Vineyard microclimate alterations induced by black inter-row mulch through transcriptome reshaped the flavoromics of cabernet sauvignon grapes.

BACKGROUND: Weed control is essential for agricultural floor management in vineyards and the inter-row mulching is an eco-friendly practice to inhibit weed growth via filtering out photosynthetically active radiation. Besides weed suppression, inter-row mulching can influence grapevine growth and the accumulation of metabolites in grape berries. However, the complex interaction of multiple factors in the field challenges the understanding of molecular mechanisms on the regulated metabolites. In the current study, black geotextile inter-row mulch (M) was applied for two vintages (2016-2017) from anthesis to harvest. Metabolomics and transcriptomics analysis were conducted in two vintages, aiming to provide insights into metabolic and molecular responses of Cabernet Sauvignon grapes to M in a semi-arid climate. RESULTS: Upregulation of genes related to photosynthesis and heat shock proteins confirmed that M weakened the total light exposure and grapes suffered heat stress, resulting in lower sugar-acid ratio at harvest. Key genes responsible for enhancements in phenylalanine, glutamine, ornithine, arginine, and C6 alcohol concentrations, and the downward trend in ε-viniferin, anthocyanins, flavonols, terpenes, and norisoprenoids in M grapes were identified. In addition, several modules significantly correlated with the metabolic biomarkers through weighted correlation network analysis, and the potential key transcription factors regulating the above metabolites including VviGATA11, VviHSFA6B, and VviWRKY03 were also identified. CONCLUSION: This study provides a valuable overview of metabolic and transcriptomic responses of M grapes in semi-arid climates, which could facilitate understanding the complex regulatory network of metabolites in response to microclimate changes.

Artificial shading of teinturier grape Kolor clusters reveals light-responsive biomarkers: focus on flavonoid profiles and metabolism.

Kolor is a teinturier grape cultivar, that accumulates flavonoids in the skin and pulp. However, the concentrations and proportions of flavonoids in Kolor skin and pulp differ, suggesting tissue specificity in teinturier grapes. Light conditions significantly influence the evolution of flavonoids. Moreover, studies on the mechanisms governing flavonoid accumulation in light response sensitivity of teinturier grapes are limited. In the three consecutive years of study, the exposure of Kolor clusters was altered by bagging from pre-veraison to harvest. QqQ/MS and RT‒qPCR wereused to determine the individual anthocyanin contents and the relative gene expression. There was a significant decrease in the total anthocyanins and flavonols in the Kolor berries, with flavonols showing greater sensitivity to bagging. Bagging did not exert a consistent impact on the flavan-3-ols in Kolor berries. The sensitivities of anthocyanins in Kolor skin and pulp differed under light exclusion conditions. The concentration of trihydroxy-substituted anthocyanins in the skin decreased, while the proportion of dihydroxy-substituted anthocyanins in the pulp significantly increased, but the anthocyanin concentration in the pulp did not change significantly after bagging. The contents of malvidins and quercetins in the skin, and myricetins and quercetins in the pulp, were significantly reduced after bagging. The expression of flavonoid synthesis genes in Kolor skin and pulp was tissue-specific. After bagging, UFGT expression increased in the pulp and decreased in the skin. In addition, LDOX, FLS-1, CHI-1, CHI-2, F3H-1, F3H-2, and MYB4a exhibited sensitive light responses in both the skin and pulp. This study offers new insights into the regulation of flavonoids in Kolor grapes under light exclusion conditions.

Imp7 siRNA nanoparticles protect against mechanical ventilation-associated liver injury by inhibiting HMGB1 production and NETs formation.

