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Background and Objectives In arid and semi-arid regions, meeting the environmental need of rivers and natural lakes is drastically diminished due to the climate changes, drought, and mismanagement of the water supply and distribution in agricultural activities. The closed basins, like Lake Urmia, are more sensitive to reducing the environmental need, climate change and drought. In Lake Urmia basin with arid and semi-arid climate, water shortage and high demand for water consumption in agricultural activities have caused to increase the free accessibility of the extraction of the surface water and groundwater resources. Therefore, in arid and semi-arid regions, it is necessary to implement an integrated dynamic system (IDS) for water consumption management in all sectors of water consumption, including drinking, industrial, and agriculture needs to stabilize the groundwater resources; hence, the optimal use of water resources to increase production capacity per unit of water consumption is a fundamental solution to meet the nutritional needs of humans and improve the economic conditions of operators. The multiplication of greenhouse agricultural products compared to the open-field cultivation for the same water consumption is one of the crucial solutions in the optimal use of water resources. Methodology The Ajichay basin with an area of 12600 km² is one of the greatest sub-basins of Lake Urmia. The average annual temperature of this basin is 11.3℃ and the average annual precipitation is 320 mm. The soil and water assessment tool (SWAT) model was used to evaluate the impacts of the implementation of development scenarios of greenhouse towns. The Soil and Water Assessment Tool (SWAT) is considered as a comprehensive hydrological model to evaluate the impacts of different factors such as climate changes, land use variations, changes in irrigation methods, agricultural management, and greenhouse development on runoff volume and groundwater level fluctuations. In this study, the SWAT model has been calibrated and verified using a 30 m digital elevation model (DEM), a soil map with 217 homogeneous zones, 5 land use maps from 1987 to 2016, data gathered from 10 hydrometric stations and more than 50 meteorological stations, hydrological studies and field measurements. In the present study, two scenarios were adopted according to the current policies of greenhouse towns development in Iran and an ideal scenario (third scenario) was also considered for the development of greenhouse towns. The first scenario for the development of greenhouse settlements was adjusted using new water resources with the aim of increasing the production of agricultural products in the region. The second scenario is based on the removal of part of the arable lands of each aquifer and the use of harvested water from the removed lands in the development of greenhouse settlements. The third scenario was based on the average production statistics in open and closed environment in Ajichay catchment, in order to maintain the current production per hectare. In modelling the Ajichay basin, the time periods of 1987-1991, 1992-2009, and 2010-2016 have been assigned to the model adaptation to the basin conditions, calibration, and verification, respectively. The statistical criteria comprising correlation coefficient (CC), Nash-Sutcliffe efficiency (NSE), and root mean square error (RMSE) have been utilized to evaluate model performance for stream flow simulation in hydrometric stations. Findings Statistical criteria indicated the high accuracy of simulation for all ten hydrometric stations. At Akhula station (watershed outlet), the statistics including correlation coefficient (R), Nash-Sutcliffe efficiency (NSE), and root mean square error (RMSE) were 0.92, 0.83 and 6.48 m³ s-1, respectively, during calibration, and 0.86, 0.73 and 3.23 m³ s-1, respectively, during verification periods. Development of 1875 hectares of greenhouse towns in the Ajichay watershed caused an average depletion of 11.68 m and 4.41 m within the first and second scenarios, respectively; in contrast, for the third scenario, an increase of 3.86 m for the average groundwater level of the aquifers of the Ajichay watershed was acquired rather than the initial condition. At the end of the simulation period of the third scenario, the flow volume increase of 28.5 MCM y-1 was observed at the Akhula hydrometric station. The results revealed that the development of greenhouse towns using new water resources can increase agricultural crop production and also intensify the downward trend in groundwater levels. The second scenario has caused a negative balance in the aquifers due to the eliminating the water withdrawal under the traditional irrigation system from the hydrological cycle. Only in the third scenario, the removal of nearly ten hectares of farmlands for the development of one hectare of greenhouse has caused the aquifers of Ajichay basin to have an increasing trend of groundwater level. The results of the third scenario revealed that 24% of the total reduced volume of groundwater abstraction, was discharged into Lake Urmia through rivers, and 38% was related to the water withdrawal of the traditional irrigation, and the other part was spent on increasing the water abstraction from groundwater and rivers for the agricultural purposes. Conclusion The results of the implementation of the scenarios to develop greenhouse towns revealed that the type of policies and how to implement the development of greenhouse towns can enhance agricultural production capacity as well as decrease/increase the flow of rivers in the Ajichay basin. The adverse effect on the groundwater resources occurs when the administrative institutions' approach is focused only on the increasing production capacity. Furthermore, when the ratio of replacing traditional farmlands with greenhouse towns is not commensurate with the corresponding irrigation efficiencies, it applies more stress to the groundwater resources to meet the evapotranspiration need of the greenhouse plants. The positive effect on aquifers and increased river flow occurs when the actual evapotranspiration of the plants cultivated in greenhouse towns is less than the eliminated traditional farmland. [ABSTRACT FROM AUTHOR]

Landslide is recognized as one of the environmental challenges that causes land degradation, fertility reduction, and other significant damages to the ecosystem. Therefore, proper identification of landslide-prone areas through modeling is significantly helpful for land development managers and planners by providing them with appropriate management strategies for preventing land degradation. In this research, landslide susceptibility mapping was carried out in West Azerbaijan province, Iran using Frequency Ratio (FR), Shannon Entropy (SE), Random Forest (RF), and an ensemble of Random Forest and Bagging (RF-BA) methods. Based on field surveys, local interviews, and review of similar studies, 12 factors were identified that affected landslide occurrence, namely altitude, slope angle, slope aspect, distance from fault, distance from river, distance from road, drainage density, road density, rainfall, soil, land use, and lithology. In the field surveys, 110 landslides in the area were specified; 70% of the data (77 landslides) were randomly selected and used for modeling and the remaining 30% (33 landslides) for validation. The results of the ROC curve exhibited the accuracy rates of 0.92, 0.91, 0.89, and 0.88 through RF-BA, RF, FR, and SE models, respectively. [ABSTRACT FROM AUTHOR]

Objective To undertake a randomized controlled trial in 196 obese subjects to examine the effect of electro-acupuncture on serum pro-oxidant antioxidant balance (PAB) values. Methods Subjects received authentic acupuncture (cases) or sham acupuncture (controls) for 6 weeks in combination with a low-calorie diet. In the following 6 weeks, they received the low-calorie diet alone. Serum PAB was measured at baseline, and 6 and 12 weeks later. Results We found that serum PAB values decreased significantly in the group receiving the authentic acupuncture compared to the sham treatment (p<0.001) at week 6, and whilst serum PAB increased significantly (p<0.05) in the second phase of the study, a significant difference between two groups remained at 12 weeks (p<0.05). Conclusions Electro-acupuncture in combination with a low-calorie diet was more effective at reducing serum PAB values in obese subjects compared to diet alone. Further work is required to determine the mechanism by which electro-acupuncture has this effect. [ABSTRACT FROM AUTHOR]

