Differential Utilization Patterns of Total Ankle Arthroplasty vs Arthrodesis: A United States National Ambulatory Database Analysis.

Background: End-stage ankle osteoarthritis is a condition that can be treated with ankle arthrodesis (AA) or total ankle arthroplasty (TAA). The goal of this study is to estimate the 2016-2017 United States' utilization of TAA and AA in specific ambulatory settings and delineate patient and hospital factors associated with the selection of TAA vs AA for treatment of ankle osteoarthritis. Methods: TAA and AA procedures performed for ankle osteoarthritis were identified in the 2016-2017 Nationwide Ambulatory Surgery Sample (NASS) Database. Notably, the NASS database only examines instances of ambulatory surgery encounters at hospital-owned facilities. As such, instances of TAA and AA performed at privately owned or freestanding ambulatory surgical centers or those performed inpatient are excluded from this analysis. Cases were weighted using nationally representative discharge weights. Univariate analyses and a combined multiple logistic regression model were used to compare demographic, hospital-related, and socioeconomic factors associated with TAA vs AA. Results: In total, 6577 cases were identified, which represents 9072 cases after weighting. Of these, TAA was performed for 2233 (24.6%). Based on the logistic regression model, several factors were associated with increased utilization of TAA vs AA. With regard to patient factors, older patients were more likely to undergo TAA, as well as females. Conversely, patients with a higher comorbidity burden were less likely to receive TAA over AA.With regard to socioeconomic factors, urban teaching and urban nonteaching hospitals were significantly more likely to use TAA compared to rural hospitals. Similarly, privately insured patients and those with a median household income of $71 000 or more were also more likely to receive TAA over AA. Private hospitals ("not-for-profit" and "investor-owned") were significantly more likely to offer TAA over AA. Conclusion: Using a large nationally representative cohort, the current data revealed that during 2016-2017, 24.6% of operatively treated cases of end-stage ankle osteoarthritis in the ambulatory setting are treated with TAA. Associations between socioeconomic and hospital-level factors with TAA utilization suggest that nonclinical factors may influence surgical treatment choice for ankle osteoarthritis. Level of Evidence: Level III, retrospective cohort study.

Evaluation of potential reference genes in the biting midge Culicoides sonorensis for real-time quantitative PCR analyses.

Studies examining differentially expressed genes and gene silencing by RNA interference (RNAi) require a set of stably expressed reference genes for accurate normalization. The biting midge Culicoides sonorensis is an important vector of livestock pathogens and is often used as a model species for biting midge research. Here, we examine the stable expression of six candidate reference genes in C. sonorensis: actin, ß-tubulin, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), ribosomal protein subunit (RPS) 18, vacuolar ATPase subunit A (VhaA), and elongation factor 1-beta (EF1b). Gene expression was assessed under seven conditions, including cells treated with double-stranded RNA (dsRNA), 3rd and 4th instar larvae treated with dsRNA, six developmental stages, four adult female body parts or tissue groups, and females injected with bluetongue virus or vesicular stomatitis virus. Stable gene expression was assessed using RefFinder, NormFinder, geNorm, and BestKeeper. The ranked results for each analysis tool under each condition and a comprehensive ranking for each condition are presented. The data show that optimal reference genes vary between conditions and that just two reference genes were necessary for each condition. These findings provide reference genes for use under these conditions in future studies using real-time quantitative PCR to evaluate gene expression in C. sonorensis.

Cancer Relevance of Circulating Antibodies Against LINE-1 Antigens in Humans.

