Characterizing Inequities in Pediatric Appendicitis Delayed Diagnosis and Perforation.

Objective: We sought to characterize the impact of a child's sociodemographic characteristics on their odds of delayed diagnosis and perforation in pediatric appendicitis. Study design: We performed a single-center, retrospective cohort study of all pediatric appendicitis admissions between 2016 and 2021. Using a multivariable model, we evaluated for associations between delayed diagnosis and perforation and a child's sociodemographic characteristics, including their age, sex, race and ethnicity, insurance status, and their home census-tract Material Community Deprivation Index value. Results: The study included 3248 patients. The median age was 12.1 years (IQR 9.5-14.9 years). Most patients were male (60.3%), identified as non-Hispanic White (78.0%), and had private insurance (55.4%). The delayed diagnosis and perforation rates were 6.4% and 25.1%, respectively. Delayed diagnosis cases had a greater perforation rate (56% compared with 21.5%, P < .001). On adjusted analysis, older age decreased the odds (OR 0.91, CI 0.87-0.94) of delayed diagnosis, whereas female sex (OR 1.50, CI 1.13-2.00) and socioeconomic disadvantage (OR 1.56 for quartile 4 vs quartile 1, CI 1.00-2.43) increased the odds. Furthermore, older age (OR 0.91, CI 0.89-0.93) decreased the odds of perforation, whereas non-Hispanic Black (OR 1.72, CI 1.3-2.29) or Hispanic (OR 1.60, CI 1.24-2.08) compared with non-Hispanic White identification and socioeconomic disadvantage (OR 1.43 Q4 vs Q1, CI 1.12-1.83) increased the odds. Conclusions: Our reported delayed diagnosis rate is greater than recent literature, highlighting the need to consider visits that occur across different health care settings. We further identify sociodemographic factors, including socioeconomic status, that impact a child's risk of delayed diagnosis and perforation.

Racial Fairness of Individual- and Community-Level Proxies of Socioeconomic Status Among Birthing Parent-Child Dyads.

BACKGROUND: While precision medicine algorithms can be used to improve health outcomes, concerns have been raised about racial equity and unintentional harm from encoded biases. In this study, we evaluated the fairness of using common individual- and community-level proxies of pediatric socioeconomic status (SES) such as insurance status and community deprivation index often utilized in precision medicine algorithms. METHODS: Using 2012-2021 vital records obtained from the Ohio Department of Health, we geocoded and matched each residential birth address to a census tract to obtain community deprivation index. We then conducted sensitivity and specificity analyses to determine the degree of match between deprivation index, insurance status, and birthing parent education level for all, Black, and White children to assess if there were differences based on race. RESULTS: We found that community deprivation index and insurance status fail to accurately represent individual SES, either alone or in combination. We found that deprivation index had a sensitivity of 61.2% and specificity of 74.1%, while insurance status had a higher sensitivity of 91.6% but lower specificity of 60.1%. Furthermore, these inconsistencies were race-based across all proxies evaluated, with greater sensitivities for Black children but greater specificities for White children. CONCLUSION: This may explain some of the racial disparities present in precision medicine algorithms that utilize SES proxies. Future studies should examine how to mitigate the biases introduced by using SES proxies, potentially by incorporating additional data on housing conditions.

Development of a multimodal geomarker pipeline to assess the impact of social, economic, and environmental factors on pediatric health outcomes.

