Biology subjects

Sanghvi, K.

Publications and source records attributed to Sanghvi, K..

12 recordsLinked to original sources

bioRxiv2026

Inflammatory endothelial cells promote infiltration of antigen-licensed cytotoxic T cells in malignant gliomas after irradiation

Insufficient T cell infiltration into malignant gliomas fundamentally limits the efficacy of adoptive T cell therapy. Here we show that fractionated irradiation overcomes this barrier by reprogramming the tumor endothelium towards an immune-recruiting interface. Using complementary murine glioma models combined with adoptive T cell transfer, antigen-specific vaccination, and single-cell transcriptomic and T cell receptor profiling, we demonstrate that irradiation enhances the accumulation, clonal expansion, and effector differentiation of tumor-specific CD8+ T cells. Irradiated tumors showed increased T cell receptor clonality and local enrichment of proliferative effector CD8 T cells with enhanced cytotoxic, interferon-responsive, and oxidative metabolic programs. Mechanistically, irradiation triggers a conserved interferon-driven endothelial program marked by antigen presentation and upregulation of adhesion molecules, including ICAM-1 and VCAM-1. This radiation-induced endothelial activation program preferentially seen in inflammatory endothelial subsets was conserved in human glioblastoma and linked to T cell recruitment and maintenance of activated CD8 T cell states. Functionally, irradiation synergized with adoptive T cell transfer and antigen-specific vaccination to promote glioma-specific T cell accumulation and effector differentiation, improving tumor control and survival. Together, these findings identify radiation-induced endothelial activation as a key regulator of T cell trafficking across the brain tumor vasculature highlighting the vascular niche as a critical determinant of immunotherapy efficacy and a rational target for combination strategies in glioblastoma.

immunology↗

bioRxiv2025

Mechanisms of phenotypic trade-offs in the resource acquisition-allocation Y-model

Phenotypic trade-offs, predicted to occur due to resource constraints, are not commonly observed. This discrepancy is often explained by the Y-model, which shows that greater variation in resource acquisition (CVA) than variation in allocation strategy (CVX) masks among-individual phenotypic trade-offs. However, the Y-model is a heuristic rather than a quantitative tool with testable predictions. Additionally, the mechanisms modulating trade-offs in the model remain unclear. Here, we simulate different parameters of the Y-model to understand their influence. We find that CVA/(CVA + CVX) accurately predicts the direction and strength of phenotypic correlations. Contrary to common assumptions, the mean resource acquired by a population does not influence trade-offs; instead, the mean allocation strategy of a population does. Importantly, within-individual dependence of allocation on acquisition exacerbates the influence of mean allocation. This causes greater sensitivity of phenotypic correlations to changes in CVA or CVX, compared to independent resource acquisition and allocation strategies. We generate novel, testable hypotheses about trade-offs in the context of dietary restriction, plasticity, polymorphism, and pace-of-life, and validate our model with empirical data to demonstrate its robustness. By systematically partitioning the influence of means, variances, and covariance, in the acquisition-allocation Y-model, we provide a simple, generalisable, quantitative synthesis for understanding phenotypic trade-offs.

evolutionary biology↗

bioRxiv2025

Sperm storage reduces sperm and embryo quality in animals

In many animals, sperm are stored for extended periods either in the reproductive tracts of males before ejaculation, or of females after copulation. Sperm storage reduces the risk of sperm limitation in both sexes and avoids the costs of female re-mating. However, sperm storage can lead to post-meiotic sperm senescence, i.e. within-sperm-age-dependent deterioration, potentially impacting conceived offspring and lowering male and female fitness. Yet, the extent and magnitude of such deterioration and the variables modulating it during sperm storage are not well understood. Using a meta-analysis across humans (115 studies) and non-human animals (56 studies from 30 species), we investigate how in-vivo sperm storage affects sperm quality, fertilisation success, and offspring quality. In humans, sperm storage leads to greater sperm oxidative stress and DNA damage, and reduces sperm viability and motility. In other animals, sperm performance and embryo quality decline. We identify the duration of sperm storage, the design used for sampling individuals, and the sex of the individual storing sperm as potentially important moderators of the effects of sperm storage. These findings have key biomedical implications, including optimising the timing of ejaculation and fertilisation in fertility clinics or captive breeding programs. Overall, our results reveal the mechanisms that cause post-meiotic sperm senescence, the fitness consequences of sperm storage, and provide evolutionary insights into sex-specific adaptations that potentially mitigate the detrimental effects of sperm storage.

evolutionary biology↗

bioRxiv2025

Does female post-copulatory preference depend on pre-copulatory choice and post-mating environment?