Mechanical ventilation (MV) has the potential to induce extra-pulmonary organ damage by adversely affecting the lungs and promoting the secretion of inflammatory cytokines. High-mobility group box 1 protein (HMGB1) is a pro-inflammatory mediator in ventilator-induced lung injury (VILI), but its effect on MV-associated liver injury and the mechanisms are poorly understood. In the present study, mice were subjected to high-volume MV (20 ml/kg) to induce VILI. MV-induced HMGB1 prompted neutrophil extracellular traps (NETs) formation and PANoptosis within the liver. Inhibiting NETs formation by DNase I or PAD4 inhibitor, or by HMGB1 neutralizing ameliorated the liver injury. HMGB1 activated neutrophils to form NETs through TLR4/MyD88/TRAF6 pathway. Importantly, Importin7 siRNA nanoparticles inhibited HMGB1 release and protected against MV-associated liver injury. These data provide evidence of MV-induced HMGB1 prompted NETs formation and PANoptosis in the liver via the TLR4/MyD88/TRAF6 pathway. HMGB1 is a potential therapeutic target for MV-associated liver injury.

ANGPT2/CAV1 regulates albumin transcytosis of glomerular endothelial cells under high glucose exposure and is impaired by losartan / ANGPT2/CAV1 regula la transcitosis de la albúmina de las células endoteliales glomerulares bajo exposición a hiperglucemia, alterándose con la intervención de losartan

Background Microalbuminuria is a common clinical symptom that manifests in the early stages of diabetic kidney disease (DKD) and is also the main feature of glomerular endothelial cells (GECs) injury. There is increasing evidence that the transcytosis of albumin across GECs is closely related to the formation of albuminuria. Our previous studies have shown that angiopoietin 2 (ANGPT2) can inhibit albumin transcytosis across renal tubular epithelial cells by activating caveolin 1 (CAV1) phosphorylation during high glucose (HG) exposure. The role of ANGPT2 in albumin transcytosis across GECs remains unclear. Losartan significantly reduces albuminuria, but the mechanism has not been clarified. Methods We established an in vitro albumin transcytosis model to investigate the change in albumin transcytosis across human renal glomerular endothelial cells (hrGECs) under normal glucose (NG), high glucose (HG) and losartan intervention. We knocked down ANGPT2 and CAV1 to evaluate their roles in albumin transcytosis across hrGECs and verified the relationship between them. In vivo, DKD mouse models were established and treated with different doses of losartan. Immunohistochemistry and Western blot were used to detect the expression of ANGPT2 and CAV1. Results In vitro, the transcytosis of albumin across hrGECs was significantly increased under high glucose stimulation, and losartan inhibited this process. The expression of ANGPT2 and CAV1 were both increased in hrGECs under HG conditions and losartan intervention reduced the expression of them. Moreover, ANGPT2 downregulation reduced albumin transcytosis in hrGECs by regulating CAV1 expression. In vivo, the expression of ANGPT2 and CAV1 in the glomerulus was both increased significantly in DKD mice. Compared with DKD mice, losartan treatment reduced albuminuria and decreased the expression of ANGPT2 and CAV1 in a dose-dependent manner (AU)

Antecedentes La microalbuminuria es un síntoma clínico común que se manifiesta en las fases tempranas de la enfermedad renal diabética (ERD), y también es característica del daño de las células endoteliales glomerulares (GEC). Existe evidencia creciente en cuanto a que la transcitosis de la albúmina a través de las GEC está estrechamente relacionada con la formación de albuminuria. Nuestros estudios previos reflejaron que angiopoyetina 2 (ANGPT2) puede inhibir la transcitosis de la albúmina a través de las células epiteliales tubulares renales activando la fosforilación de caveolina 1 (CAV1) durante la exposición a hiperglucemia (HG). El rol de ANGPT2 en la transcitosis de la albúmina a través de las GEC resulta incierto. Losartan reduce considerablemente la albuminuria, aunque no se ha esclarecido el mecanismo. Métodos Establecimos un modelo in vitro de transcitosis de la albúmina para investigar el cambio de dicho mecanismo a través de las células endoteliales glomerulares renales humanas (hrGEC) en condiciones de glucosa normal (GN), hiperglucemia (HG) e intervención de losartan. Realizamos breakdown de ANGPT2 y CAV1 para evaluar sus roles en la transcitosis de la albúmina a través de las hrGEC, y verificamos la relación entre ellas. Se establecieron modelos in vivo de ratones con ERD, tratados con diferentes dosis de losartan. Se utilizaron pruebas de inmunohistoquímica e inmunotransferencia para detectar la expresión de ANGPT2 y CAV1. Resultados In vitro, la transcitosis de la albúmina a través de hrGEC se incrementó considerablemente en condiciones de estimulación de la hiperglucemia, inhibiendo losartan este proceso. La expresión de ANGPT2 y CAV1 se incrementó en las hrGEC en condiciones de HG, reduciendo la intervención de losartan la expresión de ambas (AU)

