Diversified molecular adaptations of inorganic nitrogen assimilation and signaling machineries in plants.

Plants evolved sophisticated machineries to monitor levels of external nitrogen supply, respond to nitrogen demand from different tissues and integrate this information for coordinating its assimilation. Although roles of inorganic nitrogen in orchestrating developments have been studied in model plants and crops, systematic understanding of the origin and evolution of its assimilation and signaling machineries remains largely unknown. We expanded taxon samplings of algae and early-diverging land plants, covering all main lineages of Archaeplastida, and reconstructed the evolutionary history of core components involved in inorganic nitrogen assimilation and signaling. Most components associated with inorganic nitrogen assimilation were derived from the ancestral Archaeplastida. Improvements of assimilation machineries by gene duplications and horizontal gene transfers were evident during plant terrestrialization. Clusterization of genes encoding nitrate assimilation proteins might be an adaptive strategy for algae to cope with changeable nitrate availability in different habitats. Green plants evolved complex nitrate signaling machinery that was stepwise improved by domains shuffling and regulation co-option. Our study highlights innovations in inorganic nitrogen assimilation and signaling machineries, ranging from molecular modifications of proteins to genomic rearrangements, which shaped developmental and metabolic adaptations of plants to changeable nutrient availability in environments.

The role and mechanism of thrombospondin-4 in pulmonary arterial hypertension associated with congenital heart disease.

BACKGROUND: Due to a special hemodynamic feature, pulmonary vascular disease in pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) has two stages: reversible and irreversible. So far, the mechanism involved in the transition from reversible to irreversible stage is elusive. Moreover, no recognized and reliable assessments to distinguish these two stages are available. Furthermore, we found that compared with control and reversible PAH, thrombospondin-4 (THBS4) was significantly upregulated in irreversible group by bioinformatic analysis. Hence, we further verify and investigate the expression and role of THBS4 in PAH-CHD. METHODS: We established the monocrotaline plus aorto-cava shunt-induced (MCT-AV) rat model. We measured the expression of THBS4 in lung tissues from MCT-AV rats. Double immunofluorescence staining of lung tissue for THBS4 and α-SMA (biomarker of smooth muscle cells) or vWF (biomarker of endothelial cells) to identify the location of THBS4 in the pulmonary artery. Primary pulmonary artery smooth muscle cells (PASMCs) were cultivated, identified, and used in this study. THBS4 was inhibited and overexpressed by siRNA and plasmid, respectively, to explore the effect of THBS4 on phenotype transformation, proliferation, apoptosis, and migration of PASMCs. The effect of THBS4 on pulmonary vascular remodeling was evaluated in vivo by adeno-associated virus which suppressed THBS4 expression. Circulating level of THBS4 in patients with PAH-CHD was measured by ELISA. RESULTS: THBS4 was upregulated in the lung tissues of MCT-AV rats, and was further upregulated in severe pulmonary vascular lesions. And THBS4 was expressed mainly in PASMCs. When THBS4 was inhibited, contractile markers α-SMA and MYH11 were upregulated, while the proliferative marker PCNA was decreased, the endothelial-mensenchymal transition marker N-cad was downregulated, proapototic marker BAX was increased. Additionally, proliferation and migration of PASMCs was inhibited and apoptosis was increased. Conversely, THBS4 overexpression resulted in opposite effects. And the impact of THBS4 on PASMCs was probably achieved through the regulation of the PI3K/AKT pathway. THBS4 suppression attenuated pulmonary vascular remodeling. Furthermore, compared with patients with simple congenital heart disease and mild PAH-CHD, the circulating level of THBS4 was higher in patients with severe PAH-CHD. CONCLUSIONS: THBS4 is a promising biomarker to distinguish reversible from irreversible PAH-CHD before repairing the shunt. THBS4 is a potential treatment target in PAH-CHD, especially in irreversible stage.

