Activation of actin-depolymerizing factor by CDPK16-mediated phosphorylation promotes actin turnover in Arabidopsis pollen tubes.

As the stimulus-responsive mediator of actin dynamics, actin-depolymerizing factor (ADF)/cofilin is subject to tight regulation. It is well known that kinase-mediated phosphorylation inactivates ADF/cofilin. Here, however, we found that the activity of Arabidopsis ADF7 is enhanced by CDPK16-mediated phosphorylation. We found that CDPK16 interacts with ADF7 both in vitro and in vivo, and it enhances ADF7-mediated actin depolymerization and severing in vitro in a calcium-dependent manner. Accordingly, the rate of actin turnover is reduced in cdpk16 pollen and the amount of actin filaments increases significantly at the tip of cdpk16 pollen tubes. CDPK16 phosphorylates ADF7 at Serine128 both in vitro and in vivo, and the phospho-mimetic mutant ADF7S128D has enhanced actin-depolymerizing activity compared to ADF7. Strikingly, we found that failure in the phosphorylation of ADF7 at Ser128 impairs its function in promoting actin turnover in vivo, which suggests that this phospho-regulation mechanism is biologically significant. Thus, we reveal that CDPK16-mediated phosphorylation up-regulates ADF7 to promote actin turnover in pollen.

Dynamic Phytomeric Growth Contributes to Local Adaptation in Barley.

Vascular plants have segmented body axes with iterative nodes and internodes. Appropriate node initiation and internode elongation are fundamental to plant fitness and crop yield; however, how these events are spatiotemporally coordinated remains elusive. We show that in barley (Hordeum vulgare L.), selections during domestication have extended the apical meristematic phase to promote node initiation, but constrained subsequent internode elongation. In both vegetative and reproductive phases, internode elongation displays a dynamic proximal-distal gradient, and among subpopulations of domesticated barleys worldwide, node initiation and proximal internode elongation are associated with latitudinal and longitudinal gradients, respectively. Genetic and functional analyses suggest that, in addition to their converging roles in node initiation, flowering-time genes have been repurposed to specify the timing and duration of internode elongation. Our study provides an integrated view of barley node initiation and internode elongation and suggests that plant architecture should be recognized as a collection of dynamic phytomeric units in the context of crop adaptive evolution.

The diverse actions of cytoskeletal vimentin in bacterial infection and host defense.

Bacterial infection is a major threat to human health, with infections resulting in considerable mortality, urging the need for a more profound understanding of bacteria-host interactions. During infection of cells, host cytoskeletal networks constantly interact with bacteria and are integral to their uptake. Vimentin, an intermediate filament protein, is one such cytoskeletal component that interacts with bacteria during infection. Although vimentin is predominantly present in the cytoplasm, it also appears in a secreted form or at the surface of multiple cell types, including epithelial cells, endothelial cells, macrophages and fibroblasts. As a cytoplasmic protein, vimentin participates in bacterial transportation and the consequential immune-inflammatory responses. When expressed on the cell surface, vimentin can be both pro- and anti-bacterial, favoring bacterial invasion in some contexts, but also limiting bacterial survival in others. Vimentin is also secreted and located extracellularly, where it is primarily involved in bacterial-induced inflammation regulation. Reciprocally, bacteria can also manipulate the fate of vimentin in host cells. Given that vimentin is not only involved in bacterial infection, but also the associated life-threatening inflammation, the use of vimentin-targeted drugs might offer a synergistic advantage. In this Review, we recapitulate the abundant evidence on vimentin and its dynamic changes in bacterial infection and speculate on its potential as an anti-bacterial therapeutic target.

Porcine reproductive and respiratory syndrome virus triggers Golgi apparatus fragmentation-mediated autophagy to facilitate viral self-replication.

