An Efficient Agrobacterium-Mediated Genetic Transformation System for Gene Editing in Strawberry (Fragaria × ananassa).

The octoploid-cultivated strawberry variety Benihope (Fragaria × ananassa Duch cv. Benihope) is an important commercial plant. It is highly susceptible to different diseases, which ultimately leads to a reduction in yield. Gene-editing methods, such as CRISPR/Cas9, demonstrate potential for improving disease resistance in the strawberry cv. Benihope. Establishing a plant regeneration system suitable for CRISPR/Cas9 gene editing is crucial for obtaining transgenic plants on a large scale. This research established a callus induction and plant regeneration system for Agrobacterium-mediated CRISPR/Cas9 gene editing in strawberry cv. Benihope by evaluating multiple types of explants and various plant growth regulators throughout the entire tissue culture process. The results showed that the efficiency of callus induction is strongly influenced by the type of explant and is highly sensitive to the combination of plant growth regulators. Among the different plant growth regulators employed, thidiazuron (TDZ), in combination with 2,4-dichlorophenoxyacetic acid (2,4-D), effectively induced callus formation and plant regeneration from explants derived from nutrient tissues such as runner tips and crowns. In addition, the regeneration experiment demonstrated that the addition of polyvinylpyrrolidone (PVPP) to the shoot regeneration medium could inhibit tissue browning. The gene-edited plants in which some or all of the Fvb7-1, Fvb7-2, Fvb7-3, and Fvb7-4 genes in the MLO (Mildew resistance Locus O) gene family were knocked out by CRISPR/Cas9 system were obtained by applying the plant regeneration system developed in this study.

Cultural-Responsiveness of the Mental Health First Aid Training for Asian Immigrant Populations in Greater Boston, Massachusetts.

Background: The COVID-19 pandemic and rise in anti-Asian racism have had adverse mental health impacts in Asian communities. The lack of culturally-responsive and linguistically-accessible mental health trainings hinders access to mental health services for Asian populations. In this study, we assessed the mental health needs of Asian communities in Greater Boston and evaluated cultural responsiveness of the Mental Health First Aid (MHFA), a first-responder training teaching participants skills to recognize signs of mental health and substance use challenges, and how to appropriately respond. Methods: This community-based participatory research with the Boston Chinatown Neighborhood Center (BCNC), Asian Women For Health (AWFH), and the Addressing Disparities in Asian Populations through Translational Research (ADAPT) Coalition employed two phases. In phase 1, we conducted focus groups with BCNC and AWFH staff and peer educators to assess mental health priorities of Asian populations in Boston. Findings informed phase 2, which evaluated cultural responsiveness of the MHFA through pre- and post-training questionnaires and focus groups with community participants. The pre-training questionnaire asked about mental health needs and barriers, help-seeking behaviors, and literacy; and personal and Asian community stigma. The post-training questionnaire and focus group with community participants asked about cultural competence of MHFA training for Asian populations. Paired t-tests were used to evaluate questionnaire responses. Thematic analysis was used to analyze interviews. Results: In total, 10 staff/educators and 8 community members participated in focus groups. They identified common mental health needs and workforce and culturally-responsive community strategies to support persons with mental health issues. Twenty-four community participants completed pre- and post-training questionnaires. They reported the MHFA training reduced mental health care stigma and increased mental health literacy. Recommendations to increase cultural-responsiveness of the MHFA were to include mental health case studies common in Asian populations and provide the training in other languages (e.g., Chinese, Vietnamese). Conclusion: Cultural responsiveness of the MHFA for Asian populations could be improved with the inclusion of case studies specific to the Asian communities and accessibility of the training in other languages. Increasing the cultural relevance and language accessibility of these trainings could help reduce mental health stigma and gaps in mental health awareness and service utilization among Asian populations.

A prognostic nomogram and risk classification system of elderly patients with extraosseous plasmacytoma: a SEER database analysis.

