The complete sequence and comparative analysis of ape sex chromosomes.

Apes possess two sex chromosomes-the male-specific Y chromosome and the X chromosome, which is present in both males and females. The Y chromosome is crucial for male reproduction, with deletions being linked to infertility1. The X chromosome is vital for reproduction and cognition2. Variation in mating patterns and brain function among apes suggests corresponding differences in their sex chromosomes. However, owing to their repetitive nature and incomplete reference assemblies, ape sex chromosomes have been challenging to study. Here, using the methodology developed for the telomere-to-telomere (T2T) human genome, we produced gapless assemblies of the X and Y chromosomes for five great apes (bonobo (Pan paniscus), chimpanzee (Pan troglodytes), western lowland gorilla (Gorilla gorilla gorilla), Bornean orangutan (Pongo pygmaeus) and Sumatran orangutan (Pongo abelii)) and a lesser ape (the siamang gibbon (Symphalangus syndactylus)), and untangled the intricacies of their evolution. Compared with the X chromosomes, the ape Y chromosomes vary greatly in size and have low alignability and high levels of structural rearrangements-owing to the accumulation of lineage-specific ampliconic regions, palindromes, transposable elements and satellites. Many Y chromosome genes expand in multi-copy families and some evolve under purifying selection. Thus, the Y chromosome exhibits dynamic evolution, whereas the X chromosome is more stable. Mapping short-read sequencing data to these assemblies revealed diversity and selection patterns on sex chromosomes of more than 100 individual great apes. These reference assemblies are expected to inform human evolution and conservation genetics of non-human apes, all of which are endangered species.

Methylation profiles at birth linked to early childhood obesity.

Childhood obesity represents a significant global health concern and identifying its risk factors is crucial for developing intervention programs. Many "omics" factors associated with the risk of developing obesity have been identified, including genomic, microbiomic, and epigenomic factors. Here, using a sample of 48 infants, we investigated how the methylation profiles in cord blood and placenta at birth were associated with weight outcomes (specifically, conditional weight gain, body mass index, and weight-for-length ratio) at age six months. We characterized genome-wide DNA methylation profiles using the Illumina Infinium MethylationEpic chip, and incorporated information on child and maternal health, and various environmental factors into the analysis. We used regression analysis to identify genes with methylation profiles most predictive of infant weight outcomes, finding a total of 23 relevant genes in cord blood and 10 in placenta. Notably, in cord blood, the methylation profiles of three genes (PLIN4, UBE2F, and PPP1R16B) were associated with all three weight outcomes, which are also associated with weight outcomes in an independent cohort suggesting a strong relationship with weight trajectories in the first six months after birth. Additionally, we developed a Methylation Risk Score (MRS) that could be used to identify children most at risk for developing childhood obesity. While many of the genes identified by our analysis have been associated with weight-related traits (e.g., glucose metabolism, BMI, or hip-to-waist ratio) in previous genome-wide association and variant studies, our analysis implicated several others, whose involvement in the obesity phenotype should be evaluated in future functional investigations.

In vivo detection of DNA secondary structures using permanganate/S1 footprinting with direct adapter ligation and sequencing (PDAL-Seq).

DNA secondary structures are essential elements of the genomic landscape, playing a critical role in regulating various cellular processes. These structures refer to G-quadruplexes, cruciforms, Z-DNA or H-DNA structures, amongst others (collectively called 'non-B DNA'), which DNA molecules can adopt beyond the B conformation. DNA secondary structures have significant biological roles, and their landscape is dynamic and can rearrange due to various factors, including changes in cellular conditions, temperature, and DNA-binding proteins. Understanding this dynamic nature is crucial for unraveling their functions in cellular processes. Detecting DNA secondary structures remains a challenge. Conventional methods, such as gel electrophoresis and chemical probing, have limitations in terms of sensitivity and specificity. Emerging techniques, including next-generation sequencing and single-molecule approaches, offer promise but face challenges since these techniques are mostly limited to only one type of secondary structure. Here we describe an updated version of a technique permanganate/S1 nuclease footprinting, which uses potassium permanganate to trap single-stranded DNA regions as found in many non-B structures, in combination with S1 nuclease digest and adapter ligation to detect genome-wide non-B formation. To overcome technical hurdles, we combined this method with direct adapter ligation and sequencing (PDAL-Seq). Furthermore, we established a user-friendly pipeline available on Galaxy to standardize PDAL-Seq data analysis. This optimized method allows the analysis of many types of DNA secondary structures that form in a living cell and will advance our knowledge of their roles in health and disease.

