Biology subjects

Mathew, A.

Publications and source records attributed to Mathew, A..

17 recordsLinked to original sources

bioRxiv2025

Linking Electrophysiological Metrics to Oxidative Metabolism: Implications for EEG-fMRI Association

Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to study brain function, yet its biophysiological basis remains incompletely understood. Building on our recent work, we investigated how EEG activity and cerebral metabolic rate of oxygen (CMRO2) are related to one another, and how they jointly underpin rs-fMRI metrics. Using a multimodal dataset with macrovascular correction applied to all rs-fMRI metrics, we first examined associations between EEG metrics and CMRO2, then applied mediation analysis to evaluate how CMRO2 mediates EEG-fMRI associations. We found that bandlimited EEG theta and alphafractional power was significantly associated with CMRO2. Bandlimited EEG coherence was also associated with CMRO2 across all the bands. Bandlimited EEG fractional power and coherence were also significantly associated with cerebral blood flow (CBF) and oxygen extraction fraction (OEF) in a manner that varied by frequency. EEG broadband temporal complexity was positively associated with CMRO2 and EEG coherence was negatively associated with OEF. Notably, there are pronounced sex differences in these relationships, which suggests that the biophysical underpinnings of rs-fMRI are sex dependent. Moreover, the baseline metabolic and hemodynamic variables did partially mediate EEG-fMRI associations, with CMRO2 serving as the primary mediator. However, most of the mediations are partial, highlighting the complex interplay among electrophysiological activity, oxidative metabolism, and hemodynamics. This study advances our understanding of the biophysical basis of rs-fMRI and provides a foundation for developing sex-specific diagnostic and therapeutic strategies for neurological disorders.

neuroscience↗

bioRxiv2025

The link between steady-state EEG and rs-fMRI metrics in healthy young adults: the effect of macrovascular correction

To improve the clinical utility of resting-state fMRI (rs-fMRI), enhancing its interpretability is paramount. Establishing links with electrophysiological activities remains the benchmark for understanding the neuronal basis of rs-fMRI signals. Existing research, while informative, suffers from inconsistencies and a limited scope of rs-fMRI metrics (e.g., seed-based functional connectivity). Phenotypic variables like sex and age are suspected to obscure reliable fMRI-EEG associations. A major contributing factor to these inconsistencies may be the neglect of macrovascular correction in rs-fMRI metrics. Given that macrovascular contributions can inflate rs-fMRI connectivity and power, they may lead to misleading fMRI-EEG associations that do not reflect genuine neuronal underpinnings. In this study, we addressed this by applying macrovascular correction and performing a systematic, inter-participant analysis of multiple rs-fMRI and EEG metrics. Our key findings demonstrate that: 1) Macrovascular correction enhances the relationship between EEG and rs-fMRI metrics and improves model fit in many instances; 2) sex significantly modulates EEG-fMRI associations; 3) EEG complexity is significantly associated with resting-state functional activity (RSFA). This research provides crucial insights into the interplay between rs-fMRI and EEG, ultimately improving the interpretability of rs-fMRI measurements and building upon our prior work linking fMRI and metabolism.

neuroscience↗

bioRxiv2025

Real-Time EEG Response to Pulsed Transcranial Photobiomodulation in Healthy Young Adults: Effects of Stimulation Parameters and Skin Tone

