Leveraging Random Effects in Cistrome-Wide Association Studies for Decoding the Genetic Determinants of Prostate Cancer.

Cistrome-wide association studies (CWAS) are pivotal for identifying genetic determinants of diseases by correlating genetically regulated cistrome states with phenotypes. Traditional CWAS typically develops a model based on cistrome and genotype data to associate predicted cistrome states with phenotypes. The random effect cistrome-wide association study (RECWAS), reevaluates the necessity of cistrome state prediction in CWAS. RECWAS utilizes either a linear model or marginal effect for initial feature selection, followed by kernel-based feature aggregation for association testing is introduced. Through simulations and analysis of prostate cancer data, a thorough evaluation of CWAS and RECWAS is conducted. The results suggest that RECWAS offers improved power compared to traditional CWAS, identifying additional genomic regions associated with prostate cancer. CWAS identified 102 significant regions, while RECWAS found 50 additional significant regions compared to CWAS, many of which are validated. Validation encompassed a range of biological evidence, including risk signals from the GWAS catalog, susceptibility genes from the DisGeNET database, and enhancer-domain scores. RECWAS consistently demonstrated improved performance over traditional CWAS in identifying genomic regions associated with prostate cancer. These findings demonstrate the benefits of incorporating kernel methods into CWAS and provide new insights for genetic discovery in complex diseases.

Procyanidin B2-3'-O-Gallate Derived from Grape Seed Polymeric Procyanidins via the Galloyl-Attached Nucleophilic Degradation as a Potential Hepatoprotective Agent.

An effective method was developed for preparing galloylated procyanidins (GPCs) using galloyl-attached nucleophilic degradation. Under degradation conditions optimized through Box-Behnken design and single-factor experiments, two dimeric and three tetrameric GPCs were produced, with the yield of procyanidin B2-3'-O-gallate (B2-3'-G) reaching up to 232 mg/g (PPCs). The structure of B2-3'-G was identified by UV, FTIR, NMR, CD, MS, and phloroglucinolysis. Furthermore, the protective effect of B2-3'-G against alcohol-induced liver injury (ALI) was investigated. Compared with the parent compounds, B2-3'-G exhibited a stronger capacity for inhibiting ALI, attributed to its polymerization degree and galloyl group. Subsequent experiments revealed that the pretreatment of BRL-3A cells with B2-3'-G prior to ethanol improved ALI through activation of the Nrf2-HO-1/NQO1 pathway and initiation of enzymatic antioxidant systems. These findings suggest that GPC B2-3'-G is a potential hepatoprotective agent, which provides a new perspective for functional development of GPCs.

ARTP mutagenesis of Aureobasidium pullulans RM1603 for high pullulan production and transcriptome analysis of mutants.

Pullulan is a microbial exopolysaccharide produced by Aureobasidium spp. with excellent physical and chemical properties, resulting in great application value. In this study, a novel strain RM1603 of Aureobasidium pullulans with high pullulan production of 51.0 ± 1.0 g·L- 1 isolated from rhizosphere soil was subjected to atmospheric and room temperature plasma (ARTP) mutagenesis, followed by selection of mutants to obtain pullulan high-producing strains. Finally, two mutants Mu0816 and Mu1519 were obtained, with polysaccharide productions of 58.7 ± 0.8 and 60.0 ± 0.8 g∙L- 1 after 72-h fermentation, representing 15.1 and 17.6% increases compared with the original strain, respectively. Transcriptome analysis of the two mutants and the original strain revealed that the high expression of α/ß-hydrolase (ABHD), α-amylase (AMY1), and sugar porter family MFS transporters (SPF-MFS) in the mutants may be related to the synthesis and secretion of pullulan. These results demonstrated the effectiveness of ARTP mutagenesis in A. pullulans, providing a basis for the investigation of genes related to pullulan synthesis and secretion.

Danggui Shaoyao San and disassembled prescription: neuroprotective effects via AMPK/mTOR-mediated autophagy in mice.

