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Male house mice excrete large amounts of protein in their urinary scent marks, mainly composed of Major Urinary Proteins (MUPs), and these lipocalins function as pheromones and pheromone carriers. Here, we review studies on sexually dimorphic MUP expression in house mice, including the proximate mechanisms controlling MUP gene expression and their adaptive functions. Males excrete 2 to 8 times more urinary protein than females, though there is enormous variation in gene expression across loci in both sexes. MUP expression is dynamically regulated depending upon a variety of factors. Males regulate MUP expression according to social status, whereas females do not, and males regulate expression depending upon health and condition. Male-biased MUP expression is regulated by pituitary secretion of growth hormone (GH), which binds receptors in the liver, activating the JAK2-STAT5 signaling pathway, chromatin accessibility, and MUP gene transcription. Pulsatile male GH secretion is feminized by several factors, including caloric restriction, microbiota depletion, and aging, which helps explain condition-dependent MUP expression. If MUP production has sex-specific fitness optima, then this should generate sexual antagonism over allelic expression (intra-locus sexual conflict) selectively favoring sexually dimorphic expression. MUPs influence the sexual attractiveness of male urinary odor and increased urinary protein excretion is correlated with the reproductive success of males but not females. This finding could explain the selective maintenance of sexually dimorphic MUP expression. Producing MUPs entails energetic costs, but increased excretion may reduce the net energetic costs and predation risks from male scent marking as well as prolong the release of chemical signals. MUPs may also provide physiological benefits, including regulating metabolic rate and toxin removal, which may have sex-specific effects on survival. A phylogenetic analysis on the origins of male-biased MUP gene expression in Mus musculus suggests that this sexual dimorphism evolved by increasing male MUP expression rather than reducing female expression.

Male house mice excrete large amounts of protein in their urinary scent marks, mainly composed of Major Urinary Proteins (MUPs), and these lipocalins function as pheromones and pheromone carriers. Here, we review studies on sexually dimorphic MUP expression in house mice, including the proximate mechanisms controlling MUP gene expression and their adaptive functions. Males excrete 2 to 8 times more urinary protein than females, though there is enormous variation in gene expression across loci in both sexes. MUP expression is dynamically regulated depending upon a variety of factors. Males regulate MUP expression according to social status, whereas females do not, and males regulate expression depending upon health and condition. Male-biased MUP expression is regulated by pituitary secretion of growth hormone (GH), which binds receptors in the liver, activating the JAK2-STAT5 signaling pathway, chromatin accessibility, and MUP gene transcription. Pulsatile male GH secretion is feminized by several factors, including caloric restriction, microbiota depletion, and aging, which helps explain condition-dependent MUP expression. If MUP production has sex-specific fitness optima, then this should generate sexual antagonism over allelic expression (intra-locus sexual conflict) selectively favoring sexually dimorphic expression. MUPs influence the sexual attractiveness of male urinary odor and increased urinary protein excretion is correlated with the reproductive success of males but not females. This finding could explain the selective maintenance of sexually dimorphic MUP expression. Producing MUPs entails energetic costs, but increased excretion may reduce the net energetic costs and predation risks from male scent marking as well as prolong the release of chemical signals. MUPs may also provide physiological benefits, including regulating metabolic rate and toxin removal, which may have sex-specific effects on survival. A phylogenetic analysis on the origins of male-biased MUP gene expression in Mus musculus suggests that this sexual dimorphism evolved by increasing male MUP expression rather than reducing female expression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Penn, Zala and Luzynski.)

ABSTRACTThe gut microbiota is shaped by host metabolism. In house mice (Mus musculus), major urinary protein (MUP) pheromone production represents a considerable energy investment, particularly in sexually mature males. Deletion of the Mup gene family shifts mouse metabolism toward an anabolic state, marked by lipogenesis, lipid accumulation, and body mass increases. Given the metabolic implications of MUPs, they may also influence the gut microbiota. Here, we investigated the effect of a deletion of the Mup gene family on the gut microbiota of sexually mature mice. Shotgun metagenomics revealed distinct taxonomic and functional profiles between wild-type and knockout males but not females. Deletion of the Mup gene cluster significantly reduced diversity in microbial families and functions in male mice. Additionally, a species of Ruminococcaceae and several microbial functions, such as transporters involved in vitamin B5 acquisition, were significantly depleted in the microbiota of Mup knockout males. Altogether, these results show that MUPs significantly affect the gut microbiota of house mouse in a sex-specific manner.IMPORTANCEThe community of microorganisms that inhabits the gastrointestinal tract can have profound effects on host phenotypes. The gut microbiota is in turn shaped by host genes, including those involved with host metabolism. In adult male house mice, expression of the major urinary protein (Mup) gene cluster represents a substantial energy investment, and deletion of the Mup gene family leads to fat accumulation and weight gain in males. We show that deleting Mup genes also alters the gut microbiota of male, but not female, mice in terms of both taxonomic and functional compositions. Male mice without Mup genes harbored fewer gut bacterial families and reduced abundance of a species of Ruminococcaceae, a family that has been previously shown to reduce obesity risk. Studying the impact of the Mup gene family on the gut microbiota has the potential to reveal the ways in which these genes affect host phenotypes.

Major urinary proteins (MUPs), members of the broader lipocalin protein family, are classified as pheromones that are excreted in male rodent urine to define conspecific territoriality. In screening for differentially regulated mRNA transcripts in a mouse model of type 1 experimental diabetes mellitus (DM), we identified an unexpected upregulation of several closely related MUP transcripts within diabetic sensory dorsal root ganglia (DRG). Both sexes expressed overall MUP protein content as identified by an antibody widely targeting these upregulated family members, and immunohistochemistry identified expression within neurons, satellite glial cells, and Schwann cells. In dissociated adult sensory neurons, knockdown by an siRNA targeting upregulated MUP mRNAs, enhanced neurite outgrowth, indicating a growth-suppressive role, an impact that was synergistic with subnanomolar insulin neuronal signaling. While MUP knockdown did not generate rises in insulin signaling transcripts, the protein did bind to several mitochondrial and glial targets in DRG lysates. Analysis of a protein closely related to MUPs but that is expressed in humans, lipocalin-2, also suppressed growth, but its impact was unrelated to insulin. In a model of chronic type 1 DM, MUP siRNA knockdown improved electrophysiological and behavioral abnormalities of experimental neuropathy. MUPs have actions beyond pheromone signaling in rodents that involve suppression of growth plasticity of sensory neurons. Its hitherto unanticipated actions overlap with those of lipocalin-2 and may identify a common and widely mediated impact on neuron growth properties by members of the lipocalin family. Knockdown of MUP supports the trophic actions of insulin as a strategy that may improve features of type 1 experimental diabetic neuropathy. [ABSTRACT FROM AUTHOR]

Chemical communication is important for many social mammals. Scent-related gene clusters have undergone extraordinary expansion in some species, such as the house mouse (Mus musculus). One such family encodes major urinary proteins (MUPs). MUPs can provide recipients with complex information about the signaller and potentially serve as honest signals of social rank. In this study, we examined the development of overall MUP production in two mouse subspecies in the context of establishing their social hierarchy during the critical period between weaning and 100 days of age. We used fraternal pairs as simple social units, where dominant/subordinate ranks were naturally established between two brothers raised together, to test the hypothesis that dominant males of both taxa excrete higher amounts of MUPs in their urine than subordinates. The results were compared to data on ontogeny of steroid hormone levels gathered in the same individuals during an earlier experiment. Higher MUP levels in dominant males were only corroborated in one subspecies (domesticus), whereas musculus males revealed similar MUP quantities irrespective of rank. These results are consistent with the notion that these closely related taxa adopted different strategies for establishing social hierarchy. [ABSTRACT FROM AUTHOR]