This study is concerned with the problem of harmonic disturbance rejection in active magnetic bearing systems. A modified notch filter is presented to identify both constant and harmonic disturbances caused by sensor runout and mass unbalance. The proposed method can attenuate harmonic displacement and currents at the synchronous frequency and its integer multiples. The reduction of stability is a common problem in adaptive techniques because they alter the original closed-loop system. The main advantage of the proposed method is that it is possible to determine the stability margins of the system by few parameters. The negative phase shift of the modified notch filter can be tuned to achieve a desired phase margin, while the gain margin can also be adjusted separately. It is shown that the modified notch filter can be designed to suppress multiple harmonics at the same time. It is implemented on a three-pole magnetic bearing test rig to evaluate its performance. Simulation and experimental results indicate that the presented method can be successfully applied to compensate the periodic disturbances such as sensor runout and mass unbalance in active magnetic bearing systems. [ABSTRACT FROM AUTHOR]

This article delves into the potential of artificial intelligence (AI) to enhance early breast cancer (BC) detection for improved treatment outcomes and patient care. Utilizing a multimethod approach comprising literature review and experiments, the study systematically reviewed 310 articles utilizing 30 diverse datasets. Among the techniques assessed, recurrent neural network (RNN) emerged as the most accurate, achieving 98.58 % accuracy, followed by genetic principles (GP), transfer learning (TL), and artificial neural networks (ANNs), with accuracies exceeding 96 %. While conventional machine learning (ML) methods demonstrated accuracies above 90 %, DL techniques outperformed them. Evaluation of BC diagnostic models using the Wisconsin breast cancer dataset (WBCD) highlighted logistic regression (LR) and support vector machine (SVM) as the most accurate predictors, with minimal errors for clinical data. Conversely, decision trees (DT) exhibited higher error rates due to overfitting, emphasizing the importance of algorithm selection for complex datasets. Analysis of ultrasound images underscored the significance of preprocessing, while histopathological image analysis using convolutional neural networks (CNNs) demonstrated robust classification capabilities. These findings underscore the transformative potential of ML and DL in BC diagnosis, offering automated, accurate, and accessible diagnostic tools. Collaboration among stakeholders is crucial for further advancements in BC detection methods., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Many autism spectrum disorder (ASD)-associated genes act as transcriptional regulators (TRs). Chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify the regulatory targets of ARID1B, BCL11A, FOXP1, TBR1, and TCF7L2, ASD-associated TRs in the developing human and mouse cortex. These TRs shared substantial overlap in the binding sites, especially within open chromatin. The overlap within a promoter region, 1-2,000 bp upstream of the transcription start site, was highly predictive of brain-expressed genes. This signature was observed in 96 out of 102 ASD-associated genes. In vitro CRISPRi against ARID1B and TBR1 delineated downstream convergent biology in mouse cortical cultures. After 8 days, NeuN+ and CALB+ cells were decreased, GFAP+ cells were increased, and transcriptomic signatures correlated with the postmortem brain samples from individuals with ASD. We suggest that functional convergence across five ASD-associated TRs leads to shared neurodevelopmental outcomes of haploinsufficient disruption., Competing Interests: Declaration of interests J.L.R.R. is cofounder and stockholder, and currently on the scientific board, of Neurona, a company studying the potential therapeutic use of interneuron transplantation. S.J.S. receives research funding from BioMarin Pharmaceutical. M.W.S. is a consultant to BlackThorn and ArRett Pharmaceuticals. L.L. is a stockholder and employee of Invitae., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The association of pre-participation knee muscle strength status with lower limb injury occurrence was investigated. Knee extensors and flexors muscle strength status including the traditional hamstrings/quadriceps (H/Q), Q/Q, H/H, and the non-dominant H/Q: dominant H/Q, HQ:HQ, ratios were recorded before the 10 month judo activity. Fifteen lower limb sport injuries were recorded for 53 judokas during the follow-up questionnaires. Significant accuracy of dominant H/Q ratio 60º/s (AUC 0.702, 95% CI 0.520 to .883, p = 0.023), as well as HQ:HQ ratios 300º/s (AUC .318, 95% CI 0.138 to 0.497, p = 0.040), and 60 º/s (AUC 0.311, 95% CI 0.130 to 0.491, p = .033) were revealed discriminating between injured and uninjured judokas. The optimum cut-off of dominant H/Q ratio associated with belonging to uninjured judokas group was 43.2% (sensitivity, 0.974; specificity, 0.533). Isokinetic knee muscle dynamometry is useful for predicting the likelihood of lower limb injuries in professional judokas during competitive activity.

Purpose: Sperm DNA fragmentation (SDF) is a functional sperm abnormality that can impact reproductive potential, for which four assays have been described in the recently published sixth edition of the WHO laboratory manual for the examination and processing of human semen. The purpose of this study was to examine the global practices related to the use of SDF assays and investigate the barriers and limitations that clinicians face in incorporating these tests into their practice., Materials and Methods: Clinicians managing male infertility were invited to complete an online survey on practices related to SDF diagnostic and treatment approaches. Their responses related to the technical aspects of SDF testing, current professional society guidelines, and the literature were used to generate expert recommendations via the Delphi method. Finally, challenges related to SDF that the clinicians encounter in their daily practice were captured., Results: The survey was completed by 436 reproductive clinicians. Overall, terminal deoxynucleotidyl transferase deoxyuridine triphosphate Nick-End Labeling (TUNEL) is the most commonly used assay chosen by 28.6%, followed by the sperm chromatin structure assay (24.1%), and the sperm chromatin dispersion (19.1%). The choice of the assay was largely influenced by availability (70% of respondents). A threshold of 30% was the most selected cut-off value for elevated SDF by 33.7% of clinicians. Of respondents, 53.6% recommend SDF testing after 3 to 5 days of abstinence. Although 75.3% believe SDF testing can provide an explanation for many unknown causes of infertility, the main limiting factors selected by respondents are a lack of professional society guideline recommendations (62.7%) and an absence of globally accepted references for SDF interpretation (50.3%)., Conclusions: This study represents the largest global survey on the technical aspects of SDF testing as well as the barriers encountered by clinicians. Unified global recommendations regarding clinician implementation and standard laboratory interpretation of SDF testing are crucial., Competing Interests: The authors have nothing to disclose., (Copyright © 2024 Korean Society for Sexual Medicine and Andrology.)

