Genetic insight into putative causes of xanthelasma palpebrarum: a Mendelian randomization study.

Xanthelasma palpebrarum (XP) is the most common form of cutaneous xanthoma, with a prevalence of 1.1%~4.4% in the population. However, the cause of XP remains largely unknown. In the present study, we used Mendelian randomization to assess the genetic association between plasma lipids, metabolic traits, and circulating protein with XP, leveraging summary statistics from large genome-wide association studies (GWAS). Genetically predicted plasma cholesterol and LDL-C, but not HDL-C or triglyceride, were significantly associated with XP. Metabolic traits, including BMI, fasting glucose, type 2 diabetes, systolic and diastolic blood pressure, were not significantly associated with XP. Furthermore, we found genetically predicted 12 circulating proteins were associated with XP, including FN1, NTM, FCN2, GOLM1, ICAM5, PDE5A, C5, CLEC11A, CXCL1, CCL2, CCL11, CCL13. In conclusion, this study identified plasma cholesterol, LDL-C, and 12 circulating proteins to be putative causal factors for XP, highlighting the role of plasma cholesterol and inflammatory response in XP development.

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.

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.

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.

Myeloid BAF60a deficiency alters metabolic homeostasis and exacerbates atherosclerosis.

Atherosclerosis, a leading health concern, stems from the dynamic involvement of immune cells in vascular plaques. Despite its significance, the interplay between chromatin remodeling and transcriptional regulation in plaque macrophages is understudied. We discovered the reduced expression of Baf60a, a component of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex, in macrophages from advanced plaques. Myeloid-specific Baf60a deletion compromised mitochondrial integrity and heightened adhesion, apoptosis, and plaque development. BAF60a preserves mitochondrial energy homeostasis under pro-atherogenic stimuli by retaining nuclear respiratory factor 1 (NRF1) accessibility at critical genes. Overexpression of BAF60a rescued mitochondrial dysfunction in an NRF1-dependent manner. This study illuminates the BAF60a-NRF1 axis as a mitochondrial function modulator in atherosclerosis, proposing the rejuvenation of perturbed chromatin remodeling machinery as a potential therapeutic target.

Generating endogenous Myh11-driven Cre mice for sex-independent gene deletion in smooth muscle cells.

Specific and efficient smooth muscle cell-targeted (SMC-targeted) gene deletion is typically achieved by pairing SMMHC-CreERT2-Tg mice with mice carrying the loxP-flanked gene. However, the transgene, CreERT2, is not controlled by the endogenous Myh11 gene promoter, and the codon-modified iCreERT2 exhibits significant tamoxifen-independent leakage. Furthermore, because the Cre-bearing bacterial artificial chromosome (BAC) is inserted onto the Y chromosome, the SMMHC-CreERT2-Tg mice strain can only exhibit gene deletions in male mice. Additionally, there is a lack of Myh11-driven constitutive Cre mice when tamoxifen usage is a concern. We used CRISPR/Cas9-mediated homologous recombination between a donor vector carrying the CreNLSP2A or CreERT2-P2A sequence and homologous arm surrounding the translation start site of the Myh11 gene to generate Cre-knockin mice. The P2A sequence enables the simultaneous translation of Cre and endogenous proteins. Using reporter mice, we assessed Cre-mediated recombination efficiency, specificity, tamoxifen-dependent controllability, and functionality in both sexes. Both constitutive (Myh11-CreNLSP2A) and inducible (Myh11-CreERT2-P2A) Cre mice demonstrated efficient, SMC-specific, sex-independent Cre recombinase activity without confounding endogenous gene expression. Combined with recently generated BAC transgenic Myh11-CreERT2-RAD mice and the Itga8-CreERT2 mouse models, our models will help expand the research toolbox, facilitating unbiased and comprehensive research in SMCs and SMC-dependent cardiovascular diseases.

Novel Drug Targets for Atrial Fibrillation Identified Through Mendelian Randomization Analysis of the Blood Proteome.