The ability to recognize and differentiate between conspecifics and heterospecifics as well as their signals is critical for the coexistence of closely related species. In the genus Rattus , species are morphologically similar and multiple species often coexist. Here, we investigated the interspecific recognition and signal differentiation of two sympatric rat species, the brown rat (Rattus norvegicus , RN) and the Asian house rat (Rattus tanezumi , RT). In a two-way choice test, both RN and RT females showed a preference for conspecific male rats to heterospecific ones. RT females showed a significant preference for accessible urine of males of same species to those of other species, but not for the inaccessible urine. On the other hand, there were significant differences in the structural characteristics of the ultrasonic vocalization emitted by males of these two rat species. Sodium dodecyl sulphate‒polyacrylamide gel electrophoresis (SDS‒PAGE) and isoelectric focusing electrophoresis unveiled that major urinary proteins (MUPs) in voided urine were more highly expressed in RN males versus RT males. The interspecific differences of urinary volatile compounds were also discussed. In conclusion, female rats had the ability to distinguish between males of either species. [ABSTRACT FROM AUTHOR]

Chemical communication is important for many social mammals. Scent-related gene clusters have undergone extraordinary expansion in some species, such as the house mouse (Mus musculus). One such family encodes major urinary proteins (MUPs). MUPs can provide recipients with complex information about the signaller and potentially serve as honest signals of social rank. In this study, we examined the development of overall MUP production in two mouse subspecies in the context of establishing their social hierarchy during the critical period between weaning and 100 days of age. We used fraternal pairs as simple social units, where dominant/subordinate ranks were naturally established between two brothers raised together, to test the hypothesis that dominant males of both taxa excrete higher amounts of MUPs in their urine than subordinates. The results were compared to data on ontogeny of steroid hormone levels gathered in the same individuals during an earlier experiment. Higher MUP levels in dominant males were only corroborated in one subspecies (domesticus), whereas musculus males revealed similar MUP quantities irrespective of rank. These results are consistent with the notion that these closely related taxa adopted different strategies for establishing social hierarchy. [ABSTRACT FROM AUTHOR]

Scientific evidence suggests that not only murine scent communication is regulated by major urinary proteins, but that their expression may also vary in response to metabolism via a yet unknown mechanism. Major urinary proteins are expressed mainly in the liver, showing a sexually dimorphic pattern with substantially higher expression in males. Here, we investigate the metabolic implications of a major urinary protein knockout in twelve-week-old male and female C57BL/6N mice during ad libitum feeding. Despite both sexes of major urinary protein knockout mice displayed numerically increased body weight and visceral adipose tissue proportions compared to sex-matched wildtype mice, the main genotype-specific metabolic differences were observed exclusively in males. Male major urinary protein knockout mice exhibited plasma and hepatic lipid accumulation accompanied by a hepatic transcriptome indicating an activation of lipogenesis. These findings match the higher major urinary protein expression in male compared to female wildtype mice, suggesting a more distinct reduction in energy requirements in male compared to female major urinary protein knockout mice. The observed sex-specific anabolic phenotype confirms a role of major urinary protein in metabolism and, since major urinary proteins are not expressed in humans, suggests the major urinary protein knockout mouse as a potential alternative model for translational metabolism research which needs to be further elucidated. [ABSTRACT FROM AUTHOR]

Pheromones and olfactory communication play vital roles in sex recognition and mate choice in rodents. Asian house rats (Rattus tanezumi) (RT) often startle easily, making behavioral measurements difficult to carry out accurately in the laboratory. Here, the behavioral and olfactory preferences of the female RT between males and females were not observed using a conventional two‐choice device; we then explored the neuro‐immunohistochemical evidence in the brains of RT females. We found that male urine elicited significantly higher c‐fos expression in the accessory olfactory system and sex‐related brain regions in females than female urine did. On the other hand, the differences of volatile compounds and major urinary proteins (MUPs) in both voided urine and preputial glands (PGs) of the RT were detected using gas chromatography–mass spectrometer, sodium dodecyl sulfate‐polyacrylamide gel electrophoresis, isoelectric focusing electrophoresis, and liquid chromatography–electrospray ionization mass spectrometry. We found that PG‐derived 1‐(4,5‐dihydro‐2‐thiazolyl)‐ethanone and total MUPs were more abundant in males versus females, suggesting these sexually divergent components might activate the female's accessory olfactory system. In conclusion, the neuro‐immunohistochemical evidence indicated that potential sex pheromones might exist in RT; however, the strength of the chemical signal might be too weak to cause behavioral responses in females. [ABSTRACT FROM AUTHOR]

Calorie restriction (CR) extends life span by modulating the mechanisms involved in aging. We quantified the hepatic proteome of male C57BL/6 mice exposed to graded levels of CR (0%–40% CR) for 3 months, and evaluated which signaling pathways were most affected. The metabolic pathways most significantly stimulated by the increase in CR, included the glycolysis/gluconeogenesis pathway, the pentose phosphate pathway, the fatty acid degradation pathway, the valine, leucine, and isoleucine degradation pathway, and the lysine degradation pathway. The metabolism of xenobiotics by cytochrome P450 pathway was activated and feminized by increased CR, while production in major urinary proteins (Mups) was strongly reduced, consistent with a reduced investment in reproduction as predicted by the disposable soma hypothesis. However, we found no evidence of increased somatic protection, and none of the 4 main pathways implied to be linked to the impact of CR on life span (insulin/insulin-like growth factor [IGF-1], nuclear factor-κB [NF-κB], mammalian Target of Rapamycin [mTOR], and sirtuins) as well as pathways in cancer, were significantly changed at the protein level in relation to the increase in CR level. This was despite previous work at the transcriptome level in the same individuals indicating such changes. On the other hand, we found Aldh2 , Aldh3a2 , and Aldh9a1 in carnitine biosynthesis and Acsl5 in carnitine shuttle system were up-regulated by increased CR, which are consistent with our previous work on metabolome of the same individuals. Overall, the patterns of protein expression were more consistent with a "clean cupboards" than a "disposable soma" interpretation. [ABSTRACT FROM AUTHOR]

Chemical communication by females remains poorly understood, with most attention focused on female advertisement of sexual receptivity to males or mother--offspring communication. However, in social species, scents are likely to be important for mediating competition and cooperation between females determining individual reproductive success. Here, we explore chemical signaling by female laboratory rats (Rattus norvegicus) to test i) whether females target their deployment of scent information differentially according to their sexual receptivity and the genetic identity of both female and male conspecifics signaling in the local environment and ii) whether females are attracted to gain the same or different information from female scents compared to males. Consistent with targeting of scent information to colony members of similar genetic background, female rats increased scent marking in response to scents from females of the same strain. Females also suppressed scent marking in response to male scent from a genetically foreign strain while sexually receptive. Proteomic analysis of female scent deposits revealed a complex protein profile, contributed from several sources but dominated by clitoral gland secretion. In particular, female scent marks contained a series of clitoral-derived hydrolases and proteolytically truncated major urinary proteins (MUPs). Manipulated blends of clitoral secretion and urine from estrus females were strongly attractive to both sexes, while voided urine alone stimulated no interest. Our study reveals that information about female receptive status is shared between females as well as with males, while clitoral secretions containing a complex set of truncated MUPs and other proteins play a key role in female communication. [ABSTRACT FROM AUTHOR]