Purpose: The purpose of this meta-analysis is to study the impact of varicocele repair in the largest cohort of infertile males with clinical varicocele by including all available studies, with no language restrictions, comparing intra-person conventional semen parameters before and after the repair of varicoceles., Materials and Methods: The meta-analysis was performed according to PRISMA-P and MOOSE guidelines. A systematic search was performed in Scopus, PubMed, Cochrane, and Embase databases. Eligible studies were selected according to the PICOS model (Population: infertile male patients with clinical varicocele; Intervention: varicocele repair; Comparison: intra-person before-after varicocele repair; Outcome: conventional semen parameters; Study type: randomized controlled trials [RCTs], observational and case-control studies)., Results: Out of 1,632 screened abstracts, 351 articles (23 RCTs, 292 observational, and 36 case-control studies) were included in the quantitative analysis. The before-and-after analysis showed significant improvements in all semen parameters after varicocele repair (except sperm vitality); semen volume: standardized mean difference (SMD) 0.203, 95% CI: 0.129-0.278; p<0.001; I²=83.62%, Egger's p=0.3329; sperm concentration: SMD 1.590, 95% CI: 1.474-1.706; p<0.001; I²=97.86%, Egger's p<0.0001; total sperm count: SMD 1.824, 95% CI: 1.526-2.121; p<0.001; I²=97.88%, Egger's p=0.0063; total motile sperm count: SMD 1.643, 95% CI: 1.318-1.968; p<0.001; I²=98.65%, Egger's p=0.0003; progressive sperm motility: SMD 1.845, 95% CI: 1.537%-2.153%; p<0.001; I²=98.97%, Egger's p<0.0001; total sperm motility: SMD 1.613, 95% CI 1.467%-1.759%; p<0.001; l2=97.98%, Egger's p<0.001; sperm morphology: SMD 1.066, 95% CI 0.992%-1.211%; p<0.001; I²=97.87%, Egger's p=0.1864., Conclusions: The current meta-analysis is the largest to date using paired analysis on varicocele patients. In the current meta-analysis, almost all conventional semen parameters improved significantly following varicocele repair in infertile patients with clinical varicocele., Competing Interests: The authors have nothing to disclose., (Copyright © 2024 Korean Society for Sexual Medicine and Andrology.)

Purpose: Sperm DNA fragmentation (SDF) has been associated with male infertility and poor outcomes of assisted reproductive technology (ART). The purpose of this study was to investigate global practices related to the management of elevated SDF in infertile men, summarize the relevant professional society recommendations, and provide expert recommendations for managing this condition., Materials and Methods: An online global survey on clinical practices related to SDF was disseminated to reproductive clinicians, according to the CHERRIES checklist criteria. Management protocols for various conditions associated with SDF were captured and compared to the relevant recommendations in professional society guidelines and the appropriate available evidence. Expert recommendations and consensus on the management of infertile men with elevated SDF were then formulated and adapted using the Delphi method., Results: A total of 436 experts from 55 different countries submitted responses. As an initial approach, 79.1% of reproductive experts recommend lifestyle modifications for infertile men with elevated SDF, and 76.9% prescribe empiric antioxidants. Regarding antioxidant duration, 39.3% recommend 4-6 months and 38.1% recommend 3 months. For men with unexplained or idiopathic infertility, and couples experiencing recurrent miscarriages associated with elevated SDF, most respondents refer to ART 6 months after failure of conservative and empiric medical management. Infertile men with clinical varicocele, normal conventional semen parameters, and elevated SDF are offered varicocele repair immediately after diagnosis by 31.4%, and after failure of antioxidants and conservative measures by 40.9%. Sperm selection techniques and testicular sperm extraction are also management options for couples undergoing ART. For most questions, heterogenous practices were demonstrated., Conclusions: This paper presents the results of a large global survey on the management of infertile men with elevated SDF and reveals a lack of consensus among clinicians. Furthermore, it demonstrates the scarcity of professional society guidelines in this regard and attempts to highlight the relevant evidence. Expert recommendations are proposed to help guide clinicians., Competing Interests: The authors have nothing to disclose., (Copyright © 2023 Korean Society for Sexual Medicine and Andrology.)

Theobromine may have beneficial effects on cardiovascular risk factors. This study aimed to find molecular effects of theobromine on lipid profile, glycemic status, inflammatory factors, and vascular function through a comprehensive assessment of all in vitro and in vivo studies. The search process was started at 18 July 2022. Databases including PubMed, Scopus, and Web of Science were searched to find all articles published up to 18 July 2022. Nineteen studies were included in this study. In vitro studies showed the improving effects of theobromine on inflammatory markers. Of four animal studies assessing the effect of theobromine on inflammatory markers, two reported favorable effects. Among five animal studies assessing the effects of theobromine on lipid profile, three reported improving effects on either triglyceride, total cholesterol, low- or high-density lipoprotein cholesterol. Of the three human studies, two revealed that theobromine had improving effects on lipid profile. A favorable effect of theobromine on augmentation index was also reported in two RCTs. The results for other outcomes were inconclusive. Theobromine may have favorable effects on inflammatory factors, lipid profile, and vascular function markers. However, studies with a longer duration and lower, dietary-relevant doses are required for future confirmation., (© 2023 John Wiley & Sons Ltd.)

Purpose: Sperm DNA fragmentation (SDF) testing was recently added to the sixth edition of the World Health Organization laboratory manual for the examination and processing of human semen. Many conditions and risk factors have been associated with elevated SDF; therefore, it is important to identify the population of infertile men who might benefit from this test. The purpose of this study was to investigate global practices related to indications for SDF testing, compare the relevant professional society guideline recommendations, and provide expert recommendations., Materials and Methods: Clinicians managing male infertility were invited to take part in a global online survey on SDF clinical practices. This was conducted following the CHERRIES checklist criteria. The responses were compared to professional society guideline recommendations related to SDF and the appropriate available evidence. Expert recommendations on indications for SDF testing were then formulated, and the Delphi method was used to reach consensus., Results: The survey was completed by 436 experts from 55 countries. Almost 75% of respondents test for SDF in all or some men with unexplained or idiopathic infertility, 39% order it routinely in the work-up of recurrent pregnancy loss (RPL), and 62.2% investigate SDF in smokers. While 47% of reproductive urologists test SDF to support the decision for varicocele repair surgery when conventional semen parameters are normal, significantly fewer general urologists (23%; p=0.008) do the same. Nearly 70% would assess SDF before assisted reproductive technologies (ART), either always or for certain conditions. Recurrent ART failure is a common indication for SDF testing. Very few society recommendations were found regarding SDF testing., Conclusions: This article presents the largest global survey on the indications for SDF testing in infertile men, and demonstrates diverse practices. Furthermore, it highlights the paucity of professional society guideline recommendations. Expert recommendations are proposed to help guide clinicians., Competing Interests: The authors have nothing to disclose., (Copyright © 2023 Korean Society for Sexual Medicine and Andrology.)

