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Yu-Xian Tang,1,&ast; Zhi-Wei Fan,1,&ast; Jing Li,2,&ast; Hao-Dong Pan,3 Wen-Xin Su,1 Yusanjan Matniyaz,2 Hai-Tao Zhang,4 Yuan-Xi Luo,4 Zhi-Kang Lv,2 Wen-Zhe Wang,2 Ya-Xuan Gao,2 Tuo Pan,2,4 Wan-Zi Xu,1,2 Dong-Jin Wang1– 4 1Department of Cardiac Surgery, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2Department of Cardiac Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China; 3Department of Clinical Medicine, Norman Bethune Health Science Center of Jilin University, Changchun, People’s Republic of China; 4Department of Cardiac Surgery, Nanjing Drum Tower Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Graduate School of Peking Union Medical College, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dong-Jin Wang; Wan-Zi Xu, Department of Cardiac surgery, Nanjing Drum Tower Hospital, No. 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People’s Republic of China, Email dongjin_wang@126.com; 582321957@qq.comBackground: Sivelestat, a neutrophil elastase inhibitor, is specifically developed to mitigate the occurrence of acute lung injury (ALI) in individuals who are undergoing cardiovascular surgery. However, its impact on patients who are at a heightened risk of developing ALI after scheduled cardiac surgery has yet to be determined. In order to address this knowledge gap, we undertook a study to assess the efficacy of sivelestat in protecting the lungs of these patients.Methods: We conducted a prospective cohort study involving 718 patients who were at high risk of developing postoperative acute lung injury (ALI) and underwent scheduled cardiac surgery between April 25th, 2022, and September 7th, 2023. Among them, 52 patients received sivelestat (administered at a dosage of 0.2mg/kg/h for 3 days), while 666 patients served as controls, not receiving sivelestat. The control conditions were the same for all patients, including ventilation strategy, extubating time, and fluid management. Subsequently, a propensity-score matched cohort was established, consisting of 40 patients in both the sivelestat and control groups. The primary outcome measure encompassed a composite of adverse outcomes, including 30-day mortality, ALI, acute respiratory distress syndrome (ARDS), and others. Secondary outcomes assessed included pneumonia, ventricular arrhythmias, mechanical ventilation (MV) time, and more.Results: After conducting propensity matching in our study, we observed that there were no significant differences in 30-day mortality between the sivelestat and control groups (0% vs 2.5%, P=0.32). However, the use of sivelestat exhibited a significant reduction in the incidence of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) compared to the control group (0% vs 55%, P< 0.01), pneumonia (0 vs 37.5%, P< 0.01), MV time (median:8 hours, IQR:4– 14.8 hours vs median: 15.2 hours, IQR:14– 16.3 hours, P< 0.01). Compared to the control group, the sivelestat could significantly decrease white cell count (P< 0.01), neutrophile percentage (P< 0.01) and C-reactive protein (P< 0.01) in the period of postoperative 5 days.Conclusion: The prophylactic administration of sivelestat has shown promising results in reducing the occurrence of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) in patients with a heightened risk of developing these conditions after elective cardiac surgery. Our study findings indicate that sivelestat may provide protective effects by suppressing inflammation triggered by neutrophil activation, thereby safeguarding pulmonary function.Registration: ChiCTR2200059102, https://www.chictr.org.cn/showproj.html?proj=166643.Keywords: sivelestat, cardiac surgery, acute lung injury, inflammation

Hai-Tao Zhang,1 Kuo Wang,2 Ze-Shi Li,1 Chuang-Shi Wang,3 Xi-Kun Han,4,5 Wei Chen,6 Fu-Dong Fan,7 Jun Pan,7 Qing Zhou,7 Hai-Long Cao,7 Hao-Dong Pan,8 Xiateke Hafu,9 Chen Li,10 Guo-Liang Fan,10 Tuo Pan,1 Dong-Jin Wang,1,2,6,7 Wei Wang9 1Department of Cardio-Thoracic Surgery, Nanjing Drum Tower Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Graduate School of Peking Union Medical College, Nanjing, Jiangsu, 210008, People’s Republic of China; 2Department of Cardio-Thoracic Surgery, Nanjing Drum Tower Hospital, the Affiliated Clinical College of Xuzhou Medical University, Nanjing, Jiangsu, 210008, People’s Republic of China; 3Medical Research and Biometrics Center, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 102300, People’s Republic of China; 4Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA; 5Program in Genetic Epidemiology and Statistical Genetics, Harvard T. H. Chan School of Public Health, Boston, MA, USA; 6Department of Cardio-Thoracic Surgery, Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210008, People’s Republic of China; 7Department of Cardio-Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, 210008, People’s Republic of China; 8Department of Clinical Medicine, Norman Bethune Health Science Center of Jilin university, Changchun, Jilin, 130021, People’s Republic of China; 9The Xinhua Hospital of Ili Kazak Autonomous Prefecture, Ili, Xinjiang, People’s Republic of China; 10Department of Cardiac Surgery, Dong Fang Hospital Affiliated to Tongji University, Shanghai, 200120, People’s Republic of ChinaCorrespondence: Dong-Jin Wang, Chief of department of Cardio-Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Number 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People’s Republic of China, Email dongjin_wang@126.com Wei Wang, The Xinhua Hospital of Ili Kazak Autonomous Prefecture, Ili, Xinjiang, People’s Republic of China, Email wangwei3342@163.comBackground: Early postoperative bacterial pneumonia and sepsis (ePOPS), which occurs within the first 48 hours after cardiovascular surgery, is a serious life-threatening complication. Diagnosis of ePOPS is extremely challenging, and the existing diagnostic tools are insufficient. The purpose of this study was to construct a novel diagnostic prediction model for ePOPS.Methods: Least Absolute Shrinkage and Selection Operator (LASSO) with logistic regression was used to construct a model to diagnose ePOPS based on patients’ comorbidities, medical history, and laboratory findings. The area under the receiver operating characteristic curve (AUC) was used to evaluate the model discrimination.Results: A total of 1203 patients were recruited and randomly split into a training and validation set in a 7:3 ratio. By early morning on the 3rd postoperative day (POD3), 103 patients had experienced 133 episodes of bacterial pneumonia or sepsis (15 patients had both). LASSO logistic regression model showed that duration of mechanical ventilation (P=0.015), NYHA class ≥ III (P=0.001), diabetes (P< 0.001), exudation on chest radiograph (P=0.011) and IL-6 on POD3 (P< 0.001) were independent risk factors. Based on these factors, we created a nomogram named DICS-I with an AUC of 0.787 in the training set and 0.739 in the validation set.Conclusion: The DICS-I model may be used to predict the risk of ePOPS after cardiovascular surgery, and is also especially suitable for predicting the risk of IRAO. The DICS-I model could help clinicians to adjust antibiotics on the POD3.Keywords: early postoperative pneumonia and sepsis, IL-6, LASSO, nomogram