Methylation profiles at birth linked to early childhood obesity.

Childhood obesity represents a significant global health concern and identifying risk factors is crucial for developing intervention programs. Many 'omics' factors associated with the risk of developing obesity have been identified, including genomic, microbiomic, and epigenomic factors. Here, using a sample of 48 infants, we investigated how the methylation profiles in cord blood and placenta at birth were associated with weight outcomes (specifically, conditional weight gain, body mass index, and weight-for-length ratio) at age six months. We characterized genome-wide DNA methylation profiles using the Illumina Infinium MethylationEpic chip, and incorporated information on child and maternal health, and various environmental factors into the analysis. We used regression analysis to identify genes with methylation profiles most predictive of infant weight outcomes, finding a total of 23 relevant genes in cord blood and 10 in placenta. Notably, in cord blood, the methylation profiles of three genes (PLIN4, UBE2F, and PPP1R16B) were associated with all three weight outcomes, which are also associated with weight outcomes in an independent cohort suggesting a strong relationship with weight trajectories in the first six months after birth. Additionally, we developed a Methylation Risk Score (MRS) that could be used to identify children most at risk for developing childhood obesity. While many of the genes identified by our analysis have been associated with weight-related traits (e.g., glucose metabolism, BMI, or hip-to-waist ratio) in previous genome-wide association and variant studies, our analysis implicated several others, whose involvement in the obesity phenotype should be evaluated in future functional investigations.

Prebrief Time for Immersive Virtual and Augmented Reality Simulation: An Integrative Review.

BACKGROUND: Virtual reality and augmented technology are rapidly advancing and hold the potential to transform nursing education by offering a convenient, efficient, learner-centered way to educate students. A comprehensive and time-oriented prebrief is essential to the process. PURPOSE: This review analyzes the status of scientific exploration regarding the prebrief and time allotments for virtual and augmented reality simulation. METHODS: Whittemore and Knafl's 5-stage method guided this integrative review. The authors searched 6 databases and selected 7 articles based on inclusion criteria. RESULTS: The findings from this review demonstrated objectives, a safe learning environment, orientation, preparation materials, and time in the prebrief; yet, inconsistencies persist in the virtual and augmented reality prebrief. CONCLUSIONS: Defining a comprehensive and consistent prebrief is essential for high-quality simulation. A more standardized process, including time allotments, must be established for virtual and augmented reality.

The Complete Sequence and Comparative Analysis of Ape Sex Chromosomes.

Apes possess two sex chromosomes-the male-specific Y and the X shared by males and females. The Y chromosome is crucial for male reproduction, with deletions linked to infertility. The X chromosome carries genes vital for reproduction and cognition. Variation in mating patterns and brain function among great apes suggests corresponding differences in their sex chromosome structure and evolution. However, due to their highly repetitive nature and incomplete reference assemblies, ape sex chromosomes have been challenging to study. Here, using the state-of-the-art experimental and computational methods developed for the telomere-to-telomere (T2T) human genome, we produced gapless, complete assemblies of the X and Y chromosomes for five great apes (chimpanzee, bonobo, gorilla, Bornean and Sumatran orangutans) and a lesser ape, the siamang gibbon. These assemblies completely resolved ampliconic, palindromic, and satellite sequences, including the entire centromeres, allowing us to untangle the intricacies of ape sex chromosome evolution. We found that, compared to the X, ape Y chromosomes vary greatly in size and have low alignability and high levels of structural rearrangements. This divergence on the Y arises from the accumulation of lineage-specific ampliconic regions and palindromes (which are shared more broadly among species on the X) and from the abundance of transposable elements and satellites (which have a lower representation on the X). Our analysis of Y chromosome genes revealed lineage-specific expansions of multi-copy gene families and signatures of purifying selection. In summary, the Y exhibits dynamic evolution, while the X is more stable. Finally, mapping short-read sequencing data from >100 great ape individuals revealed the patterns of diversity and selection on their sex chromosomes, demonstrating the utility of these reference assemblies for studies of great ape evolution. These complete sex chromosome assemblies are expected to further inform conservation genetics of nonhuman apes, all of which are endangered species.

