Targeted Discovery of a Natural ortho-Quinone Methide Precursor and Green Generation of Its Oligomers.

ortho-Quinone methides (o-QMs) are a class of highly reactive intermediates that serve as important nonisolable building blocks (NBBs) in organic synthesis and small-molecule library construction. Because of their instability and nonisolability, most reported o-QMs are generated through in situ chemical synthesis, and only a few natural o-QMs have been reported due to the lack of directed discovery strategies. Herein, a new natural o-QM precursor (trichophenol A, 2) was identified from the fungal strain of Trichoderma sp. AT0167 through genome mining, which was generated by trilA (nonreducing polyketide synthase) and trilB (2-oxoglutarate dependent dioxygenase). Combinatorial biosynthesis via two other known NRPKS genes with trilA and trilB was performed, leading to the generation of five new trichophenol o-QM oligomers (trichophenols D-H, 5-9). The strategy combining genome mining with combinatorial biosynthesis not only targetedly uncovered a new natural o-QM precursor but also produced various new molecules through oligomerization of the new o-QM and its designated o-QM acceptors without chemical synthesis and isolation of intermediates, which was named NBB genome mining-combinatorial biosynthesis strategy for o-QM molecule library construction. This study provides a new strategy for the targeted discovery of natural o-QMs and small-molecule library construction with natural o-QMs.

Osteogenic differentiation of bone mesenchymal stem cells on linearly aligned triangular micropatterns.

Mesenchymal stem cells (MSCs) hold promise for regenerative medicine, particularly for bone tissue engineering. However, directing MSC differentiation towards specific lineages, such as osteogenic, while minimizing undesired phenotypes remains a challenge. Here, we investigate the influence of micropatterns on the behavior and lineage commitment of rat bone marrow-derived MSCs (rBMSCs), focusing on osteogenic differentiation. Linearly aligned triangular micropatterns (TPs) and circular micropatterns (CPs) coated with fibronectin were fabricated to study their effects on rBMSC morphology and differentiation and the underlying mechanobiological mechanisms. TPs, especially TP15 (15 µm), induced the cell elongation and thinning, while CPs also promoted the cell stretching, as evidenced by the decreased circularity and increased aspect ratio. TP15 significantly promoted osteogenic differentiation, with increased expression of osteogenic genes (Runx2, Spp1, Alpl, Bglap, Col1a1) and decreased expression of adipogenic genes (Pparg, Cebpa, Fabp4). Conversely, CPs inhibited both osteogenic and adipogenic differentiation. Mechanistically, TP15 increased Piezo1 activity, cytoskeletal remodeling including the aggregates of F-actin and myosin filaments at the cell periphery, YAP1 nuclear translocation, and integrin upregulation. Piezo1 inhibition suppressed the osteogenic genes expression, myosin remodeling, and YAP1 nuclear translocation, indicating Piezo1-mediated the mechanotransduction in rBMSCs on TPs. TP15 also induced osteogenic differentiation of BMSCs from aging rats, with upregulated Piezo1 and nuclear translocation of YAP1. Therefore, triangular micropatterns, particularly TP15, promote osteogenesis and inhibit adipogenesis of rBMSCs through Piezo1-mediated myosin and YAP1 pathways. Our study provides novel insights into the mechanobiological mechanisms governing MSC behaviors on micropatterns, offering new strategies for tissue engineering and regenerative medicine.

Syndecan-1 as a predictor of vulnerable atherosclerotic plaques.