ObjectivesTranscranial photobiomodulation (tPBM) modulates cortical activity, but how specific stimulation parameters shape the electrophysiological response remains unclear. We tested whether pulsed forehead tPBM produces frequency band-specific EEG changes, whether pulsation frequency entrains endogenous oscillations, and whether wavelength, pulsation frequency, irradiance, sex, and skin tone significantly modulate the response. Materials and MethodsForty-six healthy young adults (24M/22F, 20-32 years) each completed four 12-minute EEG recordings (256-channel; PRE-DURING-POST, 4 min each) with pulsed NIR light delivered to the right forehead. The parameter space included two wavelengths (808 nm, 1064 nm), two pulsation frequencies (10 Hz, 40 Hz), and three irradiances (100, 150, 200 mW/cm2). Forehead skin tone (ITA) and sex were included as biological moderators. EEG band power (delta through gamma) was expressed as percent change from a pre-stimulus baseline. Spatiotemporal cluster-based permutation tests (10,000 permutations, FWER alpha=0.05) identified significant electrode clusters. Linear mixed-effects models with backward elimination and FDR correction (q=0.05) quantified parameter and biological contributions. ResultstPBM produced bilateral, bidirectional EEG changes: frontal gamma enhancement and posterior theta, alpha, and beta suppression, emerging gradually during stimulation and persisting post-stimulation. Wavelength qualitatively shaped the response: 808 nm drove broadband posterior suppression while 1064 nm selectively enhanced frontal gamma. Contrary to entrainment predictions, 10 Hz pulsation produced significantly larger gamma increases and theta reductions than 40 Hz. Sex was the most consistent biological modulator: females showed greater alpha suppression during stimulation and males showed greater posterior beta and gamma suppression. Irradiance and skin tone were not significant. ConclusionsPulsed forehead tPBM produces robust, parameter-dependent EEG changes that are not consistent with neural entrainment. Wavelength determines the character of the cortical response, pulsation frequency modulates its magnitude, potentially through photobiological rather than oscillatory mechanisms, and sex is a significant biological moderator. These findings contribute toward a human-specific foundation for informing optical tPBM parameter selection.

physiology↗

bioRxiv2025

Modulating cerebrospinal fluid dynamics using pulsed photobiomodulation: feasibility, parameter and skin-colour dependence

The use of photobiomodulation (PBM) to enhance brain health, specifically glymphatic drainage and thus neurotoxic waste clearance, may make it a promising therapeutic tool against neurodegenerative diseases such as Alzheimers disease. This study investigates whether PBM can modulate cerebrospinal fluid (CSF) flow in 45 healthy young adults. We conducted forehead transcranial PBM (tPBM) and intranasal PBM (iPBM) at the nostril level, and measured CSF dynamics using blood-oxygenation level-dependent (BOLD) functional MRI (fMRI). Our data demonstrates 4 min of PBM-induced increases in CSF flow. Our data shows that (1) even a short PBM of 4 min can induce a change in CSF dynamics, in the form of an immediate increase in intracranial CSF volume and a reduction in CSF inflow; (2) skin melanin had a significant effect on the CSF response in tPBM, with lighter skin associated with higher responses; (3) both iPBM and tPBM displayed a dose-dependent effect on CSF dynamics in terms of a irradiance-wavelength interaction; (4) intranasal PBM (iPBM) can be used to produce a significant change in CSF dynamics that is equivalent to forehead transcranial PBM (tPBM) with a small fraction of the irradiance. The most likely explanation for the observed fMRI signal changes in CSF regions of interest for both tPBM and iPBM is an increased CSF outflow pressure due to PBM-induced vasodilation that transiently increases intracranial CSF volume and reduces net CSF inflow. This study establishes that PBM can modulate CSF flow in the healthy human brain in real time. This study also suggests that iPBM may be more efficient in CSF modulation due to the proximity to the olfactory system and the lack of melanin dependence. The influence of melanin on tPBM, the feasibility of iPBM and the dose dependence of both will require further investigation in healthy and patient populations.

physiology↗

bioRxiv2025

Cancer Drug Bortezomib, a Proteasomal Inhibitor, Triggers Cytotoxicity in Microvascular Endothelial Cells via Multi-Organelle Stress