Macroautophagy/autophagy is a cellular degradation and recycling process that maintains the homeostasis of organisms. A growing number of studies have reported that autophagy participates in infection by a variety of viruses. Porcine reproductive and respiratory syndrome virus (PRRSV) causes severe financial losses to the global swine industry. Although much research has shown that PRRSV triggers autophagy for its own benefits, the exact molecular mechanisms involved in PRRSV-triggered autophagy remain to be fully elucidated. In the current study, we demonstrated that PRRSV infection significantly induced Golgi apparatus (GA) fragmentation, which promoted autophagy to facilitate viral self-replication. Mechanistically, PRRSV nonstructural protein 2 was identified to interact with and degrade the Golgi reassembly and stacking protein 65 dependent on its papain-like cysteine protease 2 activity, resulting in GA fragmentation. Upon GA fragmentation, GA-resident Ras-like protein in brain 2 was disassociated from Golgi matrix protein 130 and subsequently bound to unc-51 like autophagy activating kinase 1 (ULK1), which enhanced phosphorylation of ULK1 and promoted autophagy. Taken together, all these results expand the knowledge of PRRSV-triggered autophagy as well as PRRSV pathogenesis to support novel potential avenues for prevention and control of the virus. More importantly, these results provide the detailed mechanism of GA fragmentation-mediated autophagy, deepening the understanding of autophagic processes.IMPORTANCEPorcine reproductive and respiratory syndrome virus (PRRSV) infection results in a serious swine disease affecting pig farming worldwide. Despite that numerous studies have shown that PRRSV triggers autophagy for its self-replication, how PRRSV induces autophagy is incompletely understood. Here, we identify that PRRSV Nsp2 degrades GRASP65 to induce GA fragmentation, which dissociates RAB2 from GM130 and activates RAB2-ULK1-mediated autophagy to enhance viral replication. This work expands our understanding of PRRSV-induced autophagy and PRRSV replication, which is beneficial for anti-viral drug development.

ASK1/ p38 axis inhibition blocks the release of mitochondrial "danger signals" from hepatocytes and suppresses progression to cirrhosis and liver cancer.

BACKGROUND AND AIMS: Apoptosis Signal-regulating Kinase 1 (ASK1) is activated by various pathological stimuli and induces cell apoptosis through downstream p38 activation. We studied the effect of pharmacological ASK1 inhibition on cirrhosis and its sequelae using comprehensive preclinical in vivo and in vitro systems. APPROACH AND RESULTS: Short-term (4-6 wk) and long-term (24-44 wk) ASK1 inhibition using small molecule GS-444217 was tested in thioacetamide-induced and BALB/c. Mdr2-/- murine models of cirrhosis and HCC, and in vitro using primary hepatocyte cell death assays. Short-term GS-444217 therapy in both models strongly reduced phosphorylated p38, hepatocyte death, and fibrosis by up to 50%. Profibrogenic release of mitochondrial DAMP mitochondrial deoxyribonucleic acid from dying hepatocytes was blocked by ASK1 or p38 inhibition. Long-term (24 wk) therapy in BALBc.Mdr2 - / - model resulted in a moderate 25% reduction in bridging fibrosis, but not in net collagen deposition. Despite this, the development of cirrhosis was effectively prevented, with strongly reduced p21 + hepatocyte staining (by 72%), serum ammonia levels (by 46%), and portal pressure (average 6.07 vs. 8.53 mm Hg in controls). Extended ASK1 inhibition for 44 wk in aged BALB/c. Mdr2-/- mice resulted in markedly reduced tumor number and size by ~50% compared to the control group. CONCLUSIONS: ASK1 inhibition suppresses the profibrogenic release of mitochondrial deoxyribonucleic acid from dying hepatocytes in a p38-dependent manner and protects from liver fibrosis. Long-term ASK1 targeting resulted in diminished net antifibrotic effect, but the progression to liver cirrhosis and cancer in BALBc/ Mdr2- / - mice was effectively inhibited. These data support the clinical evaluation of ASK1 inhibitors in fibrotic liver diseases.

