Hypersensitivity of the nicotinic acetylcholine receptor subunit (CHRNA2L9'S/L9'S) in female adolescent mice produces deficits in nicotine-induced facilitation of hippocampal-dependent learning and memory.

Adolescence is characterized by a critical period of maturation and growth, during which regions of the brain are vulnerable to long-lasting cognitive disturbances. Adolescent exposure to nicotine can lead to deleterious neurological and psychological outcomes. Moreover, the nicotinic acetylcholine receptor (nAChR) has been shown to play a functionally distinct role in the development of the adolescent brain. CHRNA2 encodes for the α2 subunit of nicotinic acetylcholine receptors associated with CA1 oriens lacunosum moleculare GABAergic interneurons and is associated with learning and memory. Previously, we found that adolescent male hypersensitive CHRNA2L9'S/L9' mice had impairments in learning and memory during a pre-exposure-dependent contextual fear conditioning task that could be rescued by low-dose nicotine exposure. In this study, we assessed learning and memory in female adolescent hypersensitive CHRNA2L9'S/L9' mice exposed to saline or a subthreshold dose of nicotine using a hippocampus-dependent task of pre-exposure-dependent contextual fear conditioning. We found that nicotine-treated wild-type female mice had significantly greater improvements in learning and memory than both saline-treated wild-type mice and nicotine-treated CHRNA2L9'S/L9' female mice. Thus, hyperexcitability of CHRNA2 in female adolescent mice ablated the nicotine-mediated potentiation of learning and memory seen in wild-types. Our results indicate that nicotine exposure during adolescence mediates sexually dimorphic patterns of learning and memory, with wild-type female adolescents being more susceptible to the effects of sub-threshold nicotine exposure. To understand the mechanism underlying sexually dimorphic behavior between hyperexcitable CHRNA2 mice, it is critical that further research be conducted.

Temporal sex specific brain gene expression pattern during early rat embryonic development.

Background: The classical concept of brain sex differentiation suggests that steroid hormones released from the gonads program male and female brains differently. However, several studies indicate that steroid hormones are not the only determinant of brain sex differentiation and that genetic differences could also be involved. Methods: In this study, we have performed RNA sequencing of rat brains at embryonic days 12 (E12), E13, and E14. The aim was to identify differentially expressed genes between male and female rat brains during early development. Results: Analysis of genes expressed with the highest sex differences showed that Xist was highly expressed in females having XX genotype with an increasing expression over time. Analysis of genes expressed with the highest male expression identified three early genes, Sry2, Eif2s3y, and Ddx3y. Discussion: The observed sex-specific expression of genes at early development confirms that the rat brain is sexually dimorphic prior to gonadal action on the brain and identifies Sry2 and Eif2s3y as early genes contributing to male brain development.

Deep learning in sex estimation from photographed human mandible using the Human Osteological Research Collection.

Sex estimation is a necessary part of forensic and osteological analyses of skeletal human remains in the construction of a biological profile. Several skeletal traits are sexually dimorphic and used for skeletal sex estimation. The human mandible and morphological traits therein have been long used for sex estimation, but the validity of using the mandible in this purpose has become a concern. In this study, we examined the potential of artificial intelligence (AI) and especially deep learning (DL) to provide accurate sex estimations from the mandible. We used 193 modern South African mandibles from the Human Osteological Research Collection (HORC) in the Sefako Makgatho Health Sciences university with known sex to conduct our study. All mandibles were photographed from the same angle and the photographs were analyzed with an open-source DL software. The best-performing DL algorithm estimated the sex of males with 100% accuracy and females with 76.9% accuracy. However, further studies with a higher number of specimens could provide more reliable validity for using AI when building the biological profile from skeletal remains.

Analysis of the roles of MAD proteins in the wing dimorphism of Nilaparvata lugens.