Proteasomes maintain cellular homeostasis by degrading abnormal proteins, while cancer cells exploit them for survival, becoming a key chemotherapeutic target. Bortezomib (BTZ), a reversible proteasomal inhibitor, is a front-line treatment for multiple myeloma, mantle cell lymphoma, and non-small cell lung cancer. However, its efficacy is limited by severe side effects, including neurotoxicity and cardiovascular distress, with its toxicity mechanisms largely unexplored. Here, we discover that Bortezomib (BTZ), is cytotoxic to non-cancerous cells distinctly from Carfilzomib (CFZ), the second-line irreversible PI. BTZ or CFZ is administered intravenously, impacting blood vessel (vascular) endothelial cells. We used human pulmonary microvascular endothelial cells (HPMECs) to demonstrate that BTZ but not CFZ elicits endoplasmic reticulum (ER) stress, mitochondrial membrane compromise, mitochondrial reactive oxygen species (ROS) accumulation, and Caspase (CASP)9 activation (mediator of Intrinsic apoptosis) within fifteen hours of treatment. By twenty-four hours, BTZ-treated cells display cleavage of CASP8 (mediator of extrinsic apoptosis), activation of CASP3 (terminal executioner of apoptosis), cell-death and vascular barrier loss. Pan-caspase inhibitor zVAD significantly rescues BTZ-treated cells from cytotoxicity. Both BTZ and CFZ effectively kill MM cells. These findings reveal novel insights into fundamental signaling of regular cells where reversible inhibition of the proteasome dictates a unique cascade of stress distinct from irreversible inhibition. These harmful effects of BTZ emphasize the need to re- evaluate its use as a frontline chemotherapy for MM. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/645304v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1b423dborg.highwire.dtl.DTLVardef@19e07f1org.highwire.dtl.DTLVardef@1b84f9org.highwire.dtl.DTLVardef@b70afa_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIReversible proteasomal inhibitor Bortezomib is cytotoxic to non-cancerous, microvascular endothelial cells C_LIO_LIIn endothelial cells, Bortezomib, but not irreversible inhibitor Carfilzomib, activates temporal cascade of caspases (Caspase-9, Caspase-8, Caspase-3) triggering apoptosis C_LIO_LICaspase activation results from ER stress (via the IRE1-CHOP) pathway and mitochondrial stress (ROS accumulation) independently from contribution from extrinsic signal via TNF C_LIO_LIBortezomib-dependent cytotoxicity compromises endothelial barrier potential C_LI

cell biology↗

bioRxiv2025

BORC segregates synaptic vesicle and lysosomal proteins through motors UNC-104/KIF1A and UNC-116/KIF5

While synaptic vesicle proteins (SVPs) and lysosomal proteins can be present together in axons, the origin of these compartments is unclear. These SV-lysosomes are however thought to segregate further to SVPs and lysosomal proteins. In this study, we identify genes and characterize a genetic pathway involved in the segregation of SVPs and lysosomal proteins in the neuronal cell body. We identify a novel role for BORC (BLOC-1-related complex) in segregating SVPs and lysosomal proteins in the cell body. BORC subunit SAM-4/Myrlysin acts through ARL-8 and Kinesin motor proteins UNC-116/KIF5 and UNC-104/KIF1A in segregating SVPs and lysosomal proteins. Additionally, we also show that LRK-1/LRRK2 and APB-3/AP-3 ({beta}3), involved in pre-SV biogenesis, regulate the segregation of SVPs and lysosomal proteins in the neuronal cell body. LRK-1 recruits SAM-4 that in turn governs the localisation of APB-3 suggesting a hierarchical pathway of LRK-1-SAM-4-APB-3 for the segregation of SVPs and lysosomal proteins. Additionally, we also observe that the size of lysosomal protein-containing compartments (LPCCs) is smaller in SAM-4 and LRK-1. This size regulation depends on UNC-116. Together, we show that BORC recruited by LRK-1 and in turn via motors and along with AP-3 mediates the segregation of SVPs and lysosomal proteins in the neuronal cell body.

