Biology subjects

Persson, E.

Publications and source records attributed to Persson, E..

10 recordsLinked to original sources

bioRxiv2026

MTDH-SND1 disruption sensitizes ovarian cancer to ferroptosis and PARP inhibition

BRCA-deficient high-grade serous ovarian cancer is characterized by profound genomic instability and elevated replication-associated DNA damage, rendering these tumors initially sensitive to platinum-based chemotherapy and PARP inhibition. However, despite this vulnerability, most patients ultimately develop resistance, underscoring the need for therapeutic strategies that extend beyond DNA repair-targeted mechanisms. Here, we introduce the MTDH-SND1 complex as a complementary therapeutic target that may expose additional stress vulnerabilities in ovarian cancer cells. We show that pharmacological disruption of the MTDH-SND1 interaction using C26-A6 increases susceptibility to ferroptosis-associated stress, an iron-dependent form of regulated cell death and that BRCA-deficient models are particularly more sensitive to this perturbation. Notably, when combined with PARP inhibition, MTDH-SND1 disruption is associated with increased MHC class I expression in tumor cells, suggesting enhanced tumor visibility to the immune system. Together, these findings support a combination strategy that couples DNA repair disruption with metabolic and immunogenic remodeling in BRCA-deficient ovarian cancer.

cancer biology↗

bioRxiv2026

Allometric correlates of heat tolerance in birds: A test using quail breeds with extreme size variation

Birds and mammals are shrinking and shapeshifting as global temperatures rise. Ecogeographic rules predict that such changes should ease heat stress by increasing surface-area-to-volume ratios, and thus, the capacity for heat exchange. This has led to the hypothesis that body size reductions are driven by thermoregulatory selection or adaptive plasticity, although recent syntheses point to more complex, multifactorial causes. Crucially, recent theoretical models predict that thermoregulatory benefits of smaller body size only emerge at extreme deviations from average phenotypes. Here, we exploit agricultural selection in Japanese quail to directly test this hypothesis, using three breeds spanning extreme differences in body mass, surface area, and relative appendage lengths. Evaporative cooling capacity and the scope for evaporative water loss broadly followed allometric predictions when contrasting small and larger breeds. As expected, this allowed the smallest breed to tolerate higher air temperatures. However, differences in heat tolerance limits between breeds were consistently much smaller than predicted. Additionally, the breadth of thermoneutral zones overlapped in full, and upper critical temperatures were remarkably similar, between breeds. Together, these results show that heat tolerance is only weakly linked to surface-area-to-volume relationships and cannot be explained by size alone. Thus, although smaller bodies may modestly enhance heat dissipation when size variation in a population is substantial, our findings suggest that recent body size reductions and morphological shifts are unlikely to be driven primarily by thermoregulatory benefits.

evolutionary biology↗

bioRxiv2026

SIZE DETERMINATION AND MULTIPLEXED FLUORESCENCE-BASED PHENOTYPING OF SINGLE CELL-DERIVED MEMBRANE VESICLES USING A NANOFLUIDIC DEVICE

Extracellular vesicles (EVs) are cell-secreted biological nanoparticles that play a crucial role in intercellular communication and are gaining increasing attention as diagnostic biomarkers, therapeutic agents, and drug delivery vehicles. Consequently, the development of robust and sensitive methods for their characterization is essential. Herein we present the use of a microscope-mounted nanofluidic device for direct size determination and multi-parametric (3-color) fluorescence-based phenotyping of single biological nanoparticles that are in the size range of 20-200 nm in a method we denote Nano-SMF (SMF; size and multiplexed fluorescence). We demonstrate that it is possible to accurately determine the size of nanoparticles by analyzing their one-dimensional Brownian motion during directional flow through nanochannels, achieving size distributions for monodisperse nanoparticle solutions that are on par with TEM analysis, and size discrimination of nanoparticle mixtures that is significantly improved compared to conventional nanoparticle tracking analysis (NTA). Furter, we demonstrate that the method can be applied to analyze EVs directly in minute volumes of cell supernatant, avoiding pre-isolation or concentration steps. The method was applied to phenotype CD63- and CD81-positive EVs from a human embryonic kidney cell model, demonstrating that vesicle sub-populations defined by these two tetraspanin biomarkers differ significantly in size.

biophysics↗

bioRxiv2025

It takes two (Ku) to repair: Mechanistic insights into the minimal NHEJ system of Mycobacterium Tuberculosis