Aims: Cardiovascular disease remains a major global health concern, with atherosclerosis (AS) being a significant contributor. Vulnerable plaques play a critical role in acute cardiovascular events. Syndecan-1 (SDC-1), a vital membrane proteoglycan in the vascular endothelial glycocalyx, is believed to be associated with plaque progression. However, its precise relationship with severity and vulnerability of atherosclerotic plaque remains unclear. This study aimed to investigate SDC-1 expression and its potential correlation with plaque vulnerability in ApoE-/- atherosclerosis mouse model. Methods and results: Eight-week-old mice were induced into the AS model using a high-fat diet (HFD) and/or partial ligation of the left common carotid artery (PLCA), with a chow diet (CD) control group. After 16 weeks, plaques in the aortic root showed the following order: HFD + PLCA group > HFD group > CD + PLCA group > CD group. Immunohistochemistry revealed heightened accumulation of lipid/foam cells and CD68-labeled macrophages in the plaques, elevated vascular endothelial growth factor (VEGF), and matrix Metalloproteinase-9 (MMP-9) in the HFD + PLCA group's plaques, along with reduced collagen and α-SMA-labeled smooth muscle cells, resulting in the highest vulnerability index value. Immunohistofluorescence analysis of frozen plaque sections showed significantly higher SDC-1 expression in the AS mice group compared to the CD group, both positively correlated with plaque vulnerability. Serum analysis demonstrated elevated levels of SDC1, sphingosine 1-phosphate (S1P), and VEGF-A in the AS mice, all positively correlated with plaque vulnerability. Multivariate analysis identified SDC1 as an independent predictor of plaque vulnerability. Conclusion: This study enhances our understanding of plaque vulnerability mechanisms and presents SDC1 as a potential biomarker for atherosclerosis. These findings underscore the importance of addressing modifiable risk factors, such as diet and hemodynamics and suggest the utility of serum SDC1 as a valuable clinical marker. Ultimately, these insights may lead to more effective strategies in combating cardiovascular diseases and improving patient outcomes.

Cross-sectional associations of low body mass index and being underweight with joint damage in Chinese patients with rheumatoid arthritis.

Objective: To characterize BMI in Chinese patients with RA vs US patients and examine its association with joint damage in Chinese patients. Methods: Each of the 1318 patients from a real-world Chinese RA population was first stratified by gender and then individually age-matched with one American RA patient from the US National Health and Nutritional Examination Survey 1999-2018. Data on BMI, bilateral hand radiographs and risk factors at enrolment were collected but radiographs were unavailable for the American patients. Logistic regression was used to evaluate the association of BMI with radiographic joint damage (RJD) in Chinese patients. Results: Chinese patients had a significantly lower BMI [(weighted) median 21.8 vs 29.8 kg/m2; P < 0.001] and a higher prevalence of being underweight (15.2% vs 1.1%; P < 0.05) than their American counterparts. Underweight Chinese patients (BMI <18.5) had higher modified total Sharp scores (median 17 vs 10) and joint space narrowing (JSN) subscores (median 6 vs 2) (both P < 0.05) than normal-weight patients (BMI ≥18.5-<24). After controlling for confounding, continuous BMI was cross-sectionally negatively associated with RJD [adjusted prevalence odds ratio (OR) 0.90 (95% CI 0.85, 0.96)] and JSN [adjusted prevalence OR 0.92 (95% CI 0.87, 0.96)]; being underweight vs normal weight was associated with RJD [adjusted prevalence OR 2.14 (95% CI 1.37, 3.35)] and JSN [adjusted prevalence OR 1.77 (95% CI 1.10, 2.84)]. Conclusion: Low BMI and being underweight were cross-sectionally associated with joint damage in Chinese RA patients, especially JSN, suggesting the clinical importance of identifying underweight patients and focusing on weight gain to prevent joint damage.

Harnessing Mitochondrial Stress for Health and Disease: Opportunities and Challenges.

Mitochondria, essential organelles orchestrating cellular metabolism, have emerged as central players in various disease pathologies. Recent research has shed light on mitohormesis, a concept proposing an adaptive response of mitochondria to minor disturbances in homeostasis, offering novel therapeutic avenues for mitochondria-related diseases. This comprehensive review explores the concept of mitohormesis, elucidating its induction mechanisms and occurrence. Intracellular molecules like reactive oxygen species (ROS), calcium, mitochondrial unfolded proteins (UPRmt), and integrated stress response (ISR), along with external factors such as hydrogen sulfide (H2S), physical stimuli, and exercise, play pivotal roles in regulating mitohormesis. Based on the available evidence, we elucidate how mitohormesis maintains mitochondrial homeostasis through mechanisms like mitochondrial quality control and mitophagy. Furthermore, the regulatory role of mitohormesis in mitochondria-related diseases is discussed. By envisioning future applications, this review underscores the significance of mitohormesis as a potential therapeutic target, paving the way for innovative interventions in disease management.

Spatial confinement modulates endothelial cell behavior and traction force in 3D hydrogel microgrooves.

