Investigating the Mechanisms Involved in Scopolamine-induced Memory Degradation

In the present study, the mechanisms involved in scopolamine-induced memory impairment have been investigated. The molecular events that take place during memory mostly include mechanisms that are seen in the acquisition phase. Results showed that one of the mechanisms of memory destruction caused by scopolamine, in addition to weakening the cholinergic system, is the indirect effect of scopolamine on other neurotransmitter systems, including the glutamatergic system. Scopolamine injection increases dopamine by inhibiting M2/4 muscarinic autoreceptors. These autoreceptors are located on dopaminergic presynaptic neurons, and their activation reduces the release of dopamine. Therefore, blocking these autoreceptors by scopolamine can increase the release of dopamine. Both D1 and D2 receptors are involved in learning and memory processes. In general, stimulation of dopamine D1 receptors follows an inverted U-shaped dose-response curve, meaning that both insufficient and excessive amounts of dopamine cause memory impairment. Therefore, an indirect effect on the dopaminergic system can be one of the scopolamine-induced memory impairment mechanisms. Effects on cell membrane potential and neuron plasticity, and interaction with acetylcholine are among other mechanisms. Serotonin plays a complex role in memory and learning. Serotonin receptors (5-HT2A) also play a role in memory function by affecting calcium transport. This action is similar to dopamine and other G-protein-coupled receptors, which activate phospholipase C, enter calcium into the cell, and activate calcineurin. Activation of 5-HT2A and 5-HT4 receptors by specific agonists of these receptors enhances long-term potentiation (LTP), which plays a significant role in memory. On the other hand, specific 5-HT3 receptor antagonist improves LTP. The 5-HT6 receptor antagonist can improve memory function. Therefore, different serotonin receptors have different roles in memory function, and the interaction between scopolamine and these receptors needs further study. It has been shown that histamine increases the secretion of acetylcholine in the hippocampus, and postsynaptic H1 and presynaptic H3 receptors play a major role in memory and learning; however, whether scopolamine can cause memory impairment through interaction with histamine receptors has been not reviewed