OBJECTIVES: We sought to create a computational pipeline for attaching geomarkers, contextual or geographic measures that influence or predict health, to electronic health records at scale, including developing a tool for matching addresses to parcels to assess the impact of housing characteristics on pediatric health. MATERIALS AND METHODS: We created a geomarker pipeline to link residential addresses from hospital admissions at Cincinnati Children's Hospital Medical Center (CCHMC) between July 2016 and June 2022 to place-based data. Linkage methods included by date of admission, geocoding to census tract, street range geocoding, and probabilistic address matching. We assessed 4 methods for probabilistic address matching. RESULTS: We characterized 124 244 hospitalizations experienced by 69 842 children admitted to CCHMC. Of the 55 684 hospitalizations with residential addresses in Hamilton County, Ohio, all were matched to 7 temporal geomarkers, 97% were matched to 79 census tract-level geomarkers and 13 point-level geomarkers, and 75% were matched to 16 parcel-level geomarkers. Parcel-level geomarkers were linked using our exact address matching tool developed using the best-performing linkage method. DISCUSSION: Our multimodal geomarker pipeline provides a reproducible framework for attaching place-based data to health data while maintaining data privacy. This framework can be applied to other populations and in other regions. We also created a tool for address matching that democratizes parcel-level data to advance precision population health efforts. CONCLUSION: We created an open framework for multimodal geomarker assessment by harmonizing and linking a set of over 100 geomarkers to hospitalization data, enabling assessment of links between geomarkers and hospital admissions.

Causal association and mediating effect of blood biochemical metabolic traits and brain image-derived endophenotypes on Alzheimer's disease.

Background: Recent genetic evidence supports that circulating biochemical and metabolic traits (BMTs) play a causal role in Alzheimer's disease (AD), which might be mediated by changes in brain structure. Here, we leveraged publicly available genome-wide association study data to investigate the intrinsic causal relationship between blood BMTs, brain image-derived phenotypes (IDPs) and AD. Methods: Utilizing the genetic variants associated with 760 blood BMTs and 172 brain IDPs as the exposure and the latest AD summary statistics as the outcome, we analyzed the causal relationship between blood BMTs and brain IDPs and AD by using a two-sample Mendelian randomization (MR) method. Additionally, we used two-step/mediation MR to study the mediating effect of brain IDPs between blood BMTs and AD. Results: Twenty-five traits for genetic evidence supporting a causal association with AD were identified, including 12 blood BMTs and 13 brain IDPs. For BMTs, glutamine consistently reduced the risk of AD in 3 datasets. For IDPs, specific alterations of cortical thickness (atrophy in frontal pole and insular lobe, and incrassation in superior parietal lobe) and subcortical volume (atrophy in hippocampus and its subgroups, left accumbens and left choroid plexus, and expansion in cerebral white matter) are vulnerable to AD. In the two-step/mediation MR analysis, superior parietal lobe, right hippocampal fissure and left accumbens were identified to play a potential mediating role among three blood BMTs and AD. Conclusions: The results obtained in our study suggest that 12 circulating BMTs and 13 brain IDPs play a causal role in AD. Importantly, a subset of BMTs exhibit shared genetic architecture and potentially causal relationships with brain structure, which may contribute to the alteration of brain IDPs in AD.

Spatial-temporal drivers and incidence heterogeneity of hemorrhagic fever with renal syndrome transmission in Shandong Province, China, 2016-2022.

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) signals a recurring risk in Eurasia in recent years owing to its continued rise in case notifications and the extension of geographical distribution. This study was undertaken to investigate the spatiotemporal drivers and incidence heterogeneity of HFRS transmission in Shandong Province. METHODS: The epidemiological data for HFRS, meteorological data and socioeconomic data were obtained from China Information System for Disease Control and Prevention, China Meteorological Data Sharing Service System, and Shandong Statistical Yearbook, respectively. The spatial-temporal multicomponent model was employed to analyze the values of spatial-temporal components and the heterogeneity of HFRS transmission across distinct regions. RESULTS: The total effect values of the autoregressive, epidemic, and endemic components were 0.451, 0.187, and 0.033, respectively, exhibiting significant heterogeneity across various cities. This suggested a pivotal role of the autoregressive component in propelling HFRS transmission in Shandong Province. The epidemic component of Qingdao, Weifang, Yantai, Weihai, and Jining declined sharply at the onset of 2020. The random effect identified distinct incidence levels associated with Qingdao and Weifang, signifying regional variations in HFRS occurrence. CONCLUSIONS: The autoregressive component emerged as a significant driver in the transmission of HFRS in Shandong Province. Targeted preventive measures should be strategically implemented across various regions, taking into account the predominant component influencing the epidemic.