Wing dimorphism in Nilaparvata lugens is controlled by the insulin-like growth factor 1 (IGF-1) signaling - Forkhead transcription factors (IIS-FoxO) pathway. However, the role of this signal in the wing development program remains largely unclear. Here, we identified 2 R-SMAD proteins, NlMAD1 and NlMAD2, in the brown planthopper (BPH) transcriptome, derived from the intrinsic transforming growth factor-ß pathway of insect wing development. Both proteins share high sequence similarity and conserved domains. Phylogenetic analysis placed them in the R-SMAD group and revealed related insect orthologs. The expression of Nlmad1 was elevated in the late instar stages of the macropterous BPH strain. Nlmad1 knockdown in nymphs results in malformed wings and reduced wing size in adults, which affects the forewing membrane. By contrast, Nlmad2 expression was relatively consistent across BPH strains and different developmental stages. Nlmad2 knockdown had a milder effect on wing morphology and mainly affected forewing veins and cuticle thickness in the brachypterous strain. NlMAD1 functions downstream of the IIS-FoxO pathway by mediating the FoxO-regulated vestigial transcription and wing morph switching. Inhibiting Nlmad1 partially reversed the long-winged phenotype caused by NlFoxO knockdown. These findings indicate that NlMAD1 and NlMAD2 play distinct roles in regulating wing development and morph differentiation in BPH. Generally, NlMAD1 is a key mediator of the IIS-FoxO pathway in wing morph switching.

HLH-30/TFEB mediates sexual dimorphism in immunity in caenorhabditis elegans.

Sexual dimorphism affects various biological functions, including immune responses. However, the mechanisms by which sex alters immunity remain largely unknown. Using Caenorhabditis elegans as a model species, we showed that males exhibit enhanced immunity against various pathogenic bacteria through the upregulation of HLH-30 (Helix Loop Helix 30/TFEB (transcription factor EB), a transcription factor crucial for macroautophagy/autophagy. Compared with hermaphroditic C. elegans, males displayed increased activity of HLH-30/TFEB, which contributed to enhanced antibacterial immunity. atg-2 (AuTophaGy (yeast Atg homolog) 2) upregulated by HLH-30/TFEB mediated increased immunity in male C. elegans. Thus, the males appear to be equipped with enhanced HLH-30/TFEB-mediated autophagy, which increases pathogen resistance, and this may functionally prolong mate-searching ability with reduced risk of infection.

Extreme functional specialization of fertile leaves in a widespread fern species and its implications on the evolution of reproductive dimorphism.

Resource allocation theory posits that organisms distribute limited resources across functions to maximize their overall fitness. In plants, the allocation of resources among maintenance, reproduction, and growth influences short-term economics and long-term evolutionary processes, especially during resource scarcity. The evolution of specialized structures to divide labor between reproduction and growth can create a feedback loop where selection can act on individual organs, further increasing specializaton and  resource allocation. Ferns exhibit diverse reproductive strategies, including dimorphism, where leaves can either be sterile (only for photosynthesis) or fertile (for spore dispersal). This dimorphism is similar to processes in seed plants (e.g., the production of fertile flowers and sterile leaves), and presents an opportunity to investigate divergent resource allocation between reproductive and vegetative functions in specialized organs. Here, we conducted anatomical and hydraulic analyses on Onoclea sensibilis L., a widespread dimorphic fern species, to reveal significant structural and hydraulic divergences between fertile and sterile leaves. Fertile fronds invest less in hydraulic architecture, with nearly 1.5 times fewer water-conducting cells and a nearly 0.5 times less drought-resistant xylem compared to sterile fronds. This comes at the increased relative investment in structural support, which may help facilitate spore dispersal. These findings suggest that specialization in ferns-in the form of reproductive dimorphism-can enable independent selection pressures on each leaf type, potentially optimizing spore dispersal in fertile fronds and photosynthetic efficiency in sterile fronds. Overall, our study sheds light on the evolutionary implications of functional specialization and highlights the importance of reproductive strategies in shaping plant fitness and evolution.

Mucor germinans, a novel dimorphic species resembling Paracoccidioides in a clinical sample: questions on ecological strategy.