BACKGROUND: Danggui Shaoyao San (DSS), a frequently prescribed Chinese medicine formula, has demonstrated clinical efficacy in the treatment of Alzheimer's disease (AD). This study aims to explore the differences in therapeutic effects of DSS and its disassembled prescriptions, Suangan (SG) and Xingan (XG), in treating Alzheimer's Disease and the mechanism of DSS recovering autophagy in AD. METHODS: A network pharmacology strategy was employed to delineate the bioactive constituents, associated targets, and regulatory mechanisms of DSS in AD, encompassing in silico target forecasting, the generation and scrutiny of PPI networks, alongside GO and KEGG-based pathway elucidation. An AD mouse model, induced by intracerebroventricular injection of Aß1-42, was used to evaluate the therapeutic effects of DSS and its disassembled prescriptions on AD. Cognitive function was evaluated using the Morris water maze. Expression levels of inflammatory cytokines were quantified via RT-qPCR and ELISA. Western blotting was used to detect the expression of proteins related to AD pathological markers and the AMPK/mTOR signaling pathway. RESULTS: 50 active compounds and 718 HUB genes were screened from relevant databases and literature. KEGG and GO analyses indicated that DSS's potential mechanisms against AD involved the AMPK/mTOR signaling pathway and mitophagy. In vivo animal model, the results demonstrated that DSS, SG, and XG treatments improved cognitive function and ameliorated neuroinflammation in mice. Additionally, they alleviated the pathological changes of neuronal cells. These treatments also increased the protein level of PSD-95, and decreased levels of APP and p-Tau. Among them, DSS exhibited the best efficacy. Furthermore, DSS, SG, and XG upregulated the expression of LC3, Beclin1, and p-AMPK, while decreasing the expression of P62 and p-mTOR. CONCLUSIONS: DSS, SG, and XG were found to ameliorate AD-related pathological symptoms in Aß1-42-injected mice, likely through the AMPK/mTOR autophagy signaling pathway.

Stable loading of MOF-derived carbon skeleton encapsulated Ni and BiOBr on carbonized cellulose fibers for fabricating high-performance and recyclable photocatalytic paper.

The highly dispersed small-size metal co-catalysts can effectively improve the photocatalytic efficiency of semiconductor photocatalysts by separating photogenerated electrons and enriching active sites. However, this system tends to aggregate in the absence of carrier, resulting in the decrease of active sites. Here, MOF-derived carbon skeleton (MDCS) encapsulated Ni nanoparticles (Ni@MDCS) and BiOBr was loaded onto carbonized cellulose fibers (CCF) with the help of polydopamine (PDA) to construct high-performance and recyclable photocatalytic paper for photocatalytic degradation of organic dyes in water. The characterization results showed that MDCS promoted good dispersion of Ni nanoparticles and provided sufficient active sites. And Ni@MDCS as a co-catalyst accelerated the separation of photogenerated carriers in BiOBr. The PDA improved the loading state of Ni@MDCS on CCF and converted into N-doped C in the carbonization process for further increasing the transfer efficiency of photogenerated electrons. In the composite paper, the stable loading of Ni@MDCS/BiOBr hybrid on CCF improved the dispersion and reusability of photocatalyst. The degradation rate of rhodamine B on CCF/PDA-C/Ni@MDCS/BiOBr paper was as high as 94.6 % after 60 min visible light irradiation, which was about 2.5 times higher than that of CCF/BiOBr paper. During 10 cycles, CCF/PDA-C/Ni@MDCS/BiOBr paper maintained high photocatalytic efficiency and good structural stability. This study provides a new way for developing high-performance and recyclable photocatalytic paper.

Characteristics of Subtype and Molecular Transmission Networks among Newly Diagnosed HIV-1 Infections in Patients Residing in Taiyuan City, Shanxi Province, China, from 2021 to 2023.

