Towards prolonging ovarian reproductive life: Insights into trace elements homeostasis.

Ovarian aging is marked by a reduction in the quantity and quality of ovarian follicles, leading to a decline in female fertility and ovarian endocrine function. While the biological characteristics of ovarian aging are well-established, the exact mechanisms underlying this process remain elusive. Recent studies underscore the vital role of trace elements (TEs) in maintaining ovarian function. Imbalances in TEs can lead to ovarian aging, characterized by reduced enzyme activity, hormonal imbalances, ovulatory disorders, and decreased fertility. A comprehensive understanding of the relationship between systemic and cellular TEs balance and ovarian aging is critical for developing treatments to delay aging and manage age-related conditions. This review consolidates current insights into TEs homeostasis and its impact on ovarian aging, assesses how altered TEs metabolism affects ovarian aging, and suggests future research directions to prolong ovarian reproductive life. These studies are expected to offer novel approaches for mitigating ovarian aging.

Phthalates and uterine disorders.

Humans are ubiquitously exposed to environmental endocrine disrupting chemicals such as phthalates. Phthalates can migrate out of products and enter the human body through ingestion, inhalation, or dermal application, can have potential estrogenic/antiestrogenic and/or androgenic/antiandrogenic activity, and are involved in many diseases. As a female reproductive organ that is regulated by hormones such as estrogen, progesterone and androgen, the uterus can develop several disorders such as leiomyoma, endometriosis and abnormal bleeding. In this review, we summarize the hormone-like activities of phthalates, in vitro studies of endometrial cells exposed to phthalates, epigenetic modifications in the uterus induced by phthalate exposure, and associations between phthalate exposure and uterine disorders such as leiomyoma and endometriosis. Moreover, we also discuss the current research gaps in understanding the relationship between phthalate exposure and uterine disorders.

CircSI-SSL: circRNA-binding site identification based on self-supervised learning.

MOTIVATION: In recent years, circular RNAs (circRNAs), the particular form of RNA with a closed-loop structure, have attracted widespread attention due to their physiological significance (they can directly bind proteins), leading to the development of numerous protein site identification algorithms. Unfortunately, these studies are supervised and require the vast majority of labeled samples in training to produce superior performance. But the acquisition of sample labels requires a large number of biological experiments and is difficult to obtain. RESULTS: To resolve this matter that a great deal of tags need to be trained in the circRNA-binding site prediction task, a self-supervised learning binding site identification algorithm named CircSI-SSL is proposed in this article. According to the survey, this is unprecedented in the research field. Specifically, CircSI-SSL initially combines multiple feature coding schemes and employs RNA_Transformer for cross-view sequence prediction (self-supervised task) to learn mutual information from the multi-view data, and then fine-tuning with only a few sample labels. Comprehensive experiments on six widely used circRNA datasets indicate that our CircSI-SSL algorithm achieves excellent performance in comparison to previous algorithms, even in the extreme case where the ratio of training data to test data is 1:9. In addition, the transplantation experiment of six linRNA datasets without network modification and hyperparameter adjustment shows that CircSI-SSL has good scalability. In summary, the prediction algorithm based on self-supervised learning proposed in this article is expected to replace previous supervised algorithms and has more extensive application value. AVAILABILITY AND IMPLEMENTATION: The source code and data are available at https://github.com/cc646201081/CircSI-SSL.

Advances on the Role of Ferroptosis in Ionizing Radiation Response.

Ferroptosis is an iron-dependent programmed cell death mode that is distinct from other cell death modes, and radiation is able to stimulate cellular oxidative stress and induce the production of large amounts of reactive oxygen radicals, which in turn leads to the accumulation of lipid peroxide and the onset of ferroptosis. In this review, from the perspective of the role of ferroptosis in generating a radiation response following cellular irradiation, the relationship between ferroptosis induced by ionizing radiation stress and the response to ionizing radiation is reviewed, including the roles of MAPK and Nrf2 signaling pathways in ferroptosis, resulting from the oxidative stress response to ionizing radiation, the metabolic regulatory role of the p53 gene in ferroptosis, and regulatory modes of action of iron metabolism and iron metabolism-related regulatory proteins in promoting and inhibiting ferroptosis. It provides some ideas for the follow-up research to explore the specific mechanism and regulatory network of ferroptosis in response to ionizing radiation.