Global fertility in 204 countries and territories, 1950–2021, with forecasts to 2100: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background: Accurate assessments of current and future fertility—including overall trends and changing population age structures across countries and regions—are essential to help plan for the profound social, economic, environmental, and geopolitical challenges that these changes will bring. Estimates and projections of fertility are necessary to inform policies involving resource and health-care needs, labour supply, education, gender equality, and family planning and support. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 produced up-to-date and comprehensive demographic assessments of key fertility indicators at global, regional, and national levels from 1950 to 2021 and forecast fertility metrics to 2100 based on a reference scenario and key policy-dependent alternative scenarios. Methods: To estimate fertility indicators from 1950 to 2021, mixed-effects regression models and spatiotemporal Gaussian process regression were used to synthesise data from 8709 country-years of vital and sample registrations, 1455 surveys and censuses, and 150 other sources, and to generate age-specific fertility rates (ASFRs) for 5-year age groups from age 10 years to 54 years. ASFRs were summed across age groups to produce estimates of total fertility rate (TFR). Livebirths were calculated by multiplying ASFR and age-specific female population, then summing across ages 10–54 years. To forecast future fertility up to 2100, our Institute for Health Metrics and Evaluation (IHME) forecasting model was based on projections of completed cohort fertility at age 50 years (CCF50; the average number of children born over time to females from a specified birth cohort), which yields more stable and accurate measures of fertility than directly modelling TFR. CCF50 was modelled using an ensemble approach in which three sub-models (with two, three, and four covariates variously consisting of female educational attainment, contraceptive met need, population density in habitable areas, and under-5 mortality) were given equal weights, and analyses were conducted utilising the MR-BRT (meta-regression—Bayesian, regularised, trimmed) tool. To capture time-series trends in CCF50 not explained by these covariates, we used a first-order autoregressive model on the residual term. CCF50 as a proportion of each 5-year ASFR was predicted using a linear mixed-effects model with fixed-effects covariates (female educational attainment and contraceptive met need) and random intercepts for geographical regions. Projected TFRs were then computed for each calendar year as the sum of single-year ASFRs across age groups. The reference forecast is our estimate of the most likely fertility future given the model, past fertility, forecasts of covariates, and historical relationships between covariates and fertility. We additionally produced forecasts for multiple alternative scenarios in each location: the UN Sustainable Development Goal (SDG) for education is achieved by 2030; the contraceptive met need SDG is achieved by 2030; pro-natal policies are enacted to create supportive environments for those who give birth; and the previous three scenarios combined. Uncertainty from past data inputs and model estimation was propagated throughout analyses by taking 1000 draws for past and present fertility estimates and 500 draws for future forecasts from the estimated distribution for each metric, with 95% uncertainty intervals (UIs) given as the 2·5 and 97·5 percentiles of the draws. To evaluate the forecasting performance of our model and others, we computed skill values—a metric assessing gain in forecasting accuracy—by comparing predicted versus observed ASFRs from the past 15 years (2007–21). A positive skill metric indicates that the model being evaluated performs better than the baseline model (here, a simplified model holding 2007 values constant in the future), and a negative metric indicates that the evaluated model performs worse than baseline. Findings: During the period from 1950 to 2021, global TFR more than halved, from 4·84 (95% UI 4·63–5·06) to 2·23 (2·09–2·38). Global annual livebirths peaked in 2016 at 142 million (95% UI 137–147), declining to 129 million (121–138) in 2021. Fertility rates declined in all countries and territories since 1950, with TFR remaining above 2·1—canonically considered replacement-level fertility—in 94 (46·1%) countries and territories in 2021. This included 44 of 46 countries in sub-Saharan Africa, which was the super-region with the largest share of livebirths in 2021 (29·2% [28·7–29·6]). 47 countries and territories in which lowest estimated fertility between 1950 and 2021 was below replacement experienced one or more subsequent years with higher fertility; only three of these locations rebounded above replacement levels. Future fertility rates were projected to continue to decline worldwide, reaching a global TFR of 1·83 (1·59–2·08) in 2050 and 1·59 (1·25–1·96) in 2100 under the reference scenario. The number of countries and territories with fertility rates remaining above replacement was forecast to be 49 (24·0%) in 2050 and only six (2·9%) in 2100, with three of these six countries included in the 2021 World Bank-defined low-income group, all located in the GBD super-region of sub-Saharan Africa. The proportion of livebirths occurring in sub-Saharan Africa was forecast to increase to more than half of the world's livebirths in 2100, to 41·3% (39·6–43·1) in 2050 and 54·3% (47·1–59·5) in 2100. The share of livebirths was projected to decline between 2021 and 2100 in most of the six other super-regions—decreasing, for example, in south Asia from 24·8% (23·7–25·8) in 2021 to 16·7% (14·3–19·1) in 2050 and 7·1% (4·4–10·1) in 2100—but was forecast to increase modestly in the north Africa and Middle East and high-income super-regions. Forecast estimates for the alternative combined scenario suggest that meeting SDG targets for education and contraceptive met need, as well as implementing pro-natal policies, would result in global TFRs of 1·65 (1·40–1·92) in 2050 and 1·62 (1·35–1·95) in 2100. The forecasting skill metric values for the IHME model were positive across all age groups, indicating that the model is better than the constant prediction. Interpretation: Fertility is declining globally, with rates in more than half of all countries and territories in 2021 below replacement level. Trends since 2000 show considerable heterogeneity in the steepness of declines, and only a small number of countries experienced even a slight fertility rebound after their lowest observed rate, with none reaching replacement level. Additionally, the distribution of livebirths across the globe is shifting, with a greater proportion occurring in the lowest-income countries. Future fertility rates will continue to decline worldwide and will remain low even under successful implementation of pro-natal policies. These changes will have far-reaching economic and societal consequences due to ageing populations and declining workforces in higher-income countries, combined with an increasing share of livebirths among the already poorest regions of the world. Funding: Bill & Melinda Gates Foundation

Evaluation of new bone formation in critical-sized rat calvarial defect using 3D printed polycaprolactone/tragacanth gum-bioactive glass composite scaffolds