Purpose: Despite the significant role of varicocele in the pathogenesis of male infertility, the impact of varicocele repair (VR) on conventional semen parameters remains controversial. Only a few systematic reviews and meta-analyses (SRMAs) have evaluated the impact of VR on sperm concentration, total motility, and progressive motility, mostly using a before-after analytic approach. No SRMA to date has evaluated the change in conventional semen parameters after VR compared to untreated controls. This study aimed to evaluate the effect of VR on conventional semen parameters in infertile patients with clinical varicocele compared to untreated controls., Materials and Methods: A literature search was performed using Scopus, PubMed, Embase, and Cochrane databases following the Population Intervention Comparison Outcome (PICOS) model (Population: infertile patients with clinical varicocele; Intervention: VR [any technique]; Comparison: infertile patients with clinical varicocele that were untreated; Outcome: sperm concentration, sperm total count, progressive sperm motility, total sperm motility, sperm morphology, and semen volume; Study type: randomized controlled trials and observational studies)., Results: A total of 1,632 abstracts were initially assessed for eligibility. Sixteen studies were finally included with a total of 2,420 infertile men with clinical varicocele (1,424 patients treated with VR vs. 996 untreated controls). The analysis showed significantly improved post-operative semen parameters in patients compared to controls with regards to sperm concentration (standardized mean difference [SMD] 1.739; 95% CI 1.129 to 2.349; p<0.001; I²=97.6%), total sperm count (SMD 1.894; 95% CI 0.566 to 3.222; p<0.05; I²=97.8%), progressive sperm motility (SMD 3.301; 95% CI 2.164 to 4.437; p<0.01; I²=98.5%), total sperm motility (SMD 0.887; 95% CI 0.036 to 1.738; p=0.04; I²=97.3%) and normal sperm morphology (SMD 1.673; 95% CI 0.876 to 2.470; p<0.05; I²=98.5%). All the outcomes showed a high inter-study heterogeneity, but the sensitivity analysis showed that no study was sensitive enough to change these results. Publication bias was present only in the analysis of the sperm concentration and progressive motility. No significant difference was found for the semen volume (SMD 0.313; 95% CI -0.242 to 0.868; I²=89.7%)., Conclusions: This study provides a high level of evidence in favor of a positive effect of VR to improve conventional semen parameters in infertile men with clinical varicocele. To the best of our knowledge, this is the first SRMA to compare changes in conventional semen parameters after VR with changes in parameters of a control group over the same period. This is in contrast to other SRMAs which have compared semen parameters before and after VR, without reference to a control group. Our findings strengthen the available evidence and have a potential to upgrade professional societies' practice recommendations favoring VR to improve conventional semen parameters in infertile men., Competing Interests: The authors have nothing to disclose., (Copyright © 2023 Korean Society for Sexual Medicine and Andrology.)

The development of novel therapeutic approaches is necessary to manage gastrointestinal cancers (GICs). Considering the effective molecular mechanisms involved in tumor growth, the therapeutic response is pivotal in this process. Autophagy is a highly conserved catabolic process that acts as a double-edged sword in tumorigenesis and tumor inhibition in a context-dependent manner. Depending on the stage of malignancy and cellular origin of the tumor, autophagy might result in cancer cell survival or death during the GICs' progression. Moreover, autophagy can prevent the progression of GIC in the early stages but leads to chemoresistance in advanced stages. Therefore, targeting specific arms of autophagy could be a promising strategy in the prevention of chemoresistance and treatment of GIC. It has been revealed that autophagy is a cytoplasmic event that is subject to transcriptional and epigenetic regulation inside the nucleus. The effect of epigenetic regulation (including DNA methylation, histone modification, and expression of non-coding RNAs (ncRNAs) in cellular fate is still not completely understood. Recent findings have indicated that epigenetic alterations can modify several genes and modulators, eventually leading to inhibition or promotion of autophagy in different cancer stages, and mediating chemoresistance or chemosensitivity. The current review focuses on the links between autophagy and epigenetics in GICs and discusses: 1) How autophagy and epigenetics are linked in GICs, by considering different epigenetic mechanisms; 2) how epigenetics may be involved in the alteration of cancer-related phenotypes, including cell proliferation, invasion, and migration; and 3) how epidrugs modulate autophagy in GICs to overcome chemoresistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: This study provides a comprehensive analysis of research trends on the etiology, mechanisms, potential risk factors, diagnosis, prognosis, surgical and non-surgical treatment of varicocele, and clinical outcomes before and after varicocele repair., Materials and Methods: Varicocele studies published between 1988 and 2020 were retrieved from the Scopus database on April 5, 2021. Original studies on human varicocele were included, irrespective of language. Retrieved articles were manually screened for inclusion in various sub-categories. Bibliometric data was subjected to scientometric analysis using descriptive statistics. Network, heat and geographic mapping were generated using relevant software., Results: In total, 1,943 original human studies on varicocele were published. These were predominantly from the northern hemisphere and developed countries, and published in journals from the United States and Germany. Network map analysis for countries showed several interconnected nodal points, with the USA being the largest, and Agarwal A. from Cleveland Clinic, USA, being a center point of worldwide varicocele research collaborations. Studies of adolescents were underrepresented compared with studies of adults. Studies on diagnostic and prognostic aspects of varicocele were more numerous than studies on varicocele prevalence, mechanistic studies and studies focusing on etiological and risk factors. Varicocele surgery was more investigated than non-surgical approaches. To evaluate the impact of varicocele and its treatment, researchers mainly analyzed basic semen parameters, although markers of seminal oxidative stress are being increasingly investigated in the last decade, while reproductive outcomes such as live birth rate were under-reported in the literature., Conclusions: This study analyzes the publication trends in original research on human varicocele spanning over the last three decades. Our analysis emphasizes areas for further exploration to better understand varicocele's impact on men's health and male fertility., Competing Interests: The authors have nothing to disclose., (Copyright © 2022 Korean Society for Sexual Medicine and Andrology.)

Semen analysis is the first, and frequently, the only step in the evaluation of male fertility. Although the laboratory procedures are conducted according to the World Health Organization (WHO) guidelines, semen analysis and especially sperm morphology assessment is very difficult to standardize and obtain reproducible results. This is mainly due to the highly subjective nature of their evaluation. ICSI is the choice of treatment when sperm morphology is severely abnormal (teratozoospermic). Hence, the standardization of laboratory protocols for sperm morphology evaluation represents a fundamental step to ensure reliable, accurate and consistent laboratory results that avoid misdiagnoses and inadequate treatment of the infertile patient. This article aims to promote standardized laboratory procedures for an accurate evaluation of sperm morphology, including the establishment of quality control and quality assurance policies. Additionally, the clinical importance of sperm morphology results in assisted reproductive outcomes is discussed, along with the clinical management of teratozoospermic patients., Competing Interests: The authors have nothing to disclose., (Copyright © 2022 Korean Society for Sexual Medicine and Andrology.)

Purpose: Oocytes and spermatozoa are electrogenic cells with the ability to respond to electrical stimuli and modulate their electrical properties accordingly. Determination of the ionic events during the gamete maturation helps to design suitable culture media for gametes in assisted reproductive technology (ART). The present systematic review focuses on the electrophysiology of human gametes during different stages of maturation and also during fertilization., Materials and Methods: The reports published in the English language between January 2000 and July 2021 were extracted from various electronic scientific databases following the PRISMA checklist using specific MeSH keywords., Results: Subsequent to the screening process with defined inclusion and exclusion criteria, 60 articles have been included in this review. Among them, 11 articles were directly related to the electrophysiology of human oocytes and 49 physiology department to the electrophysiology of human spermatozoa., Conclusions: Gametes generate electrical currents by ionic exchange, particularly Na + , K + , Cl - , H + , Zn 2+ , Cu 2+ , Se 2+ , Mg 2+ , HCO 3 - , and Ca 2+ through specific ion channels in different stages of gamete maturation. The ionic concentrations, pH, and other physicochemical variables are modulated during the gametogenesis, maturation, activation, and the fertilization process following gamete function and metabolism. The electrical properties of human gametes change during different stages of maturation. Although it is demonstrated that the electrical properties are significant regulators of cell signaling and are fundamental to gamete maturation and fertilization, their exact roles in these processes are still poorly understood. Further research is required to unveil the intricate electrophysiological processes of human gamete maturation., Competing Interests: The authors have nothing to disclose., (Copyright © 2022 Korean Society for Sexual Medicine and Andrology.)