BACKGROUND: The survival trends and prognostic factors of patients with extraosseous plasmacytoma (EOP) or extramedullary plasmacytoma (EMP) have not been reported in recent years. The objective of this study was to develop a novel nomogram and risk stratification system for predicting the overall survival (OS) of elderly patients with EOP based on the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: The demographic characteristics of 900 patients aged 60 years and above, diagnosed with EOP between 2000 and 2019, were extracted from the SEER database. The patient population was randomly divided into a training cohort and an internal validation cohort in a ratio of 7:3. Univariate and multivariate Cox regression analyses were conducted to identify independent predictors of prognosis in elderly EOP patients, followed by developing a nomogram for prognostic assessment. The performance of the model was evaluated through receiver-operating characteristic (ROC) curves, C-index, calibration curves for calibration accuracy assessment, and decision curve analysis (DCA) to assess its clinical utility. All elderly EOP patients were stratified into three risk subgroups by cutoff value utilizing X-tile software based on their total OS scores for comparative analysis purposes. Kaplan-Meier (K-M) survival curve analysis was employed to validate any observed differences in OS among these three risk groups. RESULTS: Six factors including age, year of diagnosis, marital status, primary site, surgery, and prior tumor history were identified to be independently predictive of the OS of elderly patients with EOP, and these predictors were included in the construction of the nomogram. The 1-, 3-, and 5-year area under the curves (AUCs) for OS were 0.717, 0.754, and 0.734 in the training cohort and 0.740, 0.730, and 0.765 in the validation cohort, respectively. The C-index values in the two cohorts were 0.695 and 0.690. The calibration curves and DCA exhibit commendable consistency and validity, respectively, thereby demonstrating their robust performance. The training set was stratified into low-, medium-, and high-risk subgroups based on the optimal cutoff points (167.8 and 264.8) identified. The K-M curve and cumulative risk curve exhibited statistically significant disparities in survival rates among the groups. CONCLUSIONS: We developed a nomogram and risk classification system, which can serve as an intuitive and effective tool for clinicians to enhance the prediction of OS in elderly EOP patients, thereby facilitating the formulation of more rational and personalized treatment strategies.

Spatial transcriptomics uncover sucrose post-phloem transport during maize kernel development.

Maize kernels are complex biological systems composed of three genetic sources, namely maternal tissues, progeny embryos, and progeny endosperms. The lack of gene expression profiles with spatial information has limited the understanding of the specific functions of each cell population, and hindered the exploration of superior genes in kernels. In our study, we conduct microscopic sectioning and spatial transcriptomics analysis during the grain filling stage of maize kernels. This enables us to visualize the expression patterns of all genes through electronical RNA in situ hybridization, and identify 11 cell populations and 332 molecular marker genes. Furthermore, we systematically elucidate the spatial storage mechanisms of the three major substances in maize kernels: starch, protein, and oil. These findings provide valuable insights into the functional genes that control agronomic traits in maize kernels.

PLK1 maintains DNA methylation and cell viability by regulating phosphorylation-dependent UHRF1 protein stability.

PLK1 is a key serine/threonine kinase as well as a master mitotic regulator, but it has never been reported that PLK1 regulates DNA methylation. In the present study, we for the first time found that PLK1 inhibition disrupted global DNA methylation and elevated the expression level of tumor suppressor genes. Mechanistically, we found that PLK1 interacts UHRF1 protein to induce its phosphorylation at serine 265. Phosphorylation is required for the maintenance of UHRF1 protein stability by recruiting a deubiquitinase USP7. Conversely, PLK1 inhibition decreases UHRF1 protein interaction with USP7 and activates the ubiquitin-proteasome pathway, thereby accelerating UHRF1 protein degradation. UHRF1 degradation decreases the recruitment of DNMT1 to chromatin, and decreases the level of genome-wide DNA methylation, thereby elevating the expression of tumor suppressor genes and decreasing cell viability. We here presented the first report on the novel role of PLK1 in DNA methylation maintenance through UHRF1-DNMT1 pathway, and revealed a novel anticancer mechanism of PLK1 inhibitors.

UHRF1 promotes spindle assembly and chromosome congression by catalyzing EG5 polyubiquitination.

