Chemotherapy-induced PTEN-L secretion promotes the selection of PTEN-deficient tumor cells.

BACKGROUND: PTEN loss has been identified in various tumor types and is linked to unfavorable clinical outcomes. In addition to PTEN mutation, multiple mechanisms contribute to PTEN loss during tumor development. However, the natural selection process of PTEN-deficient tumor cells remains unclear. Here, we aimed at further elucidating the role of PTEN-L in tumor progression. METHODS: PTEN knockout cell lines were generated using CRISPR/Cas9 technology. Ni-NTA affinity column chromatography was employed for PTEN-L purification. Tumor cell metastasis was evaluated in murine models and observed using the IVIS Spectrum Imaging System. RNA-sequencing, western blotting, PCR, flow cytometry, and cell proliferation assays were employed to investigate tumor cell dormancy and related mechanisms. RESULTS: The chemotherapeutic drugs, cisplatin, paclitaxel, and doxorubicin, induced tumor cells to secrete PTEN-long (PTEN-L), which shields PTEN-deficient tumor cells from chemotherapy-induced apoptosis better than it shields PTEN-intact cells. Further investigation revealed that PTEN-L treatment induced dormancy in PTEN-null tumor cells, characterized by an increase in p16 and p27 levels, cell-cycle arrest, reduced cell proliferation, and enhanced DNA repair. Furthermore, PTEN-L treatment selectively promoted the accumulation and growth of PTEN-null tumor cells in the lungs of C57BL/6J mice, while evading immune surveillance. Mechanistically, PTEN-L induced dormancy in PTEN-null tumor cells by activating the p38 signaling pathway. Addition of a p38 inhibitor effectively reversed dormancy and growth of PTEN-deficient tumor cells in the lungs. We also demonstrated that PTEN expression played a pivotal role in determining the outcome of PTEN-L-mediated antitumor therapy. CONCLUSIONS: In summary, PTEN-L was identified as a potent inducer of dormancy in PTEN-deficient tumor cells, which increased their efficient selection within the tumor microenvironment.

Life regression based patch slimming for vision transformers.

Vision transformers have achieved remarkable success in computer vision tasks by using multi-head self-attention modules to capture long-range dependencies within images. However, the high inference computation cost poses a new challenge. Several methods have been proposed to address this problem, mainly by slimming patches. In the inference stage, these methods classify patches into two classes, one to keep and the other to discard in multiple layers. This approach results in additional computation at every layer where patches are discarded, which hinders inference acceleration. In this study, we tackle the patch slimming problem from a different perspective by proposing a life regression module that determines the lifespan of each image patch in one go. During inference, the patch is discarded once the current layer index exceeds its life. Our proposed method avoids additional computation and parameters in multiple layers to enhance inference speed while maintaining competitive performance. Additionally, our approach1 requires fewer training epochs than other patch slimming methods.

The impact of poverty alleviation policy on the industrial structure: Evidence from the Qinba Mountain contiguous poverty-stricken areas.

In 2015, the Chinese government issued the Decision on Poverty Alleviation(DPA), requiring poverty-stricken areas to develop local characteristic industries based on their resource endowments, to promote industrial structure diversification and industrial structure upgrading through industry-driven poverty alleviation. However, existing research lacks empirical analysis to evaluate it. Therefore, this paper takes poor counties in the Qinba Mountain contiguous poverty-stricken areas(QMCPA) as an example, using the difference in difference model and boundary effect model to evaluate whether DPA has promoted industrial structure upgrading and industrial structure diversification in poor counties. The results show that the DPA has promoted industrial structure upgrading and improved industrial structure diversification in the QMCPA. However, the effectiveness of it is not sufficient. Poor counties have failed to maintain the policy requirement of developing characteristic industries based on local natural resource endowments, leading to a decline in the degree of industrial structure diversification in the later period of the policy. This study indicates that local governments should strive to develop advantageous industries and form a division of labor and cooperation with neighboring areas, strengthen inter-regional cooperation and contact, and enhance anti-risk capabilities to avoid homogenized competition. Studying the changes in industrial structure in the QMCPA has important significance for the long-term stable development and poverty elimination of various poor areas.