Critical-sized bone defects are a major challenge in reconstructive bone surgery and usually fail to be treated due to limited remaining bone quality and extensive healing time. The combination of 3D-printed scaffolds and bioactive materials is a promising approach for bone tissue regeneration. In this study, 3D-printed alkaline-treated polycaprolactone scaffolds (M-PCL) were fabricated and integrated with tragacanth gum- 45S5 bioactive glass (TG-BG) to treat critical-sized calvarial bone defects in female adult Wistar rats. After a healing period of four and eight weeks, the new bone of blank, M-PCL, and M-PCL/TG-BG groups were harvested and assessed. Micro-computed tomography, histological, biochemical, and biomechanical analyses, gene expression, and bone matrix formation were used to assess bone regeneration. The micro-computed tomography results showed that the M-PCL/TG-BG scaffolds not only induced bone tissue formation within the bone defect but also increased BMD and BV/TV compared to blank and M-PCL groups. According to the histological analysis, there was no evidence of bony union in the calvarial defect regions of blank groups, while in M-PCL/TG-BG groups bony integration and repair were observed. The M-PCL/TG-BG scaffolds promoted the Runx2 and collagen type I expression as compared with blank and M-PCL groups. Besides, the bone regeneration in M-PCL/TG-BG groups correlated with TG-BG incorporation. Moreover, the use of M-PCL/TG-BG scaffolds promoted the biomechanical properties in the bone remodeling process. These data demonstrated that the M-PCL/TG-BG scaffolds serve as a highly promising platform for the development of bone grafts, supporting bone regeneration with bone matrix formation, and osteogenic features. Our results exhibited that the 3D-printed M-PCL/TG-BG scaffolds are a promising strategy for successful bone regeneration

Identification of hub genes and pathways in hepatitis B virus‐associated hepatocellular carcinoma: A comprehensive in silico study

Background and Aim: The hepatitis B virus (HBV) is one of the most common causes of liver cancer in the world. This study aims to provide a better understanding of the mechanisms involved in the development and progression of HBV-associated hepatocellular carcinoma (HCC) by identifying hub genes and the pathways related to their functions. Methods: GSE83148 and GSE94660 were selected from the Gene Expression Omnibus (GEO) database, differentially expressed genes (DEGs) with an adjusted p-value < 0.05 and a |logFC| ≥1 were identified. Common DEGs of two data sets were identified using the GEO2R tool. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) databases were used to identify pathways. Protein−protein interactions (PPIs) analysis was performed by using the Cytoscap and Gephi. A Gene Expression Profiling Interactive Analysis (GEPIA) analysis was carried out to confirm the target genes. Results: One hundred and ninety-eight common DEGs and 49 hub genes have been identified through the use of GEO and PPI, respectively. The GO and KEGG pathways analysis showed DEGs were enriched in the G1/S transition of cell cycle mitotic, cell cycle, spindle, and extracellular matrix structural constituent. The expression of four genes (TOP2A, CDK1, CCNA2, and CCNB2) with high scores in module 1 were more in tumor samples and have been identified by GEPIA analysis. Conclusion: In this study, the hub genes and their related pathways involved in the development of HBV-associated HCC were identified. These genes, as potential diagnostic biomarkers, may provide a potent opportunity to detect HBV-associated HCC at the earliest stages, resulting in a more effective treatmen

Advances in skin gene therapy: utilizing innovative dressing scaffolds for wound healing, a comprehensive review

The skin, serving as the body's outermost layer, boasts a vast area and intricate structure, functioning as the primary barrier against external threats. Disruptions in the composition and functionality of the skin can lead to a diverse array of skin conditions, such as wounds, burns, and diabetic ulcers, along with inflammatory disorders, infections, and various types of skin cancer. These disorders not only exacerbate concerns regarding skin health and beauty but also have a significant impact on mental well-being. Due to the complexity of these disorders, conventional treatments often prove insufficient, necessitating the exploration of new therapeutic approaches. Researchers develop new therapies by deciphering these intricacies and gaining a thorough understanding of the protein networks and molecular processes in skin. A new window of opportunity has opened up for improving wound healing processes because of recent advancements in skin gene therapy. To enhance skin regeneration and healing, this extensive review investigates the use of novel dressing scaffolds in conjunction with gene therapy approaches. Scaffolds that do double duty as wound protectors and vectors for therapeutic gene delivery are being developed using innovative biomaterials. To improve cellular responses and speed healing, these state-of-the-art scaffolds allow for the targeted delivery and sustained release of genetic material. The most recent developments in gene therapy techniques include RNA interference, CRISPR-based gene editing, and the utilization of viral and non-viral vectors in conjunction with scaffolds, which were reviewed here to overcome skin disorders and wound complications. In the future, there will be rare chances to develop custom methods for skin health care thanks to the combination of modern technology and collaboration among discipline

