Biology subjects

Ryan, M. J.

Publications and source records attributed to Ryan, M. J..

At least 19 recordsLinked to original sources

bioRxiv2026

Coordination Failures Generate Selection Gradients in Animal Collectives

Collective animal behavior occurs in high-stakes contexts like predator evasion and mate attraction. Consequently, individuals that fail to effectively coordinate their behavior with neighbors can face severe costs. While the coordination strategies individuals in collectives follow are well-described, sensorimotor limitations frequently subvert successful execution of these strategies. Yet, how the resulting coordination errors influence the evolution of collective strategies remains relatively unexplored, largely because quantifying errors and their costs in dynamic animal groups is immensely challenging. To address this, we investigated the causes and consequences of coordination errors in tungara frog choruses. Here, neighboring males typically alternate their calls. However, due to sensorimotor limitations, inadvertent synchronous calls are common. Synchronous calls are highly stereotyped and strongly disfavored by mate-searching females and so represent unambiguous and costly coordination errors. Additionally, within synchronous call pairs, females strongly disfavor following calls relative to leading calls. We found that synchrony outcomes varied non-randomly by sensorimotor phenotype. Inter-male compatibility in intrinsic call rhythms structured synchrony, leading males with slower rhythms to synchronize at overall higher rates. Furthermore, during synchrony, males with lengthier response latencies more often produced costlier following calls. Data-driven simulations revealed that, due to these mechanistic linkages between sensorimotor phenotype and synchrony outcomes, female biases against synchronous and following calls systematically penalized males with slower call rhythms and longer response latencies. Thus, coordination errors are not unstructured noise. Rather, phenotype-dependent variation in the frequency and severity of coordination errors can generate strong directional selection on sensorimotor phenotypes in animal collectives.

animal behavior and cognition↗

bioRxiv2026

Inhibition of NLRP3 Differentially Regulates Blood Pressure and Inflammation in Male versus Female DOCA-Salt Sprague Dawley Rats

BackgroundDeoxycorticosterone acetate (DOCA)-salt induces greater increases in blood pressure (BP) and a more pro-inflammatory T cell profile in males compared to females. T cells contribute to DOCA-salt hypertension, however, the mechanisms driving T cell activation remain unclear. The NLRP3 inflammasome has been implicated in DOCA hypertension in male mice. Little is known regarding NLRP3 in females. The goal of the current study was to test the hypothesis that NLRP3 contributes to greater increases in BP and renal inflammation with DOCA in males vs. females. MethodsRenal NLRP3 protein levels were measured in normotensive and hypertensive male and female subjects and in male and female Sprague Dawley uni-nephrectomized (UNX) control and DOCA-salt rats. Additional 11-wk-old Sprague Dawley rats were UNX and randomized to: 1) DOCA + vehicle or 2) DOCA + the NLRP3 inhibitor MCC950 (10 mg/kg/day in saline) from 11-14 wks of age. At 14-wks-of-age rats were euthanized, terminal plasma samples and remaining kidneys were collected for flow cytometric analysis of T cells. ResultsRenal NLRP3 levels were significantly greater in hypertensive males and females vs. normotensive controls. DOCA increased BP in both sexes, with greater elevations in males. MCC950 attenuated DOCA-induced increases in BP in male, but not female rats. MCC950 decreased circulating and renal CD4 and Th17 cells in both sexes, although the effect was greater in males. ConclusionDespite both males and females exhibiting an increase in NLRP3 in hypertension, NLRP3 contributes to BP elevations only in DOCA-salt males.

physiology↗

bioRxiv2025

Sex-specific effects of chronic unpredictable stress on mitochondrial function in the HPA axis in mice

