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Natural occurrences of immunodeficiency by definition should lead to compromised immune function. The major histocompatibility complexes (MHC) are key components of the vertebrate adaptive immune system, charged with mediating allorecognition and antigen presentation functions. To this end, the genomic loss of the MHC II pathway in Syngnathus pipefishes raises questions regarding their immunological vigilance and allorecognition capabilities. Utilising allograft and autograft fin-transplants, we compared the allorecognition immune responses of two pipefish species, with (Nerophis ophidion) and without (Syngnathus typhle) a functional MHC II. Transcriptome-wide assessments explored the immunological tolerance and potential compensatory measures occupying the role of the absent MHC II. Visual observations suggested a more acute rejection response in N. ophidion allografts compared with S. typhle allografts. Differentially expressed genes involved in innate immunity, angiogenesis and tissue recovery were identified among transplantees. The intriguing upregulation of the cytotoxic T-cell implicated gzma in S. typhle allografts, suggests a prominent MHC I related response, which may compensate for the MHC II and CD4 loss. MHC I related downregulation in N. ophidion autografts hints at an immunological tolerance related reaction. These findings may indicate alternative measures evolved to cope with the MHC II genomic loss enabling the maintenance of appropriate tolerance levels. This study provides intriguing insights into the immune and tissue recovery mechanisms associated with syngnathid transplantation, and can be a useful reference for future studies focusing on transplantation transcriptomics in non-model systems. • Allorecognition assessment of fish with (N. ophidion) and without (S. typhle) MHCII. • Using fin-transplantations of self and non-self tissue with transcriptomics. • Upregulated gene expression of cytotoxic T-cell/MHCI activity in S. typhle. • Indications of cytotoxic/MHCI gene upregulation in S. typhle allografts. • MHCI downregulation in N. ophidion autografts, suggests immunological tolerance. [ABSTRACT FROM AUTHOR]

The evolution of pregnancy exposes parental tissues to new, potentially stressful conditions, which can trigger inflammation. 1 Inflammation is costly 2,3 and can induce embryo rejection, which constrains the evolution of pregnancy. 1 In contrast, inflammation can also promote morphological innovation at the maternal-embryonic interface as exemplified by co-option of pro-inflammatory signaling for eutherian embryo implantation. 1,4,5 Given its dual function, inflammation could be a key process explaining how innovations such as pregnancy and placentation evolved many times convergently. Pelvic brooding ricefishes evolved a novel "plug" tissue, 6,7 which forms inside the female gonoduct after spawning, anchors egg-attaching filaments, and enables pelvic brooders to carry eggs externally until hatching. 6,8 Compared to pregnancy, i.e., internal bearing of embryos, external bearing should alleviate constraints on inflammation in the reproductive tract. We thus hypothesized that an ancestral inflammation triggered by the retention of attaching filaments gave rise to pathways orchestrating plug formation. In line with our hypothesis, histological sections of the developing plug revealed signs of gonoduct injuries by egg-attaching filaments in the pelvic brooding ricefish Oryzias eversi. Tissue-specific transcriptomes showed that inflammatory signaling dominates the plug transcriptome and inflammation-induced genes controlling vital processes for plug development such as tissue growth and angiogenesis were overexpressed in the plug. Finally, mammalian placenta genes were enriched in the plug transcriptome, indicating convergent gene co-option for building, attaching, and sustaining a transient tissue in the female reproductive tract. This study highlights the role of gene co-option and suggests that recruiting inflammatory signaling into physiological processes provides a fast-track to evolutionary innovation. [Display omitted] • Pelvic brooding induces tissue-specific changes in gene expression • Inflammatory signaling characterizes transcriptome of the egg-anchoring plug • Similar to embryo implantation, the plug likely evolved from an inflammatory response • Mammalian placenta genes were independently co-opted into the plug Hilgers et al. combine tissue-specific transcriptomes with morphological data to investigate the evolution of a novel egg-anchoring tissue in ricefishes. Their data show convergent co-option of mammalian placenta genes and indicate that recruiting inflammatory signaling into physiological processes provides a fast-track to evolutionary innovation. [ABSTRACT FROM AUTHOR]