Sexual selection operates across pre- and post-copulatory episodes, driven by intra-sexual competition and inter-sexual choice for mates or gametes. In females, sexual selection often manifests as choosiness, however pre- and post-copulatory preferences can be in opposing directions. While relationships between male pre- and post-copulatory traits are well-studied, these relationships are less understood in females. Additionally, female post-copulatory environments can potentially influence post-copulatory choosiness, but this has been little investigated. Using Drosophila melanogaster, we explored whether mating latency, a proxy for inter-sexual pre-copulatory choosiness, correlates with female ejaculate ejection behaviour, a proxy for post-copulatory choosiness. We further tested whether the presence of a male in the females post-copulatory environment influences her ejection behaviour. We found no significant effect of male presence. However, males with longer mating latencies experience a smaller proportion of their sperm ejected, suggesting that males preferred as mates may produce sperm less favoured for fertilization. This finding might possible trade-offs between male investment in courtship and ejaculates. Our study highlights that female-mediated sexual selection at pre- and post-copulatory stages can shape sexual traits in complex ways. This has implications for sexual conflict, possibly providing an explanation for the maintenance of variation in sexually selected traits.

evolutionary biology↗

bioRxiv2024

Simulations provide a mechanistic interpretation of Bateman gradients

The Bateman gradient (BG or ) is a fundamental metric of sexual selection, and is often interpreted as the fitness advantage individuals can gain by increasing their number of mates. However, researchers commonly misconceive the relationship between mating success (MS) and reproductive success (RS) as always being causal, leading to a misinterpretation of the BG. The BG is phenomenological and therefore uninformative about the mechanisms leading to correlations between MS and RS. Here, we simulate sequential matings in males from biological systems with varying levels of anisogamy and sperm competition, to better understand the underlying processes that modulate male BGs. We show that the BG does not solely reflect the causal influence of MS on RS as is typically interpreted, but is also a consequence of covariances between male MS and male ejaculate traits, female fecundity, or female post-mating decisions. For example, we show that the BG is substantially shallower when the ejaculate size of males negatively co-varies with their MS, such as in species with alternative male reproductive tactics. Such covariances can lead to a misinterpretation of the measured BG, because here, it does not merely represent the strength of selection on intra-sexual competition for mates. We suggest how such covariances can be visually assessed, and accounted for using partial Bateman gradients, to better interpret the influence of MS on RS, thus the strength of pre-copulatory sexual selection. Among other simplifications, our simulations have a male-only focus, but they provide insights into the mechanisms driving inter- and intra-specific variation in the BG, clarify its meaning, and improve our understand of sexual selection.

evolutionary biology↗

bioRxiv2024

No evidence for paternal age effects on sons or daughters, when accounting for paternal sperm storage

O_LIThe age at which a father reproduces is predicted to affect not only his own fertility but also the fitness of his offspring. Specifically, offspring born to old fathers are assumed to be of a lower quality than those conceived by young fathers. However, when fathers have low mating rates, paternal age might be confounded with the duration for which mature sperm are stored in fathers prior to ejaculation. C_LIO_LIStudies that disentangle the confounding effects of paternal sperm storage duration from those of paternal age, on offspring, are lacking. We use Drosophila melanogaster to test the separate and interactive effects of paternal age and sperm storage duration (sexual rest) on the survival and lifetime reproduction of offspring. C_LIO_LIAs expected, old fathers produce fewer offspring than young fathers. But surprisingly, paternal age does not influence the survival or lifetime reproductive success of either sons or daughters. Instead, sons conceived by fathers with long durations of sexual rest have lower reproductive success than sons conceived by fathers with short durations of sexual rest. C_LIO_LIWe further discover that daughters of low reproductive quality selectively disappear with age, but sons do not, highlighting that demographic processes need to be accounted for when studying paternal age effects. C_LIO_LIOverall, our study suggests that paternal age effects might not be as pervasive as previously assumed. We emphasize that a more nuanced understanding of the mechanisms causing paternal age effects is required, so that studies do not misattribute effects of paternal sperm storage to age. C_LI

evolutionary biology↗

bioRxiv2024

Reproductive output of old polygynous males is limited by seminal fluid, not sperm number