Dimorphism is known among the etiologic agents of endemic mycoses as well as in filamentous Mucorales. Under appropriate thermal conditions, mononuclear yeast forms alternate with multi-nucleate hyphae. Here, we describe a dimorphic mucoralean fungus obtained from the sputum of a patient with Burkitt lymphoma and ongoing graft-versus-host reactions. The fungus is described as Mucor germinans sp. nov. Laboratory studies were performed to simulate temperature-dependent dimorphism, with two environmental strains Mucor circinelloides and Mucor kunryangriensis as controls. Both strains could be induced to form multinucleate arthrospores and subsequent yeast-like cells in vitro. Multilateral yeast cells emerge in all three Mucor species at elevated temperatures. This morphological transformation appears to occur at body temperature since the yeast-like cells were observed in the lungs of our immunocompromised patient. The microscopic appearance of the yeast-like cells in the clinical samples is easily confused with that of Paracoccidioides. The ecological role of yeast forms in Mucorales is discussed.IMPORTANCEMucormycosis is a devastating disease with high morbidity and mortality in susceptible patients. Accurate diagnosis is required for timely clinical management since antifungal susceptibility differs between species. Irregular hyphal elements are usually taken as the hallmark of mucormycosis, but here, we show that some species may also produce yeast-like cells, potentially being mistaken for Candida or Paracoccidioides. We demonstrate that the dimorphic transition is common in Mucor species and can be driven by many factors. The multi-nucleate yeast-like cells provide an effective parameter to distinguish mucoralean infections from similar yeast-like species in clinical samples.

Female alternative reproductive tactics: diversity and drivers.

It is often argued that anisogamy causes alternative reproductive tactics (ARTs) to be more common in males than females. We challenge this view by pointing out logical flaws in the argument. We then review recent work on the diversity of female ARTs, listing several understudied types such as solitary versus communal breeding and facultative parthenogenesis. We highlight an important difference between male and female ARTs that caused female ARTs to be overlooked: male ARTs tend to focus on successful fertilization, whereas female ARTs occur at many stages of reproduction and often form complex networks of decision points. We propose to study correlated female ARTs as a whole to better understand their drivers and eco-evolutionary dynamics.

The consequences of calcium: investigating intracortical reproductive signals in the American alligator for sex determination.

Identifying sex in extinct archosaurs has proven difficult due, in part, to low sample sizes, preservation biases, and methodology. While previous studies have largely focused on morphological traits, here we investigate intracortical signals of egg-shelling in extant alligators. Egg-shelling requires large mobilizations of calcium reserves. Aves utilize medullary tissue as a calcium reserve, whereas crocodylians mobilize calcium from cortical bone or osteoderms. If crocodylians derive calcium from bone cortices for egg-shelling, then egg-shelling events should be detectable in female crocodylian cortical bone. We examined mid-diaphyseal Alligator mississippiensis femoral bone cross-sections for signals of reproduction. Compaction and area of resorbed tissue were measured in femoral cross-sections from captive raised male (n = 10) and female (n = 29) A. mississippiensis of 26-27 years at age of death. This sample is more robust than previous studies, though reproductive history data is unknown. Femora from a small sample of wild caught male (n = 6) and female (n = 6) A. mississippiensis were also measured. Data were analyzed by pairwise t-tests between sex and captivity status. There was no significant difference in either compaction or resorbed tissue values between male and female alligators, regardless of habitat (wild or captive-raised). A reproductive signal was undetectable in this study and any quantifiable differences between sexes appears to be driven by size dimorphism. Cortical resorption rates in the femora of male and female alligators are reflective of normal aging processes and not indicative of egg-shelling during reproduction. Examination of younger alligators would clarify processes driving bone turnover during reproductively active years.

Development of hepatic steatosis in male and female mule ducks after respective force-feeding programs.

Male and female mule ducks were subjected to a force-feeding diet to induce liver steatosis as it is generally done only with male ducks for the production of foie gras. The different biochemical measurements indicated that the course of hepatic steatosis development was present in both sexes and associated with a huge increase in liver weight mainly due to the synthesis and accumulation of lipids in hepatocytes. In livers of male and female ducks, this lipid accumulation was associated with oxidative stress and hypoxia. However, certain specific modifications (kinetics of lipid droplet development and hepatic inflammation) indicate that female ducks may tolerate force-feeding less well, at least at the hepatic level. This is in contradiction with what is generally reported concerning hepatic steatosis induced by dietary disturbances in mammals but could be explained by the very specific conditions imposed by force-feeding. Despite this, force-feeding female ducks seems entirely feasible, provided that the final quality of the product is as good as that of the male ducks, which will remain to be demonstrated in future studies.