With the advance of assisted reproduction techniques, and the trend towards blastocyst culture and single embryo transfer, gamete and embryo assessment have gained greater importance in ART treatment. Embryo quality depends mainly on gamete quality and culture conditions. Oocyte maturity identification is necessary in order to plan fertilization timing. Mature oocytes at the metaphase II stage show a higher fertilization rate compared to immature oocytes. Morphology assessment is a critical yet challenging task that may serve as a good prognostic tool for future development and implantation potential if done effectively. Various grading systems have been suggested to assess embryos at pronuclear, cleavage, and blastocyst stages. By identifying the embryo with the highest implantation potential, it is possible to reduce the number of embryos transferred without compromising the chances of a successful pregnancy. Apart from the conventional morphology assessment, there are several invasive or non-invasive methods for embryo selection such as preimplantation genetic testing, morphokinetics, proteomics, metabolomics, oxygen consumption, and measurement of oxidative stress in culture medium. Morphokinetics is a method based on time-lapse technology and continuous monitoring of embryos. In this review, we aimed to describe and compare the most effective and widely used methods for gamete and embryo assessment as well as embryo selection.

The assisted reproductive technology (ART) laboratory is a complex system designed to sustain the fertilization, survival, and culture of the preimplantation embryo to the blastocyst stage. ART outcomes depend on numerous factors, among which are the equipment, supplies and culture media used. The number and type of incubators also may affect ART results. While large incubators may be more suitable for media equilibration, bench-top incubators may provide better embryo culture conditions in separate or smaller chambers and may be coupled with time-lapse systems that allow continuous embryo monitoring. Microscopes are essential for observation, assessment, and micromanipulation. Workstations provide a controlled environment for gamete and embryo handling and their quantity should be adjusted according to the number of ART cycles treated in order to provide a steady and efficient workflow. Continuous maintenance, quality control and monitoring of equipment are essential and quality control devices such as the thermometer, and pH-meter are necessary to maintain optimal culture conditions. Tracking, appropriate delivery and storage conditions, and quality control of all consumables are recommended so that adequate quantity and quality are available for use. Embryo culture media have evolved: preimplantation embryos are cultured either by sequential media or single-step media that can be used for interrupted or uninterrupted culture. There is currently no sufficient evidence that any individual commercially-available culture system is better than others in terms of embryo viability. In this review, we aim to analyze the various parameters that should be taken into account when choosing the essential equipment, consumables and culture media systems that will create optimal culture conditions and provide the most effective patient treatment.

Oocyte retrieval, oocyte denudation, and embryo transfer are crucial processes during assisted reproduction technology (ART). Air quality in the ART laboratory, temperature, pH of the media used and the time interval between oocyte retrieval and insemination are all critical factors. Anesthesia is required for oocyte retrieval, however, evidence regarding the potential impact of different methods (general anesthesia, conscious sedation, and local anesthesia) on the clinical outcomes is unclear. The optimal timing of oocyte denudation following retrieval has not been established. Regarding the mechanical denudation process, there is a lack of evidence to demonstrate the safest minimum inner diameter of denuding pipettes used to complete the removal of granulosa cells surrounding the oocytes. During embryo transfer, many clinics worldwide flush the catheter before embryo loading, in an attempt to potentially rinse off any toxic agents; however, there is insufficient evidence to show that flushing the embryo transfer catheter before loading increases the success of ART outcome. Considering the serious gaps in knowledge in ART practice, the aim of this review is to provide an updated overview of the current knowledge regarding the various steps and techniques involved in oocyte retrieval, oocyte denudation, and embryo loading for transfer.

Background: Tbr1 encodes a T-box transcription factor and is considered a high confidence autism spectrum disorder (ASD) gene. Tbr1 is expressed in the postmitotic excitatory neurons of the deep neocortical layers 5 and 6. Postnatally and neonatally, Tbr1 conditional mutants (CKOs) have immature dendritic spines and reduced synaptic density. However, an understanding of Tbr1's function in the adult mouse brain remains elusive., Methods: We used conditional mutagenesis to interrogate Tbr1's function in cortical layers 5 and 6 of the adult mouse cortex., Results: Adult Tbr1 CKO mutants have dendritic spine and synaptic deficits as well as reduced frequency of mEPSCs and mIPSCs. LiCl, a WNT signaling agonist, robustly rescues the dendritic spine maturation, synaptic defects, and excitatory and inhibitory synaptic transmission deficits., Conclusions: LiCl treatment could be used as a therapeutic approach for some cases of ASD with deficits in synaptic transmission., (© 2022. The Author(s).)

Health-related quality of life (HRQoL) is the prioritized measure in multiple sclerosis (MS) patients. The short quality of life scale (SQoL) developed by Devy et al. (2013) is an MS-specific and abbreviated scale with ten items suitable for routine medical care settings. The current study reported the cross-cultural validation of the scale in the Persian language. A total of 455 convenient MS patients with a mean age of 38.39 (9.28) ranged from 18 to 64 filled out the primary measure and the validating measures, including hospital anxiety and depression scale, visual analogue scale - quality of life, and a single index of the number of past-year MS relapse. The confirmatory factor analysis on original structure indicated an acceptable model fit. However, a modestly modified structure composing of physical-functional dimension (items #1-3), mental dimension (items #5-8), and pain & energy dimension (items 4 & 9,10) was also exposed with a sound fit and a meaningful structure. The overall internal consistency reliability was sound (0.88), and the concurrent validity was confirmed. The Persian short quality of life scale (P-SQoL) is the first translated and validated version of the scale, surfacing significant implications. Further cross-cultural investigations are recommended to re-examine current findings. The classic and recent suggestions concerning the close interplay between the immunity system and the psychological system and the implications based on Iran's context are discussed., (Copyright © 2021. Published by Elsevier B.V.)

Semen analysis is a basic test for evaluating male fertility potential, as it plays an essential role in driving the future management and treatment of infertility in couples. Manual semen analysis includes the evaluation of both macroscopic and microscopic parameters, whereas automated semen analysis is conducted through a computer-aided sperm analysis system and can include additional parameters that are not evaluated by manual analysis. Both quality control (QC) and quality assurance (QA) are important to ensure reproducible results for semen analysis, and represent fundamental checks and balances of all stages (pre-analytical, analytical, and post-analytical) of semen analysis. To ensure accuracy and precision, the laboratory technicians' performance should be evaluated biannually. This narrative review aims to describe standardized laboratory procedures for an accurate assessment of semen parameters that incorporate both QC and QA practices., Competing Interests: The authors have nothing to disclose., (Copyright © 2022 Korean Society for Sexual Medicine and Andrology.)

