Transcription factor Dmrt1 triggers the SPRY1-NF-κB pathway to maintain testicular immune homeostasis and male fertility

Bacterial or viral infections,such as Brucella,mumps virus,herpes simplex virus,and Zika virus,destroy immune homeostasis of the testes,leading to spermatogenesis disorder and infertility.Of note,recent research shows that SARS-CoV-2 can infect male gonads and destroy Sertoli and Leydig cells,leading to male reproductive dysfunction.Due to the many side effects associated with antibiotic therapy,finding alternative treatments for inflammatory injury remains critical.Here,we found that Dmrt1 plays an important role in regulating testicular immune homeostasis.Knockdown of Dmrt1 in male mice inhibited spermatogenesis with a broad inflammatory response in seminiferous tubules and led to the loss of spermatogenic epithelial cells.Chromatin immunoprecipitation sequencing(ChIP-seq)and RNA sequencing(RNA-seq)revealed that Dmrt1 positively regulated the expression of Spry1,an inhibitory protein of the receptor tyrosine kinase(RTK)signaling pathway.Furthermore,immunoprecipitation-mass spectrometry(IP-MS)and co-immunoprecipitation(Co-IP)analysis indicated that SPRY1 binds to nuclear factor kappa B1(NF-κB1)to prevent nuclear translocation of p65,inhibit activation of NF-κB signaling,prevent excessive inflammatory reaction in the testis,and protect the integrity of the blood-testis barrier.In view of this newly identified Dmrt1-Spry1-NF-κB axis mechanism in the regulation of testicular immune homeostasis,our study opens new avenues for the prevention and treatment of male reproductive diseases in humans and livestock.

Single-cell RNA sequencing reveals atlas of dairy goat testis cells

Single-cell RNA sequencing(scRNA-seq)is useful for exploring cell heterogeneity.For large animals,however,little is known regarding spermatogonial stem cell(SSC)selfrenewal regulation,especially in dairy goats.In this study,we described a high-resolution scRNA-seq atlas derived from a dairy goat.We identified six somatic cell and five spermatogenic cell subtypes.During spermatogenesis,genes with significantly changed expression were mainly enriched in the Notch,TGF-β,and Hippo signaling pathways as well as the signaling pathway involved in the regulation of stem cell pluripotency.We detected and screened specific candidate marker genes(TKTL1 and AES)for spermatogonia.Our study provides new insights into goat spermatogenesis and the development of testicular somatic cells.

Dmrt1 regulates the immune response by repressing the TLR4 signaling pathway in goat male germline stem cells

Double sex and mab-3-related transcription factor 1(Dmrt1),which is expressed in goat male germline stem cells(mGSCs)and Sertoli cells,is one of the most conserved transcription factors involved in sex determination.In this study,we highlighted the role of Dmrt1 in balancing the innate immune response in goat mGSCs.Dmrt1 recruited promyelocytic leukemia zinc finger(Plzf),also known as zinc finger and BTB domain-containing protein 16(Zbtb16),to repress the Toll-like receptor 4(TLR4)-dependent inflammatory signaling pathway and nuclear factor(NF)-κB.Knockdown of Dmrt1 in seminiferous tubules resulted in widespread degeneration of germ and somatic cells,while the expression of proinflammatory factors were significantly enhanced.We also demonstrated that Dmrt1 stimulated proliferation of mGSCs,but repressed apoptosis caused by the immune response.Thus,Dmrt1 is sufficient to reduce inflammation in the testes,thereby establishing the stability of spermatogenesis and the testicular microenvironment.