Rectosigmoid Adenocarcinoma Presenting As Nine Days of Constipation.

We report the case of a 56-year-old male presenting with nine days of constipation and absence of flatus without any improvement and who had received conservative management after recent admission at an external hospital. Upon further investigation, the patient was diagnosed with rectosigmoid adenocarcinoma and was successfully surgically treated without any perioperative complications. This case highlights the importance of early detection and interventions necessary to prevent progression of colorectal adenocarcinoma. Easily manageable symptoms such as constipation may require further evaluation by implementing a constipation scoring system to avoid missed diagnoses such as cancer and metastasis. Therefore, the association between constipation and colorectal carcinoma warrants further research investigations as well as clinician awareness to prevent life-threatening complications.

Constructing a polygenic risk score for childhood obesity using functional data analysis.

Obesity is a highly heritable condition that affects increasing numbers of adults and, concerningly, of children. However, only a small fraction of its heritability has been attributed to specific genetic variants. These variants are traditionally ascertained from genome-wide association studies (GWAS), which utilize samples with tens or hundreds of thousands of individuals for whom a single summary measurement (e.g., BMI) is collected. An alternative approach is to focus on a smaller, more deeply characterized sample in conjunction with advanced statistical models that leverage longitudinal phenotypes. Novel functional data analysis (FDA) techniques are used to capitalize on longitudinal growth information from a cohort of children between birth and three years of age. In an ultra-high dimensional setting, hundreds of thousands of single nucleotide polymorphisms (SNPs) are screened, and selected SNPs are used to construct two polygenic risk scores (PRS) for childhood obesity using a weighting approach that incorporates the dynamic and joint nature of SNP effects. These scores are significantly higher in children with (vs. without) rapid infant weight gain-a predictor of obesity later in life. Using two independent cohorts, it is shown that the genetic variants identified in very young children are also informative in older children and in adults, consistent with early childhood obesity being predictive of obesity later in life. In contrast, PRSs based on SNPs identified by adult obesity GWAS are not predictive of weight gain in the cohort of young children. This provides an example of a successful application of FDA to GWAS. This application is complemented with simulations establishing that a deeply characterized sample can be just as, if not more, effective than a comparable study with a cross-sectional response. Overall, it is demonstrated that a deep, statistically sophisticated characterization of a longitudinal phenotype can provide increased statistical power to studies with relatively small sample sizes; and shows how FDA approaches can be used as an alternative to the traditional GWAS.

New cells added to the preoptic area during sex change in the common clownfish Amphiprion ocellaris.

Sex differences in cell number in the preoptic area of the hypothalamus (POA) are documented across all major vertebrate lineages and contribute to differential regulation of the hypothalamic-pituitary-gonad axis and reproductive behavior between the sexes. Sex-changing fishes provide a unique opportunity to study mechanisms underlying sexual differentiation of the POA. In anemonefish (clownfish), which change sex from male to female, females have approximately twice the number of medium-sized cells in the anterior POA compared to males. This sex difference transitions from male-like to female-like during sex change. However, it is not known how this sex difference in POA cell number is established. This study tests the hypothesis that new cell addition plays a role. We initiated adult male-to-female sex change in 30 anemonefish (Amphiprion ocellaris) and administered BrdU to label new cells added to the POA at regular intervals throughout sex change. Sex-changing fish added more new cells to the anterior POA than non-changing fish, supporting the hypothesis. The observed effects could be accounted for by differences in POA volume, but they are also consistent with a steady trickle of new cells being gradually accumulated in the anterior POA before vitellogenic oocytes develop in the gonads. These results provide insight into the unique characteristics of protandrous sex change in anemonefish relative to other modes of sex change, and support the potential for future research in sex-changing fishes to provide a richer understanding of the mechanisms for sexual differentiation of the brain.

Stable and persistent male-like behavior during male-to-female sex change in the common clownfish Amphiprion ocellaris.