Dan Zong, Ning Jiang, Jian-Hua Xu, De-Jun Wang, Huan-Feng Zhu, Li-Rong Wu, Cheng Chen, Li Yin, Xia HeJiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210009, People’s Republic of ChinaBackground: ZNF488 acts as an oncogene which promotes cell invasion and endows tumor cells stem cell capacity in nasopharyngeal carcinoma (NPC), but its correlation with clinicopathologic characteristics and patients’ survival in NPC remain undefined.Methods: In this study, 158 cases of confirmed NPC were subjected to immunohistochemistry staining for evaluating endogenous expression. Kaplan–Meier method and log-rank test were used to estimate the survival rates. The relationship between ZNF488 and clinicopathological characteristics was statistically calculated by chi-squared test, univariate and multivariate analysis. In addition, adhesion assay, MTT and colony formation assays were performed for measuring adhesion and proliferation capacity. Cell cycle analysis via flow cytometry was conducted to explore cell cycle distribution. Western blot was used to detect pathway protein levels, and the pFAK (Y397) kit was used for focal adhesion kinase (FAK) activation.Results: We demonstrated that high expression of ZNF488 was significantly correlated with locoregional failure (P=0.018) and distant metastasis (P=0.001). Patients with high ZNF488 expression had poorer overall survival (P

Bing Gao,1–3 Jun Wang,2 Dunju Wang,1,2 Ziqiang Zhu,1,2 Zhiqiang Qiao,2 Guangcheng Yang,2 Fude Nie21School of Material Science and Engineering, Southwest University of Science and Technology, Mianyang, People's Republic of China, 2Institute of Chemical Materials, China Academy of Engineering Physics, Mianyang, Sichuan, People's Republic of China, 3Si Chuan Research Center of New Materials, Mianyang, People's Republic of ChinaPurpose: The purpose of this study was to develop a novel and continuous method for preparing a nanosized particle of drug crystals and to characterize its properties.Materials and methods: A new apparatus was introduced to crystallize nanosized drug crystals of amitriptyline hydrochloride as a model drug. The samples were prepared in the pure state by ultrasonic spray, and elaborated deposition was completed via electrostatic adsorption. Scanning electron microscopy, X-ray powder diffraction, and atomic force microscopy were used to characterize the size of the particles; this was subsequently followed by differential scanning calorimetry.Results and discussion: Nanoparticles of drug crystals were successfully prepared. The size of the drug crystals ranged from 20 nm to 400 nm; the particle size of amitriptyline hydrochloride was approximately 71 nm. The particles were spherical and rectangular in shape. Moreover, the melting point of the nanoparticles decreased from 198.2°C to 196.3°C when compared to raw particle crystals. Furthermore, the agglomeration effect was also attenuated as a result of electrostatic repulsion among each particle when absorbed, and depositing on the inner wall of the gathering unit occurred under the electrostatic effect.Conclusion: Ultrasonic spray-assisted electrostatic adsorption is a very effective and continuous method to produce drug nanocrystals. This method can be applied to poorly water-soluble drugs, and it can also be a very effective alternative for industrial production. Once the working parameters are given, drug nanocrystals will be produced continuously.Keywords: nanomedicine, amitriptyline hydrochloride, continuous, nanoparticles

This review provides a summary statement of recommended implementations of arterial spin labeling (ASL) for clinical applications. It is a consensus of the ISMRM Perfusion Study Group and the European ASL in Dementia consortium, both of whom met to reach this consensus in October 2012 in Amsterdam. Although ASL continues to undergo rapid technical development, we believe that current ASL methods are robust and ready to provide useful clinical information, and that a consensus statement on recommended implementations will help the clinical community to adopt a standardized approach. In this review, we describe the major considerations and trade-offs in implementing an ASL protocol and provide specific recommendations for a standard approach. Our conclusion is that as an optimal default implementation, we recommend pseudo-continuous labeling, background suppression, a segmented three-dimensional readout without vascular crushing gradients, and calculation and presentation of both label/control difference images and cerebral blood flow in absolute units using a simplified model. Magn Reson Med 73:102-116, 2015. © 2014 Wiley Periodicals, Inc.

