Single-cell analysis reveals microbial spore responses to sodium hypochlorite.

Pollution from toxic spores has caused us a lot of problems because spores are extremely resistant and can survive most disinfectants. Therefore, the detection of spore response to disinfectant is of great significance for the development of effective decontamination strategies. In this work, we investigated the effect of 0.5% sodium hypochlorite on the molecular and morphological properties of single spores of Bacillus subtilis using single-cell techniques. Laser tweezers Raman spectroscopy showed that sodium hypochlorite resulted in Ca2+-dipicolinic acid release and nucleic acid denaturation. Atomic force microscopy showed that the surface of treated spores changed from rough to smooth, protein shells were degraded at 10 min, and the permeability barrier was destroyed at 15 min. The spore volume decreased gradually over time. Live-cell imaging showed that the germination and growth rates decreased with increasing treatment time. These results provide new insight into the response of spores to sodium hypochlorite.

The regulatory relationship between NAMPT and PD-L1 in cancer and identification of a dual-targeting inhibitor.

Cancer is a heterogeneous disease. Although both tumor metabolism and tumor immune microenvironment are recognized as driving factors in tumorigenesis, the relationship between them is still not well-known, and potential combined targeting approaches remain to be identified. Here, we demonstrated a negative correlation between the expression of NAMPT, an NAD+ metabolism enzyme, and PD-L1 expression in various cancer cell lines. A clinical study showed that a NAMPTHigh PD-L1Low expression pattern predicts poor prognosis in patients with various cancers. In addition, pharmacological inhibition of NAMPT results in the transcription upregulation of PD-L1 by SIRT-mediated acetylation change of NF-κB p65, and blocking PD-L1 would induce NAMPT expression through a HIF-1-dependent glycolysis pathway. Based on these findings, we designed and synthesized a dual NAMPT/PD-L1 targeting compound, LZFPN-90, which inhibits cell growth in a NAMPT-dependent manner and blocks the cell cycle, subsequently inducing apoptosis. Under co-culture conditions, LZFPN-90 treatment contributes to the proliferation and activation of T cells and blocks the growth of cancer cells. Using mice bearing genetically manipulated tumors, we confirmed that LZFPN-90 exerted target-dependent antitumor activities, affecting metabolic processes and the immune system. In conclusion, our results demonstrate the relevance of NAD+-related metabolic processes in antitumor immunity and suggest that co-targeting NAD+ metabolism and PD-L1 represents a promising therapeutic approach.

Reduced production of Ethyl Carbamate in wine by regulating the accumulation of arginine in Saccharomyces cerevisiae.

Ethyl carbamate (EC), a multisite carcinogenic compound, is naturally produced from urea and ethanol in alcoholic beverages. In order to reduce the content of EC in wine, the accumulation of arginine in Saccharomyces cerevisiae was regulated by genetic modifying genes involved in arginine transport and synthesis pathways to reduce the production of urea. Knockout of genes encoding arginine permease (Can1p) and amino acid permease (Gap1p) on the cell membrane as well as argininosuccinate synthase (Arg1) respectively resulted in a maximum reduction of 66.88% (9.40 µg/L) in EC, while overexpressing the gene encoding amino acid transporter (Vba2) reduced EC by 52.94% (24.13 µg/L). Simultaneously overexpressing Vba2 and deleting Arg1 showed the lowest EC production with a decrease of 68% (7.72 µg/L). The yield of total higher alcohols of the mutants all decreased compared with that of the original strain. Comprehensive consideration of flavor compound contents and sensory evaluation results indicated that mutant YG21 obtained by deleting two allele coding Gap1p performed best in must fermentation of Cabernet Sauvignon with the EC content low to 9.40 µg/L and the contents of total higher alcohols and esters of 245.61 mg/L and 41.71 mg/L respectively. This study has provided an effective strategy for reducing the EC in wine.

Quantitative Evaluation of the Topographical Maps of Three-Dimensional Choroidal Vascularity Index in Children With Different Degrees of Myopia.

