Background: Sex differences are crucial to understanding neuropsychiatric disorders, yet they are often overlooked in the development of therapies. Transcranial alternating current stimulation (tACS) shows promise for cognitive enhancement, but its sex-specific effects are largely unknown.
Methods: In this study, the effects of 10 Hz and 40 Hz tACS on spatial cognition were examined in male and female mice using three tests: the Y-maze to evaluate spatial recognition memory, the Barnes maze to evaluate spatial learning and memory related to punishment, and the reversal Barnes maze to evaluate reversal learning. General behaviors, such as anxiety, exploration, and locomotion, were evaluated using the elevated plus maze and open field tests.
Results: The results showed that 40 Hz tACS improved spatial recognition memory in males, while 10 Hz and 40 Hz tACS enhanced spatial learning in females. Males learned faster, while females performed better initially in the spatial learning process. In addition, no significant effects of tACS were observed in reversal learning, spatial memory, anxiety, or exploration. Interestingly, males exhibited reduced locomotion compared to females across tasks, and tACS potentially exacerbated this difference.
Conclusions: This animal study suggests that tACS may influence spatial cognition differently in males and females. Our findings highlight the importance of considering the interaction between sex and stimulation frequency when optimizing tACS intervention parameters.
The association between exposure to particulates in polluted air and cognitive impairment is an emerging and significant health concern, particularly among younger populations. Although exposure to particulate matter ≤ 2.5 μm (PM2.5) is linked with a lower estimated risk for dementia compared to traditional risk factors such as APOEɛ4 gene variants, the widespread and long-term population exposure to PM2.5 pose substantial implications for public health. This review explores the sex differences in cognitive function induced by PM2.5, which are age-dependent and distinct from the sex bias observed in Alzheimer's disease. In addition to biological sex and sex hormones, we also discuss the role of epigenetic regulation as a mechanism underlying sex-specific cognitive vulnerabilities to environmental toxins, particularly PM2.5. Understanding these differences is important for developing targeted interventions and public health strategies to mitigate the cognitive impacts of PM2.5 exposure.
Background: To examine the impact of gender and its interaction with the side of surgery on cognition, affectivity, and quality of life (QOL) in drug-resistant epilepsy, as well as postsurgical changes in these domains.
Methods: In this prospective cohort study, 86 adults with TLE (46 women and 40 men) underwent a neuropsychological evaluation before and one year after surgery, including attention, executive function, language, verbal and visual memory, anxiety, depression, and QOL outcomes.
Results: After surgery, 84.1% of patients were seizure-free. In the group with right-sided surgery, men had poorer executive functioning (p = 0.05) and memory than women (for all, p < 0.05), independently of the time point (i.e., before or after surgery). Men with right-side surgery showed poorer executive function than those with left-side surgery (for all, p < 0.04), and a postsurgical anxiety decrease (p < 0.001). Women with right-side surgery had a better memory than those with left-side surgery, independently of the time point (for all, p < 0.001). Both genders showed postsurgical QOL improvements modulated by surgery side (p = 0.037). Regardless of the surgery side, women had poorer semantic fluency (p = 0.03) and QOL (p = 0.05) than men and postsurgical semantic fluency declines (p = 0.024), whereas men had postsurgical executive function declines (p = 0.05).
Conclusions: These findings underscore the importance of accounting for both gender and the side of surgery in understanding cognitive, affective, and QOL outcomes in patients with TLE, and could be useful for designing targeted neuropsychological interventions.
Background: Biological sex is a critical determinant in cardiovascular and renal disease outcomes. Although angiotensin II (Ang II) infusion is widely used to model hypertension in mice and rats, little is known about its effects in the Syrian hamster, a small rodent increasingly used for translational research. This study aimed to develop a model of chronic Ang II-induced hypertension in Syrian hamsters and investigate sex-specific differences in blood pressure, renal pathology, and components of the renin-angiotensin system (RAS).
Methods: Male and female Syrian hamsters (8-9 weeks old) were infused subcutaneously with Ang II (200 ng/kg/min) or saline via osmotic minipumps for four weeks. Mean arterial pressure (MAP) and kidney wet weight were determined on the euthanasia day. The kidneys were analyzed for renal pathology; renal RAS enzymes (ACE and ACE2) were measured by colorimetric assay and qPCR; cytokines (IL-6 and IL-1β) were measured by qPCR; and the angiotensin receptor type 1 (AT1R) was measured by radioligand binding and qPCR.
Results: Ang II infusion increased MAP in both sexes but elicited a significantly greater response in females (+ 50 mmHg) than males (+ 27 mmHg, p < 0.005). Female hamsters exhibited pronounced kidney injury, including acute tubular necrosis, glomerular sclerosis, and vascular fibrinoid necrosis, along with a 2-fold increase in kidney weight normalized to body weight. Ang II significantly downregulated renal ACE, ACE2, and AT1R expression and activity in females but not in males. Renal IL-6 and IL-1β mRNA levels were elevated 20-fold and 3.9-fold, respectively, in females, compared to modest increases in males.
Conclusions: Female Syrian hamsters exhibit heightened vulnerability to Ang II-induced hypertension and renal damage compared to males, marked by exaggerated blood pressure elevation, enhanced renal inflammation, and suppression of classical RAS components. This novel hamster model provides a unique platform for studying sex-specific mechanisms of hypertension and renal pathology, with translational relevance for subpopulations of women who are at increased risk of Ang II-dependent hypertension-associated renal disease.
