Cross-talk between Vimentin and autophagy regulates blood-testis barrier disruption induced by cadmium.

The blood-testis barrier (BTB) plays a vital role in mammalian spermatogenesis by separating the seminiferous epithelium into an adluminal and a basal compartment. Cadmium (Cd) is a toxic heavy metal that is widely present in the environment. We observed that Cd can induce BTB disruption, leading to apoptosis of testicular cells. However, the molecular mechanisms contributing to BTB injury induced by Cd have not yet been fully clarified. Vimentin (Vim) is an important desmosome-like junction protein that mediates robust adhesion in the BTB. In this study, we investigated how Vim responds to Cd. We found that Cd treatment led to a significant decrease in Vim expression, accompanied by a marked increase in LC3-II expression and a higer number of autophagosomes. Interestingly, we also observed that Cd-induced autophagy was associated with decreased Vim activity and enhanced apoptosis of testicular cells. To further investigate the role of autophagy in Vim regulation under Cd exposure, we treated cells with an autophagy inhibitor called 3-MA. We found that 3-MA treatment enhanced Vim expression and improved the disruption of the BTB under Cd exposure. Additionally, the inhibition of Vim confirmed the role of autophagy in modulating Vim expression. These results reveal a previously unknown regulatory mechanism of Cd involving the interplay between a heavy metal and a protein.

Cadmium exposure induces pyroptosis of TM4 cells through oxidative stress damage and inflammasome activation.

Cadmium (Cd) is a harmful metal that seriously affects the male reproductive system, but the mechanism of how Cd exposure damages Sertoli cells is not fully understood. This study used TM4 cells to explore the mechanism of Cd damage to Sertoli cells. We found that Cd was concentration- and time-dependent on TM4 cell viability. Cd exposure increased intracellular reactive oxygen species (ROS) levels, lactate dehydrogenase (LDH), and Interleukin-1ß (IL-1ß) release in TM4 cells, decreased mitochondrial function, and increased pyroptosis. N-acetylcysteine (NAC), MCC950 and BAY 11-7082 (BAY) alleviate the release of IL-1ß and LDH induced by Cd. NAC reduced Cd induced increases in ROS, NLRP3, Caspase-1, Heme oxygenase-1(HO-1), superoxide dismutase (SOD2), and increased mitochondrial function. The activation of GSDMD is the main causes of pyroptosis, and NAC significantly inhibit its activation and formation. Our results suggest that Cd exposure induces a toxic mechanism of GSDMD-mediated pyroptosis in TM4 cells by increasing ROS levels and activating the inflammasome.

MiR-484 promotes nonalcoholic fatty liver disease progression in mice via downregulation of Sorbs2.

OBJECTIVE: MicroRNA 484 (miR-484) plays a pivotal role in the development and progression of different diseases and is typically described as a mitochondrial regulator. Whether miR-484 is involved in lipid metabolism or exerts a role in nonalcoholic fatty liver disease remains unclear. METHODS: miR-484 levels were examined in the livers of male mice fed a high-fat diet and in hepatocytes treated with free fatty acids. Sorbin and SH3 structural domain-containing protein 2 (Sorbs2) were identified as a novel target of miR-484 by sequencing mRNA in the livers of miR-484 knockout mice. Sorbs2 liver-specific knockdown mice were constructed by tail vein injection of adeno-associated virus vector to miR-484 knockout mice. In addition, genetic manipulation of SORBS2 was performed in human hepatocyte lines, mouse primary hepatocytes, and the liver. RESULTS: Serum and hepatic miR-484 levels are upregulated in nonalcoholic fatty liver disease mice. miR-484 knockdown ameliorated hepatocyte steatosis, whereas miR-484 overexpression increased hepatocyte lipid load. miR-484 knockdown-mediated alleviation of hepatic steatosis, liver injury, inflammation, and apoptosis was compromised after high-fat diet-induced knockdown of Sorbs2 in mouse liver and free fatty acid-induced primary mouse hepatocytes. CONCLUSIONS: These results identify Sorbs2-mediated mitochondrial ß-oxidation and apoptosis that promote miR-484 knockdown-mediated remission of hepatic steatosis.

Paternal cadmium exposure induces glucolipid metabolic reprogramming in offspring mice via PPAR signaling pathway.