Locating the propagation source in complex networks with observers-based similarity measures and direction-induced search.

Locating the propagation source is one of the most important strategies to control the harmful diffusion process on complex networks. Most existing methods only consider the infection time information of the observers, but the diffusion direction information of the observers is ignored, which is helpful to locate the source. In this paper, we consider both of the diffusion direction information and the infection time information to locate the source. We introduce a relaxed direction-induced search (DIS) to utilize the diffusion direction information of the observers to approximate the actual diffusion tree on a network. Based on the relaxed DIS, we further utilize the infection time information of the observers to define two kinds of observers-based similarity measures, including the Infection Time Similarity and the Infection Time Order Similarity. With the two kinds of similarity measures and the relaxed DIS, a novel source locating method is proposed. We validate the performance of the proposed method on a series of synthetic and real networks. The experimental results show that the proposed method is feasible and effective in accurately locating the propagation source.

Direct Induction of Porous Graphene from Mechanically Strong and Waterproof Biopaper for On-Chip Multifunctional Flexible Electronics.

Graphene with a 3D porous structure is directly laser-induced on lignocellulosic biopaper under ambient conditions and is further explored for multifunctional biomass-based flexible electronics. The mechanically strong, flexible, and waterproof biopaper is fabricated by surface-functionalizing cellulose with lignin-based epoxy acrylate (LBEA). This composite biopaper shows as high as a threefold increase in tensile strength and excellent waterproofing compared with pure cellulose one. Direct laser writing (DLW) rapidly induces porous graphene from the biopaper in a single step. The porous graphene shows an interconnected carbon network, well-defined graphene domains, and high electrical conductivity (e.g., ≈3 Ω per square), which can be tuned by lignin precursors and loadings as well as lasing conditions. The biopaper in situ embedded with porous graphene is facilely fabricated into flexible electronics for on-chip and paper-based applications. The biopaper-based electronic devices, including the all-solid-state planer supercapacitor, electrochemical and strain biosensors, and Joule heater, show great performances. This study demonstrates the facile, versatile, and low-cost fabrication of multifunctional graphene-based electronics from lignocellulose-based biopaper.

CircSSNN: circRNA-binding site prediction via sequence self-attention neural networks with pre-normalization.

BACKGROUND: Circular RNAs (circRNAs) play a significant role in some diseases by acting as transcription templates. Therefore, analyzing the interaction mechanism between circRNA and RNA-binding proteins (RBPs) has far-reaching implications for the prevention and treatment of diseases. Existing models for circRNA-RBP identification usually adopt convolution neural network (CNN), recurrent neural network (RNN), or their variants as feature extractors. Most of them have drawbacks such as poor parallelism, insufficient stability, and inability to capture long-term dependencies. METHODS: In this paper, we propose a new method completely using the self-attention mechanism to capture deep semantic features of RNA sequences. On this basis, we construct a CircSSNN model for the cirRNA-RBP identification. The proposed model constructs a feature scheme by fusing circRNA sequence representations with statistical distributions, static local contexts, and dynamic global contexts. With a stable and efficient network architecture, the distance between any two positions in a sequence is reduced to a constant, so CircSSNN can quickly capture the long-term dependencies and extract the deep semantic features. RESULTS: Experiments on 37 circRNA datasets show that the proposed model has overall advantages in stability, parallelism, and prediction performance. Keeping the network structure and hyperparameters unchanged, we directly apply the CircSSNN to linRNA datasets. The favorable results show that CircSSNN can be transformed simply and efficiently without task-oriented tuning. CONCLUSIONS: In conclusion, CircSSNN can serve as an appealing circRNA-RBP identification tool with good identification performance, excellent scalability, and wide application scope without the need for task-oriented fine-tuning of parameters, which is expected to reduce the professional threshold required for hyperparameter tuning in bioinformatics analysis.