Purpose: To investigate topographical maps of the three-dimensional choroidal vascularity index (3D-CVI) in children with different levels of myopia. Methods: We enrolled 274 eyes from 143 children with various severity of myopia, including emmetropia (EM), low myopia (LM), and moderate-high myopia (MHM). The choroidal vessel volume (CVV), choroidal stroma volume (CSV), and 3D-CVI in different eccentricities (fovea, parafovea, and perifovea) and quadrants (nasal, temporal, superior, and inferior) were obtained from swept-source optical coherence tomography angiography (SS-OCTA) volume scans. All choroidal parameters were compared among groups, and the associated factors contributing to different 3D-CVIs were analyzed. Results: Compared to the less myopic group, the more myopic group showed a significant decrease in CVV and CSV (MHM < LM < EM) and a significant increase in the 3D-CVI (MHM > LM > EM) in most areas (all P < 0.05). The nasal quadrant had the greatest 3D-CVI and lowest CSV and CVV, and vice versa in the temporal quadrant. The 3D-CVIs of the EM and LM groups gradually increased from the fovea to the perifovea, whereas the 3D-CVI of the MHM group first decreased and then increased. Regression analysis showed that axial length was an independent risk factor affecting foveal and parafoveal 3D-CVIs. Restricted cubic spline analysis revealed that the 3D-CVI increased with spherical equivalent (SE) when the SE was less than threshold and decreased when the SE was greater than threshold (SE thresholds for foveal, parafoveal, and perifoveal 3D-CVIs were -5.25 D, -5.125 D, and -2.00 D, respectively; all P < 0.05). Conclusions: Children with myopia exhibited decreased CSV and CVV, increased 3D-CVIs, and altered 3D-CVI eccentricity characteristics (from the fovea to the perifovea). The quadratic relationship between the 3D-CVI and SE should be explored in longitudinal investigations.

An unusual dual sugar-binding lectin domain controls the substrate specificity of a mucin-type O-glycosyltransferase.

N-acetylgalactosaminyl-transferases (GalNAc-Ts) initiate mucin-type O-glycosylation, an abundant and complex posttranslational modification that regulates host-microbe interactions, tissue development, and metabolism. GalNAc-Ts contain a lectin domain consisting of three homologous repeats (α, ß, and γ), where α and ß can potentially interact with O-GalNAc on substrates to enhance activity toward a nearby acceptor Thr/Ser. The ubiquitous isoenzyme GalNAc-T1 modulates heart development, immunity, and SARS-CoV-2 infectivity, but its substrates are largely unknown. Here, we show that both α and ß in GalNAc-T1 uniquely orchestrate the O-glycosylation of various glycopeptide substrates. The α repeat directs O-glycosylation to acceptor sites carboxyl-terminal to an existing GalNAc, while the ß repeat directs O-glycosylation to amino-terminal sites. In addition, GalNAc-T1 incorporates α and ß into various substrate binding modes to cooperatively increase the specificity toward an acceptor site located between two existing O-glycans. Our studies highlight a unique mechanism by which dual lectin repeats expand substrate specificity and provide crucial information for identifying the biological substrates of GalNAc-T1.

EZH2/G9a interact to mediate drug resistance in non-small-cell lung cancer by regulating the SMAD4/ERK/c-Myc signaling axis.

Drug resistance is the leading problem in non-small-cell lung cancer (NSCLC) therapy. The contribution of histone methylation in mediating malignant phenotypes of NSCLC is well known. However, the role of histone methylation in NSCLC drug-resistance mechanisms remains unclear. Here, our data show that EZH2 and G9a, two histone methyltransferases, are involved in the drug resistance of NSCLC. Gene manipulation results indicate that the combination of EZH2 and G9a promotes tumor growth and mediates drug resistance in a complementary manner. Importantly, clinical study demonstrates that co-expression of both enzymes predicts a poor outcome in patients with NSCLC. Mechanistically, G9a and EZH2 interact and promote the silencing of the tumor-suppressor gene SMAD4, activating the ERK/c-Myc signaling pathway. Finally, SU08, a compound targeting both EZH2 and G9a, is demonstrated to sensitize resistant cells to therapeutic drugs by regulating the SMAD4/ERK/c-Myc signaling axis. These findings uncover the resistance mechanism and a strategy for reversing NSCLC drug resistance.

Dual Cannula Combined With Modified Shoelace Continuous Capsular Closure Technique in Hip Arthroscopic Surgery.

The Technical Note aims to present an arthroscopic capsular closure technique at the end of the hip arthroscopy. The technology employs a dual-channel approach and modified shoelace suture technique to continuously suture the hip capsule. Recent studies have indicated that routine intraoperative repair of the articular capsule at the end of the hip arthroscopy is advocated. However, the majority of the hip capsular closure techniques are relatively complex, time-consuming, and bring many complications, which has hindered their widespread use in clinical practice. Herein, we provide an arthroscopic capsular closure technique using the modified shoelace continuous suture in combination with a dual cannula for correcting hip instability during hip arthroscopic surgery of femoroacetabular impingement.