The HIV-1 pandemic, spanning four decades, presents a significant challenge to global public health. This study aimed to understand the molecular transmission characteristics of newly reported HIV infections in Taiyuan, Shanxi Province, China, to analyze the characteristics of subtypes and the risk factors of the transmission network, providing a scientific basis for precise prevention and intervention measures. A total of 720 samples were collected from newly diagnosed HIV-1 patients residing in Taiyuan between 2021 and 2023. Sequencing of partial genes of the HIV-1 pol gene resulted in multiple sequence acquisitions and was conducted to analyze their subtypes and molecular transmission networks. Out of the samples, 584 pol sequences were obtained, revealing 17 HIV-1 subtypes, with CRF07_BC (48.29%), CRF01_AE (31.34%), and CRF79_0107 (7.19%) being the dominant subtypes. Using a genetic distance threshold of 1.5%, 49 molecular transmission clusters were generated from the 313 pol gene sequences. Univariate analysis showed significant differences in the HIV transmission molecular network in terms of HIV subtype and household registration (p < 0.05). Multivariate logistic regression analysis showed that CRF79_0107 subtype and its migrants were associated with higher proportions of sequences in the HIV transmission network. These findings provide a scientific foundation for the development of localized HIV-specific intervention strategies.

Health literacy and associated factors in China: findings from the Wa ethnic group.

Background: The health literacy of ethnic groups in remote areas of China is far from satisfactory. However, the health literacy of ethnic groups in China remains unclear. This study aimed to explore the health literacy of the "advancing directly" ethnic group and its influencing factors. Methods: A cross-sectional study was conducted using a staged sampling method among the Wa ethnic group, who have rapidly transitioned directly from the traditional lifestyle of slash-and-burn cultivation to modern societies. We used the Health Literacy Questionnaire (HLQ) to assess health literacy. We defined low health literacy as less than 60% of the total score and adequate health literacy as more than 80% of the total score. Results: A total of 668 individuals met the inclusion criteria and the mean age was 42.19 (SD 10.56) years. The mean HLQ total score was 29.9 (SD 10.56). The prevalence of adequate health literacy was 0.89%. There were significant differences between the low and the non-low health literacy groups in terms of gender, age, education, marital status, occupation, residing place, current smoking status, and waist circumference (all p < 0.05). Multiple linear regression analysis showed that women (t = 9·418, p < 0.001), older age (B = -0.0091, t = -2.644, p = 0.008), low educational level (B = 0.766, t = 6.018, p < 0.001), current smoking (B = -2.66, t = -3.038, p = 0.008), and residence far from township (B = -5.761, t = -4.1, p < 0.001) were associated with low HLQ total score. Conclusion: Our findings suggest that the health literacy of the Wa ethnic group is far from favorable. It indicates the need for increased efforts in improving the health literacy of "advancing directly" ethnic groups.

Discovery of a Ni2+-dependent heterohexameric metformin hydrolase.

The biguanide drug metformin is a first-line blood glucose-lowering medication for type 2 diabetes, leading to its presence in the global environment. However, little is known about the fate of metformin by microbial catabolism. Here, we characterize a Ni2+-dependent heterohexameric enzyme (MetCaCb) from the ureohydrolase superfamily, catalyzing the hydrolysis of metformin into guanylurea and dimethylamine. Either subunit alone is catalytically inactive, but together they work as an active enzyme highly specific for metformin. The crystal structure of the MetCaCb complex shows the coordination of the binuclear metal cluster only in MetCa, with MetCb as a protein binder of its active cognate. An in-silico search and functional assay discover a group of MetCaCb-like protein pairs exhibiting metformin hydrolase activity in the environment. Our findings not only establish the genetic and biochemical foundation for metformin catabolism but also provide additional insights into the adaption of the ancient enzymes toward newly occurred substrate.

The effect and mechanism of patchouli alcohol on cognitive dysfunction in AD mice induced by Aß1-42 oligomers through AMPK/mTOR pathway.