The mechanical environment of vascular endothelial cells (ECs) encompasses a wide range of curvatures due to variations in blood vessel diameters. Integrins, key mediators of cell-matrix interactions, establish connections between the extracellular matrix and the actin cytoskeleton, influencing diverse cellular behaviors. In this study, we explored the impact of spatial confinement on human umbilical vein ECs (HUVECs) cultured within three-dimensional hydrogel microgrooves of varying curvatures and the underlying role of integrins in mediating cellular responses. Employing maskless lithography, we successfully fabricated precise and wall curvatures-controlled hydrogel microgrooves, conferring spatial constraints on the cells. Our investigations revealed substantial alterations in HUVEC behavior within the hydrogel microgrooves with varying sidewall curvatures, marked by reduced cell size, enhanced orientation, and increased apoptosis. Interestingly, microgroove curvature emerged as a crucial factor influencing cell orientation and apoptosis, with rectangular microgrooves eliciting distinct changes in cell orientation, while ring-form microgrooves exhibited higher apoptosis rates. The side-wall effect in the 20 µm region near the microgroove wall had the greatest influence on cell orientation and apoptosis. HUVECs within the microgrooves exhibited elevated integrin expression, and inhibition of αV-integrin by cilengitide significantly curtailed cell apoptosis without affecting proliferation. Additionally, integrin-mediated cell traction force closely correlated with the spatial confinement effect. Cilengitide not only reduced integrin and focal adhesion expression but also attenuated cell traction force and cytoskeletal actin filament alignment. Overall, our findings elucidate the spatial confinement of ECs in hydrogel microgrooves and underscores the pivotal role of integrins, particularly αV-integrin, in mediating cell traction force and apoptosis within this microenvironment.

Geriatric nutrition risk index: a more powerful index identifying muscle mass loss in patients with rheumatoid arthritis.

OBJECTIVE: To explore the association of geriatric nutrition risk index (GNRI), a traditional albumin-body weight calculation, with myopenia in patients with rheumatoid arthritis (RA) and compare its ability to identify myopenia with protein indicators. METHODS: This cross-sectional study was carried out based on a Chinese RA cohort. Clinical data and protein indicators (including albumin, globulin, albumin to globulin ratio, prealbumin, hemoglobin) were collected. GNRI was estimated by serum albumin and body weight. Myopenia was indicated as muscle mass loss measured by bioelectric impedance analysis. RESULTS: There were 789 RA patients included with mean age 52.6 ± 12.6 years and 77.6% female. There were 41.3%, 18.0%, 27.5%, 13.2% patients with no (GNRI > 98), low (GNRI 92 to ≤ 98), moderate (GNRI 82 to < 92), and major nutrition-related risk (GNRI < 82). There were 406 (51.5%) RA patients with myopenia, RA patients with major nutrition-related risk had the highest prevalence of myopenia (87.5% vs. 73.3% vs. 50.0% vs. 26.1%). Multivariate logistic analysis showed that compared with no risk, RA patients with low (OR = 3.23, 95% CI: 1.86-5.61), moderate (OR = 9.56, 95% CI: 5.70-16.01), and major nutrition-related risk (OR = 28.91, 95% CI: 13.54-61.71) were associated with higher prevalence of myopenia. Receiver operating characteristic curves showed that GNRI (AUC = 0.79) performed a better identifiable ability toward myopenia than serum albumin (AUC = 0.66) or others indicators (AUC range 0.59 to 0.65), respectively. CONCLUSION: GNRI, an objective and convenient albumin-weight index, may be preferable for identifying myopenia in RA patients. Key Points • We firstly elucidated the association of GNRI with muscle mass loss among RA patients, and compared its ability to identify muscle mass loss with serum albumin or other protein indicators. • Major nutrition-related risk identified by GNRI showed the highest risk of muscle mass loss, GNRI demonstrated a greater ability to identify myopenia in RA patients. which indicated GNRI was an objective and convenient albumin-weight index to identify myopenia in RA patients.

[Spatial Constraints of Rectangular Hydrogel Microgrooves Regulate the Morphology and Arrangement of Human Umbilical Vein Endothelial Cells]. / çŸ©å½¢æ°´å‡èƒ¶å¾®å‡¹æ§½çš„ç©ºé—´çº¦æŸè°ƒæŽ§äººè„é™è„‰å† çš®ç»†èƒžçš„å½¢æ€å’ŒæŽ’åˆ—.