Abstract: In a deep repository for spent nuclear fuel, U(VI)(aq) released upon dissolution of the fuel matrix could, in reducing parts of the system, be converted to U(IV) species which might coalesce and form nanometer-sized UO2 particles. This type of particles is expected to have different properties compared to bulk UO2(s). Hence, their properties, in particular the capacity for oxidant consumption, must be investigated in order to assess the effects of formation of such particles in a deep repository. In this work, methods for radiation chemical synthesis of nanometer-sized UO2 particles, by electron- and γ-irradiation of U(VI) solutions, are presented. Electron-irradiation proved to be the most efficient method, showing high conversions of U(VI) and yielding small particles with a narrow size distribution (22–35nm). Stable colloidal suspensions were obtained at low pH and ionic strength (pH 3, I =0.03). Furthermore, the reactivity of the produced UO2 particles towards H2O2 is investigated. The U(IV) fraction in the produced particles was found to be ∼20% of the total uranium content, and the results show that the UO2 nanoparticles are significantly more reactive than micrometer-sized UO2 when it comes to H2O2 consumption, the major part of the H2O2 being catalytically decomposed on the particle surface. [Copyright &y& Elsevier]

Abstract: In order to elucidate the effect of noble metal clusters in spent nuclear fuel on the kinetics of radiation induced spent fuel dissolution we have used Pd particle doped UO2 pellets. The catalytic effect of Pd particles on the kinetics of radiation induced dissolution of UO2 during γ-irradiation in containing solutions purged with N2 and H2 was studied in this work. Four pellets with Pd concentrations of 0%, 0.1%, 1% and 3% were produced to mimic spent nuclear fuel. The pellets were placed in 10mM aqueous solutions and γ-irradiated, and the dissolution of was measured spectrophotometrically as a function of time. Under N2 atmosphere, 3% Pd prevent the dissolution of uranium by reduction with the radiolytically produced H2, while the other pellets show a rate of dissolution of around 1.6×10−9 molm−2 s−1. Under H2 atmosphere already 0.1% Pd effectively prevents the dissolution of uranium, while the rate of dissolution for the pellet without Pd is 1.4×10−9 molm−2 s−1. It is also shown in experiments without radiation in aqueous solutions containing H2O2 and O2 that ϵ-particles catalyze the oxidation of the UO2 matrix by these molecular oxidants, and that the kinetics of the catalyzed reactions is close to diffusion controlled. [Copyright &y& Elsevier]

Abstract: Previous studies have indicated that the rate of a heterogeneous liquid–solid reaction depends on the size of the solid particles. It has been suggested that both the pre-exponential factor and the activation energy depend on the particle size. The processes involved in dissolution of UO2 have been extensively studied because of their importance for the safety analysis of a future deep repository for spent nuclear fuel and in many of these studies powder suspensions of UO2 are used as a model system. Therefore, it is of importance to investigate and quantify the particle size effect on the kinetics of UO2 oxidation in order to enable comparison of data from studies on different solid substrates. In this work the influence of particle size on the second order rate constant and on the activation energy of the reaction between and UO2 was studied using aqueous UO2-particle suspensions of four different size distributions. A comparative study of the activation energy for the reaction using a UO2 pellet was also performed. [Copyright &y& Elsevier]

