State-of-art technologies to detect the DNA damage and repair in sperm and future outlook

Editorial - State-of-art technologies to detect the DNA damage and repair in sperm and future outloo

Developing testicular organoids for assessing reproductive toxicity of antidepression drugs

Evaluating the reproductive toxicity of antidepressants is particularly important for those depressed male patients of childbearing age and crucial for the rational use of drugs in clini

A novel BRDT inhibitor NHWD870 shows potential as a male contraceptive in mice

Small molecule inhibitors of the bromodomain and extraterminal domain (BET) family proteins have emerged as a promising option for not only the treatment of multiple cancers but also for disturbing the process of sperm maturation with potential for use as a viable contraceptive target. In this paper, we report a new generation of BET family inhibitor, NHWD870, that provide a complete and reversible contraceptive effect in mice which is stronger than that of JQ1 and its synthesized derivatives. This study is hoped to lead to the clinical trial eventually

Developing rat testicular organoid models for assessing the reproductive toxicity of antidepression drugs in vitro

With the increasing incidence of depression worldwide, antidepressant medications are commonly used in males of reproductive age for long-term treatment of depression, as well as other disorders. Antidepressants are known to be associated with sexual side effects, such as decreased libido and impotence. Their effects on semen parameters and other markers of male fertility have been less thoroughly described, such as sperm motility and fertilization ability. Therefore, it is critical to determine the potential toxic effects of antidepressants on reproductive organs. A recent study systemically determined the effect of different drugs on the telomere-related DNA damage response of germ cells. In addition, another study showed that mirtazapine has less toxic effects than amitriptyline and other drugs. However, these studies used germ cell lines to determine the phenotype, which limits their potential translational value in toxicity studies in humans. Given the widespread and often long-term use of antidepressant medications, there is an urgent need for further data regarding their impact on semen quality and subsequent male fertility

A loss-of-function variant in SSFA2 causes male infertility with globozoospermia and failed oocyte activation

Globozoospermia (OMIM: 102530) is a rare type of teratozoospermia ( A; p.R1224Q) in the patient. This variant significantly reduced the protein expression of SSFA2. Immunofluorescence staining showed posi- tive SSFA2 expression in the acrosome of human sperm. Liquid chromatography–mass spectrometry/mass spectrom- etry (LC–MS/MS) and Coimmunoprecipitation (Co-IP) analyses identified that GSTM3 and Actin interact with SSFA2. Further investigation revealed that for the patient, regular intracytoplasmic sperm injection (ICSI) treatment had a poor prognosis. However, Artificial oocyte activation (AOA) by a calcium ionophore (A23187) after ICSI successfully rescued the oocyte activation failure for the patient with the SSFA2 variant, and the couple achieved a live birth. This study revealed that SSFA2 plays an important role in acrosome formation, and the homozygous c.3671G > A loss-of-function variant in SSFA2 caused globozoospermia. SSFA2 may represent a new gene in the genetic diagnosis of globozoospermia, especially the successful outcome of AOA-ICSI treatment for couples, which has potential value for clinicians in their treatment regimen selections

Rational Modeling of Arching Action in Laterally Restrained Beams

It is well known that arching action in reinforced concrete slabs resulting from surrounding restraining elements is responsible for much greater collapse loads than those estimated considering flexural effects only. However, the subject needs to be better understood and simplified if it is to be reliably applied in broader practice. This thesis presents a rational treatment of the problem. By limiting the scope of investigation to one-way slab systems, for the first time an explicit method of calculating the load-carrying capacity of elastic- plastic slab strips with a laterally rigidly restrained boundary condition is derived. Application of the proposed model to specimens selected from four experiment programs proves its reliability in ultimate strength calculations. The proposed model is then employed in a parametric study of structural responses of deck slab strips. The parametric study shows that a longer span, lightly reinforced deck slab system is still adequate in strength if it is cast in higher strength concrete and sufficient lateral restraint is available.MAS