Long interspersed nuclear element-1 (LINE-1 or L1), the most abundant family of autonomous retrotransposons occupying over 17% of human DNA, is epigenetically silenced in normal tissues by the mechanisms involving p53 but is frequently derepressed in cancer, suggesting that L1-encoded proteins may act as tumor-associated antigens recognized by the immune system. In this study, we established an immunoassay to detect circulating autoantibodies against L1 proteins in human blood. Using this assay in >2,800 individuals with or without cancer, we observed significantly higher IgG titers against L1-encoded ORF1p and ORF2p in patients with lung, pancreatic, ovarian, esophageal, and liver cancers than in healthy individuals. Remarkably, elevated levels of anti-ORF1p-reactive IgG were observed in patients with cancer with disease stages 1 and 2, indicating that the immune response to L1 antigens can occur in the early phases of carcinogenesis. We concluded that the antibody response against L1 antigens could contribute to the diagnosis and determination of immunoreactivity of tumors among cancer types that frequently escape early detection. SIGNIFICANCE: The discovery of autoantibodies against antigens encoded by L1 retrotransposons in patients with five poorly curable cancer types has potential implications for the detection of an ongoing carcinogenic process and tumor immunoreactivity.

Near-peer tutoring: an effective adjunct for virtual anatomy learning.

With recent shifts in medical education to the virtual setting during the COVID-19 pandemic, previous methods of teaching anatomy have been challenged. As such, we created the Medical Students' Society Anatomy Club (MAC), a student-led near-peer tutoring initiative providing virtual anatomy learning opportunities through interactive large and small group sessions using cadaveric prosection images and models. Sessions had high attendance rates and satisfaction among students. This pilot project demonstrated that near-peer teaching in a virtual learning environment can be an effective adjunct to traditional medical anatomy curricula.

Avec la récente transition vers l'enseignement virtuel pendant la pandémie de COVID-19, les méthodes traditionnelles d'enseigner l'anatomie devront être mises en question. À ce titre, nous avons créé le Medical Students' Society Anatomy Club (MAC), une initiative de tutorat par les pairs qui fournit des ressources d'apprentissage via des séances virtuelles interactives, en petits et en grands groupes, utilisant des images de dissections cadavériques et des modèles. Les séances ont démontré des taux de participation et de satisfaction élevés parmi les étudiants. Ce projet pilote montre que l'enseignement par les pairs dans un cadre virtuel peut être un complément très efficace aux programmes d'anatomie médicale traditionnels.

Entomology beyond research and education: 2022 student debates.

The 2022 student debates of the Entomological Society of America (ESA) happened during the Joint Annual Meeting of the Entomological Societies of America, Canada, and British Columbia in Vancouver, BC, and addressed entomological aspects beyond research and education. The Student Debates Subcommittee of the ESA Student Affairs Committee and the participating student team members communicated for 8 months and prepared for the debates. The theme of the ESA meeting in 2022 was "Entomology as inspiration: Insects through art, science, and culture". There were 2 unbiased speakers who introduced the debate topics as well as 4 teams who debated the following 2 topics: (i) Is forensic entomology viable in criminal case investigations and court cases today? and (ii) Are insects being treated ethically in scientific research? The teams prepared for about 8 months, debated their arguments, and shared their thoughts with the audience. The teams were judged by a panel and the winners were recognized at the ESA Student Awards Session during the annual meeting.

A Short Course of Celecoxib Prevents Heterotopic Ossification Following Cementless Total Hip Arthroplasty.

Heterotopic ossification (HO) is a common complication after total hip arthroplasty (THA) and can result in pain and loss of motion of the hip. This is the first study in the literature to determine if a short course of Celecoxib is effective in the prevention of HO in patients undergoing cementless THA. In this retrospective study of prospectively collected data, consecutive patients undergoing a primary cementless THA were reviewed at a 2-year follow-up. The Control group consisted of 104 hips that did not receive Celecoxib (Control group), while the 208 hips in the Celecoxib group received 100 mg twice daily for 10 days. Radiographs, patient-recorded outcome measures and range of motion (ROM) were evaluated. Overall, there was a significantly decreased incidence of HO in the Celecoxib group (18.7%) than in the Control group (31.7%) (p = 0.01). The odds that a patient developed HO using Celecoxib were 0.4965 times the odds that a patient developed HO without treatment. Clinically, the Celecoxib group demonstrated significantly greater improvement in their mean WOMAC stiffness (0.35 vs. 0.17, p = 0.02) and physical function scores (3.26 vs. 1.83, p = 0.03) compared to those in the Control group, but there was no difference in the ROM between the two groups. This study is the first to demonstrate that the lowest dose of Celecoxib for a short course of only 10 days is a simple and effective prophylactic treatment option that can significantly reduce the incidence of HO following cementless THA.

