Influence of H19 polymorphisms on breast cancer: risk assessment and prognostic implications via LincRNA H19/miR-675 and downstream pathways.

Introduction: Breast cancer, as the most prevalent malignancy among women globally, continues to exhibit rising incidence rates, particularly in China. The disease predominantly affects women aged 40 to 60 and is influenced by both genetic and environmental factors. This study focuses on the role of H19 gene polymorphisms, investigating their impact on breast cancer susceptibility, clinical outcomes, and response to treatment. Methods: We engaged 581 breast cancer patients and 558 healthy controls, using TaqMan assays and DNA sequencing to determine genotypes at specific loci (rs11042167, rs2071095, rs2251375). We employed in situ hybridization and immunohistochemistry to measure the expression levels of LincRNA H19, miR-675, MRP3, HOXA1, and MMP16 in formalin-fixed, paraffin-embedded samples. Statistical analyses included chi-squared tests, logistic regression, and Kaplan-Meier survival curves to evaluate associations between genetic variations, gene expression, and clinical outcomes. Results: Genotypes AG at rs11042167, GT at rs2071095, and AC at rs2251375 were significantly associated with increased risk of breast cancer. Notably, the AA genotype at rs11042167 and TT genotype at rs2071095 were linked to favorable prognosis. High expression levels of LincRNA H19, miR-675, MRP3, HOXA1, and MMP16 in cancer tissues correlated with advanced disease stages and poorer survival rates. Spearman correlation analysis revealed significant positive correlations between the expression of LincRNA H19 and miR-675 and specific genotypes, highlighting their potential regulatory roles in tumor progression. Discussion: The study underscores the critical roles of LincRNA H19 and miR-675 as prognostic biomarkers in breast cancer, with their overexpression associated with disease progression and adverse outcomes. The H19/LincRNA H19/miR-675/MRP3-HOXA1-MMP16 axis offers promising targets for new therapeutic strategies, reflecting the complex interplay between genetic markers and breast cancer pathology. Conclusion: The findings confirm that certain H19 SNPs are associated with heightened breast cancer risk and that the expression profiles of related genetic markers can significantly influence prognosis and treatment response. These biomarkers hold potential as targets for personalized therapy and early detection strategies in breast cancer, underscoring the importance of genetic research in understanding and managing this disease.

Elucidating the hemodynamic impact of residual stenosis post-carotid artery stenting: A numerical study.

BACKGROUND: Residual stenosis (RS) and hemodynamics demonstrate a significant correlation with postoperative in-stent restenosis/thrombosis following carotid artery stenting (CAS). PURPOSE: This study endeavors to elucidate the potential associations between RS and adverse postoperative hemodynamic factors. METHODS: This study utilized 46 patient-specific carotid artery models post-stenting, which were categorized into two groups based on the presence of RS: the normal group (N, n = 23) and the RS group (RS, n = 23). A comparative analysis was conducted to evaluate the discrepancies in geometry and adverse hemodynamic parameters, alongside investigating the potential correlation between hemodynamic and geometric parameters. RESULTS: The results reveal that a higher reflux flow volume is discernible in the RS group during low-velocity phases of the cardiac cycle, concomitant with an augmented extent of areas exposed to oscillatory shear stress and extended particle residence time. Moreover, the adverse hemodynamic parameters exhibit a positive correlation with the degree of stent expansion, stent length in the common carotid artery (CCA), and the distal slope of the RS. CONCLUSION: The distal slope and tortuosity of RS significantly influence the development of adverse hemodynamic conditions post-stenting, exacerbating the hemodynamic environment near the stenosis. Interestingly, while an extended stent length in the internal carotid artery (ICA) region improves hemodynamics by reducing flow disturbance, a longer stent in the CCA significantly worsens these conditions. Hence, it is prudent to analyze the characteristics of the local lesion regions to optimize the strategy for stent implantation.

Targeting delivery of mifepristone to endometrial dysfunctional macrophages for endometriosis therapy.