Quantifying Sexual Dimorphism by Analyzing Ramus Flexure and Bigonial Width in Orthopantomography.

Introduction The mandible constitutes one of the skull's largest and strongest bones. Growth spurts can influence it, and it has a variety of dimorphic traits that can be used to identify sex. In addition to observing, comparing, and evaluating the potential for mandibular ramus flexure and bigonial breadth to discriminate between sexes using digital orthopantomograms (OPG), a retrospective study was conducted to examine the validity of this method for sex estimation in the Indian population. Aim and objective This study aims to quantify sexual dimorphism by analyzing two mandibular parameters, the ramus flexure and the bigonial width, using orthopantomography (OPG). The objective is to determine the accuracy of sex determination using the ramus flexure and bigonial width. Materials and methods A total of 500 OPG images (250 males and 250 females) were analyzed using the Planmeca software (Helsinki, Finland). The ramus flexure was measured as the angle formed between the tangent to the inferior border of the mandible and the tangent to the posterior border of the ramus. The bigonial width was measured as the distance between the left and right gonion points. A statistical analysis was performed to assess sexual dimorphism and determine the accuracy of sex determination using these parameters. The study employed descriptive statistics, such as means and standard deviations, and an independent t-test to determine the significance of the characteristics in relation to males and females. Results The mean bigonial width for females was 193.3068 mm (SD = 13.51669 mm) and for males was 217.6308 mm (SD = 10.87453 mm), with a statistically significant difference (p = 0.000). The 95% confidence interval for the difference in the bigonial width between males and females was between -49.97173 mm and -43.93787 mm. For the ramus flexure, the mean was 0.0000 for both males and females (SD = 0.00000), with a significant difference between males and females (p = 0.003). The 95% confidence interval for the difference in the ramus flexure between males and females was between -0.59543 and -0.12457. Conclusion The results indicated significant sexual dimorphism in both the ramus flexure and bigonial width. This study demonstrated that the ramus flexure and bigonial width, measured using orthopantomography (OPG), exhibited significant sexual dimorphism. The analysis of these mandibular parameters provided valuable information for sex determination in forensic and anthropological contexts.

Is it time to revise the fighting strategy toward type 2 diabetes? Sex and pollution as new risk factors.

Diabetes mellitus, a metabolic condition affecting around 537 million individuals worldwide, poses significant challenges, particularly among the elderly population. The etiopathogenesis of type 2 diabetes (T2D) depends on a combination of the effects driven by advancing age, genetic background, and lifestyle habits, e.g. overnutrition. These factors influence the development of T2D differently in men and women, with an obvious sexual dimorphism possibly underlying the diverse clinical features of the disease in different sexes. More recently, environmental pollution, estimated to cause 9 million deaths every year, is emerging as a novel risk factor for the development of T2D. Indeed, exposure to atmospheric pollutants such as PM2.5, O3, NO2, and Persistent Organic Pollutants (POP)s, along with their combination and bioaccumulation, is associated with the development of T2D and obesity, with a 15 % excess risk in case of exposure to very high levels of PM2.5. Similar data are available for plasticizer molecules, e.g. bisphenol A and phthalates, emerging endocrine-disrupting chemicals. Even though causality is still debated at this stage, preclinical evidence sustains the ability of multiple pollutants to affect pancreatic function, promote insulin resistance, and alter lipid metabolism, possibly contributing to T2D onset and progression. In addition, preclinical findings suggest a possible role also for plastic itself in the development of T2D. Indeed, pioneeristic studies evidenced that micro- or nanoplastics (MNP)s, particles in the micro- or nano- range, promote cellular damage, senescence, inflammation, and metabolic disturbances, leading to insulin resistance and impaired glucose metabolism in animal and/or in vitro models. Here we synthesize recent knowledge relative to the association between air-related or plastic-derived pollutants and the incidence of T2D, discussing also the possible mechanistic links suggested by the available literature. We then anticipate the need for future studies in the field of candidate therapeutic strategies limiting pollution-induced damage in preclinical models, such as SGLT-2 inhibitors. We finally postulate that future guidelines for T2D prevention should consider pollution and sex an additional risk factors to limit the diabetes pandemic.