Yelong Shen,1,2 Lirong Yan,1 Xingfeng Shao,1 Bin Zhao,2 Jinlun Bai,3 Wange Lu,3 Danny JJ Wang1 1Laboratory of FMRI Technology (LOFT), Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California (USC), Los Angeles, CA, USA; 2Shandong Medical Imaging Research Institute, School of Medicine, Shandong University, Jinan, Shangdong, China; 3Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California (USC), Los Angeles, CA, USA Purpose: The purpose of this study was to investigate the feasibility and sensitivity of cellular magnetic resonance imaging (MRI) with ferumoxytol nanocomplex-labeled macrophages at ultrahigh magnetic field of 7 T.Materials and methods: THP-1-induced macrophages were labeled using self-assembling heparin + protamine + ferumoxytol nanocomplexes which were injected into a gelatin phantom visible on both microscope and MRI. Susceptibility-weighted imaging (SWI) and balanced steady-state free precession (bSSFP) pulse sequences were applied at 3 and 7 T. The average, maximum intensity projection, and root mean square combined images were generated for phase-cycled bSSFP images. The signal-to-noise ratio and contrast-to-noise ratio (CNR) efficiencies were calculated. Ex vivo experiments were then performed using a formalin-fixed pig brain injected with ~100 and ~1,000 labeled cells, respectively, at both 3 and 7 T.Results: A high cell labeling efficiency (>90%) was achieved with heparin + protamine + ferumoxytol nanocomplexes. Less than 100 cells were detectable in the gelatin phantom at both 3 and 7 T. The 7 T data showed more than double CNR efficiency compared to the corresponding sequences at 3 T. The CNR efficiencies of phase-cycled bSSFP images were higher compared to those of SWI, and the root mean square combined bSSFP showed the highest CNR efficiency with minimal banding. Following co-registration of microscope and MR images, more cells (51/63) were detected by bSSFP at 7 T than at 3 T (36/63). On pig brain, both ~100 and ~1,000 cells were detected at 3 and 7 T. While the cell size appeared larger due to blooming effects on SWI, bSSFP allowed better contrast to precisely identify the location of the cells with higher signal-to-noise ratio efficiency.Conclusion: The proposed cellular MRI with ferumoxytol nanocomplex-labeled macrophages at 7 T has a high sensitivity to detect

Reduced functional magnetic resonance imaging (fMRI)-complexity in Alzheimer's disease (AD) progression has been demonstrated and found to be associated with tauopathy and cognition. However, association of fMRI-complexity with amyloid and influence of genetic risk (APOEɛ4) remain unknown. Here we investigate the association between fMRI-complexity, tau-PET, and amyloid-PET as well as influence of APOE genotype using multivariate generalized linear models. We show that fMRI-complexity has a strong association with tau but not amyloid deposition and that the presence of an APOEɛ4 allele enhances this effect. Thus fMRI-complexity provides a surrogate marker of impaired brain functionality in AD progression.

Objective: To examine the clinical phenotype and genetic deficiencies present in Chinese aniridia families with PAX6 haplotype deficiency., Methods: A comprehensive questionnaire and ophthalmological assessments were administered to both affected patients and unaffected relatives. The clinical feature analysis included the evaluation of visual acuity, intraocular pressure, slit-lamp anterior segment examination, fundus photography, and spectral domain optical coherence tomography. To identify the mutation responsible for aniridia, targeted next-generation sequencing was used as a beneficial technique., Results: A total of 4 mutations were identified, consisting of two novel frameshift mutations (c.314delA, p.K105Sfs*33 and c.838&#95;845dup AACACACC, p.S283Tfs*85), along with two recurring nonsense mutations (c.307C>T, p.R103X and c.619A>T, p.K207*). Complete iris absence, macular foveal hypoplasia, and nystagmus were consistent in these PAX6 haplotype-deficient Chinese aniridia families, while corneal lesions, cataracts, and glaucoma exhibited heterogeneity both among the families and within the same family., Conclusion: In our study, two novel PAX6 mutations associated with aniridia were identified in Chinese families, which expanded the phenotypic and genotypic spectrum of PAX6 mutations. We also analyzed the clinical characteristics of PAX6 haplotype deficiency in Chinese aniridia families., (© 2024. Huazhong University of Science and Technology.)

Long noncoding RNAs are key players in the development of lung adenocarcinoma (LUAD). The present study elucidated the role of LINC01087 in LUAD development. Cell vitality and apoptosis were assessed by the CCK-8 assay and flow cytometry, respectively. The transwell assay was adopted to evaluate cell migration and invasion. Levels of m 6 A modification of LINC01087 were determined using the methylated RNA binding protein immunoprecipitation assay. The interactions among LINC01087, miR-514a-3p, and centrosome protein 55 (CEP55) were evaluated using dual-luciferase reporter, RNA immunoprecipitation, and RNA-RNA pull-down assays. LINC01087 was highly expressed in LUAD, and its downregulation restrained cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition in vitro as well as tumor growth in a xenograft tumor model. Overexpression of miR-514a-3p inhibited malignant phenotypes in LUAD cells by inactivating RhoA/ROCK1 signaling via the suppression of CEP55 expression. Mechanistically, RBM15 increased the expression and mRNA stability of LINC01087 by mediating its m 6 A modification and LINC01087 induced CEP55 expression by sponging miR-514a-3p. RBM15-induced LINC01087 upregulation accelerated LUAD progression by regulating the miR-514a-3p/CEP55/RhoA/ROCK1 axis, illustrating the potential of LINC01087 as a novel target for LUAD therapy., (© 2024 The Author(s). The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

