Starting around December 2019, an epidemic of pneumonia, which was named COVID-19 by the World Health Organization, broke out in Wuhan, China, and is spreading throughout the world. A new coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the Coronavirus Study Group of the International Committee on Taxonomy of Viruses was soon found to be the cause. At present, the sensitivity of clinical nucleic acid detection is limited, and it is still unclear whether it is related to genetic variation. In this
RNF126 is an E3 ubiquitin ligase. The deletion of RNF126 gene was observed in a wide range of human cancers and is correlated with improved disease-free and overall survival. These data highlights the clinical relevance of RNF126 in tumorigenesis and cancer therapy. However, the specific functions of RNF126 remain largely unknown. Homologous recombination (HR)-mediated DNA double-strand break repair is important for tumor suppression and cancer therapy resistance. Here, we demonstrate that RNF126 facilitates HR by promoting the expression of BRCA1, in a manner independent of its E3 ligase activity but depending on E2F1, a well-known transcription factor of BRCA1 promoter. In support of this result, RNF126 promotes transactivation of BRCA1 promoter by directly binding to E2F1. Most importantly, an RNF126 mutant lacking 11 amino acids that is responsible for the interaction with E2F1 has a dominant-negative effect on BRCA1 expression and HR by suppressing E2F1-mediated transactivation of BRCA1 promoter and blocking the enrichment of E2F1 on BRCA1 promoter. Lastly, RNF126 depletion leads to the increased sensitivity to ionizing radiation (IR) and poly (ADP-ribose) polymerase (PARP) inhibition. Collectively, our results suggest a novel role of RNF126 in promoting HR-mediated repair through positive regulation on BRCA1 expression by direct interaction with E2F1. This study not only offers novel insights into our current understanding of the biological functions of RNF126 but also provides a potential therapeutic target for cancer treatment.
Plant hormones can adjust the physiology and development of plants to enhance their adaptation to biotic and abiotic challenges. Jasmonic acid (JA), one of the immunity hormones in plants, triggers genome-wide transcriptional changes in response to insect attack and wounding. Although JA is known to affect the development of trichomes, epidermal appendages that form a protective barrier against various stresses, it remains unclear how JA interacts with developmental programs that regulate trichome development. In this study, we show that JA affects trichome length in tomato by releasing the transcriptional repression mediated by Jasmonate ZIM (JAZ) proteins. We identified SlJAZ4, a negative regulator preferentially expressed in trichomes, as the critical component in JA signaling in tomato trichomes. We also identified a homeodomain-leucine zipper gene, SlHD8, as the downstream regulator of JA signaling that promotes trichome elongation. SlHD8 is also highly expressed in trichomes and physically interacts with SlJAZ4. Loss-of-function mutations in SlHD8 caused shorter trichomes, a phenotype that was only partially rescued by methyl jasmonate treatment. Our dual-luciferase and chromatin immunoprecipitation-quantitative PCR assays revealed that SlHD8 regulates trichome elongation by directly binding to the promoters of a set of cellwall-loosening protein genes and activating their transcription. Together, our findings define SlHD8-SlJAZ4 as a key module mediating JA-induced trichome elongation in tomato.
The soil-borne fungal pathogen Verticillium dahliae infects a wide range of dicotyledonous plants including cotton, tobacco, and Arabidopsis. Among the effector proteins secreted by V. dahliae, the 16 kDa PevD1 induces a hypersensitive response in tobacco. Here we report the high-resolution structure of PevD1 with folds resembling a C2 domain-like structure with a calcium ion bound to the C-terminal acidic pocket. A yeast two-hybrid screen, designed to probe for molecular functions of PevD1, identified Arabidopsis asparagine-rich protein (NRP) as the interacting partner of PevD1. Extending the pathway of V. dahliae effects, which include induction of early flowering in cotton and Arabidopsis, NRP was found to interact with cryptochrome 2 (CRY2), leading to increased cytoplasmic accumulation of CRY2 in a blue light-independent manner. Further physiological and genetic evidence suggests that PevD1 indirectly activates CRY2 by antagonizing NRP functions. The promotion of CRY2-mediated flowering by a fungal effector outlines a novel pathway by which an external stimulus is recognized and transferred in changing a developmental program.
The magnitude of SARS-CoV-2 infection, the dynamic changes of immune parameters in patients with the novel coronavirus disease (COVID-19) and their correlation with the disease severity remain unclear. The clinical and laboratory results from 154 confirmed COVID-19 patients were collected. The SARS-CoV-2 RNA levels in patients were estimated using the Ct values of specific RT-PCR tests. The lymphocyte subsets and cytokine profiles in the peripheral blood were analyzed by flow cytometry and specific immunoassays. 154 confirmed COVID-19 patients were clinically examined up to 4 weeks after admission. The initial SARS-CoV-2 RNA Ct values at admission varied, but were comparable in the patient groups classified according to the age, gender, underlying diseases, and disease severity. Three days after admission, significant higher Ct values were found in severe cases. Significantly reduced counts of T cells and T cell subsets were found in patients with old age and underlying diseases at admission and were characteristic for the development of severe COVID-19. Severe COVID-19 developed preferentially in patients with underlying compromised immunity and was not associated with initial virus levels. Higher SARS-CoV-2 RNA levels in severe cases were apparently a result of impaired immune control associated with dysregulation of inflammation.
Most human diseases are systems diseases, and systems biomarkers are better fitted for diagnostic, prognostic, and treatment monitoring purposes. To search for systems biomarker candidates, lactate dehydrogenase (LDH), a housekeeping protein expressed in all living cells, was investigated. To this end, we analyzed the serum LDH activities from 172,933 patients with 48 clinically defined diseases and 9528 healthy individuals. Based on the median values, we found that 46 out of 48 diseases, leading by acute myocardial infarction, had significantly increased (p < 0.001), whereas gout and cerebral ischemia had significantly decreased (p < 0.001) serum LDH activities compared to the healthy control. Remarkably, hepatic encephalopathy and lung fibrosis had the highest AUCs (0.89, 0.80), sensitivities (0.73, 0.56), and specificities (0.90, 0.91) among 48 human diseases. Statistical analysis revealed that over-downregulation of serum LDH activities was associated with blood-related cancers and diseases. LDH activities were potential systems biomarker candidates (AUCs > 0.8) for hepatic encephalopathy and lung fibrosis.
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