An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis.

Myeloid cells are known to suppress antitumour immunity1. However, the molecular drivers of immunosuppressive myeloid cell states are not well defined. Here we used single-cell RNA sequencing of human and mouse non-small cell lung cancer (NSCLC) lesions, and found that in both species the type 2 cytokine interleukin-4 (IL-4) was predicted to be the primary driver of the tumour-infiltrating monocyte-derived macrophage phenotype. Using a panel of conditional knockout mice, we found that only deletion of the IL-4 receptor IL-4Rα in early myeloid progenitors in bone marrow reduced tumour burden, whereas deletion of IL-4Rα in downstream mature myeloid cells had no effect. Mechanistically, IL-4 derived from bone marrow basophils and eosinophils acted on granulocyte-monocyte progenitors to transcriptionally programme the development of immunosuppressive tumour-promoting myeloid cells. Consequentially, depletion of basophils profoundly reduced tumour burden and normalized myelopoiesis. We subsequently initiated a clinical trial of the IL-4Rα blocking antibody dupilumab2-5 given in conjunction with PD-1/PD-L1 checkpoint blockade in patients with relapsed or refractory NSCLC who had progressed on PD-1/PD-L1 blockade alone (ClinicalTrials.gov identifier NCT05013450 ). Dupilumab supplementation reduced circulating monocytes, expanded tumour-infiltrating CD8 T cells, and in one out of six patients, drove a near-complete clinical response two months after treatment. Our study defines a central role for IL-4 in controlling immunosuppressive myelopoiesis in cancer, identifies a novel combination therapy for immune checkpoint blockade in humans, and highlights cancer as a systemic malady that requires therapeutic strategies beyond the primary disease site.

Ultrathin ferroic HfO2-ZrO2 superlattice gate stack for advanced transistors.

With the scaling of lateral dimensions in advanced transistors, an increased gate capacitance is desirable both to retain the control of the gate electrode over the channel and to reduce the operating voltage1. This led to a fundamental change in the gate stack in 2008, the incorporation of high-dielectric-constant HfO2 (ref. 2), which remains the material of choice to date. Here we report HfO2-ZrO2 superlattice heterostructures as a gate stack, stabilized with mixed ferroelectric-antiferroelectric order, directly integrated onto Si transistors, and scaled down to approximately 20 ångströms, the same gate oxide thickness required for high-performance transistors. The overall equivalent oxide thickness in metal-oxide-semiconductor capacitors is equivalent to an effective SiO2 thickness of approximately 6.5 ångströms. Such a low effective oxide thickness and the resulting large capacitance cannot be achieved in conventional HfO2-based high-dielectric-constant gate stacks without scavenging the interfacial SiO2, which has adverse effects on the electron transport and gate leakage current3. Accordingly, our gate stacks, which do not require such scavenging, provide substantially lower leakage current and no mobility degradation. This work demonstrates that ultrathin ferroic HfO2-ZrO2 multilayers, stabilized with competing ferroelectric-antiferroelectric order in the two-nanometre-thickness regime, provide a path towards advanced gate oxide stacks in electronic devices beyond conventional HfO2-based high-dielectric-constant materials.

The potential of NO+ and O2 +• in switchable reagent ion proton transfer reaction time-of-flight mass spectrometry.

Selected ion flow tube mass spectrometry (SIFT-MS) and proton transfer reaction mass spectrometry with switchable reagent ion capability (PTR+SRI-MS) are analytical techniques for real-time qualification and quantification of compounds in gas samples with trace level concentrations. In the detection process, neutral compounds-mainly volatile organic compounds-are ionized via chemical ionization with ionic reagents or primary ions. The most common reagent ions are H3 O+ , NO+ and O2 +• . While ionization with H3 O+ occurs by means of proton transfer, the ionization via NO+ and O2 +• offers a larger variety on ionization pathways, as charge transfer, hydride abstraction and so on are possible. The distribution of the reactant into various reaction channels depends not only on the usage of either NO+ or O2 +• , but also on the class of analyte compounds. Furthermore, the choice of the reaction conditions as well as the choice of either SIFT-MS or PTR+SRI-MS might have a large impact on the resulting products. Therefore, an overview of both NO+ and O2 +• as reagent ions is given, showing differences between SIFT-MS and PTR+SRI-MS as used analytical methods revealing the potential how the knowledge obtained with H3 O+ for different classes of compounds can be extended with the usage of NO+ and O2 +• .