Melatonin relieves heat-induced spermatocyte apoptosis in mouse testes by inhibition of ATF6 and PERK signaling pathways

Normal spermatogenic processes require the scrotal temperature to be lower than that of the body as excessive heat affects spermatogenesis in the testes,reduces sperm quality and quantity,and even causes infertility.Endoplasmic reticulum stress(ERS)is a crucial factor in many pathologies.Although several studies have linked ERS to heat stress,researchers have not yet determined which ERS signaling pathways contribute to heat-induced testicular damage.Melatonin activates antioxidant enzymes,scavenges free radicals,and protects the testes from inflammation;however,few studies have reported on the influence of melatonin on heat-induced testicular damage.Using a murine model of testicular hyperthermia,we observed that heat stress causes both ERS and apoptosis in the testes,especially in the spermatocytes.These observations were confirmed using the mouse spermatocyte cell line GC2,where the Atf6 and Perk signaling pathways were activated during heat stress.Knockout of the above genes effectively reduced spermatocyte damage caused by heat stress.Pretreatment with melatonin alleviated heat-induced apoptosis by inhibiting the Atf6 and Perk signaling pathways.This mitigation was dependent on the melatonin receptors.In vivo experiments verified that melatonin treatment relieved heat-induced testicular damage.In conclusion,our results demonstrated that ATF6 and PERK are important mediators for heat-induced apoptosis,which can be prevented by melatonin treatment.Thus,our study highlights melatonin as a potential therapeutic agent in mammals for subfertility/infertility induced by testicular hyperthermia.

Compression behavior of metal foams with real pore structures through CT scan images

Based on the real pore structure obtained from computed tomography(CT)scan images,a three-dimensional(3D)model of the metal foam sample with specified porosity is established,and the model is compressed and simulated by finite element method with the simulation results compared with the experimental test results for validation.At the same time,based on the spatial distribution characteristics of cells extracted from 3D model construction,a widely used metal foam model with Voronoi pore structure or spherical pore structure was established and simulated under compression.The two compression simulation results with regular pore structure models were also compared with the experimental results and CT model results to study the influence of cell wall morphology on the compression performance of metal foams.The simulation results show that CT model agrees well with the experimental results and is more accurate than Voronoi pore or spherical pore model,which can provide a more reasonable option for investigation of metal foams.

Eleven Absorbed Constituents and 91 Metabolites of Chuanxiong Rhizoma Decoction in Rats

Objective:Chuanxiong Rhizoma(CR,the dried rhizomes of Ligusticum chuanxiong)is a well-known traditional Chinese medicine that promotes qi to activate blood,dispels wind,and relieves pain.To date,more than 118 constituents of CR have been isolated and identified.However,the in vivo mechanism of CR decoction is unclear and needs further investigation.In addition,to clarify the effective forms of CR,it is essential to reveal the absorbed constituents and metabolites of CR.Materials and Methods:The absorbed constituents and metabolites in urine and plasma samples of rats orally administered with CR decoction were screened and characterized using a high-performance liquid chromatography with diode array detector and combined with electrospray ionization ion trap time-of-flight multistage mass spectrometry technique.Results:In total,102 compounds,including 11 absorbed constituents(eight phthalides and three phthalic acids)and 91 metabolites(71 phthalide-related and 20 phenolic acid-related),were detected in drug-containing rat urine and plasma samples,among which 33 were new metabolites of either CR or its constituents.Based on the structures of these metabolites,six phthalides(ligustilide,senkyunolide I/H,senkyunolide J/N,and butylidenephthalide)and three phenolic acids(ferulic acid,isoferulic acid,and caffeic acid)were proposed as their precursors.They were also deduced to be the main absorbed constituents of CR decoction,which should have closer relationships with its pharmacological effects than other constituents.Phthalide-related metabolites were formed through the metabolic reactions of hydration,hydroxylation,cysteine conjugation,acetylcysteine conjugation,methanethiol conjugation,mercaptomethanol conjugation,glucuronidation,and sulfation,whereas the phenolic acid-related metabolites were mainly formed by glucuronidation and sulfation.Conclusions:Six phthalides and three phenolic acids were shown to be the main precursors of the metabolites of CR,and 33 compounds were new metabolites of either CR or its constituents.These results are helpful for further understanding of the in vivo mechanism and effective forms of CR.