UHRF1 is an epigenetic coordinator bridging DNA methylation and histone modifications. Additionally, UHRF1 regulates DNA replication and cell cycle, and its deletion induces G1/S or G2/M cell cycle arrest. The roles of UHRF1 in the regulation of G2/M transition remain poorly understood. UHRF1 depletion caused chromosome misalignment, thereby inducing cell cycle arrest at mitotic metaphase, and these cells exhibited the defects of spindle geometry, prominently manifested as shorter spindles. Mechanistically, UHRF1 protein directly interacts with EG5, a kinesin motor protein, during mitosis. Furthermore, UHRF1 induced EG5 polyubiquitination at the site of K1034 and further promoted the interaction of EG5 with spindle assembly factor TPX2, thereby ensuring accurate EG5 distribution to the spindles during metaphase. Our study clarifies a novel UHRF1 function as a nuclear protein catalyzing EG5 polyubiquitination for proper spindle architecture and faithful genomic transmission, which is independent of its roles in epigenetic regulation and DNA damage repair inside the nucleus. These findings revealed a previously unknown mechanism of UHRF1 in controlling mitotic spindle architecture and chromosome behavior and provided mechanistic evidence for UHRF1 deletion-mediated G2/M arrest.

AR antagonists develop drug resistance through TOMM20 autophagic degradation-promoted transformation to neuroendocrine prostate cancer.

BACKGROUND: Prostate cancer(PCa) is the most commonly occurring male cancer in the USA. Abiraterone or Enzalutamide have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). However, the treatment-emergent neuroendocrine PCa (t-NEPC) may develop, resulting in drug resistance in about 10-17% CRPC patients. The detailed mechanisms remain unclear.. METHODS: The expression correlation of TOMM20 and AR in PCa was determined by analyzing publicly available datasets, or by IHC staining in tumor specimens. The protein interaction of TOMM20 and AR was validated by co-immunoprecipitation or GST pull-down assay. The impact of TOMM20 depletion on drug sensitivity were elucidated by assays of cell proliferation, invasion, sphere formation, xenograft growth and intravenous metastasis. The intracellular ROS level was measured by flow cytometry, and the NEPC transdifferentiation and characteristics of cancer stem-like cells were validated by RNA-seq, RT-PCR and western blotting. RESULTS: The protein level of TOMM20 is positively correlated with AR in PCa cells and specimens. TOMM20 protein physically interacts with AR. AR antagonists induced the protein degradation of TOMM20 through autophagy-lysosomal pathway, thereby elevating the intracellular ROS level and activating PI3K/AKT signaling pathway. When TOMM20 was depleted, PCa cells underwent EMT, acquired the characteristics of cancer stem-like cells, and developed resistance to AR antagonists. The stable depletion of TOMM20 promoted the transdifferentiation of PCa adenocarcinoma into NEPC and metastasis. Conversely, the rescue of TOMM20 re-sensitized the resistant PCa cells to AR antagonists. CONCLUSIONS: TOMM20 protein degradation induced by AR antagonists promoted the transdifferentiation of PCa to NEPC, thereby revealing a novel molecular mechanism by which AR antagonists develop drug resistance through mitochondrial outer membrane-mediated signaling pathway. These findings suggested that the decreasing or loss of TOMM20 expression in PCa tissues might become a useful predictor of PCa resistance to AR antagonists.

Engineering lanthipeptides by introducing a large variety of RiPP modifications to obtain new-to-nature bioactive peptides.

Natural bioactive peptide discovery is a challenging and time-consuming process. However, advances in synthetic biology are providing promising new avenues in peptide engineering that allow for the design and production of a large variety of new-to-nature peptides with enhanced or new bioactivities, using known peptides as templates. Lanthipeptides are ribosomally synthesized and post-translationally modified peptides (RiPPs). The modularity of post-translational modification (PTM) enzymes and ribosomal biosynthesis inherent to lanthipeptides enables their engineering and screening in a high-throughput manner. The field of RiPPs research is rapidly evolving, with many novel PTMs and their associated modification enzymes being identified and characterized. The modularity presented by these diverse and promiscuous modification enzymes has made them promising tools for further in vivo engineering of lanthipeptides, allowing for the diversification of their structures and activities. In this review, we explore the diverse modifications occurring in RiPPs and discuss the potential applications and feasibility of combining various modification enzymes for lanthipeptide engineering. We highlight the prospect of lanthipeptide- and RiPP-engineering to produce and screen novel peptides, including mimics of potent non-ribosomally produced antimicrobial peptides (NRPs) such as daptomycin, vancomycin, and teixobactin, which offer high therapeutic potential.