Sex-specific Feeding Behavior of Adult House Flies, Musca domestica L. (Diptera: Muscidae).

House flies, Musca domestica L., (Diptera: Muscidae) mechanically vector diverse disease-causing microorganisms while foraging for food in agricultural and urban habitats. Although flies are diverse feeders, nutrient composition of food is important for both fly longevity and reproduction, especially for anautogenous females who require protein for egg production. We investigated whether fly sex and/or mating status influenced their preference for foods with varying macronutrient composition. Presumably mated or unmated male and female flies were separated by sex and offered four food, each in 10% solution offered on cotton wicks: sugar (carbohydrate-rich), fat-free milk (protein-rich, moderate carbohydrate), egg-yolk (protein and lipid-rich), and water (no macronutrients). Foods were colored with nontoxic dyes, which were rotated between replicates. After 4h exposure, flies were dissected to determine the type of food(s) ingested. The interaction of house fly sex and food type significantly influenced food preference, where females preferred milk (protein and carbohydrate-rich food), and males preferred mainly sugar (carbohydrate-rich). Furthermore, 32.8% of females and 10.6% of males foraged on multiple foods. While interaction of sex and mating status had no effect on food preference, milk preference was significantly higher in presumably mated than unmated females. We also tested whether food color influenced fly feeding preference, and found that color was most significant when flies were offered one food type, but negligible when multiple food types were present. This study suggests that bait-based fly control strategies should consider sex-specific preferences for various food attractants if aiming to target and control both male and female house flies.

Surgeon-Performed Intraoperative Peripheral Nerve Blocks and Periarticular Infiltration During Total Hip and Knee Arthroplasty: A Critical Analysis Review.

➢: Surgeon-performed intraoperative peripheral nerve blocks may improve operating room efficiency and reduce hospital resource utilization and, ultimately, costs. Additionally, these blocks can be safely performed intraoperatively by most orthopaedic surgeons, while only specifically trained physicians are able to perform ultrasound-guided peripheral nerve blocks. ➢: IPACK (infiltration between the popliteal artery and capsule of the knee) blocks are at least noninferior to periarticular infiltration when combined with an adductor canal block for analgesia following total knee arthroplasty. ➢: Surgeon-performed intraoperative adductor canal blocks are technically feasible and offer reliable anesthesia comparable with ultrasound-guided blocks performed by anesthesiologists. While clinical studies have shown promising results, additional Level-I studies are required. ➢: A surgeon-performed intraoperative psoas compartment block has been described as a readily available and safe technique, although there is some concern for femoral nerve analgesia, and temporary sensory changes have been reported.

Inflammatory response to retrotransposons drives tumor drug resistance that can be prevented by reverse transcriptase inhibitors.