A major challenge for human neuroimaging using functional MRI is the differentiation of neuronal excitation and inhibition which may induce positive and negative BOLD responses. Here we present an innovative multi-contrast laminar functional MRI technique that offers comprehensive and quantitative imaging of neurovascular (CBF, CBV, BOLD) and metabolic (CMRO 2 ) responses across cortical layers at 7 Tesla. This technique was first validated through a finger-tapping experiment, revealing 'double-peak' laminar activation patterns within the primary motor cortex. By employing a ring-shaped visual stimulus that elicited positive and negative BOLD responses, we further observed distinct neurovascular and metabolic responses across cortical layers and eccentricities in the primary visual cortex. This suggests potential feedback inhibition of neuronal activities in both superficial and deep cortical layers underlying the negative BOLD signals in the fovea, and also illustrates the neuronal activities in visual areas adjacent to the activated eccentricities., Competing Interests: 8.Declaration of Competing Interests: The authors have no competing interests.

Objectives: Cerebral blood flow (CBF) measured by arterial spin labeling (ASL) is a promising biomarker for Alzheimer's Disease (AD). ASL data from multiple vendors were included in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. However, the M0 images were missing in Siemens ASL data, prohibiting CBF quantification. Here, we utilized a generative diffusion model to impute the missing M0 and validated generated CBF data with acquired data from GE., Methods: A conditional latent diffusion model was trained to generate the M0 image and validate it on an in-house dataset ( N =55) based on image similarity metrics, accuracy of CBF quantification, and consistency with the physical model. This model was then applied to the ADNI dataset (Siemens: N =211) to impute the missing M0 for CBF calculation. We further compared the imputed data (Siemens) and acquired data (GE) regarding regional CBF differences by AD stages, their classification accuracy for AD prediction, and CBF trajectory slopes estimated by a mixed effect model., Results: The trained diffusion model generated the M0 image with high fidelity (Structural similarity index, SSIM=0.924±0.019; peak signal-to-noise ratio, PSNR=33.348±1.831) and caused minimal bias in CBF values (mean difference in whole brain is 1.07±2.12ml/100g/min). Both generated and acquired CBF data showed similar differentiation patterns by AD stages, similar classification performance, and decreasing slopes with AD progression in specific AD-related regions. Generated CBF data also improved accuracy in classifying AD stages compared to qualitative perfusion data., Interpretation/conclusion: This study shows the potential of diffusion models for imputing missing modalities for large-scale studies of CBF variation with AD.

Background: Older adults with mild cognitive impairment (MCI) exhibit deficits in cerebrovascular reactivity (CVR), suggesting CVR is a biomarker for vascular contributions to MCI. This study examined if spontaneous CVR is associated with MCI and memory impairment., Methods: 161 older adults free of dementia or major neurological/psychiatric disorders were recruited. Participants underwent clinical interviews, cognitive testing, venipuncture for Alzheimer's biomarkers, and brain MRI. Spontaneous CVR was quantified during 5 minutes of rest., Results: Whole brain CVR was negatively associated with age, but not MCI. Lower CVR in the parahippocampal gyrus (PHG) was found in participants with MCI and was linked to worse memory performance on memory tests. Results remained significant after adjusting for Alzheimer's biomarkers and vascular risk factors., Conclusion: Spontaneous CVR deficits in the PHG are observed in older adults with MCI and memory impairment, indicating medial temporal microvascular dysfunction's role in cognitive decline., Competing Interests: Authors had no conflicts of interest.

The blood-brain barrier (BBB) plays a pivotal role in protecting the central nervous system (CNS), shielding it from potential harmful entities. A natural decline of BBB function with aging has been reported in both animal and human studies, which may contribute to cognitive decline and neurodegenerative disorders. Limited data also suggest that being female may be associated with protective effects on BBB function. Here we investigated age and sex-dependent trajectories of perfusion and BBB water exchange rate (kw) across the lifespan in 186 cognitively normal participants spanning the ages of 8 to 92 years old, using a non-invasive diffusion prepared pseudo-continuous arterial spin labeling (DP-pCASL) MRI technique. We found that the pattern of BBB kw decline with aging varies across brain regions. Moreover, results from our DP-pCASL technique revealed a remarkable decline in BBB kw beginning in the early 60s, which was more pronounced in males. In addition, we observed sex differences in parietal and temporal regions. Our findings provide in vivo results demonstrating sex differences in the decline of BBB function with aging, which may serve as a foundation for future investigations into perfusion and BBB function in neurodegenerative and other brain disorders.