Sexual dimorphism is a powerful yet understudied factor that influences the timing and efficiency of gene regulation in axonal injury and repair processes in the peripheral nervous system. Here, we identified common and distinct biological processes in female and male degenerating (distal) nerve stumps based on a snapshot of transcriptional reprogramming 24 h after axotomy reflecting the onset of early phase Wallerian degeneration (WD). Females exhibited transcriptional downregulation of a larger number of genes than males. RhoGDI, ERBB, and ERK5 signaling pathways increased activity in both sexes. Males upregulated genes and canonical pathways that exhibited robust baseline expression in females in both axotomized and sham nerves, including signaling pathways controlled by neuregulin and nerve growth factors. Cholesterol biosynthesis, reelin signaling, and synaptogenesis signaling pathways were downregulated in females. Signaling by Rho Family GTPases, cAMP-mediated signaling, and sulfated glycosaminoglycan biosynthesis were downregulated in both sexes. Estrogens potentially influenced sex-dependent injury response due to distinct regulation of estrogen receptor expression. A crosstalk of cytokines and growth hormones could promote sexually dimorphic transcriptional responses. We highlighted prospective regulatory activities due to protein phosphorylation, extracellular proteolysis, sex chromosome-specific expression, major urinary proteins (MUPs), and genes involved in thyroid hormone metabolism. Combined with our earlier findings in the corresponding dorsal root ganglia (DRG) and regenerating (proximal) nerve stumps, sex-specific and universal early phase molecular triggers of WD enrich our knowledge of transcriptional regulation in peripheral nerve injury and repair. [ABSTRACT FROM AUTHOR]

Mouse wild-derived strains (WDSs) combine the advantages of classical laboratory stocks and wild animals, and thus appear to be promising tools for diverse biomedical and evolutionary studies. We employed 18 WDSs representing three non-synanthropic species (Mus spretus, Mus spicilegus, and M. macedonicus) and three house mouse subspecies (Mus musculus musculus, M. m. domesticus, M. m. castaneus), which are all important human commensals to explore whether the number of major urinary protein (MUP) genes and their final protein levels in urine are correlated with the level of commensalism. Contrary to expectations, the MUP copy number (CN) and protein excretion in the strains derived from M. m. castaneus, which is supposed to be the strongest commensal, were not significantly different from the non-commensal species. Regardless of an overall tendency for higher MUP amounts in taxa with a higher CN, there was no significant correlation at the strain level. Our study thus suggests that expansion of the Mup cluster, which appeared before the house mouse diversification, is unlikely to facilitate commensalism with humans in three house mouse subspecies. Finally, we found considerable variation among con(sub)specific WDSs, warning against generalisations of results based on a few strains. [ABSTRACT FROM AUTHOR]

Reproductive success in mice depends on sexually dimorphic major urinary proteins (Mup) that facilitate interactions between females and males. Deletion of cystathionine β-synthase (Cbs) gene, a metabolic gene important for homeostasis of one-carbon metabolism, impairs reproduction by causing female infertility in mice. Here, we examined Mup biogenesis and sexual signaling in Cbs -/- versus Cbs +/- mice. We found significantly reduced levels of total urinary Mup protein in male and female Cbs -/- versus Cbs +/- mice. SDS-PAGE/Western blot, ESI-MS, and RT-qPCR analyses of the liver, plasma, and urinary proteins identified a male-specific Mup20 in Cbs -/- , but not in Cbs +/- females. The 18 893 Da Mup20 became the most abundant in urine of Cbs -/- females and males. Effects of Cbs genotype on 18 645 Da, 18 693 Da, and 18 709 Da Mup species abundance were Mup- and sex-specific. Cbs genotype-dependent changes in hepatic Mups and Mup20 expression were similar at the protein and mRNA level. Changes in Mups, but not in Mup20, can be explained by downregulation of hepatic Zhx2 and Ghr receptors in Cbs -/- mice. Behavioral testing showed that Cbs +/- females ignored Cbs -/- male urine but were attracted to Cbs +/- male urine. Cbs +/- males ignored urine of Cbs -/- males but countermarked urine of other Cbs +/- males and were attracted to urines of Cbs -/- as well as Cbs +/- females. Cbs -/- males did not countermark urine of Cbs +/- males but were attracted to urines of Cbs +/- females. Taken together, these findings show that Cbs, a metabolic gene, interacts with the processes involved in Mup biogenesis that are essential for the maintenance of sexual dimorphism and signaling and suggest that dysregulation of these interactions impairs reproductive fitness in mice., (© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

For individuals to survive and function in society, it is essential that they recognize, interact with, and learn from other conspecifics. Observational fear (OF) is the well-conserved empathic ability of individuals to understand the other's aversive situation. While it is widely known that factors such as prior similar aversive experience and social familiarity with the demonstrator facilitate OF, the neural circuit mechanisms that explicitly regulate experience-dependent OF (Exp OF) were unclear. In this review, we examine the neural circuit mechanisms that regulate OF, with an emphasis on rodent models, and then discuss emerging evidence for the role of fear memory engram cells in the regulation of Exp OF. First, we examine the neural circuit mechanisms that underlie Naive OF, which is when an observer lacks prior experiences relevant to OF. In particular, the anterior cingulate cortex to basolateral amygdala (BLA) neural circuit is essential for Naive OF. Next, we discuss a recent study that developed a behavioral paradigm in mice to examine the neural circuit mechanisms that underlie Exp OF. This study found that fear memory engram cells in the BLA of observers, which form during a prior similar aversive experience with shock, are reactivated by ventral hippocampal neurons in response to shock delivery to the familiar demonstrator to elicit Exp OF. Finally, we discuss the implications of fear memory engram cells in Exp OF and directions of future research that are of both translational and basic interest., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Abstract Scientific evidence suggests that not only murine scent communication is regulated by major urinary proteins, but that their expression may also vary in response to metabolism via a yet unknown mechanism. Major urinary proteins are expressed mainly in the liver, showing a sexually dimorphic pattern with substantially higher expression in males. Here, we investigate the metabolic implications of a major urinary protein knockout in twelve-week-old male and female C57BL/6N mice during ad libitum feeding. Despite both sexes of major urinary protein knockout mice displayed numerically increased body weight and visceral adipose tissue proportions compared to sex-matched wildtype mice, the main genotype-specific metabolic differences were observed exclusively in males. Male major urinary protein knockout mice exhibited plasma and hepatic lipid accumulation accompanied by a hepatic transcriptome indicating an activation of lipogenesis. These findings match the higher major urinary protein expression in male compared to female wildtype mice, suggesting a more distinct reduction in energy requirements in male compared to female major urinary protein knockout mice. The observed sex-specific anabolic phenotype confirms a role of major urinary protein in metabolism and, since major urinary proteins are not expressed in humans, suggests the major urinary protein knockout mouse as a potential alternative model for translational metabolism research which needs to be further elucidated.