Many fish species exhibit natural sex change as part of their life, providing unique opportunities to study sexually-differentiated social behaviors and their plasticity. Past research has shown that behavioral sex change in the female-to-male (protogynous) direction occurs rapidly and well before gonadal sex change. However, little is known about the timecourse of behavioral sex change in male-to-female (protandrous) sex-changing species, limiting our ability to compare patterns of behavioral sex change across species and identify conserved or divergent underlying mechanisms. Using the protandrous sex changing anemonefish Amphiprion ocellaris, we assessed behavior (aggression and parental care) and hormones (estradiol and 11-ketotestosterone) in fish over six months of sex change, and compared those fish against their non-changing partners as well as control males and females. Contrary to expectations, we found that sex-changing fish displayed behavior that was persistently male-like, and that their behavior did not become progressively female-like as sex change progressed. Hormones shifted to an intermediate profile between males and females and remained stable until gonads changed. These results support a new perspective that the timecourse for protandrous sex change in anemonefish is completely distinct from other well-established models, such that behavioral sex change does not occur until after gonadal sex change is complete, and that sex-changing fish have a stable and unique behavioral and hormonal phenotype that is distinct from a male-typical or female-typical phenotype. The results also identify aspects of sex change that may fundamentally differ between protandrous and protogynous modes, motivating further research into these remarkable examples of phenotypic plasticity.

Predictors of access to healthcare professionals for people with intellectual disability in Ireland.

The Irish National Intellectual Disability Database is updated annually and in 2017 contained records for nearly 22,000 persons aged 15 years and over. Information was extracted on the contacts each person had with one of eight health professionals in the years 2007, 2012 and 2017. Over these years, there was an increase in the number of people in contact with any professional or with four and more professionals. Nevertheless, the people less likely to have contact were those with milder forms of intellectual disability, persons living with family carers or independently and those linked to smaller provider agencies. By contrast, the odds of people with more severe disability in residential settings were up to eight times greater for having contact with four or more different professionals. As demand for healthcare grows due to increased longevity and service models shift to the community, redeployment of existing professional resources will be needed along with a review of the skill mix.

Metabolomic profiling of stool of two-year old children from the INSIGHT study reveals links between butyrate and child weight outcomes.

BACKGROUND: Metabolomic analysis is commonly used to understand the biological underpinning of diseases such as obesity. However, our knowledge of gut metabolites related to weight outcomes in young children is currently limited. OBJECTIVES: To (1) explore the relationships between metabolites and child weight outcomes, (2) determine the potential effect of covariates (e.g., child's diet, maternal health/habits during pregnancy, etc.) in the relationship between metabolites and child weight outcomes, and (3) explore the relationship between selected gut metabolites and gut microbiota abundance. METHODS: Using 1 H-NMR, we quantified 30 metabolites from stool samples of 170 two-year-old children. To identify metabolites and covariates associated with children's weight outcomes (BMI [weight/height2 ], BMI z-score [BMI adjusted for age and sex], and growth index [weight/height]), we analysed the 1 H-NMR data, along with 20 covariates recorded on children and mothers, using LASSO and best subset selection regression techniques. Previously characterized microbiota community information from the same stool samples was used to determine associations between selected gut metabolites and gut microbiota. RESULTS: At age 2 years, stool butyrate concentration had a significant positive association with child BMI (p-value = 3.58 × 10-4 ), BMI z-score (p-value = 3.47 × 10-4 ), and growth index (p-value = 7.73 × 10-4 ). Covariates such as maternal smoking during pregnancy are important to consider. Butyrate concentration was positively associated with the abundance of the bacterial genus Faecalibacterium (p-value = 9.61 × 10-3 ). CONCLUSIONS: Stool butyrate concentration is positively associated with increased child weight outcomes and should be investigated further as a factor affecting childhood obesity.

INSIGHT responsive parenting educational intervention for firstborns is associated with growth of second-born siblings.

OBJECTIVE: The aim of this study was to test whether the Intervention Nurses Start Infants Growing on Healthy Trajectories (INSIGHT) responsive parenting (RP) intervention, delivered to parents of firstborn children, is associated with the BMI of first- and second-born siblings during infancy. METHODS: Participants included 117 firstborn infants enrolled in a randomized controlled trial and their second-born siblings enrolled in an observation-only ancillary study. The RP curriculum for firstborn children included guidance on feeding, sleep, interactive play, and emotion regulation. The control curriculum focused on safety. Anthropometrics were measured in both siblings at ages 3, 16, 28, and 52 weeks. Growth curve models for BMI by child age were fit. RESULTS: Second-born children were delivered 2.5 (SD 0.9) years after firstborns. Firstborn and second-born children whose parents received the RP intervention with their first child had BMI that was 0.44 kg/m2 (95% CI: -0.82 to 0.06) and 0.36 kg/m2 (95% CI: -0.75 to 0.03) lower than controls, respectively. Linear and quadratic growth rates for BMI for firstborn and second-born cohorts were similar, but second-born children had a greater average BMI at 1 year of age (difference = -0.33 [95% CI: -0.52 to -0.15]). CONCLUSIONS: A RP educational intervention for obesity prevention delivered to parents of firstborns appears to spill over to second-born siblings.