Contemporary experience with the Commando procedure for anterior mitral anular calcification.

Objective: Anterior mitral anular calcification, particularly in radiation heart disease, and previous valve replacement with destroyed intervalvular fibrosa are challenging for prosthesis sizing and placement. The Commando procedure with intervalvular fibrosa reconstruction permits double-valve replacement in these challenging conditions. We referenced outcomes after Commando procedures to standard double-valve replacements. Methods: From January 2011 to January 2022, 129 Commando procedures and 1191 aortic and mitral double-valve replacements were performed at the Cleveland Clinic, excluding endocarditis. Reasons for the Commando were severe calcification after radiation (n = 67), without radiation (n = 43), and others (n = 19). Commando procedures were referenced to a subset of double-valve replacements using balancing-score methods (109 pairs). Results: Between balanced groups, Commando versus double-valve replacement had higher total calcium scores (median 6140 vs 2680 HU, P = .03). Hospital outcomes were similar, including operative mortality (12/11% vs 8/7.3%, P = .35) and reoperation for bleeding (9/8.3% vs 5/4.6%, P = .28). Survival and freedom from reoperation at 5 years were 54% versus 67% (P = .33) and 87% versus 100% (P = .04), respectively. Higher calcium score was associated with lower survival after double-valve replacement but not after the Commando. The Commando procedure had lower aortic valve mean gradients at 4 years (9.4 vs 11 mm Hg, P = .04). After Commando procedures for calcification, 5-year survival was 60% and 59% with and without radiation, respectively (P = .47). Conclusions: The Commando procedure with reconstruction of the intervalvular fibrosa destroyed by mitral anular calcification, radiation, or previous surgery demonstrates acceptable outcomes similar to standard double-valve replacement. More experience and long-term outcomes are required to refine patient selection for and application of the Commando approach.

Bio-inspired bimetallic models for electrochemical CO2 reduction.

Inspired by the carbon monoxide dehydrogenase (CODH) active site where two metal ions synergistically catalyze the interconversion between CO2 and CO, we have developed a family of rhenium dipyridine derivatives (1-3), in which potassium 1-aza-18-crown-6-ether (KN18C6) moiety functions as a Lewis acid to assist the CO2 reduction reaction (CO2RR). We found that such design leads to dramatically strong deposition on the electrode under CO2 in the presence of potassium cation, and a clear trend for the deposition rate was observed following the flexibility of linkage between the framework and the KN18C6 moiety; the more flexible, the faster. The origin of deposition was further characterized by a series of control experiments and infrared spectroelectrochemistry (IR-SEC). Unfortunately, the deposition suppresses the subsequent C-O bond cleavage reaction.

Prognostic and immunotherapeutic implications of bilirubin metabolism-associated genes in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a major subtype of non-small-cell lung cancer and accompanies high mortality rates. While the role of bilirubin metabolism in cancer is recognized, its specific impact on LUAD and patient response to immunotherapy needs to be elucidated. This study aimed to develop a prognostic signature of bilirubin metabolism-associated genes (BMAGs) to predict outcomes and efficacy of immunotherapy in LUAD. We analysed gene expression data from The Cancer Genome Atlas (TCGA) to identify survival-related BMAGs and construct a prognostic model in LUAD. The prognostic efficacy of our model was corroborated by employing TCGA-LUAD and five Gene Expression Omnibus datasets, effectively stratifying patients into risk-defined cohorts with marked disparities in survival. The BMAG signature was indeed an independent prognostic determinant, outperforming established clinical parameters. The low-risk group exhibited a more favourable response to immunotherapy, highlighted by increased immune checkpoint expression and immune cell infiltration. Further, somatic mutation profiling differentiated the molecular landscapes of the risk categories. Our screening further identified potential drug candidates preferentially targeting the high-risk group. Our analysis of critical BMAGs showed the tumour-suppressive role of FBP1, highlighting its suppression in LUAD and its inhibitory effects on tumour proliferation, migration and invasion, in addition to its involvement in cell cycle and apoptosis regulation. These findings introduce a potent BMAG-based prognostic indicator and offer valuable insights for prognostication and tailored immunotherapy in LUAD.

