Biology subjects

Lucas, R.

Publications and source records attributed to Lucas, R..

8 recordsLinked to original sources

bioRxiv2026

VPS34 regulation in pulmonary arterial vascular smooth muscle cells in pulmonary hypertension

Pulmonary arterial hypertension (PAH) is characterized by the hyperproliferative phenotype of pulmonary arterial smooth muscle cells (PAVSMCs) and extensive extracellular matrix (ECM) remodeling. Vacuolar protein sorting 34 (VPS34), a Class III Phosphatidylinositol-3 Kinase (PI3K), regulates cell proliferation, but its specific function in pulmonary vascular remodeling remains poorly understood. We aim to determine the role of VPS34 activation and regulation in PAVSMC proliferation, matrix deposition, and the progression of PAH. First, we found a marked decrease in the inhibitory phosphorylation of VPS34 at Ser164 (P-S164-VPS34), indicative of constitutive VPS34 activation, in remodeled pulmonary arteries (PAs) from human PAH patients and male mice exposed to Sugen/Hypoxia (SuHx). In human PAH PAVSMCs, siRNA-mediated knockdown of VPS34 or pharmacological inhibition via the selective inhibitor SAR405 significantly blunted cell proliferation and reduced the production of fibronectin, a major component of the remodeled ECM. Mechanistically, we found that Akt activation in PAH PAVSMCs promotes VPS34 activation; Protein Phosphatase 1 Catalytic Subunit Alpha is a potential effector in VPS34 activation; and active VPS34 led to the activation of the mTOR/S6 signaling pathway with tuberous sclerosis complex 2 downregulation. Finally, in vivo treatment with SAR405 attenuated right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in SuHx mice, while concurrently decreasing vascular fibronectin deposition. Our study demonstrates that VPS34 activation, driven by an Akt-mediated loss of the inhibitory P-S164, is crucial in PAVSMC proliferation and fibrotic vascular remodeling in PAH. Targeting the VPS34 axis represents a promising anti-remodeling therapeutic strategy for the treatment of PAH. Keywords: Pulmonary arterial hypertension, vacuolar protein sorting 34, pulmonary vascular remodeling, pulmonary arterial vascular smooth muscle

cell biology↗

bioRxiv2025

Cold-water gut isolate from threespine stickleback (Gasterosteus aculeatus) reveals polypropylene surface oxidation and co-culture inhibition

Polyethylene terephthalate (PET) and polypropylene (PP), two of the most widely produced plastics in the United States, persist in cold-water environments where plastic-degrading microbes have been poorly characterized. Understanding how gut microbes interact and contribute to plastic degradation is essential for developing potential microbiome-based bioremediation strategies. We isolated 184 microbes from wild Alaskan threespine stickleback (Gasterosteus aculeatus) guts across six lakes and screened for plastic degrading potential using lipase/esterase assays and biofilm formation on PET and PP. During the screen for microbes with plastic degrading potential, we discovered that stickleback gut microbiota members enhance and suppressed the lipase, esterase, and biofilm activity of other microbes. Isolates with the highest plastic degrading potential were incubated in minimal media with PET or PP as the sole carbon source to determine whether plastic degradation potential is enhanced. Surface analysis identified a Pseudomonas trivialis strain that exhibited degradation of PP in monoculture; however, this activity was suppressed in the presence of another gut isolate, Pseudomonas germanica. These results demonstrate that microbes associated with the wild threespine stickleback gut microbiome possess plastic degradation potential and provide insights into how microbial interactions can either promote or inhibit bioremediation of plastic pollution in cold-water environments.

microbiology↗

bioRxiv2025

Climate-driven mangrove dieback and recovery: a case study in Albert and Leichhardt Rivers, Australia

