Gamma-glutamyl transferase 5 overexpression in cerebrovascular endothelial cells improves brain pathology, cognition, and behavior in APP/PS1 mice.

JOURNAL/nrgr/04.03/01300535-202502000-00030/figure1/v/2024-05-28T214302Z/r/image-tiff In patients with Alzheimer's disease, gamma-glutamyl transferase 5 (GGT5) expression has been observed to be downregulated in cerebrovascular endothelial cells. However, the functional role of GGT5 in the development of Alzheimer's disease remains unclear. This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer's disease, as well as the underlying mechanism. We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer's disease (Aß1-42-treated hCMEC/D3 and bEnd.3 cells), as well as in the APP/PS1 mouse model. Additionally, injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits. Interestingly, increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-ß in the brains of APP/PS1 mice. This effect may be attributable to inhibition of the expression of ß-site APP cleaving enzyme 1, which is mediated by nuclear factor-kappa B. Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer's disease pathogenesis, and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice. These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer's disease.

[Prenatal diagnosis of a fetus with Rubinstein-Taybi syndrome].

OBJECTIVE: To explore the clinical characteristics and variant of CREBBP gene in a fetus with Rubinstein-Taybi syndrome (RSTS). METHODS: A fetus with RSTS diagnosed at the Third Affiliated Hospital of Zhengzhou University in August 2022 was selected as the study subject. Clinical data, amniotic fluid sample of the fetus and peripheral blood samples of its parents were collected for whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: Foot malformation, cerebellar vermis agenesis, brain agenesis, polysyndactyly of the big toes and other phenotypes were found by prenatal ultrasound. WES revealed that the fetus has harbored a heterozygous c.4684G>T (p.E1562*) variant in exon 28 of the CREBBP gene (NM_004380.3), which was de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic (PVS1+PS2_Moderate+PM2_Supporting). After genetic counseling, the couple had opted to terminate the pregnancy and refused autopsy of the fetus. CONCLUSION: The c.4684G>T (p.E1562*) variant of the CREBBP gene probably underlay the RSTS in this fetus. The newly discovered variant has enriched the mutational spectrum of the CREBBP gene and illustrated that WES is an efficient tool for the prenatal diagnosis of RSTS.

Homocysteine levels are associated with diabetes mellitus in Chinese with H-type hypertension.

BACKGROUND/OBJECTIVES: The study examined the association between homocysteine and diabetes mellitus in patients with H-type hypertension and assessed the possible effect modifiers. SUBJECTS/METHODS: This cross-sectional study included 1,255 eligible participants in the 'H-type Hypertension Management and Stroke Prevention Strategic International Science and Technology Innovation Cooperation Project' among rural Chinese people with H-type hypertension. A multivariate logistic regression model was used to evaluate the relationship between homocysteine and diabetes mellitus. RESULTS: The mean level of total homocysteine (tHcy) in the diabetes mellitus population was 19.37 µmol/L, which was significantly higher than the non-diabetic patients (18.18 µmol/L). When tHcy was analyzed as a continuous variable, the odds ratio (OR) of diabetes was 1.17 (95% confidence interval [CI], 1.01-1.35; per interquartile range). When tHcy was stratified according to the quintile, the ORs for diabetes were 2.86 (95% CI, 1.22-6.69) in the highest quintile (tHcy ≥ 20.60 µmol/L) compared to the reference group (tHcy < 12.04 µmol/L). When tHcy was grouped by 15 µmol/L and 20 µmol/L, patients with tHcy ≥ 20 µmol/L had a significantly (P = 0.037) higher risk of diabetes (OR, 2.03; 95% CI, 1.04-3.96) than in those with tHcy < 15 µmol/L. Subgroup analysis showed that the tHcy-diabetes association was unaffected by other variables. CONCLUSION: In this study of rural Chinese people with H-type hypertension, the tHcy levels showed a positive association with diabetes mellitus. This independent association is unaffected by other potential risk factors.

PDCL3 as a prognostic factor and associated with the VEGF signaling pathway in glioma.