Understanding the Relationship Between Vascular Smooth Muscle Cell Function and the Efficacy of Acupuncture in Treating Cerebral Ischemic Stroke: A Preclinical Meta-Analysis and Systematic Review.

Background: Cerebral blood flow and vascular structures serve as the fundamental components of brain metabolism and circulation. Acupuncture, an alternative and complementary medical approach, has demonstrated efficacy in treating cerebral ischemic stroke (CIS). Nevertheless, the mechanisms underlying the impact of acupuncture on vascular smooth muscle cell (VSMC) function remain uncertain. The objective of this systematic review and meta-analysis is to assess the alterations in VSMC function following acupuncture stimulation in CIS models. Methods: The databases PubMed, Web of Science, SCOPUS, and EMBASE were queried until November 2022 using a predetermined search strategy. The FORMAT BY SYRCLE guidelines were adhered to, and the risk of bias of the included studies was evaluated using the Risk of Bias tool developed by the Systematic Review Centre for Laboratory Animal Experimentation. The random-effects model was employed to estimate the standardized mean difference (SMD). Results: Eighteen articles are included in this review. Acupuncture showed significant positive effects on the region cerebral blood flow (SMD=8.15 [95% CI, 4.52 to 11.78]) and neurological deficiency (SMD=-3.75 [95% CI, -5.54 to -1.97]). Descriptive analysis showed a probable mechanism of acupuncture stimulation in CIS rats related to VSMC function. Limitations and publication bias were presented in the studies. Conclusion: In this systematic review and meta-analysis, our findings indicate that acupuncture stimulation has the potential to improve regional cerebral blood flow and alleviate neurological deficits, possibly by regulating VSMC function. However, it is important to exercise caution when interpreting these results due to the limitations of animal experimental design and methodological quality.

[Modified QuEChERS method combined with ultra performance liquid chromatography-tandem mass spectrometry for detection of cyclopiazonic acid in feeds].