MiR-145 regulates steroidogenesis in mouse primary granulosa cells by targeting Arpc5 and subsequent cytoskeleton remodeling.

MicroRNA (miR)-145 is enriched in the follicular granulosa cells (GCs) of 3-week-old mice. Downregulating miR-145 inhibits the proliferation and differentiation of GCs and induces evident changes in their cytoskeleton. In this study, we examined how miR-145 induces cytoskeletal changes in mouse GCs and its potential mechanism in regulating GC steroidogenesis. We found that actin related protein 2/3 complex subunit 5 (Arpc5) is a target of miR-145. The miR-145 antagomir increased ARPC5 expression but not ß-ACTIN, ß-TUBULIN, and PAXILLIN expression. Arpc5 overexpression inhibited GC proliferation, differentiation, and progesterone synthesis. Furthermore, the expression of progesterone synthesis-associated enzymes was downregulated in the Arpc5 overexpression group, and the GC cytoskeleton exhibited evident changes. We conclude that Arpc5, a new target of miR-145, regulates primary GC proliferation and progesterone production by regulating the cytoskeleton remodeling.

A plant-unique protein BLISTER coordinates with core retromer to modulate endosomal sorting of plasma membrane and vacuolar proteins.

The retromer is a heteromeric protein complex that localizes to endosomal membranes and drives the formation of endosomal tubules that recycle membrane protein cargoes. In plants, the retromer plays essential and canonical functions in regulating the transport of vacuolar storage proteins and the recycle of endocytosed plasma membrane proteins (PM); however, the mechanisms underlying the regulation of assembly, protein stability, and membrane recruitment of the plant retromer complex remain to be elucidated. In this study, we identify a plant-unique endosomal regulator termed BLISTER (BLI), which colocalizes and associates with the retromer complex by interacting with the retromer core subunits VPS35 and VPS29. Depletion of BLI perturbs the assembly and membrane recruitment of the retromer core VPS26-VPS35-VPS29 trimer. Consequently, depletion of BLI disrupts retromer-regulated endosomal trafficking function, including transport of soluble vacuolar proteins and recycling of endocytosed PIN-FORMED (PIN) proteins from the endosomes back to the PM. Moreover, genetic analysis in Arabidopsis thaliana mutants reveals BLI and core retromer interact genetically in the regulation of endosomal trafficking. Taken together, we identified BLI as a plant-specific endosomal regulator, which functions in retromer pathway to modulate the recycling of endocytosed PM proteins and the trafficking of soluble vacuolar cargoes.

Stephtetrandrine A-D, bisbenzylisoquinoline alkaloids from Stephania tetrandra.

Four undescribed bisbenzylisoquinoline alkaloids, designated as Stephtetrandrine A-D, were isolated from the roots of Stephania tetrandra. Their structures were elucidated by IR, HRESIMS, ECD spectra, 1 D and 2 D NMR spectra and comparison with the literature data. Additional five known compounds (limacine, tetrandrine, N-trans-Feruloyltyramine, 2'-N-chloromethyltetrandrine, 2,2'-N-N-dichloromethyltetrandrine) were also isolated. N-trans-Feruloyltyramine was isolated from Stephania tetrandra for the first time. The isolated compounds were tested for monoamine oxidase, acetylcholinesterase, phosphoinositide 3-kinase α and human hepatoma cell HepG2 inhibitory activities. Stephtetrandrine C showed obvious inhibitory effect on human hepatoma HepG2, with IC50 value of 16.2 µM. Limacine and 2'-N-chloromethyltetrandrine showed moderate monoamine oxidase inhibitory effect with the IC50 values of 37.7 and 29.2 µM, respectively.

Basigin is necessary for normal decidualization of human uterine stromal cells.