The pyroptosis mediated biomarker pattern: an emerging diagnostic approach for Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) affects 1% of people over 60, and long-term levodopa treatment can cause side effects. Early diagnosis is of great significance in slowing down the pathological process of PD. Multiple pieces of evidence showed that non-coding RNAs (ncRNAs) could participate in the progression of PD pathology. Pyroptosis is known to be regulated by ncRNAs as a key pathological feature of PD. Therefore, evaluating ncRNAs and pyroptosis-related proteins in serum could be worthy biomarkers for early diagnosis of PD. METHODS: NcRNAs and pyroptosis/inflammation mRNA levels were measured with reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). Luciferase assays were performed to confirm GSDME as a target of miR-675-5p and HMGB1 as a target of miR-1247-5p. In the serum of healthy controls (n = 106) and PD patients (n = 104), RT-qPCR was utilized to assess miR-675-5p, miR-1247-5p, and two related ncRNAs (circSLC8A1and lncH19) levels. The enzyme-linked immunosorbent assay measured serum levels of pyroptosis-related proteins in controls (n = 54) and PD patients (n = 70). RESULTS: Our data demonstrated that miR-675-5p and miR-1247-5p significantly changed in PD neuron and animal models. Overexpressed miR-675-5p or downregulated miR-1247-5p could regulate pyroptosis and inflammation in PD neuron models. Using the random forest algorithm, we constructed a classifier based on PD neuron-pyroptosis pathology (four ncRNAs and six proteins) having better predictive power than single biomarkers (AUC = 92%). Additionally, we verified the performance of the classifier in early-stage PD patients (AUC ≥ 88%). CONCLUSION: Serum pyroptosis-related ncRNAs and proteins could serve as reliable, inexpensive, and non-invasive diagnostic biomarkers for PD. LIMITATIONS: All participants were from the same region. Additionally, longitudinal studies in the aged population are required to explore the practical application value of the classifier.

From metabolomics to therapeutics: identifying causal metabolites and potential drugs for the treatment of osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a common age-related disease that causes pain and impaired mobility. Various blood metabolites are reportedly associated with bone health; however, their impact on OA remains unclear. Therefore, we conducted a metabolome-wide Mendelian randomization (MR) study to identify causal metabolites and therapeutic targets in OA. METHODS: Genetic associations of metabolites were derived from the largest genome-wide association study (GWAS) of the blood metabolome, which provided summary-level data on 1091 blood metabolites. Genetic associations with OA were obtained from four large-scale GWAS: McDonald's study (140,025 cases, 344,349 controls), Zengini's study (12,658 cases, 50,898 controls), Dönertas's study (39,515 cases, 445,083 controls), and Tachmazidou's study (39,427 cases, 378,169 controls). MR and colocalization analyses were performed to validate the causal roles of the candidate metabolites. Further analyses were conducted using expression quantitative trait locus-based MR, single-cell sequencing data, protein-protein interaction networks, and druggability assessments. These analyses aimed to identify the differentially expressed genes and prioritize them as potential therapeutic targets. RESULTS: The genetically predicted levels of 10 metabolites were associated with OA. Elevated levels of five metabolites and reduced levels of another five metabolites were associated with an increased OA risk. Among these, five metabolites were prioritized based on the most compelling evidence. Seven genes were identified as potentially involved and could serve as novel therapeutic targets for OA. CONCLUSION: Several blood metabolites were associated with OA, providing new insights into the etiology of OA and highlighting promising therapeutic targets.

The impact of negative cognitive bias on NSSI: mediating non-adaptive cognitive emotion regulation strategies.

BACKGROUND: Individuals may be more likely to engage in NSSI due to negative cognitive bias, while the use of negative emotional regulation mechanisms may further contribute to NSSI. Currently, there is a dearth of studies regarding the correlation among the three variables. METHOD: The study employed convenience sampling to collect data via online platforms from a total of 572 college students in Harbin, Heilongjiang Province, China, over the period of January 2024 to February 2024. The questionnaires comprise the Non-Adaptive Cognitive Emotion Srategy Regulation Subscale, the Negative Cognitive Processing Bias Questionnaire, and the NSSI Questionnaire. OUTCOME: Negative cognitive bias significantly and directly influences NSSI, as indicated by a beta coefficient of 0.3788 and a confidence interval of [0.2878, 0.4698]. The existence of negative cognitive bias significantly enhances the impact of non-adaptive cognitive emotion control approaches (ß = 0.5613, CI [0.4808, 0.6418]). Non-adaptive cognitive emotion regulation strategies showed a significant effect on NSSI, as indicated by a beta coefficient of 0.2033 and a confidence interval of [0.0942, 0.3125]. The non-adaptive cognitive emotion control strategy serves as an intermediary between negative cognitive bias and NSSI, explaining 30.12% of the overall impact. IN CONCLUSION: The results demonstrate that non-adaptive cognitive emotion regulation strategies play a partially moderating role in the relationship between negative cognitive bias and NSSI among nursing students. We emphasize the importance of non-adaptive cognitive emotion regulation strategies, negative cognitive biases, and NSSI among nursing students. In order to reduce the occurrence of NSSI, it is important for schools, families, and teachers to work together closely and implement a well-organized and efficient intervention to protect the mental well-being of nursing students.