Assessing Endoscopic Response in Locally Advanced Rectal Cancer Treated with Total Neoadjuvant Therapy: Development and Validation of a Highly Accurate Convolutional Neural Network.

BACKGROUND: Rectal tumors display varying degrees of response to total neoadjuvant therapy (TNT). We evaluated the performance of a convolutional neural network (CNN) in interpreting endoscopic images of either a non-complete response to TNT or local regrowth during watch-and-wait surveillance. METHODS: Endoscopic images from stage II/III rectal cancers treated with TNT from 2012 to 2020 at a single institution were retrospectively reviewed. Images were labelled as Tumor or No Tumor based on endoscopy timing (before, during, or after treatment) and the tumor's endoluminal response. A CNN was trained using ResNet-50 architecture. The area under the curve (AUC) was analyzed during training and for two test sets. The main test set included images of tumors treated with TNT. The other contained images of local regrowth. The model's performance was compared to sixteen surgeons and surgical trainees who evaluated 119 images for evidence of tumor. Fleiss' kappa was calculated by respondent experience level. RESULTS: A total of 2717 images from 288 patients were included; 1407 (51.8%) contained tumor. The AUC was 0.99, 0.98, and 0.92 for training, main test, and local regrowth test sets. The model performed on par with surgeons of all experience levels for the main test set. Interobserver agreement was good ( k = 0.71-0.81). All groups outperformed the model in identifying tumor from images of local regrowth. Interobserver agreement was fair to moderate ( k = 0.24-0.52). CONCLUSIONS: A highly accurate CNN matched the performance of colorectal surgeons in identifying a noncomplete response to TNT. However, the model demonstrated suboptimal accuracy when analyzing images of local regrowth.

Identification and expression analysis of two steamer-like retrotransposons in the Chilean blue mussel (Mytilus chilensis).

BACKGROUND: Disseminated neoplasia (DN) is a proliferative cell disorder of the circulatory system of bivalve mollusks. The disease is transmitted between individuals and can also be induced by external chemical agents such as bromodeoxyuridine. In Mya arenaria, we have cloned and characterized an LTR-retrotransposon named Steamer. Steamer mRNA levels and gene copy number correlates with DN and can be used as a marker of the disease. So far, the only mollusk where a retrotransposon expression relates to DN is Mya arenaria. On the other hand, it has been reported that the Chilean blue mussel Mytilus chilensis can also suffers DN. Our aim was to identify retrotransposons in Mytilus chilensis and to study their expression levels in the context of disseminated neoplasia. RESULTS: Here we show that 7.1% of individuals collected in August 2018, from two farming areas, presents morphological characteristics described in DN. Using Steamer sequence to interrogate the transcriptome of M. chilensis we found two putative retrotransposons, named Steamer-like elements (MchSLEs). MchSLEs are present in the genome of M. chilensis and MchSLE1 is indeed an LTR-retrotransposon. Neither expression, nor copy number of the reported MchSLEs correlate with DN status but both are expressed at different levels among individual animals. We also report that in cultured M. chilensis haemocytes MchSLEs1 expression can be induced by bromodeoxyuridine. CONCLUSIONS: We conclude that SLEs present in Mytilus chilensis are differentially expressed among individuals and do not correlate with disseminated neoplasia. Treatment of haemocytes with a stressor like bromodeoxyuridine induces expression of MchSLE1 suggesting that in Mytilus chilensis environmental stressors can induce activation of LTR-retrotransposon.