Chemical signaling through pheromones is an ancient and widespread mode of communication. Turtles and tortoises (chelonians) secrete pheromones via mental (chin) glands and have superior olfactory capacities rendering them a promising group to study the evolution and function of chemical communication in vertebrates. Here, we use state-of-the art proteomics and lipidomics techniques to identify and explore the possible functions of proteins and lipids secreted by mental glands in turtles. We examined four turtle species all from the family Geoemydidae, to understand among-species as well as sexual variation in the composition of mental gland secretions. Differential expression of a relatively small number (ca. 65) of proteins explained a large portion of the proteome variation across species, highlighting the existence of specific signals evolving even in closely related species. Lipidomic analysis revealed high inter-individual variation, but species differences could be attributed to five different lipid classes. The lipids found in mental glands could have a dietary origin or be related to individual condition, but may nonetheless be used in communication. We also examined sex-specific differences in the proteome of a single species (Mauremys leprosa) and found that males expressed a much larger array of proteins than females. Our findings establish a group of candidate proteins potentially involved in chemical signaling in freshwater geoemydid turtles. Alternatively, differently expressed proteins in mental glands could have an indirect link to chemical communication, being involved in pheromone transport and/or antioxidant protection. [ABSTRACT FROM AUTHOR]

Proximal tubule endocytosis is essential to produce protein-free urine as well as to regulate system-wide metabolic pathways, such as the activation of Vitamin D. We have determined that the proximal tubule expresses an endolysosomal membrane protein, protein spinster homolog1 (Spns1), which engenders a novel iron conductance that is indispensable during embryonic development. Conditional knockout of Spns1 with a novel Cre-LoxP construct specific to megalin-expressing cells led to the arrest of megalin receptor-mediated endocytosis as well as dextran pinocytosis in proximal tubules. The endocytic defect was accompanied by changes in megalin phosphorylation as well as enlargement of lysosomes, confirming previous findings in Drosophila and Zebrafish. The endocytic defect was also accompanied by iron overload in proximal tubules. Remarkably, iron levels regulated the Spns1 phenotypes because feeding an iron-deficient diet or mating Spns1 knockout with divalent metal transporter1 knockout rescued the phenotypes. Conversely, iron-loading wild-type mice reproduced the endocytic defect. These data demonstrate a reversible, negative feedback for apical endocytosis and raise the possibility that regulation of endocytosis, pinocytosis, megalin activation, and organellar size and function is nutrient-responsive. NEW & NOTEWORTHY: Spns1 mediates a novel iron conductance essential during embryogenesis. Spns1 knockout leads to endocytic and lysosomal defects, accompanied by iron overload in the kidney. Reversal of iron overload by restricting dietary iron or by concurrent knockout of the iron transporter, DMT1 rescued the endocytic and organellar defects and reverted markers of iron overload. These data suggest feedback between iron and proximal tubule endocytosis. [ABSTRACT FROM AUTHOR]

Kin discrimination, the differential treatment of conspecifics based on kinship, occurs across the tree of life, from animals to plants to fungi to bacteria. When kin and nonkin interact, the ability to identify kin enables individuals to increase their inclusive fitness by helping kin, harming nonkin, and avoiding inbreeding. For a given species, the strength of selection for kin discrimination mechanisms is influenced by demographic, ecological, and life-history processes that collectively determine the scope for discrimination and the payoffs from kin-biased behavior. In this review, we explore how these processes drive variation in kin discrimination across taxa, highlighting contributions of recent empirical, comparative, and theoretical work to our understanding of when, how, and why kin discrimination evolves. [ABSTRACT FROM AUTHOR]

The characterization of genes and biological functions underlying functional diversification and the formation of species is a major goal of evolutionary biology. In this study, we investigated the fast radiation of Microtus voles, one of the most speciose group of mammals, which shows strong genetic divergence despite few readily observable morphological differences. We produced an annotated reference genome for the common vole, Microtus arvalis , and resequenced the genomes of 10 different species and evolutionary lineages spanning the Microtus speciation continuum. Our full-genome sequences illustrate the recent and fast diversification of this group, and we identified genes in highly divergent genomic windows that have likely particular roles in their radiation. We found three biological functions enriched for highly divergent genes in most Microtus species and lineages: olfaction, immunity and metabolism. In particular, olfaction-related genes (mostly olfactory receptors and vomeronasal receptors) are fast evolving in all Microtus species indicating the exceptional importance of the olfactory system in the evolution of these rodents. Of note is e.g. the shared signature among vole species on Olfr1019 which has been associated with fear responses against predator odors in rodents. Our analyses provide a genome-wide basis for the further characterization of the ecological factors and processes of natural and sexual selection that have contributed to the fast radiation of Microtus voles. [ABSTRACT FROM AUTHOR]

Nanomedicine holds great potential for revolutionizing medical treatment. Ongoing research and advancements in nanotechnology are continuously expanding the possibilities, promising significant advancements in healthcare. To fully harness the potential of nanotechnology in medical applications, it is crucial to conduct safety evaluations for the nanomedicines that offer effective benefits in the preclinical stage. Our recent efficacy studies indicated that rapamycin perfluorocarbon (PFC) nanoparticles showed promise in mitigating cisplatin-induced acute kidney injury (AKI). As cisplatin is routinely administered to ovarian cancer patients as their first-line chemotherapy, in this study, we focused on evaluating the safety of rapamycin PFC nanoparticles in mice bearing ovarian tumor xenografts. Specifically, this study evaluated the effects of repeat-dose rapamycin PFC nanoparticle treatment on vital organs, the immune system, and tumor growth and assessed pharmacokinetics and biodistribution. Our results indicated that rapamycin PFC nanoparticle treatment did not cause any detectable adverse effects on cardiac, renal, or hepatic functions or on splenocyte populations, but it reduced the splenocyte secretion of IL-10, TNFα, and IL12p70 upon IgM stimulation. The pharmacokinetics and biodistribution results revealed a significant enhancement in the delivery of rapamycin to tumors by rapamycin PFC nanoparticles, which, in turn, led to a significant reduction in ovarian tumor growth. Therefore, rapamycin PFC nanoparticles have the potential to be clinically beneficial in cisplatin-treated ovarian cancer patients. [ABSTRACT FROM AUTHOR]

Introduction: Up to 40% of patients with typical hemolytic-uremic syndrome (HUS), characterized by microangiopathic hemolytic anemia and acute kidney injury (AKI), develop long-term consequences, most prominently chronic kidney disease (CKD). The transition from AKI to CKD, particularly in the context of HUS, is not yet fully understood. The objective of this study was to establish and characterize a Shiga toxin (Stx)-induced long-term HUS model to facilitate the study of mechanisms underlying the AKI-to-CKD transition. Methods: C57BL/6J mice were subjected to 5, 10, 15, or 20 ng/kg Stx on days 0, 3, and 6 of the experiment and were sacrificed on day 14 or day 21 to identify the critical time of turnover from the acute to the chronic state of HUS disease. Results: Acute disease, indicated by weight loss, plasma neutrophil gelatinaseassociated lipocalin (NGAL) and urea, and renal neutrophils, diminished after 14 days and returned to sham level after 21 days. HUS-associated hemolytic anemia transitioned to non-hemolytic microcytic anemia along with unchanged erythropoietin levels after 21 days. Renal cytokine levels indicated a shift towards pro-fibrotic signaling, and interstitial fibrosis developed concentration-dependently after 21 days. While Stx induced the intrarenal invasion of pro-inflammatory M1 and pro-fibrotic M2 macrophages after 14 days, pro-fibrotic M2 macrophages were the dominant phenotype after 21 days. Conclusion: In conclusion, we established and characterized the first Stxinduced long-term model of HUS. This tool facilitates the study of underlying mechanisms in the early AKI-to-CKD transition following HUS and allows the testing of compounds that may protect patients with AKI from developing subsequent CKD. [ABSTRACT FROM AUTHOR]