Stress, whether real or perceived, activates physiological and behavioral responses via the hypothalamic- pituitary-adrenal (HPA) axis and sympathetic nervous system activation. Under chronic stress, however, these adaptive responses become dysfunctional leading to pathological changes in behavior and health. Mitochondria are dynamic organelles essential for cellular energy production and for initiating glucocorticoid synthesis and release from adrenal glands during stress. Thus, mitochondria may represent a first line of response to environmental challenges. However, the effects of chronic stress on mitochondrial function within the HPA axis, particularly regarding sex differences, are unexplored. We exposed adult male and female C57BL6/J mice to four weeks of chronic unpredictable stress and examined behavioral and mitochondrial responses in the hypothalamus and adrenal glands - two key HPA axis regions. As previous reports indicated sex differences in stress responsivity, we hypothesized that chronic stress would differentially impact mitochondrial respiration within HPA axis regions in a sex-specific manner. Chronic stress increased avoidance behavior in males and passive coping behavior in females, indicating sex-specific behavioral responses. In females, stress significantly decreased mitochondrial respiration in both the hypothalamus and adrenal glands, while males were not significantly affected. In males, stress increased adrenal expression of mitochondrial complex II protein, which may have served a compensatory role to preserve mitochondrial function. Mitochondrial respiration significantly correlated with behavioral measures in stressed animals, highlighting a relationship between metabolism and stress-induced impairments. These findings reveal sex-specific metabolic adaptations to chronic stress and suggest that females may be more vulnerable to stress-induced mitochondrial dysfunction within the HPA axis. Clinical PerspectivesO_LIChronic stress is widely prevalent, associated with neuropsychiatric disease that affect women at a rate twice as high as men, and mediated by mitochondria, yet sex differences in the effects of chronic stress on mitochondrial function have not been characterized. C_LIO_LIDespite similar behavioral outcomes, chronic unpredictable stress exposure significantly decreases mitochondrial respiration only in the hypothalamus and adrenal glands from females, in association with stress-induced behavioral alterations. C_LIO_LIFemales may have increased vulnerability to metabolic effects of chronic stress and therapies targeting mitochondrial function may be more efficacious in preventing behavioral impacts of stress in females. C_LI

neuroscience↗

bioRxiv2025

Humans share acoustic preferences with other animals

Many animals produce sounds during courtship and receivers prefer some sounds over others. Shared ancestry and convergent evolution may generate similarities in preference across species and could underlie Darwins conjecture that some animals "have nearly the same taste for the beautiful as we have". Here, we show that humans share acoustic preferences with a wide range of animals, that the strength of human preferences correlates with that in other animals, and that human responses are quicker when in agreement with animals. Furthermore, we found greatest agreement in preference for adorned, evolutionarily ancestral, and lower frequency sounds. Humans music listening experience was associated with preferences. These results are consistent with theories arguing that biases in sensory and cognitive processing sculpt acoustic preferences and confirm Darwins century-old hunch about the conservation of aesthetics in nature.

animal behavior and cognition↗

bioRxiv2025

If memory serves: Multisensory male display improves female memory during mate sampling

Across many taxa, males gather in leks to perform multisensory courtship displays for females. At a lek, changes in the sensory scene over the course of mate evaluation are inevitable. This dynamic nature makes a females ability to recall the location of individual signalers an important component of female mate choice. It is hypothesized that complex (especially multimodal) displays may improve a females ability to remember and thus discriminate amongst potential mates. To test this hypothesis, we presented female tungara frogs (Physalaemus (=Engystomops) pustulosus) with male calls (auditory) and robotic frogs (visual) that could later be obstructed from view via the lowering of blinds. Specifically, we asked if the visual component of a multimodal display improves the ability of a receiver to remember a signaler. While our initial experiment did not find memory instantiation in female frogs, subsequent experiments with a longer presentation time and a brief period of silence successfully instantiated memories in females. Moreover, females continued to demonstrate significant preferences for calls associated with the visual cue even after 25 s following the obstruction of the visual stimulus (robotic frog). Thus, we propose that the duration of presentation and/or the silent period impact memory capability. Silence is common in choruses, and our data suggest that complex, multisensory stimuli may have evolved to help females remember their preferred mate even with such fluctuations in signal production. LAY SUMMARYMultisensory signals function to stimulate one or more of a receivers senses, and in doing so, may make signalers more memorable to receivers. Multisensory signals are common in mating displays, including the advertisement of a male tungara frog: a call (acoustic) and a vocal sac inflation (visual). Here, we demonstrate that female tungara frogs were more likely to remember a multisensory male display over a unisensory display, but only after fluctuations in the signals intensity.