Objective: To construct microscale rectangular hydrogel grooves and to investigate the morphology and alignment of human umbilical vein endothelial cells (HUVECs) under spatial constraints. Vascular endothelial cell morphology and alignment are important factors in vascular development and the maintenance of homeostasis. Methods: A 4-arm polyethylene glycol-acrylate (PEG-acrylate) hydrogel was used to fabricate rectangular microgrooves of the widths of 60 µm, 100 µm, and 140 µm. The sizes and the fibronectin (FN) adhesion of these hydrogel microgrooves were measured. HUVECs were seeded onto the FN-coated microgrooves, while the flat surface without micropatterns was used as the control. After 48 hours of incubation, the morphology and orientation of the cells were examined. The cytoskeleton was labelled with phalloidine and the orientation of the cytoskeleton in the hydrogel microgrooves was observed by laser confocal microscopy. Results: The hydrogel microgrooves constructed exhibited uniform and well-defined morphology, a complete structure, and clear edges, with the width deviation being less than 3.5%. The depth differences between the hydrogel microgrooves of different widths were small and the FN adhesion is uniform, providing a micro-patterned growth interface for cells. In the control group, the cells were arranged haphazardly in random orientations and the cell orientation angle was (46.9±1.8)°. In contrast, the cell orientation angle in the hydrogel microgrooves was significantly reduced (P<0.001). However, the cell orientation angles increased with the increase in hydrogel microgroove width. For the 60 µm, 100 µm, and 140 µm hydrogel microgrooves, the cell orientation angles were (16.4±2.8)°, (24.5±3.2)°, and (30.3±3.5)°, respectively. Compared to that of the control group (35.7%), the number of cells with orientation angles <30° increased significantly in the hydrogel microgrooves of different widths (P<0.001). However, as the width of the hydrogel microgrooves increased, the number of cells with orientation angles <30° gradually decreased (79.9%, 62.3%, 54.7%, respectively), while the number of cells with orientation angles between 60°-90° increased (P<0.001). The cell bodies in the microgrooves were smaller and more rounded in shape. The cells were aligned along the direction of the microgrooves and corresponding changes occurred in the arrangement of the cell cytoskeleton. In the control group, cytoskeletal filaments were aligned in random directions, presenting an orientation angle of (45.5±3.7)°. Cytoskeletal filaments were distributed evenly within various orientation angles. However, in the 60 µm, 100 µm, and 140 µm hydrogel microgrooves, the orientation angles of the cytoskeletal filaments were significantly decreased, measuring (14.4±3.1)°, (24.7±3.5)°, and (31.9±3.3)°, respectively. The number of cytoskeletal filaments with orientation angles <30° significantly increased in hydrogel microgrooves of different widths (P<0.001). However, as the width of the hydrogel microgrooves increased, the number of cytoskeletal filaments with orientation angles <30° gradually decreased, while the number of cytoskeletal filaments with orientation angles between 60°-90° gradually increased (P<0.001). Conclusion: Hydrogel microgrooves can regulate the morphology and orientation of HUVECs and mimic to a certain extent the in vivo microenvironment of vascular endothelial cells, providing an experimental model that bears better resemblance to human physiology for the study of the unique physiological functions of vascular endothelial cells. Nonetheless, the molecular mechanism of spatial constraints on the morphology and the assembly of vascular endothelial cell needs to be further investigated.

Effects of hypertension on subcortical nucleus morphological alternations in patients with type 2 diabetes.

Objectives: Type 2 diabetes mellitus(T2DM) and hypertension(HTN) are common comorbidities, and known to affect the brain. However, little is known about the effects of the coexisting HTN on brain in T2DM patients. So we aim to investigate the impact of HTN on the subcortical nucleus morphological alternations in T2DM patients. Materials & methods: This work was registered by the clinicaltrials.gov (grant number NCT03564431). We recruited a total of 92 participants, comprising 36 only T2DM patients, 28 T2DM patients with HTN(T2DMH) and 28 healthy controls(HCs) in our study. All clinical indicators were assessed and brain image data was collected for each participant. Voxel-based morphometry(VBM), automatic volume and vertex-based shape analyses were used to determine the subcortical nucleus alternations from each participant's 3D-T1 brain images and evaluate the relationship between the alternations and clinical indicators. Results: T2DMH patients exhibited volumetric reduction and morphological alterations in thalamus compared to T2DM patients, whereas T2DM patients did not demonstrate any significant subcortical alterations compared to HCs. Furthermore, negative correlations have been found between thalamic alternations and the duration of HTN in T2DMH patients. Conclusion: Our results revealed that HTN may exacerbate subcortical nucleus alternations in T2DM patients, which highlighted the importance of HTN management in T2DM patients to prevent further damage to the brain health.