Activation of endogenous retrotransposons frequently occurs in cancer cells and contributes to tumor genomic instability. To test whether inhibition of retrotranspositions has an anticancer effect, we used treatment with the nucleoside reverse transcriptase inhibitor (NRTI) stavudine (STV) in mouse cancer models, MMTV-HER2/Neu and Th-MYCN, that spontaneously develop breast cancer and neuroblastoma, respectively. In both cases, STV in drinking water did not affect tumor incidence nor demonstrate direct antitumor effects. However, STV dramatically extended progression-free survival in both models following an initial complete response to chemotherapy. To approach the mechanism underlying this phenomenon, we analyzed the effect of NRTI on the selection of treatment-resistant variants in tumor cells in culture. Cultivation of mouse breast carcinoma 4T1 in the presence of STV dramatically reduced the frequency of cells capable of surviving treatment with anticancer drugs. Global transcriptome analysis demonstrated that the acquisition of drug resistance by 4T1 cells was accompanied by an increase in the constitutive activity of interferon type I and NF-κB pathways and an elevated expression of LINE-1 elements, which are known to induce inflammatory responses via their products of reverse transcription. Treatment with NRTI reduced NF-κB activity and reverted drug resistance. Furthermore, the inducible expression of LINE-1 stimulated inflammatory response and increased the frequency of drug-resistant variants in a tumor cell population. These results indicate a mechanism by which retrotransposon desilencing can stimulate tumor cell survival during treatment and suggest reverse transcriptase inhibition as a potential therapeutic approach for targeting the development of drug-resistant cancers.

Immune checkpoint protein VSIG4 as a biomarker of aging in murine adipose tissue.

Adipose tissue is recognized as a major source of systemic inflammation with age, driving age-related tissue dysfunction and pathogenesis. Macrophages (Mφ) are central to these changes yet adipose tissue Mφ (ATMs) from aged mice remain poorly characterized. To identify biomarkers underlying changes in aged adipose tissue, we performed an unbiased RNA-seq analysis of ATMs from young (8-week-old) and healthy aged (80-week-old) mice. One of the genes identified, V-set immunoglobulin-domain-containing 4 (VSIG4/CRIg), encodes a Mφ-associated complement receptor and B7 family-related immune checkpoint protein. Here, we demonstrate that Vsig4 expression is highly upregulated with age in perigonadal white adipose tissue (gWAT) in two mouse strains (inbred C57BL/6J and outbred NIH Swiss) independent of gender. The accumulation of VSIG4 was mainly attributed to a fourfold increase in the proportion of VSIG4+ ATMs (13%-52%). In a longitudinal study, VSIG4 expression in gWAT showed a strong correlation with age within a cohort of male and female mice and correlated strongly with physiological frailty index (PFI, a multi-parameter assessment of health) in male mice. Our results indicate that VSIG4 is a novel biomarker of aged murine ATMs. VSIG4 expression was also found to be elevated in other aging tissues (e.g., thymus) and was strongly induced in tumor-adjacent stroma in cases of spontaneous and xenograft lung cancer models. VSIG4 expression was recently associated with cancer and several inflammatory diseases with diagnostic and prognostic potential in both mice and humans. Further investigation is required to determine whether VSIG4-positive Mφ contribute to immunosenescence and/or systemic age-related deficits.

Acute and chronic interactive treatments of serotonin 5HT2C and dopamine D1 receptor systems for decreasing nicotine self-administration in female rats.

A variety of neural systems are involved in the brain bases of tobacco addiction. Animal models of nicotine addiction have helped identify a variety of interacting neural systems involved in the pathophysiology of tobacco addiction. We and others have found that drug treatments affecting many of those neurotransmitter systems significantly decrease nicotine self-administration. These treatments include dopamine D1 receptor antagonist, histamine H1 antagonist, serotonin 5HT2C agonist, glutamate NMDA antagonist, nicotinic cholinergic α4ß2 partial agonist and nicotinic cholinergic α3ß4 antagonist acting drugs. It may be the case that combining treatments that affect different neural systems underlying addiction may be more efficacious than single drug treatment. In the current study, we tested the interactions of the D1 antagonist SCH-23390 and the serotonin 5HT2c agonist lorcaserin, both of which we have previously shown to significantly reduce nicotine self-administration. In the acute interactions study, both SCH-23390 and lorcaserin significantly reduced nicotine self-administration when given alone and had additive effects when given in combination. In the chronic study, each drug alone caused a significant decrease in nicotine self-administration. No additive effect was seen in combination because SCH-23390 given alone chronically was already highly effective. Chronic administration of the combination was not seen to significantly prolong reduced nicotine self-administration into the post-treatment period. This research shows that unlike lorcaserin and SCH-23390 interactions when given acutely, when given chronically in combination they do not potentiate or prolong each other's effects in reducing nicotine self-administration.