Across taxa, breeding among close relatives is usually avoided because it incurs fitness costs to offspring. Incest is often averted through the dispersal of either sex from the natal area to breed. In some philopatric species, association among relatives extends into adulthood, and an ability to discriminate kin may be required for individuals to reduce inbreeding risk. Here, we aim to determine the mechanism of kin recognition for incest avoidance in the Damaraland mole-rat Fukomys damarensis, a cooperative breeder characterized by extreme reproductive skew. Pairs of opposite-sex adults were formed in the laboratory and, within pairs, genetic relatedness and degree of familiarity were manipulated through cross-fostering experiments. We found that unfamiliar pairs were more likely to engage in sexual behaviours and bred more successfully than familiar pairs, regardless of their genetic similarity. Females paired with unfamiliar males were also more likely to exhibit reproductive activation, characterized by increased levels of oestradiol and progesterone. This study shows that in Damaraland mole-rats, inbreeding avoidance can be achieved through a discrimination mechanism that relies on association during rearing, and that ovulation is induced by mating. This study advances our understanding of incest avoidance in species with constrained dispersal. [ABSTRACT FROM AUTHOR]

Purpose: Hepatocellular carcinoma (HCC) related to metabolic dysfunction-associated steatotic liver disease (MASLD) is often diagnosed at a late stage, and its incidence is increasing. Predictive biomarkers are therefore needed to identify individuals at high risk of HCC. We aimed to characterize the gut microbiome and hepatic transcriptome associated with HCC development in female mice with hepatocyte-deletion of Pten (HepPten−). These mice present with large variations in HCC development, making them a powerful model for biomarker discovery. Methods & Results: Sequencing of stool 16S and hepatic RNA was performed on a first set of mice. Among all liver histology parameters measured, the strongest association with microbiome composition changes was with the number of tumors detected at necropsy, followed by inflammation. The gut microbiome of mice with more than 2 tumors was enriched with Lachnospiraceae UCG and depleted of Palleniella intestinalis and Odoribacter. In contrast, hepatic transcriptomic changes were most strongly associated with tumor burden, followed by liver fibrosis. The 840 differentially expressed genes correlating with tumor burden were enriched in leukocyte extravasation and interleukin 10 receptor A (IL10RA) pathways. In addition, the abundance of Spp1-high epithelial cells is correlated with tumor burden. Association between tumor number and depletion of Palleniella intestinalis, and between tumor burden and circulating levels of C-X-C motif chemokine ligand 13 (CXCL13) and stem cell factor (SCF), was further validated in an independent set of mice. Conclusion: We identified microbiome components contributing to liver carcinogenesis by inducing inflammation, and changes in hepatic gene expression and hepatic cells distribution that contribute to tumor growth. Such information can be highly valuable for the development of new prevention strategies as well as of new biomarkers for risk modeling in HCC. [ABSTRACT FROM AUTHOR]

Relationships between adult females are fundamental to understanding diversity in animal social systems. While cooperative relationships between kin are known to promote fitness benefits, the proximate mechanisms underlying this are not well understood. Here we show that when related female house mice (Mus musculus domesticus) cooperate to rear young communally, those with higher endogenous oxytocin levels have more egalitarian and successful cooperative relationships. Sisters with higher oxytocin concentrations in the paraventricular nucleus (PVN) of the hypothalamus weaned significantly more offspring, had lower reproductive skew and spent more equal proportions of time in the nest. By contrast, PVN oxytocin was unrelated to the number of weaned offspring produced in the absence of cooperation, and did not vary in response to manipulation of nest site availability or social cues of outgroup competition. By linking fitness consequences of cooperation with oxytocin, our findings have broad implications for understanding the evolution of egalitarian social relationships. Fitness consequences of communal breeding suggest a role for oxytocin in the evolution of egalitarian social relationships - cooperating sisters with higher hypothalamic oxytocin levels have more equal and greater combined reproductive success. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease (NAFLD) is a type of liver metabolic syndrome. Employing multi-omics analyses encompassing the microbiome, metabolome and transcriptome is crucial for comprehensively elucidating the biological processes underlying NAFLD. Methods: Hepatic tissue, blood and fecal samples were obtained from 9 NAFLD model mice and 8 normal control mice. Total fecal microbiota DNA was extracted, and 16S rRNA was amplified, to analyze alterations in the gut microbiota (GM) induced by NAFLD. Subsequently, diagnostic strains for NAFLD were screened, and their functional aspects were examined. Differential metabolites and differentially expressed genes were also screened, followed by enrichment analysis. Correlations between the differential microbiota and metabolites, as well as between the DEGs and differential metabolites were studied. A collinear network involving key genes-, microbiota-and metabolites was constructed. Results: Ileibacterium and Ruminococcaceae, both belonging to Firmicutes; Olsenella, Duncaniella and Paramuribaculum from Bacteroidota; and Bifidobacterium, Coriobacteriaceae_UCG_002 and Olsenella from Actinobacteriota were identified as characteristic strains associated with NAFLD. Additionally, differentially expressed metabolites were predominantly enriched in tryptophan, linoleic acid and methylhistidine metabolism pathways. The functions of 2,510 differentially expressed genes were found to be associated with disease occurrence. Furthermore, a network comprising 8 key strains, 14 key genes and 83 key metabolites was constructed. Conclusion: Through this study, we conducted a comprehensive analysis of NAFLD alterations, exploring the gut microbiota, genes and metabolites of the results offer insights into the speculated biological mechanisms underlying NAFLD. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic fatty liver disease (NAFLD) constitutes an independent risk factor for the development of coronary heart disease. Low-grade inflammation has been shown to play an important role in the development of atherosclerosis and NAFLD. Free fatty acid receptor 4 (FFAR4/GPR120), which is involved in damping inflammatory reactions, may represent a promising target for the treatment of inflammatory diseases. Our objective was to evaluate the effect of TUG-891, the synthetic agonist of FFAR4/GPR120, on fatty liver in vivo. Methods: The effect of TUG-891 on fatty liver was investigated in apoE−/− mice fed a high-fat diet (HFD), using microscopic, biochemical, molecular, and proteomic methods. Results: Treatment with TUG-891 inhibited the progression of liver steatosis in apoE−/− mice, as evidenced by histological analysis, and reduced the accumulation of TG in the liver. This action was associated with a decrease in plasma AST levels. TUG-891 decreased the expression of liver genes and proteins involved in de novo lipogenesis (Srebp-1c, Fasn and Scd1) and decreased the expression of genes related to oxidation and uptake (Acox1, Ehhadh, Cd36, Fabp1). Furthermore, TUG-891 modified the levels of selected factors related to glucose metabolism (decreased Glut2, Pdk4 and Pklr, and increased G6pdx). Conclusion: Pharmacological stimulation of FFAR4 may represent a promising lead in the search for drugs that inhibit NAFLD. [ABSTRACT FROM AUTHOR]

Hydronephrosis, the dilation of kidneys due to abnormal urine retention, occurs spontaneously in certain inbred mouse strains. In humans, its occurrence is often attributed to acquired urinary tract obstructions in adults, whereas in children, it can be congenital. However, the genetic factors underlying hydronephrosis pathogenesis remain unclear. We investigated the cause of hydronephrosis by analyzing tetraspanin 7 (Tspan7) gene-modified mice, which had shown a high incidence of hydronephrosis-like symptoms. We found that these mice were characterized by low liver weights relative to kidney weights and elevated blood ammonia levels, suggesting liver involvement in hydronephrosis. Gene expression analysis of the liver suggested that dysfunction of ornithine transcarbamylase (OTC), encoded by the X chromosome gene Otc and involved in the urea cycle, may contribute as a congenital factor in hydronephrosis. This OTC dysfunction may be caused by genomic mutations in X chromosome genes contiguous to Otc, such as Tspan7, or via the genomic manipulations used to generate transgenic mice, including the introduction of Cre recombinase DNA cassettes and cleavage of loxP by Cre recombinase. Therefore, caution should be exercised in interpreting the hydronephrosis phenotype observed in transgenic mice as solely a physiological function of the target gene. [ABSTRACT FROM AUTHOR]