Influence of physical activity level and perceived social support on mental health and psychological distress in women with menopause problems.

Perceived Social Support (PSS) and Physical Activity (PA) could have an important role in reducing psychological distress in women with problems in the menopausal period. The aim was to analyze the associations between a) Self-Perceived Health (SPH), prevalence of self-reported depression and anxiety, and mental health and its subscales, through the Goldberg General Health Questionnaire (GHQ-12) with b) the Physical Activity Level (PAL) and c) the PSS, through the Duke-UNC-11 functional social support questionnaire in Spanish women with problems in the menopausal period. This document uses data from the Spanish National Health Survey of 2017, focusing on women between 40 and 69 years of age with problems in the menopausal period. Dependency relationships were found between the prevalence of depression and PAL, anxiety and PAL, and SPH with PAL (p < 0.001). Weak inverse correlations were found between PAL and mental health, Coping Success, Self-confidence, and Stress (rho: - 0.214 to - 0.258; p < 0.001). Also, weak and very weak significant inverse correlations were found between PAL and all items of the GHQ-12. Weak inverse correlations were found between PSS scores and mental health, Coping, and Stress (r: -0.201 to - 0.304; p < 0.001). Likewise, weak and very weak inverse correlations, although statistically significant, were found between the PSS scores and the responses to the GHQ-12 items. Very active women with higher PSS have less psychological distress, higher self-esteem, and better prevalence of positive health.

Characterization of cornea donors at a tissue center in the city of Medellin, Colombia.

The cornea transplant is considered the most frequently performed type of transplant in the world, with a demand that has been increasing in recent years. An observational descriptive study was conducted, focusing on the ocular tissue extracted from cadaveric donors from January 2019 to December 2021 at the Red Cross Eye Bank in Medellin, Colombia. This is the first epidemiological characterization of corneal donor tissues within the eye banks of our city, where high rates of violence-related deaths explain that tissue donors are mostly young individuals. This, in turn, results in excellent counts of endothelial cells and tissue viability in their microscopic studies. Additionally, there are lower rates of discarded tissues compared to similar studies.

Antimicrobial resistance of Neisseria gonorrhoeae in Latin American countries: a systematic review.

BACKGROUND: Detailed information is needed on the dynamic pattern of antimicrobial resistance (AMR) in Neisseria gonorrhoeae in Latin America and the Caribbean (LAC). OBJECTIVES: To conduct a systematic review of AMR in N. gonorrhoeae in LAC. METHODS: Electronic searches without language restrictions were conducted in PubMed, Embase, Cochrane Library, EconLIT, Cumulative Index of Nursing and Allied Health Literature, Centre for Reviews and Dissemination, and Latin American and Caribbean Literature in Health Sciences. Studies were eligible if published between 1 January 2011 and 13 February 2021, conducted in any LAC country (regardless of age, sex and population) and measured frequency and/or patterns of AMR to any antimicrobial in N. gonorrhoeae. The WHO Global Gonococcal Antimicrobial Surveillance Programme (WHO-GASP) for LAC countries and Latin American AMR SurveillanceNetwork databases were searched. AMR study quality was evaluated according to WHO recommendations. RESULTS: AMR data for 38, 417 isolates collected in 1990-2018 were included from 31 publications, reporting data from Argentina, Brazil, Colombia, Peru, Uruguay, Venezuela and WHO-GASP. Resistance to extended-spectrum cephalosporins was infrequent (0.09%-8.5%). Resistance to azithromycin was up to 32% in the published studies and up to 61% in WHO-GASP. Resistance to penicillin, tetracycline and ciprofloxacin was high (17.6%-98%, 20.7%-90% and 5.9%-89%, respectively). Resistance to gentamicin was not reported, and resistance to spectinomycin was reported in one study. CONCLUSIONS: This review provides data on resistance to azithromycin, potentially important given its use as first-line empirical treatment, and indicates the need for improved surveillance of gonococcal AMR in LAC. Trial registration: Registered in PROSPERO, CRD42021253342.