The National Institutes of Health INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project: Accelerating research discoveries for people with Down syndrome across the lifespan.

The National Institutes of Health (NIH) has a long-standing history of support for research in Down syndrome (DS). In response to a 2018 congressional directive for a trans-NIH initiative to address medical issues in DS, NIH launched the INCLUDE Project (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE). Reflecting the three INCLUDE components of basic science research, cohort development, and clinical trials, the Project has published funding opportunities to address conditions such as immune disorders and Alzheimer's disease. Due to a steady expansion in dedicated funding over its first 5 years, INCLUDE has invested $258 M in over 250 new research projects. INCLUDE also supports training initiatives to expand the number and diversity of investigators studying DS. NIH has funded an INCLUDE Data Coordinating Center that is collecting de-identified clinical information and multi-omics data from research participants for broad data sharing and secondary analyses. Through the DS-Connect® registry, INCLUDE investigators can access recruitment support. The INCLUDE Research Plan articulates research goals for the program, with an emphasis on diversity of research participants and investigators. Finally, a new Cohort Development Program is poised to increase the impact of the INCLUDE Project by recruiting a large DS cohort across the lifespan.

Adjusting the pomace ratio during red wine fermentation: Effects of adding white grape pomace and juice runoff on wine flavoromics and sensory qualities.

Adding pomace or juice runoff during maceration is a traditional winemaking process. To mitigate the negative effects of rainfall during harvest and examine the effects of adjusting the pomace ratio during fermentation on the flavor profile of Marselan grape wines, the prefermentation addition of Petit Manseng grape pomace (PAP) and prefermentation juice runoff (PJR) was determined. The phenolic and volatile compounds were investigated using HPLC-MS and GC-MS. PAP enriched the flavanols and PJR enriched the pigment and copigment matrix. Approximate 10% increase in the ratio of pomace promoted the formation of anthocyanin derivatives. The increased pomace ratio reduced the concentration of volatile compounds without impacting the aroma quality. Sensory analysis revealed PAP wines scored higher for acidity and astringency and PJR wines scored higher for color. In conclusion, an appropriate increase in the pomace ratio of approximately 10% can enhance the color and mouthfeel of the wine while having a limited influence on aroma.

Red Emission Carbon Nanoparticles Which Can Simultaneously Responding to Hypochlorite and pH.

Multi-targets detection has obtained much attention because this sensing mode can realize the detection of multi-targets simultaneously, which is helpful for biomedical analysis. Carbon nanoparticles have attracted extensive attention due to their superior optical and chemical properties, but there are few reports about red emission carbon nanoparticles for simultaneous detection of multi-targets. In this paper, a red emission fluorescent carbon nanoparticles were prepared by 1, 2, 4-triaminobenzene dihydrochloride at room temperature. The as-prepared red emission fluorescent carbon nanoparticles exhibited strong emission peak located at 635 nm with an absolute quantum yield up to 24%. They showed excellent solubility, high photostability and good biocompatibility. Furthermore, it could sensitively and selectively response to hypochlorite and pH, thus simultaneous detection of hypochlorite and pH was achieved by combining the red emission fluorescent carbon nanoparticles with computational chemistry. The formation mechanisms of red emission fluorescent carbon nanoparticles and their response to hypochlorite and pH were investigated, respectively.