A severe dieback event occurred in 2015/2016 in the Gulf of Carpentaria, northern Australia, which was later attributed to El Nino-Southern Oscillation (ENSO) and unusually low sea levels associated with the lunar nodal cycle. However, the long-term drivers of mangrove changes, their resilience, and species-specific responses to these environmental events remain insufficiently understood. This study applies an integration of k-means clustering and random forest classification on the Landsat archive to address knowledge gaps regarding mangrove dynamics. Despite episodic dieback in 2002/2004 (9.1 km2), 2008 (2.9 km2), and 2015/2016 (8.1 km2), mangrove zones showed a net increase in area (+260%, from 21.4 km2 to 55.7 km2) and greenness (NDVI, +18%) over the period 1987-2023. These results indicate cyclical patterns of decline in extent and condition followed by rapid recovery. Landward edges, dominated by Avicennia marina, presented the lowest NDVI values during extreme negative ENSO phases, particularly when unusually low sea levels driven by the lunar nodal cycle further reduced tidal inundation. This pattern suggests greater vulnerability to water deficits and salinity stress in these zones. The mature R. stylosa dominated areas in the central zone of the mangrove forest remained stable throughout the study period, and significant progradation was observed at the seaward margins, dominated by A. marina, likely driven by sediment accretion during increased river discharge years. This highly dynamic mangrove forest demonstrates capacity to extend both landwards and seawards. However, as climate variability intensifies, particularly with more frequent extreme events and shifting tidal regimes projected with sea-level rise, understanding the long-term resilience of mangrove forests and their capacity to recover will be crucial for informing conservation strategies focused on specific zones and maintaining blue carbon stocks of mature mangrove forests.

ecology↗

bioRxiv2024

Endothelial Drp1 Couples VEGF-induced Redox Signaling with Glycolysis Through Cysteine Oxidation to Drive Angiogenesis

Angiogenesis plays a vital role for postnatal development and tissue repair following ischemia. Reactive oxygen species (ROS) generated by NADPH oxidases (NOXes) and mitochondria act as signaling molecules that promote angiogenesis in endothelial cells (ECs) which mainly relies on aerobic glycolysis for ATP production. However, the connections linking redox signaling with glycolysis are not well understood. The GTPase Drp1 is a member of the dynamin superfamily that moves from cytosol to mitochondria through posttranslational modifications to induce mitochondrial fission. The role of Drp1 in ROS-dependent VEGF signaling and angiogenesis in ECs has not been previously described. Here, we identify an unexpected function of endothelial Drp1 as a redox sensor, transmitting VEGF-induced H2O2 signals to enhance glycolysis and angiogenesis. Loss of Drp1 expression in ECs inhibited VEGF-induced angiogenic responses. Mechanistically, VEGF rapidly induced the NOX4-dependent sulfenylation (CysOH) of Drp1 on Cys644, promoting disulfide bond formation with the metabolic kinase AMPK and subsequent sulfenylation of AMPK at Cys299/304 via the mitochondrial fission-mitoROS axis. This cysteine oxidation of AMPK, in turn, enhanced glycolysis and angiogenesis. In vivo, mice with EC-specific Drp1 deficiency or CRISPR/Cas9-engineered "redox-dead" (Cys to Ala) Drp1 knock-in mutations exhibited impaired retinal angiogenesis and post-ischemic neovascularization. Our findings uncover a novel role for endothelial Drp1 in linking VEGF-induced mitochondrial redox signaling to glycolysis through a cysteine oxidation-mediated Drp1-AMPK redox relay, driving both developmental and reparative angiogenesis.

cell biology↗

bioRxiv2024

Mitochondrial genome variation affects humoral and cell-mediated innate immune responses and infection outcomes

The role of mitochondria in both adaptive and innate immune responses is increasingly recognized, but the role of mitochondrial DNA (mtDNA) variation as an immunomodulatory factor has received less attention. One reason for this is the difficulty of separating the effect of mtDNA from that of the nuclear genome. By utilizing the fruit fly Drosophila melanogaster, a powerful model system, we created cytoplasmic hybrids, aka. cybrid lines, where unique mtDNAs (mitotypes) were introgressed into a controlled isogenic nuclear background. We harnessed a panel of cybrid lines to study the effect of mtDNA variation on humoral and cell-mediated innate immune responses. Mitotypes exhibited heterogeneity in infection outcomes upon bacterial, viral and parasitoid infections. One mitotype of note (mtKSA2) was more immunocompetent when compared to other mitotypes. We performed transcriptomic profiling of uninfected and infected flies to find the mechanistic basis of the immunocompetence of the mtKSA2 line. We found that in uninfected flies mtKSA2 caused an upregulation of oxidative phosphorylation (OXPHOS) and tricarboxylic acid cycle (TCA) related genes and a downregulation of a set of antimicrobial peptides (AMPs). Upon infection, mtKSA2 flies produced transcriptomic changes that were infection type and duration specific. When we examined immune cells (hemocytes) in mtKSA2 larvae, we noted an increase in hemocyte numbers. These hemocytes were activated in the absence of infection, increased their production of ROS, and showed evidence of increased encapsulation efficiency upon parasitoid wasp infection. Overall, our results show that mtDNA variation acts as an immunomodulatory factor in both humoral and cell-mediated innate immunity and that specific mitotypes can provide enhanced protection against various infections.