Parental age impacts offspring quantity and quality. Most prior research focused on maternal age. Since in most organisms the mother produces the costly eggs plus provides all or most parental care, it is difficult to distinguish maternal effects mediated via the egg from later maternal care. Here, we addressed the effects of parental age on offspring in Syngnathus typhle, a pipefish with male pregnancy. The divide between one parent producing the eggs and the second parent being the exclusive provider of parental care facilitates a distinction between the effects of parental age on egg quality versus parental age on early development. We fully reciprocally crossed young and old mothers and young and old fathers and assessed impact of parental age combination on offspring number, offspring size, and offspring gene expression patterns. Neither parental combination significantly influenced offspring size or male gestation duration; however, they influenced the number of offspring. Paternal, but not maternal, age strongly affected the offspring gene expression. Offspring from old fathers exhibited substantial changes in the expression of genes related to cell cycle regulation, protein synthesis, DNA repair, and neurogenesis. Our findings thus highlight the importance of gestation, as opposed to gamete production, in shaping the parental contribution to offspring development. [ABSTRACT FROM AUTHOR]

After publication of the original article [1], the authors have notified us that the incorrect version of Fig. 4 was used. Below you can find the both incorrect and correct versions of the figure. [ABSTRACT FROM AUTHOR]

While originally acquired from the environment, a fraction of the microbiota is transferred from parents to offspring. The immune system shapes the microbial colonization, while commensal microbes may boost host immune defences. Parental transfer of microbes in viviparous animals remains ambiguous, as the two transfer routes (transovarial vs. pregnancy) are intermingled within the maternal body. Pipefishes and seahorses (syngnathids) are ideally suited to disentangle transovarial microbial transfer from a contribution during pregnancy due to their maternal egg production and their unique male pregnancy. We assessed the persistency and the changes in the microbial communities of the maternal and paternal reproductive tracts over proceeding male pregnancy by sequencing microbial 16S rRNA genes of swabs from maternal gonads and brood pouches of non-pregnant and pregnant fathers. Applying parental immunological activation with heat-killed bacteria, we evaluated the impact of parental immunological status on microbial development. Our data indicate that maternal gonads and paternal brood pouches harbor distinct microbial communities, which could affect embryonal development in a sex-specific manner. Upon activation of the immune system, a shift of the microbial community was observed. The activation of the immune system induced the expansion of microbiota richness during late pregnancy, which corresponds to the time point of larval mouth opening, when initial microbial colonization must take place. [ABSTRACT FROM AUTHOR]

Virus discovery by genomics and metagenomics empowered studies of viromes, facilitated characterization of pathogen epidemiology, and redefined our understanding of the natural genetic diversity of viruses with profound functional and structural implications. Here we employed a data-driven virus discovery approach that directly queries unprocessed sequencing data in a highly parallelized way and involves a targeted viral genome assembly strategy in a wide range of sequence similarity. By screening more than 269,000 datasets of numerous authors from the Sequence Read Archive and using two metrics that quantitatively assess assembly quality, we discovered 40 nidoviruses from six virus families whose members infect vertebrate hosts. They form 13 and 32 putative viral subfamilies and genera, respectively, and include 11 coronaviruses with bisegmented genomes from fishes and amphibians, a giant 36.1 kilobase coronavirus genome with a duplicated spike glycoprotein (S) gene, 11 tobaniviruses and 17 additional corona-, arteri-, cremega-, nanhypo- and nangoshaviruses. Genome segmentation emerged in a single evolutionary event in the monophyletic lineage encompassing the subfamily Pitovirinae. We recovered the bisegmented genome sequences of two coronaviruses from RNA samples of 69 infected fishes and validated the presence of poly(A) tails at both segments using 3'RACE PCR and subsequent Sanger sequencing. We report a genetic linkage between accessory and structural proteins whose phylogenetic relationships and evolutionary distances are incongruent with the phylogeny of replicase proteins. We rationalize these observations in a model of inter-family S recombination involving at least five ancestral corona- and tobaniviruses of aquatic hosts. In support of this model, we describe an individual fish co-infected with members from the families Coronaviridae and Tobaniviridae. Our results expand the scale of the known extraordinary evolutionary plasticity in nidoviral genome architecture and call for revisiting fundamentals of genome expression, virus particle biology, host range and ecology of vertebrate nidoviruses. Author summary: Research in virology is primarily motivated by human pathogens, such as SARS-CoV-2 in the case of the family Coronaviridae in the order Nidovirales. Studies of these and few model viruses describe virus-host interactions on the molecular level and are essential for developing virus control measures, but they must accommodate a vast range of viral natural diversity to allow generalizations. Here, we redefine our understanding of the genetic and genomic diversity in corona- and other nidoviruses of poorly sampled hosts. We mine more than 269,000 publicly accessible raw sequencing datasets for the presence of viral sequences using high-performance computing and discover 40 nidoviruses including 13 coronaviruses from a wide range of vertebrates. Some of the novel viruses from aquatic hosts have extraordinary features such as segmented genomes and recombinant genes coding for structural proteins. Our study suggests that gene exchange between diverse nidovirus species from different virus families might be more frequent than previously thought and can result in abrupt genomic innovations that in turn might facilitate host jumps even across vertebrate class borders. The growing list of newly discovered (corona)viruses enables an evolutionary perspective across virus divergency scales in different hosts on the wet lab-acquired knowledge about few viruses. [ABSTRACT FROM AUTHOR]