Mycotoxins are toxic secondary metabolites produced by fungal species that can cause acute, subacute, and chronic toxicity in humans and animals. Thus, these toxins pose a significant threat to health and safety. Owing to the lack of effective antimold measures in the agricultural industry, feed ingredients such as corn, peanuts, wheat, barley, millet, nuts, oily feed, forage, and their byproducts are prone to mold and mycotoxin contamination, which can affect animal production, product quality, and safety. Cyclopiazonic acid (CPA), which is mainly biosynthesized from mevalonate, tryptophan, and diacetate units, is a myotoxic secondary metabolite produced by Penicillium and Aspergillus fungi. CPA is widely present as a copollutant with aflatoxins in various crops. Compared with some common mycotoxins such as aflatoxins, fumonisins, ochratoxins, zearalenones, and their metabolites, CPA has not been well investigated. In the United States, a survey showed that 51% of corn and 90% of peanut samples contained CPA, with a maximum level of 2.9 mg/kg. In Europe, CPA was found in Penicillium-contaminated cheeses as high as 4.0 mg/kg. Some studies have shown that CPA can cause irreversible damage to organs such as the liver and spleen in mice. Therefore, the establishment of a rapid and efficient analytical method for CPA is of great significance for the risk assessment of CPA in feeds, the development of standard limits, and the protection of feed product quality and safety. The QuEChERS method, a sample pretreatment method that is fast, simple, cheap, effective, and safe, is widely used in the analysis of pesticide residues in food. In this study, a modified QuEChERS method combined with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to determine CPA levels in feeds. The chromatographic separation and MS detection of CPA as well as the key factors affecting the extraction efficiency of CPA, including the type of extraction solvent, type of inorganic salt, and type and dosage of adsorbent, were optimized in detail. During the optimization of the chromatographic-separation step, the acid and salt concentrations of the mobile phase affected the separation and detection of CPA. During the optimization of the QuEChERS method, the addition of a certain amount of acetic acid improved the extraction efficiency of CPA because of its acidic nature; in addition, GCB and PSA significantly adsorbed CPA from the feed extract. Under optimal conditions, the CPA in the feed sample (1.0 g) was extracted with 2 mL of water and 4 mL of acetonitrile (ACN) containing 0.5% acetic acid. After salting out with 0.4 g of NaCl and 1.6 g of MgSO4, 1 mL of the ACN supernatant was purified by dispersive solid-phase extraction using 150 mg of MgSO4 and 50 mg of C18 and analyzed by UPLC-MS/MS. The sample was separated on a Waters HSS T3 column (100 mm×2.1 mm, 1.8 µm) using 2 mmol/L ammonium acetate aqueous solution with 0.5% formic acid and ACN as the mobile phases and then analyzed by positive electrospray ionization in multiple reaction monitoring mode. CPA exhibited good linearity in the range of 2-200 ng/mL, with a high correlation coefficient (r=0.9995). The limits of detection and quantification of CPA, which were calculated as 3 and 10 times the signal-to-noise ratio, respectively, were 0.6 and 2.0 µg/kg, respectively. The average recoveries in feed samples spiked with 10, 100, and 500 µg/kg CPA ranged from 70.1% to 78.5%, with an intra-day precision of less than 5.8% and an inter-day precision of less than 7.2%, indicating the good accuracy and precision of the proposed method. Finally, the modified QuEChERS-UPLC-MS/MS method was applied to the analysis of CPA in 10 feed samples obtained from Wuhan market. The analysis results indicated that the developed method has good applicability for CPA analysis in feed samples. In summary, an improved QuEChERS method was applied to the extraction and purification of CPA from feeds for the first time; this method provides a suitable analytical method for the risk monitoring, assessment, and standard-limit setting of CPA in feed samples.

The application of deep learning in abdominal trauma diagnosis by CT imaging.

BACKGROUND: Abdominal computed tomography (CT) scan is a crucial imaging modality for creating cross-sectional images of the abdominal area, particularly in cases of abdominal trauma, which is commonly encountered in traumatic injuries. However, interpreting CT images is a challenge, especially in emergency. Therefore, we developed a novel deep learning algorithm-based detection method for the initial screening of abdominal internal organ injuries. METHODS: We utilized a dataset provided by the Kaggle competition, comprising 3,147 patients, of which 855 were diagnosed with abdominal trauma, accounting for 27.16% of the total patient population. Following image data pre-processing, we employed a 2D semantic segmentation model to segment the images and constructed a 2.5D classification model to assess the probability of injury for each organ. Subsequently, we evaluated the algorithm's performance using 5k-fold cross-validation. RESULTS: With particularly noteworthy performance in detecting renal injury on abdominal CT scans, we achieved an acceptable accuracy of 0.932 (with a positive predictive value (PPV) of 0.888, negative predictive value (NPV) of 0.943, sensitivity of 0.887, and specificity of 0.944). Furthermore, the accuracy for liver injury detection was 0.873 (with PPV of 0.789, NPV of 0.895, sensitivity of 0.789, and specificity of 0.895), while for spleen injury, it was 0.771 (with PPV of 0.630, NPV of 0.814, sensitivity of 0.626, and specificity of 0.816). CONCLUSIONS: The deep learning model demonstrated the capability to identify multiple organ injuries simultaneously on CT scans and holds potential for application in preliminary screening and adjunctive diagnosis of trauma cases beyond abdominal injuries.