Integrated Analysis of Transcriptome and Metabolome to Unveil Impact on Enhancing Grape Aroma Quality with Synthetic Auxin: Spotlight the Mediation of ABA in Crosstalk with Auxin.

It is widely accepted that prevéraison application of naphthaleneacetic acid (NAA) can delay the ripening of grapes and improve their quality. However, how NAA impacts grape aroma compound concentrations remains unclear. This study incorporated the analyses of aroma metabolome, phytohormones, and transcriptome of Vitis vinifera L. cv. Cabernet Sauvignon grapes cultivated in continental arid/semiarid regions of western China. The analyses demonstrated that NAA application increased ß-damascenone and 1,1,6-trimethyl-1,2-dihydronaphthalene (TDN) in the harvested grapes by delaying véraison and upregulating VvPSY1 and VvCCD4b expressions. Additionally, NAA treatment decreased 2-isobutyl-3-methoxypyrazine (IBMP) at the same phenological stage. Notably, abscisic acid (ABA) levels increased in NAA-treated grapes during véraison, which triggered further changes in norisoprenoid metabolisms. The ABA-responsive factor VvABF2 was potentially involved in VvPSY1 positive modulation, while the auxin response factor VvARF10 may play a role in VvCCD4b upregulation and VvOMT2 downregulation during NAA induction. VvARF10 possibly acts as a crosstalk node between the ABA and auxin signaling pathways following NAA treatment in regulating aroma biosynthesis.

Biotemplated fabrication of N/O co-doped porous carbon confined spinel NiFe2O4 heterostructured mimetics for triple-mode sensing of antioxidants and ameliorating packaging properties.

In this work, shrimp shell-derived magnetic NiFe2O4/N, O co-doped porous carbon nanozyme with superior oxidase (OXD)-like activity was prepared and used for colorimetric/photothermal/smartphone dual-signal triple-mode detection of antioxidants in fruits and beverages. The magnetic NiFe2O4/N, O co-doped porous carbon (MNPC) material was triumphantly fabricated using a combined in-situ surface chelation and pyrolysis method. The resultant MNPC composite exhibits a superior OXD-like activity, which can effectively oxidize 3,3',5,5'-tetramethylbenzidine (TMB) for yielding colorimetric/temperature dual-signal (CTDS) in absence of H2O2. This CTDS output sensor was successfully used for the determination of ascorbic acid and tannic acid. The proposed CTDS sensor with good specificity and high sensitivity can satisfy different on-site analysis requirements. Interestingly, the MNPC as a sustainable filler was further used for improving packaging properties of polyvinyl alcohol film. In short, this work offers a large-scale and cheap method to fabricate magnetic carbon-based nanozyme for monitoring antioxidants and ameliorating packaging properties.

Meeting Report on the 3rd Chinese American Society for Mass Spectrometry Conference-Advancing Biological and Pharmaceutical Mass Spectrometry.

Following the highly successful Chinese American Society for Mass Spectrometry (CASMS) conferences in the previous 2 years, the 3rd CASMS Conference was held virtually on August 28-31, 2023, using the Gather.Town platform to bring together scientists in the MS field. The conference offered a 4-day agenda with a scientific program consisting of two plenary lectures, and 14 parallel symposia in which a total of 70 speakers presented technological innovations and their applications in proteomics and biological MS and metabo-lipidomics and pharmaceutical MS. In addition, 16 invited speakers/panelists presented at two research-focused and three career development workshops. Moreover, 86 posters, 12 lightning talks, 3 sponsored workshops, and 11 exhibitions were presented, from which 9 poster awards and 2 lightning talk awards were selected. Furthermore, the conference featured four young investigator awardees to highlight early-career achievements in MS from our society. The conference provided a unique scientific platform for young scientists (i.e. graduate students, postdocs, and junior faculty/investigators) to present their research, meet with prominent scientists, learn about career development, and job opportunities (http://casms.org).

ASSOCIATION OF TESSELLATION DENSITY WITH PROGRESSION OF AXIAL LENGTH AND REFRACTION IN CHILDREN: An Artificial Intelligence-Assisted 4-Year Study.