The Role of Cytokines in Acute and Chronic Postsurgical Pain in Pediatric Patients after Major Musculoskeletal Surgeries.

Study Objective: To determine if baseline cytokines and their changes over postoperative days 0-2 (POD0-2) predict acute and chronic postsurgical pain (CPSP) after major surgery. Design: Prospective, observational, longitudinal nested study. Setting: University-affiliated quaternary children's hospital. Patients: Subjects (≥8 years old) with idiopathic scoliosis undergoing spine fusion or pectus excavatum undergoing Nuss procedure. Measurements: Demographics, surgical, psychosocial measures, pain scores, and opioid use over POD0-2 were collected. Cytokine concentrations were analyzed in serial blood samples collected before and after (up to two weeks) surgery, using Luminex bead arrays. After data preparation, relationships between pre- and post-surgical cytokine concentrations with acute (% time in moderate-severe pain over POD0-2) and chronic (pain score>3/10 beyond 3 months post-surgery) pain were analyzed. After adjusting for covariates, univariate/multivariate regression analyses were conducted to associate baseline cytokine concentrations with postoperative pain, and mixed effects models were used to associate longitudinal cytokine concentrations with pain outcomes. Main Results: Analyses included 3,164 measures of 16 cytokines from 112 subjects (median age 15.3, IQR 13.5-17.0, 54.5% female, 59.8% pectus). Acute postsurgical pain was associated with higher baseline concentrations of GM-CSF (ß=0.95, SE 0.31; p=.003), IL-1ß (ß=0.84, SE 0.36; p=.02), IL-2 (ß=0.78, SE 0.34; p=.03), and IL-12 p70 (ß=0.88, SE 0.40; p=.03) and longitudinal postoperative elevations in GM-CSF (ß=1.38, SE 0.57; p=.03), IFNγ (ß=1.36, SE 0.6; p=.03), IL-1ß (ß=1.25, SE 0.59; p=.03), IL-7 (ß=1.65, SE 0.7, p=.02), and IL-12 p70 (ß=1.17, SE 0.58; p=.04). In contrast, CPSP was associated with lower baseline concentration of IL-8 (ß= -0.39, SE 0.17; p=.02), and the risk of developing CPSP was elevated in patients with lower longitudinal postoperative concentrations of IL-6 (ß= -0.57, SE 0.26; p=.03), IL-8 (ß= -0.68, SE 0.24; p=.006), and IL-13 (ß= -0.48, SE 0.22; p=.03). Furthermore, higher odds for CPSP were found for females (vs. males) for IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNFα, and for pectus (vs. spine) surgery for IL-8 and IL-10. Conclusion: We identified pro-inflammatory cytokines associated with increased acute postoperative pain and anti-inflammatory cytokines associated with lower CPSP risk, with potential to serve as predictive and prognostic biomarkers.

Causal Mediation of Neighborhood-Level Pediatric Hospitalization Inequities.

BACKGROUND AND OBJECTIVES: Population-wide racial inequities in child health outcomes are well documented. Less is known about causal pathways linking inequities and social, economic, and environmental exposures. Here, we sought to estimate the total inequities in population-level hospitalization rates and determine how much is mediated by place-based exposures and community characteristics. METHODS: We employed a population-wide, neighborhood-level study that included youth <18 years hospitalized between July 1, 2016 and June 30, 2022. We defined a causal directed acyclic graph a priori to estimate the mediating pathways by which marginalized population composition causes census tract-level hospitalization rates. We used negative binomial regression models to estimate hospitalization rate inequities and how much of these inequities were mediated indirectly through place-based social, economic, and environmental exposures. RESULTS: We analyzed 50 719 hospitalizations experienced by 28 390 patients. We calculated census tract-level hospitalization rates per 1000 children, which ranged from 10.9 to 143.0 (median 45.1; interquartile range 34.5 to 60.1) across included tracts. For every 10% increase in the marginalized population, the tract-level hospitalization rate increased by 6.2% (95% confidence interval: 4.5 to 8.0). After adjustment for tract-level community material deprivation, crime risk, English usage, housing tenure, family composition, hospital access, greenspace, traffic-related air pollution, and housing conditions, no inequity remained (0.2%, 95% confidence interval: -2.2 to 2.7). Results differed when considering subsets of asthma, type 1 diabetes, sickle cell anemia, and psychiatric disorders. CONCLUSIONS: Our findings provide additional evidence supporting structural racism as a significant root cause of inequities in child health outcomes, including outcomes at the population level.

TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro.

BACKGROUND: There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment. METHODS: To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models. RESULTS: Through MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation. CONCLUSIONS: Our MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation.

Discovery and Exploration of Lipid-Modifying Drug Targets for ALS by Mendelian Randomization.

Observational studies have faced challenges in identifying replicable causes for amyotrophic lateral sclerosis (ALS). To address this, we employed an unbiased and data-driven approach to discover and explore potential causal exposures using two-sample Mendelian randomization (MR) analyses. In the phenotype discovery stage, we assessed 3948 environmental exposures from the UK Biobank and utilized ALS summary statistics (Europeans, 20,806 cases, 59,804 controls) as the outcome within a phenome-wide MR pipeline. Through a range of sensitivity analyses, two medication traits were identified to be protective for ALS. In the target exploration stage, we further conducted drug target MR analyses using the latest and trans-ethnic summary data on lipid-related traits and ALS (Europeans, 27,205 cases, 110,881 controls; East Asians, 1234 cases, 2850 controls). Our aim was to explore potential causal drug targets through six lipid-modifying effects. These comprehensive analyses revealed significant findings. Specifically, "cholesterol-lowering medication" and "atorvastatin" survived predefined criteria in the phenotype discovery stage and exhibited a protective effect on ALS. Further in the target exploration stage, we demonstrated that the therapeutic effect of APOB through LDL-lowering was associated with reduced ALS liability in Europeans (OR = 0.835, P = 5.61E - 5). Additionally, the therapeutic effect of APOA1 and LDLR through TC-lowering was associated with reduced ALS liability in East Asians (APOA1, OR = 0.859, P = 5.38E - 4; LDLR, OR = 0.910, P = 2.73E - 5). Overall, we propose potential protective effects of cholesterol-lowering drugs or statins on ALS risk from thousands of exposures. Our research also suggests APOB, APOA1, and LDLR as novel therapeutic targets for ALS and supports their potential protective mechanisms may be mediated by LDL-lowering or TC-lowering effects.

Morphologies and magnetic properties of α-Fe2O3 nanoparticles calcined at different temperatures.

Different morphologies and sizes of α-Fe2O3 were prepared by a coprecipitation method using polyvinylpyrrolidone as a dispersant. In the preparation process, homogeneous and dispersed nanoscale FeOOH particles were first obtained by the coprecipitation method, and then the FeOOH particles were calcined at high temperature to form α-Fe2O3. The growth and aggregation of the α-Fe2O3 particles at different calcination temperatures resulted in α-Fe2O3 powders with diversiform morphologies (nanoscale microsphere, pinecone ellipsoidal, polyhedral, and quasi-spherical structures). By analyzing the SEM images, it was inferred that the polyhedral structure of α-Fe2O3 particles was formed by the accumulation of rhomboid sheet structures and high-temperature growth. In terms of the magnetic properties, the samples belonged to the class of canted antiferromagnetic materials, and the morphology, particle size, and crystallite size of the α-Fe2O3 particles were important factors affecting the coercivity. Among these, when the calcination temperature was increased from 700 °C to 800 °C, the growth rate of the particle size was significantly faster than that of the crystallite size, and the coercivity increased substantially from 1411 Oe to 2688 Oe.