Endometriosis seriously affects 6-10 % of reproductive women globally and poses significant clinical challenges. The process of ectopic endometrial cell colonization shares similarities with cancer, and a dysfunctional immune microenvironment, characterized by non-classically polarized macrophages, plays a critical role in the progression of endometriosis. In this study, a targeted nano delivery system (BSA@Mif NPs) was developed using bovine serum albumin (BSA) as the carrier of mifepristone. The BSA@Mif NPs were utilized to selectively target M2 macrophages highly enriched in ectopic endometrial tissue via the SPARC receptor. This targeting strategy increases drug concentration at ectopic lesions while minimizing its distribution to normal tissue, thereby reducing side effects. In vitro studies demonstrated that BSA@Mif NPs not only enhanced the cellular uptake of M2-type macrophages and ectopic endometrial cells but also improved the cytotoxic effect of mifepristone on ectopic endometrial cells. Furthermore, the BSA@Mif NPs effectively induced immunogenic cell death (ICD) in ectopic endometrial cells and repolarized M2-type macrophages toward the M1 phenotype, resulting in a synergistic inhibition of ectopic endometrial cell growth. In vivo experiments revealed that BSA@Mif NPs exhibited significant therapeutic efficacy in endometriosis-bearing mice by increasing drug accumulation in the endometriotic tissues and modulating the immune microenvironment. This targeted biomimetic delivery strategy presents a promising approach for the development of endometriosis-specific therapies based on existing drugs. STATEMENT OF SIGNIFICANCE: Macrophages play an essential role in immune dysfunctional microenvironment promoting the occurrence and progression of endometriosis and can be a crucial target for developing immune microenvironment regulation strategies for the unmet long-term management of endometriosis. The albumin nanoparticles constructed based on SPARC overexpression in macrophages and endometrial cells and albumin biosafety can achieve the targeted therapy of endometriosis by increasing the passive- and active-mediated drug accumulation in ectopic endometrium and remodeling the immune microenvironment based on macrophage regulation. This study has the following implications: i) overcoming the inherent shortcomings of clinical drugs by nanotechnology is an alternative way of developing medication; ii) developing microenvironment modulation strategies based on macrophage regulation for endometriosis management is feasible.

Multimorbidity patterns, leisure activities, and cognitive function: A population-based longitudinal study.

BACKGROUND: There is limited knowledge about the effect of leisure activities on cognitive decline related to different multimorbidity patterns. The study aimed to examine the role of leisure activities in the association between multimorbidity patterns and cognitive function. METHODS: We conducted a community-based cohort study based on the 2002-2018 Chinese Longitudinal Health Longevity Survey (CLHLS). Multimorbidity patterns were examined by exploratory factor analysis. Multivariable linear and logistic regression models were used to assess the associations between multimorbidity, leisure activities and cognitive function. RESULTS: The study included 14,093 older adults. Those with specific multimorbidity patterns had lower MMSE scores. Compared to individuals with cardio-metabolic and sensory patterns who frequently engaged in activities such as housework, garden work, and watching TV/listening to the radio, those who participated in these activities less regularly had lower MMSE scores. Furthermore, a higher frequency change of participation and a greater variety of leisure activities were associated with better cognitive function. CONCLUSIONS: The older individuals with multimorbidity are associated with lower MMSE scores, while those who participated in more leisure activities had higher cognitive function. Diverse, and frequent leisure activities may help delay cognitive decline in Chinese older adults with different multimorbidities.

Investigation of tumour environments through advancements in microtechnology and nanotechnology.

Cancer has a significant negative social and economic impact on both developed and developing countries. As a result, understanding the onset and progression of cancer is critical for developing therapies that can improve the well-being and health of individuals with cancer. With time, study has revealed, the tumor microenvironment has great influence on this process. Micro and nanoscale engineering techniques can be used to study the tumor microenvironment. Nanoscale and Microscale engineering use Novel technologies and designs with small dimensions to recreate the TME. Knowing how cancer cells interact with one another can help researchers develop therapeutic approaches that anticipate and counteract cancer cells' techniques for evading detection and fighting anti-cancer treatments, such as microfabrication techniques, microfluidic devices, nanosensors, and nanodevices used to study or recreate the tumor microenvironment. Nevertheless, a complicated action just like the growth and in cancer advancement, and their intensive association along the environment around it that has to be studied in more detail.

Evaluation of the value of Synechococcus 7942 as a sensitizer for photo-sonodynamic therapy against breast cancer.