PURPOSE: To investigate fundus tessellation density (TD) and its association with axial length (AL) elongation and spherical equivalent (SE) progression in children. METHODS: The school-based prospective cohort study enrolled 1,997 individuals aged 7 to 9 years in 11 elementary schools in Mojiang, China. Cycloplegic refraction and biometry were performed at baseline and 4-year visits. The baseline fundus photographs were taken, and TD, defined as the percentage of exposed choroidal vessel area in the photographs, was quantified using an artificial intelligence-assisted semiautomatic labeling approach. After the exclusion of 330 ineligible participants because of loss to follow-up or ineligible fundus photographs, logistic models were used to assess the association of TD with rapid AL elongation (>0.36 mm/year) and SE progression (>1.00 D/year). RESULTS: The prevalence of tessellation was 477 of 1,667 (28.6%) and mean TD was 0.008 ± 0.019. The mean AL elongation and SE progression in 4 years were 0.90 ± 0.58 mm and -1.09 ± 1.25 D. Higher TD was associated with longer baseline AL (ß, 0.030; 95% confidence interval: 0.015-0.046; P < 0.001) and more myopic baseline SE (ß, -0.017; 95% confidence interval: -0.032 to -0.002; P = 0.029). Higher TD was associated with rapid AL elongation (odds ratio, 1.128; 95% confidence interval: 1.055-1.207; P < 0.001) and SE progression (odds ratio, 1.123; 95% confidence interval: 1.020-1.237; P = 0.018). CONCLUSION: Tessellation density is a potential indicator of rapid AL elongation and refractive progression in children. TD measurement could be a routine to monitor AL elongation.

The association of serum uric acid with all-cause and cardiovascular mortality among adults with rheumatoid arthritis: a cohort study.

OBJECTIVES: Serum uric acid (SUA) is associated with poor outcomes in patients with numerous types of disease. However, the association between SUA and the outcomes of patients with rheumatoid arthritis (RA) remains to be fully elucidated. Thus, the present study aimed to determine the associations between SUA and all-cause or cardiovascular disease (CVD)-associated mortality in adults with RA. METHODS: The data of patients with RA were collected from the National Health and Nutrition Examination Survey from 2001 to 2018. All-cause and CVD-associated mortality were identified using national death records through 31 December 2019. Weighted survival curves, Cox proportional hazards regression models, restricted cubic splines (RCS) and stratified analyses were used to assess the association between SUA levels and mortality. RESULTS: Among 2,312 patients with RA, a total of 597 all-cause deaths and 198 CVD-associated deaths were recorded during 19,133 person-years of follow-up. The results of the Kaplan-Meier curves for long-term all-cause and CVD-associated mortality demonstrated that increased levels of SUA were associated with a higher incidence of mortality. In the fully adjusted models, the highest SUA quartile exhibited hazard ratios [(HRs); 95% confidence intervals (CIs)] of 1.53 (1.10, 2.14) for all-cause mortality and 1.93 (1.14, 3.27) for CVD-associated mortality, compared with the lowest SUA quartile. The results of the RCS analysis confirmed a strong linear association between SUA levels and the HR of all-cause mortality, while a U-shaped association was observed between SUA and CVD-associated mortality. CONCLUSIONS: The results of the present study demonstrated that high SUA levels were significantly associated with increased risks of all-cause and CVD-associated mortality in patients with RA. Further studies are required to elucidate the potential impact of treatments on reducing SUA levels.

Comparison of Clarus and Optomap Ultra-Widefield Imaging Systems before and after EVO-ICL Implantation in High Myopia.

INTRODUCTION: The aim of this study was to investigate the features of imaging differences between Clarus and Optomap ultra-widefield imaging systems after implantable collamer lens (ICL) implantation. METHODS: This was a non-randomized controlled study. Ninety-two eyes of 46 consecutive patients were enrolled. Full-scale ophthalmological examinations were conducted preoperatively. All patients underwent Clarus (CLARUS 500; Carl Zeiss, Dublin, USA) and Optomap (Daytona; Optos, UK) ultra-wide imaging sequentially under the same circumstance preoperatively and 1 month after EVO-ICL implantation. A single image was acquired from each. Dx was defined as the distance between the upper furcation of the central retinal artery and the central fovea of macula. Pixels of the optic cup and disc and Dx as well as the optic cup/disc ratio were calculated and compared on each machine before and after surgery. RESULTS: All surgeries were uneventful without complications. Safety and efficacy indices were both 100% at 1 month. Values of both optic cup and disc areas were in decrease after surgery with statistically significant differences (p < 0.001), while the cup/disc ratio remained the same (Clarus mean of differences = -0.0028, p = 0.83; Optomap mean of differences = -0.0016, p = 0.76). Dx of images captured with either machine was statistically significantly decreased (p < 0.001). Differences of both optic cup (p = 0.057) and disc (p = 0.041) areas of Clarus were more obvious than that of Optomap, while only the latter was with statistical significance. Difference of Dx of Clarus was statistically significantly larger than Optomap. CONCLUSIONS: Display ranges tend to be broadened after EVO-ICL implantation in both Clarus and Optomap ultra-widefield imaging systems, while Clarus shows a wider display range of the two, which encourages the application of Clarus when it comes to the detection of more peripheral retinal lesions.