Paternal THC exposure in rats causes long-lasting neurobehavioral effects in the offspring.

Developmental neurotoxicity of a wide variety of toxicants mediated via maternal exposure during gestation is very well established. In contrast, the impacts of paternal toxicant exposure on offspring neurobehavioral function are much less well studied. A vector for paternal toxicant exposure on development of his offspring has been identified. Sperm DNA can be imprinted by chemical exposures of the father. Most but not all of the epigenetic marks in sperm are reprogrammed after fertilization. The persisting epigenetic marks can lead to abnormal genetic expression in the offspring. We have found that paternal delta-9-tetrohydrocannabinol (THC) exposure in rats causes changes in methylation of sperm (Murphy et al., 2018). This is similar to cannabis-associated changes in sperm DNA methylation we found in human males who smoke cannabis (Murphy et al., 2018). In the current study we investigated the intergeneration effects of THC exposure of young adult male rats (0 or 2 mg/kg/day orally for 12 days) to the neurobehavioral development of their offspring. This paternal THC exposure was not found to significantly impact the clinical health of the offspring, including litter size, sex ratio, pup birth weight, survival and growth. However, it did cause a long-lasting significant impairment in attentional performance in the offspring relative to controls when they were tested in adulthood. There was also a significant increase in habituation of locomotor activity in the adult offspring of the males exposed to THC prior to mating. This study shows that premating paternal THC exposure even at a modest dose for a brief period can cause deleterious long-term behavioral effects in the offspring, notably significant impairment in an operant attention task. Further research should be conducted to determine the degree to which this type of risk is seen in humans and to investigate the mechanisms underlying these effects and possible treatments to ameliorate these long-term adverse behavioral consequences of paternal THC exposure.

Cells exhibiting strong p16INK4a promoter activation in vivo display features of senescence.

The activation of cellular senescence throughout the lifespan promotes tumor suppression, whereas the persistence of senescent cells contributes to aspects of aging. This theory has been limited, however, by an inability to identify and isolate individual senescent cells within an intact organism. Toward that end, we generated a murine reporter strain by "knocking-in" a fluorochrome, tandem-dimer Tomato (tdTom), into exon 1α of the p16INK4a locus. We used this allele (p16tdTom ) for the enumeration, isolation, and characterization of individual p16INK4a -expressing cells (tdTom+). The half-life of the knocked-in transcript was shorter than that of the endogenous p16INK4a mRNA, and therefore reporter expression better correlated with p16INK4a promoter activation than p16INK4a transcript abundance. The frequency of tdTom+ cells increased with serial passage in cultured murine embryo fibroblasts from p16tdTom/+ mice. In adult mice, tdTom+ cells could be readily detected at low frequency in many tissues, and the frequency of these cells increased with aging. Using an in vivo model of peritoneal inflammation, we compared the phenotype of cells with or without activation of p16INK4a and found that tdTom+ macrophages exhibited some features of senescence, including reduced proliferation, senescence-associated ß-galactosidase (SA-ß-gal) activation, and increased mRNA expression of a subset of transcripts encoding factors involved in SA-secretory phenotype (SASP). These results indicate that cells harboring activation of the p16INK4a promoter accumulate with aging and inflammation in vivo, and display characteristics of senescence.

Persistent attenuation of nicotine self-administration in rats by co-administration of chronic nicotine infusion with the dopamine D1 receptor antagonist SCH-23390 or the serotonin 5-HT2C agonist lorcaserin.