Synthesis, Docking and Acetylcholinesterase Inhibitory Evaluation of 1,3,4-Thiadiazole Derivatives as Potential Anti-Alzheimer Agents

Background: According to the cholinergic hypothesis for Alzheimer’s disease, potentiation of cholinergic neurotransmission is one of the best strategies for combating dementia. Methods: A new series of benzamide derivatives bearing 1,3,4-thiadiazole nucleus were synthesized and subsequently, their anticholinesterase activity was evaluated. Molecular docking was carried out to explore the likely binding mode and interactions. Results: Fortunately, some of the tested compounds exhibited more activity than donepezil as a reference drug (IC50 = 0.6 ± 0.05 µM). Some of the evaluated derivatives displayed potency in the nanomolar range. Compound 7e with fluorine atom on the meta position of the phenyl ring was the most active compound in this series (IC50 = 1.82 ± 0.6 nM). Conclusion: The 1,3,4-thiadiazole derivatives that were synthesized and tested in the current manuscript demonstrated remarkable anticholinesterase activity. Therefore, these compounds could be suggested as potential anti-Alzheimer agents

Wastewater surveillance of antibiotic resistance and class 1 integron-integrase genes: Potential impact of wastewater characteristics on genes profile

Antibiotic resistance (AR) is a major global health concern, but current surveillance efforts primarily focus on healthcare settings, leaving a lack of understanding about AR across all sectors of the One Health approach. To bridge this gap, wastewater surveillance provides a cost-effective and efficient method for monitoring AR within a population. In this study, we implemented a surveillance program by monitoring the wastewater effluent from two large-scale municipal treatment plants situated in Isfahan, a central region of Iran. These treatment plants covered distinct catchment regions and served a combined population about two million of residents. Furthermore, the effect of physicochemical and microbial characteristics of wastewater effluent including biological oxygen demand (BOD), chemical oxygen demand (COD), total suspended solids (TSS), temperature, total coliforms and Escherichia coli concentration on the abundance of ARGs (blaCTX-M, tetW, sul1, cmlA, and ermB) and class 1 integron-integrase gene (intI1) were investigated. Sul1 and blaCTX-M were the most and least abundant ARGs in the two WWTPs, respectively. Principal Component Analysis showed that in both of the WWTPs all ARGs and intI1 gene abundance were positively correlated with effluent temperature, but all other effluent characteristics (BOD, COD, TSS, total coliforms and E. coli) showed no significant correlation with ARGs abundance. Temperature could affect the performance of conventional activated sludge process, which in turn could affect the abundance of ARGs. The results of this study suggest that other factors than BOD, COD and TSS may affect the ARGs abundance. The predicted AR could lead to development of effective interventions and policies to combat AR in the clinical settings. However, further research is needed to determine the relationship between the AR in wastewater and clinical settings as well as the effect of other influential factors on ARGs abundance

Relationship between placental thickness, grading, and heterogeneity in fetal growth restriction in the third trimester of pregnancy by ultrasonography and pathology tests and their relationship with estimated fetal weight and neonatal outcome

Introduction: The placenta is the influencing factor on the fetal weight and is as the first organ that reveals the pathological changes of pregnancy. Therefore, placental ultrasound findings influence the diagnosis of fetal growth restriction (FGR). Objectives: This study examines the relationship between placental thickness, grading and heterogeneity during ultrasound and placental pathology in third trimester FGR fetuses and its effect on neonatal outcome. Patients and Methods: This prospective observational study included 67 pregnant women with FGR fetuses in the third trimester of pregnancy with the mean gestational age of 34.52 ± 2.65 weeks and possible termination of pregnancy within the next seven days. The placental thickness, grading, and heterogeneity in ultrasonography were examined and compared with thickness and grading. Their effect was also considered in neonatal outcome and the results were analyzed. Results: In this study, there is a significant relationship between the thickness of the placenta before and after birth with the weight of the placenta, weight and Apgar score, neonatal arterial pH at birth and fetal growth restriction grading in ultrasound, and neonatal outcome. Conclusion: This study shows that ultrasonic placental findings can be effective in determining the final weight of the placenta and fetus and also the final outcome of the baby at birth. Therefore, ultrasound of the placenta should be performed along with pregnancy ultrasound