PI-RR: The Prostate Imaging for Recurrence Reporting System for MRI Assessment of Local Prostate Cancer Recurrence After Radiation Therapy or Radical Prostatectomy-A Review.

The purpose of this article is to review clinical application of the Prostate Imaging for Recurrence Reporting (PI-RR) system. This system, released in 2021, represents international consensus-based guidelines for the acquisition, interpretation, and reporting of multiparametric MRI performed to detect locally recurrent prostate cancer after radiation therapy or radical prostatectomy. The system reduces variability through use of a standardized and structured reporting approach whereby the overall level of suspicion of recurrence is classified on a 5-point scale. The overall suspicion score is derived from 5-point scales for assessing DWI and dynamic contrast-enhanced (DCE) imaging. Separate scales for both DWI and DCE imaging are provided for evaluation after radiation therapy and after radical prostatectomy. These scales account for the relation between detected abnormalities and the location of the primary tumor on pretreatment imaging. T2-weighted imaging is also assessed on a 5-point scale and is useful for anatomic imaging but does not influence the overall score. Initial retrospective studies have shown promising results with respect to the reproducibility and accuracy of PI-RR in detecting locally recurrent tumor.

Prevalence and predictors of Twiddler's syndrome.

BACKGROUND: Twiddler's syndrome is a poorly understood clinical phenomenon when patients either consciously or subconsciously rotate their cardiac device resulting in lead dislodgement. We aimed to determine the true prevalence and risk factors associated with Twiddler's syndrome in a real-world population. METHODS: A retrospective chart review was performed on all patients who underwent cardiac device implantation from January 1st 2017 until Jan 1st 2022. We specifically searched for the terms "Twiddler" or "Twiddler's" imbedded within the text of the medical chart. Demographic and clinical variables were collected from the electronic medical record system. We utilized multivariable logistic regression analysis as well as Kaplan-Meier prediction models to determine independent clinical predictors of Twiddler's syndrome as well as associated mortality, respectively. RESULTS: Twenty one out of 1793 patients (1.2%) were identified as having Twiddler's syndrome after chart review. Independent variables associated with Twiddler's syndrome were female sex (OR 3.76; 95% CI 1.29-10.95), antidepressant medications (OR 3.58; 95% CI 1.07-11.99), and BMI (OR 1.08; 95% CI 1.03-1.31). There was no increased six-month mortality via Kaplan-Meier analysis. CONCLUSION: Our study shows that 1.2% of patients in our real-world population had evidence of Twiddler's syndrome. Independent predictors of Twiddler's syndrome include female sex, antidepressant medications as well as BMI.

Correction: Back et al. A New Micromonospora Strain with Antibiotic Activity Isolated from the Microbiome of a Mid-Atlantic Deep-Sea Sponge. Mar. Drugs 2021, 19, 105.

After publication of this article [...].

Murine typhus and other potentially lethal rickettsial diseases in Chiapas, Mexico.

Not available.

Modulation of chemoimmunotherapy efficacy in non-small cell lung cancer by sex and histology: a real-world, patient-level analysis.