Alzheimer's disease (AD) is a neurodegenerative brain disorder that progressively impairs long-term and working memory. The function and mechanism of PA(Patchouli alcohol) in improving AD in the external treatment of encephalopathy remain unclear. This study aimed to investigate the therapeutic effect of PA on AD using an Aß1-42 induced AD mouse model with LPS(Lipopolysaccharide) stimulation of BV2 microglial cells. Additionally, we aimed to explore the potential mechanism of PA in enhancing autophagy and reducing neuroinflammation through the AMPK (AMP-activated protein kinase)/mTOR (Mammaliam target of rapamycin) signaling pathway. The Morris water maze was used to assess cognitive function, and cortical and hippocampal tissues were collected for further analysis of the corresponding signaling pathways and inflammatory changes through biological experiments. Our research findings demonstrate that PA has a significant positive impact on cognitive and memory impairments in mice that have been induced with Aß1-42-induced AD. Additionally, PA was also found to revert the activation of microglia induced by LPS. These effects may be attributed to the reduction of neuroinflammation and enhancement of the AMPK/mTOR autophagy pathway. Therefore, PA may serve as an effective therapeutic option to prevent or delay the progression of AD-associated memory dysfunction.

Immune checkpoint inhibitors-related endocrinopathies exhibit increased severity in breast cancer patients: a real-world study.

PURPOSE: This study aims to systematically evaluate the incidence of immune checkpoint inhibitors (ICIs)-related endocrinopathies and their onset time in patients with breast cancer (BC) in a real-world setting. METHODS: An analysis was conducted on the medical records of 122 BC patients who underwent ICIs therapy at the Department of Breast Surgery, Guangdong Provincial People's Hospital, from April 2019 to September 2021. Follow-up data continued until October 2022. RESULTS: The research indicated that 60.66% of BC patients experienced ICI-related endocrinopathies. The endocrinopathies included pituitary injury (7.38%), primary thyroid dysfunction (34.43%), supranormal fasting blood glucose or glycohemoglobin levels (16.39%), and adrenal injury (2.46%). Subgroup analyses were further performed based on clinical characteristics, demonstrated variability in the incidence of ICI-related endocrinopathies. Notably, subpopulations harboring genetic mutations exhibited a markedly higher prevalence of hypophysitis, as evidenced by a statistically significant association (P = 0.022). Similarly, individuals with HER2 positivity were found to have a significantly increased incidence of pancreatic islet injury (P = 0.023). Moreover, the study documented that the median onset times of ICIs-related endocrinopathies in pituitary, thyroid, pancreatic, and adrenal damage were 264, 184, 99 and 141 days, respectively, which were substantially longer compared to previous reports involving other tumors. Remarkably, even after 500 days of initiating ICI therapy, new cases of ICI-related endocrine disorders continue to emerge, suggesting a situation of delayed onset of ICI-related endocrinopathies in BC patients. CONCLUSION: The retrospective analysis confirmed a higher incidence and longer median onset time of ICI-related endocrinopathies in BC patients compared to other cancers. These outcomes underscore the critical need for regular and extended monitoring of endocrine functions in BC patients receiving ICI therapy, advocating for personalized monitoring approaches based on individual clinical profiles.

The correlation analysis between incisal guidance angle and occlusal plane angles and temporomandibular joint morphology.