cell biology↗

bioRxiv2024

Signal Antagonists Suppress Pseudomonas syringae Pathogenicity

The bacterial plant pathogen Pseudomonas syringae causes significant damage to economically important crops worldwide. These bacteria coordinate their behavior and virulence through specific signaling compounds, such as the diazeniumdiolate leudiazen. Conventional antibacterial treatments enable the development of resistant strains. A more attractive treatment strategy would involve antagonists that suppress the expression of virulence factors without killing the pathogen, potentially reducing the risk of resistance development. Herein, we present the design and synthesis of analogs of leudiazen, which positively regulates the production of mangotoxin in P. syringae pv. syringae (Pss). Several compounds display inhibitory activity towards mangotoxin production, and a lead compound abolishes necrosis in infected tomato leaves, without significantly affecting bacterial growth. Thus, this study represents a promising advance towards developing effective and sustainable methods for bacterial disease control.

microbiology↗

bioRxiv2024

Functional Biosynthetic Stereodivergence in a Gene Cluster via a Dihydrosydnone N-oxide

Chirality features a critical role in the biochemistry of life and often only one enantiomeric series is observed (homochirality). Only few natural products have been obtained as racemates, e.g. the quorum-sensing signal valdiazen produced by Burkholderia cenocepacia H111. In this study, we investigated its biosynthetic gene cluster and discovered that both the enantiomerically pure (R)-fragin and the racemic valdiazen are obtained from the same pathway. This stereodivergence is based on the unusual heterocycle dihydrosydnone N-oxide intermediate, as evident from gene knockout, stable isotope feeding experiments, and mass spectrometry experiments. Both non-enzymatic racemisation via keto-enol tautomerisation and enzyme-mediated dynamic kinetic resolution were found to be crucial to this stereodivergent pathway. This novel mechanism underpins the production of configurationally and biologically distinct metabolites from a single gene cluster. Our findings highlight the intricate design of an intertwined biosynthesis pathway, providing a deeper understanding of microbial secondary metabolism related to microbial communication. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/591611v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@11b63corg.highwire.dtl.DTLVardef@d339e6org.highwire.dtl.DTLVardef@17e34b1org.highwire.dtl.DTLVardef@b58692_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2023

Olfactomedin-4+ neutrophils exacerbate intestinal epithelial damage and worsen host survival after Clostridioides difficile infection.

Neutrophils are key first responders to Clostridioides difficile infection (CDI). Excessive tissue and blood neutrophils are associated with worse histopathology and adverse outcomes, however their functional role during CDI remains poorly defined. Utilizing intestinal epithelial cell (IEC)-neutrophil co-cultures and a pre-clinical animal model of CDI, we show that neutrophils exacerbate C. difficile-induced IEC injury. We utilized cutting-edge single-cell transcriptomics to illuminate neutrophil subtypes and biological pathways that could exacerbate CDI-associated IEC damage. As such, we have established the first transcriptomics atlas of bone marrow (BM), blood, and colonic neutrophils after CDI. We found that CDI altered the developmental trajectory of BM and blood neutrophils towards populations that exhibit gene signatures associated with pro-inflammatory responses and neutrophil-mediated tissue damage. Similarly, the transcriptomic signature of colonic neutrophils was consistent with hyper-inflammatory and highly differentiated cells that had amplified expression of cytokine-mediated signaling and degranulation priming genes. One of the top 10 variable features in colonic neutrophils was the gene for neutrophil glycoprotein, Olfactomedin 4 (OLFM4). CDI enhanced OLFM4 mRNA and protein expression in neutrophils, and OLFM4+ cells aggregated to areas of severe IEC damage. Compared to uninfected controls, both humans and mice with CDI had higher concentrations of circulating OLFM4; and in mice, OLFM4 deficiency resulted in faster recovery and better survival after infection. Collectively, these studies provide novel insights into neutrophil-mediated pathology after CDI and highlight the pathogenic role of OLFM4+ neutrophils in regulating CDI-induced IEC damage. One Sentence SummaryUtilizing single-cell transcriptomics, IEC-epithelial co-cultures, and pre-clinical models of CDI, we have identified a subset of neutrophils that are marked by OLFM4 expression as pathogenic determinants of IEC barrier damage after CDI.