BACKGROUND: New targeted drugs about angiogenesis could develop the treatment of glioma. We aimed to explore the role of phosducin like 3 (PDCL3) in angiogenesis of glioma. MATERIALS AND METHODS: RNA sequencing data and matched clinical data were downloaded from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. To screen for the reliable genes with the filtering analyses, survival, multivariate Cox, receiver operating characteristic (ROC) curve filtration, and clinical correlation analyses were performed. The PDCL3 gene was validated by immunohistochemistry as a reliable gene for further analysis. Then we used the combined data of TCGA and Genotype-Tissue Expression from UCSC to detect the differential gene expression of PDCL3. Related signal pathways in glioma were explored by the gene set enrichment analysis and co-expression analysis. Lastly, we performed in vitro experiments to verify the gene functions and related mechanisms. RESULTS: The three filtering analyses and immunostaining indicated that the expression of PDCL3 in glioma tissues was higher than the normal tissues. Gene function analysis showed that PDCL3 activated the vascular endothelial growth factor (VEGF) signal pathway, and its mechanism was related to pathways in cancer, like NOD like receptor signaling pathway, the RIG-I like receptor signaling pathway and the P53 signaling pathway by MAPK/AKT in gliomas. This suggested that the proliferation, migration and invasion of glioma cells might be inhibited by the downregulation of PDCL3 in vitro, which may be related to the activation of VEGF signaling pathway. CONCLUSION: We demonstrated that PDCL3 could function as an independent adverse prognostic marker in glioma. Its pro-oncogenic mechanism may be related to the VEGF signaling pathway.

A multi-mode stretching apparatus for in situ synchrotron x-ray scattering of polymer materials.

A compact and versatile tensile apparatus for polymer materials is designed and fabricated. Three distinct stretching modes are developed: constant speed, cyclic, and sinusoidal, with adjustable speeds ranging from 0.001 to 120 mm/s. To capture the true strain of the central region, a high-speed camera has been integrated into the apparatus. The temperature of the sample chamber is controlled by flowing air, enabling a homogeneous temperature in the range of RT ∼200 °C. The apparatus is particularly suitable for a synchrotron beamline. The structural evolution of natural rubber during sinusoidal stretching is investigated by in situ wide-angle x-ray scattering. Scattering patterns, force, clamp position, and sample images are saved simultaneously during stretching. Notably, the results reveal a sinusoidal variation in the crystallinity of crosslinked natural rubber when a sinusoidal strain was applied to the sample. The integration of advanced measurement techniques and controlled experimental conditions ensures the acquisition of reliable and accurate data, providing valuable insights into the structural evolution of materials under dynamic deformation conditions.

Saikosaponin-d mediates FOXG1 to reverse docetaxel resistance in prostate cancer through oxidative phosphorylation.

BACKGROUND: Prostate cancer (PCa), a prevalent malignancy worldwide, is frequently identified in advanced stages due to the absence of distinctive early symptoms, thereby culminating in the development of chemotherapy-induced drug resistance. Exploring novel resistance mechanisms and identifying new therapeutic agents can facilitate the advancement of more efficacious strategies for PCa treatment. METHODS: Bioinformatics analysis was employed to investigate the expression of FOXG1 in PCa tissues. Subsequently, qRT-PCR was utilized to validate FOXG1 mRNA expression levels in corresponding PCa cell lines. FOXG1 knockdown was performed, and cell proliferation was assessed using CCK-8 assays, while cell migration and invasion capabilities were evaluated through wound healing and Transwell assays. Western blot and Seahorse analyzer were used to measure oxidative phosphorylation (OXPHOS) levels. Additionally, to explore potential approaches to alleviate PCa drug resistance, this study assessed the impact of biologically active saikosaponin-d (SSd) on PCa malignant progression and resistance by regulating FOXG1 expression. RESULTS: FOXG1 exhibited high expression in PCa tissues and cell lines. Knockdown of FOXG1 inhibited the proliferation, migration, and invasion of PCa cells, while FOXG1 overexpression had the opposite effect and promoted OXPHOS levels. The addition of an OXPHOS inhibitor prevented this outcome. Finally, SSd was shown to suppress FOXG1 expression and reverse docetaxel resistance in PCa cells through the OXPHOS pathway. CONCLUSION: This work demonstrated that SSd mediated FOXG1 to reverse malignant progression and docetaxel resistance in PCa through OXPHOS.

Preserving mitochondrial homeostasis protects against drug-induced liver injury via inducing OPTN (optineurin)-dependent Mitophagy.