Antibody and transcription landscape in peripheral blood mononuclear cells of elderly adults over 70 years of age with third dose of COVID-19 BBIBP-CorV and ZF2001 booster vaccine.

BACKGROUND: In the context of the COVID-19 pandemic and extensive vaccination, it is important to explore the immune response of elderly adults to homologous and heterologous booster vaccines of COVID-19. At this point, we detected serum IgG antibodies and PBMC sample transcriptome profiles in 46 participants under 70 years old and 25 participants over 70 years old who received the third dose of the BBIBP-CorV and ZF2001 vaccines. RESULTS: On day 7, the antibody levels of people over 70 years old after the third dose of booster vaccine were lower than those of young people, and the transcriptional responses of innate and adaptive immunity were also weak. The age of the participants showed a significant negative correlation with functions related to T-cell differentiation and costimulation. Nevertheless, 28 days after the third dose, the IgG antibodies of elderly adults reached equivalence to those of younger adults, and immune-related transcriptional regulation was significantly improved. The age showed a significant positive correlation with functions related to "chemokine receptor binding", "chemokine activity", and "chemokine-mediated signaling pathway". CONCLUSIONS: Our results document that the response of elderly adults to the third dose of the vaccine was delayed, but still able to achieve comparable immune effects compared to younger adults, in regard to antibody responses as well as at the transcript level.

Assessing Mailuoning injection in wound healing and thrombophlebitis management: A rat model study.

Thrombophlebitis is the inflammatory condition characterized by obstruction of one or more vessels, commonly in the legs, due to the formation of blood clots. It has been reported that traditional Chinese medicine, including Mailuoning injection, is advantageous for treating inflammatory and blood disorders. This research assessed the therapeutic efficacy of Mailuoning injection in the treatment of thrombophlebitis in rodents, as well as investigated its impact on fibrinolysis, inflammation, and coagulation. An experimental setup for thrombophlebitis was established in rodents via modified ligation technique. Five groups comprised the animals: sham operation group, model group, and three Mailuoning treatment groups (low, medium, and high dosages). The pain response, edema, coagulation parameters (PT, APTT, TT, FIB), serum inflammatory markers (IL-6, TNF-α, CRP), and expression levels of endothelial markers (ICAM-1, VCAM-1, NF-κB) were evaluated. Blood flow and vascular function were further assessed by measuring hemorheological parameters and the concentrations of TXB2, ET, and 6-k-PGF1α. In contrast to the sham group, model group demonstrated statistically significant increases in endothelial expression levels, coagulation latencies, and inflammatory markers (p < 0.05). The administration of mailing, specifically at high and medium dosages, resulted in a substantial reduction in inflammatory markers, enhancement of coagulation parameters, suppression of ICAM-1 and VCAM-1 expression, and restoration of hemorheological measurements to baseline (p < 0.05). Significantly higher concentrations of 6-k-PGF1α and lower levels of TXB2 and ET were observed in high-dose group, suggesting that pro- and anti-thrombotic factors were restored to equilibrium. Utilization of Mailuoning injection in rat model of thrombophlebitis exhibited significant therapeutic impact. This effect was manifested through pain alleviation, diminished inflammation, enhanced blood viscosity and facilitation of fibrinolysis. The study indicated that Mailuoning injection may serve as a viable therapeutic option for thrombophlebitis, potentially aiding in the improvement of wound healing by virtue of its anti-inflammatory and blood flow-enhancing characteristics.

Education-related needs for children with cystic fibrosis: Perspectives of US pediatric care teams.