animal behavior and cognition↗

bioRxiv2025

Cadences of the Collective: Conspecific Stimulation Patterns Interact with Endogenous Rhythms to Cue Socially Mediated Response Shifts

Many animals form behavioral collectives, and optimal interaction patterns often differ across social contexts. Sensory scenes generated by many interacting conspecifics are complex. Thus, maintaining socially-calibrated interaction patterns necessitates that individuals distill key features from conspecific scenes to guide continued adjustments to social fluctuations. Tungara frogs produce mating calls in choruses varying in size, and interaction patterns differ across social environments; rivals alternate their calls in smaller choruses, but increasingly overlap one anothers calls in a stereotyped fashion as choruses increase in size. We used automated playback to investigate the cues guiding this socially-mediated shift in response modes. We played conspecific stimulus calls to males at various delays relative to their own calls, preceded by various acoustic motifs mimicking conspecific interaction patterns observed across varied chorusing environments. Males almost never overlapped isolated stimulus calls at any delays. However, their probabilities of overlapping stimulus calls increased markedly when stimulus calls were preceded by motifs exhibiting intense conspecific stimulation patterns characteristic of larger choruses, especially when these stimulus calls were also presented at later delays. Thus, a multifaceted cue to social context primes varied interaction patterns on a call-by-call basis: that, in larger choruses, males experience intense conspecific stimulation during their inter-call periods, and that this stimulation extends throughout the latter reaches of their call cycles. Our results highlight that inactive phases within behavioral rhythms provide critical assessment windows for fine-tuning upcoming responses, and that behavioral rhythms act as crucial temporal filters for mapping conspecific stimulation patterns to behavioral outputs.

animal behavior and cognition↗

bioRxiv2025

Stochastically Emergent Tumors offer in vivo whole genome interrogation of cancer evolution from non-malignant precursors

Interrogating the stochastic events underlying tumor evolution from non-malignant precursors is crucial for understanding therapy resistance. Current methods are complicated by chromosomal instability, obscuring driver identification and yielding non-representative genetics. Inspired by patient tumors that evolve without chromosomal instability, we developed Stochastically Emergent Tumors (SETs) by inducing mismatch repair deficiency in non-malignant precursors, then engrafting in mice. Barcoded SETs exhibited increased tumoral and drug target heterogeneity over current models. SETs delineated the stochastic contributions, mutational landscapes, and selective pressures distinguishing tumorigenesis from non-malignant precursor in vitro growth. SETs are an unlimited source for diverse Stochastically Emergent cell Lines (SELs), bolstering under-represented cancers. Since SETs composition dynamically reflects therapy exposure, they are a whole-genome platform for precision oncology. We identified three novel genetic drivers (ZFHX3, CIC, KMT2D) of differential prostate cancer therapy responses. These alterations are enriched in patients of African and Chinese ancestry and correlate with significant differences in survival.

cancer biology↗

bioRxiv2024

Female Tungara Frogs Discriminate against the Call of Males Infected by Chytridiomycosis

Species worldwide are disappearing in the most devastating mass extinction in human history and one of the six most profound extinctions in the history of life. Amphibians are greatly affected, approximately one third of living species are threatened, and many others are extinct. One of the main causes of amphibian species extinctions and population declines is the emerging infectious disease chytridiomycosis, caused by the fungus Batrachochytrium dendrobatidis (Bd). Although some species are somewhat tolerant of the disease, the non-lethal effects of the infection with Bd and their short or long term consequences are poorly understood. In these species there is the potential for behavioral responses to mitigate the spread of the fungus. Here we show that in tungara frogs, infection status influences the males mating calls. These infection-induced changes in the quality of males mating calls ultimately reduce the calls attractiveness to females making females less likely to respond to and thus mate with infected males. More broadly, our results imply that females might avoid mating with disease-infected males by assessing the acoustic signal only, and that such recruitment of behavioral responses might potentially ameliorate some of the effects of this sixth mass extinction. Lay summaryChytridiomycosis is an amphibian disease well known for its lethal effects. Tungara frogs are infected in nature, but seem to be resistant to the disease. Here we show that chytridiomycosis has non-lethal behavioral effects on tungara frogs. Females discriminate against infected males by assessing only their acoustic signal. The mating call of a male that is not infected with the disease is more attractive to females than the call of that same male when he is infected.