[Research progress on vascularization of organoids].

Organoids are three-dimensional structures formed by self-organizing growth of cells in vitro, which own many structures and functions similar with those of corresponding in vivo organs. Although the organoid culture technologies are rapidly developed and the original cells are abundant, the organoid cultured by current technologies are rather different with the real organs, which limits their application. The major challenges of organoid cultures are the immature tissue structure and restricted growth, both of which are caused by poor functional vasculature. Therefore, how to develop the vascularization of organoids has become an urgent problem. We presently reviewed the progresses on the original cells of organoids and the current methods to develop organoids vascularization, which provide clues to solve the above-mentioned problems.

Low intensity pulsed ultrasound ameliorates Adriamycin-induced chronic renal injury by inhibiting ferroptosis.

OBJECTIVE: It is very important to develop a new therapeutic strategy to cope with the increasing morbidity and mortality of chronic kidney disease (CKD). As a kind of physical therapy, low intensity pulsed ultrasound (LIPUS) has remarkable anti-inflammatory and repair-promoting effects and is expected to become a new therapeutic method for CKD. This study aims to clarify the treatment effect of LIPUS on CKD-related renal inflammation and fibrosis, and to further explore the potential signal network of LIPUS treatment for ameliorating chronic renal injury. METHODS: A rat model simulating the progress of CKD was established by twice tail-vein injection of Adriamycin (ADR). Under anesthesia, bilateral kidneys of CKD rats were continuously stimulated by LIPUS for four weeks. The parameters of LIPUS were 1.0 MHz, 60 mW/cm2, 50% duty cycle and 20 min/d. RESULTS: LIPUS treatment effectively inhibited ADR-induced renal inflammation and fibrosis, and improved CKD-related to oxidative stress and ferroptosis. In addition, the therapeutic effect of LIPUS is closely related to the regulation of TGF-ß1/Smad and Nrf2/keap1/HO-1 signalling pathways. DISCUSSION: This study provides a new direction for further mechanism research and lays an important foundation for clinical trials.

Diagnostic accuracy of glioma pseudoprogression identification with positron emission tomography imaging: a systematic review and meta-analysis.

Background: Positron emission tomography (PET) imaging is a promising molecular neuroimaging technique and has been proposed as one of the criteria for glioma management. However, there is some controversy concerning the diagnostic accuracy of PET using different radiotracers to differentiate between glioma pseudoprogression (PsP) and true progression (TPR). The purpose of this meta-analysis was to systematically evaluate the methodological quality and clinical value of original studies for distinguishing PsP from TPR in glioma. Methods: The Medline, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov were searched from inception until September 1, 2022. Retrieved clinical studies only investigated the PsP cases but did not include the cases of radiation necrosis or other treatment-related changes. Eligible studies were screened for data extraction and evaluated by 2 independent reviewers using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. A random effects model was used to describe summary receiver operating characteristics. Meta-regression and subgroup analyses were applied to identify any sources of heterogeneity. Results: The meta-analysis included 20 studies, comprising 317 (30.9%) patients with PsP and 708 (69.1%) with TPR. The summary sensitivity and specificity of general PET for identifying PsP were 0.86 [95% confidence interval (CI): 0.77-0.91] and 0.84 (95% CI: 0.79-0.88), respectively. The statistical heterogeneity was explained by sample size, study design, World Health Organization (WHO) grade, gold standard, and radiotracer type. The summary sensitivity and specificity of O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET PET) were 0.80 (95% CI: 0.68-0.88) and 0.81 (95% CI: 0.75-0.85), respectively. The maximum tumor-to-brain ratio (TBRmax) and the mean tumor-to-brain ratio (TBRmean) both showed excellent diagnostic performance in 18F-FET studies, the summary sensitivity was 0.83 (95% CI: 0.72-0.91) and 0.79 (95% CI: 0.65-0.98), respectively, and the specificity was 0.76 (95% CI: 0.68-0.84) and 0.78 (95% CI: 0.64-0.88), respectively. Conclusions: PET imaging is generally accurate in identifying glioma PsP. Considering the credibility of meta-evidence and the practicability of using radiotracer, 18F-FET PET holds the highest clinical value, while TBRmax and TBRmean should be regarded as reliable parameters. PET used with the radiotracers and multiple-parameter combinations of PET with magnetic resonance imaging (MRI) and radiomics analysis have broad research and application prospects, whose diagnostic values for identifying glioma PsP warrant further investigation.