Background: Mouse allergy is an important cause of indoor asthma and allergic rhinoconjunctivitis. The major mouse allergen, Mus m 1, is a complex of homologous pheromone‐binding lipocalins called major urinary proteins (MUPs). Methods: We analyzed the proteome of MUPs in mouse urine, commercial mouse epithelial extracts, and environmental samples using several approaches. These include as follows: two‐dimensional electrophoresis and immunoblotting; liquid chromatography‐high‐resolution mass spectrometry (LC/HRMS); multiple reaction monitoring (MRM) mass spectrometry; and LC/HRMS analysis of glycans at the N‐66 residue of MUP3. Results: Albumin is predominant in the extracts, while MUPs are predominant in urine. LC/HRMS of 4 mouse allergen extracts revealed surprising heterogeneity. Of 22 known mouse MUPs, only 6 (MUP3, MUP4, MUP5, MUP13, MUP20, and MUP21) could be identified with MRM using unique peptides. Assessment of MUP content in urine, extracts, and dust samples showed good correlation between MRM and other methods working with different detection principles. All 6 identifiable MUPs were found in electrophoretically separated urine bands, but only MUP3 and MUP20 were above LOQ in unseparated mouse urine, and only MUP3, MUP4, and MUP20 were found in mouse epithelial extracts. Glycan heterogeneity was noted among 4 individual inbred mice: of 13 glycan structures detected, 8 were unique to one mouse, and only 2 glycan modifications were present in all 4 mice. Conclusions: Using mass spectrometry and MRM, mouse allergen extracts and urine samples are shown to be complex and heterogeneous. The efficacy and safety of commercial mouse allergen extracts will be improved with better controls of allergen content. [ABSTRACT FROM AUTHOR]

Global climate change has led to shifts in the distribution ranges of many terrestrial species, promoting their migration from lower altitudes or latitudes to higher ones. Meanwhile, successful invaders have developed genetic adaptations enabling the colonization of new environments. Over the past 40 years, Rattus tanezumi (RT) has expanded into northern China (Northwest and North China) from its southern origins. We studied the cold adaptation of RT and its potential for northward expansion by comparing it with sympatric Rattus norvegicus (RN), which is well adapted to cold regions. Through population genomic analysis, we revealed that the invading RT rats have split into three distinct populations: the North, Northwest, and Tibetan populations. The first two populations exhibited high genetic diversity, while the latter population showed remarkably low genetic diversity. These rats have developed various genetic adaptations to cold, arid, hypoxic, and high-UV conditions. Cold acclimation tests revealed divergent thermoregulation between RT and RN. Specifically, RT exhibited higher brown adipose tissue activity and metabolic rates than did RN. Transcriptome analysis highlighted changes in genes regulating triglyceride catabolic processes in RT, including Apoa1 and Apoa4 , which were upregulated, under selection and associated with local adaptation. In contrast, RN showed changes in carbohydrate metabolism genes. Despite the cold adaptation of RT, we observed genotypic and phenotypic constraints that may limit its ability to cope with severe low temperatures farther north. Consequently, it is less likely that RT rats will invade and overlap with RN rats in farther northern regions. [ABSTRACT FROM AUTHOR]

Pheromones are specialized chemical messengers used for inter-individual communication within the same species, playing crucial roles in modulating behaviors and physiological states. The detection mechanisms of these signals at the peripheral organ and their transduction to the brain have been unclear. However, recent identification of pheromone molecules, their corresponding receptors, and advancements in neuroscientific technology have started to elucidate these processes. In mammals, the detection and interpretation of pheromone signals are primarily attributed to the vomeronasal system, which is a specialized olfactory apparatus predominantly dedicated to decoding socio-chemical cues. In this mini-review, we aim to delineate the vomeronasal signal transduction pathway initiated by specific vomeronasal receptor-ligand interactions in mice. First, we catalog the previously identified pheromone ligands and their corresponding receptor pairs, providing a foundational understanding of the specificity inherent in pheromonal communication. Subsequently, we examine the neural circuits involved in processing each pheromone signal. We focus on the anatomical pathways, the sexually dimorphic and physiological state-dependent aspects of signal transduction, and the neural coding strategies underlying behavioral responses to pheromonal cues. These insights provide further critical questions regarding the development of innate circuit formation and plasticity within these circuits. [ABSTRACT FROM AUTHOR]

Introduction: It may take decades to develop cardiovascular dysfunction following exposure to high doses of ionizing radiation from medical therapy or from nuclear accidents. Since astronauts may be exposed continually to a complex space radiation environment unlike that experienced on Earth, it is unresolved whether there is a risk to cardiovascular health during long-term space exploration missions. Previously, we have described that mice exposed to a single dose of simplified Galactic Cosmic Ray (GCR5-ion) develop cardiovascular dysfunction by 12 months post-radiation. Methods: To investigate the biological basis of this dysfunction, here we performed a quantitative mass spectrometry-based proteomics analysis of heart tissue (proteome and phosphoproteome) and plasma (proteome only) from these mice at 8 months post-radiation. Results: Differentially expressed proteins (DEPs) for irradiated versus sham irradiated samples (fold-change ≥1.2 and an adjusted p-value of ≤0.05) were identified for each proteomics data set. For the heart proteome, there were 87 significant DEPs (11 upregulated and 76 downregulated); for the heart phosphoproteome, there were 60 significant differentially phosphorylated peptides (17 upregulated and 43 downregulated); and for the plasma proteome, there was only one upregulated protein. A Gene Set Enrichment Analysis (GSEA) technique that assesses canonical pathways from BIOCARTA, KEGG, PID, REACTOME, and WikiPathways revealed significant perturbation in pathways in each data set. For the heart proteome, 166 pathways were significantly altered (36 upregulated and 130 downregulated); for the plasma proteome, there were 73 pathways significantly altered (25 upregulated and 48 downregulated); and for the phosphoproteome, there were 223 pathways significantly affected at 0.1 adjusted p-value cutoff. Pathways related to inflammation were the most highly perturbed in the heart and plasma. In line with sustained inflammation, neutrophil extracellular traps (NETs) were demonstrated to be increased in GCR5-ion irradiated hearts at 12-month post irradiation. NETs play a fundamental role in combating bacterial pathogens, modulating inflammatory responses, inflicting damage on healthy tissues, and escalating vascular thrombosis. Discussion: These findings suggest that a single exposure to GCR5-ion results in long-lasting changes in the proteome and that these proteomic changes can potentiate acute and chronic health issues for astronauts, such as what we have previously described with late cardiac dysfunction in these mice. [ABSTRACT FROM AUTHOR]

