Biology subjects

Short, A.

Publications and source records attributed to Short, A..

6 recordsLinked to original sources

bioRxiv2025

Age-dependent tumor-immune interactions underlie immunotherapy response in pediatric cancer

Pediatric cancers originate in rapidly growing tissues within the context of a developing host. However, the interactions between cancer cells and the developing immune system are incompletely understood. Here, we established a suite of pediatric syngeneic mouse cancer models across diverse anatomical sites and compared their tumor immune microenvironment with that in adult mice. Tumors in pediatric mice exhibited significantly accelerated growth and diminished leukocyte infiltration, dominated by naive-like PD-1low/CD8+ T cells, and proliferative MHCIIlow/PD-L1hi/CD86low macrophages. Tumor-infiltrating leukocytes in pediatric mice were enriched for MYC targets, which was also observed in pediatric patient samples. Furthermore, pediatric mice displayed poor responses to anti-PD-1/PD-L1 or bispecific T cell engager antibodies, which could be reversed by inducing a proinflammatory microenvironment via MYC inhibition or inducing macrophage polarization to an MHCIIhi phenotype. These findings underscore the significant influence of young age on cancer immune responses and reveal potential new therapeutic opportunities for pediatric cancers. HIGHLIGHTSO_LIAllograft tumors exhibit markedly accelerated growth in pediatric hosts compared to adults. C_LIO_LITumors growing in pediatric mice have reduced leukocyte infiltration, dominated by naive-like PD-1low/CD8+ T cells, and MHCIIlow/M2-like macrophages. C_LIO_LIEnrichment of MYC target genes is observed in pediatric mouse tumors and confirmed in primary patient tumor samples. C_LIO_LIPediatric mice display reduced response to anti-PD-1/PD-L1 and BiTE immunotherapy, which can be reversed by remodeling the TIME, using either MYC inhibition or macrophage polarization. C_LI

cancer biology↗

bioRxiv2025

Natural Variation in Photoprotection: Rapid NPQ Kinetics in Ferns

Land plants perform oxygenic photosynthesis but are unable to use all of the solar radiation that they absorb on a daily basis. To minimize the production of reactive oxygen species in excess light, photosynthetic organisms use non-photochemical quenching (NPQ) mechanisms to dissipate excess excitation energy. However, the on-off transition of these mechanisms is slower than the light fluctuations themselves. In high-to-low light transitions, this can be costly to the overall productivity and carbon gain of the organism across its lifetime, because useful light energy is wasted. Here, we characterize the rapid kinetics of NPQ found in species across the fern lineage. Most of the 23 examined fern species showed faster NPQ induction and faster and more complete NPQ relaxation. Curve fitting suggested that energy-dependent quenching was the dominant contributor to the kinetics. The xerophytic fern Astrolepis windhamii exhibited rapid, dithiothreitol-resistant accumulation of zeaxanthin during NPQ induction, and it maintained low residual NPQ after NPQ relaxation, which however was not associated with rapid re-epoxidation of zeaxanthin. Rapid NPQ kinetics might have been an adaptive trait as ferns radiated in sunflecked forest understories during angiosperm diversification and expansion during the Cretaceous.

plant 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↗

bioRxiv2023

To design or not to design? Comparison of beetle ultraconserved element probe set utility based on phylogenetic distance, breadth, and method of probe design

Tailoring ultraconserved element (UCE) probe set design to focal taxa has been demonstrated to improve locus recovery and phylogenomic inference. However, beyond conducting expensive in vitro testing, it remains unclear how best to determine whether an existing UCE probe set is likely to suffice for phylogenomic inference, or if tailored probe design will be desirable. Here we investigate the utility of eight different UCE probe sets for the in silico phylogenomic inference of scarabaeoid beetles. Probe sets tested differed in terms of (1) how phylogenetically distant from Scarabaeoidea taxa those used during probe design are, (2) breadth of phylogenetic inference probe set was designed for, and (3) method of probe design. As part of this study, two new UCE probe sets are produced for the beetle family Scarabaeidae and superfamily Hydrophiloidea. We find that, predictably, probe set utility decreases with increasing phylogenetic distance of design taxa from focal taxa, as well as with narrower breadth of phylogenetic inference probes were designed for. We also confirm previous findings regarding ways to optimize UCE probe design. Finally, we make suggestions regarding assessment of need for de novo probe design and reinforce previous proposed methods for maximizing UCE probe design to improve phylogenomic inference.

evolutionary biology↗

bioRxiv2022

Interplay between LHCSR proteins and state transitions governs the NPQ response in intact cells of Chlamydomonas during light fluctuations.