Comparison of the effect of quercetin and daidzein on production performance, anti-oxidation, hormones, and cecal microflora in laying hens during the late laying period.

This study aims to compare the effect of quercetin and daidzein on production performance, anti-oxidation, hormones, and cecal microflora in laying hens during the late laying period. A total of 360 53-week-old healthy Hyline brown laying hens were randomly divided into 3 groups (control, 0.05% quercetin, and 0.003% daidzein). Diets were fed for 10 wk, afterwards 1 bird per replicate (6 replicates) were euthanized for sampling blood, liver and cecal digesta. Compared with the control, quercetin significantly increased laying rate and decreased feed-to-egg weight ratio from wk 1 to 4, wk 5 to 10, and wk 1 to 10 (P < 0.05). Quercetin significantly increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased catalase (CAT) activity and malondialdehyde (MDA) content in serum and liver (P < 0.05) and increased content of total antioxidant capacity (T-AOC) in liver (P < 0.05). Quercetin increased content of estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), insulin-like growth factor 1 (IGF-1), triiodothyronine (T3) and thyroxine (T4) in serum (P < 0.05). Quercetin significantly decreased the relative abundance of Bacteroidaceae and Bacteroides (P < 0.01) and significantly increased the relative abundance of Lactobacillaceae and Lactobacillus (P < 0.05) at family and genus levels in cecum. Daidzein did not significantly influence production performance from wk 1 to 10. Daidzein significantly increased SOD activity and decreased CAT activity and MDA content in serum and liver (P < 0.05), and increased T-AOC content in liver (P < 0.05). Daidzein increased content of FSH, IGF-1, T3 in serum (P < 0.05). Daidzein increased the relative abundance of Rikenellaceae RC9 gut group at genus level in cecum (P < 0.05). Quercetin increased economic efficiency by 137.59% and 8.77%, respectively, compared with daidzein and control. In conclusion, quercetin improved production performance through enhancing antioxidant state, hormone levels, and regulating cecal microflora in laying hens during the late laying period. Quercetin was more effective than daidzein in improving economic efficiency.

Selenium Deficiency Caused Fibrosis as an Oxidative Stress-induced Inflammatory Injury in the Lungs of Mice.

Selenium (Se) is a vital trace element in the regulation of inflammation and antioxidant reactions in both animals and humans. Se deficiency is rapidly affecting lung function. The present study investigated the molecular mechanism of Se deficiency aggravates reactive oxygen species (ROS)-induced inflammation, leading to fibrosis in lung. Mice fed with different concentrations of Se to establish the model. In the Se-deficient group, the ROS and malondialdehyde (MDA) was increased, and the activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and catalase (CAT) reduced. The histopathological observation showed that Se deficiency lead to lung texture damage with varying degrees of degeneration, necrosis, shedding of some alveolar epithelial cells, and inflammatory cell infiltration. Immunohistochemistry showed that the expression of α-smooth muscle actin (α-SMA) increased. The fibrosis index was verified with Sirius red staining. The ELISA and qPCR results showed that the inflammatory cytokines (TNF-α and IL-1ß) and ECM (collagen I, collagen IV, fibronectin, and laminin) were increased with ROS increasing, which was induced by Se deficiency. The results displayed that oxidative stress with Se deficiency led to an increase in tissue inhibitors of metalloproteinase (TIMPs), but a decrease in matrix metalloproteinases (MMPs). All the results indicated that Se deficiency induced excessive ROS accumulation to generate inflammation, which disrupted ECM homeostasis and aggravated fibrosis in the lung.

Effects of quercetin and daidzein on egg quality, lipid metabolism, and cecal short-chain fatty acids in layers.