Advancing male age can lead to reproductive senescence, which in males is thought to be largely driven by declines in the numbers of sperm transferred by old males. This decline is predicted to be particularly pronounced in polygynous species, where males become sperm limited over a mating sequence. However, males also transfer seminal fluid to females, and little is known about the contribution of seminal fluid to constrain the reproductive output of old, multiply-mating males. Using Drosophila melanogaster, we investigated whether age-related variation in male reproductive output is driven by differential limitation of sperm or seminal fluid, over a series of experimental matings. Consistent with reproductive senescence, old males produced fewer offspring than young males. However, this pattern was not driven by sperm limitation, with old males having more sperm and transferring similar numbers of sperm to a female, compared to young males. Yet surprisingly, females stored fewer sperm when mated to old than young males. Notably, females mated to old multiply-mating males produced more offspring when supplemented with seminal fluid, suggesting that fertility of old males over successive matings was limited by seminal fluid availability. Generally, our study indicates that germline maintenance might be prioritised over somatic maintenance as hypothesized by the disposable soma theory of ageing, and that seminal fluid senescence is a key contributor of reproductive decline with age. While other factors such as differential sperm viability and female post-mating responses could have also influenced our results, our study highlights the under-appreciated role of seminal fluid in mediating male reproductive senescence in polygynous species. Significance statementA key assumption in ageing research is that old males are less fertile than young males, and that this reduced fertility is partly driven by old males producing fewer sperm. However, senescence in male fertility can be caused via other ejaculate-mediated pathways, which we investigate using fruit flies. Contrary to expectations, we reveal that senescence in male fertility is not because of declines in male sperm reserves, but is instead due to age-related changes in seminal fluid and differences in female sperm storage with male age. These declines in the reproductive output of old, multiply-mating males are alleviated by supplementing females with "extra" seminal fluid. Our study demonstrates that male reproductive senescence is reversible, highlighting the underappreciated role of seminal fluid in modulating senescence in polygynous species. These results have potential for improving animal fertility and our understanding of sexual selection.

evolutionary biology↗

bioRxiv2023

What doesn't kill you makes you stronger? Effects of paternal age at conception on fathers and sons

Advancing male age is often hypothesised to reduce both male fertility and offspring quality through reproductive senescence. However, the effects of advancing male age on reproductive output and offspring quality need not always be deleterious. For example, older fathers might compensate for reproductive senescence by terminally investing in reproduction. Similarly, males that survive to reproduce at an old age, might carry alleles that confer high viability (viability selection) which are then inherited by offspring, or might have high reproductive potential (selective disappearance). Differentiating these mechanisms requires an integrated experimental study of paternal survival and reproductive performance, as well as offspring quality, which is currently lacking. Using Drosophila melanogaster, we test the effects of paternal age at conception (PAC) on paternal survival and reproductive success, and the lifespans of sons. We discover that mating at an old age is temporarily linked with decreased future male survival, suggesting that mating-induced mortality is possibly due to old fathers being frail. We also find a quadratic reproductive ageing pattern, with an onset of senescence in late-life. We discover no evidence for terminal investment, and instead discover positive covariances between a fathers lifespan and his probability of siring offspring, for older PAC groups. Lastly, we show that sons born to older fathers live longer than those born to younger fathers, due to viability selection. Collectively, our results suggest that effects of advancing PAC need not be deleterious for fathers or offspring, and can increase fitness if older fathers produce more viable offspring. Lay summaryIts often assumed that old fathers have fewer or lower-quality offspring than young fathers. However, old fathers have on average, usually survived to and reproduced at an older age than young fathers, which might be signals of high quality of old fathers, and benefit offspring. These opposing predictions have rarely been tested, and its unclear what their combined influence is, in determining the fathers and offsprings fitness. Using fruit flies, we explored how old paternal age affects a fathers reproduction and his sons lifespans. We find evidence for age-related reproductive decline in fathers. However, we also discover that fathers who mate at an older age live longer than fathers who mate at a younger age, and subsequently, the sons of older fathers live longer than sons of younger fathers. We suggest that the relationship between paternal age, paternal reproduction and lifespan, and offspring quality, is more complex than previously assumed, and that old fathers might provide benefits to their offspring that future studies need to consider. Teaser textIs an old dad really that bad? While old fathers might in some cases produce fewer offspring or offspring of worse quality than young fathers, they have also survived to an older age, thus might be of higher quality. We test how reproducing at an old age affects a father and his sons fitness. We show that old fathers show evidence of reproductive senescence, but, surprisingly, produce sons that are longer lived than the sons of young fathers. This effect is driven largely by old fathers themselves living longer than young fathers, thus possibly passing alleles conferring higher viability to their sons. Our research is important because it reveals specific mechanisms that drive multifaceted effects of age on fitness.

evolutionary biology↗

bioRxiv2023

No general effects of advancing male age on ejaculates: a meta-analysis across the animal kingdom