Phosphatidylinositol 3-phosphate regulates SCAB1-mediated F-actin reorganization during stomatal closure in Arabidopsis.

Stomatal movement is critical for plant responses to environmental changes and is regulated by the important signaling molecule phosphatidylinositol 3-phosphate (PI3P). However, the molecular mechanism underlying this process is not well understood. In this study, we show that PI3P binds to stomatal closure-related actin-binding protein1 (SCAB1), a plant-specific F-actin-binding and -bundling protein, and inhibits the oligomerization of SCAB1 to regulate its activity on F-actin in guard cells during stomatal closure in Arabidopsis thaliana. SCAB1 binds specifically to PI3P, but not to other phosphoinositides. Treatment with wortmannin, an inhibitor of phosphoinositide kinase that generates PI3P, leads to an increase of the intermolecular interaction and oligomerization of SCAB1, stabilization of F-actin, and retardation of F-actin reorganization during abscisic acid (ABA)-induced stomatal closure. When the binding activity of SCAB1 to PI3P is abolished, the mutated proteins do not rescue the stability and realignment of F-actin regulated by SCAB1 and the stomatal closure in the scab1 mutant. The expression of PI3P biosynthesis genes is consistently induced when the plants are exposed to drought and ABA treatments. Furthermore, the binding of PI3P to SCAB1 is also required for vacuolar remodeling during stomatal closure. Our results illustrate a PI3P-regulated pathway during ABA-induced stomatal closure, which involves the mediation of SCAB1 activity in F-actin reorganization.

Host cytoskeletal vimentin serves as a structural organizer and an RNA-binding protein regulator to facilitate Zika viral replication.

Emerging microbe infections, such as Zika virus (ZIKV), pose an increasing threat to human health. Investigations on ZIKV replication have revealed the construction of replication complexes (RCs), but the role of cytoskeleton in this process is largely unknown. Here, we investigated the function of cytoskeletal intermediate filament protein vimentin in the life cycle of ZIKV infection. Using advanced imaging techniques, we uncovered that vimentin filaments undergo drastic reorganization upon viral protein synthesis to form a perinuclear cage-like structure that embraces and concentrates RCs. Genetic removal of vimentin markedly disrupted the integrity of RCs and resulted in fragmented subcellular dispersion of viral proteins. This led to reduced viral genome replication, viral protein production, and release of infectious virions, without interrupting viral binding and entry. Furthermore, mass spectrometry and RNA-sequencing screens identified interactions and interplay between vimentin and hundreds of endoplasmic reticulum (ER)-resident RNA-binding proteins. Among them, the cytoplasmic-region of ribosome receptor binding protein 1, an ER transmembrane protein that directly binds viral RNA, interacted with and was regulated by vimentin, resulting in modulation of ZIKV replication. Together, the data in our work reveal a dual role for vimentin as a structural element for RC integrity and as an RNA-binding-regulating hub during ZIKV infection, thus unveiling a layer of interplay between Zika virus and host cell.

Anlotinib alone or in combination with bevacizumab in the treatment of recurrent high-grade glioma: a prospective single-arm, open-label phase II trial.