immunology↗

bioRxiv2022

A comprehensive analysis of immune landscape of Indian triple negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) is a heterogeneous disease with a significant clinical challenge. TNBC alarmingly comprises 25-30% of breast cancers in India compared with only 10-15% in the West. However, immunotherapy was approved for high-risk early-stage TNBCs in the West. Hence, a long-standing question is whether Indian TNBCs immunologically and clinically resemble Western TNBCs such that they respond similarly to immunotherapies. Here we sought to elucidate the immune landscape of Indian TNBCs for the first time, compare them to Western disease and associate them with clinical parameters, cellular types/signaling, and immunotherapy response. MethodsWe profiled 730 immune genes in 88 retrospective Indian TNBC samples using NanoString platform, clustered them into subtypes using a machine-learning approach, and compared them with Western TNBCs (n=422; public datasets). Subtype-specific gene signatures were identified, followed by clinicopathological, immune cell type, and pathway (multiomics) analyses. We also assessed responses to (cross-cancer) immunotherapy. Tumor-infiltrating lymphocytes (TILs) and pan-macrophage marker were evaluated using hematoxilin-eosin staining and immunohistochemistry, respectively. ResultsWe identified three robust and similarly distributed TNBC immune transcriptome subtypes (Subtypes-1-3) in Indian women, and they are represented correspondingly in Western TNBCs and associated with well-known TNBC subtypes. Irrespective of the ethnicity, Subtype-1 harbored tumor microenvironmental and anti-tumor immune events associated with smaller tumors, younger age, and a better prognosis. Subtype-1 mainly represented basal-like/claudin-low breast cancer and immunomodulatory TNBC subtypes. Subtype-1 showed an increase in a cascade of events, including damage-associated molecular patterns, acute inflammation, Th1 responses, T-cell receptor-related and chemokine-specific signaling, antigen presentation, and viral-mimicry pathways. Subtype-1 was significantly (p<0.05) associated with pre-menopausal women, dense TILs and responses and/or improved prognosis to anti-PD-L1 and MAGEA3 immunotherapies. Subtype-2 was enriched for Th2/Th17 responses, CD4+ regulatory cells, basal-like/mesenchymal subtypes, and an intermediate prognosis. Subtype-3 patients expressed innate immune genes/proteins, including those representing macrophages and neutrophils, and had poor survival. ConclusionWe identified three immune-specific TNBC subtypes in Indian patients with differential clinical and immune behaviors, which largely overlapped with the Western TNBC cohorts. This study suggests cancer immunotherapy in TNBC may work similarly in both populations. Hence, this may expedite pharmaceutical adoption of immunotherapy to Indian TNBC patients.

cancer biology↗

bioRxiv2021

Annotation of glycolysis, gluconeogenesis, and trehaloneogenesis pathways provide insight into carbohydrate metabolism in the Asian citrus psyllid

Citrus greening disease is caused by the pathogen Candidatus Liberibacter asiaticus, which is transmitted by the Asian citrus psyllid, Diaphorina citri. There is no curative treatment or significant prevention mechanism for this detrimental disease that causes continued economic losses from reduced citrus production. A high quality genome of D. citri is being manually annotated to provide accurate gene models required to identify novel control targets and increase understanding of this pest. Here, we annotated genes involved in glycolysis, gluconeogenesis, and trehaloneogenesis in the D. citri genome, as these are core metabolic pathways and suppression could reduce this pest. Specifically, twenty-five genes were identified and annotated in the glycolysis and gluconeogenesis pathways and seven genes for the trehaloneogenesis pathway. Comparative analysis showed that the glycolysis genes in D. citri are highly conserved compared to orthologs in other insect systems, but copy numbers vary in D. citri. Expression levels of the annotated gene models were analyzed and several enzymes in the glycolysis pathway showed high expression in the thorax. This is consistent with the primary use of glucose by flight muscles located in the thorax. A few of the genes annotated in D. citri have been targeted for gene knockdown as a proof of concept, for RNAi therapeutics. Thus, manual annotation of these core metabolic pathways provides accurate genomic foundations for developing gene-targeting therapeutics to reduce D. citri.