Background: Postoperative pneumonia (POP) is the most prevalent of all nosocomial infections in patients who underwent cardiac surgery. The aim of this study was to identify independent risk factors for pneumonia after cardiac surgery, from which we constructed a nomogram for prediction., Methods: The clinical data of patients admitted to the Department of Cardiothoracic Surgery of Nanjing Drum Tower Hospital from October 2020 to September 2021 who underwent cardiac surgery were retrospectively analyzed, and the patients were divided into two groups according to whether they had POP: POP group (n=105) and non-POP group (n=1083). Preoperative, intraoperative, and postoperative indicators were collected and analyzed. Logistic regression was used to identify independent risk factors for POP in patients who underwent cardiac surgery. We constructed a nomogram based on these independent risk factors. Model discrimination was assessed via area under the receiver operating characteristic curve (AUC), and calibration was assessed via calibration plot., Results: A total of 105 events occurred in the 1188 cases. Age (>55 years) (OR: 1.83, P=0.0225), preoperative malnutrition (OR: 3.71, P<0.0001), diabetes mellitus(OR: 2.33, P=0.0036), CPB time (Cardiopulmonary Bypass Time) > 135 min (OR: 2.80, P<0.0001), moderate to severe ARDS (Acute Respiratory Distress Syndrome )(OR: 1.79, P=0.0148), use of ECMO or IABP or CRRT (ECMO: Extra Corporeal Membrane Oxygenation; IABP: Intra-Aortic Balloon Pump; CRRT: Continuous Renal Replacement Therapy )(OR: 2.60, P=0.0057) and MV( Mechanical Ventilation )> 20 hours (OR: 3.11, P<0.0001) were independent risk factors for POP. Based on those independent risk factors, we constructed a simple nomogram with an AUC of 0.82. Calibration plots showed good agreement between predicted probabilities and actual probabilities., Conclusion: We constructed a facile nomogram for predicting pneumonia after cardiac surgery with good discrimination and calibration. The model has excellent clinical applicability and can be used to identify and adjust modifiable risk factors to reduce the incidence of POP as well as patient mortality., (© 2024. The Author(s).)

In insects, chemosensory proteins (CSPs) play an important role in the perception of the external environment and have been widely used for protein-binding characterization. Riptortus pedestris has received increased attention as a potential cause of soybean staygreen syndrome in recent years. In this study, we found that RpedCSP4 expression in the antennae of adult R. pedestris increased with age, with no significant difference in expression level observed between males and females, as determined through quantitative real-time polymerase chain reaction (qRT-PCR). Subsequently, we investigated the ability of RpedCSP4 to bind various ligands (five aggregated pheromone components and 13 soybean volatiles) using a prokaryotic expression system and fluorescence competitive binding assays. We found that RpedCSP4 binds to three aggregated pheromone components of R. pedestris, namely, ((E)-2-hexenyl (Z)-3-hexenoate (E2Z3), (E)-2-hexenyl (E)-2-hexenoate (E2E2), and (E)-2-hexenyl hexenoate (E2HH)), and that its binding capacities are most stable under acidic condition. Finally, the structure and protein-ligand interactions of RpedCSP4 were further analyzed via homology modeling, molecular docking, and targeted mutagenesis experiments. The L29A mutant exhibited a loss of binding ability to these three aggregated pheromone components. Our results show that the olfactory function of RpedCSP4 provides new insights into the binding mechanism of RpedCSPs to aggregation pheromones and contributes to discover new target candidates that will provide a theoretical basis for future population control of R. pedestris., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rubus, the largest genus in Rosaceae, contains over 1400 species that distributed in multiple habitats across the world, with high species diversity in the temperate regions of Northern Hemisphere. Multiple Rubus species are cultivated for their valuable fruits. However, the intrageneric classification and phylogenetic relationships are still poorly understood. In this study, we sequenced, assembled, and characterized 17 plastomes of Rubus, and conducted comparative genomics integrating with 47 previously issued plastomes of this genus. The 64 plastomes of Rubus exhibited typical quadripartite structure with sizes ranging from 155,144 to 156,700 bp, and contained 132 genes including 87 protein-coding genes, 37 tRNA genes and eight rRNA genes. All plastomes are conservative in the gene order, the frequency of different types of long repeats and simple sequence repeats (SSRs), the codon usage, and the selection pressure of protein-coding genes. However, there are also some differences in the Rubus plastomes, including slight contraction and expansion of the IRs, a variation in the numbers of SSRs and long repeats, and some genes in certain clades undergoing intensified or relaxed purifying selection. Phylogenetic analysis based on whole plastomes showed that the monophyly of Rubus was strongly supported and resolved it into six clades corresponding to six subgenera. Moreover, we identified 12 highly variable regions that could be potential molecular markers for phylogenetic, population genetic, and barcoding studies. Overall, our study provided insight into plastomic structure and sequence diversification of Rubus, which could be beneficial for future studies on identification, evolution, and phylogeny in this genus., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of competing interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Oxidative alkene functionalization reactions are a fundamental class of complexity-building organic transformations. However, the majority of established approaches rely on electrophilic reagents that limit the diversity of groups that can be installed. Recent advances have established a new approach that instead relies on the transformation of alkenes into thianthrene-derived cationic electrophiles. These linchpin intermediates can be generated selectively and undergo a diverse array of mechanistically distinct reactions with abundant nucleophiles. Taken together, this unlocks a suite of net oxidative alkene transformations that have been elusive using conventional strategies. This Minireview describes these advances and is organized around the three distinct synthons formally accessible from alkenes via thianthrenation: 1) alkenyl cations; 2) vicinal dications; 3) allyl cations. Throughout the Minireview, we illustrate how thianthrenium salts address key limitations endemic to classic alkene-derived electrophiles and highlight the mechanistic origins of these distinctions wherever possible., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background: Pancreatic ductal adenocarcinoma (PDAC) presents with a high mortality rate. Two important features of PDAC contribute to this poor outcome. The first is metastasis which occurs in ~ 80% of PDAC patients. The second is cachexia, which compromises treatment tolerance for patients and reduces their quality of life. Although various mouse models of PDAC exist, recapitulating both metastatic and cachectic features have been challenging., Methods: Here, we optimize an orthotopic mouse model of PDAC by altering several conditions, including the subcloning of parental murine PDAC cells, implantation site, number of transplanted cells, and age of recipient mice. We perform spatial profiling to compare primary and metastatic immune microenvironments and RNA sequencing to gain insight into the mechanisms of muscle wasting in PDAC-induced cachexia, comparing non-metastatic to metastatic conditions., Results: These modifications extend the time course of the disease and concurrently increase the rate of metastasis to approximately 70%. Furthermore, reliable cachexia endpoints are achieved in both PDAC mice with and without metastases, which is reminiscent of patients. We also find that cachectic muscles from PDAC mice with metastasis exhibit a similar transcriptional profile to muscles derived from mice and patients without metastasis., Conclusion: Together, this model is likely to be advantageous in both advancing our understanding of the mechanism of PDAC cachexia, as well as in the evaluation of novel therapeutics., (© 2024. The Author(s).)