BACKGROUND: Anlotinib is a multi-target tyrosine kinase inhibitor (TKI) targeting the vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and c-Kit. This phase II study aimed to assess the efficacy and safety of anlotinib, either alone or in combination with bevacizumab (Bev) for recurrent high-grade glioma (rHGG) (NCT04822805, 30/03/2021). METHODS: Eligible patients had a histological diagnosis of rHGG with first or subsequent recurrences. All patients received oral anlotinib 12 mg or 10 mg on days 1-14 (repeated every 21 days). In cases where brain magnetic resonance imaging examination revealed an increase in peritumoral edema without worsening of symptoms, patients received a temporary treatment of intravenous bevacizumab 10 mg/kg to alleviate edema. The primary endpoint was the median progression-free survival (mPFS), and the secondary endpoints included median overall survival (mOS), objective response rate (ORR), disease control rate (DCR), and safety. RESULTS: Twenty-five patients with rHGG were included in the efficacy and safety assessments. Eighteen patients received anlotinib alone, and seven patients received anlotinib in combination with Bev. For all patients, the mPFS and mOS were 5.0 months and 13.6 months, respectively. The ORR was 32%, and the DCR was 96%. It is noteworthy that the survival and response data of recurrent glioblastoma (rGBM) exhibit similarities to those of rHGG. For rGBM patients, there were no significant differences in mPFS, mOS, ORR, or DCR between the anlotinib alone and anlotinib + Bev groups. However, the incidence of treatment-related adverse events of any grade was higher in the anlotinib + Bev group compared to the anlotinib alone group (100% vs. 78%, p = 0.041). CONCLUSIONS: Both anlotinib alone and its combination with Bev demonstrated good efficacy and safety in the treatment of rHGG.

Imprinted gene detection effectively improves the diagnostic accuracy for papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most frequent histological type of thyroid carcinoma. Although an increasing number of diagnostic methods have recently been developed, the diagnosis of a few nodules is still unsatisfactory. Therefore, the present study aimed to develop and validate a comprehensive prediction model to optimize the diagnosis of PTC. METHODS: A total of 152 thyroid nodules that were evaluated by postoperative pathological examination were included in the development and validation cohorts recruited from two centres between August 2019 and February 2022. Patient data, including general information, cytopathology, imprinted gene detection, and ultrasound features, were obtained to establish a prediction model for PTC. Multivariate logistic regression analysis with a bidirectional elimination approach was performed to identify the predictors and develop the model. RESULTS: A comprehensive prediction model with predictors, such as component, microcalcification, imprinted gene detection, and cytopathology, was developed. The area under the curve (AUC), sensitivity, specificity, and accuracy of the developed model were 0.98, 97.0%, 89.5%, and 94.4%, respectively. The prediction model also showed satisfactory performance in both internal and external validations. Moreover, the novel method (imprinted gene detection) was demonstrated to play a role in improving the diagnosis of PTC. CONCLUSION: The present study developed and validated a comprehensive prediction model for PTC, and a visualized nomogram based on the prediction model was provided for clinical application. The prediction model with imprinted gene detection effectively improves the diagnosis of PTCs that are undetermined by the current means.

Oncological and reproductive outcomes of endometrial atypical hyperplasia and endometrial cancer patients undergoing conservative therapy with hysteroscopic resection: A systematic review and meta-analysis.

INTRODUCTION: Our objective was to conduct a systematic review and meta-analysis of studies evaluating the oncological and reproductive outcomes of patients with endometrial atypical hyperplasia (AH) and endometrioid endometrial cancer (EEC) undergoing conservative therapy with hysteroscopic resection (HR). MATERIAL AND METHODS: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for systematic reviews and meta-analyses. The study strictly followed the methodological framework proposed by the Cochrane Handbook and was retrospectively registered in PROSPERO (CRD42023469986). Searches were conducted in PubMed, Embase, and the Cochrane Library, from inception to October 10, 2023. A checklist based on items of the Newcastle-Ottawa Scale and the Methodological Index for Non-randomized Studies was used for quality assessment. The primary end points for this meta-analysis were complete response (CR), pregnancy, and live birth rates following HR-based therapy in patients with EEC or AH. The secondary end point was the recurrence rate (RR). RESULTS: Twenty-one articles involving 407 patients with clinical stage IA, low or intermediate grade, EEC, and 444 patients with AH managed with HR-based conservative treatment were included for this systematic review. CR to HR-based conservative therapy was achieved in 88.6% of patients with EEC and 97.0% of patients with AH. Of these, 30.6% and 24.2%, respectively, had live births. The overall pooled disease RR was 18.3% and 10.8% in patients with EEC and AH, respectively. Further subset analyses revealed that EEC patients with body mass index (BMI) ≤28 kg/m2 had higher CR rates as well as higher chances of pregnancy and live birth (91.6% CR, 32.9% pregnancy, 31.1% live birth) compared with patients with BMI >28 kg/m2 (86.4% CR, 28.4% pregnancy, 23.0% live birth). The HR followed by oral progestogen subgroup had higher CR rates and higher chances of pregnancy and live birth (91.8% CR, 36.3% pregnancy, 28.2% live birth) than the HR followed by the levonorgestrel intrauterine system subgroup (82.5% CR, 25.3% pregnancy, 16.3% live birth). CONCLUSIONS: Hysteroscopic resection followed by progestins appears to be a promising choice for fertility-sparing treatment in young patients with AH and EEC, with effective and safe responses. The live birth rate remains to be improved by providing medical guidance and encouragement.