bioinformatics↗

bioRxiv2021

Specific and dynamic lignification at the cell-type level controls plant physiology and adaptability

The biopolymer lignin, deposited in the cell walls of vascular cells, is essential for long-distance water conduction and structural support of plants. Independently of the species, each different vascular cell type contains a conserved lignin chemistry with specific aromatic and aliphatic substitutions. Yet, the biological role of this conserved and specific lignin chemistry for each cell type remained unclear. Herein, we investigate the role of specific lignin chemistries for cellular function by producing single cell analyses on vascular cell morphotypes, all enabling sap conduction but differing in morphology. We found that specific lignin chemistries accumulate in each morphotype. Moreover, lignin accumulates dynamically, increasing in quantity and changing composition, to alter the cell wall biomechanics of each morphotype during their maturation. For similar aromatic substitution, residues with alcohol aliphatic functions increased stiffness whereas aldehydes increased flexibility. Modifying this specific lignin chemistry impairs the cell wall biomechanics of each morphotype and consequently reduces their capacity to optimally conduct water in normal conditions, and to recover from drought. Altogether, lignin chemistry is differently controlled for each sap conducting cell types during their maturation to dynamically adjust their biomechanics and hydraulic properties to adapt to developmental and environmental constraints.

plant biology↗

bioRxiv2021

Antifungal activities of artesunate, chloramphenicol, and cotrimoxazole against Basidiobolus species, the causal agents of gastrointestinal basidiobolomycosis

Basidiobolus species (n =13) isolated from human gastrointestinal basidiobolomycosis and lizards were tested against artesunate, chloramphenicol, and cotrimoxazole. The three agents exhibited inhibitory actions against Basidiobolus species comparable to the known antifungals. The combined effects of artesunate + voriconazole and cotrimoxazole + voriconazole have significant synergic effects, p = 0.003 and p = 0.021, respectively. These are promising results that enhance accelerated combined treatment of GIB in humans particularly the combination of artesunate and voriconazole.

microbiology↗

bioRxiv2021

Priming mycobacterial ESX-secreted protein B to form a channel-like structure

ESX-1 is a major virulence factor of Mycobacterium tuberculosis, a secretion machinery directly involved in the survival of the microorganism from the immune system defence. It disrupts the phagosome membrane of the host cell through a contact-dependent mechanism. Recently, the structure of the inner-membrane core complex of the homologous ESX-3 and ESX-5 was resolved; however, the elements involved in the secretion through the outer membrane or those acting on the host cell membrane are unknown. Protein substrates might form this missing element. Here, we describe the oligomerisation process of the ESX-1 substrate EspB, which occurs upon cleavage of its C-terminal region and is favoured by an acidic environment. Cryo-electron microscopy data are presented which show that EspB from different mycobacterial species have a conserved quaternary structure, except for the non-pathogenic species M. smegmatis. EspB assembles into a channel with dimensions and characteristics suitable for the transit of ESX-1 substrates, as shown by the presence of another EspB trapped within. Our results provide insight into the structure and assembly of EspB, and suggests a possible function as a structural element of ESX-1.

biochemistry↗

bioRxiv2020

A Volatile Signal Controls Virulence in the Plant Pathogen Pseudomonas syringae pv. syringae and a Strategy for Infection Control in Organic Farming