OBJECTIVE: Patients with cystic fibrosis (CF) often bring education-related concerns to their medical teams. Concerns around the ability for CF care teams to identify and address these concerns exist. We sought to describe CF care team perceptions of (1) patient and family education-related needs, (2) how these needs are identified, documented and addressed, and (3) education-related resource gaps. METHODS: A survey was emailed to pediatric care teams in the CF Foundation Care Center Network in April 2022. Individuals or care teams could complete the survey. Responses were aggregated for descriptive analysis. RESULTS: Sixty-seven programs responded representing 52% of United States pediatric CF centers. Most centers (88%) indicated social workers primarily address school concerns. Care teams often complete school forms (99%), coach families to communicate with schools (96%), communicate with schools directly (90%), and develop educational plans (76%). Formal education risk assessment and support programs are relatively uncommon (19%). Common student-specific needs include carrying medications (75%) and leaving class for gastrointestinal issues (54%). Needs reported are informational materials for families and schools (94%), staff education about school concerns and how to address them (91%), additional staff for education-related issues (65%), and expertise in education plan development (62%). CONCLUSION: CF care teams often lack comprehensive resources to identify and address education-related concerns. Systematically performing needs assessments, improving training for providers, and evaluating the benefits of education specialists on care teams may better identify and address education-related needs. Supporting educational progression will foster continued independence and well-being in adulthood.

Spatiotemporal distribution and environmental influences of severe fever with thrombocytopenia syndrome in Shandong Province, China.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease discovered in China in 2009. The purpose of this study was to describe the spatiotemporal distribution of SFTS and to identify its environmental influencing factors and potential high-risk areas in Shandong Province, China. METHODS: Data on the SFTS incidence from 2010 to 2021 were collected. Spatiotemporal scan statistics were used to identify the time and area of SFTS clustering. The maximum entropy (MaxEnt) model was used to analyse environmental influences and predict high-risk areas. RESULTS: From 2010 to 2021, a total of 5705 cases of SFTS were reported in Shandong. The number of SFTS cases increased yearly, with a peak incidence from April to October each year. Spatiotemporal scan statistics showed the existence of one most likely cluster and two secondary likely clusters in Shandong. The most likely cluster was in the eastern region, from May to October 2021. The first secondary cluster was in the central region, from May to October 2021. The second secondary cluster was in the southeastern region, from May to September 2020. The MaxEnt model showed that the mean annual wind speed, NDVI, cattle density and annual cumulative precipitation were the key factors influencing the occurrence of SFTS. The predicted risk map showed that the area of high prevalence was 28,120 km2, accounting for 18.05% of the total area of the province. CONCLUSIONS: The spatiotemporal distribution of SFTS was heterogeneous and influenced by multidimensional environmental factors. This should be considered as a basis for delineating SFTS risk areas and developing SFTS prevention and control measures.

Disruption of the Contents of Endogenous Hormones Cause Pollen Development Obstruction and Abortion in Male-Sterile Hybrid Lily Populations.

Lilies are well-known flowers with large anthers and a high quantity of pollen that easily contaminates clothing and tepals. The anthers need to be artificially removed, leading to production problems. Cultivating male-sterile or pollen-free lilies could solve these problems. The key period of male sterility in a specific male-sterile hybrid lily population was determined through cytological observation. The contents of hormones, soluble sugar, soluble protein, and proline were determined by high-performance liquid chromatography, tandem mass spectrometry and colorimetry. Transcriptome sequencing was used to identify the genes with altered expression. The key period of male sterility was determined to be the microspore mother and tetrad stages. The hormone contents were abnormal in the sterile line compared with the fertile line. The indole-3-acetic acid (IAA) content was higher in the sterile line than in the fertile line at all stages, while the gibberellic acid 4 (GA4) content showed the opposite result. Abscisic acid (ABA) accumulated in the sterile line in both the microspore mother and tetrad stages, and the zeatin riboside (ZR) content in the sterile line increased at the microspore mother stage but decreased at the tetrad stage. The contents of soluble sugar, soluble protein and proline were higher in the fertile line than in the sterile line. Genes involved in auxin and ABA synthesis and signalling pathways were highly expressed in the male-sterile line. Our data suggested that abnormal contents of hormones in the microspore mother and tetrad stages resulted in pollen abortion in a male-sterile hybrid lily population, which indicated that the hormone balance in specific stages plays critical functions in pollen development in lilies.