SDCBP promotes pancreatic cancer progression by preventing YAP1 from ß-TrCP-mediated proteasomal degradation.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal tumour with limited treatment options. Here, we identified syndecan binding protein (SDCBP), also known as syntenin1, as a novel targetable factor in promoting PDAC tumour progression. We also explored a therapeutic strategy for suppressing SDCBP expression. DESIGN: We used samples from patients with PDAC, human organoid models, LSL-KrasG12D/+mice, LSL-Trp53R172H/+ and Pdx1-Cre (KPC) mouse models, and PDX mouse models. Immunostaining, colony formation assay, ethynyl-2-deoxyuridine incorporation assay, real-time cell analysis, cell apoptosis assay, automated cell tracking, invadopodia detection and gelatin degradation assays, coimmunoprecipitation, and pull-down assays were performed in this study. RESULTS: The median overall survival and recurrence-free survival rates in the high-SDCBP group were significantly shorter than those in the low-SDCBP group. In vitro and in vivo studies have demonstrated that SDCBP promotes PDAC proliferation and metastasis. Mechanically, SDCBP inhibits CK1δ/ε-mediated YAP-S384/S387 phosphorylation, which further suppresses ß-TrCP-mediated YAP1 ubiquitination and proteasome degradation by directly interacting with YAP1. SDCBP interacts with the TAD domain of YAP1, mainly through its PDZ1 domain. Preclinical KPC mouse cohorts demonstrated that zinc pyrithione (ZnPT) suppresses PDAC tumour progression by suppressing SDCBP. CONCLUSIONS: SDCBP promotes the proliferation and metastasis of PDAC by preventing YAP1 from ß-TrCP-mediated proteasomal degradation. Therefore, ZnPT could be a promising therapeutic strategy to inhibit PDAC progression by suppressing SDCBP.

Opposing manner of miR-455-3p against NR2B-PSD-95-nNOS complex in the cortex and hippocampus of depressive rats under simulated complex space environment.

Depression in astronauts is one of the consequences of space flight effects, negatively impacting their work performances. Unfortunately, the underlying molecular mechanisms in space flight-induced depression are still unknown; however, various neuropsychiatric disorders reported that overexpressed NR2B-PSD-95-nNOS complex in the brain triggers various pathological pathways, and inhibiting NR2B-PSD-95-nNOS complex asserts antidepressant effects. Through our in silico analysis, we found that epigenetic regulator miR-445-3p targets PSD-95 and is hypothesized to down-regulate NR2B-PSD-95-nNOS complex to prevent neuronal damage associated with depression. Therefore, the present study is aimed to determine the novel insight of the miR-455-3p against the NR2B-PSD-95-nNOS complex in the neurobiology of space flight-induced depressive behavior. Using a simulated space environment complex model (SCSE) for 21 days, we induced depressive behavior in rats to analyze miR-455-3p expression and NR2B-PSD-95-nNOS complex in the cortex and hippocampus of the SCSE depressed rats through qRT-PCR and western blot analysis. Further, an in vitro microgravity model using rat hippocampus cell lines (RHNC) was utilized to identify the independent role of miR-455-3p on (1) NR2B-PSD-95-nNOS complex and TrKB-BDNF proteins, (2) oxidative stress, (3) nitric oxide level, (4) inflammatory cytokines, (5) mitochondrial biogenesis/ dynamics, and (6) cell survival. Our results showed that miR-455-3p regulates NR2B-PSD-95-nNOS complex in the SCSE depressed rats in opposite ways, with the cortex revealing a higher level of miR-455-3p and low-level NR2B-PSD-95-nNOS complex and the hippocampus showing down-regulated miR-455-3p and up-regulated NR2B-PSD-95-nNOS complex, indicating a region-specific change in the miR-455-3p and NR2B-PSD-95-nNOS complex in the SCSE depressed rats. Further RHNC results also confirmed down-regulated miR-455-3p and up-regulated NR2B-PSD-95-nNOS complex expression, similar to the findings in the hippocampus of SCSE rats, suggesting that microgravity influences miR-455-3p and associated changes. Additional investigations revealed that miR-455-3p targets PSD-95 and co-regulates NR2B-PSD-95-nNOS complex along with TrkB-BDNF signaling and exert protective effects against NR2B-PSD-95-nNOS complex, oxidative stress, nitric oxide, inflammatory cytokines, and mitochondrial defects, suggesting a valuable biomarker for devising depressive disorders.

PCA-based GRS analysis enhances the effectiveness for genetic correlation detection.