STUDY QUESTION: Does basigin (BSG) regulate human endometrial stromal cell (HESC) decidualization in vitro? SUMMARY ANSWER: BSG regulates HESCs proliferation and decidualization. WHAT IS KNOWN ALREADY: Studies have shown that in the human endometrium, BSG expression is menstrual-cycle dependent and its expression was significantly lower in uterine endometrium during the luteal phase of women experiencing multiple implantation failures after IVF than in women with normal fertility. STUDY DESIGN, SIZE, DURATION: We utilized a telomerase-immortalized HESCs in an in vitro cell culture model system to investigate whether BSG regulates decidualization of stromal cells. Further, we used microarray analysis to identify changes in the gene expression profile of HESCs treated with BSG small interfering RNA (siRNA). All experiments were repeated at least three times. PARTICIPANTS/MATERIALS, SETTING, METHODS: The effect of BSG knockdown (using siRNA) on HESC proliferation was determined by counting cell number and by tritiated thymidine incorporation assays. The effect of BSG on decidualization of HESCs was determined by RT-qPCR for the decidualization markers insulin-like growth factor-binding protein 1 (IGFBP1) and prolactin (PRL). Immunoblotting was used to determine the effect of BSG siRNA on the expression of MMP-2,3. Microarray analysis was used to identify BSG-regulated genes in HESCs at Day 6 of decidualization. Functional and pathway enrichment analyses were then carried out on the differentially expressed genes (DEGs). The STRING online database was used to analyze protein-protein interaction (PPI) between DEG-encoded proteins, and CytoScape software was used to visualize the interaction. MCODE and CytoHubba were used to construct functional modules and screen hub genes separately. Several BSG-regulated genes identified in the microarray analysis were confirmed by qPCR. MAIN RESULTS AND THE ROLE OF CHANCE: Knockdown of BSG expression in cultured stromal cells by siRNA significantly (P < 0.05) inhibited HESC proliferation, disrupted cell decidualization and down-regulated MMP-2 and MMP-3 expression. Microarray analysis identified 721 genes that were down-regulated, and 484 genes up-regulated with P < 0.05 in BSG siRNA treated HESCs. GO term enrichment analysis showed that the DEGs were significantly enriched in cell communication, signaling transduction and regulation, response to stimulus, cell adhesion, anatomical structure morphogenesis, extracellular matrix organization, as well as other functional pathways. KEGG pathway analysis identified upregulated gene enriched in pathways such as the MAPK signaling pathway, colorectal cancer, melanoma and axon guidance. In contrast, downregulated genes were mainly enriched in pathways including ECM-receptor interaction, PI3K-Akt signaling pathway, pathways in cancer, antigen processing, type I diabetes mellitus and focal adhesion. The top 10 hub nodes were identified using 12 methods analyses. The hub genes that showed up in two methods were screened out. Among these genes, upregulated genes included EGFR, HSP90AA1, CCND1, PXN, PRKACB, MGAT4A, EVA1A, LGALS1, STC2, HSPA4; downregulated genes included WNT4/5, FOXO1, CDK1, PIK3R1, IGF1, JAK2, LAMB1, ITGAV, HGF, MXRA8, TMEM132A, UBE2C, QSOX1, ERBB2, GNB4, HSP90B1, LAMB2, LAMC1 and ITGA1. Hub genes and module genes involved in the top three modules of PPI analysis were analyzed through the string database. Analysis showed that hub and module genes were related mainly to the WNT signaling pathway, PI3K-AKT signaling pathway and pathways in cancer. LARGE SCALE DATA: The microarray data set generated in this study has been published online at databank.illinois.edu. LIMITATIONS, REASONS FOR CAUTION: Most of the findings were obtained using an in vitro cell culture system that may not necessarily reflect in vivo functions. WIDER IMPLICATIONS OF THE FINDINGS: Our results demonstrate that BSG plays a vital role in decidualization and that downregulation of BSG in the uterine endometrium may be associated with infertility in women. The identified hub genes and pathways increase our understanding of the genetic etiology and molecular mechanisms underlying the regulation of decidualization by BSG. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the NIH U54 HD40093 (R.A.N.). The authors have no competing interests to declare.