PURPOSE: Novel, effective, and safe preventive therapy targets for AF are still needed. Circulating proteins with causal genetic evidence are promising candidates. We aimed to systematically screen circulating proteins for AF drug targets and determine their safety and efficacy using genetic methods. METHODS: The protein quantitative trait loci (pQTL) of up to 1949 circulating proteins were retrieved from nine large genome-proteome-wide association studies. Two-sample Mendelian Randomization (MR) and colocalization analyses were used to estimate the causal effects of proteins on the risk of AF. Furthermore, phenome-wide MR was conducted to depict side effects and the drug-target databases were searched for drug validation and repurposing. RESULTS: Systematic MR screen identified 30 proteins as promising AF drug targets. Genetically predicted 12 proteins increased AF risk (TES, CFL2, MTHFD1, RAB1A, DUSP13, SRL, ANXA4, NEO1, FKBP7, SPON1, LPA, MANBA); 18 proteins decreased AF risk (PMVK, UBE2F, SYT11, CHMP3, PFKM, FBP1, TNFSF12, CTSZ, QSOX2, ALAD, EFEMP1, FLRT2, LRIG1, OLA1, SH3BGRL3, IL6R, B3GNT8, FCGR2A). DUSP13 and TNFSF12 possess strong colocalization evidence. For the proteins that were identified, extended phe-MR analysis was conducted to assess their side-effect profiles, while drug-target databases provided information on their approved or investigated indications. CONCLUSION: We identified 30 circulating proteins as potential preventive targets for AF.

PRDM16 deficiency in vascular smooth muscle cells aggravates abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is usually asymptomatic until life-threatening complications occur, predominantly involving aortic rupture. Currently, no drug-based treatments are available, primarily due to limited understanding of AAA pathogenesis. The transcriptional regulator PR domain-containing protein 16 (PRDM16) is highly expressed in the aorta, but its functions in the aorta are largely unknown. By RNA-seq analysis, we found that vascular smooth muscle cell-specific (VSMC-specific) Prdm16-knockout (Prdm16SMKO) mice already showed extensive changes in the expression of genes associated with extracellular matrix (ECM) remodeling and inflammation in the abdominal aorta under normal housing conditions without any pathological stimuli. Human AAA lesions displayed lower PRDM16 expression. Periadventitial elastase application to the suprarenal region of the abdominal aorta aggravated AAA formation in Prdm16SMKO mice. During AAA development, VSMCs undergo apoptosis because of both intrinsic and environmental changes, including inflammation and ECM remodeling. Prdm16 deficiency promoted inflammation and apoptosis in VSMCs. A disintegrin and metalloproteinase 12 (ADAM12) is a gelatinase that can degrade various ECMs. We found that ADAM12 is a target of transcriptional repression by PRDM16. Adam12 knockdown reversed VSMC apoptosis induced by Prdm16 deficiency. Our study demonstrated that PRDM16 deficiency in VSMCs promoted ADAM12 expression and aggravates AAA formation, which may provide potential targets for AAA treatment.

Genetic ablation of diabetes-associated gene Ccdc92 reduces obesity and insulin resistance in mice.

Multiple genome-wide association studies (GWAS) have identified specific genetic variants in the coiled-coil domain containing 92 (CCDC92) locus that is associated with obesity and type 2 diabetes in humans. However, the biological function of CCDC92 in obesity and insulin resistance remains to be explored. Utilizing wild-type (WT) and Ccdc92 whole-body knockout (KO) mice, we found that Ccdc92 KO reduced obesity and increased insulin sensitivity under high-fat diet (HFD) conditions. Ccdc92 KO inhibited macrophage infiltration and fibrosis in white adipose tissue (WAT), suggesting Ccdc92 ablation protects against adipose tissue dysfunction. Ccdc92 deletion also increased energy expenditure and further attenuated hepatic steatosis in mice on an HFD. Ccdc92 KO significantly inhibited the inflammatory response and suppressed the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome in WAT. Altogether, we demonstrated the critical role of CCDC92 in metabolism, constituting a potential target for treating obesity and insulin resistance.

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.

Manipulating the severe shoot topping delays the harvest date and modifies the flavor composition of Cabernet Sauvignon wines in a semi-arid climate.