Disruption of mitochondrial function is observed in multiple drug-induced liver injuries (DILIs), a significant global health threat. However, how the mitochondrial dysfunction occurs and whether maintain mitochondrial homeostasis is beneficial for DILIs remains unclear. Here, we show that defective mitophagy by OPTN (optineurin) ablation causes disrupted mitochondrial homeostasis and aggravates hepatocytes necrosis in DILIs, while OPTN overexpression protects against DILI depending on its mitophagic function. Notably, mass spectrometry analysis identifies a new mitochondrial substrate, GCDH (glutaryl-CoA dehydrogenase), which can be selectively recruited by OPTN for mitophagic degradation, and a new cofactor, VCP (valosin containing protein) that interacts with OPTN to stabilize BECN1 during phagophore assembly, thus boosting OPTN-mediated mitophagy initiation to clear damaged mitochondria and preserve mitochondrial homeostasis in DILIs. Then, the accumulation of OPTN in different DILIs is further validated with a protective effect, and pyridoxine is screened and established to alleviate DILIs by inducing OPTN-mediated mitophagy. Collectively, our findings uncover a dual role of OPTN in mitophagy initiation and implicate the preservation of mitochondrial homeostasis via inducing OPTN-mediated mitophagy as a potential therapeutic approach for DILIs.Abbreviation: AILI: acetaminophen-induced liver injury; ALS: amyotrophic lateral sclerosis; APAP: acetaminophen; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DILI: drug-induced liver injury; FL: full length; GCDH: glutaryl-CoA dehydrogenase; GOT1/AST: glutamic-oxaloacetic transaminase 1; GO: gene ontology; GSEA: gene set enrichment analysis; GPT/ALT: glutamic - pyruvic transaminase; INH: isoniazid; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MMP: mitochondrial membrane potential; MST: microscale thermophoresis; MT-CO2/COX-II: mitochondrially encoded cytochrome c oxidase II; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; TSN: toosendanin; VCP: valosin containing protein, WIPI2: WD repeat domain, phosphoinositide interacting 2.

Inhibition of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptors Ameliorates Atrial Inflammation and Vulnerability to Atrial Fibrillation in Rats with Anxiety Disorders.

ABSTRACT: Previous studies have found that anxiety disorders may increase the incidence of atrial fibrillation (AF). More and more studies have shown that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are involved in the occurrence and development of cardiovascular diseases. However, the role of AMPARs in AF associated with anxiety disorder remains unclear. The aim of this study was to investigate the effect of AMPARs on AF susceptibility in rats with anxiety disorder and its possible mechanism. The anxiety disorder rat model was established by unpredictable empty bottle stimulation and was treated with AMPARs agonist and antagonist. Our results showed that AMPARs antagonist treatment significantly reduced sympathetic activity, improved heart rate variability, shortened action potential duration, prolonged effective refractory period, reduced AF induction rate, and improved cardiac electrical remodeling and the expression of inflammatory factors. In addition, inhibition of AMPARs reduced the phosphorylation of IκBα and p65. Our experimental results suggest that inhibition of AMPARs can reduce autonomic remodeling, improve atrial electrical remodeling, and suppress myocardial inflammation, which provides a potential therapeutic strategy for the treatment of AF associated with anxiety disorder.

Causal link between docosahexaenoic acid and osteoporosis: A 2-sample Mendelian randomization study.

To explore the causal relationship between docosahexaenoic acid and osteoporosis. Possible causal links were investigated using a 2-sample Mendelian randomization study. Its genetic correlation was estimated using chained disequilibrium regression. Sensitivity tests were also performed. There was a causal association between docosahexaenoic acid and osteoporosis, and docosahexaenoic acid was a risk factor for osteoporosis (P = .033, odds ratio [95% CI] = 1.099 [1.008-1.198]). For every 1 standard deviation increase in docosahexaenoic acid lev, the risk of developing osteoporosis increased by 9.900%. The genetic correlation between docosahexaenoic acid (h2_Z = 5.260, P = 1.430e-7), osteoporosis (h2_Z = 8.780, P = 1.160e-98), and genes was significant, but there was a weak genetic correlation between docosahexaenoic acid and osteoporosis (rg = -0.040, P = 1.630e-18). Blood levels of docosahexaenoic acid are causally linked to osteoporosis and are a risk factor for osteoporosis. However, this causal link is not brought about by genetic variation. The exact mechanism needs to be explored further.