Vineyard soil heterogeneity and harvest date affect volatolomics and sensory attributes of Cabernet Sauvignon wines on a meso-terroir scale.

To produce premium wines in a specific region is the goal of local oenologists. This study aimed to investigate the influence of soil properties and harvest date on the volatolomics of wine to provide a better insight into single-vineyard wines. Six Cabernet Sauvignon vineyards were selected in a semi-arid region to produce their wines at three harvest ripeness levels ranging from 23°Brix-28°Brix in three seasons (2019-2021). Results showed that among all six vineyards, the vineyard with the highest soil pH produced wines with lower C6 alcohols and herbaceous aroma. Moderate nutrition in soils was beneficial for the accumulation of ß-damascenone and enhanced fruity and floral aroma in wines while over-fertile soil produced wines with the lowest sensory score. As the harvest ripeness elevated, the wine's fruity and floral aroma intensity decreased. Through advanced network analysis, the key volatiles such as ß-damascenone, ethy1 lactate, and isoamyl octanoate, and their interaction in affecting wine sensory scores were evaluated. Our study provided a concept for producing premium single-vineyard wines.

The key role of vineyard parcel in shaping flavonoid profiles and color characteristics of Cabernet Sauvignon wines combined with the influence of harvest ripeness, vintage and bottle aging.

Recently, revealing the terroir influence on wine chemical features has drawn increasing interest. This study aimed to explain how wine flavonoid signatures were altered by vineyard parcel, harvest ripeness, vintage and bottle aging. Six commercial Cabernet Sauvignon vineyards were selected in the Manas region to produce wines at three harvest ripeness in three seasons (2019-2021) and aged for three years. The six vineyards had little difference in mesoclimate conditions while varying greatly in soil composition. Results showed high vineyard pH (> 8.5) could accelerate grape ripening rate and increase wine flavonol concentration. Vineyards with moderate nutrition produced wines with abundant anthocyanin derivatives and maintained color characteristics during aging. The role of detailed anthocyanin derivatives in regulating wine color was clarified. As the harvest ripeness elevated, wine's flavonoid profiles were altered and gained a higher red color intensity. This work provides chemical mechanisms underlying single-vineyard wines and a theoretical basis for targeted wine production.

Prevalence of cerebral palsy comorbidities in China: a systematic review and meta-analysis.

Objectives: This systematic review aimed to comprehensively understand the comorbidity of cerebral palsy (CP) in China. Methods: We searched through databases in both Chinese and English until December 2022 to gather cross-sectional studies on the comorbidity of CP in China. After two reviewers independently screened the articles, collected the data, and assessed the bias risk, a meta-analysis was conducted using the Stata 17.0 software. Results: A total of 73 articles were included. Of these, 16 articles reported total comorbidity, with a prevalence of 79.7% (95% CI: 73.8-85.7%); 56 articles reported epilepsy, with a prevalence of 17.9% (95% CI: 15.4-20.4%); 48 articles reported intellectual disability, with a prevalence of 58.0% (95% CI: 51.8-64.3%); 32 articles reported speech disorders, with a prevalence of 48.0% (95% CI: 41.6-54.4%); 41 articles reported hearing disorders, with a prevalence of 17.2% (95% CI: 13.0-21.4%); and 35 articles reported vision disorders, with a prevalence of 23.1% (95% CI: 16.3-29.8%). The topographical type of CP was the primary source of heterogeneity in the prevalence of epilepsy. Diagnostic criteria for CP, clinical type of CP, GMFCS, publishing time, and topographical type of CP were the primary sources of heterogeneity in the prevalence of intellectual disability. Clinical type of CP and topographical type were the primary sources of heterogeneity in the prevalence of speech disorders. Finally, the region was the primary source of heterogeneity in the prevalence of hearing disorders. Conclusion: The prevalence of comorbidities in CP is high in China. Comorbidities are related to the characteristics, severity, and risk factors of brain insult and have a particular relationship with regional economic development and medical and health levels.