This study aimed to mitigate the adverse effects of global warming by applying severe shoot topping (SST) to grapevines in a semi-arid climate. A three-year study (2018-2020) was performed to investigate the impact of SST on wine flavor composition. Results showed that SST effectively delayed the grape harvest date, which was more evident in the dry and warm vintage (7-11 d). SST significantly increased the concentration of myricetin-based flavonols in wines which were 18% higher than in untreated wines. Through orthogonal partial least squares discriminant analysis (OPLS-DA), SST wines were characterized by more abundant phenolic compounds and higher sensory scores. The carry-over effect of applying SST in consecutive years in the same vines could be reflected in wine color. The correlations among wine metabolites, color and aroma parameters, and sensory parameters were evaluated through multiple analyses. This study provided an idea for delaying grape ripening in a semi-arid climate.

Volatomics of 'Cabernet Sauvignon' grapes and wines under the fan training system revealed the nexus of microclimate and volatile compounds.

The cluster-zone of the fan training system with multiple trunks (F-MT) distribute >1.5 m vertically and 1.0 m horizontally, which leads to microclimate heterogeneity around clusters. In the current study, clusters were divided into eight spatial positions according to the cluster growing height and light conditions, and the aroma profiles of grapes and wines were evaluated by HS-SPME-GC-MS. Results showed that the microclimate varied in different spatial positions. Light exposure promotes the accumulation of terpenes and C13-norisoprenoids, while inhibiting C6/C9 compounds in grape berries. Zone 2 wine presented the highest global aroma concentration. Floral and fruity were the main aromas in F-MT wines, but the herbaceous was more prominent in lower-position wines. C6/C9 compounds in grapes negatively correlated with terpenes and C13-norisoprenoids in wines. In conclusion, the aroma profiles of grapes and wines varied from different cluster positions, and graded harvesting will be helpful to produce quality wines.

Effect of Inter-Row Peanut Growing in the Vineyard on the Quality of 'Cabernet Sauvignon' Grape Fruits and Wines in Northwest China.

In order to solve the problem of premature grape ripening due to global warming, inter-row peanut growing in viticulture was applied. In this two-year (2018-2019) study, the peanut (Arachis hypogaea L.) was used to cover the ground between rows in the vineyards located in the semi-arid Northwest China, Xinjiang. The results showed that reflected solar radiation and temperature around the fruit zone with the peanuts growing were decreased. Compared with clean tillage, the grapes with covering peanuts had lower total soluble solids (TSS) and higher titratable acidity (TA) in the berries. Lower alcohol content and higher total acid (TA) was also found in their corresponding wines. Inter-row peanut growing treatment significantly decreased the contents of flavonols in the grapes and their wines in the two consecutive years, but no significant effect on flavanols was observed in the resulting wines. Norisoprenoids and esters in the grapes and the wines were increased with the peanut growing treatment, respectively. Additionally, compared to clean tillage, the peanut covering significantly improved the sensory value of the wines, especially the aroma complexity of the wines. This study helps us to better understand the feasibility of applying inter-row peanut growing in the viticulture of ground management in the semi-arid climate of Northwest China.

Reducing the source/sink ratio of grapevine to face global warming in a semi-arid climate: Effects on volatile composition of Cabernet Sauvignon grapes and wines.

The heterogeneity of the vineyard environment caused high variability in grape metabolites and flavor profiles, and the phenomenon was more prominent in recent years of climate change. Herein, distal leaf removal was applied in semi-arid Xinjiang to adjust the source to sink ratio of grapevines for three consecutive years (2018-2020). The grape-derived volatiles showed high correlations with specific climate factors such as temperature changes in the growth period. Results showed that distal leaf removal increased the solar radiation reaching the clusters in the first few days after applying LR treatments while not affecting the temperature. The improvement in fruity and floral aroma intensity by distal leaf removal was founded not only in grape metabolites but also in wines. Moderate cluster exposure brought by distal leaf removal was beneficial for the accumulation of isoprenoids, which therefore increased the fruity and floral intensity of wines. The carry-over effect did not show in consecutively defoliated vines among vintages regarding the wine aroma profile.

The combined influence of rootstock and vintage climate on the grape and wine flavonoids of Vitis vinifera L. cv. Cabernet Sauvignon in eastern China.