A Fusion Model for Saliency Detection Based on Semantic Soft Segmentation

With the rapid development of neural networks in recent years, saliency detection based on deep learning has made great breakthroughs. Most deep saliency detection algorithms are based on convolutional neural networks, which still have great room for improvement in the edge accuracy of salient objects recognition, which may lead to fuzzy results in practical applications such as image matting. In order to improve the accuracy of detection, a saliency detection model based on semantic soft segmentation is proposed in this paper. Firstly, the semantic segmentation module combines spectral extinction and residual network model to obtain low-level color features and high-level semantic features, which can clearly segment all kinds of objects in the image. Then, the saliency detection module locates the position and contour of the main body of the object, and the edge accurate results are obtained after the processing of the two modules. Finally, compared with the other 11 algorithms on the DUTS-TEST data set, the weighted F-measure value of the proposed algorithm ranked first, which was 5.8% higher than the original saliency detection algorithm, and the accuracy was significantly improved

ETA-mediated anti-TNF-α therapy ameliorates the phenotype of PCOS model induced by letrozole.

Chronic inflammation is a typical characteristic of polycystic ovary syndrome (PCOS), in which, tumor necrosis factor (TNF)-α plays an important role. We investigated whether anti-TNF-α therapy can alleviate the core phenotypes of PCOS. In pubertal female Wistar rats, release pellets of letrozole (LET) were administered continuously for 90 days to induce PCOS-like phenotypes, followed by treatment with etanercept (ETA), a TNF-α inhibitor. ETA significantly inhibited increases in body weight and androgen, TNF-α, and MCP-1 levels, excessive recruitment of lipid droplets, altered levels of pre-adipose differentiation markers, and abnormal development of follicles. In addition, TNF-α and testosterone (T) levels in the rat sera were significantly positively correlated. Further experiments were performed to investigate the relationship between TNF-α and androgen. Persistent exposure of the RAW 264.7 cell line to low doses of testosterone significantly enhanced TNF-α expression and activated the NF-κB signaling pathway, which were blocked by ETA. Furthermore, treatment with TNF-α promoted the production of testosterone in KGN granulosa cells by reducing CYP19A1 expression, whereas ETA treatment blocked this process. In conclusion, anti-TNF-α therapy with ETA may be an efficient method to alleviate PCOS, whose underlying mechanism may be associated with its ability to reduce excessive androgen levels

Coupling of co-transcriptional splicing and 3’ end Pol II pausing during termination in Arabidopsis

Abstract Background In Arabidopsis, RNA Polymerase II (Pol II) often pauses within a few hundred base pairs downstream of the polyadenylation site, reflecting efficient transcriptional termination, but how such pausing is regulated remains largely elusive. Result Here, we analyze Pol II dynamics at 3’ ends by combining comprehensive experiments with mathematical modelling. We generate high-resolution serine 2 phosphorylated (Ser2P) Pol II positioning data specifically enriched at 3’ ends and define a 3’ end pause index (3’PI). The position but not the extent of the 3’ end pause correlates with the termination window size. The 3’PI is not decreased but even mildly increased in the termination deficient mutant xrn3, indicating 3’ end pause is a regulatory step early during the termination and before XRN3-mediated RNA decay that releases Pol II. Unexpectedly, 3’PI is closely associated with gene exon numbers and co-transcriptional splicing efficiency. Multiple exons genes often display stronger 3’ end pauses and more efficient on-chromatin splicing than genes with fewer exons. Chemical inhibition of splicing strongly reduces the 3’PI and disrupts its correlation with exon numbers but does not globally impact 3’ end readthrough levels. These results are further confirmed by fitting Pol II positioning data with a mathematical model, which enables the estimation of parameters that define Pol II dynamics. Conclusion Our work highlights that the number of exons via co-transcriptional splicing is a major determinant of Pol II pausing levels at the 3’ end of genes in plants