Study on inflammation and fibrogenesis in MAFLD from 2000 to 2022: a bibliometric analysis.

Chronic inflammation and fibrosis are significant factors in the pathogenesis of metabolic-associated fatty liver disease (MAFLD). In this study, we conducted a bibliometric analysis of publications on inflammation and fibrogenesis in MAFLD, with a focus on reporting publication trends. Our findings indicate that the USA and China are the most productive countries in the field, with the University of California San Diego being the most productive institution. Over the past 23 years, Prof. Diehl AM has published 25 articles that significantly contributed to the research community. Notably, the research focus of the field has shifted from morbid obesity and adiponectin to metabolic syndrome, genetics, and microbiome. Our study provides a comprehensive and objective summary of the historical characteristics of research on inflammation and fibrogenesis in MAFLD, which will be of interest to scientific researchers in this field.

Systemic cytokines inhibition with Imp7 siRNA nanoparticle ameliorates gut injury in a mouse model of ventilator-induced lung injury.

Mechanical ventilation (MV) may negatively affect the lungs and cause the release of inflammatory mediators, resulting in extra-pulmonary organ dysfunction. Studies have revealed systemically elevated levels of proinflammatory cytokines in animal models of ventilator-induced lung injury (VILI); however, whether these cytokines have an effect on gut injury and the mechanisms involved remain unknown. In this study, VILI was generated in mice with high tidal volume mechanical ventilation (20 ml/kg). Tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 concentrations in serum and gut measured by ELISA showed significant elevation in the VILI mice. Significant increases in gut injury and PANoptosis were observed in the VILI mice, which were positively correlated with the serum levels of TNF-α, IL-1ß, and IL-6. The VILI mice displayed intestinal barrier defects, decreased expressions of occludin and zonula occludin-1 (ZO-1), and increased expression of claudin-2 and the activation of myosin light chain (MLC). Importantly, intratracheal administration of Imp7 siRNA nanoparticle effectively inhibited cytokines production and protected mice from VILI-induced gut injury. These data provide evidence of systemic cytokines contributing to gut injury following VILI and highlight the possibility of targeting cytokines inhibition via Imp7 siRNA nanoparticle as a potential therapeutic intervention for alleviating gut injury following VILI.

Proceedings of the NHLBI Workshop on Artificial Intelligence in Cardiovascular Imaging: Translation to Patient Care.

Artificial intelligence (AI) promises to revolutionize many fields, but its clinical implementation in cardiovascular imaging is still rare despite increasing research. We sought to facilitate discussion across several fields and across the lifecycle of research, development, validation, and implementation to identify challenges and opportunities to further translation of AI in cardiovascular imaging. Furthermore, it seemed apparent that a multidisciplinary effort across institutions would be essential to overcome these challenges. This paper summarizes the proceedings of the National Heart, Lung, and Blood Institute-led workshop, creating consensus around needs and opportunities for institutions at several levels to support and advance research in this field and support future translation.

Comparative efficacy of aromatase inhibitors and gonadotropin-releasing hormone analogue in increasing final height of idiopathic short stature boys: a network meta-analysis.