In this study, the effects of quercetin and daidzein on egg quality, lipid metabolism, and cecal short-chain fatty acids (SCFAs) were compared in layers. Hyline brown layers at 385 days of age with a similar laying rate (81.36% ± 0.62%) and body weight (2.10 kg ± 0.04 kg) were randomly divided into three treatments, six replicates per treatment, and 20 layers per replicate. Layers in control, quercetin, and daidzein treatment were fed by a basal diet supplemented with 0 mg/kg, 500 mg/kg quercetin, and 30 mg/kg of daidzein for 10 weeks. Results showed that eggshell strength and albumen height in week 4, egg yolk diameter in week 10, and eggshell thickness and egg yolk height in weeks 4 and 10 were significantly increased in the quercetin treatment (P ≤ 0.05); contents of phospholipid (PL) and lecithin (LEC) in egg yolk and high-density lipoprotein (HDL) content in serum were significantly increased; however, contents of malondialdehyde (MDA), total cholesterol (TC), and triglyceride (TG) in egg yolk, contents of TC, TG, low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) in serum, and contents of TC and TG in the liver were significantly decreased in the quercetin treatment (P ≤ 0.05); contents of isobutyric acid and valeric acid were significantly increased in the cecum of the quercetin treatment (P ≤ 0.05), compared with control. Moreover, egg yolk height in week 10 and eggshell thickness in weeks 4 and 10 were significantly increased in the daidzein treatment (P ≤ 0.05); contents of MDA, TC, and TG in egg yolk, TC, TG, and VLDL in serum, and TC and TG in liver were significantly decreased in the daidzein treatment (P ≤ 0.05); and HDL content was significantly increased in serum of the daidzein treatment (P ≤ 0.05) compared with control. However, daidzein did not affect SCFA content in the cecum. In conclusion, egg quality was improved by quercetin and daidzein by increasing the antioxidant ability of egg yolk and by regulating lipid metabolism in layers. Quercetin worked better than daidzein in improving egg quality under this experimental condition.

Norcantharidin promotes cancer radiosensitization through Cullin1 neddylation-mediated CDC6 protein degradation.

Radiotherapy (RT) is a conventional cancer therapeutic modality. However, cancer cells tend to develop radioresistance after a period of treatment. Diagnostic markers and therapeutic targets for radiosensitivity are severely lacking. Our recently published studies demonstrated that the cell division cycle (CDC6) is a critical molecule contributing to radioresistance, and maybe a potential therapeutic target to overcome radioresistance. In the present study, we for the first time reported that Norcantharidin (NCTD), a demethylated form of cantharidin, re-sensitized radioresistant cancer cells to overcome radioresistance, and synergistically promoted irradiation (IR)-induced cell killing and apoptosis by inducing CDC6 protein degradation. Mechanistically, NCTD induced CDC6 protein degradation through the ubiquitin-proteasome pathways. By using small interfering RNA (siRNA) interference or small compound inhibitors, we further determined that NCTD induced CDC6 protein degradation through a neddylation-dependent pathway, but not through Huwe1, Cyclin F, and APC/C-mediated ubiquitin-proteasome pathways. We screened the six most relevant Cullin subunits (CUL1, 2, 3, 4A, 4B, and 5) using siRNAs. The knockdown of Cullin1 but not the other five cullins remarkably elevated CDC6 protein levels. NCTD promoted the binding of Cullin1 to CDC6, thereby promoting CDC6 protein degradation through a Cullin1 neddylation-mediated ubiquitin-proteasome pathway. NCTD can be used in combination with radiotherapy to achieve better anticancer efficacy, or work as a radiosensitizer to overcome cancer radioresistance.

The PGS1 basic helix-loop-helix protein regulates Fl3 to impact seed growth and grain yield in cereals.

Plant transcription factors (TFs), such as basic helix-loop-helix (bHLH) and AT-rich zinc-binding proteins (PLATZ), play critical roles in regulating the expression of developmental genes in cereals. We identified the bHLH protein TaPGS1 (T. aestivum Positive Regulator of Grain Size 1) specifically expressed in the seeds at 5-20 days post-anthesis in wheat. TaPGS1 was ectopically overexpressed (OE) in wheat and rice, leading to increased grain weight (up to 13.81% in wheat and 18.55% in rice lines) and grain size. Carbohydrate and total protein levels also increased. Scanning electron microscopy results indicated that the starch granules in the endosperm of TaPGS1 OE wheat and rice lines were smaller and tightly embedded in a proteinaceous matrix. Furthermore, TaPGS1 was bound directly to the E-box motif at the promoter of the PLATZ TF genes TaFl3 and OsFl3 and positively regulated their expression in wheat and rice. In rice, the OsFl3 CRISPR/Cas9 knockout lines showed reduced average thousand-grain weight, grain width, and grain length in rice. Our results reveal that TaPGS1 functions as a valuable trait-associated gene for improving cereal grain yield.