BACKGROUND: It has been postulated that patient's sex impacts response to immunotherapy. Sex modulation of immunotherapy benefit, however, has not yet been explored using patient-level data, where potential confounders, as well as histologic type, can be accounted for. Here we investigated the association between sex and chemoimmunotherapy efficacy for non-small cell lung cancer (NSCLC) using a large, nation-wide dataset. PATIENTS & METHODS: Stage IV NSCLC patients diagnosed in 2015 were identified in the National Cancer Database (NCDB). Patients were treated with either chemoimmunotherapy or chemotherapy alone. The efficacy of the addition of immunotherapy treatment by sex was investigated using both an adjusted Cox proportional hazards model and propensity-score matching, in both the overall cohort and stratified by histological subtype. RESULTS: 2064 (16%) patients received chemoimmunotherapy and10,733 (84%) received chemotherapy alone. Adjusted survival analysis in the overall cohort showed that both males (hazards ratio (HR)adj: 0.80, 95% CI: 0.74-0.87) and females (HRadj: 0.83, 95% CI: 0.76-0.90) had better OS when treated with chemoimmunotherapy than chemotherapy alone, with no statistically significant interaction between sex and receipt of immunotherapy (p = 0.63). Propensity matching confirmed these results. However, for those with squamous cell histology, male patients derived more benefit from chemoimmunotherapy treatment than females (HRadj: 0.73, 95% CI: 0.58-0.91 vs HRadj: 1.03, 95% CI: 0.76-1.38; p for interaction = 0.07). CONCLUSION: Male patients with squamous cell carcinoma may derive more benefit from chemoimmunotherapy treatment. Histology likely plays an important role in how sex modulates immunotherapy efficacy.

Evaluation of the T2-weighted (T2W) adrenal MRI calculator to differentiate adrenal pheochromocytoma from lipid-poor adrenal adenoma.

OBJECTIVES: To evaluate the T2-weighted (T2W) MRI calculator to differentiate adrenal pheochromocytoma from lipid-poor adrenal adenoma. METHODS: Twenty-nine consecutive pheochromocytomas resected between 2010 and 2019 were compared to 23 consecutive lipid-poor adrenal adenomas. Three blinded radiologists (R1, R2, R3) subjectively evaluated T2W signal intensity and heterogeneity and extracted T2W signal intensity ratio (SIR) and entropy. These values were imputed into a quantitative and qualitative T2W adrenal MRI calculator (logistic regression model encompassing T2W SIR + entropy and subjective SI [relative to renal cortex] and heterogeneity) using a predefined threshold to differentiate metastases from adenoma and accuracy derived by a 2 × 2 table analysis. RESULTS: Subjectively, pheochromocytomas were brighter (p < 0.001) and more heterogeneous (p < 0.001) for all three radiologists. Inter-observer agreement was fair-to-moderate for T2W signal intensity (K = 0.37-0.46) and fair for heterogeneity (K = 0.24-0.32). Pheochromocytoma had higher T2W-SI-ratio (p < 0.001) and entropy (p < 0.001) for all three readers. The quantitative calculator differentiated pheochromocytoma from adenoma with high sensitivity, specificity, and accuracy (100% [95% confidence intervals 88-100%], 87% [66-97%], and 94% [86-100%] R1; 93% [77-99%], 96% [78-100%], and 94% [88-100%] R2; 97% [82-100%], 96% [78-100%], and 96% [91-100% R3]). The qualitative calculator was specific with lower sensitivity and overall accuracy (48% [29-68%], 100% [85-100%], and 74% [65-83%] R1; 45% [26-64%], 100% [85-100%], and 72% [63-82%] R2; 59% [39-77%], 100% [85-100%], and 79% [70-88% R3]). CONCLUSIONS: T2W signal intensity and heterogeneity differ, subjectively and quantitatively, in pheochromocytoma compared to adenoma. Use of a quantitative T2W adrenal calculator which combines T2W signal intensity ratio and entropy was highly accurate to diagnose pheochromocytoma outperforming subjective analysis. KEY POINTS: • Pheochromocytomas have higher T2-weighted signal intensity and are more heterogeneous compared to lipid-poor adrenal adenomas evaluated subjectively and quantitatively. • The quantitative T2-weighted adrenal MRI calculator, a logistic regression model combining T2-weighted signal intensity ratio and entropy, is highly accurate for diagnosis of pheochromocytoma. • The qualitative T2-weighed adrenal MRI calculator had high specificity but lower sensitivity and overall accuracy compared to quantitative assessment and agreement was only fair-to-moderate.

Psychosocial factors related to physical activity in frail and prefrail elderly people.