CBX2 enhances the progression and TMZ chemoresistance of glioma via EZH2-mediated epigenetic silencing of PTEN expression.

Chromobox (CBX) 2, a member of the CBX protein family and a crucial component of the polycomb repressive complex (PRC), exerts significant influence on the epigenetic regulation of tumorigenesis, including glioma. However, the precise role of CBX2 in glioma has remained elusive. In our study, we observed a substantial upregulation of CBX2 expression in glioma, which displayed a strong correlation with pathological grade, chemoresistance, and unfavorable prognosis. Through a series of in vivo and in vitro experiments, we established that heightened CBX2 expression facilitated glioma cell proliferation and bolstered resistance to chemotherapy. Conversely, CBX2 knockdown led to a significant inhibition of glioma cell growth and a reduction in chemoresistance. Notably, our investigation uncovered the underlying mechanism by which CBX2 operates, primarily by inhibiting PTEN transcription and activating the AKT/mTOR signalling pathway. Conversely, silencing CBX2 curtailed cell proliferation and attenuated chemoresistance by impeding the activation of the PTEN/AKT/mTOR signalling pathway. Delving deeper into the molecular intricacies, we discovered that CBX2 can recruit EZH2 and modulate the trimethylation of histone H3 lysine 27 (H3K27me3) levels on the PTEN promoter, effectively suppressing PTEN transcription. Our research unveils a comprehensive understanding of how CBX2 impacts the tumorigenesis, progression, chemoresistance, and prognosis of glioma. Furthermore, it presents CBX2 as a promising therapeutic target for drug development and clinical management of glioma.

Aortic Annular Enlargement versus Isolated Aortic Valve Replacement in Patients with Matched Annulus.

BACKGROUND: We aimed to determine the effect of aortic annular enlargement on the mid-term outcomes of aortic valve replacement surgery by comparing patients with the same-sized (≤23 mm) native aortic annuli. METHODS: From January 2011 to June 2022, 1,328 patients underwent isolated aortic valve replacement-1,163 without aortic annular enlargement (AVR group) and 165 with aortic annular enlargement (AVR+AAE group). Propensity score matching identified 112 pairs, controlling for native aortic annulus diameter, age, sex, diabetes, chronic lung disease, dialysis, ejection fraction, prior cardiac surgery, indication, hypertension, dyslipidemia, valve type, prior stroke, prior myocardial infarction, and case status. RESULTS: Demographic and preoperative parameters were similar, except body surface area was larger in the AVR+AAE group (2.1 m2 vs 1.9 m2). Median native aortic annulus diameter was 23 mm in both groups. Median prosthesis size was 25 and 23 in the AVR+AAE and AVR groups, respectively. The AVR+AAE group had longer cardiopulmonary bypass (143 vs 111 mins) and cross-clamp (115 vs 82 mins) times. Incidences of perioperative complications including operative mortality (1.8% AVR+AAE vs 3.6% AVR) were similar between groups. 6-year survival was 98% in the AVR+AAE group and 74% in the AVR group (p=0.016). Aortic annular enlargement was an independent protective factor for mid-term mortality with a hazard ratio of 0.19 (p=0.006). The rate of moderate/severe patient-prosthesis mismatch was 19% in the AVR+AAE group and 31% in the AVR group (p=0.16). CONCLUSIONS: Patients with small native aortic annuli (≤23 mm) undergoing isolated aortic valve replacement may benefit from aortic annular enlargement.

DEAF-Net: Detail-Enhanced Attention Feature Fusion Network for Retinal Vessel Segmentation.

Retinal vessel segmentation is crucial for the diagnosis of ophthalmic and cardiovascular diseases. However, retinal vessels are densely and irregularly distributed, with many capillaries blending into the background, and exhibit low contrast. Moreover, the encoder-decoder-based network for retinal vessel segmentation suffers from irreversible loss of detailed features due to multiple encoding and decoding, leading to incorrect segmentation of the vessels. Meanwhile, the single-dimensional attention mechanisms possess limitations, neglecting the importance of multidimensional features. To solve these issues, in this paper, we propose a detail-enhanced attention feature fusion network (DEAF-Net) for retinal vessel segmentation. First, the detail-enhanced residual block (DERB) module is proposed to strengthen the capacity for detailed representation, ensuring that intricate features are efficiently maintained during the segmentation of delicate vessels. Second, the multidimensional collaborative attention encoder (MCAE) module is proposed to optimize the extraction of multidimensional information. Then, the dynamic decoder (DYD) module is introduced to preserve spatial information during the decoding process and reduce the information loss caused by upsampling operations. Finally, the proposed detail-enhanced feature fusion (DEFF) module composed of DERB, MCAE and DYD modules fuses feature maps from both encoding and decoding and achieves effective aggregation of multi-scale contextual information. The experiments conducted on the datasets of DRIVE, CHASEDB1, and STARE, achieving Sen of 0.8305, 0.8784, and 0.8654, and AUC of 0.9886, 0.9913, and 0.9911 on DRIVE, CHASEDB1, and STARE, respectively, demonstrate the performance of our proposed network, particularly in the segmentation of fine retinal vessels.