Senescence, the deterioration of organismal function with advancing age, is a puzzling biological phenomenon. While actuarial senescence (i.e., age-dependent increases in mortality rates) is well described across some taxa, reproductive senescence (i.e. age- dependent declines in reproduction) is less understood, especially in males, with mixed patterns reported across studies. To examine the evidence for male reproductive senescence, we investigated how advancing male age affects ejaculate traits across non-human animals via a meta-analysis yielding 1814 effect sizes from 379 studies. We found no evidence for a general pattern of reproductive senescence. Instead, we found high heterogeneity for how reproduction changes with male age across animals. Some of this heterogeneity (>10%) was associated with biological factors. For example, there were taxonomical differences for some ejaculate traits -- sperm motility declined with male age in lab rodents and fish, whereas ejaculate size improved with male age in bulls, fish, and insects. Some methodological factors were also important in explaining this heterogeneity: studies sampling a larger proportion of a species lifespan were more likely to detect senescence in ejaculate traits, emphasising the need to examine the full life cycle of species to document senescence. Contrary to predictions, we reveal that the evidence for senescence in ejaculate traits is sporadic. Our findings will help generate novel hypotheses and identify more effective methodological approaches for studying male reproductive senescence.

evolutionary biology↗

bioRxiv2022

MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors

Cancer immunotherapy critically depends on fitness of cytotoxic and helper T cell responses. Dysfunctional cytotoxic T cell states in the tumor microenvironment (TME) are a major cause of resistance to immunotherapy. Intratumoral myeloid cells, particularly blood-borne myeloids (bbm), are key drivers of T cell dysfunction in the TME. We show here that major histocompatibility complex (MHC) class II (MHCII)-restricted antigen presentation on bbm is essential to control the growth of brain tumors. Loss of MHCII on bbm drives dysfunctional intratumoral tumor-reactive CD8+ T cell states through increased chromatin accessibility and expression of Tox, a critical regulator of T cell exhaustion. Mechanistically, MHCII-dependent activation of CD4+ T cells restricts myeloid-derived osteopontin that triggers a chronic activation of nuclear factor of activated T cells (Nfat)2 in tumor-reactive CD8+ T cells. In summary, we provide evidence that MHCII-restricted antigen presentation on bbm is a key mechanism to directly maintain functional cytotoxic T cell states in brain tumors. Highlights- MHCII on intratumoral blood-borne myeloid cells is required for sustained anti-glioma T cell response - Loss of myeloid MHCII drives dysfunction of CD8+ T cells by activating TOX - Tox expression is induced by osteopontin-triggered chronic NFAT2 signaling in tumor-reactive CD8+ T cells - steopontin production is restricted upon intratumoral T helper cell activation via MHCII - MHCII expression on tumor-infiltrating bbm correlates with osteopontin expression and cytotoxic T cell dysfunction in human glioblastoma tissue O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/495502v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@1fbedc7org.highwire.dtl.DTLVardef@b7dc3aorg.highwire.dtl.DTLVardef@db7fe6org.highwire.dtl.DTLVardef@aa06b7_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Effects of early and late life environments on ageing

Early and late life environments can interact in complex ways to influence the fitness of individuals. Most studies investigating effects of the environment on fitness focus on environments experienced and traits expressed at a single point in an organisms life. However, environments vary with time, thus the environments organisms experience at different ages may interact to affect how traits change throughout life. Here, we test whether thermal stress experienced during development leads individuals to cope better with thermal stress as adults. We manipulated temperature during both development and adulthood and measured a range of life-history traits, including senescence, in male and female seed beetles, Callosobruchus maculatus. We found that favourable developmental conditions increased reproductive performance of females (i.e. silver-spoon effects). In contrast, non-reproductive traits such as lifespan and survival senescence were only affected by adult environments- high adult temperatures decreased longevity and survival. Additionally, developmental and adult environments interacted to affect age-dependent changes in male weight. Overall, our results show that effects of early and late environments can be both sex- and trait- specific, and that a full understanding of how environments interact to affect fitness and ageing requires the integrated study of conditions experienced during different stages of ontogeny.

evolutionary biology↗

bioRxiv2020

Sex-specific effects of developmental density on life history and age-dependent flight traits

The environment organisms experience during development can have effects which carry over into their adult lives. These developmental environments may not only affect adult traits at a given point in time, but also how these traits change with age. Generally, stressful developmental environments can lead to sub-optimal adult fitness traits and a faster deterioration of these traits with age. But whether these environments affect how performance traits change with age or whether they affect males and females differently lacks evidence. Here, we test the sex-specific effects of crowding during development on life history traits such as lifespan, fecundity, age-dependent survival, and reproductive senescence, as well as flight performance traits, in the seed beetle-Callosobruchus maculatus. We show that although developmental crowding has no effect on flight performance of either sex, on male adult lifespan, or on female age-dependant survival, it is detrimental to female lifespan and fecundity, as well as female age-dependent reproduction. Additionally, we show that flight traits can change with age and differ between males and females, which may be reflective of sex-specific life-histories and behaviour. Our study has implications for understanding how developmental environments affect life history and behavioural strategies of both males and females.

evolutionary biology↗