animal behavior and cognition↗

bioRxiv2023

Horizontal transfers between fungal Fusarium species contributed to successive outbreaks of coffee wilt disease

Outbreaks of fungal disease have devastated plants and animals throughout history. Over the past century, the repeated emergence of coffee wilt disease caused by the fungal pathogen Fusarium xylarioides severely impacted coffee production across sub-Saharan Africa. To improve the disease management of such pathogens, it is crucial to understand their genetic structure and evolutionary potential. We compared the genomes of 13 historic strains spanning six decades and multiple disease outbreaks to investigate population structure and host specialisation. We found F. xylarioides comprises at least four distinct lineages: one host-specific to Coffea arabica, one to C. canephora var. robusta, and two historic lineages isolated from various Coffea species. Mapping variation onto a new long-read reference genome showed that host-specificity appears to be acquired through horizontal transfer of effector genes from members of the F. oxysporum species complex. This species complex is known to cause wilt disease in over 100 plant species. Multiple transfers into the F. xylarioides populations matched to different parts of the F. oxysporum mobile pathogenicity chromosome and were enriched in effector genes and transposons. Effector genes in this region and other horizontally transferred carbohydrate-active enzymes important in the breakdown of plant cell walls were shown by transcriptomics to be highly expressed during infection of C. arabica by the fungal arabica strains. Widespread sharing of specific transposons between F. xylarioides and F. oxysporum, and the presence of large Starship elements, indicate that transposons were involved in horizontal transfers. Our results support the hypothesis that horizontal gene transfers contributed to the repeated emergence of this fungal disease.

evolutionary biology↗

bioRxiv2023

Water inside the selectivity filter of a K+ ion channel: structural heterogeneity, picosecond dynamics, and hydrogen-bonding

Water inside biological ion channels regulates the key properties of these proteins such as selectivity, ion conductance, and gating. In this Article we measure the picosecond spectral diffusion of amide I vibrations of an isotope labeled KcsA potassium channel using two-dimensional infrared (2D IR) spectroscopy. By combining waiting time (100 - 2000 fs) 2D IR measurements of the KcsA channel including 13C18O isotope labeled Val76 and Gly77 residues with molecular dynamics simulations, we elucidated the site-specific dynamics of water and K+ ions inside the selectivity filter of KcsA. We observe inhomogeneous 2D lineshapes with extremely slow spectral diffusion. Our simulations quantitatively reproduce the experiments and show that water is the only component with any appreciable dynamics, whereas K+ ions and the protein are essentially static on a picosecond timescale. By analyzing simulated and experimental vibrational frequencies, we find that water in the selectivity filter can be oriented to form hydrogen bonds with adjacent, or non-adjacent carbonyl groups with the reorientation timescales being three times slower and comparable to that of water molecules in liquid, respectively. Water molecules can reside in the cavity sufficiently far from carbonyls and behave essentially like "free" gas-phase-like water with fast reorientation times. Remarkably, no interconversion between these configurations were observed on a picosecond timescale. These dynamics are in stark contrast with liquid water that remains highly dynamic even in the presence of ions at high concentrations.

biophysics↗

bioRxiv2023

Clinical prediction of wound re-epithelisation outcomes in non-severe burn injury using the plasma lipidome