Temporary neurological dysfunction (TND), a common complication following surgical repair of Type A Aortic Dissection (TAAD), is closely associated with increased mortality and long-term cognitive impairment. Currently, effective treatment options for TND remain elusive. Therefore, we sought to investigate the potential of postoperative relative band power (RBP) in predicting the occurrence of postoperative TND, with the aim of identifying high-risk patients prior to the onset of TND. We conducted a prospective observational study between February and December 2022, involving 165 patients who underwent surgical repair for TAAD at our institution. Bedside Quantitative electroencephalography (QEEG) was utilized to monitor the post-operative brain electrical activity of each participant, recording changes in RBP (RBP Delta, RBP Theta, RBP Beta and RBP Alpha), and analyzing their correlation with TND. Univariate and multivariate analyses were employed to identify independent risk factors for TND. Subsequently, line graphs were generated to estimate the incidence of TND. The primary outcome of interest was the development of TND, while secondary outcomes included intensive care unit (ICU) admission and length of hospital stay. A total of 165 patients were included in the study, among whom 68 (41.2%) experienced TND. To further investigate the independent risk factors for postoperative TND, we conducted both univariate and multivariate logistic regression analyses on all variables. In the univariate regression analysis, we identified age (Odds Ratio [OR], 1.025; 95% CI, 1.002-1.049), age ≥ 60 years (OR, 2.588; 95% CI, 1.250-5.475), hemopericardium (OR, 2.767; 95% CI, 1.150-7.009), cardiopulmonary bypass (CPB) (OR, 1.007; 95% CI, 1.001-1.014), RBP Delta (OR, 1.047; 95% CI, 1.020-1.077), RBP Alpha (OR, 0.853; 95% CI, 0.794-0.907), and Beta (OR, 0.755; 95% CI, 0.649-0.855) as independent risk factors for postoperative TND. Further multivariate regression analyses, we discovered that CPB time ≥ 180 min (OR, 1.021; 95% CI, 1.011-1.032), RBP Delta (OR, 1.168; 95% CI, 1.105-1.245), and RBP Theta (OR, 1.227; 95% CI, 1.135-1.342) emerged as independent risk factors. TND patients had significantly longer ICU stays (p < 0.001), and hospital stays (p = 0.002). We obtained the simplest predictive model for TND, consisting of three variables (CPB time ≥ 180 min, RBP Delta, RBP Theta, upon which we constructed column charts. The areas under the receiver operating characteristic (AUROC) were 0.821 (0.755, 0.887). Our study demonstrates that postoperative RBP monitoring can detect changes in brain function in patients with TAAD during the perioperative period, providing clinicians with an effective predictive method that can help improve postoperative TND in TAAD patients. These findings have important implications for improving clinical care in this population.Trial registration ChiCTR2200055980. Registered 30th Jan. 2022. This trial was registered before the first participant was enrolled., (© 2024. The Author(s).)

Background: Acute Type A aortic dissection (ATAAD) is a life-threatening cardiovascular disease associated with high mortality rates, where surgical intervention remains the primary life-saving treatment. However, the mortality rate for ATAAD operations continues to be alarmingly high. To address this critical issue, our study aimed to assess the correlation between preoperative laboratory examination, clinical imaging data, and postoperative mortality in ATAAD patients. Additionally, we sought to establish a reliable prediction model for evaluating the risk of postoperative death., Methods: In this study, a total of 384 patients with acute type A aortic dissection (ATAAD) who were admitted to the emergency department for surgical treatment were included. Based on preoperative laboratory examination and clinical imaging data of ATAAD patients, logistic analysis was used to obtain independent risk factors for postoperative in-hospital death. The survival prediction model was based on cox regression analysis and displayed as a nomogram., Results: Logistic analysis identified several independent risk factors for postoperative in-hospital death, including Marfan syndrome, previous cardiac surgery history, previous renal dialysis history, direct bilirubin, serum phosphorus, D-dimer, white blood cell, multiple aortic ruptures and age. A survival prediction model based on cox regression analysis was established and presented as a nomogram. The model exhibited good discrimination and significantly improved the prediction of death risk in ATAAD patients., Conclusions: In this study, we developed a novel survival prediction model for acute type A aortic dissection based on preoperative clinical features. The model demonstrated good discriminatory power and improved accuracy in predicting the risk of death in ATAAD patients undergoing open surgery., (© 2024. The Author(s).)