Photosynthetic organisms use sunlight as the primary energy source to fix CO2. However, in the environment, light energy fluctuates rapidly and often exceeds saturating levels for periods ranging from seconds to hours, which can lead to detrimental effects for cells. Safe dissipation of excess light energy occurs primarily by non-photochemical quenching (NPQ) processes. In the model green microalga Chlamydomonas reinhardtii, photoprotective NPQ is mostly mediated by pH-sensing light-harvesting complex stress-related (LHCSR) proteins and the redistribution of light-harvesting antenna proteins between the photosystems (state transition). Although each component underlying NPQ has been documented, their relative contributions to the dynamic functioning of NPQ under fluctuating light conditions remains unknown. Here, by monitoring NPQ throughout multiple high light-dark cycles with fluctuation periods ranging from 1 to 10 minutes, we show that the dynamics of NPQ depend on the frequency of light fluctuations. Mutants impaired in the accumulation of LHCSRs (npq4, lhcsr1, and npq4lhcsr1) showed significantly less quenching during illumination, demonstrating that LHCSR proteins are responsible for the majority of NPQ during repetitive exposure to high light fluctuations. Activation of NPQ was also observed during the dark phases of light fluctuations, and this was exacerbated in mutants lacking LHCSRs. By analyzing 77K chlorophyll fluorescence spectra and chlorophyll fluorescence lifetimes and yields in a mutant impaired in state transition, we show that this phenomenon arises from state transition. Finally, we quantified the contributions of LHCSRs and state transition to the overall NPQ amplitude and dynamics for all light periods tested and show that both processes interact to facilitate NPQ during light fluctuations. We further assess the role of LHCSRs in cell growth under various periods of fluctuating light. These results highlight the dynamic functioning of photoprotection under light fluctuations and open a new way to systematically characterize the photosynthetic response to an ever-changing light environment. One sentence summaryThe roles of LHCSR and STT7 in NPQ vary with the light fluctuation period and duration of light fluctuation.

plant biology↗

bioRxiv2021

The immunophilin protein FKBPL and its peptide derivatives are novel regulators of vascular integrity and inflammation via NF-kappaB signaling

A breakdown in vascular integrity and excessive inflammation are hallmarks of serious pathological conditions including sepsis, acute respiratory distress syndrome (ARDs) and most recently, severe COVID-19. FK506 - binding protein like (FKBPL) is a member of the immunophilin protein superfamily with potent anti-tumor activity through inhibition of angiogenesis and cancer stemness. An FKBPL-based 23mer peptide, ALM201, displayed a good safety and pharmacokinetic profile in a Phase 1a oncology clinical trial and was subsequently designated orphan drug status by the FDA in ovarian cancer. Here we describe a novel role for FKBPL and its peptides in regulating vascular integrity and cytokine production though modulating NF-{kappa}B signaling. FKBPL knockdown promoted endothelial cell barrier permeability, which was further exacerbated upon stimulation with lipopolysaccharide (LPS) and accompanied by increased expression of TNF mRNA and phosphorylation of p65(RelA). Whilst treatment with the FKBPL based pre-clinical peptide, AD-01, increased VE-cadherin endothelial tight junctions following LPS stimulation. Bone marrow derived macrophages (BMDM) from FKBPL haploinsufficient mice (Fkbpl+/-) also demonstrated increased phosphorylation of p65(RelA) in response to LPS stimulation compared to wild-type mice. Furthermore, treatment with AD-01 inhibited p65(RelA) phosphorylation following LPS stimulation resulting in reduced NF-{kappa}B target gene expression and proinflammatory cytokine production. In an in vivo LPS survival model, Fkbpl+/- mice have reduced survival compared to wild-type mice. Moreover, treatment of wild-type mice with the clinical FKBPL-based peptide, ALM201, following LPS injection resulted in a 100% survival rate in mice at experimental endpoint, as well as an abrogation of production of pro-inflammatory cytokines, TNF and IL-6, in peritoneal lavage washings. Analysis of human genetic biobanks found an association between common genetic variants associated with FKBPL and traits associated with inflammatory disorders such as psoriasis, rheumatoid arthritis and high lymphocyte count. In summary, for the first time, we describe a novel role for FKBPL as a regulator of inflammation and vascular integrity through modulating NF-{kappa}B signaling and FKBPL based therapies demonstrate potent anti-inflammatory activity.

immunology↗