The Formulation And Evaluation Of 6-Thioguanine As A Nanostructure Lipid Carrier For The Targeted Delivery Of Breast Cancer

Objective: The main goal was to avoid all the problems associated with usual breast cancer treatment by using 6-thioguanine as a nanostructure lipid carrier (TG-NLCS). This was accomplished by administering an effective and targeted dose of 6-thioguanine (TG) to the tumour site using a long-lasting and biodegradable delivery system. Methods: A combination of heat homogenization and ultrasonication was used to implement the emulsification process. To obtain the optimal formulation, the prepared formulations were first assessed for particle size, Polydispersity Index (PDI), zeta potential, entrapment efficiency, and drug loading capacity. Additionally, a range of physicochemical characterization techniques were employed, including dissolution studies, melting point determination, Fourier-Transform Infrared (FTIR) spectroscopy, and Field Emission Scanning Electron Microscopy (FESEM), as well as cytotoxicity assessment of TG-NLCs in MCF-7 breast cancer cells. Results: The selected formula, TG03, showed a zeta potential of-13.5±0.27 mV and a particle size of 149±0.55 nm. This was further examined using a FESEM. In the in vitro drug release study, the formula demonstrated better-controlled drug release for 48 h in comparison to other formulations. In addition, the significant anti-proliferation activity of TG-NLCs against the MCF-7 breast cancer cell line. Conclusion: Nanostructured lipid carriers (NLCs) are one type of multifunctional nanoparticle that includes many combinations of lipids and medicines for various delivery routes

The Effect of Yoga and Pelvic Floor Muscle Exercise on Sexual Function and Sexual Self-esteem of Reproductive-age Women: A Randomized Clinical Trial

Background: Sexual function is a part of sexual health which is an important aspect of the quality of life. Physical activity is one of the healthiest activities that can effectively reduce the risk of sexual disorders. Therefore, this study was conducted with the aim of evaluating the effect of yoga and pelvic floor muscle exercises on the sexual function and sexual self-esteem of reproductive-age women. Methods: This randomized clinical trial study was conducted from September to December 2023 on 46 women of reproductive age working in the Shahrekord University of Medical Sciences and its affiliated health centers. Multi-stage cluster sampling was used to select the subjects; later, they were randomly divided into two intervention groups A (N=21) and B (N=25). Participants in intervention groups A and B performed pelvic floor muscle exercises at home using an educational pamphlet 3 times a week for 6 weeks, with 3 times a day repetition. In addition, women in the intervention group A participated in a yoga training program for 2 sessions per week for 6 weeks. Data collection tools included a demographic information form, the Female Sexual Function Index, and Sexual Self-Esteem Inventory for women. Questionnaires were completed by both groups before, immediately, and one month after the intervention. The data were analyzed using the chi-square test, fisher’s exact test, independent two-sample t-test, repeated measures test, and analysis of covariance in SPSS software version 16. A significance level of less than 0.05 was considered. Results: The results showed no statistically significant difference between the two groups in sexual function (P=0.21) and sexual self-esteem (P=0.22) scores before the intervention. Also, the results showed no statistically significant difference between the two groups in terms of sexual function (P=0.35) and sexual self-esteem (P=0.59) scores one month after the intervention. However, the mean score of the sexual function index immediately after intervention showed a statistically significant difference between the intervention groups A (31.43±3.76) and B (29.41±2.38) (P<0.001). The mean score of the sexual self-esteem immediately after the intervention showed a statistically significant difference between the intervention groups A (181.19±19.90) and B (171.32±15.02) (P<0.001). Conclusion: Adding yoga exercises to pelvic floor muscle exercises can improve the sexual function and sexual self-esteem of women at their reproductive age. Trial Registration Number: IRCT20100524004015N1