Arabidopsis SRPKII family proteins regulate flowering via phosphorylation of SR proteins and effects on gene expression and alternative splicing.

Alternative splicing of pre-mRNAs is crucial for plant growth and development. Serine/arginine-rich (SR) proteins are a conserved family of RNA-binding proteins that are critical for both constitutive and alternative splicing. However, how phosphorylation of SR proteins regulates gene transcription and alternative splicing during plant development is poorly understood. We found that the Arabidopsis thaliana L. SR protein-specific kinase II family proteins (SRPKIIs) play an important role in plant development, including flowering. SRPKIIs regulate the phosphorylation status of a subset of specific SR proteins, including SR45 and SC35, which subsequently mediates their subcellular localization. A phospho-dead SR45 mutant inhibits the assembly of the apoptosis-and splicing-associated protein complex and thereby upregulates the expression of FLOWERING LOCUS C (FLC) via epigenetic modification. The splicing efficiency of FLC introns was significantly increased in the shoot apex of the srpkii mutant. Transcriptomic analysis revealed that SRPKIIs regulate the alternative splicing of c. 400 genes, which largely overlap with those regulated by SR45 and SC35-SCL family proteins. In summary, we found that Arabidopsis SRPKIIs specifically affect the phosphorylation status of a subset SR proteins and regulate the expression and alternative splicing of FLC to control flowering time.

Comparison of the effectiveness of lauromacrogol injection for ablation and microwave ablation in the treatment of predominantly cystic thyroid nodules: a multicentre study.

PURPOSE: To compare the therapeutic efficacy and safety of microwave ablation (MWA) and lauromacrogol injection for ablation (LIA) for benign predominantly cystic thyroid nodules. MATERIALS AND METHODS: In this retrospective study, 85 patients with predominantly cystic thyroid nodules (PCTNs) who underwent microwave ablation (MWA) or lauromacrogol injection for ablation (LIA) between June 2019 and August 2022 at three hospitals were included in our research. Forty-six patients were treated with microwave ablation, and thirty-nine patients were treated with lauromacrogol injection for ablation. The baseline characteristics, nodal volume, volume reduction rate (VRR), and incidence of postoperative complications were compared between these two groups. RESULTS: After treatment, there were significant differences in the thyroid nodule volume and the volume reduction rate (VRR) at different follow-up times between the groups (p < 0.001). There were no significant differences in the nodal volume or the volume reduction rate (VRR) between the MWA group and the LIA group at 1, 3, 6, and 12 months (p > 0.05). Of note, no serious intraoperative or postoperative complications occurred in the corresponding group. CONCLUSION: MWA and LIA are very effective and safe strategies for the treatment of predominantly cystic thyroid nodules. However, LIA is more advantageous in that it is less expensive and has a shorter length of hospital stay than MWA.

Association of Endocrine-Disrupting Chemicals with All-Cause and Cause-Specific Mortality in the U.S.: A Prospective Cohort Study.