Hyperuricemia and its related diseases: mechanisms and advances in therapy.

Hyperuricemia, characterized by elevated levels of serum uric acid (SUA), is linked to a spectrum of commodities such as gout, cardiovascular diseases, renal disorders, metabolic syndrome, and diabetes, etc. Significantly impairing the quality of life for those affected, the prevalence of hyperuricemia is an upward trend globally, especially in most developed countries. UA possesses a multifaceted role, such as antioxidant, pro-oxidative, pro-inflammatory, nitric oxide modulating, anti-aging, and immune effects, which are significant in both physiological and pathological contexts. The equilibrium of circulating urate levels hinges on the interplay between production and excretion, a delicate balance orchestrated by urate transporter functions across various epithelial tissues and cell types. While existing research has identified hyperuricemia involvement in numerous biological processes and signaling pathways, the precise mechanisms connecting elevated UA levels to disease etiology remain to be fully elucidated. In addition, the influence of genetic susceptibilities and environmental determinants on hyperuricemia calls for a detailed and nuanced examination. This review compiles data from global epidemiological studies and clinical practices, exploring the physiological processes and the genetic foundations of urate transporters in depth. Furthermore, we uncover the complex mechanisms by which the UA induced inflammation influences metabolic processes in individuals with hyperuricemia and the association with its relative disease, offering a foundation for innovative therapeutic approaches and advanced pharmacological strategies.

The HOXC10/NOD1/ERK axis drives osteolytic bone metastasis of pan-KRAS-mutant lung cancer.

While KRAS mutation is the leading cause of low survival rates in lung cancer bone metastasis patients, effective treatments are still lacking. Here, we identified homeobox C10 (HOXC10) as a lynchpin in pan-KRAS-mutant lung cancer bone metastasis. Through RNA-seq approach and patient tissue studies, we demonstrated that HOXC10 expression was dramatically increased. Genetic depletion of HOXC10 preferentially impeded cell proliferation and migration in vitro. The bioluminescence imaging and micro-CT results demonstrated that inhibition of HOXC10 significantly reduced bone metastasis of KRAS-mutant lung cancer in vivo. Mechanistically, the transcription factor HOXC10 activated NOD1/ERK signaling pathway to reprogram epithelial-mesenchymal transition (EMT) and bone microenvironment by activating the NOD1 promoter. Strikingly, inhibition of HOXC10 in combination with STAT3 inhibitor was effective against KRAS-mutant lung cancer bone metastasis by triggering ferroptosis. Taken together, these findings reveal that HOXC10 effectively alleviates pan-KRAS-mutant lung cancer with bone metastasis in the NOD1/ERK axis-dependent manner, and support further development of an effective combinatorial strategy for this kind of disease.

Repetitive transcranial magnetic stimulation reshaped the dynamic reconfiguration of the executive and reward networks in individuals with tobacco use disorder.