Genetic risk score (GRS, also known as polygenic risk score) analysis is an increasingly popular method for exploring genetic architectures and relationships of complex diseases. However, complex diseases are usually measured by multiple correlated phenotypes. Analyzing each disease phenotype individually is likely to reduce statistical power due to multiple testing correction. In order to conquer the disadvantage, we proposed a principal component analysis (PCA)-based GRS analysis approach. Extensive simulation studies were conducted to compare the performance of PCA-based GRS analysis and traditional GRS analysis approach. Simulation results observed significantly improved performance of PCA-based GRS analysis compared to traditional GRS analysis under various scenarios. For the sake of verification, we also applied both PCA-based GRS analysis and traditional GRS analysis to a real Caucasian genome-wide association study (GWAS) data of bone geometry. Real data analysis results further confirmed the improved performance of PCA-based GRS analysis. Given that GWAS have flourished in the past decades, our approach may help researchers to explore the genetic architectures and relationships of complex diseases or traits.

Single-Surgeon Experience for Maximizing Outcomes in Implant-Based Breast Reconstruction in Chinese Patients.

INTRODUCTION: Breast reconstruction for Chinese patients is vastly different given cultural differences, patient preferences, access to resources, and insurance coverage in China. Given these unique factors, a different approach for optimizing outcomes should be considered. METHODS: Retrospective review of all patients undergoing implant-based breast reconstruction from January 2013 to May 2016 was performed. Esthetic evaluations were made both by the patients and 1 nonoperative surgeon at least 6 months postoperative, and patient satisfaction was assessed using the Breast-Q. RESULTS: Overall, 135 patients undergoing 141 implant-based breast reconstructions were reviewed. The majority of implants (n = 134) were placed in a subpectoral position, whereas 7 were placed prepectorally, and no acellular dermal matrix was used. Given the limitations in acellular dermal matrix usage, soft-tissue coverage was augmented with local regional flaps. Ninety-four reconstructions (66.7%) used latissimus dorsi, 39 (27.7%) used serratus anterior, and 7 (5.0%) used mastectomy skin flaps only for implant coverage. Four patients (2.8%) underwent revision surgery to the reconstructed breasts. Grade III and grade IV capsular contracture was observed in 10 (7.1%) and 2 (1.4%) reconstructions, respectively. Both the patient's and the surgeon's satisfaction were higher than 80% in breast symmetry. CONCLUSIONS: Our implant selection method fit the Chinese population characteristics and could be extended to different types of implant-based breast reconstruction. It produced good esthetic outcomes and was reproducible, predictable, and simple to master in the clinical setting.

Considering the Optimal Timing of Breast Reconstruction With Abdominal Flaps With Adjuvant Irradiation in 370 Consecutive Pedicled Transverse Rectus Abdominis Myocutaneous Flap and Free Deep Inferior Epigastric Perforator Flap Performed in a Chinese Oncology Center: Is There a Significant Difference Between Immediate and Delayed?

PURPOSE: There is an ongoing debate on the optimal sequence of radiation and breast reconstruction. The purpose of this article was to (a) assess the impact of radiation on autologous breast reconstruction and (b) analyze the best timing for autologous breast reconstruction in the setting of radiation in a Chinese population. METHODS: A retrospective review of patients undergoing breast reconstruction with autologous lower abdominal flaps between 2001 and 2014 in the Tianjin Medical University and Cancer Hospital was performed. Patients were grouped by their irradiation status (irradiated vs nonirradiated). The irradiated group was further stratified into 2 groups by the timing of irradiation (immediate breast reconstruction followed by radiation vs prior radiation and delayed breast reconstruction). The primary outcomes were early and late breast complications, secondary and revision surgeries to the reconstructed breast, whereas the secondary outcomes were aesthetic and psychological evaluations of the patients. Logistic regression was used to assess the potential association between irradiation, patient and treatment variables, and surgical outcomes. RESULTS: Three hundred sixty patients with 370 reconstructed breasts were included in the study. Two hundred seventy-eight cases were nonirradiated, of which 158 were immediate and 120 were delayed. Ninety-two cases were irradiated, of which 61 were immediate, and 31 were delayed. Three hundred thirty-two cases underwent pedicled transverse rectus abdominis myocutaneous flap, 38 had deep inferior epigastric perforator flap. The irradiated group had a significant increase in secondary surgery due to fat necrosis (P < 0.001) and in late complications (P = 0.011). A significant increase in flap contracture (P = 0.043) and an increasing trend in the severity of fat necrosis were observed when radiation was performed after breast reconstruction. However, radiation and its timing did not have an adverse impact on patients' aesthetic and psychological evaluations by the Breast-Q survey. CONCLUSIONS: Radiation administered to the reconstructed breast mound increased the rate of late complications and the need for secondary surgery with increased abdominal flap shrinkage and contracture and the severity of flap fat necrosis. Irradiation on the reconstructed breast did not lead to worse aesthetic outcomes due to the generally different expectation in the Chinese female patients in that they were more focused on the breast shape when clothed. Immediate breast reconstruction followed by irradiated was a generally successful treatment sequence in the Chinese module.