Application of a new self-regulating temperature magnetic material Fe83Zr10B7 in magnetic induction hyperthermia.

INTRODUCTION: The temperature control of magnetic hyperthermia therapy mainly relies on circulating water cooling and regulating magnetic field intensity, which increases complexity in clinical applications. Using magnetic materials with appropriate Curie temperature has become an effective means to solve temperature monitoring and potentially achieve self-regulating temperature. METHODS: A self-temperature-regulating Fe83Zr10B7 magnetic material was prepared. Based on this material, a simplified model of magnetic hyperthermia for arm tumors was established and verified using the finite- element method. The influence of magnetic field intensity and frequency on the heating power and temperature rise rate of different-sized and shaped magnetic media was studied. Additionally, factors such as the size, quantity, and spatial arrangement of the magnetic media were analyzed for their impact on the damage to tumors with different volumes and shapes. RESULTS: Spherical shape is the most suitable for magnetic hyperthermia media, and the radius of the spherical magnetic media can be chosen according to the size of the tumor. For tumors with a radius below 10 mm, using magnetic media with a particle size of 3.5 mm is recommended. The optimal magnetic field conditions are H0 (10-12 kA/m) and f (110-120 kHz). CONCLUSION: Based on the good magnetic properties and heating performance of the Fe83Zr10B7 magnetic material, it is feasible to use it as a magnetic medium for magnetic hyperthermia. The results of this study provide references for the selection of thermal seed size and magnetic field parameters in magnetic hyperthermia.

Corrigendum: Coexpression of HHLA2 and PD-L1 on tumor cells independently predicts the survival of spinal chordoma patients.

[This corrects the article DOI: 10.3389/fimmu.2021.797407.].

The cell origins of foam cell and lipid metabolism regulated by mechanical stress in atherosclerosis.

Atherosclerosis is an inflammatory disease initiated by endothelial activation, in which lipoprotein, cholesterol, extracellular matrix, and various types of immune and non-immune cells are accumulated and formed into plaques on the arterial wall suffering from disturbed flow, characterized by low and oscillating shear stress. Foam cells are a major cellular component in atherosclerotic plaques, which play an indispensable role in the occurrence, development and rupture of atherosclerotic plaques. It was previously believed that foam cells were derived from macrophages or smooth muscle cells, but recent studies have suggested that there are other sources of foam cells. Many studies have found that the distribution of atherosclerotic plaques is not random but distributed at the bend and bifurcation of the arterial tree. The development and rupture of atherosclerotic plaque are affected by mechanical stress. In this review, we reviewed the advances in foam cell formation in atherosclerosis and the regulation of atherosclerotic plaque and lipid metabolism by mechanical forces. These findings provide new clues for investigating the mechanisms of atherosclerotic plaque formation and progression.

Heat waves accelerate the spread of infectious diseases.

COVID-19 pandemic appeared summer surge in 2022 worldwide and this contradicts its seasonal fluctuations. Even as high temperature and intense ultraviolet radiation can inhibit viral activity, the number of new cases worldwide has increased to >78% in only 1 month since the summer of 2022 under unchanged virus mutation influence and control policies. Using the attribution analysis based on the theoretical infectious diseases model simulation, we found the mechanism of the severe COVID-19 outbreak in the summer of 2022 and identified the amplification effect of heat wave events on its magnitude. The results suggest that approximately 69.3% of COVID-19 cases this summer could have been avoided if there is no heat waves. The collision between the pandemic and the heatwave is not an accident. Climate change is leading to more frequent extreme climate events and an increasing number of infectious diseases, posing an urgent threat to human health and life. Therefore, public health authorities must quickly develop coordinated management plans to deal with the simultaneous occurrence of extreme climate events and infectious diseases.

Contrast enhanced magnetic resonance imaging-based radiomics nomogram for preoperatively predicting expression status of Ki-67 in meningioma: a two-center study.