Expanding causal genes for Parkinson's disease via multi-omics analysis.

Genome­wide association studies (GWASs) have revealed numerous loci associated with Parkinson's disease (PD). However, some potential causal/risk genes were still not revealed and no etiological therapies are available. To find potential causal genes and explore genetically supported drug targets for PD is urgent. By integrating the expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) datasets from multiple tissues (blood, cerebrospinal fluid (CSF) and brain) and PD GWAS summary statistics, a pipeline combing Mendelian randomization (MR), Steiger filtering analysis, Bayesian colocalization, fine mapping, Protein-protein network and enrichment analysis were applied to identify potential causal genes for PD. As a result, GPNMB displayed a robust causal role for PD at the protein level in the blood, CSF and brain, and transcriptional level in the brain, while the protective role of CD38 (in brain pQTL and eQTL) was also identified. We also found inconsistent roles of DGKQ on PD between protein and mRNA levels. Another 9 proteins (CTSB, ARSA, SEC23IP, CD84, ENTPD1, FCGR2B, BAG3, SNCA, FCGR2A) were associated with the risk for PD based on only a single pQTL after multiple corrections. We also identified some proteins' interactions with known PD causative genes and therapeutic targets. In conclusion, this study suggested GPNMB, CD38, and DGKQ may act in the pathogenesis of PD, but whether the other proteins involved in PD needs more evidence. These findings would help to uncover the genes underlying PD and prioritize targets for future therapeutic interventions.

Heterologous Expression of Platycodon grandiflorus PgF3'5'H Modifies Flower Color Pigmentation in Tobacco.

Flavonoid-3',5'-hydroxylase (F3'5'H) is the key enzyme for the biosynthesis of delphinidin-based anthocyanins, which are generally required for purple or blue flowers. Previously, we isolated a full-length cDNA of PgF3'5'H from Platycodon grandiflorus, which shared the highest homology with Campanula medium F3'5'H. In this study, PgF3'5'H was subcloned into a plant over-expression vector and transformed into tobacco via Agrobacterium tumefaciens to investigate its catalytic function. Positive transgenic tobacco T0 plants were obtained by hygromycin resistance screening and PCR detection. PgF3'5'H showed a higher expression level in all PgF3'5'H transgenic tobacco plants than in control plants. Under the drive of the cauliflower mosaic virus (CaMV) 35S promoter, the over-expressed PgF3'5'H produced dihydromyricetin (DHM) and some new anthocyanin pigments (including delphinidin, petunidin, peonidin, and malvidin derivatives), and increased dihydrokaempferol (DHK), taxifolin, tridactyl, cyanidin derivatives, and pelargonidin derivatives in PgF3'5'H transgenic tobacco plants by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis, resulting in a dramatic color alteration from light pink to magenta. These results indicate that PgF3'5'H products have F3'5'H enzyme activity. In addition, PgF3'5'H transfer alters flavonoid pigment synthesis and accumulation in tobacco. Thus, PgF3'5'H may be considered a candidate gene for gene engineering to enhance anthocyanin accumulation and the molecular breeding project for blue flowers.

Primary urachal leiomyosarcoma: a case report and literature review of clinical, pathological, and medical imaging features.

Background: Urachal tumors are exceedingly rare, and adenocarcinoma is the most common malignant urachal neoplasm. Here, an especially rare patient of primary urachal leiomyosarcoma from our hospital was reported, and only five patients have been reported thus far since 1981. Case description: A 24-year-old man was admitted due to urinary tract symptoms. Both urogenital ultrasonography and contrast-enhanced computed tomography showed a mass at the dome of the urinary bladder. Laparoscopic surgical resection was performed, and histopathologic examination of the mass confirmed the diagnosis of urachal leiomyosarcoma. No recurrence was noted after one and a half years. Conclusions: Because the leiomyosarcoma located in the extraperitoneal space of Retzius and may manifest with nonspecific abdominal or urinary symptoms, early and definitive preoperative diagnosis is challenging. Partial cystectomy with complete excision of the urachus is recommended. Because only a few patients have been recorded, clinical outcomes and recurrence risks are difficult to assess.