Early life microbial colonizers shape and support the immature vertebrate immune system. Microbial colonization relies on the vertical route via parental provisioning and the horizontal route via environmental contribution. Vertical transmission is mostly a maternal trait making it hard to determine the source of microbial colonization in order to gain insight into the establishment of the microbial community during crucial development stages. The evolution of unique male pregnancy in pipefishes and seahorses enables the disentanglement of both horizontal and vertical transmission, but also facilitates the differentiation of maternal versus paternal provisioning ranging from egg development, to male pregnancy and early juvenile development. Using 16S rRNA amplicon sequencing and source-tracker analyses, we revealed how the distinct origins of transmission (maternal, paternal and horizontal) shaped the juvenile internal and external microbiome establishment in the broad-nosed pipefish Syngnathus typhle. Our data suggest that transovarial maternal microbial contribution influences the establishment of the juvenile gut microbiome whereas paternal provisioning mainly shapes the juvenile external microbiome. The identification of juvenile key microbes reveals crucial temporal shifts in microbial development and enhances our understanding of microbial transmission routes, colonization dynamics and their impact on lifestyle evolution. [ABSTRACT FROM AUTHOR]

The unique male pregnancy in pipefishes and seahorses ranges from basic attachment (pouch‐less species: Nerophinae) of maternal eggs to specialized internal gestation in pouched species (e.g. Syngnathus and Hippocampus) with many transitions in between. Due to this diversity, male pregnancy offers a unique platform for assessing physiological and molecular adaptations in pregnancy evolution. These insights will contribute to answering long‐standing questions of why and how pregnancy evolved convergently in so many vertebrate systems. To understand the molecular congruencies and disparities in male pregnancy evolution, we compared transcriptome‐wide differentially expressed genes in four syngnathid species, at four pregnancy stages (nonpregnant, early, late and parturition). Across all species and pregnancy forms, metabolic processes and immune dynamics defined pregnancy stages, especially pouched species shared expression features akin to female pregnancy. The observed downregulation of adaptive immune genes in early‐stage pregnancy and its reversed upregulation during late/parturition in pouched species, most notably in Hippocampus, combined with directionless expression in the pouch‐less species, suggests immune modulation to be restricted to pouched species that evolved placenta‐like systems. We propose that increased foeto‐paternal intimacy in pouched syngnathids commands immune suppression processes in early gestation, and that the elevated immune response during parturition coincides with pouch opening and reduced progeny reliance. Immune response regulation in pouched species supports the recently described functional MHC II pathway loss as critical in male pregnancy evolution. The independent co‐option of similar genes and pathways both in male and female pregnancy highlights immune modulation as crucial for the evolutionary establishment of pregnancy. see also the Perspective by Nuno Monteiro. [ABSTRACT FROM AUTHOR]