In industrialized societies, the prevalence of metabolic diseases has substantially increased over the past few decades, yet the underlying causes remain unclear. Cadmium (Cd) is a hazardous heavy metal and pervasive environmental endocrine disruptor. Here, we investigate the effects of paternal Cd exposure on offspring glucolipid metabolism. Paternal Cd exposure (1 mg kg-1 body weight) impaired glucose tolerance, increased random serum glucose and fasting serum insulin, elevated serum total cholesterol, and low-density lipoprotein in offspring mice. Untargeted metabolomics analysis of male offspring liver tissue revealed that paternal Cd exposure can affect offspring glucolipid metabolic reprogramming, which involved biosynthesis of phenylalanine, tyrosine and tryptophan, biosynthesis of unsaturated fatty acids, metabolism of linoleic acid, arachidonic acid and α-linolenic acid. Transcriptome sequencing of male offspring liver tissue showed that arachidonic acid metabolism, AMPK signaling pathway, PPAR signaling pathway and adipocytokine signaling pathway were significantly inhibited in the Cd-exposed group. The mRNA expression levels of PPAR signaling pathway related genes (Acsl1, Cyp4a14, Cyp4a10, Cd36, Ppard and Pck1) were significantly decreased. The protein expression levels of ACSL1, CD36, PPARD and PCK1 were also significantly reduced. Collectively, our findings suggest that paternal Cd exposure affect offspring glucolipid metabolic reprogramming via PPAR signaling pathway.

Paternal cadmium exposure affects estradiol synthesis by impairing intracellular cholesterol homeostasis and mitochondrial function in offspring female mice.

Cadmium (Cd) is a toxic heavy metal commonly found in nature and an endocrine disrupting chemical (EDC). Previous studies found that Cd can damage several organs, including the kidneys, bones, cardiovascular system and reproductive system. However, the effect of paternal Cd exposure on the offspring is unclear. In this study, 1 mg/kg of cadmium chloride (CdCl2) was injected intraperitoneally every other day in 8-week-old C57BL/6 J male mice to study the effects on their female offspring. Our results showed an increase in body weight, water intake and food intake in F1 female mice from the Cd-exposed group. The development of secondary follicles and antral follicles in the ovaries of Cd-treated was inhibited. Serum estradiol (E2) was found to be decreased. Further analysis revealed significant downregulation of StAR, P450scc, 17ß-HSD, CYP17A1 and CYP19A1, which are related to E2 synthesis. Serum total cholesterol was increased and free cholesterol was reduced. Total cholesterol in ovarian tissue was decreased. qRT-PCR and Western blot analysis revealed a decrease in the mRNA and protein expression of HMGCR, LDLR, and ABCA1, which are associated with cholesterol homeostasis. Oil red O staining indicated that lipid droplets (LDs) were accumulated in ovarian tissues, while the expression of ATGL and HSL proteins associated with lipid droplet degradation was significantly downregulated. In juvenile female mice, ultrastructural alterations of mitochondria in the ovaries were observed by transmission electron microscopy (TEM). In adult female mice, the expression of proteins associated with mitochondrial dynamics (DRP1 and MFN2) was significantly reduced in the ovaries. Overall, our study suggests that paternal Cd exposure inhibits follicular development, and affects serum E2 synthesis by impairing cholesterol homeostasis and affecting mitochondrial function.

Speech2EEG: Leveraging Pretrained Speech Model for EEG Signal Recognition.

Identifying meaningful brain activities is critical in brain-computer interface (BCI) applications. Recently, an increasing number of neural network approaches have been proposed to recognize EEG signals. However, these approaches depend heavily on using complex network structures to improve the performance of EEG recognition and suffer from the deficit of training data. Inspired by the waveform characteristics and processing methods shared between EEG and speech signals, we propose Speech2EEG, a novel EEG recognition method that leverages pretrained speech features to improve the accuracy of EEG recognition. Specifically, a pretrained speech processing model is adapted to the EEG domain to extract multichannel temporal embeddings. Then, several aggregation methods, including the weighted average, channelwise aggregation, and channel-and-depthwise aggregation, are implemented to exploit and integrate the multichannel temporal embeddings. Finally, a classification network is used to predict EEG categories based on the integrated features. Our work is the first to explore the use of pretrained speech models for EEG signal analysis as well as the effective ways to integrate the multichannel temporal embeddings from the EEG signal. Extensive experimental results suggest that the proposed Speech2EEG method achieves state-of-the-art performance on two challenging motor imagery (MI) datasets, the BCI IV-2a and BCI IV-2b datasets, with accuracies of 89.5% and 84.07% , respectively. Visualization analysis of the multichannel temporal embeddings show that the Speech2EEG architecture can capture useful patterns related to MI categories, which can provide a novel solution for subsequent research under the constraints of a limited dataset scale.

Cohesive Multi-Modality Feature Learning and Fusion for COVID-19 Patient Severity Prediction.