Objective: To investigate the efficacy of monotherapy with AIs or GnRHa in improving the height of boys with idiopathic short stature (ISS). Method: We performed a systematic search in Pubmed, The Cochrane Library, Chinese National Knowledge Infrastructure databases, and Wanfang Database for eligible studies. The network meta-analysis was conducted using STATA software. Results: We identified a total of four studies that included 136 individuals. We used FAH/PAH as the main outcome of final height. The results revealed a statistically higher final height after treatment with AI or GnRHa in idiopathic short stature children(MD= 4.63, 95% CI[3.29,5.96]). In network meta-analysis, the direct and indirect comparison between AI and GnRHa was presented in the forest plot. Compared with control group, both AI and GnRHa were effective in increasing the final height, with the mean effect of 4.91(95%CI:1.10,8.17) and 5.55(95%CI:1.12,9.98) respectively. However, there was no statistical difference between the GnRHa and AI treatment, of which the mean effect was 0.65(95%CI: -4.30,5.60). Conclusion: Both AIs and GnRHa monotherapy were effective in augmenting the final height of boys with idiopathic short stature when compared to placebo groups. However, there was no statistical difference between the GnRHa and AI treatments.

Inhibition of importin-7 attenuates ventilator-induced lung injury by targeting nuclear translocation of p38.

BACKGROUND: The ability of p38 to phosphorylate substrates in the nucleus and the role of nuclear p38 in the regulation of inflammation have focused attention on the subcellular localization of the kinase. Although it is clear that p38 shuttles to the nucleus upon stimulation, the mechanisms that regulate p38 nuclear input in response to mechanical stretch remain to be determined. METHODS: Cyclic stretch (CS)-induced nuclear translocation of p38 was determined by Western blotting and immunofluorescence. The p38 interacting protein was identified using endogenous pull-down and protein binding assays. The potential role of importin-7 (Imp7) in CS-induced nuclear translocation of p38 and p38-dependent gene expression was confirmed using a series of in vitro and in vivo experiments. Furthermore, we tested the therapeutic potential of intratracheal administration of Imp7 siRNA-loaded nanoparticles in the ventilator-induced lung injury (VILI) mouse model. RESULTS: We show that CS induced phosphorylation-dependent nuclear translocation of p38, which required the involvement of microtubules and dynein. Endogenous pull-down assay revealed Imp7 to be a potential p38-interacting protein, and the direct interaction between p38 and Imp7 was confirmed by in vitro and in vivo binding assays. Furthermore, silencing Imp7 inhibited CS-induced nuclear translocation of p38 and subsequent cytokine production. Notably, intratracheal administration of Imp7 siRNA nanoparticles attenuated lung inflammation and histological damage in the VILI mouse model. CONCLUSIONS: Our findings uncover a key role for Imp7 in the process of p38 nuclear import after CS stimulation and highlight the potential of preventing p38 nuclear translocation in treatment of VILI.

Allometry of bud dynamic pattern and linkage between bud traits and ecological stoichiometry of Nitraria tangutorum under fertilizer addition.

Affected by the pressure and constraints of available resources, plant growth and development, as well as plant life history strategies, usually vary with environmental conditions. Plant buds play a crucial role in the life history of woody plants. Nitraria tangutorum is a common dominant woody species in desertified areas of northern China and its growth is critical to the desert ecosystem. Revealing the allometry of N. tangutorum aboveground bud fates and the linkage between bud traits and plant nutrient contents and stoichiometric ratios can be useful in understanding plant adaptation strategy. We applied seven nitrogen and phosphorus fertilizer addition treatments to natural N. tangutorum ramets in Ulan Buh Desert in three consecutive years. We surveyed three types of aboveground buds (dormant buds, vegetative buds, and reproductive buds) in each N. tangutorum ramet, then measured the plant carbon (C), nitrogen (N), and phosphorus (P) contents and ratios during three consecutive years. We specified that reserve growth potential (RGP), vegetative growth intensity (VGI) and sexual reproduction effort (SRE) are the three indices of bud dynamic pattern. The results showed that the bud dynamic pattern of N. tangutorum ramets differed significantly among different fertilizer addition treatments and sampling years. The allometry of RGP, VGI, and SRE was obvious, showing size dependence. The allometric growth relationship fluctuated among the sampling years. The linkage between bud traits and plant stoichiometric characteristics of N. tangutorum ramets showed close correlation with plant P content, C:P and N:P ratios, no significant correlation with plant C content, N content and C:N ratio. These results contribute to an improved understanding of the adaptive strategies of woody plants growing in desert ecosystems and provide insights for adoption of effective measures to restore and conserve plant communities in arid and semi-arid regions.