Pathogens vary strikingly in their virulence and the selection they impose on their hosts. While the evolution of different virulence levels is well studied, the evolution of host resistance in response to different virulence levels is less understood and, at present, mainly based on observations and theoretical predictions with few experimental tests. Increased virulence can increase selection for host resistance evolution if the benefits of avoiding infection outweigh resistance costs. To test this, we experimentally evolved the bacterium Vibrio alginolyticus in the presence of two variants of a filamentous phage that differ in their virulence. The bacterial host exhibited two alternative defence strategies: (1) super infection exclusion (SIE), whereby phage-infected cells were immune to subsequent infection at the cost of reduced growth, and (2) surface receptor mutations (SRM), providing resistance to infection by preventing phage attachment. While SIE emerged rapidly against both phages, SRM evolved faster against the high- than the low-virulence phage. Using a mathematical model of our system, we show that increasing virulence strengthens selection for SRM owing to the higher costs of infection suffered by SIE immune hosts. Thus, by accelerating the evolution of host resistance, more virulent phages caused shorter epidemics. [ABSTRACT FROM AUTHOR]

Gene flow shapes spatial genetic structure and the potential for local adaptation. Among marine animals with nonmigratory adults, the presence or absence of a pelagic larval stage is thought to be a key determinant in shaping gene flow and the genetic structure of populations. In addition, the spatial distribution of suitable habitats is expected to influence the distribution of biological populations and their connectivity patterns. We used whole genome sequencing to study demographic history and reduced representation (double‐digest restriction associated DNA) sequencing data to analyse spatial genetic structure in broadnosed pipefish (Syngnathus typhle). Its main habitat is eelgrass beds, which are patchily distributed along the study area in southern Norway. Demographic connectivity among populations was inferred from long‐term (~30‐year) population counts that uncovered a rapid decline in spatial correlations in abundance with distance as short as ~2 km. These findings were contrasted with data for two other fish species that have a pelagic larval stage (corkwing wrasse, Symphodus melops; black goby, Gobius niger). For these latter species, we found wider spatial scales of connectivity and weaker genetic isolation‐by‐distance patterns, except where both species experienced a strong barrier to gene flow, seemingly due to lack of suitable habitat. Our findings verify expectations that a fragmented habitat and absence of a pelagic larval stage promote genetic structure, while presence of a pelagic larvae stage increases demographic connectivity and gene flow, except perhaps over extensive habitat gaps. [ABSTRACT FROM AUTHOR]

Abstract: Understanding UO2 matrix dissolution is of major importance for the safety assessment of a future deep geological repository. Oxidative dissolution of UO2 and SIMFUEL pellets have been extensively studied in solutions, while less is known about systems with no or very low concentrations. The aim of this work is to elucidate the oxidative dissolution of UO2 and SIMFUEL pellets in free solutions by studying the dissolution of U (VI) and consumption of H2O2 over time. The results are compared with previous experiments performed in solutions. The oxidative dissolution rate is higher for the UO2 pellet in compared to the other systems. It is evident that the kinetics of the reaction with H2O2 is qualitatively different for SIMFUEL in comparison with pure UO2. For the UO2 pellet in pure water, the presence of a secondary phase (meta) studtite, on the surface of the pellet is confirmed by Raman spectroscopy. The kinetic impact of the secondary phase is evaluated in separate UO2 powder experiments. The (meta) studtite (surface) precipitation leads to a slower release of uranium into the solution. Numerical simulations using experimentally determined rate constants are used to evaluate a simple mechanism of surface precipitation. The numerical results are in fair agreement with the experimental observations given certain criteria. In addition, the γ-radiation induced dissolution of UO2 and SIMFUEL pellets were investigated in pure water, and compared with systems. Also here the dissolution rate of uranium is higher for UO2 in compared to pure water, while for SIMFUEL longer irradiation times are needed to observe any difference between pure and containing water. [Copyright &y& Elsevier]