Wide exposure to endocrine-disrupting chemicals (EDCs) poses a great risk on human health. However, few large-scale cohort studies have comprehensively estimated the association between EDCs exposure and mortality risk. This study aimed to investigate the association of urinary EDCs exposure with mortality risk and quantify attributable mortality and economic loss. Multivariable Cox proportional hazards regression models were performed to investigate the association of 38 representative EDCs exposure with mortality risk in the National Health and Nutrition Examination Survey (NHANES). During a median follow-up of 7.7 years, 47,279 individuals were enrolled. All-cause mortality was positively associated with 1-hydroxynaphthalene, 2-hydroxynaphthalene, cadmium, antimony, cobalt, and monobenzyl phthalate. Cancer mortality was positively associated with cadmium. Cardiovascular disease (CVD) mortality was positively associated with 1-hydroxynaphthalene, 2-hydroxynaphthalene, and 2-hydroxyfluorene. Nonlinear U-shaped relationships were found between all-cause mortality and cadmium and cobalt, which was also identified between 2-hydroxyfluorene and CVD mortality. J-shaped association of cadmium exposure with cancer mortality was also determined. EDCs exposure may cause 56.52% of total deaths (1,528,500 deaths) and around 1,897 billion USD in economic costs. Exposure to certain phthalates, polycyclic aromatic hydrocarbons, phytoestrogens, or toxic metals, even at substantially low levels, is significantly associated with mortality and induces high economic costs.

CCNE1 is a predictive and immunotherapeutic indicator in various cancers including UCEC: a pan-cancer analysis.

BACKGROUND: CCNE1 plays an important oncogenic role in several tumors, especially high-stage serous ovarian cancer and endometrial cancer. Nevertheless, the fundamental function of CCNE1 has not been explored in multiple cancers. Therefore, bioinformatics analyses of pan-cancer datasets were carried out to explore how CCNE1 regulates tumorigenesis. METHODS: A variety of online tools and cancer databases, including GEPIA2, SangerBox, LinkedOmics and cBioPortal, were applied to investigate the expression of CCNE1 across cancers. The pan-cancer datasets were used to search for links between CCNE1 expression and prognosis, DNA methylation, m6A level, genetic alterations, CCNE1-related genes, and tumor immunity. We verified that CCNE1 has biological functions in UCEC cell lines using CCK-8, EdU, and Transwell assays. RESULTS: In patients with different tumor types, a high mRNA expression level of CCNE1 was related to a poor prognosis. Genes related to CCNE1 were connected to the cell cycle, metabolism, and DNA damage repair, according to GO and KEGG enrichment analyses. Genetic alterations of CCNE1, including duplications and deep mutations, have been observed in various cancers. Immune analysis revealed that CCNE1 had a strong correlation with TMB, MSI, neoantigen, and ICP in a variety of tumor types, and this correlation may have an impact on the sensitivity of various cancers to immunotherapy. CCK-8, EdU and Transwell assays suggested that CCNE1 knockdown can suppress UCEC cell proliferation, migration and invasion. CONCLUSION: Our study demonstrated that CCNE1 is upregulated in multiple cancers in the TCGA database and may be a promising predictive biomarker for the immunotherapy response in some types of cancers. Moreover, CCNE1 knockdown can suppress the proliferation, migration and invasion of UCEC cells.

CKL2 mediates the crosstalk between abscisic acid and brassinosteroid signaling to promote swift growth recovery after stress in Arabidopsis.