Clinicopathologic characteristics and prognosis of primary squamous cell carcinoma of the breast.

Primary squamous cell carcinoma of the breast (PSCCB) is a rare type of breast carcinoma, the clinical behavior of which has not been accurately characterized. The aim of this study was to evaluate its prevalence, characteristics, prognosis, and effective treatment modalities in patients attending our institution. The records of the Cancer Institute and Hospital of Tianjin Medical University from 1985 to 2013 were searched and 29 patients with PSCCB (0.086 % of all patients with breast cancer) identified. Their clinicopathological features, treatment methods used, and outcomes were analyzed. The median tumor size was 4.50 cm. Axillary lymph nodes metastases were present in 41.4 % of patients. The median overall survival was 39 months (range 7-144 months), with 34.5 % surviving at 5 years. The median relapse-free survival was 32 months (range 4-144 months), with 27.6 % relapse-free surviving at 5 years. According to univariate analysis, the time interval between onset of the first symptom and first presentation to a health professional (TI) (P = 0.017), use of adjuvant chemotherapy (P = 0.044), and T stage (P = 0.048, T1 vs. T2, T3, T4) were significant prognostic factors for overall survival. PSCCB is an extremely aggressive disease associated with large tumor size, rapid progression, frequent relapse, and a high death rate. Imaging findings are nonspecific and easily misinterpreted as benign. Cisplatin-based chemotherapy may be effective. Early diagnosis and treatment of this rare entity are critical to patient prognosis.

Mitochondria Targetable Time-Gated Luminescence Probe for Singlet Oxygen Based on a ß-Diketonate-Europium Complex.

Singlet oxygen ((1)O2) plays a key role in the photodynamic therapy (PDT) technique of neoplastic diseases. In this work, by using a 9,10-dimethyl-2-anthryl-containing ß-diketone, 1,1,1,2,2-pentafluoro-5-(9',10'-dimethyl-2'-anthryl)-3,5-pentanedione (Hpfdap), as a (1)O2-recognition ligand, a novel ß-diketonate-europium(III) complex that can act as a luminescence probe for (1)O2, [Eu(pfdap)3(tpy)] (tpy = 2,2',2″-terpyridine), has been designed and synthesized for the time-gated luminescence detection of (1)O2 in living cells. The complex is weakly luminescent due to the quenching effect of 9,10-dimethyl-2-anthryl groups. After reaction with (1)O2, accompanied by the formation of endoperoxides of 9,10-dimethyl-2-anthryl groups, the luminescence quenching disappears, so that the long-lived luminescence of the europium(III) complex is switched on. The complex showed highly selective luminescence response to (1)O2 with a remarkable luminescence enhancement. Combined with the time-gated luminescence imaging technique, the complex was successfully used as a luminescent probe for the monitoring of the time-dependent generation of (1)O2 in 5-aminolevulinic acid (a PDT drug) loaded HepG2 cells during the photodynamic process. In addition, by coloading the complex and a mitochondrial indicator, Mito-Tracker Green, into HepG2 cells, the specific localization of [Eu(pfdap)3(tpy)] molecules in mitochondria of HepG2 cells was demonstrated by confocal fluorescence imaging measurements.

[Effects of simulated repeated transcranial acupuncture on learning and memory and cerebral microvascular flow in vascular dementia rats]. / æ¨¡æ‹Ÿç»é¢ é‡å¤é’ˆåˆºæ‰‹æ³•å¯¹è¡€ç®¡æ€§ç—´å‘†å¤§é¼ å­¦ä¹ è®°å¿†åŠè„‘å¾®è¡€æµçš„å½±å“.