Abstract: Oxidative dissolution of spent nuclear fuel is an important issue in the safety assessment of a future geological repository for spent nuclear fuel. Although UO2 constitutes, in terms of mass, the majority of the spent fuel material, its main radiotoxicity is (after extended storage times) contained in actinides with half lives shorter than that of 238-uranium, such as isotopes of Np and Pu. Relatively little information is available on the dissolution behavior of Np and Pu in comparable environments. This work investigates the oxidative dissolution of NpO2 and PuO2 in non-complexing aqueous solutions containing H2O2 and compares their behavior with that of UO2. We have found that oxidative dissolution takes place for all three actinides in the presence of H2O2. Based on the obtained dissolution rates, we would not expect the dissolution of the actinides to be congruent. Instead, in a system without complexing agent, the release rates of Np and Pu are expected to be lower than the U release rate. [Copyright &y& Elsevier]

Evolutionary adaptations in the Syngnathidae teleost family (seahorses, pipefish and seadragons) culminated in an array of spectacular morphologies, key immune gene losses, and the enigmatic male pregnancy. In seahorses, genome modifications associated with immunoglobulins, complement, and major histocompatibility complex (MHC II) pathway components raise questions concerning their immunological efficiency and the evolution of compensatory measures that may act in their place. In this investigation heat-killed bacteria (Vibrio aestuarianus and Tenacibaculum maritimum) were used in a two-phased experiment to assess the immune response dynamics of Hippocampus erectus. Gill transcriptomes from double and single-exposed individuals were analysed in order to determine the differentially expressed genes contributing to immune system responses towards immune priming. Double-exposed individuals exhibited a greater adaptive immune response when compared with single-exposed individuals, while single-exposed individuals, particularly with V. aestuarianus replicates, associated more with the innate branch of the immune system. T. maritimum double-exposed replicates exhibited the strongest immune reaction, likely due to their immunological naivety towards the bacterium, while there are also potential signs of innate trained immunity. MHC II upregulated expression was identified in selected V. aestuarianus -exposed seahorses, in the absence of other pathway constituents suggesting a possible alternative or non-classical MHC II immune function in seahorses. Gene Ontology (GO) enrichment analysis highlighted prominent angiogenesis activity following secondary exposure, which could be linked to an adaptive immune process in seahorses. This investigation highlights the prominent role of T-cell mediated adaptive immune responses in seahorses when exposed to sequential foreign bacteria exposures. If classical MHC II pathway function has been lost, innate trained immunity in syngnathids could be a potential compensatory mechanism. • Transcriptomic immune response assessments in seahorse (Hippocampus erectus). • Seahorses exposed in two phases to heat-killed Vibrio and Tenacibaculum strains. • Adaptive immune memory evidence (double-exposed) and increased naivety to Tenacibaculum. • Upregulated gene expression pertaining to potential innate 'trained immunity'. • Trained immunity potential compensator for deduced MHC II loss of function. [ABSTRACT FROM AUTHOR]

Abstract: The stability of UO2 spent nuclear fuel in an oxygen-free geological repository depends on the absence of oxidizing reaction partners in the near field. This work investigates the reactions between the products of water radiolysis by alpha radiation and Fe(II) an the effect on UO2 dissolution. Solid 238PuO2 powder and UO2 pellet were allowed to react in Fe(II) solution in oxygen-free batch reactor tests and kinetics of the subsequent redox reactions were measured. Depending on the concentration of Fe(II) (tests with 10−5 and 10−4 molL−1 were made), the induced redox reactions took place between 20 and 400h. Dissolved uranium concentrations went first through a minimum caused by reduction, followed by a maximum caused by radiolytic oxidation, and eventually reached another minimum, probably due to sorption on precipitated Fe(III). Plutonium concentrations were decreasing steadily after going through a maximum about 70h from the start of the experiments. The results show that in the presence of the strong alpha-radiolytic field induced by the presence of solid 238Pu, the behavior of the system is largely governed by Fe(II) as it controls the H2O2 concentration, reduces U(VI) in solution and drives the Fenton reaction leading to the oxidation of Pu(IV). [Copyright &y& Elsevier]

