Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer

Lacking targetable molecular drivers, triple-negative breast cancer (TNBC) is the most clinically challenging subtype of breast cancer. In this study, we reveal that Death Effector Domain-containing DNA-binding protein (DEDD), which is overexpressed in > 60% of TNBCs, drives a mitogen-independent G1/S cell cycle transition through cytoplasm localization. The gain of cytosolic DEDD enhances cyclin D1 expression by interacting with heat shock 71 kDa protein 8 (HSC70). Concurrently, DEDD interacts with Rb family proteins and promotes their proteasome-mediated degradation. DEDD overexpression renders TNBCs vulnerable to cell cycle inhibition. Patients with TNBC have been excluded from CDK 4/6 inhibitor clinical trials due to the perceived high frequency of Rb-loss in TNBCs. Interestingly, our study demonstrated that, irrespective of Rb status, TNBCs with DEDD overexpression exhibit a DEDD-dependent vulnerability to combinatorial treatment with CDK4/6 inhibitor and EGFR inhibitor in vitro and in vivo. Thus, our study provided a rationale for the clinical application of CDK4/6 inhibitor combinatorial regimens for patients with TNBC

Transgenerational Effects of Hexavalent Chromium on Marine Medaka (Oryzias melastigma) Reveal Complex Transgenerational Adaptation in Offspring

Hexavalent chromium [Cr(VI)] pollution is one of most serious heavy metal pollutants in the coastal area and posed serious threats to marine organisms and human beings. Many studies have been conducted on its toxicological effects on living organisms from morphological to physiological aspects. However, there are few studies about the transgenerational toxicological of Cr(VI). In this study, we exposed adult marine medaka fishes with Cr(VI) and their offspring with Cr(VI) to examine transgenerational effects of Cr(VI). We found that there were mechanisms such as changing reproduction modes in males to compensate for impacts on the reproduction. There were differences and similarities between the parental effect and the environmental effect, with the former one causing more serious adverse effects on the offspring of Cr(VI)-exposed fish. It was noteworthy that there was an interaction between the parental and offspring treatment which leads to the attenuation of the parental effects on offspring when the offspring also underwent the same treatment. In addition, physiological adaptation has also been observed in fish to improve their fitness. Overall, effects of Cr(VI) on fish and their offspring were studied to pave a way to study the of mechanisms of adaptation

Transgenerational Effects of Hexavalent Chromium on Marine Medaka (<i>Oryzias melastigma</i>) Reveal Complex Transgenerational Adaptation in Offspring

Hexavalent chromium [Cr(VI)] pollution is one of most serious heavy metal pollutants in the coastal area and posed serious threats to marine organisms and human beings. Many studies have been conducted on its toxicological effects on living organisms from morphological to physiological aspects. However, there are few studies about the transgenerational toxicological of Cr(VI). In this study, we exposed adult marine medaka fishes with Cr(VI) and their offspring with Cr(VI) to examine transgenerational effects of Cr(VI). We found that there were mechanisms such as changing reproduction modes in males to compensate for impacts on the reproduction. There were differences and similarities between the parental effect and the environmental effect, with the former one causing more serious adverse effects on the offspring of Cr(VI)-exposed fish. It was noteworthy that there was an interaction between the parental and offspring treatment which leads to the attenuation of the parental effects on offspring when the offspring also underwent the same treatment. In addition, physiological adaptation has also been observed in fish to improve their fitness. Overall, effects of Cr(VI) on fish and their offspring were studied to pave a way to study the of mechanisms of adaptation

Wheat ABA Receptor TaPYL5 Constitutes a Signaling Module with Its Downstream Partners TaPP2C53/TaSnRK2.1/TaABI1 to Modulate Plant Drought Response