Causal association between autoimmune liver disease and Sjögren's syndrome: A Mendelian randomization study.

BACKGROUND: Observational studies have found an association between autoimmune liver disease (AILD) and Sjögren's syndrome (SS). However, the causal relationship between the two remains unknown. Clinical guidelines indicate that the coexistence of AILD with other autoimmune diseases may impact prognosis and quality of life; hence, early recognition and management of extrahepatic autoimmune diseases is particularly crucial. Against this backdrop, this study aimed to utilize Mendelian randomization (MR) methods to investigate the potential causal relationship between AILD and SS. METHODS: We extracted summary statistics on AILD and SS from publicly available genome-wide association studies (GWAS) databases to identify appropriate instrumental variables (IVs). The inverse-variance weighted (IVW) method was utilized as the primary approach, with the weighted median (WM) method and MR-Egger method employed as supplementary methods to evaluate the potential causal relationship between the two conditions. Sensitivity analyses, including Cochran's Q test, MR-polynomial residuals and outliers (MR-PRESSO), MR-Egger intercept test, and the leave-one-out test, were performed to assess the stability of the results. RESULTS: The MR study results indicate a significant causal relationship between PBC and PSC with the risk of SS in the European population (IVW: odds ratio [OR] = 1.155, 95% confidence interval [CI]: 1.092-1.222, p < .001; IVW: OR = 1.162, 95% CI: 1.051-1.284, p = .003). A series of sensitivity analyses have confirmed the reliability of the results. CONCLUSIONS: Our study indicates that the presence of both PBC and PSC increases the susceptibility to SS. However, no reliable causal relationship was found between SS and the risk of PBC or PSC. These findings contribute to elucidating the potential pathogenic mechanisms of the disease and are of significant importance for the management of patients with PBC and PSC.

Molecular phylogenetic analysis of the East Asian hemicultrine fishes (Teleostei: Cyprinidae: Xenocypridinae), with suggestions to their generic classification and redescription of the recently described species Hemiculter yungaoi Vasil'eva et al. 2022.

The hemicultrine fishes are a group of small-sized cyprinids, widely distributed but endemic to East Asian rivers and lakes. Till now, the taxonomic boundaries and relationships within this group remain poorly explored. In the present study, we study the phylogeny of this group, providing suggestions for classification of the hemicultrine group. Using two mitochondrial and three nuclear genes, and samples representing all genera, our results showed that the group consists of seven major lineages, of which four (Hemiculterella, Hainania, Pseudolaubuca, and Anabarilius) were monophyletic and three (Hemiculter, Toxabramis, and Pseudohemiculter) were not. Based on the phylogenetic tree, we redefined the genera. We revive the genus Siniichthys, which has three species, Siniichthys bleekeri, Siniichthys lucidus, and S. varpachovskii, that were previously treated as members of the genus Hemiculter but showed distant relationships to the genus Hemiculter in our phylogenetic tree. With the new results, a diagnostic key for clades of the hemicultrine group is provided. Furthermore, we provide more detailed information on diagnostic features of the recently described species Hemiculter yungaoi (Vasil'eva et al., 2022). This work will facilitate future systematic studies, pave the way for evolutionary studies, and provide valuable information for the urgent conservation of hemicultrine fishes.

Cordycepin enhances anti-tumor immunity in breast cancer by enhanceing ALB expression.

Objective: The treatment of breast cancer still faces great challenges, and it is necessary to continuously explore effective drugs and targets to promote immune precision medicine. This study aims to investigate the immune-related regulatory mechanism of cordycepin in breast cancer. Methods: Network pharmacology was employed to discovery the action of cordyceps on breast cancer targets, molecular docking was employed to analyze the interaction pattern between core components and targets, and biological information analysis was used to explore the target-related immune mechanism and verified in vitro experiments. Results: The results of this study indicate that cordycepin can effectively inhibit breast cancer. The roles of cordycepin's active component and its target gene ALB were elucidated through the combined use of network pharmacology and molecular docking. Bioinformatics analysis revealed convincing associations between ALB and many immune pathway marker genes. ALB was inhibited in tumor expression, and cordycepin was found to enhance the expression of ALB in vitro to play an anti-tumor role. Conclusion: Cordycepin regulates immune suppression of tumor, which is expected to open a new chapter of breast cancer immunotherapy.