OBJECTIVES: To observe the effect of simulated repeated transcranial acupuncture (rTAS) on learning and memory abilities and cerebral microvascular flow in vascular dementia (VD) model rats, so as to explore the potential mechanism of rTAS in treating VD. METHODS: Thirty-two Wistar rats were randomly divided into normal, model, acupuncture and rTAS groups (n=8 rats in each group). The VD model was established by permanent ligation of bilateral common carotid arteries. For rats of the acupuncture group, "Baihui" (GV20) and "Shenting" (GV24) were needled, and for rats of the rTAS group, GV20 and GV24 were stimulated by simulated repeated transcranial manipulation (200 r/min, for 5 min). The treatment was conducted once daily for 14 days. After the intervention, learning and memory abilities were evaluated using the Morris water maze test. Laser speckle technology was used to measure the average cerebral microvascular flow. ELISA was performed to measure the contents of vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), nitric oxide (NO), and inducible nitric oxide synthase (iNOS) in the hippocampal tissues. RESULTS: In comparison with the normal group, the escape latency of rats in the model group was prolonged (P<0.01), and the times of crossing the platform were decreased (P<0.01). The average cerebral microvascular flow and the VEGF content in the hippocampus were significantly decreased, while the contents of NO, iNOS, and ET-1 were significantly increased (P<0.01). In comparison with the model group, the escape latency was significantly shortened (P<0.01), the average cerebral microvascular flow and VEGF content in the hippocampus were significantly increased (P<0.05, P<0.01), while contents of iNOS were significantly decreased (P<0.05, P<0.01) in both acupuncture and rTAS groups；and the times of crossing the platform were increased (P<0.01), the contents of NO and ET-1 in hippocampus were significantly decreased (P<0.01) in the rTAS group. The effects of rTAS were significantly superior to those of acupuncture in up-regulating the average cerebral microvascular flow (P<0.05) and VEGF content (P<0.01), and down-regulating the NO, iNOS and ET-1 contents (P<0.01, P<0.05). CONCLUSIONS: rTAS can increase cerebral microvascular flow, improve spatial cognition and enhance learning and memory abilities of VD rats. The underlying mechanism may be involved in promoting angiogenesis, improving endothelial function and mitigating oxidative stress.

The origin, evolution and functional divergence of HOOKLESS1 in plants.

Apical hooks are functional innovations only observed in angiosperms, which effectively protect the apical meristems out of damage during plant seedlings penetrating soil covers. Acetyltransferase like protein HOOKLESS1 (HLS1) in Arabidopsis thaliana is required for hook formation. However, the origin and evolution of HLS1 in plants are still not solved. Here, we traced the evolution of HLS1 and found that HLS1 originated in embryophytes. Moreover, we found that Arabidopsis HLS1 delayed plant flowering time, in addition to their well-known functions in apical hook development and newly reported roles in thermomorphogenesis. We further revealed that HLS1 interacted with transcription factor CO and repressed the expression of FT to delay flowering. Lastly, we compared the functional divergence of HLS1 among eudicot (A. thaliana), bryophytes (Physcomitrium patens and Marchantia polymorpha) and lycophyte (Selaginella moellendorffii). Although HLS1 from these bryophytes and lycophyte partially rescued the thermomorphogenesis defects in hls1-1 mutants, the apical hook defects and early flowering phenotypes could not be reversed by either P. patens, M. polymorpha or S. moellendorffii orthologs. These results illustrate that HLS1 proteins from bryophytes or lycophyte are able to modulate thermomorphogenesis phenotypes in A. thaliana likely through a conserved gene regulatory network. Our findings shed new light on the understanding of the functional diversity and origin of HLS1, which controls the most attractive innovations in angiosperms.

Novel nomograms for predicting survival for immediate breast reconstruction patients diagnosed with invasive breast cancer-a single-center 15-year experience.

Background: Immediate breast reconstruction is widely accepted following oncologic mastectomy. This study aimed to build a novel nomogram predicting the survival outcome for Chinese patients undergoing immediate reconstruction following mastectomy for invasive breast cancer. Methods: A retrospective review of all patients undergoing immediate reconstruction following treatment for invasive breast cancer was performed from May 2001 to March 2016. Eligible patients were assigned to a training set or a validation set. Univariate and multivariate Cox proportional hazard regression models were used to select associate variables. Two nomograms were developed based on the training cohort for breast cancer-specific survival (BCSS) and disease-free survival (DFS). Internal and external validations were performed, and the C-index and calibration plots were generated to evaluate the performance (discrimination and accuracy) of the models. Results: The 10-year estimated BCSS and DFS were 90.80% (95% CI: 87.30%-94.40%) and 78.40% (95% CI: 72.50%-84.70%), respectively, in the training cohort. In the validation cohort, they were and 85.60% (95% CI, 75.90%-96.50%) and 84.10% (95% CI, 77.80%-90.90%), respectively. Ten independent factors were used to build a nomogram for prediction of 1-, 5- and 10-year BCSS, while nine were used for DFS. The C-index was 0.841 for BCSS and 0.737 for DFS in internal validation, and the C-index was 0.782 for BCSS and 0.700 for DFS in external validation. The calibration curve for both BCSS and DFS demonstrated acceptable agreement between the predicted and actual observation in the training and the validation cohorts. Conclusion: The nomograms provided valuable visualization of factors predicting BCSS and DFS in invasive breast cancer patients with immediate breast reconstruction. The nomograms may have tremendous potential in guiding individualized decision-making for physicians and patients in choosing the optimized treatment methods.