Tobacco addiction each year causes millions of deaths worldwide. Brain nicotinic acetylcholine receptors have been shown to be central to tobacco addiction. Nicotine replacement therapy aids tobacco cessation, but the success rate is still far too low. This may in part be due to the fact that neurons with nicotinic receptors are not the only neural systems involved in tobacco addiction. Interacting neural systems also play important roles in tobacco addiction. Nicotine increases the release of a variety of neurotransmitters, including dopamine and serotonin. Dopamine, in particular dopamine D1 receptors, has been shown to be involved in the reinforcing action of nicotine. Serotonin through its actions on 5-HT2C receptors has been shown to play a key role in modulating the reinforcement of addictive drugs, including nicotine and alcohol. Combination of treatments could provide greater treatment efficacy. These studies were conducted to evaluate combination therapies utilizing nicotine replacement therapy in conjunction with either a dopamine D1 receptor antagonist SCH-23390 or a serotonin 5-HT2C receptor agonist, lorcaserin. Female Sprague-Dawley rats were given access to self-administer nicotine via IV infusions. Osmotic pumps were implanted to reproduce the kinetic of chronic nicotine patch therapy. SCH-23390 (0.02 mg/kg) or lorcaserin (0.6 mg/kg) were administered prior to nicotine self-administration sessions. Reproducing earlier findings SCH-23390, lorcaserin and nicotine replacement therapy were effective at reducing IV nicotine self-administration. 5HT2C agonist treatment had additive effects with chronic nicotine infusion for significantly lowering nicotine self-administration. This study demonstrates the feasibility of combination of chronic nicotine with therapies targeting non-nicotinic receptors as treatment options for tobacco addiction.

Cannabinoid exposure and altered DNA methylation in rat and human sperm.

Little is known about the reproductive effects of paternal cannabis exposure. We evaluated associations between cannabis or tetrahydrocannabinol (THC) exposure and altered DNA methylation in sperm from humans and rats, respectively. DNA methylation, measured by reduced representation bisulfite sequencing, differed in the sperm of human users from non-users by at least 10% at 3,979 CpG sites. Pathway analyses indicated Hippo Signaling and Pathways in Cancer as enriched with altered genes (Bonferroni p < 0.02). These same two pathways were also enriched with genes having altered methylation in sperm from THC-exposed versus vehicle-exposed rats (p < 0.01). Data validity is supported by significant correlations between THC exposure levels in humans and methylation for 177 genes, and substantial overlap in THC target genes in rat sperm (this study) and genes previously reported as having altered methylation in the brain of rat offspring born to parents both exposed to THC during adolescence. In humans, cannabis use was also associated with significantly lower sperm concentration. Findings point to possible pre-conception paternal reproductive risks associated with cannabis use.

Critical developmental periods for effects of low-level tobacco smoke exposure on behavioral performance.

Tobacco exposure during development leads to neurobehavioral dysfunction in children, even when exposure is limited to secondhand smoke. We have previously shown in rats that developmental exposure to tobacco smoke extract (TSE), at levels mimicking secondhand smoke, starting preconception and extending throughout gestation, evoked subsequent locomotor hyperactivity and cognitive impairment. These effects were greater than those caused by equivalent exposures to nicotine alone, implying that other agents in tobacco smoke contributed to the adverse behavioral effects. In the present study, we examined the critical developmental windows of vulnerability for these effects, restricting TSE administration (0.2 mg/kg/day nicotine equivalent, or DMSO vehicle, delivered by subcutaneously-implanted pumps) to three distinct 10 day periods: the 10 days preceding mating, the first 10 days of gestation (early gestation), or the second 10 days of gestation (late gestation). The principal behavioral effects revealed a critical developmental window of vulnerability, as well as sex selectivity. Late gestational TSE exposure significantly increased errors in the initial training on the radial-arm maze in female offspring, whereas no effects were seen in males exposed during late gestation, or with either sex in the other exposure windows. In attentional testing with the visual signal detection test, male offspring exposed to TSE during early or late gestation showed hypervigilance during low-motivating conditions. These results demonstrate that gestational TSE exposure causes persistent behavioral effects that are dependent on the developmental window in which exposure occurs. The fact that effects were seen at TSE levels modeling secondhand smoke, emphasizes the need for decreasing involuntary tobacco smoke exposure, particularly during pregnancy.

p16(Ink4a) and senescence-associated ß-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli.