Eco-geographic and sexual variation of the ribcage in Homo sapiens.

Up to now, Allen and Bergmann's rules have been studied in modern humans by analyzing differences in limb length, height, or body mass. However, there are no publications studying the effects of latitude in the 3D configuration of the ribcage. To assess this issue, we digitally reconstructed the ribcages of a balanced sample of 109 adult individuals of global distribution. Shape and size of the ribcage was quantified using geometric morphometrics. Our results show that the ribcage belonging to tropical individuals is smaller and slenderer compared to others living in higher latitudes, which is in line with Allen and Bergmann's rules and suggests an allometric relationship between size and shape. Although sexual dimorphism was observed in the whole sample, significant differences were only found in tropical populations. Our proposal is that, apart from potential sexual selection, avoiding heat loss might be the limiting factor for sexual dimorphism in cold-adapted populations.

Radiomorphometric analysis of the metapodial bones in the Scottish fold cats.

Scottish Fold cats (Felis catus, Linnaeus 1758) are one of the most well-known and popular cat breeds in the world, characterized by their folded ears attached to the head. Very frequently, cats fall prey of different trauma and accidents that can cause bone fractures especially in the metapodial bones. The method of radiometry is used in veterinary practice to visualize and measure different parts of the animal skeleton. The aim of this study was to assess the linear parameters derived from radiographic images of the metacarpals and metatarsals in Scottish Fold cats and additionally detecting potential sexual dimorphism. Radiographic images of 24 adult Scottish Fold cats (12 male and 12 females) of different ages and weights were analysed. Six linear measurements of the metapodial bones were evaluated to investigate any differences between the sexes. The linear radiometric measurements of the five metacarpals (MC1-5) and the four metatarsals (MT2-5) bones were larger in male metapodial bones than that of female cats. The maximum length (Ml) of the MC1 and MC2 was statistically different between sex, respectively, (p = 0.001) and (p = 0.05). The others metacarpal bones were different in mostly all linear parameters but not statistically significant. The most significant differences between sexes were observed in the parameter of width proximal end (Wp) of MC1-3 (p = 0.001) and MC4 (p = 0.05). More statistical different was MT2 and less MT3. The linear parameter of Bd of the MT4 was the most different statistically between sex (p = 0.001). The results of the study will be useful in function of comparative anatomy, in veterinary clinical practice, in zoo archaeology and in the veterinary forensic investigation.

Sex differences in patellar facet shape among healthy and osteoarthritic cohorts.

OBJECTIVE: Patellofemoral osteoarthritis (OA) may be more common in females than males. Reasons for this are not fully understood, but sex differences in patellar morphology may help explain this phenomenon. We quantified differences in patellar morphology between males and females in healthy and patellofemoral OA populations. DESIGN: 97 (50F, 47M) healthy and 67 (40F, 27M) OA knees were scanned via computed tomography. OA individuals were on a wait list for total knee replacement. Patella 3D models were segmented and 2D measurements were recorded: patellar width and height, lateral and medial facet width, and surface area. Medial and lateral facet surface topography was mapped using 81 points to describe 3D articular surface shape. Sex and group differences were assessed using Procrustes ANOVA. Data were ordinated using Principal Component Analysis. RESULTS: Differences in patellar 2D measurements between healthy and OA individuals were smaller than were differences between males and females from healthy and OA groups. Sex and healthy/OA differences were most pronounced for medial facet shape, which featured a posteriorly-curving facet and taller, narrower facet shape in males compared to females. Lateral facet shape variance was higher in OA cohorts compared to healthy groups. CONCLUSIONS: Medial and lateral facet shapes showed different patterning of variation by sex and healthy/OA status. Lateral facet shape may be of interest in future models of OA risk in the patellofemoral joint, here showing increased magnitudes of variance associated with increased severity of disease (patellofemoral KL score).