Infections by filamentous phages, which are usually nonlethal to the bacterial cells, influence bacterial fitness in various ways. While phage-encoded accessory genes, for example virulence genes, can be highly beneficial, the production of viral particles is energetically costly and often reduces bacterial growth. Consequently, if costs outweigh benefits, bacteria evolve resistance, which can shorten phage epidemics. Abiotic conditions are known to influence the net-fitness effect for infected bacteria. Their impact on the dynamics and trajectories of host resistance evolution, however, remains yet unknown. To address this, we experimentally evolved the bacterium Vibrio alginolyticus in the presence of a filamentous phage at three different salinity levels, that is (1) ambient, (2) 50% reduction and (3) fluctuations between reduced and ambient. In all three salinities, bacteria rapidly acquired resistance through super infection exclusion (SIE), whereby phage-infected cells acquired immunity at the cost of reduced growth. Over time, SIE was gradually replaced by evolutionary fitter surface receptor mutants (SRM). This replacement was significantly faster at ambient and fluctuating conditions compared with the low saline environment. Our experimentally parameterized mathematical model explains that suboptimal environmental conditions, in which bacterial growth is slower, slow down phage resistance evolution ultimately prolonging phage epidemics. Our results may explain the high prevalence of filamentous phages in natural environments where bacteria are frequently exposed to suboptimal conditions and constantly shifting selections regimes. Thus, our future ocean may favour the emergence of phage-born pathogenic bacteria and impose a greater risk for disease outbreaks, impacting not only marine animals but also humans., (© 2023 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Sexual dimorphism, the divergence in morphological traits between males and females of the same species, is often accompanied by sex-biased gene expression. However, the majority of research has focused on species with conventional sex roles, where females have the highest energy burden with both egg production and parental care, neglecting the diversity of reproductive roles found in nature. We investigated sex-biased gene expression in Syngnathus typhle , a sex-role reversed species with male pregnancy, allowing us to separate two female traits: egg production and parental care. Using RNA sequencing, we examined gene expression across organs (brain, head kidney and gonads) at various life stages, encompassing differences in age, sex and reproductive status. While some gene groups were more strongly associated with sex roles, such as stress resistance and immune defence, others were driven by biological sex, such as energy and lipid storage regulation in an organ- and age-specific manner. By investigating how genes regulate and are regulated by changing reproductive roles and resource allocation in a model system with an unconventional life-history strategy, we aim to better understand the importance of sex and sex role in regulating gene expression patterns, broadening the scope of this discussion to encompass a wide range of organisms., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors.)

Although sex and gender are recognized as major determinants of health and immunity, their role is rarely considered in clinical practice and public health. We identified six bottlenecks preventing the inclusion of sex and gender considerations from basic science to clinical practice, precision medicine and public health policies. (i) A terminology-related bottleneck, linked to the definitions of sex and gender themselves, and the lack of consensus on how to evaluate gender. (ii) A data-related bottleneck, due to gaps in sex-disaggregated data, data on trans/non-binary people and gender identity. (iii) A translational bottleneck, limited by animal models and the underrepresentation of gender minorities in biomedical studies. (iv) A statistical bottleneck, with inappropriate statistical analyses and results interpretation. (v) An ethical bottleneck posed by the underrepresentation of pregnant people and gender minorities in clinical studies. (vi) A structural bottleneck, as systemic bias and discriminations affect not only academic research but also decision makers. We specify guidelines for researchers, scientific journals, funding agencies and academic institutions to address these bottlenecks. Following such guidelines will support the development of more efficient and equitable care strategies for all., Competing Interests: K.A.-P.'s institution has received travel grants and advisory fees from MSD, Gilead and ViiV healthcare unrelated to this work. I.A.A. has received travel grants and advisory fees from Gilead and Sanofi unrelated to this work. R.D.K. has received research fundings from Gilead unrelated to this work., (© 2023 The Authors.)