Effect of wearing peripheral focus-out glasses on emmetropization in Chinese children aged 6-8 years: study protocol for a 2-year randomized controlled intervention trial.

BACKGROUND: Myopia is one of the most common eye diseases causing visual impairment and blindness, and the high prevalence in adolescents remains a major public health concern. Based on clinical studies using optical defocus to regulate ocular growth and refractive changes through visual feedback, we hypothesize that early wearing of peripheral myopic defocusing spectacles in children with high risk of myopia may slow the process of emmetropization and even prevent the onset of myopia by inducing more peripheral myopic defocus. The aim of this study is to investigate whether the wearing of peripheral focus-out glasses can be effective in delaying emmetropization in non-myopic children aged 6-8 years. METHODS: The study is a 2-year randomized controlled trial. A total of 160 subjects will be randomized into the experimental group or the control group. The experimental group will be fitted with direct emmetropia with focus-out glasses (DEFOG) to guide the emmetropization process. The control group will not receive any treatment and will serve as a blank control group. The primary aim is to determine whether non-myopic children wearing DEFOG lenses are superior to those who do not receive any intervention on the progression of cycloplegic objective refraction over 2 years. DISCUSSION: This is the first randomized controlled trial aiming at myopic prevention by non-invasive intervention in non-myopic children. This study aims to initially investigate whether wearing peripheral focus-out glasses can effectively delay the process of emmetropization in children aged 6-8 years with high risk of myopia, which might give potential clues for further exploration on early prevention of myopia. TRIAL REGISTRATION: ClinicalTrials.gov NCT05689567. Registered on 10 January 2023.

Quantitative mapping of the in vivo O-GalNAc glycoproteome in mouse tissues identifies GalNAc-T2 O-glycosites in metabolic disorder.

The family of GalNAc-Ts (GalNAcpolypeptide:N-Acetylgalactosaminyl transferases) catalyzes the first committed step in the synthesis of O-glycans, which is an abundant and biologically important protein modification. Abnormalities in the activity of individual GalNAc-Ts can result in congenital disorders of O-glycosylation (CDG) and influence a broad array of biological functions. How site-specific O-glycans regulate biology is unclear. Compiling in vivo O-glycosites would be an invaluable step in determining the function of site-specific O-glycans. We integrated chemical and enzymatic conditions that cleave O-glycosites, a higher-energy dissociation product ions-triggered electron-transfer/higher-energy collision dissociation mass spectrometry (MS) workflow and software to study nine mouse tissues and whole blood. We identified 2,154 O-glycosites from 595 glycoproteins. The O-glycosites and glycoproteins displayed consensus motifs and shared functions as classified by Gene Ontology terms. Limited overlap of O-glycosites was observed with protein O-GlcNAcylation and phosphorylation sites. Quantitative glycoproteomics and proteomics revealed a tissue-specific regulation of O-glycosites that the differential expression of Galnt isoenzymes in tissues partly contributes to. We examined the Galnt2-null mouse model, which phenocopies congenital disorder of glycosylation involving GALNT2 and revealed a network of glycoproteins that lack GalNAc-T2-specific O-glycans. The known direct and indirect functions of these glycoproteins appear consistent with the complex metabolic phenotypes observed in the Galnt2-null animals. Through this study and interrogation of databases and the literature, we have compiled an atlas of experimentally identified mouse O-glycosites consisting of 2,925 O-glycosites from 758 glycoproteins.

Myopic Vascular Changes Revealed by Optical Tomography Angiography and Their Association with Myopic Fundus Manifestations.