Pseudomonas syringae is an important pathogen of many agriculturally valuable crops. Among the various pathovars described P. syringae pv. syringae (Pss) has a particularly wide host range, infecting primarily woody and herbaceous host plants. The ability of Pss to cause bacterial apical necrosis of mango trees is dependent on the production of the antimetabolite toxin mangotoxin. The production of this toxin was shown to be regulated by a self-produced signaling molecule. In this study, we determined the structure of the Pss signal molecule belonging to the recently described family of diazeniumdiolate communication molecules. Employing a targeted mass spectrometry-based approach, we provide experimental evidence that the major signal produced by Pss is the volatile compound leudiazen, which controls mangotoxin production and virulence in a detached tomato leaflet infection model. Experimental results demonstrate that KMnO4 solution inactivates leudiazen and that treatment of infected leaves with KMnO4 abolishes necrosis. This strategy represents the first example of chemically degrading a signaling molecule to interfere with bacterial communication. The application of KMnO4 solution, which is regulatorily approved in organic farming, may constitute an environmentally friendly strategy to control Pss infections.

microbiology↗

bioRxiv2019

Platinum chemotherapy induces lymphangiogenesis to prime tissues for tumor metastasis

Chemotherapy has been used to inhibit cancer growth for decades, but emerging evidence shows it can affect the tumor stroma unintentionally promoting cancer malignancy. After treatment of primary tumors, remaining drugs drain via lymphatics. Though all drugs interact with the lymphatics, we know little of their impact on them. Here, we show a previously unknown effect of platinums, a widely used class of chemotherapeutics, to directly induce systemic lymphangiogenesis and activation. These changes are dose-dependent, long-lasting, and occur in healthy and cancerous tissue in multiple mouse models of breast cancer. We saw similar effects in human ovarian and breast cancer patients whose treatment regimens included platinums. Carboplatin treatment of healthy mice prior to mammary tumor inoculation increases cancer metastasis as compared to no pre-treatment. These platinum-induced phenomena could be blocked by VEGFR3 inhibition. These findings have implications for cancer patients receiving platinums and may support the inclusion of anti-VEGFR3 therapy into treatment regimens or differential design of treatment regimens to alter these potential effects. SummaryPlatinum chemotherapy induces VEGFR3-dependent lymphangiogenesis, priming tissues for metastasis of breast cancer. Inhibition of VEGFR3 via antibody blockade can reverse these effects.

cancer biology↗

bioRxiv2019

Genetic architecture constrains exploitation of siderophore cooperation in Burkholderia cenocepacia

Explaining how cooperation can persist in the presence of cheaters, exploiting the cooperative acts, is a challenge for evolutionary biology. While microbial systems have proved extremely useful to test evolutionary theory and identify mechanisms maintaining cooperation, our knowledge is often limited to insights gained from a few model organisms. Here, we introduce siderophore secretion by the bacterium Burkholderia cenocepacia as a novel study system. Using a combination of phenotypic and competition assays we found that ornibactin, the main siderophore used for iron scavenging in this species, is secreted into the media, can be shared as public good between cells, but cannot be exploited by ornibactin-defective mutants. Molecular analysis revealed that cheating is compromised because the ornibactin receptor gene and genes involved in ornibactin synthesis are co-expressed from the same operon, such that disruptive mutations in the upstream synthesis genes compromise receptor availability. To prove that it is the genetic architecture of the siderophore locus that prevents cheating, we broke the linked traits by expressing the ornibactin receptor from a plasmid, a measure that turned the ornibactin mutant into a functional cheater. A literature survey across Burkholderia species suggests that the genetic linkage independently broke over evolutionary time scales in several lineages, indicating that cheating and countermeasures might be under selection. Altogether, our results highlight that expanding our repertoire of microbial study systems leads to new discoveries and reinforce the view that social interactions shape evolutionary dynamics in microbial communities.

evolutionary biology↗