OBJECTIVES: The correlations between the incisal guidance angle (IGA) and occlusal plane angles and temporomandibular joint (TMJ) morphology were investigated in adults with skeletal Class II division II malocclusion. MATERIALS AND METHODS: CBCT images of 37 patients were analyzed. It included 19 cases of skeletal Class II division II malocclusion with low angle (study group) and 18 cases of skeletal Class I average angle (control group). The Invivo Dental 5 software was employed to acquire the data of the incisal guidance angle (IGA), occlusal plane angle (FH-OP), anterior occlusal plane angle (FH-AOP) and the TMJ measurement items. RESULTS: The results of IGA, FH-AOP angle and FH-OP angle showed the study group > the control group (P < 0.05). There were statistically difference in the condylar mediolateral diameters, articular eminence inclination and height, and posterior joint spaces between two groups. No differences were revealed in the condylar anteroposterior diameters, the condylar inclination angle, condylar head width and height, condylar length, glenoid fossa depth and width between two groups. In the study group, IGA showed a moderate correlation with FH-AOP, a weak correlation with FH-OP and condylar mediolateral diameters. Meanwhile, there was a correlation between FH-AOP, FH-OP, and TMJ indicators. CONCLUSIONS: The IGA was not only related to FH-AOP and FH-OP, but also to the condylar mediolateral diameters. In addition, there was a correlation between the occlusal plane angles and TMJ morphology in skeletal Class II division II low angle malocclusion. CLINICAL RELEVANCE: For patients with skeletal Class II division II low angle malocclusion, adjusting the IGA and the occlusal plane angles could improve the esthetic appearance of the anterior teeth, occlusal function, and TMJ morphology.

Luteolin-7-O-ß-d-Glucuronide Attenuated Cerebral Ischemia/Reperfusion Injury: Involvement of the Blood-Brain Barrier.

Ischemic stroke is a common cerebrovascular disease with high mortality, high morbidity, and high disability. Cerebral ischemia/reperfusion injury seriously affects the quality of life of patients. Luteolin-7-O-ß-d-glucuronide (LGU) is a major active flavonoid compound extracted from Ixeris sonchifolia (Bge.) Hance, a Chinese medicinal herb mainly used for the treatment of coronary heart disease, angina pectoris, cerebral infarction, etc. In the present study, the protective effect of LGU on cerebral ischemia/reperfusion injury was investigated in an oxygen-glucose deprivation/reoxygenation (OGD/R) neuronal model and a transient middle cerebral artery occlusion (tMCAO) rat model. In in vitro experiments, LGU was found to improve the OGD/R-induced decrease in neuronal viability effectively by the MTT assay. In in vivo experiments, neurological deficit scores, infarction volume rates, and brain water content rates were improved after a single intravenous administration of LGU. These findings suggest that LGU has significant protective effects on cerebral ischemia/reperfusion injury in vitro and in vivo. To further explore the potential mechanism of LGU on cerebral ischemia/reperfusion injury, we performed a series of tests. The results showed that a single administration of LGU decreased the content of EB and S100B and ameliorated the abnormal expression of tight junction proteins ZO-1 and occludin and metalloproteinase MMP-9 in the ischemic cerebral cortex of the tMCAO 24-h injury model. In addition, LGU also improved the tight junction structure between endothelial cells and the degree of basement membrane degradation and reduced the content of TNF-α and IL-1ß in the brain tissue. Thereby, LGU attenuated cerebral ischemia/reperfusion injury by improving the permeability of the blood-brain barrier. The present study provides new insights into the therapeutic potential of LGU in cerebral ischemia.

Structural studies of WDR5 in complex with MBD3C WIN motif reveal a unique binding mode.

The nucleosome remodeling and deacetylase (NuRD) complex plays a pivotal role in chromatin regulation and transcriptional repression. In mice, methyl-CpG binding domain 3 isoform C (MBD3C) interacts specifically with the histone H3 binding protein WD repeat-containing protein 5 (WDR5) and forms the WDR5-MBD3C/Norde complex. Despite the functional significance of this interaction on embryonic stem cell gene regulation, the molecular mechanism underlying MBD3C recognition by WDR5 remains elusive. Here, we determined the crystal structure of WDR5 in complex with the peptide (residues 40-51) derived from the MBD3C protein at a resolution of 1.9 Å. Structural analysis revealed that MBD3C utilizes a unique binding mode to interact with WDR5, wherein MBD3C Arg43 and Phe47 are involved in recognizing the WDR5-interacting (WIN) site and Tyr191-related B site on the small surface of WDR5, respectively. Notably, the binding induces a ∼91° rotation of WDR5 Tyr191, generating the hydrophobic B site. Furthermore, mutation experiments combined with isothermal titration calorimetry (ITC) assays confirmed the importance of both Arg43 and Phe47 in mediating WDR5 binding affinity. By determining structures of various peptides bound to WDR5, we demonstrated that the WDR5 WIN site and B site can be concurrently recognized by WIN motif peptides containing ''Arg-Cies/Ser-Arg-Val-Phe'' consensus sequence. Overall, this study reveals the structural basis for the formation of the WDR5-MBD3C subcomplex and provides new insights into the recognition mode of WDR5 for the WIN motif. Moreover, these findings shed light on structural-based designs of WDR5-targeted anti-cancer small molecule inhibitors or peptide-mimic drugs.