Xenin and Related Peptides: Potential Therapeutic Role in Diabetes and Related Metabolic Disorders.

Xenin bioactivity and its role in normal physiology has been investigated by several research groups since its discovery in 1992. The 25 amino acid peptide hormone is secreted from the same enteroendocrine K-cells as the incretin hormone glucose-dependent insulinotropic polypeptide (GIP), with early studies highlighting the biological significance of xenin in the gastrointestinal tract, along with effects on satiety. Recently there has been more focus directed towards the role of xenin in insulin secretion and potential for diabetes therapies, especially through its ability to potentiate the insulinotropic actions of GIP as well as utilisation in dual/triple acting gut hormone therapeutic approaches. Currently, there is a lack of clinically approved therapies aimed at restoring GIP bioactivity in type 2 diabetes mellitus, thus xenin could hold real promise as a diabetes therapy. The biological actions of xenin, including its ability to augment insulin secretion, induce satiety effects, as well as restoring GIP sensitivity, earmark this peptide as an attractive antidiabetic candidate. This minireview will focus on the multiple biological actions of xenin, together with its proposed mechanism of action and potential benefits for the treatment of metabolic diseases such as diabetes.

Impact of bisphenol-A and synthetic estradiol on brain, behavior, gonads and sex hormones in a sexually labile coral reef fish.

Endocrine disrupting chemicals, such as bisphenol A (BPA) and ethinylestradiol (EE2), are detected in the marine environment from plastic waste and wastewater effluent. However, their impact on reproduction in sexually labile coral reef fish is unknown. The objective of this study was to determine impacts of environmentally relevant concentrations of BPA and EE2 on behavior, brain gene expression, gonadal histology, sex hormone profile, and plasma vitellogenin (Vtg) levels in the anemonefish, Amphiprion ocellaris. A. ocellaris display post-maturational sex change from male to female in nature. Sexually immature, male fish were paired together and fed twice daily with normal food (control), food containing BPA (100 µg/kg), or EE2 (0.02 µg/kg) (n = 9 pairs/group). Aggression toward an intruder male was measured at 1, 3, and 6 months. Blood was collected at 3 and 6 months to measure estradiol (E2), 11-ketotestosterone (11-KT), and Vtg. At the end of the study, fish were euthanized to assess gonad morphology and to measure expression of known sexually dimorphic genes in the brain. Relative to control, BPA decreased aggression, altered brain transcript levels, increased non-vitellogenic and vitellogenic eggs in the gonad, reduced 11-KT, and increased plasma Vtg. In two BPA-treated pairs, both individuals had vitellogenic eggs, which does not naturally occur. EE2 reduced 11-KT in subordinate individuals and altered expression of one transcript in the brain toward the female profile. Results suggest BPA, and to a lesser extent EE2, pollution in coral reef ecosystems could interfere with normal reproductive physiology and behavior of the iconic sexually labile anemonefish.

A Study to See the Effect of Social Media Usage Among Healthcare Providers.

Purpose This study aimed to assess how healthcare professionals (HCPs) use social media to determine how it influences the quality of patient care. Materials and methods This is a cross-sectional study conducted over eight months, between August 2020 and March 2021 using a questionnaire and checked amongst investigators. Results One hundred fifty-eight participants had electronic devices and 145 (91.9%) used social media at work. 26.6% of these HCPs said they spent less than an hour on social media forums, 31% said they spent one to two hours, 28.5% said two to three hours, and 13.9% said they spent more than four hours. As compared to nurses (46%), consultants and pharmacists use social media at a much lower rate (1% for each group). Compared to junior doctors, a higher percentage of nurses (40%) said they were aware of a social media policy at their hospital (8%). A quarter of healthcare employees (20%) were unaware of their workplace policy, potentially exposing sensitive medical details to the public. More research is needed to assess the particular effects of these results on patient care quality and can help in providing literature informing applications encrypted and secure patient data. Conclusion According to our results, a large percentage of healthcare quality professionals used social media networks. A significant proportion of doctors and nurses use it to visit online medical forums for improving education. A large portion of surveyed sample was unaware of hospital policy on social media usage. Further education is required to improve the right use of social media in the hospital setting.