Fabrication of AI foam without thickening process through melt-foaming method

By using calcium carbonate （CaCO3） powder as the blowing agent, Al foams with porosities of - 60 to 85% and pore size of - 1.5 mm were fabricated via melt-foaming method. Instead of adding a thickening agent to increase Al melt viscosity, a small amount of Mg ingot （5.0 wt%） was added first, and then A1 melt was foamed by adding calcium carbonate via the impellor stirring. The effect of Mg addition on the gas release behavior of calcium carbonate in the Al melt was investigated. The compression behavior of fabricated Al foams was examined. The results show that the blowing gas is possibly from the reaction between Mg and calcium carbonate, and this reaction can produce solid oxides with micrometer level size, which leads to increasing the Al melt viscosity and is beneficial for inhibiting pores coarsening. Besides, the micrometer level cracks in the cell walls make the strength of Al foam decrease.

Recent progress in porous Mg-based foam preparation approaches:effect of processing parameters on structure and mechanical property

Porous metals are a class of cellular materials with lightweight and unique mechanical,electrical,thermal,physical and acoustic characteristics.Magnesium and magnesium alloy foams have exhibited excellent advantages.In particular,open-cell Mg-based foams(porous Mg/Mg alloy foams)have been used for bioresorbable implants,CO_(2)trapping systems,filters,heat exchangers,absorbent panels and many other applications.While significant progress has been taken in producing porous Mg-based foams with good structure-property relations,but with a large number of different processing parameters,different mechanical properties and pore morphologies of each porous Mg-based foam,it is essential to understand the individual effects of each aspect of the parameters.Therefore,the present article summarized the effects of available processing parameters on the structure and mechanical properties of the porous Mg-based foams.Finally,the future perspectives to enhance the structure and properties of porous Mg/Mg alloy foams were discussed.

Scaling laws and mechanical properties of nanoporous copper

Through molecular dynamics simulations,the mechanical behavior of nanoporous copper under impact loading was investigated with relative densities ranging from 77.91% to 98.36%,focusing on deformation mechanism,the scaling laws and influence of ligament sizes.Results show that the classical Gibson-Ashby′s scaling laws should be modified for prediction of both the Young′s modulus and yield stress.A proportional relationship is established between cell wall thickness and yield stress,and new modified scaling equations are built for nanoporous copper with consideration on both relative mass density and size effects of ligaments.The size effect can be explained by larger surface area/volume ratio of samples with thinner ligament size and limited dislocation source activation due to narrow space between larger numbers of voids.

Exploiting the Community Structure of Fraudulent Keywords for Fraud Detection in Web Search

Internet users heavily rely on web search engines for their intended information.The major revenue of search engines is advertisements(or ads).However,the search advertising suffers from fraud.Fraudsters generate fake traffic which does not reach the intended audience,and increases the cost of the advertisers.Therefore,it is critical to detect fraud in web search.Previous studies solve this problem through fraudster detection(especially bots)by leveraging fraudsters'unique behaviors.However,they may fail to detect new means of fraud,such as crowdsourcing fraud,since crowd workers behave in part like normal users.To this end,this paper proposes an approach to detecting fraud in web search from the perspective of fraudulent keywords.We begin by using a unique dataset of 150 million web search logs to examine the discriminating features of fraudulent keywords.Specifically,we model the temporal correlation of fraudulent keywords as a graph,which reveals a very well-connected community structure.Next,we design DFW(detection of fraudulent keywords)that mines the temporal correlations between candidate fraudulent keywords and a given list of seeds.In particular,DFW leverages several refinements to filter out non-fraudulent keywords that co-occur with seeds occasionally.The evaluation using the search logs shows that DFW achieves high fraud detection precision(99%)and accuracy(93%).A further analysis reveals several typical temporal evolution patterns of fraudulent keywords and the co-existence of both bots and crowd workers as fraudsters for web search fraud.