Transcriptome Profiling and Chlorophyll Metabolic Pathway Analysis Reveal the Response of Nitraria tangutorum to Increased Nitrogen.

To identify genes that respond to increased nitrogen and assess the involvement of the chlorophyll metabolic pathway and associated regulatory mechanisms in these responses, Nitraria tangutorum seedlings were subjected to four nitrogen concentrations (N0, N6, N36, and N60: 0, 6, 36, and 60 mmol·L-1 nitrogen, respectively). The N. tangutorum seedling leaf transcriptome was analyzed by high-throughput sequencing (Illumina HiSeq 4000), and 332,420 transcripts and 276,423 unigenes were identified. The numbers of differentially expressed genes (DEGs) were 4052 in N0 vs. N6, 6181 in N0 vs. N36, and 3937 in N0 vs. N60. Comparing N0 and N6, N0 and N36, and N0 and N60, we found 1101, 2222, and 1234 annotated DEGs in 113, 121, and 114 metabolic pathways, respectively, classified in the Kyoto Encyclopedia of Genes and Genomes database. Metabolic pathways with considerable accumulation were involved mainly in anthocyanin biosynthesis, carotenoid biosynthesis, porphyrin and chlorophyll metabolism, flavonoid biosynthesis, and amino acid metabolism. N36 increased δ-amino levulinic acid synthesis and upregulated expression of the magnesium chelatase H subunit, which promoted chlorophyll a synthesis. Hence, N36 stimulated chlorophyll synthesis rather than heme synthesis. These findings enrich our understanding of the N. tangutorum transcriptome and help us to research desert xerophytes' responses to increased nitrogen in the future.

Efficacy and Safety of Dl-3-n-Butylphthalide Combined With Human Urinary Kallidinogenase in the Treatment of Acute Ischemic Stroke.

OBJECTIVES: Intravenous thrombolysis and mechanical endovascular thrombectomy are recommended for patients whose stroke onsets are within the first 6 hours; however, patients beyond this time window have very limited options. Dl-3-n-butylphthalide (NBP) and human urinary kallidinogenase (HUK) have shown potential clinical benefits in the treatment of acute ischemic stroke (AIS) patients. This research aims to investigate the efficacy and safety of NBP combined with HUK in the treatment of ischemic stroke patients. PATIENTS AND METHODS: We reviewed the 215 AIS patients registered in the database of the Fifth Affiliated Hospital of Sun Yat-sen University from April 2019 to October 2020. Among them, 65 patients received NBP sodium chloride injection treatment, 55 patients received HUK treatment, and 95 patients received NBP sodium chloride injection combined with HUK treatment. The recovery of neural function was evaluated by the National Institutes of Health Stroke Scale (NIHSS), and the recovery of daily function was evaluated by the modified Rankin Scale (mRS). The NIHSS and mRS scores after the 7-day treatment, 6-month independency rate (6-month mRS score ≤1), and related factors were compared among the 3 groups. The safety was monitored by recording adverse events. RESULTS: The NIHSS and mRS scores of 7-day and 6-month treatment in the NBP combined with HUK group were lower than the monotherapy ( P < 0.05). In addition, the NBP combined with HUK treatment achieved an independency rate of 82.1%, whereas NBP and HUK treatments achieved only 53.8% and 63.6%, respectively ( P < 0.001). Binary logistic regression showed that NBP combined with HUK therapy treatment could lead to a 5.28 times higher rate of patients' 6-month independency after AIS occurrence. No serious adverse events occurred in both the combined therapy and monotherapy. CONCLUSIONS: Dl-3-n-butylphthalide combined with HUK is safe to treat AIS patients. It can significantly improve the neural function and the 6-month recovery of AIS patients.