Plants must adapt to the constantly changing environment. Adverse environmental conditions trigger various defensive responses, including growth inhibition mediated by phytohormone abscisic acid (ABA). When the stress recedes, plants must transit rapidly from stress defense to growth recovery, but the underlying mechanisms by which plants switch promptly and accurately between stress resistance and growth are poorly understood. Here, using quantitative phosphoproteomics strategy, we discovered that early ABA signaling activates upstream components of brassinosteroid (BR) signaling through CASEIN KINASE 1-LIKE PROTEIN 2 (CKL2). Further investigations showed that CKL2 interacts with and phosphorylates BRASSINOSTEROID INSENSITIVE1 (BRI1), the main BR receptor, to maintain the basal activity of the upstream of BR pathway in plants exposed to continuous stress conditions. When stress recedes, the elevated phosphorylation of BRI1 by CKL2 contributes to the swift reactivation of BR signaling, which results in quick growth recovery. These results suggest that CKL2 plays a critical regulatory role in the rapid switch between growth and stress resistance. Our evidence expands the understanding of how plants modulate stress defense and growth by integrating ABA and BR signaling cascades.

MYB30 and ETHYLENE INSENSITIVE3 antagonistically modulate root hair growth in Arabidopsis.

Root hair (RH) is essential for plant nutrient acquisition and the plant-environment communication. Here we report that transcription factors MYB30 and ETHYLENE INSENSITIVE3 (EIN3) modulate RH growth/elongation in Arabidopsis in an antagonistic way. The MYB30 loss-of-function mutant displays enhanced RH length, whereas the RH elongation in MYB30-overexpressing plants is highly repressed. MYB30 physically interacts with EIN3, a master transcription factor in ethylene signaling. MYB30 directly binds the promoter region of ROOT HAIR DEFECTIVE SIX-LIKE4 (RSL4) and represses its transcription. RSL4 loss-of-function suppresses the enhanced RH growth in myb30 mutant plants. Ethylene enhances MYB30-EIN3 complex formation, and reduces the association between MYB30 and RSL4 promotor via the action of EIN3. MYB30 and EIN3 antagonistically regulate the expression of RSL4 and a subset of core RH genes in a genome-wide way. Taken together, our work revealed a novel transcriptional network that modulates RH growth in plants.

Endometrial cancer in Lynch syndrome.

Lynch syndrome (LS) is an autosomal dominant inherited disease caused by germline pathogenic variants (PVs) in mismatch repair (MMR) genes. LS-associated endometrial cancer (LS-EC) is the most common extraintestinal sentinel cancer caused by germline PVs in MMR genes, including MLH1, MSH2, MSH6 and PMS2. The clinicopathologic features of LS-EC include early age of onset, lower body mass index (BMI), endometrioid carcinoma and lower uterine segment involvement. There has been significant progress in screening, diagnosis, surveillance, prevention and treatment of LS-EC. Many studies support universal screening for LS among patients with EC. Screening mainly involves a combination of traditional clinical criteria and molecular techniques, including MMR-immunohistochemistry (MMR-IHC), microsatellite instability (MSI) testing, MLH1 promoter methylation testing and gene sequencing. The effectiveness of endometrial biopsy and transvaginal ultrasound (TVS) for clinical monitoring of asymptomatic women with LS are uncertain yet. Preventive strategies include hysterectomy and bilateral salpingo-oophorectomy (BSO) as well as chemoprophylaxis using exogenous progestin or aspirin. Recent research has revealed the benefits of immunotherapy for LS-EC. The NCCN guidelines recommend pembrolizumab and nivolumab for treating patients with advanced or recurrent microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) EC.

The PYR-PP2C-CKL2 module regulates ABA-mediated actin reorganization during stomatal closure.

Limiting water loss by reducing transpiration helps plants survive when water is limited. Under drought stress, abscisic acid (ABA)-mediated gene expression and anion channel activation regulate stomatal closure and stress responses. ABA-induced actin reorganization also affects stomatal closure, but the underlying molecular mechanism remains unclear. In this study, we discovered that under nonstress conditions, the clade A PP2C phosphatases, such as ABI1 and ABI2, interact with CKL2 and inhibit its kinase activity in Arabidopsis. Under drought stress, CKL2 kinase activity was released through the formation of a complex containing ABA, PP2C and a PYR1/PYL/RCAR family (PYL) receptor. The activated CKL2 regulating actin reorganization is another important process to maintain stomatal closure besides ABA-activated SnRK2 signaling. Moreover, CKL2 phosphorylated PYR1-LIKE 1, ABI1 and ABI2 at amino acid residues conserved among PYLs and PP2Cs, and stabilized ABI1 protein. Our results reveal that ABA signaling regulates actin reorganization to maintain stomatal closure during drought stress, and the feedback regulation of PYL1, ABI1 and ABI2 by the CKL2 kinase might fine-tune ABA signaling and affect plant ABA responses.