Sexual Dimorphism in Lipid Metabolism and Gut Microbiota in Mice Fed a High-Fat Diet.

The gut microbiome plays an essential role in regulating lipid metabolism. However, little is known about how gut microbiome modulates sex differences in lipid metabolism. The present study aims to determine whether gut microbiota modulates sexual dimorphism of lipid metabolism in mice fed a high-fat diet (HFD). Conventional and germ-free male and female mice were fed an HFD for four weeks, and lipid absorption, plasma lipid profiles, and apolipoprotein levels were then evaluated. The gut microbiota was analyzed by 16S rRNA gene sequencing. After 4-week HFD consumption, the females exhibited less body weight gain and body fat composition and significantly lower triglyceride levels in very-low-density lipoprotein (VLDL) and cholesterol levels in high-density lipoprotein (HDL) compared to male mice. The fecal microbiota analysis revealed that the male mice were associated with reduced gut microbial diversity. The female mice had considerably different microbiota composition compared to males, e.g., enriched growth of beneficial microbes (e.g., Akkermansia) and depleted growth of Adlercreutzia and Enterococcus. Correlation analyses suggested that the different compositions of the gut microbiota were associated with sexual dimorphism in body weight, fat mass, and lipid metabolism in mice fed an HFD. Our findings demonstrated significant sex differences in lipid metabolism and the microbiota composition at baseline (during LFD), along with sex-dependent responses to HFD. A comprehensive understanding of sexual dimorphism in lipid metabolism modulated by microbiota will help to develop more sex-specific effective treatment options for dyslipidemia and metabolic disorders in females.

LIM Homeobox 2 Increases Adhesion-Regulating Molecule 1 Transcription to Facilitate the Pathological Progression of Oxidized Low-Density Lipoprotein-Stimulated Atherosclerotic Cell Models.

Endothelial-mesenchymal transition (EndMT) and endothelial cell apoptosis have been documented to have a role in atherosclerosis (AS) progression. To deepen knowledge in this aspect, our study investigated the effect of LIM homeobox 2 (LHX2) and adhesion-regulating molecule 1 (ADRM1) on EndMT and endothelial cell apoptosis in the oxidized low-density lipoprotein (ox-LDL) -stimulated AS cell model.Ox-LDL was utilized to treat human umbilical vein endothelial cells (HUVECs) for constructing an AS model in vitro, followed by measurement of LHX2 and ADRM1 expressions. Afterward, gain- and loss-of-function assays were performed in HUVECs, followed by detection of cell viability, invasion, migration, and apoptosis and the expression of inflammatory factors [tumor necrosis factor (TNF) -α, interleukin (IL) -1ß, and IL-6], EndMT-related proteins [CD31, vascular epithelium (VE) -cadherin, vimentin, α-smooth muscle actin (SMA), Snai1, Snai2, and Twist1], and the apoptotic protein cleaved caspase-3. Interactions between LHX2 and ADRM1 were analyzed with dual-luciferase reporter gene and chromatin immunoprecipitation assays.High levels of LHX2 and ADRM1 were observed in ox-LDL-induced HUVECs. In ox-LDL-treated HUVECs, LHX2, or ADRM1 knockdown promoted CD31 and VE-cadherin levels, viability, invasion, and migration and reduced apoptosis and the expressions of TNF-α, IL-1ß, IL-6, vimentin, α-SMA, Snai1, Snai2, Twist1, and cleaved caspase-3. Mechanistically, LHX2 bound to the ADRM1 promoter to promote ADRM1 transcription. Overexpression of ADRM1 annulled the aforementioned effects of LHX2 knockdown on ox-LDL-induced HUVECs.LHX2 facilitates the pathological progression of ox-LDL-stimulated AS cell models by increasing ADRM1 transcription.