Objective: Autosomal recessive bestrophinopathy (ARB), a retinal degenerative disease, is characterized by central visual loss, yellowish multifocal diffuse subretinal deposits, and a dramatic decrease in the light peak on electrooculogram. The potential pathogenic mechanism involves mutations in the BEST1 gene, which encodes Ca 2+ -activated Cl - channels in the retinal pigment epithelium (RPE), resulting in degeneration of RPE and photoreceptor. In this study, the complete clinical characteristics of two Chinese ARB families were summarized., Methods: Pacific Biosciences (PacBio) single-molecule real-time (SMRT) sequencing was performed on the probands to screen for disease-causing gene mutations, and Sanger sequencing was applied to validate variants in the patients and their family members., Results: Two novel mutations, c.202T>C (chr11:61722628, p.Y68H) and c.867+97G>A, in the BEST1 gene were identified in the two Chinese ARB families. The novel missense mutation BEST1 c.202T>C (p.Y68H) resulted in the substitution of tyrosine with histidine in the N-terminal region of transmembrane domain 2 of bestrophin-1. Another novel variant, BEST1 c.867+97G>A (chr11:61725867), located in intron 7, might be considered a regulatory variant that changes allele-specific binding affinity based on motifs of important transcriptional regulators., Conclusion: Our findings represent the first use of third-generation sequencing (TGS) to identify novel BEST1 mutations in patients with ARB, indicating that TGS can be a more accurate and efficient tool for identifying mutations in specific genes. The novel variants identified further broaden the mutation spectrum of BEST1 in the Chinese population., (© 2024. Huazhong University of Science and Technology.)

Objectives: Misdiagnosis of acute aortic syndrome (AAS) significantly increases mortality. Tenascin-C (TN-C) is an extracellular matrix glycoprotein related to cardiovascular injury. The elevation of TN-C in AAS and whether it can discriminate sudden-onset of acute chest pain in Chinese remains unclear., Methods: We measured the plasma concentration of TN-C by ELISA in a cohort of 376 patients with chest or back pain. Measures to discriminate AAS from acute coronary syndrome (ACS) were compared and calculated., Results: From October 2016 to September 2021, 376 undiagnosed patients with chest or back pain were enrolled. 166 of them were finally diagnosed as AAS, 100 were ACS and 110 without cardiovascular diseases (NCV). TN-C was significantly elevated in AAS at 18.18 ng/mL (IQR: 13.10-27.68) compared with 7.51 ng/mL (IQR: 5.67-11.38) in ACS ( P < 0.001) and 3.68 ng/mL (IQR: 2.50-5.29) in NCV ( P < 0.001). There was no significant difference in TN-C level among the subtypes of AAS. Of the 166 AAS patients, the peaked level of TN-C was at acute stage ( P = 0.012), then a slight of decrease was observed at subacute stage. The area under receiver operating characteristic curve for AAS patients versus NCV was 0.979 (95% CI: 0.964-0.994) for TN-C. At a cutoff level of 11.474 ng/mL, TN-C has a sensitivity of 76.0%, specificity of 85.5%, accuracy of 82.0%, positive predictive value (PPV) of 76.0%, negative predictive value (NPV) of 85.5%. Diagnostic performance of TN-C was superior to D-dimer and hs-cTnT., Conclusions: The concentration of serum TN-C in AAS patients was significantly higher than that in ACS patients and NCV. TN-C could be a new biomarker to distinguish AAS patients in the early stage after symptoms onset from other pain diseases., (© 2024 JGC All rights reserved; www.jgc301.com.)

Background: Postoperative hyper-inflammation is a frequent event in patients with acute Stanford type A aortic dissection (ATAAD) after surgical repair. This study's objective was to determine which inflammatory biomarkers could be used to make a better formula for identifying postoperative hyper-inflammation, and which risk factors were associated with hyper-inflammation., Methods: A total of 405 patients were enrolled in this study from October 1, 2020 to April 1, 2023. Of these patients, 124 exhibited poor outcomes. In order to investigate the optimal cut-off values for poor outcomes, logistic and receiver operating characteristic analyses were performed on the following parameters on the first postoperative day: procalcitonin (PCT), C-reactive protein (CRP), interleukin-6 (IL-6), and systemic immune-inflammation index (SII). These cut-off points were used to separate the patients into hyper-inflammatory (n = 52) and control (n = 353) groups. Finally, the logistic were used to find the risk factors of hyper-inflammatory., Results: PCT, CRP, IL-6, and SII were independent risk factors of poor outcomes in the multivariate logistic model. Cut-off points of these biomarkers were 2.18 ng/ml, 49.76 mg/L, 301.88 pg/ml, 2509.96 × 10 9 /L respectively. These points were used to define postoperative hyper-inflammation (OR 2.97, 95% CI 1.35-6.53, P < 0.01). Cardiopulmonary bypass (CPB) > 180 min, and deep hypothermia circulatory arrest (DHCA) > 40 min were the independent risk factors for hyper-inflammation., Conclusions: PCT > 2.18, CRP > 49.76, IL-6 > 301.88, and SII < 2509.96 could be used to define postoperative hyper-inflammation which increased mortality and morbidity in patients after ATAAD surgery. Based on these findings, we found that CPB > 180 min and DHCA > 40 min were separate risk factors for postoperative hyper-inflammation., (© 2024. The Author(s).)