The outbreak of coronavirus disease (COVID-19) has been a nightmare to citizens, hospitals, healthcare practitioners, and the economy in 2020. The overwhelming number of confirmed cases and suspected cases put forward an unprecedented challenge to the hospital's capacity of management and medical resource distribution. To reduce the possibility of cross-infection and attend a patient according to his severity level, expertly diagnosis and sophisticated medical examinations are often required but hard to fulfil during a pandemic. To facilitate the assessment of a patient's severity, this paper proposes a multi-modality feature learning and fusion model for end-to-end covid patient severity prediction using the blood test supported electronic medical record (EMR) and chest computerized tomography (CT) scan images. To evaluate a patient's severity by the co-occurrence of salient clinical features, the High-order Factorization Network (HoFN) is proposed to learn the impact of a set of clinical features without tedious feature engineering. On the other hand, an attention-based deep convolutional neural network (CNN) using pre-trained parameters are used to process the lung CT images. Finally, to achieve cohesion of cross-modality representation, we design a loss function to shift deep features of both-modality into the same feature space which improves the model's performance and robustness when one modality is absent. Experimental results demonstrate that the proposed multi-modality feature learning and fusion model achieves high performance in an authentic scenario.

Paternal cadmium exposure affects testosterone synthesis by reducing the testicular cholesterol pool in offspring mice.

Cadmium（Cd） is a heavy metal that is harmful to human health. Early studies have shown that cadmium can damage testicular structure, affecting testosterone synthesis and spermatogenesis. However, the effect of paternal Cd exposure on the reproductive system of offspring remains unclear. In this study, male 8-week C57BL/6 J mice were used as research objects, and Cd was injected intraperitoneally every other day at a dose of 1 mg/kg for 5 weeks, after which the effect on the reproductive system of offspring male mice was studied. Our results showed that the body weight of the offspring male mice increased faster, with increases of the testicular and epididymis indices under Cd exposure. At the same time, the serum testosterone and free cholesterol decreased, total cholesterol increased, and the sperm concentration decreased. Further qRT-PCR and western blot analyses showed that the expressions of StAR, P450scc, 3ß-HSD and 17ß-HSD, which are related to testosterone synthesis, was significantly downregulated. Additionally, ATGL, LDLR and SR-BI, which are related to the intracellular cholesterol pool were downregulated, leading to the reduction of the cholesterol pool and the accumulation of lipid droplets. Oil red O and BODIPY staining revealed an increase in the abundance of lipid droplets in testicular tissue of newborn and adult mice. Prediction of tsRNA target genes in the sperm of parents and testicular transcriptome of newborn mice showed that the differentially expressed genes were associated with catabolism of fatty acids, cholesterol and ion channels, while the mitochondrial and lysosome functions of testicular tissue of adult offspring mice were decreased. Overall, our results suggest that paternal Cd exposure reduced the intracellular cholesterol pool of testicular of offspring, affected testosterone synthesis and reproductive system development.

Cadmium exposure induces pyroptosis in testicular tissue by increasing oxidative stress and activating the AIM2 inflammasome pathway.

High doses of cadmium (Cd) cause irreversible injury to the reproductive system, especially testicular tissue. Studies have shown that pyroptosis is involved in Cd-induced tissue damage, but whether pyroptosis is involved in damage to testicular tissue following Cd exposure remains unclear. To investigate the mechanism of pyroptosis in testicular injury induced by Cd exposure, we used 8-week-old male C57BL/6J mice subjected to consecutive 7 days of intraperitoneal injection of cadmium chloride (CdCl2) at concentrations of 0, 1.0 and 3.0 mg/kg. The results indicated that 3.0 mg/kg CdCl2 significantly decreased serum testosterone levels, sperm concentration and sperm motility, while increased LDH and IL-1ß levels. Testicular HE staining indicated that Cd exposure damaged the interstitial cells and increased the atypical residual bodies. Fluorescence results indicated that 3.0 mg/kg CdCl2 increased ROS levels, DNA damage, and the number of TUNEL-positive seminiferous tubule cells in testicular tissue. Transcriptome analysis showed that Cd exposure mainly induced inflammatory and chemokine signaling pathways in testicular tissue, with upregulated mRNA levels of Aim2, and reduced mRNA levels of Nlrp3. Further analysis showed that 3.0 mg/kg CdCl2 increased the expression of testicular HO-1, SOD2, γH2AX and PARP-1, as well as the pyroptosis-related factors GSDMD, GSDME, Caspase-1, ASC and IL-1ß. In conclusion, our results provide a possible mechanism by which Cd exposure activates the AIM2 pathway by increasing oxidative stress injury to induce pyroptosis in testicular tissue. This provides a new perspective on testicular damage caused by Cd exposure.