The APETALA2-Like Transcription Factor SUPERNUMERARY BRACT Controls Rice Seed Shattering and Seed Size.

The elimination of seed shattering was a crucial event during crop domestication. Improving and fine-tuning the regulation of this process will further enhance grain yield by avoiding seed losses during crop production. In this work, we identified the loss-of-shattering mutant suppression of shattering1 (ssh1) through a screen of mutagenized wild rice (Oryza rufipogon) introgression lines with naturally high shattering. Using the MutMap approach and transformation experiments, we isolated a genetic factor for seed shattering, SSH1, which is an allele of SUPERNUMERARY BRACT (SNB), a gene encoding a plant-specific APETALA2-like transcription factor. A C-to-A point mutation in the ninth intron of SNB altered the splicing of its messenger RNA, causing the reduced shattering of the ssh1 mutant by altering the development of the abscission layer and vascular bundle at the junction between the seed and the pedicel. Our data suggest that SNB positively regulates the expression of two rice REPLUMLESS orthologs, qSH1 and SH5 In addition, the ssh1 mutant had larger seeds and a higher grain weight, resulting from its increased elongation of the glume longitudinal cells. The further identification of favorable SNB alleles will be valuable for improving rice seed shattering and grain yield using molecular breeding strategies.

Integrating BRAFV600E mutation, ultrasonic and clinicopathologic characteristics for predicting the risk of cervical central lymph node metastasis in papillary thyroid carcinoma.

BACKGROUND: The advantages of prophylactic central lymph node dissection (CLND) for clinically node-negative patients remained a great deal of controversies. Our research was aimed to analyze the relationship between cervical central lymph node metastasis (CLNM) and BRAFV600E mutation, ultrasonic and clinicopathologic characterizes in papillary thyroid carcinoma (PTC). METHODS AND MATERIALS: In current study, a total of 112 consecutive PTC patients who experienced thyroidectomy plus cervical central neck dissection were included in our research. All PTC were pre-operatively analyzed by ultrasonic features, including tumor size, multifocality or not, tumor location, internal components, echogenicity, microcalcification, margins, orientation, taller than wide shape, and internal vascularity. The presence of clinicopathologic factors, including age, sex, T stage, Hashimoto's thyroiditis, and BRAFV600E mutation was then investigated. Univariate and multivariate analysis were conducted to check into the relationship between predictive factors and cervical CLNM in PTC patients, and then a predictive model was also established. RESULTS: Pathologically, 58.0% (65/112) of the PTC patients harbored cervical CLNM. Univariate and multivariate analysis were conducted to identify age < 55 years, tumor size > 10 mm, microcalcification, non-concomitant Hashimoto's thyroiditis and BRAFV600E mutation were predictive factors for cervical CLNM in PTC. The risk score for cervical CLNM in PTC patients was calculated: risk score = 1.284 × (if age < 55 years) + 1.241 × (if tumor size > 10 mm) + 1.143 × (if microcalcification) - 2.097 × (if concomitant Hashimoto's thyroiditis) + 1.628 × (if BRAFV600E mutation). CONCLUSION: Age < 55 years old, PTC > 10 mm, microcalcification, non-concomitant Hashimoto's thyroiditis and BRAFV600E mutation are predictive factors for cervical CLNM. BRAFV600E mutation by pre-operative US-FNA technology synergized with clinicopathologic and ultrasonic features is expected to guide the appropriate surgical management for PTC patients.