Whilst wound repair in severe burns has received substantial research attention, non-severe burns (<20% total body surface area) remain relatively understudied, despite causing considerable physiological impact and constituting most of the hospital admissions for burns. Early prediction of healing outcomes would decrease financial and patient burden, and aid in preventing long-term complications from poor wound healing. Lipids have been implicated in inflammation and tissue repair and may play essential roles in burn wound healing. In this study, plasma samples were collected from 20 non-severe burn patients over 6 weeks from admission, including surgery, and analysed by liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance spectroscopy to detect 850 lipids and 112 lipoproteins. Orthogonal projections to latent structures-discriminant analysis was performed to identify changes associated with re-epithelialisation and delayed re-epithelisation. We demonstrated that the lipid and lipoprotein profiles at admission could predict re-epithelisation outcomes at 2 weeks post-surgery, and that these discriminatory profiles were maintained up to 6 weeks post-burn. Inflammatory markers GlycB and C-reactive protein indicated divergent systemic responses to the burn injury at admission. Triacylglycerols, diacylglycerols and low-density lipoprotein subfractions were associated with delayed wound closure (p-value <0.02, Cliffs delta >0.7), whilst high-density lipoprotein subfractions, phosphatidylinositols, phosphatidylcholines, and phosphatidylserines were associated with re-epithelisation at 2 weeks post-surgery (p-value <0.01, Cliffs delta <-0.7). Further model validation will potentially lead to personalised intervention strategies to reduce the risk of chronic complications post-burn injury.

systems biology↗

bioRxiv2023

Metabolic consequences of non-severe burn injury are associated with increased plasma markers of inflammation and cardiovascular disease risk.

Globally, burns are a significant cause of injury that can cause substantial acute trauma as well as lead to increased incidence of chronic co-morbidity and disease. To date, research has primarily focused on the systemic response to severe injury, with little in the literature reported on impact of non-severe injuries (<15% total burn surface area; TBSA). To elucidate the metabolic consequences of non-severe burn injury, longitudinal plasma was collected from adults (n=35) who presented at hospital with a non-severe burn injury at admission, and at 6 week follow up. A cross-sectional baseline sample was also collected from non-burn control participants (n=14). Samples underwent multiplatform metabolic phenotyping using 1H nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry to quantify 112 lipoprotein and glycoproteins signatures and 852 lipid species from across 20 subclasses. Multivariate data modelling (Orthogonal projection to latent structures-discriminate analysis) revealed alterations in lipoprotein and lipid metabolism when comparing baseline control to hospital admission samples, with the phenotypic signature found to be sustained at follow up. Univariate (Mann-Whitney U) testing and OPLS-DA indicated specific increases in GlycB (p-value <1.0e-4), low density lipoprotein-2 subfractions (Variable importance in projection score; VIP >6.83e-1) and monoacyglyceride (20:4)(p-value <1.0e-4) and decreases in circulating anti-inflammatory high-density lipoprotein-4 subfractions (VIP >7.75e-1), phosphatidylcholines, phosphatidylglycerols, phosphatidylinositols and phosphatidylserines. The results indicate a persistent systemic metabolic phenotype that occurs even in cases of non-severe burn injury. The phenotype is indicative of an acute inflammatory profile which continues to be sustained post-injury, suggesting an impact on systems health beyond the site of injury. The phenotypes contained metabolic signatures consistent with chronic inflammatory states reported to have elevated incidence post-burn injury. Such phenotypic signatures may provide patient stratification opportunities, to identify individual responses to injury, personalise intervention strategies and improve acute care, reducing risk of chronic co-morbidity.

systems biology↗

bioRxiv2022

Spatial learning overshadows learning novel odors and sounds in both a predatory and a frugivorous bat

AO_SCPLOWBSTRACTC_SCPLOWTo be efficient while foraging, animals should be selective about attending to and remembering the cues of food that best predict future meals. One hypothesis is that animals with different foraging strategies should vary in their reliance on spatial and feature cues. Animals that store food or feed on spatially stable food, like fruit or flowers, should be predisposed to learning a meals location, whereas predators that hunt mobile prey should instead be biased towards learning feature cues such as color or sound. Previous studies suggest that nectar- and fruit-feeding bats should rely relatively more on spatial cues, whereas predatory bats should rely more on feature cues, yet no experiment has compared these two foraging strategies under the same conditions. To test this hypothesis, we compared learning in the frugivorous bat, Artibeus jamaicensis, and the predatory bat, Lophostoma silvicolum, which hunts katydids using acoustic cues. We trained bats to find food paired with a unique odor, sound, and location. We then dissociated these cues to assess which cue each bat had learned. Rather than finding that the frugivore and predator are on opposite ends of a continuum in their relative reliance on spatial and feature cues, we found that both species learned spatial cues with no evidence that either learned the sounds or odors. We discuss interpretations of these results in the context of past work on use of spatial cues versus feature cues. Compared to feature cues, spatial cues may be fundamentally more rich, salient, or memorable. LO_SCPLOWAYC_SCPLOW SO_SCPLOWUMMARYC_SCPLOWWhen animals learn how to obtain food, they could attend to many possible cues--such as the associated smells, sights, sounds, or locations of the food. It has been hypothesized that natural selection has shaped animals to pay particular attention to the types of cues that are most useful for finding their typical food. In bats, this would predict that predatory species that hunt mobile, noisy insects by sound should be biased towards learning a food-associated sound, whereas bats that eat stationary and silent fruit should be biased towards learning a foods location. We gave predatory and fruit-eating bats the opportunity to simultaneously learn food-rewarded odors, sounds, or locations. Regardless of their diets, both species of bats learned locations rather than the odors or sounds associated with food. Spatial cues may be particularly rich or salient, and when they are reliable, animals may use them for learning over other cues regardless of their typical food.