Study on the Compositional Analysis, Extraction Process, and Hemostatic and Anti-Inflammatory Activities of Cirsium japonicum Fisch. ex DC.-Cirsium setosum (Willd.) MB Extracts.

Cirsium japonicum Fisch. ex DC. (CF) and Cirsium setosum (Willd.) MB (CS) are commonly used clinically to stop bleeding and eliminate carbuncles. Still, CF is mainly used for treating inflammation, while CS favors hemostasis. Therefore, the present study used UHPLC-MS to analyze the main chemical constituents in CF-CS extract. We optimized the extraction process using single-factor experiments and response surface methodology. Afterward, the hemostatic and anti-inflammatory effects of CF-CS extract were investigated by determining the clotting time in vitro, the bleeding time of rabbit trauma, and the induction of rabbit inflammation using xylene and lipopolysaccharide. The study of hemostatic and anti-inflammatory effects showed that the CF-CS, CF, and CS extract groups could significantly shorten the coagulation time and bleeding time of rabbits compared with the blank group (p < 0.01); compared with the model group, it could dramatically inhibit xylene-induced ear swelling in rabbits and the content of TNF-α, IL-6, and IL-1ß in the serum of rabbits (p < 0.01). The results showed that combined CF and CS synergistically increased efficacy. CF-CS solved the problem of the single hemostatic and anti-inflammatory efficacy of a single drug, which provided a new idea for the research and development of natural hemostatic and anti-inflammatory medicines.

Pore walls as high-way for efficient bulk charge transfer in porous SrTiO3 single crystals boosting photocatalytic overall water splitting.

Suppressing carrier recombination in bulk and facilitating carrier transfer to surface via rational structure design is of great significance to improve solar-to-H2 conversion efficiency. We demonstrate a facile hydrothermal method to synthesize porous SrTiO3 single crystals (SrTiO3-P) with exposed (001) facets by introducing carbon spheres as templates. The obviously increased surface photovoltage and photocurrent response indicate that the interconnected pore walls act as enormous charge transfer "highways", accelerating carrier transport from bulk to surface. Furthermore, the absence of grain boundaries and high crystallinity could also lower the carrier recombination rate. Thus, the SrTiO3-P photocatalyst loaded with Rh/Cr2O3 as cocatalyst exhibits 1.5 times higher overall water splitting activity than that of solid SrTiO3, with gas evolution rate of 19.99 µmol h-1 50 mg-1 for H2 and 11.37 µmol h-1 50 mg-1 for O2. Additionally, SrTiO3-P also shows superior stability without any decay during cycling testing. This work provides a new insight into designing efficient multicomponent photocatalysts with a single-crystal porous structure.

Efficacy and safety of Ferrous iron on the prevention of Vascular cOgnitive impaiRment among patients with cerebral Infarction/TIA (FAVORITE): rationale and design of a multicentre randomised trial.