Varicocele, a condition associated with increased oxidative stress, negatively affects sperm DNA integrity and reduces pregnancy rates. However, the molecular mechanisms related to DNA integrity, damage, and repair in varicocele patients remain unclear. This study aimed to determine the role of DNA repair molecular mechanisms in varicocele-related infertility by combining an in silico proteomics approach with wet-laboratory techniques. Proteomics results previously generated from varicocele patients (n=50) and fertile controls (n=10) attending our Andrology Center were reanalyzed using bioinformatics tools, including the WEB-based Gene SeT AnaLysis Toolkit, Open Target Platform, and Ingenuity Pathway Analysis (IPA), to identify differentially expressed proteins (DEPs) involved in DNA repair. Subsequently, selected DEPs in spermatozoa were validated using western blotting in varicocele (n = 13) and fertile control (n = 5) samples. We identified 99 DEPs mainly involved in male reproductive system disease (n=66) and male infertility (n=47). IPA analysis identified five proteins [fatty acid synthase (FASN), myeloperoxidase (MPO), mitochondrial aconitate hydratase (ACO2), nucleoporin 93 (NUP93), and 26S proteasome non-ATPase regulatory subunit 14 (PSMD14)] associated with DNA repair deficiency, which showed altered expression in varicocele (P <0.03). We validated ACO2 downregulation (fold change=0.37, change%=-62.7%, P=0.0001) and FASN overexpression (fold change = 4.04, change %= 303.7%, P = 0.014) in men with varicocele compared to controls. This study combined a unique in silico approach with an in vitro validation of the molecular mechanisms that may be responsible for varicocele-associated infertility. We identified ACO2 and FASN as possible proteins involved in DNA repair, whose altered expression may contribute to DNA damage in varicocele pathophysiology., Competing Interests: Author RH was employed by company LogixX Pharma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Finelli, Darbandi, Pushparaj, Henkel, Ko and Agarwal.)

The Dlx homeodomain transcription factors play important roles in the differentiation and migration of GABAergic interneuron precursors. The mouse and human genomes each have six Dlx genes organized into three convergently transcribed bigene clusters ( Dlx1/2 , Dlx3/4 , and Dlx5/6 ) with cis -regulatory elements (CREs) located in the intergenic region of each cluster. Amongst these, the I56i and I12b enhancers from the Dlx1/2 and Dlx5/6 locus, respectively, are active in the developing forebrain. I56i is also a binding site for GTF2I, a transcription factor whose function is associated with increased sociability and Williams-Beuren syndrome. In determining the regulatory roles of these CREs on forebrain development, we have generated mutant mouse-lines where Dlx forebrain intergenic enhancers have been deleted (I56i (-/-) , I12b (-/-) ). Loss of Dlx intergenic enhancers impairs expression of Dlx genes as well as some of their downstream targets or associated genes including Gad2 and Evf2 . The loss of the I56i enhancer resulted in a transient decrease in GABA + cells in the developing forebrain. The intergenic enhancer mutants also demonstrate increased sociability and learning deficits in a fear conditioning test. Characterizing mice with mutated Dlx intergenic enhancers will help us to further enhance our understanding of the role of these Dlx genes in forebrain development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fazel Darbandi, Esau, Lesage-Pelletier, Monis, Poitras, Yu, Perin, Hatch and Ekker.)

Purpose: In response to the COVID-19 pandemic, the American Center for Reproductive Medicine (ACRM) transitioned its annual training in assisted reproductive technology (ART) from a hands-on, laboratory-based training course to a fully online training endorsed by the American College of Embryology. Here we describe our experience and assess the quality of an online training format based on participant outcomes for the first three modules of a planned series of online ART training., Materials and Methods: These modules included manual semen analysis, sperm morphology and ancillary semen tests (testing for leukocytospermia, sperm vitality, and anti-sperm antibody screening). The virtual format consisted of lecture presentations featuring laboratory protocols with corresponding video demonstrations of routine techniques and best practices. Practical scenarios, troubleshooting, and clinical interpretation of laboratory results were also discussed. At the end of each module, an optional multiple choice question test was held as a prerequisite to obtain certification on the topics presented. Course quality was assessed using participant responses collected via online surveys., Results: The digital delivery methods used were found to have largely or completely met the participants' expectations for all questions (>85%). The majority (>87%) of the participants either strongly agreed or agreed that the course content was well-structured with appropriate depth, and that their overall expectations of the course had been met., Conclusions: This training format appears to be a realistic teaching option to freely share highly specialized expertise and technical knowledge with participants from anywhere in the world with varying levels of competency or experience., Competing Interests: The authors have nothing to disclose., (Copyright © 2021 Korean Society for Sexual Medicine and Andrology.)

Background: Genetic variants in the voltage-gated sodium channels SCN1A, SCN2A, SCN3A, and SCN8A are leading causes of epilepsy, developmental delay, and autism spectrum disorder. The mRNA splicing patterns of all four genes vary across development in the rodent brain, including mutually exclusive copies of the fifth protein-coding exon detected in the neonate (5N) and adult (5A). A second pair of mutually exclusive exons is reported in SCN8A only (18N and 18A). We aimed to quantify the expression of individual exons in the developing human brain., Methods: RNA-seq data from 783 human brain samples across development were analyzed to estimate exon-level expression. Developmental changes in exon utilization were validated by assessing intron splicing. Exon expression was also estimated in RNA-seq data from 58 developing mouse neocortical samples., Results: In the mature human neocortex, exon 5A is consistently expressed at least 4-fold higher than exon 5N in all four genes. For SCN2A, SCN3A, and SCN8A, a brain-wide synchronized 5N to 5A transition occurs between 24 post-conceptual weeks (2nd trimester) and 6 years of age. In mice, the equivalent 5N to 5A transition begins at or before embryonic day 15.5. In SCN8A, over 90% of transcripts in the mature human cortex include exon 18A. Early in fetal development, most transcripts include 18N or skip both 18N and 18A, with a transition to 18A inclusion occurring from 13 post-conceptual weeks to 6 months of age. No other protein-coding exons showed comparably dynamic developmental trajectories., Conclusions: Exon usage in SCN1A, SCN2A, SCN3A, and SCN8A changes dramatically during human brain development. These splice isoforms, which alter the biophysical properties of the encoded channels, may account for some of the observed phenotypic differences across development and between specific variants. Manipulation of the proportion of splicing isoforms at appropriate stages of development may act as a therapeutic strategy for specific mutations or even epilepsy in general., (© 2021. The Author(s).)

3D imaging data necessitate 3D reference atlases for accurate quantitative interpretation. Existing computational methods to generate 3D atlases from 2D-derived atlases result in extensive artifacts, while manual curation approaches are labor-intensive. We present a computational approach for 3D atlas construction that substantially reduces artifacts by identifying anatomical boundaries in the underlying imaging data and using these to guide 3D transformation. Anatomical boundaries also allow extension of atlases to complete edge regions. Applying these methods to the eight developmental stages in the Allen Developing Mouse Brain Atlas (ADMBA) led to more comprehensive and accurate atlases. We generated imaging data from 15 whole mouse brains to validate atlas performance and observed qualitative and quantitative improvement (37% greater alignment between atlas and anatomical boundaries). We provide the pipeline as the MagellanMapper software and the eight 3D reconstructed ADMBA atlases. These resources facilitate whole-organ quantitative analysis between samples and across development., Competing Interests: DY, SF, GS, ZB, DY, MN, LG, JR, WY, SS No competing interests declared, (© 2021, Young et al.)