BACKGROUND: Increased physical activity (PA) is a very important factor in a healthy aging lifestyle. Psychosocial factors have also a main role in the initiation and maintenance of this behavior, but nowadays its implications for frailty elderly people are unknown, therefore, the aim of this study was to identify the psychosociological variables of behavior change that influence the practice of (PA) in frail and prefrail elderly. METHODS: A total of 103 frail and pre-frail elderly people (72 females) participated in this cross-sectional study, on the framework of the EXERNET-Elder3.0 project. Age ranged from 68-94 years (mean = 80.4 ± 5.9 years). Individualized face-to-face interviews according to the constructs of the Transtheoretical Model of Change (TTM) [(decisional balance (DB) and self-efficacy (SE)], social support (SS) (family and friends) and outcome expectations (OE) were administered to all participants. RESULTS: Significant differences were found in DB, perceived benefits (PBn), SE, family-related SS and OE as a function of stages of change (SoC) (p < 0.005), but no significant were found in perceived barriers (PBrr) (p = 0.259) and friends-related SS (p = 0.068). According to the Scheffé post-hoc test, those in advanced SoC (Action-Maintenance), scored higher than those in lower SoC (Precontemplation-Contemplation and Preparation). CONCLUSION: The scores obtained from the study variables differed according to the SoC, supporting the external validity for the use of the TTM in frailty elderly. Further research is needed to determine the impact of PBrr and friends-related SS on this people, as well as to identify the validity of this model in the long-term in this population.

Intravaginal misoprostol versus uterine curettage for missed abortion: A cost-effectiveness analysis.

PURPOSE: To evaluate the cost-effectiveness of a strategy based on direct-acting uterine curettage (UC) versus a pre-direct-acting misoprostol (1600 mg) in patients with missed abortion (MA), from the perspective of a National Health System. METHODS: An open prospective cohort study was carried out at Reina Sofía University Hospital (Córdoba, Spain) from January 1, 2019 to December 31, 2019 in 180 patients diagnosed with MA. The patients chose medical treatment with intravaginal misoprostol (800 µg/4 h) or UC after receiving complete and detailed information. The effectiveness, clinical characteristics of the patients, costs of treating and managing the disease, and satisfaction with the procedures were recorded. RESULTS: One hundred and forty-five patients (80.6%) chose misoprostol versus 35 patients (19.4%) who chose UC. The effectiveness of misoprostol has been 42% evaluated at 48 h; UC success rate has been 100%. The incidence of side effects is significantly higher in patients treated with misoprostol (p < 0.05); as well as the number of care received by the patient (p < 0.05). Satisfaction is higher in patients treated with UC (p < 0.05). However, the cost is almost 5-folds higher in patients treated with UC (p < 0.05). CONCLUSION: UC has a higher success rate, greater satisfaction, and a lower incidence of side effects, although significantly increases the cost compared to misoprostol in MA.

Biogeographic regionalization of the Neotropical region: New map and shapefile.

We provide a map and shapefile of the 57 biogeographic provinces of the Neotropical region. Recognition of these provinces is based on their endemic species, but their delimitation on the map is based on ecoregions combining climatic, geological, and biotic criteria. These provinces belong to the Antillean, Brazilian and Chacoan subregions, and the Mexican and South American transition zones. We provide a vector file of the biogeographical regionalization by converting the map into a polygon shapefile and a raster file with all provinces.

Argentina's National Program for Control of Breast Cancer: Time 1, Patient Navigation, and Patient Cancer Education Experience.

