraclass correlation coefficients (ICCs) and 95% confidence intervals (CIs). Absolute test-retest reliability was assessed using the standard error of the measurement (SEM). ResultsFoot-off and swing times had the highest between- and within-session test-retest reliabilities regardless of perturbation size (between-session ICC=0.898-0.942; within-session ICC=0.455-0.753). Conversely, step onset and restabilization time had lower ICCs and wider CIs (between-session ICC=0.495-0.825; within-session ICC=-0.040-0.174). Between-session test-retest reliability was higher (ICC=0.495-0.942) for all measures than within-session test-retest reliability (ICC=-0.040-0.753). SEMs were low (3-10% of mean) for all measures, except time to restabilization (SEM=15-20% of mean), indicating good absolute reliability. SignificanceThese findings suggest multiple baseline sessions are needed for measuring restabilization and step onset times. The SEMs provide an index for measuring meaningful change due to an intervention.

bioengineering↗

bioRxiv2019

Novel insights into expansion and functional diversification of MIR169 family in tomato

MIR169 family is an evolutionarily conserved miRNA family in plants. A systematic in-depth analysis of MIR169 family in tomato is lacking. We report eighteen miR169 precursors, annotating new loci for MIR169a, b and d, as well as four novel mature isoforms (MIR169f/g/h/i). The family has expanded by both tandem- and segmental-duplication events during evolution. A tandem-pair MIR169b/b-1 and MIR169b-2/h is polycistronic in nature coding for three MIR169b isoforms and a new variant miR169h, that is evidently absent in the wild relatives S. pennellii and S. pimpinellifolium. Seven novel miR169 targets including RNA-binding-protein, protein-phosphatase, aminotransferase, chaperone, tetratricopeptide-repeat-protein, and transcription factors ARF-9B and SEPELLATA-3 were established by efficient target cleavage in presence of specific precursors as well as increased target abundance upon miR169 chelation by short-tandem-target-mimic construct in transient assays. Comparative antagonistic expression profiles of MIR169:target pairs suggest MIR169 family as ubiquitous regulator of various abiotic stresses (heat, cold, dehydration and salt) and developmental pathways. This regulation is partly brought about by acquisition of new promoters as demonstrated by promoterMIR169:GUS-reporter assays as well as differential processivity of different precursors and miRNA cleavage efficiencies. Thus, the current study augments the functional horizon of MIR169 family with applications for stress tolerance in crops.\n\nHighlightExpansion of MIR169 members by duplication and new mature forms, acquisition of new promoters, differential precursor-miRNA processivity and engaging novel targets increases the functional diversification of MIR169 in tomato. (29/30)

genomics↗

bioRxiv2019

Characterization of novel regulators for heat stress tolerance in tomato from Indian sub-continent

The footprint of tomato cultivation, a cool region crop that exhibits heat stress (HS) sensitivity, is increasing in the tropics/sub-tropics. Knowledge of novel regulatory hot-spots from varieties growing in the Indian sub-continent climatic zones could be vital for developing HS-resilient crops. Comparative transcriptome-wide signatures of a tolerant (CLN1621L) and sensitive (CA4) cultivar-pair short-listed from a pool of varieties exhibiting variable thermo-sensitivity using physiological, survival and yield-related traits revealed redundant to cultivar-specific HS-regulation with more up-regulated genes for CLN1621L than CA4. The anatgonisiticly-expressing genes include enzymes; have roles in plant defense and response to different abiotic stresses. Functional characterization of three antagonistic genes by overexpression and TRV-VIGS silencing established Solyc09g014280 (Acylsugar acyltransferase) and Solyc07g056570 (Notabilis), that are up-regulated in tolerant cultivar, as positive regulators of HS-tolerance and Solyc03g020030 (Pin-II proteinase inhibitor), that is down-regulated in CLN1621L, as negative regulator of thermotolerance. Transcriptional assessment of promoters of these genes by SNPs in stress-responsive cis-elements and promoter swapping experiments in opposite cultivar background showed inherent cultivar-specific orchestration of transcription factors in regulating transcription. Moreover, overexpression of three ethylene response transcription factors (ERF.C1/F4/F5) also improved HS-tolerance in tomato. This study identifies several novel HS-tolerance genes and provides proof of their utility in tomato-thermotolerance.\n\nHighlightNovel heat stress regulatory pathways uncovered by comparative transcriptome profiling between contrasting tomato cultivars from Indian sub-continent for improving thermotolerance. (20/30)

genomics↗

bioRxiv2019

Hypoxia in cancer chemo- and immunotherapy: foe or friend?

Hypoxia, a low level of oxygen in the tissue, is a feature of most solid tumors. It arises due to an imbalance between the oxygen supply from the abnormal vasculature and oxygen demand by the large number of tumor and stromal cells. Hypoxia has been implicated in the development of aggressive tumors and tumor resistance to various therapies. This makes hypoxia a negative marker of patients survival. However, recent advances in designing new hypoxia-activated pro-drugs and adoptive T cell therapies provide an opportunity for exploiting hypoxia in order to improve cancer treatment. We used novel mathematical models of micro-pharmacology and computational optimization techniques for determining the most effective treatment protocols that take advantage of heterogeneous and dynamically changing oxygenation in in vivo tumors. These models were applied to design schedules for a combination of three therapeutic compounds in pancreatic cancers and determine the most effective adoptive T cell therapy protocols in melanomas.

systems biology↗