In this study, we used a combination of structural simulations, ensemble assays and single molecule analysis to shed light on Non-Homologous End-Joining (NHEJ) in Mycobacterium Tuberculosis (Mtb), executed by the homodimeric Ku and Ligase D (LigD). We used a monomeric form of the Ku protein to confirm the necessity of homodimerization of Ku to bind DNA. We demonstrated that Mtb Ku and shows limited translocation on DNA and primarily instead stays bound at the DNA ends. The reconstitution of an active Mtb NHEJ machinery, consisting of Ku and LigD, allowed us to characterize the dynamics of each step of the assembly of the Mtb NHEJ machinery at the single molecule level, revealing competition between Ku and LigD for DNA binding. In silico investigations highlighted key residues in Mtb LigD - Ku complex formation. We conducted a mutational analysis of these residues in the polymerase and the ligase domains, respectively. This investigation demonstrated that, although formation of the NHEJ complex is preserved in LigD mutants, mutations in the polymerase domain result in reduced enzymatic activity, whereas mutations in the ligase domain led to its enhancement. Finally, we present a model for NHEJ in M. tuberculosis, where Ku must stay tightly at the DNA ends to properly recruit and regulate LigD enzymatic activity. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/694593v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@9724ccorg.highwire.dtl.DTLVardef@f0dcc4org.highwire.dtl.DTLVardef@12df36dorg.highwire.dtl.DTLVardef@1c881ea_HPS_FORMAT_FIGEXP M_FIG C_FIG Mtb Ku and LigD compete for DNA binding, while interactions between Ku and the LigD polymerase (POL) and ligase (LIG) domains differentially modulate enzymatic activity. This image was generated with the assistance of ChatGPT and Gemini and subsequently edited by the authors.

biochemistry↗

bioRxiv2025

Postnatal developmental temperature affects the ontogeny of heat- and cold tolerance

Thermoregulatory precision is key to maintaining fitness in thermally unstable environments. Previous research found that development in the warmth renders birds better able to handle mild heat stress, while cold postnatal development gives no apparent benefit upon mild cold exposure. It is still not known how developmental temperature affects maximal heat tolerance limits, or if there is a physiological trade-off between heat and cold tolerance. We investigated how postnatal developmental under simulated cold snap- or heatwave-like conditions from hatching until reproductive maturity impacted the ontogeny of maximal heat- and cold tolerance in Japanese quail (Coturnix japonica). To study if any such effects were reversible or permanently programmed, we transferred half of each treatment group to intermediate common garden conditions once reproductive maturity was reached and repeated the measurements several weeks later. Development in heatwave-like conditions increased evaporative water loss rate and moved heat tolerance limits upwards, whereas cold snap-like development rendered more thermogenic birds with improved cold tolerance limits. However, we found no evidence for a trade-off between thermogenic performance and evaporative cooling capacity. The common garden birds converged in nearly all thermoregulatory traits at the end of the study, suggesting that the prior emergence of temperature-dependent phenotypes reflected reversible plasticity. We suggest that improved temperature tolerance limits improve performance in matched thermal conditions, reducing the rate at which thermal injury accrues. Yet, in the short term, we found markedly lower capacity to acclimate heat tolerance compared to cold tolerance, with possible implications for life in a warming world.

ecology↗

bioRxiv2024

FunCoup 6: advancing functional association networks across species with directed links and improved user experience

FunCoup 6 (https://funcoup6.scilifelab.se/, will be https://funcoup.org after publication) represents a significant advancement in global functional association networks, aiming to provide researchers with a comprehensive view of the functional coupling interactome. This update introduces novel methodologies and integrated tools for improved network inference and analysis. Major new developments in FunCoup 6 include vastly expanding the coverage of gene regulatory links, a new framework for bin-free Bayesian training, and a new website. FunCoup 6 integrates a new tool for disease and drug target module identification using the TOPAS algorithm. To expand the utility of the resource for biomedical research, it incorporates pathway enrichment analysis using the ANUBIX and EASE algorithms. The unique comparative interactomics analysis in FunCoup provides insights of network conservation, now allowing users to align orthologs only or query each species network independently. Bin-free training was applied to 23 primary species, and in addition networks were generated for all remaining 618 species in InParanoiDB 9. Accompanying these advancements, FunCoup 6 features a new redesigned website, together with updated API functionalities, and represents a pivotal step forward in functional genomics research, offering unique capabilities for exploring the complex landscape of protein interactions. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=66 SRC="FIGDIR/small/612391v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1cf674eorg.highwire.dtl.DTLVardef@18737f0org.highwire.dtl.DTLVardef@699d88org.highwire.dtl.DTLVardef@1e57910_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Development in the cold renders bird mitochondria more susceptible to heat stress