Argentina has the second highest mortality rate for breast cancer (BC) in South America. The age-standardized incidence of BC in Argentina is 73 per 100,000. Despite the availability of early detection services, 30% of BCs are diagnosed at advanced disease stages. The National Cancer Institute (NCI) of Argentina and the National Program for Control of Breast Cancer (NPCBC) focus on two main objectives: guaranteeing adequate and timely BC treatment and reducing BC mortality in Argentina. These objectives are addressed by maintaining three core concepts: quality control, disease monitoring, and wide coverage of available early detection and treatment services. The NPCBC is currently implementing the "Time 1 Survey Study." Time 1 is defined as the time from the first appearance of BC signs or symptoms to the first consult within the public healthcare system. This timeframe is important in Argentina because it is outside of the health timeframes and data parameters monitored by the national cancer data registry system. The Time 1 Survey study has the potential to serve as an informational tool for BC patient navigation efforts in Argentina because it can be used to identify and characterize the barriers and delays that women face during Time 1. Lessons and experiences included in this study could be translated to other Latin American and middle-income countries for developing cancer control programs that can lead to improving treatment and reducing mortality through patient navigation and cancer education efforts for the public, health professionals, and patients.

Current lifestyle and exclusive breastfeeding: an impossible balance?

427 women were included in this observational cohort study to determine the rate of exclusive (EB), mixed (MB) and artificial breastfeeding (AB) and the personal reasons and social factors influencing this decision. An initial survey was conducted within the first 36 h postpartum and a second wave was carried out 3 months after delivery. 55.74% (238) of the patients intended to EB, 32.55% (139) AB and 11.71% (50) MB. After 3 months, a high percentage in group EB (75.23%) maintained EB. The main reason for switching to AB was the absence of milk or weight loss of the newborn. In conclusion, EB is the preferred form for feeding newborns. When these women returned to their workplace, most of them wanted to continue with EB. Women with higher academic degrees chose more often EB.IMPACT STATEMENTWhat is already known on this subject? The benefits of exclusive breastfeeding are well known. However, in modern western societies, it is not easy to combine breastfeeding with day-to-day activity. Work activity, age or previous parity are some of the factors that may influence the election of the type of lactation.What do the results of this study add? Exclusive breastfeeding is the preferred method for feeding newborns immediately postpartum and 3 months later. Work activity does not seem to influence or to switch the choice. However, the level of education could be a determinant of adherence to exclusive breastfeeding.What are the implications of these findings for clinical practice and/or further research? Assessing the factors that favour adherence to exclusive breastfeeding might be a useful tool to its promotion. This study warrants further multivariate analyses on the same topic and additional studies in other social contexts.

Endurance exercise improves avoidance learning and spatial memory, through changes in genes of GABA and relaxin-3, in rats.

Different exercise patterns, neurotransmitters, and some genes have numerous effects on learning and memory. This research aims to investigate the long-term effects of submaximal aerobic exercise on spatial memory (SM), passive avoidance learning (PAL), levels of serum relaxin-3, gamma-aminobutyric acid (GABA), RLN3 gene, and glutamic acid decarboxylase (GAD65/67 genes) in the brainstem of adult male Wistar rats. Fifty male Wistar rats were randomly divided into five groups: aerobic exercise groups, performed on a treadmill running (TR), for 5 weeks (Ex5, n = 10), 10 weeks (Ex10, n = 10), involuntary running wheel group for 5 weeks (IRW5, n = 10), sham (Sh, n = 10) and control (Co, n = 10). Consequently, SM, PAL, serum relaxin-3, GABA, and GAD65/67 and RLN3 genes were measured by ELISA and PCR. Ex5, Ex10 and IRW5 improved significantly SM (p ≤ 0.05), PAL (p ≤ 0.001) and decreased significantly relaxin-3 (p ≤ 0.001). RLN3 in the brain also decreased. However, it was not significant. GABA and GAD65/GAD67 increased significantly (p ≤ 0.05) in Ex5, Ex10 compared to Sh and Co. Aerobic exercise enhanced SM and PAL in Ex compared to Co and Sh. However, duration and type of exercise affected the level of enhancement. The serum relaxin-3 and RLN3 gene displayed reverse functions compared to GABA and GAD65/67 genes in Ex. Therefore, the changes of neurotransmitters in serum relaxin-3, GABA, and their genes: RLN3 and GAD65/67 respectively, influenced learning and memory meaningfully.