immunology↗

bioRxiv2020

Peripheral Taenia infection increases immunoglobulins in the central nervous system.

Human cysticercosis is a disease caused by larvae of the cestode Taenia solium. It is the most common cause of adult-acquired epilepsy world-wide where it exacts a debilitating toll on the health and well-being of affected communities. It is commonly assumed that the major symptoms associated with cysticercosis are a result of the direct presence of larvae in the brain. As a result, the possible effect of peripherally located larvae on the central nervous system are not well understood. To address this question, we utilised the Taenia crassiceps intra-peritoneal murine model of cysticercosis, where larvae are restricted to the peritoneal cavity. In this model, previous research has observed behavioural changes in rodents but not the development of seizures. Here we used ELISAs, immunoblotting and the Evans Blue test for blood-brain barrier permeability to explore the central effects of peripheral infection of mice with Taenia crassiceps. We identified high levels of parasite-targeting immunoglobulins in the serum of Taenia crassiceps infected mice. We show that the Taenia crassciceps larvae themselves also contain and release host immunoglobulins over time. Additionally, we describe, for the first time, significantly increased levels of IgG within the hippocampi of infected mice, which are accompanied by changes in blood-brain barrier permeability. However, these Taenia crassiceps induced changes were not accompanied by alterations to the levels of proinflammatory, pro-seizure cytokines in the hippocampus. These findings contribute to the understanding of systemic and neuroimmune responses in the Taenia crassiceps model of cysticercosis, with implications for the pathogenesis of human cysticercosis. Graphical abstract created with BioRender.com O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

neuroscience↗

bioRxiv2018

Pupil responses to hidden photoreceptor-specific modulations in movies

Under typical daytime light levels, the human pupillary light response (PLR) is driven by the activity of the L, M, and S cones, and melanopsin expressed in the so-called intrinsically photosensitive retinal ganglion cells (ipRGCs). However, the importance of each of these photoreceptive mechanisms in defining pupil size under real-world viewing conditions remains to be established. To address this question, we embedded photoreceptor-specific modulations in a movie displayed using a novel projector-based five-primary spatial stimulation system, which allowed for the precise control of photoreceptor activations in time and space. We measured the pupillary light response in eleven observers, who viewed short cartoon movies which contained hidden low-frequency (0.25 Hz) silent-substitution modulations of the L, M and S cones (no stimulation of melanopsin), melanopsin (no stimulation of L, M and S cones), both L, M, and S cones and melanopsin or no modulation at all. We find that all photoreceptors active at photopic light levels regulate pupil size under this condition. Our data imply that embedding modulations in photoreceptor contrast could provide a method to manipulate key adaptive aspects of the human visual system in everyday, real-world activities such as watching a movie.

neuroscience↗

bioRxiv2018

Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design

Protein glycosylation is a widespread post-translational modification. The first committed step to the lipid-linked glycan used for this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and congenital disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use as antibiotics. However, little is known about the mechanism or the effects of disease-associated mutations in this essential enzyme. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (and thus cause disease) and allow design of non-toxic lipid-altered tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed design of potent antibiotics for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo thereby providing a promising new class of antimicrobial drug.\n\nHighlightsO_LIStructures of DPAGT1 with UDP-GlcNAc and tunicamycin reveal mechanisms of catalysis\nC_LIO_LIDPAGT1 mutants in patients with glycosylation disorders modulate DPAGT1 activity\nC_LIO_LIStructures, kinetics and biosynthesis reveal role of lipid in tunicamycin\nC_LIO_LILipid-altered, tunicamycin analogues give non-toxic antibiotics against TB\nC_LI

biochemistry↗