Anatomical liver resection improves surgical outcomes for combined hepatocellular-cholangiocarcinoma: A propensity score matched study.

Background: The efficacies of anatomical resection (AR) and non-anatomical resection (NAR) in the treatment of combined hepatocellular-cholangiocarcinoma (cHCC-CCA) remain unclear. This study aimed to compare the prognostic outcomes of AR with those of NAR for cHCC-CCA. Method: Patients diagnosed with pathology-confirmed cHCC-CCA, and who underwent curative resection at Tongji hospital between January 2010 and December 2019 were included in this retrospective study. A one-to-one propensity score matching (PSM) analysis was used to compare the long-term outcomes of AR to those of NAR. Results: A total of 105 patients were analyzed, of whom 48 (45.7%) and 57 (54.3%) underwent AR and NAR, respectively. There were no significant differences in short-term outcomes between the two groups, including duration of postoperative hospital stay, the incidence of perioperative complications, and incidence of 30-day mortality. However, both, the 5-year overall survival (OS) and recurrence-free survival (RFS) rates of AR were significantly better than those of NAR (40.5% vs. 22.4%, P=0.002; and 37.3% vs. 14.4%, P=0.002, respectively). Multivariate analysis showed that NAR, multiple tumors, larger-sized tumors (>5 cm), cirrhosis, lymph node metastasis, and vascular invasion were independent risk factors for poor prognoses. Stratified analysis demonstrated similar outcomes following AR versus NAR for patients with tumors > 5cm in diameter, while AR had better survival than NAR in patients with tumors ≤5 cm in diameter. After PSM, when 34 patients from each group were matched, the 5-year OS and RFS rates of AR were still better than those of NAR. Conclusion: Patients with cHCC-CCA who underwent AR had better long-term surgical outcomes than those who underwent NAR, especially for those with tumors ≤5 cm in diameter. However, no differences in the risk of surgical complications were detected between the two groups.

Hydrophilic CO-Releasing Material of PEGlyated Ruthenium Carbonyl Complex.

The poor water-solubility and instability of Ru(II) carbonyl complex hamper the therapeutic application as CO releasing materials (CO-RMs). To enhance the hydrophilicity and bio-utility of CO, a robust Ru(I) carbonyl sawhorse skeleton was grafted with water-soluble PEGylated sidearm. In this case, 12 PEGylated sawhorse Ru2(CO)4 complexes were prepared with satisfactory yields and characterized by IR and 1H- and 13C- NMR. X-ray diffraction analysis of CO-RM 8, 13 and 14 revealed the featured diruthenium sawhorse skeleton and PEGylated axial ligands. The flask-shaking method measures the water-solubility of CO-RMs, indicating that both bridging carboxylate ligands and PEGlyated axial ligands regulate the hydrophilicity of these CO-RMs. Under photolysis conditions, CO-RM 4-13 sustainable released therapeutic amounts of CO in the myoglobin assay. The correlation of the CO release kinetics and hydrophilicity of CO-RMs demonstrated that the more hydrophilic CO-RM released CO faster. The biological test found that the low cytotoxic CO-RM 4 showed a specific anticancer activity toward HT-29 tumour cells.

MLKs kinases phosphorylate the ESCRT component FREE1 to suppress abscisic acid sensitivity of seedling establishment.