A hypothesis: Retrotransposons as a relay of epigenetic marks in intergenerational epigenetic inheritance.

Epigenetic marks in gametes, which both respond to the parental environmental factors and shape offspring phenotypes, are usually positioned to mediate intergenerational or transgenerational epigenetic inheritance. Nonetheless, the mechanisms through which gametic epigenetic signatures encode parental acquired phenotypes, and further initiate a cascade of molecular events to affect offspring phenotypes during early embryonic development, remain unclear. Retrotransposons are mobile DNA elements that could resist to genomic epigenetic reprogramming at specific loci and rewire the core regulatory networks of embryogenesis. Increasing evidences show that retrotransposons in the embryonic genome could interact with gametic epigenetic marks, which provides a tentative possibility that retrotransposons may serve as a relay of gametic epigenetic marks to transmit parental acquired traits. Here, we summarize the recent progress in exploring the crosstalk between gametic epigenetic marks and retrotransposons, and the regulation of gene expression and early embryonic development by retrotransposons. Accordingly, deciphering the mystery of interactions between gametic epigenetic marks and retrotransposons during early embryonic development will provide valuable insights into the intergenerational or transgenerational transmission of acquired traits.

Cadmium attenuates testosterone synthesis by promoting ferroptosis and blocking autophagosome-lysosome fusion.

Ferroptosis is a newly defined programmed cell death pathway characterized by iron overload and lipid peroxidation. Increasing studies show that autophagy regulates testosterone synthesis and promotes ferroptosis. Testosterone is essential for sexual development and the maintenance of male characteristics. The deficiency of testosterone induced by cadmium (Cd) can severely affect male fertility. However, the underlying mechanism of testosterone reduction after Cd exposure remains blurry. In this study, we found that Cd affected iron homeostasis and elicited ferroptosis, ultimately reducing testosterone production. Mechanically, our findings revealed that Cd-induced ferroptosis depended upon the excessive activation of Heme oxygenase 1 (HMOX1) and the release of free iron from heme. Additionally, Cd exposure promoted autophagosome formation but blocked autophagosome-lysosome fusion, which attenuated the absorption of total cholesterol and triglycerides, further aggravating testosterone synthesis disorder. Collectively, Cd induced ferroptosis by iron homeostasis dysregulation, mediated by excessive activation of HMOX-1. The disruption of autophagy flow contributed to Cd-induced testicular dysfunction and attenuated testosterone synthesis.

Classification of COVID-19 by Compressed Chest CT Image through Deep Learning on a Large Patients Cohort.

Corona Virus Disease (COVID-19) has spread globally quickly, and has resulted in a large number of causalities and medical resources insufficiency in many countries. Reverse-transcriptase polymerase chain reaction (RT-PCR) testing is adopted as biopsy tool for confirmation of virus infection. However, its accuracy is as low as 60-70%, which is inefficient to uncover the infected. In comparison, the chest CT has been considered as the prior choice in diagnosis and monitoring progress of COVID-19 infection. Although the COVID-19 diagnostic systems based on artificial intelligence have been developed for assisting doctors in diagnosis, the small sample size and the excessive time consumption limit their applications. To this end, this paper proposed a diagnosis prototype system for COVID-19 infection testing. The proposed deep learning model is trained and is tested on 2267 CT sequences from 1357 patients clinically confirmed with COVID-19 and 1235 CT sequences from non-infected people. The main highlights of the prototype system are: (1) no data augmentation is needed to accurately discriminate the COVID-19 from normal controls with the specificity of 0.92 and sensitivity of 0.93; (2) the raw DICOM image is not necessary in testing. Highly compressed image like Jpeg can be used to allow a quick diagnosis; and (3) it discriminates the virus infection within 6 seconds and thus allows an online test with light cost. We also applied our model on 48 asymptomatic patients diagnosed with COVID-19. We found that: (1) the positive rate of RT-PCR assay is 63.5% (687/1082). (2) 45.8% (22/48) of the RT-PCR assay is negative for asymptomatic patients, yet the accuracy of CT scans is 95.8%. The online detection system is available: http://212.64.70.65/covid .

[Effects of bisphenol A on apoptosis of ovarian preantral follicular granulosa cells and ovarian development in mice].