Objective: Sperm DNA fragmentation and maturation directly interferes with reproductive efficiency. Although there are several methods for assessing sperm DNA integrity, however, many of them are laborious and require high-precision equipment in the clinics. Thus, evaluating economic and reliable methods to prepare suitable sperm for assisted reproductive technologies without DNA damage is critical., Material and Methods: A total of 114 semen samples were collected and analyzed using computer-assisted semen analysis. The DNA fragmentation index (DFI) of all samples was evaluated by two methods of sperm chromatin dispersion (SCD) and sperm chromatin structure assay (SCSA). Besides, chromatin maturation index (CMI) was assessed by three methods including aniline blue (AB)-sperm chromatin maturation assay (SCMA), fluorescence microscopic chromomycin A3 (fmCMA3), and flow cytometric CMA3 (fcCMA3)., Results: The result showed that the DFI had no statistically significant differences (p>0.05) between SCSA (26.98%±1.28%) and SCD (27.88%±1.278%), although SCD demonstrated a strong correlation with DNA maturity (p<0.001), which had not been seen in SCSA. Besides, the CMI demonstrated significant differences (p<0.001) when assessed by AB-SCMA (14.86%±0.65%), fmCMA3 (29.18%±1.01%), and fcCMA3 (22.45%±0.62%). Among these, only the fmCMA3 showed a significant correlation with semen parameters (p<0.01) and embryo development (p<0.001)., Conclusion: It seems that SCD and fmCMA3 were more accessible, affordable, and reliable tests for assessing DFI and CMI. It appeared these two methods may be the best choices for evaluating sperm DNA integrity in clinics.

Background: The three-parent assisted reproductive technique may increase oocyte competence., Objective: In this case-control study, the suitability of germinal vesicle transfer (GVT), synchronous ooplasmic transfer (sOT), asynchronous ooplasmic transfer using cryopreserved MII oocyte (caOT), and asynchronous ooplasmic transfer using waste MII oocyte (waOT) for maturation of the human-aged non-surrounded nucleolus germinal vesicle-stage (NSN-GV) oocyte were investigated., Materials and Methods: NSN-GV oocytes were subjected to four methods: group A (GVT), B (sOT), C (caOT) D (waOT), and E (Control). The fusion rates, MI, MII, ICSI observations and cleavage at 2-cell, 4-cell, and 8-cell stages were compared in the groups., Results: In GVT, none of the oocytes fused. In sOT, all oocytes fused, 20 achieved the MI, 14 progressed to MII, 8 fertilized, 6 cleaved and 5, 4, and 3 achieved the 2-cells, 4-cells and 8-cells, respectively. In caOT, all oocytes fused and achieved the MI, 8 progressed to MII and fertilized, 6 cleaved and 6, 5, and 5 achieved the 2-cells, 4-cells, and 8-cells respectively. In waOT, all oocytes fused, 5 and 3 progressed to MI and MII, respectively, but only one fertilized, cleaved and reached a 4-cells stage. In group E, 6 and 2 oocytes progressed to MI and MII, respectively, and only one fertilized but arrested at the zygote stage. caOT had the highest survival rate when compared to sOT (p = 0.04), waOT (p = 0.002), and control (p = 0.001)., Conclusion: The caOT method was beneficial over sOT, waOT, and GVT in supplementing the developmental capacity of human-aged NSN-GV oocytes., Competing Interests: All authors declare no financial or commercial competing interest., (Copyright © 2020 Darbandi et al.)

​Maf ( c-Maf ) and Mafb transcription factors (TFs) have compensatory roles in repressing somatostatin (SST + ) interneuron (IN) production in medial ganglionic eminence (MGE) secondary progenitors in mice. Maf and Mafb conditional deletion (cDKO) decreases the survival of MGE-derived cortical interneurons (CINs) and changes their physiological properties. Herein, we show that (1) Mef2c and Snap25 are positively regulated by Maf and Mafb to drive IN morphological maturation; (2) Maf and Mafb promote Mef2c expression which specifies parvalbumin (PV + ) INs; (3) Elmo1 , Igfbp4 and Mef2c are candidate markers of immature PV + hippocampal INs (HIN). Furthermore, Maf / Mafb neonatal cDKOs have decreased CINs and increased HINs, that express Pnoc , an HIN specific marker. Our findings not only elucidate key gene targets of Maf and Mafb that control IN development, but also identify for the first time TFs that differentially regulate CIN vs. HIN production., Competing Interests: EP, JC, SF, FC, JC, SL, JC, JP, DV, MP No competing interests declared, JR is cofounder, stockholder, and currently on the scientific board of Neurona, a company studying the potential therapeutic use of interneuron transplantation, (© 2020, Pai et al.)

Tbr1 is a high-confidence autism spectrum disorder (ASD) gene encoding a transcription factor with distinct pre- and postnatal functions. Postnatally, Tbr1 conditional knockout (CKO) mutants and constitutive heterozygotes have immature dendritic spines and reduced synaptic density. Tbr1 regulates expression of several genes that underlie synaptic defects, including a kinesin (Kif1a) and a WNT-signaling ligand (Wnt7b). Furthermore, Tbr1 mutant corticothalamic neurons have reduced thalamic axonal arborization. LiCl and a GSK3β inhibitor, two WNT-signaling agonists, robustly rescue the dendritic spines and the synaptic and axonal defects, suggesting that this could have relevance for therapeutic approaches in some forms of ASD., Competing Interests: Declaration of Interests J.L.R.R. is cofounder and stockholder, and currently on the scientific board, of Neurona, a company studying the potential therapeutic use of interneuron transplantation. A.J.W. is a paid consultant for Daiichi Sankyo. M.W.S. is a consultant to BlackThorn and ArRett Pharmaceuticals. All other authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Studies showed a decrease of the semen analysis parameters and an increase in the average age of first-time fathers over the past several decades. The aim of the present study was to assess the influence of paternal age on semen quality and fertilization outcomes in men with normal sperm DNA fragmentation and chromatin maturation index (DFI and CMI), reactive oxygen species (ROS), and total antioxidant capacity (TAC) levels., Material and Methods: The study was performed on 70 men with their wife's age ≤38 years and normal sperm DFI, CMI, ROS, and TAC levels. None of the couples had a history of genital inflammation, chronic diseases, endocrine abnormality, chromosomal aberrations, Y chromosome microdeletion, azoospermia, and leukocytospermia. These men were separated into 2 groups according to their age (group A: age <45 years and group B: age ≥45 years). Semen analysis and fertilization outcome after using the intracytoplasmic sperm injection were assessed in both groups., Result: Sperm concentration showed a significant reduction in group B (p=0.04). Although semen volume, sperm normal morphology, and progressive motility were decreased in group B, the reduction was not significant when compared with group A (p=0.09, p=0.47, and p=0.77, respectively). In addition, the differences of embryo quality with grades A, B, and C and 8-cell embryo formation were not statistically significant between the 2 groups., Conclusion: These results demonstrated that in men with normal sperm DFI, CMI, ROS, and TAC levels, there were no significant changes in semen parameters and fertilization outcomes with an increasing age.