The FYVE domain protein required for endosomal sorting 1 (FREE1), which was previously identified as a plant-specific component of the endosomal sorting complex required for transport machinery, plays an essential role in endosomal trafficking. Moreover, FREE1 also functions as an important negative regulator in abscisic acid (ABA) signalling. Multiple phosphorylations and ubiquitination sites have been identified in FREE1, hence unveiling the factors involved in posttranslational regulation of FREE1 is critical for comprehensively understanding FREE1-related regulatory networks during plant growth. Here, we demonstrate that plant-specific casein kinase I members MUT9-like kinases 1-4 (MLKs 1-4)/Arabidopsis EL1-like 1-4 interact with and phosphorylate FREE1 at serine residue S582, thereby modulating the nuclear accumulation of FREE1. Consequently, mutation of S582 to non-phosphorylable residue results in reduced nuclear localization of FREE1 and enhanced ABA response. In addition, mlk123 and mlk134 triple mutants accumulate less FREE1 in the nucleus and display hypersensitive responses to ABA treatment, whereas overexpression of the nuclear-localized FREE1 can restore the ABA sensitivity of seedling establishment in mlks triple mutants. Collectively, our study demonstrates a previously unidentified function of MLKs in attenuating ABA signalling in the nucleus by regulating the phosphorylation and nuclear accumulation of FREE1.

Effects of different exercise methods of calf muscles on the hemodynamics of lower extremity vein.

OBJECTIVE: To compare the effects of active and passive calf muscle contraction on the hemodynamics of the lower extremity vein. METHODS: 30 females were selected by convenient sampling. The hemodynamic indexes of the common femoral vein were measured by Duplex ultrasound during the active ankle pump exercise, active circular exercise, passive ankle pump exercise, passive circular exercise, and massage the calf muscles. RESULTS: There was no significant difference in the velocity of common femoral vein when the subjects do active ankle pump exercise, active circular exercise, and massage the calf muscles (p > .05), but the velocity of common femoral vein was faster than that of passive ankle pump exercise and passive circular exercise (p < .01). CONCLUSION: The effects of active ankle exercise and massage on promoting venous blood return of lower extremity are better than that of passive ankle exercise.

Epidemiological status and risk factors of deep vein thrombosis in patients with femoral neck fracture.

OBJECTIVES: The purpose of this study was to investigate the incidence of deep vein thrombosis (DVT) and clarify the risk factors of DVT in patients with femoral neck fracture. METHODS: A self-designed questionnaire was used to collect the clinical data of 1209 patients with femoral neck fracture in our hospital from January 2019 to December 2019. The content of the questionnaire mainly includes general information, past medical history, history of present illness, operation related information, occurrence of DVT. The collected data were entered into Excel to analyze the incidence and risk factors of DVT in patients with femoral neck fracture. Chi square test and binary logistic regression model was used to screen the risk factors of DVT. RESULTS: 1209 cases of femoral neck fracture were included in this study. The incidence of DVT was 28.0% (339 patients). Among them, 71.7% (243 patients) were preoperative DVT and 28.3% (96 patients) were postoperative DVT. For the risk-factor analysis, gender, age, time from injury to hospitalization, operative method, anesthesia method and intraoperative blood loss were independent risk factors for DVT. CONCLUSION: The incidence of DVT in patients with femoral neck fracture is relatively high, and there are many related risk factors.

MiR-145 regulates steroidogenesis in mouse primary granulosa cells through targeting Crkl.

AIMS: It has been demonstrated that miR-145 is expressed in primordial follicles and modulates the initiation of primordial follicle development. We aimed to explore the function of miR-145 in mouse granulosa cells (mGCs). MATERIALS AND METHODS: The proliferation and differentiation of GCs were examined via MTT, EDU assay, QRT-PCR, ELISA and electron microscope analysis. The target of miR-145 was determined by bioinformatics analysis and luciferase reporter assay and the molecular mechanisms were examined via western blot and quantitative Real-Time RT-PCR. KEY FINDINGS: We proved that down-regulation of miR-145 could inhibit GCs proliferation and differentiation. In addition, we provided evidence that Crkl was the target gene of miR-145. The miR-145 antagomir caused an increase in Crkl expression and activation of the JNK/p38 MAPK pathway. Overexpression of Crkl with pEGFP-N1-Crkl vector inhibited GCs differentiation and progesterone synthesis as well as activation of the JNK/p38 MAPK pathway. SIGNIFICANCE: Our study shows that miR-145 targets Crkl and through the JNK/p38 MAPK signaling pathway promotes the GCs proliferation, differentiation, and steroidogenesis. MiR-145 may play an important role in the ovarian physiology and pathology.