Rootstocks are commonly utilized owing to their resistance to abiotic and biotic stress in viticulture. This study evaluated the effects of three rootstocks (1103P, SO4, and 5A) on the Cabernet Sauvignon (CS) vine growth, and their berries and wines flavonoids profiles in four consecutive vintages. The results showed that 1103P increased the pruning weight of CS and decreased the anthocyanin concentration in berries and wines, especially in the vintages with more rainy and cloudy days. 5A tended to decrease the pruning weight of CS and increase the anthocyanin concentration in berries and wines. Orthogonal partial least squares discriminant analysis (OPLS-DA) showed that the concentrations of total anthocyanins, F3'H-anthocyanins, malvidin-3-O-glucoside (Mv-glu), and malvidin-3-O-acetylglucoside (Mv-acglu) were the key substances affected by the rootstocks in CS berries and were significantly decreased by 1103P. Total anthocyanins, pinotins, Mv-glu, epicatechin, and vitisins were the rootstock-sensitive compounds that commonly differed in wines among the three comparison groups in the two vintages. Furthermore, 1103P brought more brightness to the wine and 5A gave the wine more red tones. In conclusion, rootstock 5A was recommended in the rainy and cloudy climate regions with regard to the berry flavonoids accumulation and the wine color.

BAF60c prevents abdominal aortic aneurysm formation through epigenetic control of vascular smooth muscle cell homeostasis.

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease. BAF60c, a unique subunit of the SWItch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, is critical for cardiac and skeletal myogenesis, yet little is known about its function in the vasculature and, specifically, in AAA pathogenesis. Here, we found that BAF60c was downregulated in human and mouse AAA tissues, with primary staining to vascular smooth muscle cells (VSMCs), confirmed by single-cell RNA-sequencing. In vivo studies revealed that VSMC-specific knockout of Baf60c significantly aggravated both angiotensin II- (Ang II-) and elastase-induced AAA formation in mice, with a significant increase in elastin degradation, inflammatory cell infiltration, VSMC phenotypic switch, and apoptosis. In vitro studies showed that BAF60c knockdown in VSMCs resulted in loss of contractile phenotype, increased VSMC inflammation, and apoptosis. Mechanistically, we demonstrated that BAF60c preserved VSMC contractile phenotype by strengthening serum response factor (SRF) association with its coactivator P300 and the SWI/SNF complex and suppressing VSMC inflammation by promoting a repressive chromatin state of NF-κB target genes as well as preventing VSMC apoptosis through transcriptional activation of KLF5-dependent B cell lymphoma 2 (BCL2) expression. Our identification of the essential role of BAF60c in preserving VSMC homeostasis expands its therapeutic potential in preventing and treating AAA.

Myeloid TM6SF2 Deficiency Inhibits Atherosclerosis.

Genetic variants in transmembrane 6 superfamily member 2 (TM6SF2), such as E167K, are associated with atherosclerotic cardiovascular disease (ASCVD). Chronic inflammation and lipid-laden macrophage foam cell formation are the central pathogeneses in the development of atherosclerosis. This study was undertaken to illustrate the biological function of TM6SF2 in macrophages and its role during atherosclerosis development. We generated myeloid cell-specific Tm6sf2 knockout mice on ApoE-deficient background (LysM Cre+/Tm6sf2fl/fl/ApoE-/-, TM6 mKO) with littermate LysM Cre-/Tm6sf2fl/fl/ApoE-/- (Control) mice as controls. Mice were fed a Western diet for 12 weeks to induce atherosclerosis. Myeloid Tm6sf2 deficiency inhibited atherosclerosis and decreased foam cells in the plaques without changing the plasma lipid profile. RNA sequencing of bone marrow-derived macrophages (BMDMs) from TM6 mKO mice demonstrated the downregulation of genes associated with inflammation, cholesterol uptake, and endoplasmic reticulum (ER) stress. TM6SF2 was upregulated by oxidized low-density lipoprotein (oxLDL) in macrophages. Silencing TM6SF2 in THP-1-derived macrophages and Tm6sf2 deficiency in BMDMs reduced inflammatory responses and ER stress and attenuated cholesterol uptake and foam cell formation, while the overexpression of TM6SF2 showed opposite effects. In conclusion, myeloid TM6SF2 deficiency inhibits atherosclerosis development and is a potential therapeutic target for the treatment of atherogenesis.