The gradual loss of kidney function due to increasing age is accompanied by structural changes such as fibrosis of the tissue. The underlying molecular mechanisms are complex, but not yet fully understood. Non-fibrillar collagen type VIII (COL8) could be a potential factor in the fibrosis processes of the aging kidney. A pathophysiological significance of COL8 has already been demonstrated in the context of diabetic kidney disease, with studies showing that it directly influences both the development and progression of renal fibrosis occurring. The aim of this study was to investigate whether COL8 impacts age-related micro-anatomical and functional changes in a mouse model. The kidneys of wild-type (Col8-wt) and COL8-knockout (Col8-ko) mice of different age and sex were characterized with regard to the expression of molecular fibrosis markers, the development of nephrosclerosis and renal function. The age-dependent regulation of COL8 mRNA expression in the wild-type revealed sex-dependent effects that were not observed with collagen IV (COL4). Histochemical staining and protein analysis of profibrotic cytokines TGF-β1 (transforming growth factor) and CTGF (connective tissue growth factor) in mouse kidneys showed significant age effects as well as interactions of the factors age, sex and Col8 genotype. There were also significant age and Col8 genotype effects in the renal function data analyzed by urinary cystatin C. In summary, the present study shows, for the first time, that COL8 is regulated in an age- and sex-dependent manner in the mouse kidney and that the expression of COL8 influences the severity of age-induced renal fibrosis and function. [ABSTRACT FROM AUTHOR]

Introduction: The Aster-C protein (encoded by the Gramd1c gene) is an endoplasmic reticulum (ER) resident protein that has been reported to transport cholesterol from the plasma membrane to the ER. Although there is a clear role for the closely-related Aster-B protein in cholesterol transport and downstream esterification in the adrenal gland, the specific role for Aster-C in cholesterol homeostasis is not well understood. Here, we have examined whole body cholesterol balance in mice globally lacking Aster-C under low or high dietary cholesterol conditions. Method: Age-matched Gramd1c+/+ and Gramd1c-/- mice were fed either low (0.02%, wt/wt) or high (0.2%, wt/wt) dietarycholesterol and levels of sterolderived metabolites were assessed in the feces, liver, and plasma. Results: Compared to wild type controls (Gramd1c+/+) mice, mice lackingGramd1c (Gramd1c-/-) have no significant alterations in fecal, liver, or plasma cholesterol. Given the potential role for Aster C in modulating cholesterol metabolism in diverse tissues, we quantified levels of cholesterol metabolites such as bile acids, oxysterols, and steroid hormones. Compared to Gramd1c+/+ controls, Gramd1c-/- mice had modestly reduced levels of select bile acid species and elevated cortisol levels, only under low dietary cholesterol conditions. However, the vast majority of bile acids, oxysterols, and steroid hormones were unaltered in Gramd1c-/- mice. Bulk RNA sequencing in the liver showed that Gramd1c-/- mice did not exhibit alterations in sterol-sensitive genes, but instead showed altered expression of genes in major urinary protein and cytochrome P450 (CYP) families only under low dietary cholesterol conditions. Discussion: Collectively, these data indicate nominal effects of Aster-C on whole body cholesterol transport and metabolism under divergent dietary cholesterol conditions. These results strongly suggest that Aster-C alone is not sufficient to control whole body cholesterol balance, but can modestly impact circulating cortisol and bile acid levels when dietary cholesterol is limited. [ABSTRACT FROM AUTHOR]

Growth hormone (GH) modifies liver gene transcription in a sexually dimorphic manner to meet liver metabolic demands related to sex; thus, GH dysregulation leads to sex-biased hepatic disease. We dissected the steps of the GH regulatory cascade modifying GH-dependent genes involved in metabolism, focusing on the male-predominant genes Lcn13 , Asns , and Cyp7b1 , and the female-predominant genes Hao2 , Pgc1a , Hamp2 , Cyp2a4 , and Cyp2b9. We explored mRNA expression in 2 settings: (i) intact liver GH receptor (GHR) but altered GH and insulin-like growth factor 1 (IGF1) levels (NeuroDrd2KO, HiGH, aHepIGF1kd, and STAT5bCA mouse lines); and (ii) liver loss of GHR, with or without STAT5b reconstitution (aHepGHRkd, and aHepGHRkd + STAT5bCA). Lcn13 was downregulated in males in most models, while Asns and Cyp7b1 were decreased in males by low GH levels or action, or constant GH levels, but unexpectedly upregulated in both sexes by the loss of liver Igf1 or constitutive Stat5b expression. Hao , Cyp2a4 , and Cyp2b9 were generally decreased in female mice with low GH levels or action (NeuroDrd2KO and/or aHepGHRkd mice) and increased in HiGH females, while in contrast, Pgc1a was increased in female NeuroDrd2KO but decreased in STAT5bCA and aHepIGF1kd females. Bioinformatic analysis of RNAseq from aHepGHRkd livers stressed the greater impact of GHR loss on wide gene expression in males and highlighted that GH modifies almost completely different gene signatures in each sex. Concordantly, we show that altering different steps of the GH cascade in the liver modified liver expression of Lcn13 , Asns , Cyp7b1 , Hao2 , Hamp2 , Pgc1a , Cyp2a4 , and Cyp2b9 in a sex- and gene-specific manner. [ABSTRACT FROM AUTHOR]

Chemical signals are frequently utilised by male mammals for intersexual communication and females are often attracted to male scent. However, the mechanism underlying female attraction has only been identified in a small number of mammalian species. Mammalian scents contain airborne volatiles, that are detected by receivers at a distance from the scent source, as well as non-volatile molecules, such as proteins, that require physical contact for detection. Lipocalin proteins, produced within the scent secretions of many terrestrial mammals, are thought to be particularly important in chemical signalling. Here, we explore if the male-specific protein, glareosin, expressed by adult male bank voles, Myodes glareolus, stimulates female attraction to male scent. We show that female bank voles are more attracted to male compared to female scent, supporting the results of previous studies. Increased investigation and attraction to male scent occurred to both airborne volatiles and non-volatile proteins when they were presented separately. However, we found no evidence that attraction to male scent was driven by glareosin. Our results differ from those previously described in house mice, where a single protein induces female attraction to male scent, suggesting the mechanism underlying female attraction to male scent differs between species. [ABSTRACT FROM AUTHOR]

Theories of ageing predict that investment in reproduction will trade-off against survival and later-life reproduction. Recent evidence from invertebrates suggests that just perceiving cues of a potential mate's presence can reduce lifespan, particularly in males, and that activation of neuroendocrine reward pathways associated with mating can alleviate these effects. Whether similar effects occur in vertebrates remains untested. We tested whether exposure to olfactory cues from the opposite sex would influence mortality and reproductive senescence in male mice. We observed that males exposed to female olfactory cues from middle- to old age (from 10 to 24 months of age) showed reduced late-life fertility, irrespective of whether they had also been allowed to mate with females earlier in life. Males that were exposed to female odours in conjunction with mating also showed an increased mortality rate across the exposure period, indicating that olfactory cues from females can increase male mortality in some environments. Our results show that exposure to female odours can influence reproductive ageing and mortality in male mice, highlighting that sensory perception of mates may be an important driver of life-history trade-offs in mammals. [ABSTRACT FROM AUTHOR]

This review covers the volatile organic compounds (VOCs) emitted by the bodies and secretions of introduced mammalian predators in New Zealand forests, with a specific focus on mice, rats, ferrets, stoats, and possums. The primary aim is to compile information on these VOCs and assess the potential of exploiting these VOCs as unique biomarkers for predator detection in the forest. While a universal VOC has yet to be identified, the review discusses various VOCs associated with predators and their potential as unique biomarkers for detecting the presence of predators, including 2-heptanone, 4-heptanone, 2-octanone, and benzaldehyde. Furthermore, a brief overview of different VOC detection techniques is provided, connecting the selection of biosensing techniques with the detection of volatile biomarkers. Further research and advancement in the biosensing field hold substantial potential to enhance biomarker detection technologies and elevate predator management strategies within New Zealand forests. [ABSTRACT FROM AUTHOR]