Effects of Chronic Dietary Exposure to Phytoestrogen Genistein on Uterine Morphology in Mice.

Genistein is naturally occurring in plants and binds to estrogen receptors. Humans are mainly exposed through diet, but the use of supplements is increasing as genistein is claimed to promote health and alleviate menopausal symptoms. We analyzed diverse uterine features in adult mice chronically fed genistein for different times. The luminal epithelium height was increased in females treated with 500 and 1000 ppm at PND 95, and the width of the outer myometrium was increased in females treated with 1000 ppm at PND 65 compared to that in controls. An increase in proliferation was noted in the inner myometrium layer of animals exposed to 300 ppm genistein at PND 185 compared to that in controls. Luminal hyperplasia was greater in the 1000 ppm group at PND 65, 95, and 185, although not statistically different from control. These results indicate that genistein may exert estrogenic activity in the uterus, without persistent harm to the organ.

The effects of the phthalate DiNP on reproduction†.

Di-isononyl phthalate (DiNP) is a high molecular weight, general purpose, plasticizer used primarily in the manufacture of polymers and consumer products. It can be metabolized rapidly and does not bioaccumulate. The primary metabolite of DiNP is monoisononyl-phthalate (MiNP) and the secondary metabolites include three oxidative derivatives of DiNP, which have been identified mainly in urine: mono-oxoisononyl phthalate (MOINP or oxo-MiNP), mono-carboxyisooctyl phthalate (MCIOP, MCOP or cx-MiNP), and mono-hydroxyisononyl phthalate (MHINP or OH-MiNP). The secondary metabolites are very sensitive biomarkers of DiNP exposure while primary metabolites are not. As the usage of DiNP worldwide increases, studies evaluating its potential reproductive toxicity are becoming more prevalent in the literature. In studies on female animals, the researchers found that the exposure to DiNP appears to induce negative effects on ovarian function and fertility in animal models. Whether or not DiNP has direct effects on the uterus is still controversial, and the effects on human reproduction require much more research. Studies on males indicate that DiNP exposure has disruptive effects on male reproduction and fertility. Occupational studies also indicate that the exposure to DiNP might induce negative effects on male reproduction, but larger cohort studies are needed to confirm this. This review presents an overview of the literature regarding the reproductive effects of exposure to DiNP.

SINAT E3 ligases regulate the stability of the ESCRT component FREE1 in response to iron deficiency in plants.

The endosomal sorting complex required for transport (ESCRT) machinery is an ancient, evolutionarily conserved membrane remodeling complex that is essential for multivesicular body (MVB) biogenesis in eukaryotes. FYVE DOMAIN PROTEIN REQUIRED FOR ENDOSOMAL SORTING 1 (FREE1), which was previously identified as a plant-specific ESCRT component, modulates MVB-mediated endosomal sorting and autophagic degradation. Although the basic cellular functions of FREE1 as an ESCRT component have been described, the regulators that control FREE1 turnover remain unknown. Here, we analyzed how FREE1 homeostasis is mediated by the RING-finger E3 ubiquitin ligases, SINA of Arabidopsis thaliana (SINATs), in response to iron deficiency. Under iron-deficient growth conditions, SINAT1-4 were induced and ubiquitinated FREE1, thereby promoting its degradation and relieving the repressive effect of FREE1 on iron absorption. By contrast, SINAT5, another SINAT member that lacks ubiquitin ligase activity due to the absence of the RING domain, functions as a protector protein which stabilizes FREE1. Collectively, our findings uncover a hitherto unknown mechanism of homeostatic regulation of FREE1, and demonstrate a unique regulatory SINAT-FREE1 module that subtly regulates plant response to iron deficiency stress.