Phylotranscriptomics unveil a Paleoproterozoic-Mesoproterozoic origin and deep relationships of the Viridiplantae.

The Viridiplantae comprise two main clades, the Chlorophyta (including a diverse array of marine and freshwater green algae) and the Streptophyta (consisting of the freshwater charophytes and the land plants). Lineages sister to core Chlorophyta, informally refer to as prasinophytes, form a grade of mainly planktonic green algae. Recently, one of these lineages, Prasinodermophyta, which is previously grouped with prasinophytes, has been identified as the sister lineage to both Chlorophyta and Streptophyta. Resolving the deep relationships among green plants is crucial for understanding the historical impact of green algal diversity on marine ecology and geochemistry, but has been proven difficult given the ancient timing of the diversification events. Through extensive taxon and gene sampling, we conduct large-scale phylogenomic analyses to resolve deep relationships and reveal the Prasinodermophyta as the lineage sister to Chlorophyta, raising questions about the necessity of classifying the Prasinodermophyta as a distinct phylum. We unveil that incomplete lineage sorting is the main cause of discordance regarding the placement of Prasinodermophyta. Molecular dating analyses suggest that crown-group green plants and crown-group Prasinodermophyta date back to the Paleoproterozoic-Mesoproterozoic. Our study establishes a plausible link between oxygen levels in the Paleoproterozoic-Mesoproterozoic and the origin of Viridiplantae.

Irbesartan overcomes gemcitabine resistance in pancreatic cancer by suppressing stemness and iron metabolism via inhibition of the Hippo/YAP1/c-Jun axis.

BACKGROUND: Chemoresistance is the main reason for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Thus, there is an urgent need to screen out new targets and compounds to reverse chemotherapeutic resistance. METHODS: We established a bio-bank of human PDAC organoid models, covering a representative range of PDAC tumor subtypes. We screened a library of 1304 FDA-approved compounds to identify candidates efficiently overcoming chemotherapy resistance. The effects of the compounds were evaluated with a CellTiter-Glo-3D assay, organoid apoptosis assay and in vivo patient-derived xenograft (PDX), patient-derived organoid (PDO) and LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) genetically engineered mouse models. RNA-sequencing, genome editing, sphere formation assays, iron assays and luciferase assays were conducted to elucidate the mechanism. RESULTS: High-throughput drug screening of chemotherapy-resistant PDOs identified irbesartan, an angiotensin ‖ type 1 (AT1) receptor antagonist, which could synergistically enhance the ability of chemotherapy to kill PDAC cells. In vitro and in vivo validation using PDO, PDX and KPC mouse models showed that irbesartan efficiently sensitized PDAC tumors to chemotherapy. Mechanistically, we found that irbesartan decreased c-Jun expression by inhibiting the Hippo/YAP1 pathway and further overcame chemotherapy resistance in PDAC. We also explored c-Jun, a potential target of irbesartan, which can transcriptionally upregulate the expression of key genes involved in stemness maintenance (SOX9/SOX2/OCT4) and iron metabolism (FTH1/FTL/TFRC). More importantly, we observed that PDAC patients with high levels of c-Jun expression demonstrated poor responses to the current standard chemotherapy regimen (gemcitabine plus nab-paclitaxel). Moreover, patients with PDAC had significant survival benefits from treatment with irbesartan plus a standard chemotherapy regimen in two-center retrospective clinical cohorts and patients with high c-Jun expression exhibited a better response to combination chemotherapy. CONCLUSIONS: Irbesartan could be used in combination with chemotherapy to improve the therapeutic efficacy in PDAC patients with high levels of c-Jun expression. Irbesartan effectively inhibited chemotherapy resistance by suppressing the Hippo/YAP1/c-Jun/stemness/iron metabolism axis. Based on our findings, we are designing an investigator-initiated phase II clinical trial on the efficacy and safety of irbesartan plus a standard gemcitabine/nab-paclitaxel regimen in the treatment of patients with advanced III/IV staged PDAC and are hopeful that we will observe patient benefits.

Interaction in acting training and its different manifestations in novice and professional actors.