BACKGROUND: Studies have demonstrated the potential of repetitive transcranial magnetic stimulation (rTMS) to decrease smoking cravings in individuals with tobacco use disorder (TUD). However, the neural features underlying the effects of rTMS treatment, especially the dynamic attributes of brain networks associated with the treatment, remain unclear. METHODS: Using dynamic functional connectivity analysis, this study first explored the differences in dynamic functional network features between 60 subjects with TUD and 64 nonsmoking healthy controls (HCs). Then, the left dorsolateral prefrontal cortex (DLPFC) was targeted for a five-day course of rTMS treatment in the 60 subjects with TUD (active rTMS in 42 subjects and sham treatment in 18 subjects). We explored the effect of rTMS on the dynamic network features associated with rTMS by comparing the actively treated group and the sham group. RESULTS: Compared to nonsmokers, TUD subjects exhibited an increased integration coefficient between the frontoparietal network (FPN) and the basal ganglia network (BGN) and a reduced integration coefficient between the medial frontal network (MFN) and the FPN. Analysis of variance revealed that rTMS treatment reduced the integration coefficient between the FPN and BGN and improved the recruitment coefficient of the FPN. LIMITATIONS: This study involved a limited sample of young male smokers, and the findings may not generalize to older smokers or female smokers with an extensive history of smoking. CONCLUSION: rTMS treatment of the left DLPFC exhibited significant effectiveness in restructuring the neural circuits associated with TUD while significantly mitigating smoking cravings.

Variation in plant functional traits explains the substitution distribution and allocation strategy of Stipa species across natural grasslands of Ningxia, Northern China.

Functional traits reflect plants' adaptability to their environment, and environmental gradients influence their distribution. But few studies have investigated the link between these traits and species substitution patterns or the relevant ecological factors. We measured the aboveground (leaf) and belowground (root) functional traits of Stipa species in 17 plots across natural grasslands in Ningxia in Northern China. Redundancy analysis was used to explore the relationships between Stipa's functional traits and its species substitution distribution. Then, on the species substitution gradient, principal component analysis (PCA) was used to verify and quantify the leaf economic spectrum (LES), root economic spectrum (RES), and whole-plant economic spectrum (WPES), with the relation between these spectra investigated by fitting standardized major axis regressions. The effects of aboveground, belowground, and whole-plant ecological factors were quantified and ranked by variance decomposition and hierarchical partitioning. Our results showed that functional traits drive the substitution distribution of Stipa species, in being variously coupled with its desert, typical, and meadow steppe habitat types. The leaf, root, and whole-plant economic spectra of Stipa species in desert steppe exhibit a "quick investment-acquisition" strategy. In typical steppe, the leaf and whole-plant economic spectra of Stipa species correspond to a "fast investment-acquisition" strategy, whereas the root economic spectrum adopts a "slow investment-acquisition" strategy. On meadow steppe, the leaf, root, and whole-plant economic spectra of Stipa species similarly adopt a "slow investment-acquisition" strategy. Finally, when considering the environmental factors involved, we find that the substitution distribution of Stipa spp. is chiefly a response to shifting soil patterns, these mainly driven by soil total nitrogen and nitrogen/phosphorus ratio. Collectively, these findings provide an important reference for the ecological restoration and reconstruction of grassland ecosystems, to better understand the relationship between plant functional traits and ecological niche attributes, and thus guide the reasonable restoration of grassland vegetation.

Development and validation of an integrated system for lung cancer screening and post-screening pulmonary nodules management: a proof-of-concept study (ASCEND-LUNG).