Introduction: Ginkgo biloba extract (GBE) is an effective substance from traditional Chinese medicine (TCM) G. biloba for treating ischaemic stroke (IS). However, its active ingredients and mechanism of action remain unclear., Objectives: This study aimed to reveal the potential active component group and possible anti-IS mechanism of GBE., Materials and Methods: The network pharmacology method was used to reveal the possible anti-IS mechanism of these active ingredients in GBE. An ultra-high-performance liquid chromatography triple quadrupole electrospray tandem mass spectrometry (UPLC-MS/MS) method was established for the simultaneous detection of the active ingredients of GBE., Results: The active components of GBE anti-IS were screened by literature integration. Network pharmacology results showed that the anti-IS effect of GBE is achieved through key active components such as protocatechuic acid, bilobalide, ginkgolide A, and so on. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the possible anti-IS mechanism of GBE is regulating the PI3K-Akt signalling pathway and other signal pathways closely related to inflammatory response and apoptosis regulation combined with AKT1, MAPK, TNF, ALB, CASP3, and other protein targets. Nineteen main constituents in seven batches of GBE were successfully analysed using the established UPLC-MS/MS method, and the results showed that the content of protocatechuic acid, gallic acid, ginkgolide A, and so forth was relatively high, which was consistent with network pharmacology results, indicating that these ingredients may be the key active anti-IS ingredients of GBE., Conclusion: This study revealed the key active components and the anti-IS mechanism of GBE. It also provided a simple and sensitive method for the quality control of related preparations., (© 2023 John Wiley & Sons, Ltd.)

This study aims to investigate the component variations and spatial distribution of ginsenosides in Panax quinquefolium roots during repeated steaming and drying. Ultra performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS/MS) was employed to identify the ginsenosides in the root extract. Matrix-assisted laser desorption/ionization mass spectrometry imaging(MALDI-MSI) was employed to visualize the spatial distribution and spatiotemporal changes of prototype ginsenosides and metabolites in P. quinquefolium roots. The UPLC results showed that 90 ginsenosides were identified during the steaming process of the roots, and polar ginsenosides were converted into low polar or non-polar ginsenosides. The content of prototype ginsenosides decreased, while that of rare ginsenosides increased, which included 20(S/R)-ginsenoside Rg&#95;3, 20(S/R)-ginsenoside Rh&#95;2, and ginsenosides Rk&#95;1, Rg&#95;5, Rs&#95;5, and Rs&#95;4. MALDI-MSI results showed that ginsenosides were mainly distributed in the epidermis and phloem. As the steaming times increased, ginsenosides were transported to the xylem and medulla. This study provides fundamental information for revealing the changes of biological activity and pharmacological effect of P. quinquefolium roots that are caused by repeated steaming and drying and gives a reference for expanding the application scope of this herbal medicine.

This study aims to explore the roles of phenylacetyl glutamine (PAGln) on myocardial infarction (MI) pathogenesis. Here, using targeted metabolomics analysis, it was found that the plasma metabolite PAGln was upregulated in coronary artery disease (CAD) patients and MI mice and could be an independent risk factor for CAD. In vivo and in vitro functional experiments revealed that PAGln pretreatment enhanced MI-induced myocardial injury and cardiac fibrosis, as evident by the increased infarct size, cardiomyocyte death, and the upregulated expression of cardiac fibrosis markers (Col1a1 and α-SMA). Combined with RNA-sequencing analysis and G protein-coupled receptor (GPCR) inhibitor, we found that the GPCR signaling activation is essential for PAGln-mediated effects on cardiomyocyte death. Furthermore, drug affinity responsive target stability and cellular thermal shift assay demonstrated that PAGln could interact with β1-adrenergic receptor (AR). Moreover, β1-AR blocker treatment indeed extended the cardiac remodeling after PAGln-enhanced MI. These results suggest that PAGln might be a potential therapeutic target for extending the cardiac remodeling window in MI patients that signals via β1-AR., (© 2023 Wiley Periodicals LLC.)

Introduction: We investigated whether retinal capillary perfusion is a biomarker of cerebral small vessel disease and impaired cognition among Black Americans, an understudied group at higher risk for dementia., Methods: We enrolled 96 Black Americans without known cognitive impairment. Four retinal perfusion measures were derived using optical coherence tomography angiography. Neurocognitive assessment and brain magnetic resonance imaging (MRI) were performed. Multiple linear regression analyses were performed., Results: Lower retinal capillary perfusion was correlated with worse Oral Symbol Digit Test (P < = 0.005) and Fluid Cognition Composite scores (P < = 0.02), but not with the Crystallized Cognition Composite score (P > = 0.41). Lower retinal perfusion was also correlated with higher free water and peak width of skeletonized mean diffusivity, and lower fractional anisotropy (all P < 0.05) on MRI (N = 35)., Discussion: Lower retinal capillary perfusion is associated with worse information processing, fluid cognition, and MRI biomarkers of cerebral small vessel disease, but is not related to crystallized cognition., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)