This study aimed to identify the characteristics of interactions during acting training and the underlying intrapersonal changes evoked by a training process that emphasizes paying attention to a partner (the Meisner technique). This was operationalized by conducting a post-hoc analysis and categorizing the utterances made by novice and professional actors during acting training based on video and audio recordings. In Study 1, novice participants tended to change their way of communication as the course progressed, decreasing the number of utterances that simply described the partner's behavior and increasing those that speculated about the partner's inner state. We then used a different focus placed on the interaction, as implied by the different kinds of utterances used, to describe the divergences between novice and professional actors regarding their interaction characteristics. In Study 2, results showed that while professional actors devoted themselves more to the connection with their partner and demonstrated more balanced communication, novice actors relied on general inference to speculate about others' affective states. By comparing the characteristics of the utterances between novice and professional actors as they played different roles or made switches (i.e., changing from passive to active utterance in communication), this study suggests that an important impact of acting training on social abilities relates to its potential to increase the levels of involvement in on-going interactions.

A Single-Center Retrospective Analysis of Local and Distant Relapse of Breast Cancer Following Immediate Breast Reconstruction According to Molecular Subtypes.

Purpose: Concerns have been raised about the oncologic safety of immediate breast reconstruction (IBR) following mastectomy for breast cancer. This study aimed to evaluate locoregional recurrence (LRR) and distant metastasis (DM) of breast cancer according to its molecular subtype in patients who underwent mastectomy alone or IBR after mastectomy. Methods: In this retrospective cohort study, consecutive breast cancer patients treated by the single senior surgeon (XZ) between February 2010 and December 2014 were eligible. In total, 389 consecutive patients were included; 295 patients underwent mastectomy alone and 94 patients underwent mastectomy with IBR. Data were retrospectively collected and analyzed for LRR and DM stratified by molecular subtypes. Results: With a median follow-up of 73 and 87.5 months, 1.69% of patients in the mastectomy alone group developed LRR compared to 0% in the reconstruction group (p = 0.342) and the total incidence of DMs was 11.52% in patients who received mastectomy alone and 7.44% in patients who received postmastectomy IBR (p = 0.262), respectively. The cumulative incidence of LRR was 2.1% vs. 0% for luminal A, 0% vs. 0% for luminal B, 0% vs. 0% for human epidermal growth factor receptor 2 (HER2)-enriched, and 4.5% vs. 0% for triple-negative in the mastectomy alone group compared to the postmastectomy IBR group. The cumulative incidence of DM was 15.5% vs. 5.7% for luminal A, 10% vs. 8.7% for luminal B, 17.3% vs. 0% for HER2-enriched, and 6.8% vs. 7.1% for triple-negative in the mastectomy alone group compared to the postmastectomy IBR group. On multivariable Cox regression analysis, lymph node metastasis was associated with an increased risk of DM in the mastectomy alone group (p = 0.03) and neoadjuvant chemotherapy was associated with an increased risk of DM in the postmastectomy IBR group (p = 0.021). Conclusion: This study suggests that IBR does not have a negative impact on the LRR and DM of breast cancer according to molecular subtypes.

Change in patent foramen ovale height is associated with cryptogenic stroke and the construction of a morphology-based scoring system.

Introduction: Current guidelines recommended patent foramen ovale (PFO) occlusion as the preferred treatment for PFO-related cryptogenic stroke (CS); however, finding the causative foramen ovale remains challenging. This study aimed to identify predictors and establish a scoring system by assessing PFO morphology and stroke-related factors. Methods: Based on a prospective multicenter registered clinical trial, we compared data mainly derived from transesophageal echocardiography (TEE) and clinical history in patients with PFO-related CS and those without CS (non-CS) with incidental PFO. Subsequently, we explored independent predictors using logistic analysis, established a scoring system based on the results, and finally evaluated the scoring system using receiver operating characteristic (ROC) analysis and internal validation. Results: 75 patients with PFO-related CS and 147 non-CS patients were enrolled. Multivariate logistic analysis showed that the change in PFO height, large PFO, atrial septal aneurysm (ASA), and sustained right-to-left shunt (RLS) had independent relationships with CS. Based on the odds ratio value of each independent factor, a scoring system was built: change in PFO height ≥ 1.85 mm (3 points), large PFO (2 points), ASA (5 points), sustained RLS (2 points). 0-2 points correspond to low-risk PFO, 3-5 points medium-risk PFO, and 7-12 points high-risk PFO. ROC analysis showed an area under the curve of 0.80 to predict CS. The proportion of patients with CS is increasing based on these points. Conclusions: Our study screened out the change in PFO height as an independent predictor of CS. A simple and convenient scoring system can provide constructive guidance for identifying whether the PFO is causal and consequently selecting patients more likely to benefit from closure.