Constitutive p16Ink4a expression, along with senescence-associated ß-galactosidase (SAßG), are commonly accepted biomarkers of senescent cells (SCs). Recent reports attributed improvement of the healthspan of aged mice following p16Ink4a-positive cell killing to the eradication of accumulated SCs. However, detection of p16Ink4a/SAßG-positive macrophages in the adipose tissue of old mice and in the peritoneal cavity of young animals following injection of alginate-encapsulated SCs has raised concerns about the exclusivity of these markers for SCs. Here we report that expression of p16Ink4a and SAßG in macrophages is acquired as part of a physiological response to immune stimuli rather than through senescence, consistent with reports that p16Ink4a plays a role in macrophage polarization and response. Unlike SCs, p16Ink4a/SAßG-positive macrophages can be induced in p53-null mice. Macrophages, but not mesenchymal SCs, lose both markers in response to M1- [LPS, IFN-α, Poly(I:C)] and increase their expression in response to M2-inducing stimuli (IL-4, IL-13). Moreover, interferon-inducing agent Poly(I:C) dramatically reduced p16Ink4a expression in vivo in our alginate bead model and in the adipose tissue of aged mice. These observations suggest that the antiaging effects following eradication of p16Ink4a-positive cells may not be solely attributed to SCs but also to non-senescent p16Ink4a/SAßG-positive macrophages.

Murine mesenchymal cells that express elevated levels of the CDK inhibitor p16(Ink4a) in vivo are not necessarily senescent.

Age-related health decline has been attributed to the accumulation of senescent cells recognized in vivo by p16(Ink4a) expression. The pharmacological elimination of p16(Ink4a)-positive cells from the tissues of mice was shown to extend a healthy lifespan. Here, we describe a population of mesenchymal cells isolated from mice that are highly p16(INK4a)-positive are proficient in proliferation but lack other properties of cellular senescence. These data, along with earlier reports on p16(Ink4a)-positive macrophages, indicate that p16(Ink4a)-positive and senescent cell populations only partially intersect, therefore, extending the list of potential cellular targets for anti- aging therapies.

The ventral hippocampal muscarinic cholinergic system plays a key role in sexual dimorphisms of spatial working memory in rats.

Sex differences in cognitive processing and function have been documented in human and animal studies. Females have been found to perform better than males on non-spatial memory tasks, while males tend to outperform females on spatial memory tasks. The neural mechanisms underlying these sexual dimorphisms are unclear. However, it is known that the cholinergic system is critically involved in memory processes, and there are notable differences between males and females in cholinergic system function and receptor expression. In particular, there are sex differences in the processing of information in the frontal cortex and hippocampus. In this study, we examined the roles of muscarinic and nicotinic acetylcholine receptors in the medial frontal cortex (MfC) and ventral hippocampus (VH) on spatial working memory in male and female rats. Local infusions of scopolamine (SCOP) and mecamylamine (MEC) (10, 20, 50 µg/side) were used to antagonize these receptors in each respective brain region during performance in the 16-arm radial arm maze. Infusions of SCOP into the VH caused a significant increase in memory errors in female rats, but had no significant effect on males, while infusions of MEC into the VH had no effect on either sex. Infusions of both SCOP (50 µg/side) and MEC (20 µg/side) into the MfC caused working memory impairments in both sexes. These results show that muscarinic acetylcholine receptors in the VH are differentially vulnerable to spatial memory impairments in females. Ventral hippocampal muscarinic acetylcholine receptors may play a key role in male-female differences in spatial memory.