Sphingosine kinase 2 and p62 regulation are determinants of sexual dimorphism in hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality, and its incidence is increasing due to endemic obesity. HCC is sexually dimorphic in both humans and rodents with higher incidence in males, although the mechanisms contributing to these correlations remain unclear. Here, we examined the role of sphingosine kinase 2 (SphK2), the enzyme that regulates the balance of bioactive sphingolipid metabolites, sphingosine-1-phosphate (S1P) and ceramide, in gender specific MASH-driven HCC. METHODS: Male and female mice were fed a high fat diet with sugar water, a clinically relevant model that recapitulates MASH-driven HCC in humans followed by physiological, biochemical cellular and molecular analyses. In addition, correlations with increased risk of HCC recurrence were determined in patients. RESULTS: Here, we report that deletion of SphK2 protects both male and female mice from Western diet-induced weight gain and metabolic dysfunction without affecting hepatic lipid accumulation or fibrosis. However, SphK2 deficiency decreases chronic diet-induced hepatocyte proliferation in males but increases it in females. Remarkably, SphK2 deficiency reverses the sexual dimorphism of HCC, as SphK2-/- male mice are protected whereas the females develop liver cancer. Only in male mice, chronic western diet induced accumulation of the autophagy receptor p62 and its downstream mediators, the antioxidant response target NQO1, and the oncogene c-Myc. SphK2 deletion repressed these known drivers of HCC development. Moreover, high p62 expression correlates with poor survival in male HCC patients but not in females. In hepatocytes, lipotoxicity-induced p62 accumulation is regulated by sex hormones and prevented by SphK2 deletion. Importantly, high SphK2 expression in male but not female HCC patients is associated with a more aggressive HCC differentiation status and increased risk of cancer recurrence. CONCLUSIONS: This work identifies SphK2 as a potential regulator of HCC sexual dimorphism and suggests SphK2 inhibitors now in clinical trials could have opposing, gender-specific effects in patients.

Dimorphic Regulation of the MafB Gene by Sex Steroids in Hamsters, Mesocricetus auratus.

MafB is a transcription factor that regulates macrophage differentiation. Macrophages are a traditional feature of the hamster Harderian gland (HG); however, studies pertaining to MafB expression in the HG are scant. Here, the full-length cDNA of the MafB gene in hamsters was cloned and sequenced. Molecular characterization revealed that MafB encodes a protein containing 323 amino acids with a DNA-binding domain, a transactivation domain, and a leucine zipper domain. qPCR assays indicated that MafB was expressed in different tissues of both sexes. The highest relative expression levels in endocrine tissues were identified in the pancreas. Gonadectomy in male hamsters was associated with significantly higher mRNA levels in the HG; replacement with dihydrotestosterone restored mRNA expression. The HG in male hamsters contained twofold more MafB mRNA than the HG of female hamsters. Adrenals revealed similar mRNA relative expression levels during the estrous cycle. The estrous phase was associated with higher mRNA levels in the ovary. A significantly up-regulated expression and sexual dimorphism of MafB was found in the pancreas. Therefore, MafB in the HG may play an active role in the macrophage differentiation required for phagocytosis activity and intraocular repair. Additionally, sex steroids appear to strongly influence the MafB expression in the HG and pancreas. These studies highlight the probable biological importance of MafB in immunological defense and pancreatic ß cell regulation.

Acrobatic training prevents learning impairments and astrocyte remodeling in the hippocampus of rats undergoing chronic cerebral hypoperfusion: sex-specific benefits.

Background: Chronic cerebral hypoperfusion (CCH) leads to memory and learning impairments associated with degeneration and gliosis in the hippocampus. Treatment with physical exercise carries different therapeutic benefits for each sex. We investigated the effects of acrobatic training on astrocyte remodeling in the CA1 and CA3 subfields of the hippocampus and spatial memory impairment in male and female rats at different stages of the two-vessel occlusion (2VO) model. Methods: Wistar rats were randomly allocated into four groups of males and females: 2VO acrobatic, 2VO sedentary, sham acrobatic, and sham sedentary. The acrobatic training was performed for 4 weeks prior to the 2VO procedure. Brain samples were collected for morphological and biochemical analysis at 3 and 7 days after 2VO. The dorsal hippocampi were removed and prepared for Western blot quantification of Akt, p-Akt, COX IV, cleaved caspase-3, PARP, and GFAP. GFAP immunofluorescence was performed on slices of the hippocampus to count astrocytes and apply the Sholl's circle technique. The Morris water maze was run after 45 days of 2VO. Results: Acutely, the trained female rats showed increased PARP expression, and the 2VO-trained rats of both sexes presented increased GFAP levels in Western blot. Training, mainly in males, induced an increase in the number of astrocytes in the CA1 subfield. The 2VO rats presented branched astrocytes, while acrobatic training prevented branching. However, the 2VO-induced spatial memory impairment was partially prevented by the acrobatic training. Conclusion: Acrobatic training restricted the astrocytic remodeling caused by 2VO in the CA1 and CA3 subfields of the hippocampus. The improvement in spatial memory was associated with more organized glial scarring in the trained rats and better cell viability observed in females.