ANGPT2/CAV1 regulates albumin transcytosis of glomerular endothelial cells under high glucose exposure and is impaired by losartan.

BACKGROUND: Microalbuminuria is a common clinical symptom that manifests in the early stages of diabetic kidney disease (DKD) and is also the main feature of glomerular endothelial cells (GECs) injury. There is increasing evidence that the transcytosis of albumin across GECs is closely related to the formation of albuminuria. Our previous studies have shown that angiopoietin 2 (ANGPT2) can inhibit albumin transcytosis across renal tubular epithelial cells by activating caveolin 1 (CAV1) phosphorylation during high glucose (HG) exposure. The role of ANGPT2 in albumin transcytosis across GECs remains unclear. Losartan significantly reduces albuminuria, but the mechanism has not been clarified. METHODS: We established an in vitro albumin transcytosis model to investigate the change in albumin transcytosis across human renal glomerular endothelial cells (hrGECs) under normal glucose (NG), high glucose (HG) and losartan intervention. We knocked down ANGPT2 and CAV1 to evaluate their roles in albumin transcytosis across hrGECs and verified the relationship between them. In vivo, DKD mouse models were established and treated with different doses of losartan. Immunohistochemistry and Western blot were used to detect the expression of ANGPT2 and CAV1. RESULTS: In vitro, the transcytosis of albumin across hrGECs was significantly increased under high glucose stimulation, and losartan inhibited this process. The expression of ANGPT2 and CAV1 were both increased in hrGECs under HG conditions and losartan intervention reduced the expression of them. Moreover, ANGPT2 downregulation reduced albumin transcytosis in hrGECs by regulating CAV1 expression. In vivo, the expression of ANGPT2 and CAV1 in the glomerulus was both increased significantly in DKD mice. Compared with DKD mice, losartan treatment reduced albuminuria and decreased the expression of ANGPT2 and CAV1 in a dose-dependent manner. CONCLUSIONS: ANGPT2 exacerbated albumin transcytosis across GECs by increasing CAV1 expression during HG exposure, thereby increasing albuminuria. Losartan reduces albumin transcytosis and albuminuria formation in DKD by inhibiting the upregulation of ANGPT2 under HG conditions. Our findings suggest that ANGPT2 and CAV1 may be novel therapeutic targets for diabetic albuminuria. In addition, we provide new evidence to elaborate on the mechanism of losartan in the development of DKD.

Region, vintage, and grape maturity co-shaped the ionomic signatures of the Cabernet Sauvignon wines.

The ionic elements in wine and in vineyards are gaining attention due to characterization of the wine traits, wine origin tracing, and vine nutrient judging. In this experiment, 19 elements were detected by inductively coupled plasma mass spectrometry (ICP-MS) in 69 wine samples from 4 regions, 3 vintages, and 3 grape maturity levels. Furthermore, the elements related to vine development, such as N, P, K, Ca, Mg, Cu, Fe, Zn and Cu in the vineyard soil and petioles were determined. Two orthogonal partial least squares discriminant analysis (O2PLS-DA) showed that K, Mn, Co, Sr, B, Si, Pb, Ni, Cu, and Zn were important elements in distinguishing the regions. High-temperature vintages can bring wines with high levels of Sr in wine. Na, Ca, K, Mg, Rb, Al, Rb, Pb and Fe can be used as signature elements to distinguish wines made from 2 grape maturities. And Cu, Zn, and Mn were the key elements used to differentiate the petioles in the 4 regions. Partial square regression (PLSR) analysis showed that soil pH was positively correlated with Al, B, Ba, K, Pb, Mn, Sr and Rb in wine, and K in wine was significantly positively correlated with element K in the soil. In conclusion, the elemental contents in wine are shaped by the combination of origin, vintage and grape maturity, while some key elements can be used as indicators of origin traceability.