Purpose: This study was conducted in order to investigate the effects of reactive oxygen species (ROS) levels on the seminal plasma (SP) metabolite milieu and sperm dysfunction., Methods: Semen specimens of 151 normozoospermic men were analyzed for ROS by chemiluminescence and classified according to seminal ROS levels [in relative light units (RLU)/s/10 6 sperm]: group 1 (n = 39): low (ROS < 20), group 2 (n = 38): mild (20 ≤ ROS < 40), group 3 (n = 31): moderate (40 ≤ ROS < 60), and group 4 (n = 43): high (ROS ≥ 60). A comprehensive analysis of SP and semen parameters, including conventional semen characteristics, measurement of total antioxidant capacity (TAC), sperm DNA fragmentation index (DFI), chromatin maturation index (CMI), H19-Igf2 methylation status, and untargeted seminal metabolic profiling using nuclear magnetic resonance spectroscopy (1H-NMR), was carried out., Result(s): The methylation status of H19 and Igf2 was significantly different in specimens with high ROS (P < 0.005). Metabolic fingerprinting of these SP samples showed upregulation of trimethylamine N-oxide (P < 0.001) and downregulations of tryptophan (P < 0.05) and tyrosine/tyrosol (P < 0.01). High ROS significantly reduced total sperm motility (P < 0.05), sperm concentration (P < 0.001), and seminal TAC (P < 0.001) but increased CMI and DFI (P < 0.005). ROS levels have a positive correlation with Igf2 methylation (r = 0.19, P < 0.05), DFI (r = 0.40, P < 0.001), CMI (r = 0.39, P < 0.001), and trimethylamine N-oxide (r = 0.45, P < 0.05) and a negative correlation with H19 methylation (r = - 0.20, P < 0.05), tryptophan (r = - 0.45, P < 0.05), sperm motility (r = - 0.20, P < 0.05), sperm viability (r = - 0.23, P < 0.01), and sperm concentration (r = - 0.30, P < 0.001)., Conclusion(s): Results showed significant correlation between ROS levels and H19-Igf2 gene methylation as well as semen parameters. These findings are critical to identify idiopathic male infertility and its management through assisted reproduction technology (ART).

Kelch-like ECH-associated protein 1 (keap1)-nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway is one of the master regulators of cellular defence against oxidative stress. Epigenetic alterations like hypermethylation of keap1 gene impair keap1-Nrf2 system in several oxidative stress-associated diseases. The objective of this study was to evaluate the epigenetic status of keap1 in sperm DNA of normozoospermic subjects, having different levels of reactive oxygen species (ROS) in seminal plasma. Semen samples were obtained from 151 apparently healthy male partners of couples who attended the Avicenna infertility clinic. Samples were categorised into four groups according to their ROS levels: group A (n = 39, ROS < 20 RLU/s per 10 6 spermatozoa), group B (n = 38, 20 ≤ ROS < 40 RLU/s per 10 6 spermatozoa), group C (n = 31, 40 ≤ ROS < 60 RLU/s per 10 6 spermatozoa) and group D; (n = 43, ROS ≥ 60 RLU/s per 10 6 spermatozoa). Keap1 methylation status was assessed using methylation-specific PCR along with seminal total antioxidant capacity. The results showed no significant alterations in keap1 methylation in any groups, whereas the total antioxidant capacity enhanced with increasing levels of ROS exposure. These results indicate that keap1 was not methylated during ROS elevation and oxidative stress, suggesting that the cells have adopted other mechanisms to elevate antioxidant level., (© 2018 Blackwell Verlag GmbH.)

Mafb and c-Maf transcription factor (TF) expression is enriched in medial ganglionic eminence (MGE) lineages, beginning in late-secondary progenitors and continuing into mature parvalbumin (PV + ) and somatostatin (SST + ) interneurons. However, the functions of Maf TFs in MGE development remain to be elucidated. Herein, Mafb and c-Maf were conditionally deleted, alone and together, in the MGE and its lineages. Analyses of Maf mutant mice revealed redundant functions of Mafb and c-Maf in secondary MGE progenitors, where they repress the generation of SST + cortical and hippocampal interneurons. By contrast, Mafb and c-Maf have distinct roles in postnatal cortical interneuron (CIN) morphological maturation, synaptogenesis, and cortical circuit integration. Thus, Mafb and c-Maf have redundant and opposing functions at different steps in CIN development., (Copyright © 2019 UCSF. Published by Elsevier Inc. All rights reserved.)

Objective: Fibronectin (FN) is a multifunctional diametric glycoprotein on the surface of the sperm that plays an important role in the sperm-oocyte interaction and fertilization process. The aim of the present study was to assess the FN levels as a sperm surface biomarker for sperm selection in assisted reproductive technology., Material and Methods: Polyclonal antibody against human FN was produced in rabbit. Its quality, purity, and immune reactivity were assessed by SDS-PAGE and western blot. In addition, the presence of FN on the sperm surface was assessed through immunocytochemistry and flow cytometry. The amount of FN and the sperm quality were assessed in normozoospermia (N) (42 men) and asthenoteratozoospermia (AT) (72 men) groups through sperm chromatin dispersion (SCD), sperm chromatin structure assay (SCSA), and chromatin maturation index (CMI)., Results: The results showed the distribution of FN protein on the equatorial region of the human sperm surface. In addition, the FN levels were found to have a significant difference between the two groups with 24.64±9.08% in N and 16.90±7.27% in AT (p≤0.0001). In addition, FN level negatively correlated with SCD (p≤0.0001), SCSA (p≤0.0001), and CMI (p≤0.001). Threshold values of FN level and DNA fragmentation index (DFI) percentage were 16 and 30 and were identified as cut-off values to determine the N group with a specificity of 83.3% and 81.0% and a sensitivity of 16.8% and 19.0%, respectively. The specificity and sensitivity of FN-DFI were 91.2% and 8.8%, respectively., Conclusion: It appears that FN can be used for the selection of sperm with suitable quality, although future studies are recommended.

An understanding of how heterozygous loss-of-function mutations in autism spectrum disorder (ASD) risk genes, such as TBR1, contribute to ASD remains elusive. Conditional Tbr1 deletion during late mouse gestation in cortical layer 6 neurons (Tbr1 layer6 mutants) provides novel insights into its function, including dendritic patterning, synaptogenesis, and cell-intrinsic physiology. These phenotypes occur in heterozygotes, providing insights into mechanisms that may underlie ASD pathophysiology. Restoring expression of Wnt7b largely rescues the synaptic deficit in Tbr1 layer6 mutant neurons. Furthermore, Tbr1 layer6 heterozygotes have increased anxiety-like behavior, a phenotype seen ASD. Integrating TBR1 chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) data from layer 6 neurons and activity of TBR1-bound candidate enhancers provides evidence for how TBR1 regulates layer 6 properties. Moreover, several putative TBR1 targets are ASD risk genes, placing TBR1 in a central position both for ASD risk and for regulating transcriptional circuits that control multiple steps in layer 6 development essential for the assembly of neural circuits., (Copyright © 2018 Elsevier Inc. All rights reserved.)