A novel neurotensin/xenin fusion peptide enhances ß-cell function and exhibits antidiabetic efficacy in high-fat fed mice.

Neurotensin and xenin possess antidiabetic potential, mediated in part through augmentation of incretin hormone, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), action. In the present study, fragment peptides of neurotensin and xenin, acetyl-neurotensin and xenin-8-Gln, were fused together to create Ac-NT/XN-8-Gln. Following assessment of enzymatic stability, effects of Ac-NT/XN-8-Gln on in vitro ß-cell function were studied. Subchronic antidiabetic efficacy of Ac-NT/XN-8-Gln alone, and in combination with the clinically approved GLP-1 receptor agonist exendin-4, was assessed in high-fat fed (HFF) mice. Ac-NT/XN-8-Gln was highly resistant to plasma enzyme degradation and induced dose-dependent insulin-releasing actions (P<0.05 to P<0.01) in BRIN-BD11 ß-cells and isolated mouse islets. Ac-NT/XN-8-Gln augmented (P<0.001) the insulinotropic actions of GIP, while possessing independent ß-cell proliferative (P<0.001) and anti-apoptotic (P<0.01) actions. Twice daily treatment of HFF mice with Ac-NT/XN-8-Gln for 32 days improved glycaemic control and circulating insulin, with benefits significantly enhanced by combined exendin-4 treatment. This was reflected by reduced body fat mass (P<0.001), improved circulating lipid profile (P<0.01) and reduced HbA1c concentrations (P<0.01) in the combined treatment group. Following an oral glucose challenge, glucose levels were markedly decreased (P<0.05) only in combination treatment group and superior to exendin-4 alone, with similar observations made in response to glucose plus GIP injection. The combined treatment group also presented with improved insulin sensitivity, decreased pancreatic insulin content as well as increased islet and ß-cell areas. These data reveal that Ac-NT/XN-8-Gln is a biologically active neurotensin/xenin fusion peptide that displays prominent antidiabetic efficacy when administered together with exendin-4.

Ultraviolet light-induced collagen degradation inhibits melanoma invasion.

Ultraviolet radiation (UVR) damages the dermis and fibroblasts; and increases melanoma incidence. Fibroblasts and their matrix contribute to cancer, so we studied how UVR modifies dermal fibroblast function, the extracellular matrix (ECM) and melanoma invasion. We confirmed UVR-damaged fibroblasts persistently upregulate collagen-cleaving matrix metalloprotein-1 (MMP1) expression, reducing local collagen (COL1A1), and COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, inhibiting ECM degradation and MMP1 expression restored melanoma invasion. Primary cutaneous melanomas of aged humans show more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen, and collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. Thus, primary melanomas arising over collagen-degraded skin are less invasive, and reduced invasion improves survival. However, melanoma-associated fibroblasts can restore invasion by increasing collagen synthesis. Finally, high COL1A1 gene expression is a biomarker of poor outcome across a range of primary cancers.

Female Immunity Protects from Cutaneous Squamous Cell Carcinoma.

PURPOSE: Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women present with less aggressive primary cutaneous squamous cell carcinoma (cSCC) and early strong immune activation. EXPERIMENTAL DESIGN: We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients with primary cSCC (N = 738, N = 160), advanced-stage cSCC (N = 63, N = 20) and FVB/N mice exposed to equal doses of DMBA, as well as in human keratinocytes by whole-exome, bulk, and single-cell RNA sequencing. RESULTS: We show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test whether sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present with more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T-cell infiltration independently of mutations, a response that is absent in prednisolone-treated animals. In contrast, males increase the rate of mitosis and proliferation in response to carcinogen. Women's skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at UV radiation-damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women. CONCLUSIONS: This work shows the immune response is sex biased in cSCC and highlights female immunity offers greater protection than male immunity.