Zinc Deficiency Aggravates Oxidative Stress Leading to Inflammation and Fibrosis in Lung of Mice.

Zinc (Zn) is an essential trace element for the body. Studies have confirmed that Zn deficiency can cause oxidative stress. The purpose of the present study was designed to investigate the effect of Zn on fibrosis in lung of mice and its mechanism. Mice were fed with different Zn levels dietary, then we found that the Zn-deficient diet induced a decrease of Zn level in lung tissue. The results also revealed the alveolar structure hyperemia and an inflammatory exudated in the alveolar cavity. Moreover, immunohistochemical results showed that the expression of α-smooth muscle actin (α-SMA) increased. And the Sirius red staining indicated an increase in collagen with Zn deficiency. Furthermore, oxygen radicals (ROS) levels were significantly increased, and the antioxidants were significantly decreased. Meanwhile, inflammatory factors (TNF-α and IL-1ß) were remarkably increased, and the ELISA results showed that collagen I, III, and IV and fibronectin (FN) were increased. In addition, the expressions of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) were detected by qPCR. The results showed that the expression of TIMPs was increased but the expression of MMPs was decreased. The results of the experiment in vitro were consistent with that in vivo. All the results indicated that Zn deficiency aggravated the oxidative stress response of lung tissue to induce inflammation, leading to fibrosis in lung.

The O2-ZmGRAS11 transcriptional regulatory network orchestrates the coordination of endosperm cell expansion and grain filling in maize.

Maize (Zea mays) endosperm filling is coordinated with cell expansion to enlarge the grain size, but the mechanism coupling the two processes is poorly understood. Starchy endosperm cells basically contain no visible vacuoles for cell expansion. During grain filling, efficient synthesis of storage compounds leads to reduced cytoplasm and thus lowered cell turgor pressure. Although bioactive gibberellins (GAs) are essential for cell expansion, they accumulate at a low level at this stage. In this study, we identified an endosperm-specific GRAS domain-containing protein (ZmGRAS11) that lacks the DELLA domain and promotes cell expansion in the filling endosperm. The zmgras11 loss-of-function mutants showed normal grain filling but delayed cell expansion, thereby resulting in reduced kernel size and weight. Overexpression of ZmGRAS11 led to larger endosperm cells and therefore increased kernel size and weight. Consistent with this, ZmGRAS11 positively regulates the expression of ZmEXPB12, which is essential for cell expansion, at the endosperm filling stage. Moreover, we found that Opaque2 (O2), a central transcription factor that regulates endosperm filling, could directly bind to the promoter of ZmGRAS11 and activate its expression. Taken together, these results suggest that endosperm cell expansion is coupled with endosperm filling, which is orchestrated by the O2-ZmGRAS11-centered transcriptional regulatory network. Our findings also provide potential targets for maize yield improvement by increasing the storage capacity of endosperm cells.

Case report: A unusual case of delayed propionic acidemia complicated with subdural hematoma.

Background: Propionic acidemia (PA) is an inherited autosomal recessive metabolic disorder that is classified as early-onset or late-onset, depending on the onset time of clinical symptoms. It clinically manifests as numerous lesions in the brain, pancreas, liver, and muscle. Muscle biopsies show myopathic changes, which help to distinguish late-onset propionic acidemia from other metabolic diseases involving muscles. Case presentation: A 19-year-old Chinese girl was admitted to the hospital because of poor eating and fatigue. Head magnetic resonance imaging suggested metabolic diseases, and we administered symptomatic support treatment. Her symptoms gradually worsened, and she began to show convulsions and disturbances of consciousness. Muscle pathology showed myopathy-like changes. The presence of organic acids in the blood and urine suggested PA. Genetic analyses identified two compound heterozygous mutations in the patient's PCCB gene, confirming the diagnosis of delayed PA. Conclusions: The muscle pathological examination of late-onset PA provides valuable information that is helpful for distinguishing delayed-onset PA from metabolic diseases. In the absence of a history of trauma, subdural hematoma may be a very rare complication of late-onset PA and can be regarded as a poor prognostic sign; therefore, it is suggested to perform head computed tomography as part of the routine neurological evaluation of PA patients.