INTRODUCTION: We aimed to quantify and evaluate fundal vascular changes at different severities of myopia using optical tomography angiography (OCTA) and explore their association with fundus changes captured by ultra-widefield (UWF) fundus cameras. METHODS: Seventy-four participants with myopia were enrolled in the study and underwent basic ophthalmic examination, OCTA, and UWF fundus photography. Multiple parameters were obtained using OCTA (flow area, structure thickness, and vessel density) and UWF fundus cameras (tessellation and parapapillary atrophy [PPA]). RESULTS: The right eye of 30 participants with low and moderate myopia and 44 participants with high myopia (HM) were included. Patients with HM had a larger flow area of the outer retina (FA-OR) and a smaller thickness of choroid (TC). Axial length was significantly correlated with retinal and choroidal flow area and thickness in the different zones. The PPA area was positively correlated with FA-OR and negatively correlated with TC. Tessellation exhibited different levels of correlation with OCTA parameters regarding the flow area, thickness, and vessel density of the fundal layers, mainly in the inner retina. CONCLUSION: FA-OR and TC exhibited sensitive changes in patients with HM and axial elongation; therefore, they could serve as predictive OCTA biomarkers. The PPA and tessellation were connected to the vascular and structural changes revealed by OCTA.

Effects of Inner-Row Ground Management on the Volatomics of 'Cabernet Sauvignon' Grapes and Wines in the Region of the Eastern Foothills of the Ningxia Helan Mountains in Northwest China.

This two-consecutive-year study aimed to evaluate the effects of ground management methods on the volatomics of 'Cabernet Sauvignon' grapes and wines in Northwest China, in which inner-row crop covering with purslane (GRASS) and mulching with black plastic film (FILM) treatments were carried out, respectively. Compared with clean tillage (CK), the GRASS and FILM treatments changed the microclimates of grapevine fruit zones and rhizospheres, which delayed the ripening of grape berries and affected the accumulation of aroma substances in the mature grapes effectively. GRASS increased the concentration of terpenes and C13-norisoprenoids in berries and gave more floral, fruity, and caramel fragrances to wines, while FILM had the opposite effect of significantly increasing the synthesis of C6/C9 compounds and brought more green leaf flavors, showing that inner-row purslane covering is a potential and stable viticultural practice to improve the wine quality in this booming wine region.

Network pharmacology and molecular docking reveal the immunomodulatory mechanism of rhubarb peony decoction for the treatment of ulcerative colitis and irritable bowel syndrome.

Background: Ulcerative colitis (UC) and irritable bowel syndrome (IBS) share various similarities in clinical symptoms, pathogenesis, and treatment. UC concurrent IBS tends toward more severe symptoms and worse prognosis, and promising feasible therapies for the overlapping symptoms remains a challenge. Rhubarb peony decoction (RPD) is a well-known traditional Chinese medicine that has been widely applied in treating UC. RPD may exert extensive therapeutic effects on both IBS and UC. However, the common mechanism of its treatment remains unclear. We aimed to assess the potential pharmacological mechanism of RPD in the treatment of overlapping IBS and UC. Methods: The active components and targets of RPD were retrieved from ETCM, TCMSP, BATMAN-TCM, and TCM databases. The disease targets were screened by searching the DrugBank, OMIM, TTD, and PharmGKB databases. PPI network analysis was performed and visualized via the STRING platform and Cytoscape software. GO and KEGG enrichment analyses of the hub genes of RPD were predicted to elucidate the potential molecular mechanism. Subsequently, molecular docking was carried out to verify the combination of active compounds with core targets. Results: By integrating all targets of RPD and disease, a total of 31 bioactive ingredients were identified including quercetin, kaempferol, aloe-emodin, beta-sitosterol, and (+)-catechin, etc. JUN, TP53, MAPK1, RELA, MYC, and ESR1 were explored as potential therapeutic targets among 126 common drug-disease-related targets. They were enriched in the AGE-RAGE signaling pathway in diabetic complications, as well as the NF-kappa B signaling pathway and MAPK signaling pathway. Additionally, some active ingredients were identified as candidates for binding to the hub targets via molecular docking, further suggesting their anti-inflammatory and antioxidative properties. Conclusion: RPD may exert the overall treatment effect for UC and IBS overlap syndrome via the biological mechanism of "multi-ingredients, multi-targets, and multi-pathways" on inflammation, oxidative stress, immune, oncogenicity, and gut microbiota dysbiosis.