BACKGROUND: The incidence of vascular cognitive impairment (VCI) is high in patients suffering from ischaemic stroke or transient ischaemic attack (TIA) or with vascular risk factors. Effective prevention strategies for VCI remain limited. Anaemia or low haemoglobin was found as an independent risk factor for adverse outcomes after acute stroke. Anaemia or low haemoglobin was possibly associated with an increased risk of poststroke cognitive impairment. Whether supplement of ferrous iron to correct anaemia reduces the risk of VCI and improves adverse outcomes in patients with ischaemic cerebrovascular disease remains uncertain. AIM: We aim to introduce the design and rationale of the safety and efficacy of Ferrous iron on the prevention of Vascular cOgnitive impaiRment in patients with cerebral Infarction or TIA (FAVORITE) trial. DESIGN: FAVORITE is a randomised, placebo-controlled, double-blind, multicentre trial that compares supplement of ferrous iron with placebo for recent minor stroke/TIA patients complicated with mild anaemia or iron deficiency: Ferrous succinate sustained-release tablet 0.2 g (corresponding to 70 mg of elemental iron) once daily after or during breakfast for 12 weeks or placebo with much the same colour, smell and size as ferrous iron once daily during or after breakfast for 12 weeks. All paticipants will be followed within the next year. STUDY OUTCOMES: The primary effective outcome is the incidence of VCI at 3 months after randomisation and the primary safety outcome includes any gastrointestinal adverse event during 3 months. DISCUSSION: The FAVORITE trial will clarify whether supplement of ferrous iron to correct low haemoglobin reduces the risk of VCI in patients with recent ischaemic stroke or TIA complicated with mild anaemia or iron deficiency compared with placebo. TRIAL REGISTRATION NUMBER: NCT03891277.

Differential risk factor profile and neuroimaging markers of small vessel disease between lacunar ischemic stroke and deep intracerebral hemorrhage.

Background: Lacunar ischemic stroke (LIS) and deep intracerebral hemorrhage (dICH) are two stroke phenotypes of deep perforator arteriopathy. It is unclear what factors predispose individuals with deep perforator arteriopathy to either ischemic or hemorrhagic events. Objectives: We aimed to investigate risk factors and neuroimaging features of small vessel disease (SVD) associated with LIS versus dICH in a cross-sectional study. Methods: We included patients with clinically presenting, magnetic resonance imaging-confirmed LIS or dICH from two tertiary hospitals between 2010 and 2021. We recorded vascular risk factors and SVD markers, including lacunes, white matter hyperintensities (WMH), perivascular spaces (PVS), and cerebral microbleeds (CMB). Logistic regression modeling was used to determine the association between vascular risk factors, SVD markers, and stroke phenotype. We further created WMH probability maps to compare WMH distribution between LIS and dICH. Results: A total of 834 patients with LIS (mean age 61.7 ± 12.1 years) and 405 with dICH (57.7 ± 13.2 years) were included. Hypertension was equally frequent between LIS and dICH (72.3% versus 74.8%, p = 0.349). Diabetes mellitus, hyperlipidemia, smoking, and prior ischemic stroke were more associated with LIS [odds ratio (OR) (95% confidence interval (CI)), 0.35 (0.25-0.48), 0.32 (0.22-0.44), 0.31 (0.22-0.44), and 0.38 (0.18-0.75)]. Alcohol intake and prior ICH were more associated with dICH [OR (95% CI), 2.34 (1.68-3.28), 2.53 (1.31-4.92)]. Lacunes were more prevalent in LIS [OR (95% CI) 0.23 (0.11-0.43)], while moderate-to-severe basal-ganglia PVS and CMB were more prevalent in dICH [OR (95% CI) 2.63 (1.35-5.27), 4.95 (2.71-9.42)]. WMH burden and spatial distribution did not differ between groups. Conclusion: The microangiopathy underlying LIS and dICH reflects distinct risk profiles and SVD features, hence possibly SVD subtype susceptibility. Prospective studies with careful phenotyping and genetics are needed to clarify the mechanisms underlying this difference.

Choriocapillaris reduction accurately discriminates against early-onset Alzheimer's disease.