Abscisic acid receptors (ABR) play crucial roles in transducing the ABA signaling initiated by osmotic stresses, which has a significant impact on plant acclimation to drought by modulating stress-related defensive physiological processes. We characterized TaPYL5, a member of the ABR family in wheat (Triticum aestivum), as a mediator of drought stress adaptation in plants. The signals derived from the fusion of TaPYL5-GFP suggest that the TaPYL5 protein was directed to various subcellular locations, namely stomata, plasma membrane, and nucleus. Drought stress significantly upregulated the TaPYL5 transcripts in roots and leaves. The biological roles of ABA and drought responsive cis-elements, specifically ABRE and recognition sites MYB, in mediating gene transcription under drought conditions were confirmed by histochemical GUS staining analysis for plants harbouring a truncated TaPYL5 promoter. Yeast two-hybrid and BiFC assays indicated that TaPYL5 interacted with TaPP2C53, a clade A member of phosphatase (PP2C), and the latter with TaSnRK2.1, a kinase member of the SnRK2 family, implying the formation of an ABA core signaling module TaPYL5/TaPP2C53/TaSnRK2.1. TaABI1, an ABA responsive transcription factor, proved to be a component of the ABA signaling pathway, as evidenced by its interaction with TaSnRK2.1. Transgene analysis of TaPYL5 and its module partners, as well as TaABI1, revealed that they have an effect on plant drought responses. TaPYL5 and TaSnRK2.1 positively regulated plant drought acclimation, whereas TaPP2C53 and TaABI1 negatively regulated it. This coincided with the osmotic stress-related physiology shown in their transgenic lines, such as stomata movement, osmolytes biosynthesis, and antioxidant enzyme function. TaPYL5 significantly altered the transcription of numerous genes involved in biological processes related to drought defense. Our findings suggest that TaPYL5 is one of the most important regulators in plant drought tolerance and a valuable target for engineering drought-tolerant cultivars in wheat

ViSTA: A Novel Network Improving Lung Adenocarcinoma Invasiveness Prediction from Follow-Up CT Series

To investigate the value of the deep learning method in predicting the invasiveness of early lung adenocarcinoma based on irregularly sampled follow-up computed tomography (CT) scans. In total, 351 nodules were enrolled in the study. A new deep learning network based on temporal attention, named Visual Simple Temporal Attention (ViSTA), was proposed to process irregularly sampled follow-up CT scans. We conducted substantial experiments to investigate the supplemental value in predicting the invasiveness using serial CTs. A test set composed of 69 lung nodules was reviewed by three radiologists. The performance of the model and radiologists were compared and analyzed. We also performed a visual investigation to explore the inherent growth pattern of the early adenocarcinomas. Among counterpart models, ViSTA showed the best performance (AUC: 86.4% vs. 60.6%, 75.9%, 66.9%, 73.9%, 76.5%, 78.3%). ViSTA also outperformed the model based on Volume Doubling Time (AUC: 60.6%). ViSTA scored higher than two junior radiologists (accuracy of 81.2% vs. 75.4% and 71.0%) and came close to the senior radiologist (85.5%). Our proposed model using irregularly sampled follow-up CT scans achieved promising accuracy in evaluating the invasiveness of the early stage lung adenocarcinoma. Its performance is comparable with senior experts and better than junior experts and traditional deep learning models. With further validation, it can potentially be applied in clinical practice

Auricularia auricula Melanin Protects against Alcoholic Liver Injury and Modulates Intestinal Microbiota Composition in Mice Exposed to Alcohol Intake

The potential effects of Auricularia auricula melanin (AAM) on the intestinal flora and liver metabolome in mice exposed to alcohol intake were investigated for the first time. The results showed that oral administration of AAM significantly reduced the abnormal elevation of serum total triglyceride (TG), cholesterol (TC), low density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and significantly inhibited hepatic lipid accumulation and steatosis in mice exposed to alcohol intake. Besides, the abnormally high levels of bile acids (BAs) and lactate dehydrogenase (LDH) in the liver of mice with alcohol intake were significantly decreased by AAM intervention, while the hepatic levels of glutathione (GSH) and superoxide dismutase (SOD) were appreciably increased. Compared with the model group, AAM supplementation significantly changed the composition of intestinal flora and up-regulated the levels of Akkermansia, Bifidobacterium, Romboutsia, Muribaculaceae, Lachnospiraceae_NK4A136_group, etc. Furthermore, liver metabolomics demonstrated that AAM had a significant regulatory effect on the composition of liver metabolites in mice with alcohol intake, especially the metabolites involved in phosphatidylinositol signaling system, ascorbate and aldarate metabolism, starch and sucrose metabolism, galactose metabolism, alpha-linolenic acid metabolism, glycolysis/gluconeogenesis, and biosynthesis of unsaturated fatty acids. At the gene level, AAM treatment regulated the mRNA levels of lipid metabolism and inflammatory response related genes in liver, including ACC-1, FASn, CPT-1, CD36, IFN-γ, LDLr and TNF-α. Conclusively, these findings suggest that AAM has potential beneficial effects on alleviating alcohol-induced liver injury and is expected to become a new functional food ingredient