animal behavior and cognition↗

bioRxiv2022

Long-term memory in frog-eating bats

Long-term memory has clear advantages but also has neurological and behavioral costs1-3. Given these opposing selection pressures, understanding how long memories last can shed light on how memory enhances or constrains animals abilities to exploit their niches. Although testing memory retention in wild animals is difficult, it is important because captive conditions do not reflect the complex cognitive demands of wild environments, and long-term captivity changes the brain4 (past studies on nonhuman long-term memory are reviewed in Table S1). Here, we trained wild-caught frog-eating bats (Trachops cirrhosus) to find prey by flying to a novel acoustic cue, released them back into the wild, and then re-captured some of them 1-4 years later. When re-tested, all eight experienced bats that previously learned the novel prey sounds flew to those sounds within seconds, whereas 17 naive bats tested with the same sounds showed weak responses. Experienced bats also showed behavior indicating generalization of memories between novel sounds and rewards over time. The frog-eating bats remarkably long memory for novel acoustic cues indicates that an ability to remember rarely encountered prey may be advantageous for this predator, and suggests hitherto unknown cognitive abilities in bats. O_TBL View this table: org.highwire.dtl.DTLVardef@15a8294org.highwire.dtl.DTLVardef@132eb3forg.highwire.dtl.DTLVardef@1f29583org.highwire.dtl.DTLVardef@135dff2org.highwire.dtl.DTLVardef@19cfa_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable S1:C_FLOATNO O_TABLECAPTIONStudies of animal memory durations documenting memories of months or years. Memory duration = the longest duration demonstrated in the study. Wild or captive = where animals spent the time of memory retention; some "captive" animals were originally wild caught. Context = the ecological context and memory task being tested. 2-AFC = Two-alternative forced choice. C_TABLECAPTION C_TBL

animal behavior and cognition↗

bioRxiv2021

Conserved chromatin and repetitive patterns reveal slow genome evolution in frogs

Frogs are an ecologically diverse and phylogenetically ancient group of living amphibians that include important vertebrate cell and developmental model systems, notably the genus Xenopus. Here we report a high-quality reference genome sequence for the western clawed frog, Xenopus tropicalis, along with draft chromosome-scale sequences of three distantly related emerging model frog species, Eleutherodactylus coqui, Engystomops pustulosus and Hymenochirus boettgeri. Frog chromosomes have remained remarkably stable since the Mesozoic Era, with limited Robertsonian (i.e., centric) translocations and end-to-end fusions found among the smaller chromosomes. Conservation of synteny includes conservation of centromere locations, marked by centromeric tandem repeats associated with Cenp-a binding, surrounded by pericentromeric LINE/L1 elements. We explored chromosome structure across frogs, using a dense meiotic linkage map for X. tropicalis and chromatin conformation capture (HiC) data for all species. Abundant satellite repeats occupy the unusually long ([~]20 megabase) terminal regions of each chromosome that coincide with high rates of recombination. Both embryonic and differentiated cells show reproducible association of centromeric chromatin, and of telomeres, reflecting a Rabl configuration similar to the "bouquet" structure of meiotic cells. Our comparative analyses reveal 13 conserved ancestral anuran chromosomes from which contemporary frog genomes were constructed.