Deciphering Charge Transfer Processes in Transition Metal Complexes from the Perspective of Ultrafast Electronic and Nuclear Motions.

Chemical transformations in charge transfer states result from the interplay between electronic dynamics and nuclear reorganization along excited-state trajectories. Here, we investigate the ultrafast structural dynamics following photoinduced electron transfer from the metal-metal-to-ligand charge transfer state of an electron donor, a Pt dimer complex, to a covalently linked electron acceptor group using ultrafast time-resolved wide-angle X-ray scattering and optical transient absorption spectroscopy methods to disentangle the interdependence of the excited-state electronic and nuclear dynamics. Following photoexcitation, Pt-Pt bond formation and contraction takes up to 1 ps, much slower than the corresponding process in analogous complexes without electron acceptor groups. Because the Pt-Pt distance change is slow with respect to excited-state electron transfer, it can affect the rate of electron transfer. These results have potential impacts on controlling electron transfer rates via structural alterations to the electron donor group, tuning the charge transfer driving force.

A Multifunctional Nanoreactor-Induced Dual Inhibition of HSP70 Strategy for Enhancing Mild Photothermal/Chemodynamic Synergistic Tumor Therapy.

Mild photothermal therapy (PTT) is a spatiotemporally controllable method that utilizes the photothermal effect at relatively low temperatures (40-45 °C) to especially eliminate tumor tissues with negligible side effects on the surrounding normal tissues. However, the overexpression of heat shock protein 70 (HSP70) and limited effect of single treatment drastically impeded the therapeutic efficacy. Herein, the constructed multifunctional core-shell structured Ag-Cu@SiO2-PDA/GOx nanoreactors (APG NRs) that provide a dual inhibition of HSP70 strategy for the second near-infrared photoacoustic (NIR-II PA) imaging-guided combined mild PTT/chemodynamic therapy (CDT). The Ag-Cu cores can convert endogenous H2O2 to hydroxyl radical (•OH), which could induce lipid peroxidation (LPO) and further degrade HSP70. The polydopamine (PDA)/glucose oxidase (GOx) shells were utilized as the NIR-II photothermal agent to generate low temperature, and the GOx could reduce the energy supplies and inhibit energy-dependent HSP70 expression. Furthermore, both the generation of •OH and GOx-mediated energy shortage can reduce HSP70 expression to sensitize mild PTT under 1064 nm laser, and in turn, GOx and laser self-amplify the catalytic reactions of APG NRs for more production of •OH. The multifunctional nanoreactors will provide more potential possibilities for the clinical employment of mild PTT and the advancement of tumor combination therapies. This article is protected by copyright. All rights reserved.

Involvement of E3 ubiquitin ligase NEDD4-mediated YY1 ubiquitination in alleviating idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and lethal lung disease characterized by progressive lung scarring. This study aims to elucidate the role of the E3 ubiquitin ligase NEDD4 in the ubiquitination of YY1 and its subsequent impact on TAB1 transcription, revealing a possible molecular mechanism in the development of IPF. Through bioinformatics analysis and both in vitro and in vivo experiments, we observed differential expression levels of NEDD4 and YY1 between normal and IPF samples, identifying NEDD4 as an upstream E3 ubiquitin ligase of YY1. Furthermore, binding sites for the transcription factor YY1 on the promoter region of TAB1 were discovered, indicating a direct interaction. In vitro experiments using HEPF cells showed that NEDD4 mediates the ubiquitination and degradation of YY1, leading to suppressed TAB1 transcription, thereby inhibiting cell proliferation and fibrogenesis. These findings were corroborated by in vivo experiments in an IPF mouse model, where the ubiquitination pathway facilitated by NEDD4 attenuated IPF progression through the downregulation of YY1 and TAB1 transcription. These results suggest that NEDD4 plays a crucial role in the development of IPF by modulating YY1 ubiquitination and TAB1 transcription, providing new insights into potential therapeutic targets for treating IPF.