Effects of methylphenidate on mitochondrial dynamics and bioenergetics in the prefrontal cortex of juvenile rats are sex-dependent.

Methylphenidate (MPH) is a central nervous system stimulant drug and a first order prescription in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Although MPH biochemistry in neurodevelopment is not completely understood, studies showed it alters energy metabolism in rat brains. ADHD prevalence during neurodevelopment is related to males and the investigation has been mainly done in these subjects, therefore, little is known about MPH action in females and, consequently, about sexual dimorphism. In the present study we evaluated markers of mitochondrial dynamics (DRP1 and MFN2, fission and fusion, respectively), biogenesis (mtTFA) and bioenergetics (respiratory chain complexes) in prefrontal cortex of male and female juvenile rats submitted to exposure to MPH to better understand MPH effect during postnatal neurodevelopment. ATP and oxidative stress levels were also evaluated. Wistar rats received intraperitoneal injection of MPH (2.0 mg/kg) or control (saline), once a day, from 15th to 45th day of age. Results showed that MPH increased DRP1 and decreased MFN2, as well as increased mtTFA in prefrontal cortex of male rats. In female, MPH decreased NRF1 and increased Parkin, which are mitochondrial regulatory proteins. Respiratory chain complexes (complex I, SDH, complexes III and IV), ATP production and oxidative stress parameters were altered and shown to be sex-dependent. Taken together, results suggest that chronic MPH exposure at an early age in healthy animals changes mitochondrial dynamics, biogenesis and bioenergetics differently depending on the sex of the subjects.

Sex dimorphism of IL-17-secreting peripheral blood mononuclear cells in ankylosing spondylitis based on bioinformatics analysis and machine learning.

BACKGROUND: Ankylosing spondylitis (AS) with radiographic damage is more prevalent in men than in women. IL-17, which is mainly secreted from peripheral blood mononuclear cells (PBMCs), plays an important role in the development of AS. Its expression is different between male and female. However, it is still unclear whether sex dimorphism of IL-17 contribute to sex differences in AS. METHODS: GSE221786, GSE73754, GSE25101, GSE181364 and GSE205812 datasets were collected from the Gene Expression Omnibus (GEO) database. Differential expressed genes (DEGs) were analyzed with the Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) methods. CIBERSORTx and EcoTyper algorithms were used for immune infiltration analyses. Machine learning based on the XGBoost algorithm model was used to identify the impact of DEGs. The Connectivity Map (CMAP) database was used as a drug discovery tool for exploring potential drugs based on the DEGs. RESULTS: According to immune infiltration analyses, T cells accounted for the largest proportion of IL-17-secreting PBMCs, and KEGG analyses suggested an enhanced activation of mast cells among male AS patients, whereas the expression of TNF was higher in female AS patients. Other signaling pathways, including those involving metastasis-associated 1 family member 3 (MAT3) or proteasome, were found to be more activated in male AS patients. Regarding metabolic patterns, oxidative phosphorylation pathways and lipid oxidation were significantly upregulated in male AS patients. In XGBoost algorithm model, DEGs including METRN and TMC4 played important roles in the disease process. we integrated the CMAP database for systematic analyses of polypharmacology and drug repurposing, which indicated that atorvastatin, famciclocir, ATN-161 and taselisib may be applicable to the treatment of AS. CONCLUSIONS: We analyzed the sex dimorphism of IL-17-secreting PBMCs in AS. The results showed that mast cell activation was stronger in males, while the expression of TNF was higher in females. In addition, through machine learning and the CMAP database, we found that genes such as METRN and TMC4 may promote the development of AS, and drugs such as atorvastatin potentially could be used for AS treatment.