genomics↗

bioRxiv2020

Modulation of ferroptosis sensitivity by TXNRD1 in pancreatic cancer cells

AO_SCPLOWBSTRACTC_SCPLOWThe selenoprotein thioredoxin reductase 1 (TXNRD1) plays a central role in ameliorating oxidative stress. Inhibition of TXNRD1 has been explored as a means of killing cancer cells that are thought to develop an enhanced reliance on such antioxidant proteins. In the context of ferroptosis, a non-apoptotic form of oxidative cell death, TXNRD1 has been proposed to cooperate with the phospholipid hydroperoxidase enzyme glutathione peroxidase 4 (GPX4) to protect cells from the lethal accumulation of lipid peroxides. Here, we report our unexpected finding that in pancreatic cancer cells, CRISPR-Cas9-mediated loss of TXNRD1 confers protection from ferroptosis induced by small-molecule inhibition of GPX4. Insights stemming from mechanistic interrogation of this phenomenon suggest that loss of TXNRD1 results in increased levels of GPX4 protein, potentially by influencing availability of selenocysteine, a scarce amino acid required by both proteins for proper synthesis and function. Increased abundance of GPX4 protein, in turn, protects cells from the effects of small-molecule GPX4 inhibition. These findings implicate selenoprotein regulation in governing ferroptosis sensitivity. Furthermore, by delineating a relationship between GPX4 and TXNRD1 contrary to that observed in numerous other settings, our discoveries underscore the context-specific nature of ferroptosis circuitry and its modulators.

cell biology↗

bioRxiv2020

Floating frogs sound larger: environmental constraints on signal production drives call frequency changes

In animal communication, receivers benefit from signals providing reliable information on signallers traits of interest. Individuals involved in conflicts, such as competition between rivals, should pay particular attention to cues that are unfakeable by the senders due to the intrinsic properties of the production process. In bioacoustics, the best-known example of such index signals is the relationship between a senders body size and the dominant frequency of their vocalizations. Dominant frequency may however not only depend on an animals morphology but also on the interaction between the sound production system and its immediate environment. Here, we experimentally altered the environment surrounding calling frogs and assessed its impact on the signal produced. More specifically, we altered water level, which forced frogs to float on the surface and tested how this manipulation affected the shuttling of air between the lungs and the vocal sac, and how this in turn impacted the calls dominant frequency. Our results show that frogs that are floating are able to fully inflate their lungs and vocal sacs, and that the associated change in airflow or air pressure is correlated with a decrease of call dominant frequency.

evolutionary biology↗

bioRxiv2018

Targeting a Therapy-Resistant Cancer Cell State Using Masked Electrophiles as GPX4 Inhibitors

We recently discovered that inhibition of the lipid peroxidase GPX4 can selectively kill cancer cells in a therapy-resistant state through induction of ferroptosis. Although GPX4 lacks a conventional druggable pocket, covalent small-molecule inhibitors are able to overcome this challenge by reacting with the GPX4 catalytic selenocysteine residue to eliminate enzymatic activity. Unfortunately, all currently-reported GPX4 inhibitors achieve their activity through reactive chloroacetamide groups. We demonstrate that such chloroacetamide-containing compounds are poor starting points for further advancement given their promiscuity, instability, and low bioavailability. Development of improved GPX4 inhibitors, including those with therapeutic potential, requires the identification of new electrophilic chemotypes and mechanisms of action that do not suffer these shortcomings. Here, we report our discovery that nitrile oxide electrophiles, and a set of remarkable chemical transformations that generates them in cells from masked precursors, provide an effective strategy for selective targeting of GPX4. Our results, which include structural insights, target engagement assays, and diverse GPX4-inhibitor tool compounds, provide critical insights that may galvanize development of improved compounds that illuminate the basic biology of GPX4 and therapeutic potential of ferroptosis induction. In addition, our discovery that nitrile oxide electrophiles engage in highly selective cellular interactions and are bioavailable in their masked forms may be relevant for targeting other currently undruggable proteins, such as those revealed by recent proteome-wide ligandability studies.

biochemistry↗