Gain-of-function mutations in the catalytic domain of DOT1L promote lung cancer malignant phenotypes via the MAPK/ERK signaling pathway.

Lung cancer is a lethal malignancy lacking effective therapies. Emerging evidence suggests that epigenetic enzyme mutations are closely related to the malignant phenotype of lung cancer. Here, we identified a series of gain-of-function mutations in the histone methyltransferase DOT1L. The strongest of them is R231Q, located in the catalytic DOT domain. R231Q can enhance the substrate binding ability of DOT1L. Moreover, R231Q promotes cell growth and drug resistance of lung cancer cells in vitro and in vivo. Mechanistic studies also revealed that the R231Q mutant specifically activates the MAPK/ERK signaling pathway by enriching H3K79me2 on the RAF1 promoter and epigenetically regulating the expression of downstream targets. The combination of a DOT1L inhibitor (SGC0946) and a MAPK/ERK axis inhibitor (binimetinib) can effectively reverse the R231Q-induced phenomena. Our results reveal gain-of-function mutations in an epigenetic enzyme and provide promising insights for the precise treatment of lung cancer patients.

Evaluation of Hypertensive Disorder of Pregnancy and High Refractive Error in Offspring During Childhood and Adolescence.

Importance: Growing evidence indicates that adverse prenatal or intrauterine environments might contribute to the development of high refractive error (RE) later in life. However, the association of maternal hypertensive disorder of pregnancy (HDP) with high RE in offspring during childhood and adolescence remains unknown. Objective: To investigate the association between maternal HDP and overall and type-specific high REs in offspring in childhood and adolescence. Design, Setting, and Participants: This nationwide population-based cohort study included live-born individuals born in Denmark from 1978 to 2018 in the Danish national health registers. Follow-up started at the date of birth and ended at the date of RE diagnosis, 18th birthday, death, emigration, or December 31, 2018, whichever came first. Data analyses were conducted from November 12, 2021, through June 30, 2022. Exposures: Maternal HDP (n = 104 952), including preeclampsia or eclampsia (n = 70 465) and hypertension (n = 34 487). Main Outcomes and Measures: The main outcomes were the first occurrence of high RE (hyperopia, myopia, and astigmatism) in offspring. A Cox proportional hazards regression model was used to examine the association between maternal HDP and risk of high RE in offspring from birth until age 18 years, adjusting for multiple potential confounders. Results: This study included 2 537 421 live-born individuals, 51.30% of whom were male. During the follow-up of up to 18 years, 946 offspring of 104 952 mothers with HDP (0.90%) and 15 559 offspring of 2 432 469 mothers without HDP (0.64%) were diagnosed with high RE. The cumulative incidence of high RE was higher in the exposed cohort (1.12%; 95% CI, 1.05%-1.19%) than in the unexposed cohort (0.80%; 95% CI, 0.78%-0.81%) at 18 years of age (difference: 0.32%; 95% CI, 0.25%-0.40%). Offspring born to mothers with HDP had a 39% increased risk of overall high RE (hazard ratio [HR], 1.39; 95% CI, 1.31-1.49). Sibling-matched analysis revealed an increased risk of overall high RE in half siblings (HR, 1.21; 95% CI, 1.05-1.39) and full siblings (HR, 1.15; 95% CI, 0.99-1.34), but the difference was not significant for the latter. The elevated risks were observed for hypermetropia (HR, 1.41; 95% CI, 1.30-1.52), myopia (HR, 1.30; 95% CI, 1.10-1.53), and astigmatism (HR, 1.45; 95% CI, 1.22-1.71). The increased risk of high RE persisted among offspring aged 0 to 6 years (HR, 1.51, 95% CI, 1.38-1.65), 7 to 12 years (HR, 1.28; 95% CI, 1.11-1.47), and 13 to 18 years (HR, 1.16; 95% CI, 0.95-1.41), but the difference was not significant for the oldest group. When considering both timing of diagnosis and severity of maternal preeclampsia, the highest risk was observed in offspring prenatally exposed to early-onset and severe preeclampsia (HR, 2.59; 95% CI, 2.17-3.08). Conclusions and Relevance: In this cohort study of the Danish population, maternal HDP, especially early-onset and severe preeclampsia, was associated with an increased risk of high RE in offspring during childhood and adolescence. These findings suggest that early and regular RE screening should be recommended for children of mothers with HDP.