Norditerpenoid alkaloids from Aconitum refractum var. circinatum as autophagy inducers.

A total of twenty-two diterpenoid alkaloids, including ten unprecedented ones, namely refractines C-L, were isolated from the roots of Aconitum refractum (Finet et Gagnep.) Hand.-Mazz. Refractine C was the first example of a natural diterpenoid alkaloid wherein C-19 is linked to N position by an oxaziridine ring. Refractine L was a rare glycosidic diterpenoid alkaloid with fructofuranoside. Most of the isolated compounds obtained from a previous study were screened for their anti-inflammatory and myocardial protective activities. The autophagy-inducing effects of some of these compounds on RAW 264.7 cells were evaluated by assessing the expression of microtubule-associated protein 1 light chain 3 (LC3-II/LC3-I). Results revealed that some compounds exerted varying levels of inhibitory effects on the proliferative activity of RAW 264.7 cells.

Hot Cordilleran hinterland promoted lower crust mobility and decoupling of Laramide deformation.

The Late Cretaceous to Paleogene Laramide orogen in the North American Cordillera involved deformation >1,000 km from the plate margin that has been attributed to either plate-boundary end loading or basal traction exerted on the upper plate from the subducted Farallon flat slab. Prevailing tectonic models fail to explain the relative absence of Laramide-aged (ca. 90-60 Ma) contractional deformation within the Cordillera hinterland. Based on Raman spectroscopy of carbonaceous material thermometry and literature data from the restored upper 15-20 km of the Cordilleran crust we reconstruct the Late Cretaceous thermal architecture of the hinterland. Interpolation of compiled temperature data (n = 200) through a vertical crustal column reveals that the hinterland experienced a continuous but regionally elevated, upper-crustal geothermal gradient of >40 °C/km during Laramide orogenesis, consistent with peak metamorphic conditions and synchronous peraluminous granitic plutonism. The hot and partially melted hinterland promoted lower crust mobility and crust-mantle decoupling during flat-slab traction.

Competing risk nomogram predicting cause-specific mortality in older patients with testicular germ cell tumors.

Background: Testicular germ cell tumor (TGCT) is the most common type of malignancy in young men, but rarely in older adults. We aimed to construct a competing risk model to predict the prognosis for older patients with TGCT. Methods: We collected TGCT patients aged 50 years or older diagnosed between 2004 and 2015 from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. We estimated the cumulative incidences of cause-specific death (CSD) and other causes of death and established a nomogram predicting cause-specific mortality in older patients with TGCT by Fine-Gray competing risk regression. The concordance index (C-index), calibration curves, area under the receiver operating characteristic curve (AUC), and decision analysis curves (DCA) were used to evaluate the differentiation, accuracy, and clinical significance of the nomogram. Results: A total of 2,751 older TGCT patients were included in the study. The 3-, 5-, and 10-year cumulative incidences were 4.4, 5.0 and 6.1%, respectively, for cause-specific death, and 3.8, 6.2, 13.1%, respectively, for other causes of death. Predictors of cause-specific mortality in older TGCT included age, marital status, annual household income, histology, tumor size, stage and surgery. In the training and validation sets, the C-indexes were greater than 0.8, indicating that the nomogram had good discrimination. The AUC revealed the same result. The calibration curves showed good agreement between the predicted and observed results of the nomogram. DCA curves indicated that the nomogram had more clinical significance than the conventional American Joint Committee on Cancer (AJCC) staging. Based on the total nomogram score of each case, all patients were categorized into low-risk and high-risk groups, and risk categorization allowed the identification of cases with a high risk of death. Conclusion: We established a competing risk nomogram with good performance that may help clinicians accurately predict the prognosis of older TGCT patients.