When used as variables in biomedical research, sex and gender can be difficult to operationalize and measure. Questions have arisen about whether either category is stable or causally meaningful in a research context. Here, we discuss some of the limitations of using both or even one of these categories in correlational or experimental work. We argue that attempting to draw a distinction between sex and gender can reignite the nature/nurture debate, inadvertently bringing outdated metaphors and assumptions about innateness and causation into our research. Many researchers, including ourselves, have described sex and gender as separate collections of causal factors (which we describe as a "bucket" metaphor) or as entangled (a "knot" metaphor). Because they regard sex and gender as conceptually separable and internally consistent, such metaphors have limited value for understanding the drivers of diversity in our data. Rather than continuing to reify sex and gender as distinct buckets or threads of explanatory variables, we call for deconstruction of these categories by focusing instead on clearly operationalized, instantiating variables that researchers can manipulate or measure. Our proposed approach differs from recent, similar calls in that we are not suggesting the exclusion of a sex/gender category from statistical models; instead, we recommend keeping it-not as a representation of biological reality, but as a tool used under a careful set of assumptions. We provide example datasets to illustrate how a sex/gender category can, when thoughtfully operationalized, be used to improve statistical rigor and inferential precision. In addition, we advocate for attention to variation within sex/gender, which is more informative in investigations of mechanism than comparing means across sex/gender categories.
Background: Plectropomus leopardus is a hermaphrodite fish with a unique pattern of gonadal development. However, the molecular mechanism of sexual differentiation in this species remains unclear. The Doublesex and Mab-3 related transcription factor (dmrt) gene family are known to play a crucial role in gonad differentiation and development. Notably, systematic investigations into the composition and function of the dmrt gene family in this hermaphrodite fish remain conspicuously lacking.
Methods: In this study, we systematically identified members of the dmrt gene family through genomic database mining in P. leopardus. Tissue and stage-specific expression profiles of dmrt paralogs were quantitatively analyzed using reverse transcription quantitative PCR (qPCR), revealing sexually dimorphic expression patterns in the gonads at various developmental stages. Furthermore, the expression distribution of dmrt2a at different developmental stages was explored using fluorescence in situ hybridization (FISH). Subsequently, dmrt2a was interfered with using RNAi technology, and the regulatory effect of dmrt2a on oocytes was verified by combining FISH and TUNEL assays.
Results: In this study, we identified six members of the dmrt gene family in P. leopardus and designated them as dmrt1, dmrt2a, dmrt2b, dmrt3, dmrta1 and dmrta2 based on the homology analysis results, respectively. Whole-tissue expression analysis revealed that the dmrt genes exhibit tissue-specific expression pattern in P. leopardus. Notably, dmrt1 and dmrt2a are highly expressed in the gonads, suggesting their potential role in gonadal development. Further qPCR results showed that dmrt genes are differentially expressed between males and females at different developmental stages. Among them, dmrt2a is highly expressed in the ovary at different developmental stages and is found to be a pivotal factor in ovarian development. FISH was used to further verify the expression of dmrt2a in oocytes. In addition, knockdown of dmrt2a in gonads caused oocyte apoptosis and decreased oocyte number, demonstrating the critical role of dmrt2a in oocyte development.
Conclusions: This study demonstrates that dmrt2a plays a crucial regulatory role in the development of the oocytes in P. leopardus, supplementing the understanding of the functional roles of the dmrt gene family in vertebrate sex differentiation. These findings will help to understand the properties and functions of the dmrt genes in P. leopardus and provide a solid basis for further studies on the functional mechanisms of dmrt genes in hermaphroditic fish.
To explain observed disparities in health outcomes between men and women, sex essentialist approaches assign causal primacy to sex-related biology. In this essay, we present three case studies to illustrate how sex essentialism can distort human biomedical research and distill three maxims for countering this distortion: (1) engage in responsible citation practices; (2) generate and weigh alternative hypotheses for apparent observations of sex differences; (3) take care in constructing the appropriate denominator when making sex comparisons. We offer these maxims as broadly applicable standards of evidence to guide biomedical research that includes analysis of potential sex differences, as well as to support Institutional Review Boards (IRBs), funders, publishers, and peer reviewers in evaluating sex difference findings. If widely applied, these maxims would substantially improve the rigor, precision, and utility of the knowledge base of sex and gender science.
Despite a substantial therapeutic arsenal to treat patients affected by heart failure (HF), no treatment specifically targets alterations of cardiac energy metabolism described in HF. Based on the results of previous studies demonstrating the cardiac preventive effects of B vitamins when introduced before inducing cardiac pressure overload in mice, we investigated the efficacy of a diet supplemented with a B vitamin cocktail (B3, B9 and B12 (3VitB)) to restore energy metabolism and improve cardiac function in an animal model of established HF. Four weeks after transverse aortic constriction (TAC) induction, male and female mice were treated with 3VitB. 3VitB increased life expectancy and reduced the TAC-induced alterations of cardiac parameters in males. Although these effects on survival and cardiac function were less clear in females due to their higher resistance to TAC, the 3VitB cocktail was beneficial in females as 8 weeks of treatment improved physical capacities and led to milder cardiomyocyte stress-induced hypertrophy in similar ways to those observed in males. In both sexes, 3VitB protected cardiac mitochondrial oxidative capacities, at least by supporting the process of mitochondrial biogenesis. Interestingly, our results revealed sex-specificities not only in response to cardiac pressure overload but also in response to 3VitB treatment. Overall, this study demonstrated the efficacy of 3VitB to preserved cardiac function and energy metabolism in an established HF model, especially in males that are more sensitive to cardiac pressure overload. This confers credit to vitamin supplementations and to metabolic therapy as new strategies to treat HF.
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