Background: The American Bashkir Curly Horse is frequently advertised to horse‐allergic riders and claimed to be a so‐called hypoallergenic breed that elicits fewer symptoms. Previous studies quantifying selected allergens in different breeds did not find a reduced allergen content in Curly Horses. Here, we provide a comprehensive proteomic analysis of horse hair extracts and a molecular analysis of the major allergen Equ c 1 with the aim of identifying differences in the Curly Horse breed that might explain their presumed reduced allergenic potential. Methods: Horse hair extracts were prepared from Curly and American Quarter Horse breeds, separated by gender and castration status, extracts from other breeds served as controls. Extracts and native Equ c 1 (nEqu c 1) were analyzed by mass spectrometry. IgE‐binding capacities of nEqu c 1 and its recombinant variants were tested by ELISA using sera of patients sensitized to horses. Structures and ligand binding abilities were analyzed by computational modeling and fluorescence quenching assays. Results: All known respiratory horse allergens are present in hair extracts of Curly and Quarter Horses and share identical allergen‐specific peptides. Lipocalin allergens are the most abundant proteins in horse hair extracts and contain several post‐translational modifications. We identified two new variants of Equ c 1 that have similar IgE‐binding capacities but show structural differences in their binding cavities and altered ligand binding behavior. There are no differences in IgE‐binding of Equ c 1 derived from Curly Horses compared to other horse breeds. Conclusion: Our data do not support the claim that Curly Horses are less allergenic than other breeds. [ABSTRACT FROM AUTHOR]

Recent genome- and exome-wide association studies suggest that the human APOE e4 allele protects against non-alcoholic fatty liver disease (NAFLD), while ε3 promotes hepatic steatosis and steatohepatitis. The present study aimed at examining the APOE genotype-dependent development of fatty liver disease and its underlying mechanisms in a targeted replacement mouse model. Male mice expressing the human APOE3 or APOE4 protein isoforms on a C57BL/6J background and unmodified C57BL/6J mice were chronically fed a high-fat and high-sucrose diet to induce obesity. After 7 months, body weight gain was more pronounced in human APOE than endogenous APOE expressing mice with elevated plasma biomarkers suggesting aggravated metabolic dysfunction. APOE3 mice exhibited the highest liver weights and, compared to APOE4, massive hepatic steatosis. An untargeted quantitative proteome analysis of the liver identified a high number of proteins differentially abundant in APOE3 versus APOE4 mice. The majority of the higher abundant proteins in APOE3 mice could be grouped to inflammation and damage-associated response, and lipid storage, amongst others. Results of the targeted qRT-PCR and Western blot analyses contribute to the overall finding that APOE3 as opposed to APOE4 promotes hepatic steatosis, inflammatory- and damage-associated response signaling and fibrosis in the liver of obese mice. Our experimental data substantiate the observation of an increased NAFLDrisk associated with the human APOEε3 allele, while APOEε4 appears protective. The underlying mechanisms of the protection possibly involve a higher capacity of nonectopic lipid deposition in subcutaneous adipose tissue and lower hepatic pathogen recognition in the APOE4 mice. [ABSTRACT FROM AUTHOR]

Simple Summary: The risk of parasitic infection has a major influence on animal behaviour. Organisms must adjust their behaviour to avoid various modes of parasitic infection and pathogen acquisition. Social species are at an increased risk of parasitic transmission as they spend more time in the proximity of others that may carry parasites. The detection of parasitic risk is also critical in mate assessment and choice. Perceptual systems and behavioural responses have evolved to detect individuals who are parasitized and pose the risk of parasitic transmission. This includes the integration of inputs from various sensory modalities (e.g., olfaction), brain regions and networks, and neuromodulatory systems. Understanding the neurobiological systems involved in detecting the parasite infection risk and the expression of disgust will allow us to better understand the evolution and regulation of pathogen avoidance and mate choice. Animals are under constant threat of parasitic infection. This has influenced the evolution of social behaviour and has strong implications for sexual selection and mate choice. Animals assess the infection status of conspecifics based on various sensory cues, with odours/chemical signals and the olfactory system playing a particularly important role. The detection of chemical cues and subsequent processing of the infection threat that they pose facilitates the expression of disgust, fear, anxiety, and adaptive avoidance behaviours. In this selective review, drawing primarily from rodent studies, the neurobiological mechanisms underlying the detection and assessment of infection status and their relations to mate choice are briefly considered. Firstly, we offer a brief overview of the aspects of mate choice that are relevant to pathogen avoidance. Then, we specifically focus on the olfactory detection of and responses to conspecific cues of parasitic infection, followed by a brief overview of the neurobiological systems underlying the elicitation of disgust and the expression of avoidance of the pathogen threat. Throughout, we focus on current findings and provide suggestions for future directions and research. [ABSTRACT FROM AUTHOR]

Results obtained from rat studies indicate that, even at low concentrations, mercurial species cause harmful effects on the kidneys, by inducing the nephrotic oxidative stress response. In the present work, Hg-associated proteins were identified as possible mercury-exposure biomarkers in rat kidneys exposed to low mercury chloride concentrations for 30 days (Hg-30) and 60 days (Hg-60), using metalloproteomic strategies. The renal proteomic profile was fractioned by two-dimensional electrophoresis and the mercury determinations in kidney samples, protein pellets and protein spots were performed using graphite furnace atomic absorption spectrometry. The characterization of Hg-associated protein spots and the analysis of differentially expressed proteins were performed by liquid chromatography, coupled with tandem mass spectrometry. Eleven Hg-associated protein spots with a concentration range of 79 ± 1 to 750 ± 9 mg kg−1 in the Hg-60 group were identified. The characterization and expression analyses allowed the identification of 53 proteins that were expressed only in the Hg-60 group, 13 "upregulated" proteins (p > 0.95) and 47 "downregulated" proteins (p < 0.05). Actin isoforms and hemoglobin subunits were identified in protein spots of the Hg-60 group, with mercury concentrations in the range of 138 to 750 mg kg−1, which qualifies these proteins as potential mercury-exposure biomarkers. [ABSTRACT FROM AUTHOR]

Thioacetamide (TAA) was administered orally at 0, 10, and 30 mg/kg body weight (BW) daily to Sprague-Dawley rats aged 6-7 weeks for 28 consecutive days. Nephrotoxicity and proteomics were evaluated in the kidneys of rats exposed to TAA. The BW decreased, however, the relative kidneys weight increased. No significant histopathologic abnormalities were found in the kidneys. The numbers of monocytes and platelets were significantly increased. However, the mean corpuscular volume and hematocrit values were decreased significantly in rats exposed to 30 mg/kg BW TAA. The expression levels of Kim-1 and NGAL were increased 4 to 5-fold in the kidneys, resulting in significant nephrotoxicity. Proteomic analysis was conducted and a total of 5221 proteins spots were resolved. Of these, 3 and 21 protein spots were up- and downregulated, respectively. The validation of seven proteins was performed by Western blot analysis. The expression level of ASAP2 was significantly upregulated, whereas RGS14, MAP7Dl, IL-3Rα, Tmod1, NQO2, and MUP were reduced. Sixteen isoforms of MUP were found by the 2DE immunoblot assay and were significantly downregulated with increasing exposure to TAA. MUP isoforms were compared in the liver, kidneys, and urine of untreated rats and a total of 43 isoforms were found., (© 2022. The Author(s).)