OBJECTIVE: To investigate the effect of environmental estrogen bisphenol A (BPA) exposure on apoptosis of mouse ovarian preantral follicular granulosa cells and ovarian development and explore the underlying mechanism. METHODS: Mouse ovarian preantral follicular granulosa cells were isolated from female ICR mice at postnatal day (PND) 10 and cultured in vitro. The cultured cells were treated with 0, 1, 10, 50, 100, 150, 200 and 500 µmol/L BPA, and the changes in cell proliferation, cell cycle, apoptosis and mitochondrial membrane potential were analyzed with CCK-8 method and flow cytometry. The protein expressions of Bcl-2, Bax, p53 and cyclin D1 in the treated cells were determined with Western blotting. Pregnant ICR mice were treated for a week with BPA at the concentration that produced significant effects on the preantral follicular granulosa cells, and the weight changes of the pregnant mice were recorded. The ovarian tissues of the offspring female mice were weighed at PND 10, 17, 21 and 42 followed by histological observation with HE staining and examination of Bcl-2 mRNA expression level with RT-qPCR. RESULTS: Compared with the control cells group, the isolated cells exposed to a low concentration of BPA (50 µmol/L) showed a significantly lowered apoptosis rate, increased mitochondrial membrane potential, and enhanced cellular proliferation (P < 0.05). Exposure to a higher BPA concentration at 200 µmol/L obviously enhanced cell apoptosis by reducing the mitochondrial membrane potential and repressed the cell proliferation (P < 0.05). BPA exposure at 50 µmol/L and 200 µmol/L produced opposite effects on the protein expressions of Bcl-2 (P < 0.01), Bax (P < 0.05) and p53 (P < 0.05) in mouse ovarian preantral follicular granulosa cells. BPA exposure at the doses of 10 and 35 mg/kg caused rapid weight increment of the pregnant mice and changes in ovarian index of the offspring female mice. In the offspring female mice, the changes in Bcl-2 mRNA expression in the ovarian tissue showed a similar pattern to that of ovarian index. Exposure of the pregnant mice to a high BPA concentration at 35 mg/kg resulted in accelerated follicular development into antral follicular stage in PND 21 offspring female mice. CONCLUSIONS: BPA can concentration-dependently regulate the function of ovarian preantral follicular granulosa cells in mice and potentially affects both the pregnant mice and the offspring female mice in light of early ovarian development.

Differential Expression Profiles and Potential Intergenerational Functions of tRNA-Derived Small RNAs in Mice After Cadmium Exposure.

Cadmium (Cd) is a toxic heavy metal and ubiquitous environmental endocrine disruptor. Previous studies on Cd-induced damage to male fertility mainly focus on the structure and function of testis, including cytoskeleton, blood-testis barrier, and steroidogenesis. Nevertheless, to date, no studies have investigated the effects of Cd exposure on sperm epigenetic inheritance and intergenerational inheritance. In our study, we systematically revealed the changes in sperm tRNA-derived small RNAs (tsRNA) profiles and found that 14 tsRNAs (9 up-regulated and 5 down-regulated) were significantly altered after Cd exposure. Bioinformatics of tsRNA-mRNA-pathway interactions revealed that the altered biological functions mainly were related to ion transmembrane transport, lipid metabolism and cell membrane system. In addition, we focused on two stages of early embryo development and selected two organs to study the impact of these changes on cell membrane system, especially mitochondrion and lysosome, two typical membrane-enclosed organelles. Surprisingly, we found that the content of mitochondrion was significantly decreased in 2-cell stage, whereas remarkably increased in the morula stage. The contents of mitochondrion and lysosome were increased in the testes of 6-day-old offspring and livers of adult offspring, whereas remarkably decreased in the testes of adult offspring. This provides a possible basis to further explore the effects of paternal Cd exposure on offspring health.

Upregulated lncRNA Gm2044 inhibits male germ cell development by acting as miR-202 host gene.

Long non-coding RNAs (lncRNAs) have been found to participate in the regulation of human spermatogenic cell development. However, little is known about the abnormal expression of lncRNAs associated with spermatogenic failure and their molecular mechanisms. Using lncRNA microarray of testicular tissue for male infertility and bioinformatics methods, we identified the relatively conserved lncRNA Gm2044 which may play important roles in non-obstructive azoospermia. The UCSC Genome Browser showed that lncRNA Gm2044 is the miR-202 host gene. This study revealed that lncRNA Gm2044 and miR-202 were significantly increased in non-obstructive azoospermia of spermatogonial arrest. The mRNA and protein levels of Rbfox2, a known direct target gene of miR-202, were regulated by lncRNA Gm2044. Furthermore, the miR-202-Rbfox2 signalling pathway was shown to mediate the suppressive effects of lncRNA Gm2044 on the proliferation of human testicular embryonic carcinoma cells. Understanding of the molecular signalling pathways for lncRNA-regulated spermatogenesis will provide new clues into the pathogenesis and treatment of patients with male infertility.