INTRODUCTION: This study addresses the urgent need for non-invasive early-onset Alzheimer's disease (EOAD) prediction. Using optical coherence tomography angiography (OCTA), we present a choriocapillaris model sensitive to EOAD, correlating with serum biomarkers. METHODS: Eighty-four EOAD patients and 73 controls were assigned to swept-source OCTA (SS-OCTA) or the spectral domain OCTA (SD-OCTA) cohorts. Our hypothesis on choriocapillaris predictive potential in EOAD was tested and validated in these two cohorts. RESULTS: Both cohorts revealed diminished choriocapillaris signals, demonstrating the highest discriminatory capability (area under the receiver operating characteristic curve: SS-OCTA 0.913, SD-OCTA 0.991; P < 0.001). A sparser SS-OCTA choriocapillaris correlated with increased serum amyloid beta (Aß)42, Aß42/40, and phosphorylated tau (p-tau)181 levels (all P < 0.05). Apolipoprotein E status did not affect choriocapillaris measurement. DISCUSSION: The choriocapillaris, observed in both cohorts, proves sensitive to EOAD diagnosis, and correlates with serum Aß and p-tau181 levels, suggesting its potential as a diagnostic tool for identifying and tracking microvascular changes in EOAD. HIGHLIGHTS: Optical coherence tomography angiography may be applied for non-invasive screening of Alzheimer's disease (AD). Choriocapillaris demonstrates high sensitivity and specificity for early-onset AD diagnosis. Microvascular dynamics abnormalities are associated with AD.

Chemical composition analysis and transcriptomics reveal the R2R3-MYB genes and phenol oxidases regulating the melanin formation in black radish.

Melanins are dark-brown to black-colored biomacromolecules which have been thoroughly studied in animals and microorganisms. However, the biochemical and molecular basis of plant melanins are poorly understood. We first characterized melanin from the black radish (Raphanus sativus var. niger) 'HLB' through spectroscopic techniques. p-Coumaric acid was identified as the main precursor of radish melanin. Moreover, a joint analysis of transcriptome and coexpression network was performed for the two radish accessions with black and white cortexes, 'HLB' and '55'. A set of R2R3-type RsMYBs and enzyme-coding genes exhibited a coexpression pattern, and were strongly correlated with melanin formation in radish. Transient overexpression of two phenol oxidases RsLAC7 (laccase 7) or RsPOD22-1 (peroxidase 22-1) resulted in a deeper brown color around the infiltration sites and a significant increase in the total phenol content. Furthermore, co-injection of the transcriptional activator RsMYB48/RsMYB97 with RsLAC7 and/or RsPOD22-1, markedly increased the yield of black extracts. Spectroscopic analyses revealed that these extracts are similar to the melanin found in 'HLB'. Our findings advance the understanding of structural information and the transcriptional regulatory mechanism underlying melanin formation in radish.

Identification and fine mapping of Brmmd1 gene controlling recessive genic male sterility in Brassica rapa L.

Recessive genic male sterility (RGMS) provides an effective approach for the commercial exploitation of heterosis, especially in Brassica crops. Although some artificial RGMS mutants have been reported in B. rapa, no causal genes derived from these natural mutants have been identified so far. In this study, a spontaneous RGMS mutant Bcajh97-01A derived from the 'Aijiaohuang' line traced back to the 1980 s was identified. Genetic analysis revealed that the RGMS trait was controlled by a single locus in the Bcajh97-01A/B system. Bulk segregant analysis (BSA) in combination with linkage analysis was employed to delimit the causal gene to an approximate 129 kb interval on chromosome A02. The integrated information of transcriptional levels and the predicted genes in the target region indicated that the Brmmd1 (BraA02g017420) encoding a PHD-containing nuclear protein was the most likely candidate gene. A 374 bp miniature inverted-repeat transposable element (MITE) was inserted into the first exon to prematurely stop the Brmmd1 gene translation, thus blocking the normal expression of this gene at the tetrad stage in the Bcajh97-01A. Additionally, a co-segregating structure variation (SV) marker was developed to rapidly screen the RGMS progenies from Bcajh97-01A/B system. Our findings reveal that BraA02g017420 is the causal gene responsible for the RGMS trait. This study lays a foundation for marker-assisted selection and further molecular mechanism exploration of pollen development in B. rapa.