Identifying optimal surgical approach among T1N2-3M0 non-small cell lung cancer patients: a population-based analysis.

Background: Whether stage T1N2-3M0 non-small cell lung cancer (NSCLC) patients could benefit from surgery and the optimal surgical procedure have remained controversial and unclear. This study aimed to investigate whether stage T1N2-3M0 NSCLC can benefit from different surgery types and develop a tool for survival prediction. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients diagnosed with stage T1N2-3M0 NSCLC between 2000 and 2015. A 1:1 propensity score-matched (PSM) analysis was used to balance the distribution of clinical characteristics. Survival analyses were performed by using the Kaplan-Meier (KM) curves and Cox proportional hazards regression. All patients were randomly split at a ratio of 7:3 into training and validation cohorts. The nomogram was constructed by integrating all independent predictors for overall survival (OS) and cancer-specific survival (CSS). The model's performance was evaluated by discrimination, calibration ability, and risk stratification ability. Results: A total of 4,671 patients were enrolled. After 1:1 PSM, the distribution proportions of clinical characteristics in 1,146 patients were balanced (all P>0.05). The non-surgical approach was associated with worse survival compared with sublobectomy and lobectomy in the unmatched and matched cohorts. The multivariate Cox analysis showed that sublobectomy and lobectomy were both related to better OS and CSS rates compared with no surgery (P<0.001). Moreover, the results of subgroup analyses based on age, N stage, and radiotherapy or chemotherapy strategy were consistent. A total of 801 patients were included in the training cohort and 345 cases constituted the validation cohort. The nomogram constructed for the 1-, 3-, and 5-year OS and CSS prediction showed good discrimination, performance, and calibration both in the training and validation sets. Significant distinctions in survival curves between different risk groups stratified by prognostic scores were also observed (all P<0.001). Conclusions: Stage T1N2-3M0 NSCLC patients could benefit from sublobectomy or lobectomy, and lobectomy provides better survival benefits. We developed and validated nomograms, which could offer clinicians instructions for strategy making.

CaWRKY01-10 and CaWRKY08-4 Confer Pepper's Resistance to Phytophthora capsici Infection by Directly Activating a Cluster of Defense-Related Genes.

Phytophthora blight of pepper, which is caused by the notorious oomycete pathogen Phytophthora capsici, is a serious disease in global pepper production regions. Our previous study had identified two WRKY transcription factors (TFs), CaWRKY01-10 and CaWRKY08-4, which are prominent modulators in the resistant pepper line CM334 against P. capsici infection. However, their functional mechanisms and underlying signaling networks remain unknown. Herein, we determined that CaWRKY01-10 and CaWRKY08-4 are localized in plant nuclei. Transient overexpression assays indicated that both CaWRKY01-10 and CaWRKY08-4 act as positive regulators in pepper resistance to P. capsici. Besides, the stable overexpression of CaWRKY01-10 and CaWRKY08-4 in transgenic Nicotiana benthamiana plants also significantly enhanced the resistance to P. capsici. Using comprehensive approaches including RNA-seq, CUT&RUN-qPCR, and dual-luciferase reporter assays, we revealed that overexpression of CaWRKY01-10 and CaWRKY08-4 can activate the expressions of the same four Capsicum annuum defense-related genes (one PR1, two PR4, and one pathogen-related gene) by directly binding to their promoters. However, we did not observe protein-protein interactions and transcriptional amplification/inhibition effects of their shared target genes when coexpressing these two WRKY TFs. In conclusion, these data suggest that both of the resistant line specific upregulated WRKY TFs (CaWRKY01-10 and CaWRKY08-4) can confer pepper's resistance to P. capsici infection by directly activating a cluster of defense-related genes and are potentially useful for genetic improvement against Phytophthora blight of pepper and other crops.