Research on birds suggests that extreme weather events during development may have long-lasting consequences on form and function. The underlying cellular mechanisms mediating such phenotypic effects are poorly studied. We raised Japanese quail in warm (30{degrees}C) or cold (10{degrees}C) temperatures from hatching until adulthood, and then measured mitochondrial metabolism in intact blood cells at representative normothermic body temperature (41{degrees}C) and a hyperthermic temperature (45{degrees}C) that quail commonly attain when heat stressed. To investigate whether any developmental effects were reversible, half of the cold- and warm-acclimated birds were assigned to a common garden (20{degrees}C) 3 weeks before the measurements. Across groups, hyperthermia was associated with increased proton leak, but decreases in both phosphorylating respiration (where ATP is produced) and working capacity of the mitochondria. Cold-acclimated birds were more strongly affected by heat stress: the increase in proton leak was 1.6-fold higher, and the decrease in phosphorylating capacity during endogenous respiration was 1.7-fold greater, compared to warm-acclimated birds. These differences did not remain in the common-garden birds. Our study suggests that developmental cold acclimation is traded off against heat tolerance at the level of cellular metabolism, with implications for our understanding of avian responses to climate change.

physiology↗

bioRxiv2024

No evidence that shrinking and shapeshifting meaningfully affect how birds respond to warming and cooling

Across the globe, birds and mammals are becoming smaller and longer-limbed. Although the cause of these changes is unclear, many argue that each provide thermoregulatory benefits in a warmer world by easing heat dissipation. Here, we show that neither body size nor limb length in a model species (the Japanese quail) influenced metabolic costs of warming during a cold challenge. In the heat, larger body sizes increased metabolic costs of thermoregulation, however, this effect was moderate and almost always negated by cooling from the limbs (>97% of cases). Rearing in the warmth (30{degrees}C) relative to the cold (10{degrees}C) reduced body sizes and increased limb lengths at adulthood but thermoregulatory benefits of these changes in later heat exposures were absent. Our findings demonstrate that shrinking and shape-shifting are unlikely to ease thermoregulation in contemporary birds or reflect selection for such. Alternative contributors, including neutral or non-adaptive plasticity, should be further investigated. TeaserUsing experimental data, we show for the first time that shrinking and shape-shifting - which has been described as the third general response to climate change in animals - does not inherently provide thermoregulatory benefits to birds in a warming world. Further research evaluating the drivers of shape-shifts (including neutral plasticity and temporal reductions in resource abundance) is needed before we can determine why animals shrink under climate change.

physiology↗

bioRxiv2023

Permeabilization status affects the relationship between basal metabolic rate and mitochondrial respiration in great tit blood cells

Although mitochondrial respiration is believed to explain a substantial part of the variation in whole-animal basal (BMR) or resting metabolic rate (RMR), few studies have addressed the relationship between organismal and cellular metabolism and how this may vary in environments where individual demands for energy differ. We investigated the relationship between whole-individual metabolic rate, measured in temperatures ranging thermoneutrality to far below thermoneutrality, and mitochondrial respiration of intact or permeabilized blood cells in two separate studies on wild great tits (Parus major L.). Our results show that, in permeabilized cells, there are significant positive relationships between BMR or RMR and several mitochondrial traits, including phosphorylating respiration rate through both complexes I and II (i.e., OXPHOS respiration). However, surprisingly, the LEAK respiration (i.e., basal respiration that mainly counteract for proton leakage) was not related to BMR or RMR. When measurements were performed using intact blood cells, BMR was positively related to ROUTINE respiration (i.e., mitochondrial respiration on endogenous substrates) in one of the two studies, but no other mitochondrial traits could explain variation in BMR or RMR in any thermal environment. These studies seem to show that the level of activation of mitochondrial metabolism as well as the permeabilization status of blood cells play a primary role on the extent to which blood metabolism might explain variations in the whole-individual metabolic rate.

physiology↗

bioRxiv2023

Thermoregulatory consequences of growing up during a heatwave

Changes in environmental temperature during the developmental period can affect growth, metabolism, and temperature tolerance of the offspring. We know little about whether such changes remain to adulthood, which is important to understand the links between climate change, development, and fitness. We investigated if phenotypic consequences of the thermal environment in early life remained in adulthood in two studies on Japanese quail (Coturnix japonica). Birds were raised under simulated heatwave-, cold snap-or control conditions, from hatching until halfway through the growth period, and then in a common garden until reproductively mature. We measured biometric and thermoregulatory (metabolic heat production [MHP], evaporative water and heat loss [EWL, EHL] and body temperature) responses to variation in submaximal air temperature at the end of the thermal acclimation period and in adulthood. Warm birds had lower MHP than control birds at the end of the thermal acclimation period and, in the warmest temperature studied (40{degrees}C), also had higher evaporative cooling capacity compared to controls. No analogous responses were recorded in cold birds, though they had higher EWL than controls in all but the highest test temperature. None of the effects found at the end of the heatwave-or cold snap period remained until adulthood. This implies that chicks exposed to higher temperatures could be more prepared to counter heat stress as juveniles, but that they do not enjoy any advantages of such developmental conditions when facing high temperatures as adults. Conversely, cold temperature does not seem to confer any priming effects in adolescence.

physiology↗