Background: In order to address the low compliance and dissatisfied specificity of low-dose computed tomography (LDCT), efficient and non-invasive approaches are needed to complement its limitations for lung cancer screening and management. The ASCEND-LUNG study is a prospective two-stage case-control study designed to evaluate the performance of a liquid biopsy-based comprehensive lung cancer screening and post-screening pulmonary nodules management system. Methods: We aimed to develop a comprehensive lung cancer system called Peking University Lung Cancer Screening and Management System (PKU-LCSMS) which comprises a lung cancer screening model to identify specific populations requiring LDCT and an artificial intelligence-aided (AI-aided) pulmonary nodules diagnostic model to classify pulmonary nodules following LDCT. A dataset of 465 participants (216 cancer, 47 benign, 202 non-cancer control) were used for the two models' development phase. For the lung cancer screening model development, cancer participants were randomly split at a ratio of 1:1 into the train and validation cohorts, and then non-cancer controls were age-matched to the cancer cases in a 1:1 ratio. Similarly, for the AI-aided pulmonary nodules model, cancer and benign participants were also randomly divided at a ratio of 2:1 into the train and validation cohorts. Subsequently, during the model validation phase, sensitivity and specificity were validated using an independent validation cohort consisting of 291 participants (140 cancer, 25 benign, 126 non-cancer control). Prospectively collected blood samples were analyzed for multi-omics including cell-free DNA (cfDNA) methylation, mutation, and serum protein. Computerized tomography (CT) images data was also obtained. Paired tissue samples were additionally analyzed for DNA methylation, DNA mutation, and messenger RNA (mRNA) expression to further explore the potential biological mechanisms. This study is registered with ClinicalTrials.gov, NCT04817046. Findings: Baseline blood samples were evaluated for the whole screening and diagnostic process. The cfDNA methylation-based lung cancer screening model exhibited the highest area under the curve (AUC) of 0.910 (95% CI, 0.869-0.950), followed by the protein model (0.891 [95% CI, 0.845-0.938]) and lastly the mutation model (0.577 [95% CI, 0.482-0.672]). Further, the final screening model, which incorporated cfDNA methylation and protein features, achieved an AUC of 0.963 (95% CI, 0.942-0.984). In the independent validation cohort, the multi-omics screening model showed a sensitivity of 99.2% (95% CI, 0.957-1.000) at a specificity of 56.3% (95% CI, 0.472-0.652). For the AI-aided pulmonary nodules diagnostic model, which incorporated cfDNA methylation and CT images features, it yielded a sensitivity of 81.1% (95% CI, 0.732-0.875), a specificity of 76.0% (95% CI, 0.549-0.906) in the independent validation cohort. Furthermore, four differentially methylated regions (DMRs) were shared in the lung cancer screening model and the AI-aided pulmonary nodules diagnostic model. Interpretation: We developed and validated a liquid biopsy-based comprehensive lung cancer screening and management system called PKU-LCSMS which combined a blood multi-omics based lung cancer screening model incorporating cfDNA methylation and protein features and an AI-aided pulmonary nodules diagnostic model integrating CT images and cfDNA methylation features in sequence to streamline the entire process of lung cancer screening and post-screening pulmonary nodules management. It might provide a promising applicable solution for lung cancer screening and management. Funding: This work was supported by Science, Science, Technology & Innovation Project of Xiongan New Area, Beijing Natural Science Foundation, CAMS Innovation Fund for Medical Sciences (CIFMS), Clinical Medicine Plus X-Young Scholars Project of Peking University, the Fundamental Research Funds for the Central Universities, Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, Peking University People's Hospital Research and Development Funds, National Key Research and Development Program of China, and the fundamental research funds for the central universities.

Mantle plume trail beneath the ca. 1.1 Ga North American Midcontinent Rift revealed by magnetotelluric data.

Whilst the 1.1 Ga North American Midcontinent Rift (MCR) system is formed in association with the Keweenaw mantle plume, the absence of a northern third rift arm or aulacogen (a general characteristic of mantle plumes) has previously not been well understood. To help clarify this unusual plume-rift relationship and to better establish the region affected by the Keweenaw mantle plume, we present the first electrical resistivity model of the MCR derived from 3D inversion of EarthScope USArray and Lithoprobe magnetotelluric (MT) data, extending northwards into the Archean Superior Province. Our model shows a prominent highly conductive anomaly trending NW-SE at the base of Western Superior's cratonic lithospheric mantle, cross-cutting and extending for over 300 km on both sides of the western rift branch. We propose that this anomaly reflects the ancient signature of a plume trail, resulting from metasomatism and/or partial melting of the sulfide-rich basal lithospheric mantle during impingement of the Keweenaw mantle plume.

Proteomic landscape profiling of primary prostate cancer reveals a 16-protein panel for prognosis prediction.

Prostate cancer (PCa) is the most common malignant tumor in men. Currently, there are few prognosis indicators for predicting PCa outcomes and guiding treatments. Here, we perform comprehensive proteomic profiling of 918 tissue specimens from 306 Chinese patients with PCa using data-independent acquisition mass spectrometry (DIA-MS). We identify over 10,000 proteins and define three molecular subtypes of PCa with significant clinical and proteomic differences. We develop a 16-protein panel that effectively predicts biochemical recurrence (BCR) for patients with PCa, which is validated in six published datasets and one additional 99-biopsy-sample cohort by targeted proteomics. Interestingly, this 16-protein panel effectively predicts BCR across different International Society of Urological Pathology (ISUP) grades and pathological stages and outperforms the D'Amico risk classification system in BCR prediction. Furthermore, double knockout of NUDT5 and SEPTIN8, two components from the 16-protein panel, significantly suppresses the PCa cells to proliferate, invade, and migrate, suggesting the combination of NUDT5 and SEPTIN8 may provide new approaches for PCa treatment.