Background: The aim of this study was to develop and validate a radiomics nomogram for preoperative prediction of Ki-67 proliferative index (Ki-67 PI) expression in patients with meningioma. Methods: A total of 280 patients from 2 independent hospital centers were enrolled. Patients from center I were randomly divided into a training cohort of 168 patients and a test cohort of 72 patients, and 40 patients from center II served as an external validation cohort. Interoperator reproducibility test, Z-score standardization, analysis of variance (ANOVA), and least absolute shrinkage and selection operator (LASSO) binary logistic regression were used to select radiomics features, which were extracted from contrast-enhanced T1-weighted imaging (CE-T1WI) imaging. The radiomics signature for predicting Ki-67 PI expression was developed and validated using 4 classifiers including logistic regression (LR), decision tree (DT), support vector machine (SVM), and adaptive boost (AdaBoost). Finally, combined radiological characteristics with radiomics signature were used to establish the nomogram to predict the risk of high Ki-67 PI expression in patients with meningioma. Results: Fourteen radiomics features were used to construct the radiomics signature. The radiomics nomogram that incorporated the radiomics signature and radiological characteristics showed excellent discrimination in the training, test, and validation cohorts with areas under the curve of 0.817 (95% CI: 0.753-0.881), 0.822 (95% CI: 0.727-0.916), and 0.845 (95% CI: 0.708-0.982), respectively. In addition, the calibration curve for the nomogram demonstrated good agreement between prediction and actual observation. Conclusions: The proposed contrast enhanced magnetic resonance imaging (MRI)-based radiomics nomogram could be an effective tool to predict the risk of Ki-67 high expression in patients with meningioma.

Two new isoquinolines from Corydalis saxicola.

Two new isoquinolines (1 and 3), along with 4 known isoquinolines were obtained from the ethanol extract of Corydalis saxicola Bunting. Their structures were elucidated based on detailed spectroscopic data (NMR, HR-ESIMS) and comparison with literature data. The absolute configurations of the new compounds were assigned by comparing computed electronic circular dichroism (ECD). The anti-inflammatory effects of the isolates were assessed by inhibiting NO production in LPS-induced RAW264.7 macrophage cells, and the results showed that compounds 1-6 exhibited anti-inflammatory activities, with IC50 values ranged from 44.24 ± 1.16 to 69.00 ± 5.41 µM.

[Evaluation of ecological-economic-social synergy in urban area of China]. / 中国城市生态与经济社会协同性评估.

To understand the synergetic features of economy, society, and ecology in cities, we established an urban ecological-economic-social synergetic index evaluation system from three aspects (per capita green area, per capita GDP, and life expectancy per capita) and created an urban ecological-economic-social synergetic index eva-luation method. We analyzed the synergetic features by comparing the ecological-economic-social synergetic index and comprehensive function scores of 35 typical cities in China. The differences in ecological-economic-social synergy and function score for different city sizes and administrative divisions were investigated, while the synergy level of cities were classified. The results showed that the average ecological-economic-social synergetic index of 35 cities in China was 28.79, with the highest of 3.83 and the lowest of 63.04 in 2016. The synergetic index, urban econo-mic function, and social function were significantly positively correlated with urban population sizes and economic sizes. There were significant differences in synergetic index among cities with different population sizes, economic sizes, and administrative functions. The urbanization in China was still in the status of functional imbalance. Urban development was conducive to improve cities' function, but did not effectively improve the synergy of ecology, economy, and society. The ecological function of cities significantly affected urban synergy, which indicated that the poor urban ecological function was the main restrictive factor for urban synergy in China.

Mills' syndrome is a unique entity of upper motor neuron disease with N-shaped progression: Three case reports.

BACKGROUND: Mills' syndrome is an extremely rare degenerative motor neuron disorder first described by Mills in 1900, but its nosological status is still not clear. We aimed to analyze the clinical features of Mills' syndrome. CASE SUMMARY: Herein, we present 3 cases with similar features as those described in Mills' original paper and review the related literature. Our patients showed middle- and older-age onset, with only upper motor neuron symptoms evident throughout the course of the disease. Spastic hemiplegia began in the lower extremity with a unique progressive pattern. CONCLUSION: We consider that Mills' syndrome is a unique entity of motor neuron disorder with an N-shaped progression. Clinicians should maintain a high index of suspicion for the diagnosis of Mills' syndrome when the onset involves lower extremity paralysis without evidence of lower motor neuron or sensory involvement.