UHRF1 promotes androgen receptor-regulated CDC6 transcription and anti-androgen receptor drug resistance in prostate cancer through KDM4C-Mediated chromatin modifications.

The UHRF1 and CDC6, oncogenes play critical roles in therapeutic resistance. In the present study, we found that UHRF1 mediates androgen receptor (AR)-regulated CDC6 transcription in prostate cancer cells. In prostate cancer tissues and cell lines, levels of UHRF1 and CDC6 were simultaneously upregulated, and this was associated with worse survival. UHRF1 silencing significantly promoted the cytotoxicity and anti-prostate cancer efficacy of bicalutamide in mouse xenografts by inhibiting CDC6 gene expression. UHRF1 promoted AR-regulated CDC6 transcription by binding to the CCAAT motif near the androgen response element (ARE) in the CDC6 promoter. We further found that UHRF1 promoted androgen-dependent chromatin occupancy of AR protein by recruiting the H3K9me2/3-specific demethyltransferase KDM4C and modifying the intense heterochromatin status. Altogether, we found for the first time that UHRF1 promotes AR-regulated CDC6 transcription through a novel chromatin modification mechanism and contributes to anti-AR drug resistance in prostate cancer. Targeting AR and UHRF1 simultaneously may be a novel and promising therapeutic modality for prostate cancer.

Myb10-D confers PHS-3D resistance to pre-harvest sprouting by regulating NCED in ABA biosynthesis pathway of wheat.

Pre-harvest sprouting (PHS), the germination of grain before harvest, is a serious problem resulting in wheat yield and quality losses. Here, we mapped the PHS resistance gene PHS-3D from synthetic hexaploid wheat to a 2.4 Mb presence-absence variation (PAV) region and found that its resistance effect was attributed to the pleiotropic Myb10-D by integrated omics and functional analyses. Three haplotypes were detected in this PAV region among 262 worldwide wheat lines and 16 Aegilops tauschii, and the germination percentages of wheat lines containing Myb10-D was approximately 40% lower than that of the other lines. Transcriptome and metabolome profiling indicated that Myb10-D affected the transcription of genes in both the flavonoid and abscisic acid (ABA) biosynthesis pathways, which resulted in increases in flavonoids and ABA in transgenic wheat lines. Myb10-D activates 9-cis-epoxycarotenoid dioxygenase (NCED) by biding the secondary wall MYB-responsive element (SMRE) to promote ABA biosynthesis in early wheat seed development stages. We revealed that the newly discovered function of Myb10-D confers PHS resistance by enhancing ABA biosynthesis to delay germination in wheat. The PAV harboring Myb10-D associated with grain color and PHS will be useful for understanding and selecting white grained PHS resistant wheat cultivars.

Antiviral activities and applications of ribosomally synthesized and post-translationally modified peptides (RiPPs).

The emergence and re-emergence of viral epidemics and the risks of antiviral drug resistance are a serious threat to global public health. New options to supplement or replace currently used drugs for antiviral therapy are urgently needed. The research in the field of ribosomally synthesized and post-translationally modified peptides (RiPPs) has been booming in the last few decades, in particular in view of their strong antimicrobial activities and high stability. The RiPPs with antiviral activity, especially those against enveloped viruses, are now also gaining more interest. RiPPs have a number of advantages over small molecule drugs in terms of specificity and affinity for targets, and over protein-based drugs in terms of cellular penetrability, stability and size. Moreover, the great engineering potential of RiPPs provides an efficient way to optimize them as potent antiviral drugs candidates. These intrinsic advantages underscore the good therapeutic prospects of RiPPs in viral treatment. With the aim to highlight the underrated antiviral potential of RiPPs and explore their development as antiviral drugs, we review the current literature describing the antiviral activities and mechanisms of action of RiPPs, discussing the ongoing efforts to improve their antiviral potential and demonstrate their suitability as antiviral therapeutics. We propose that antiviral RiPPs may overcome the limits of peptide-based antiviral therapy, providing an innovative option for the treatment of viral disease.