This study was conducted to investigate the value of Synechococcus 7942 (Syne) as a sensitizer for photo-sonodynamic therapy (PSDT). Syne was characterized. The efficacy of Syne-mediated PSDT were verified in vitro (in 4T1 breast cancer cells) and in vivo (in a breast tumor-bearing mouse model). The safety of Syne-mediated PSDT was verified in vivo. Results indicated that Syne triggered the generation of oxygen and ROS during PSDT, thereby inducing cell death in 4T1 cells. Syne-mediated PSDT induced the death of tumor cells both in vitro and in vivo. The speed of tumor growth was delayed in animals receiving PSDT. Syne-mediated PSDT was more effective than photodynamic therapy or sonodynamic therapy alone. In addition, administration of a Syne monomer resulted in satisfactory tumor targeting. Syne-mediated PSDT affected neither the animal body weight nor the major organs, indicating satisfactory safety. Accordingly, Syne is an efficient, safe, and readily available sensitizer that is ideal for potential clinical use of PSDT to treat breast cancer. The findings of this study are useful for exploration of a novel sensitizer for PSDT, which might be a promising alternative therapy against breast cancer.

Pd(II)-Catalyzed C4-Selective Alkynylation of Indoles by a Transient Directing Group.

With alanine as a transient directing group, Pd-catalyzed regioselective alkynylation at the indole C4-position was successfully established in a good yield. The total synthesis of the PAF antagonist demonstrated the synthetic utility of this protocol. The regioselectivity was explicitly proven by the prepared C4-selective palladacycle intermediate in the catalytic process and the DFT calculation of the energy barriers of C4- and C2-site-selective C-H activation of indole.

Spatial position changes in the semicircular canals may be the anatomical basis of Meniere's disease: a preliminary study based on ultra-high-resolution computed tomography (CT) and intelligent segmentation.

Background: Meniere's disease (MD) is an ear-related vestibular disorder accompanied by vertigo, hearing loss, and tinnitus. The anatomical structure and spatial position of the semicircular canals are important for understanding vestibular function and disease; however, research on MD and the effect of anatomical changes in the semicircular canals is limited. This study explored the relationship between the spatial location of the semicircular canals and MD using ultra-high-resolution computed tomography (U-HRCT) and intelligent segmentation. Methods: Isotropic U-HRCT images obtained from patients with MD and healthy controls (HCs) were retrospectively analyzed. We extracted the semicircular canal structures and extracted their skeleton. The plane of the skeleton of each semicircular canal was fitted separately. The mutual angles between the semicircular canals, and the angles between each semicircular canal and each plane of the coordinate system were measured. Results: Among 45 MD-affected ears (MDAEs), 33 MD-healthy ears (MDHEs), and 45 HC ears, the angle between the superior and lateral semicircular canals (LSCs) and the angle between the superior and posterior semicircular canals (PSCs) were larger in the MDAE and MDHE groups than the HC group (P<0.01), while the angle between the posterior and LSCs was smaller in the MDAE group than the HC group (P<0.001). The angles between the superior and PSCs and coronal plane (CP) of the coordinate system were significantly smaller in the MDAE and MDHE groups than the HC group (P<0.01); however, the angles between the LSC and axial plane and CP were significantly larger in the MDAE and MDHE groups than the HC group (P<0.001). Conclusions: Spatial position changes in the semicircular canals may be the anatomical basis of MD.

Equipping Uridine with Three Dipeptide Motifs for the Inhibition of Radical-Induced DNA Oxidation.

We report the discovery and characterization of antioxidative effects of uridine linked with three dipeptide motifs against DNA oxidation induced by peroxyl radicals. First, the dipeptide motifs are constructed by using the Ugi four-component reaction (Ugi 4CR), in which caffeic, ferulic, sinapic, and syringic acids are used as the carboxylic acid resources, vanillin, benzaldehyde, and p-hydroxybenzaldehyde are used as the aldehyde resources, tyramine- and dopamine-related isocyanides as well as ethyl isocyanoacetate are used as the isocyanide resources, and 2-(p-aminophenyl)ethanol is used as the amine component. We found that the antioxidative effects of the Ugi 4CR products are 1.3-2.8 times higher than those of caffeic, ferulic, sinapic, and syringic acids in the protection of DNA against peroxyl radical-induced oxidation. Moreover, when three Ugi 4CR products are linked with three hydroxyl groups of uridine by using three succinic anhydrides as the linkage, the inhibitory effects of the afforded uridine-dipeptide hybrids against the DNA oxidation increase 4.4-8.9 times (>3 times) compared to that of the Ugi 4CR product. This is due to the hybrid structure consisting of uridine and three motifs of the Ugi 4CR product enabling binding with the DNA strand more efficiently and quenching free radicals more rapidly. Therefore, the hybrid structure constructed by the nucleoside with antioxidative dipeptides offers an additional advantage for protecting DNA against radical-induced oxidation.

Multimorbidity measures associated with cognitive function among community-dwelling older Chinese adults.

INTRODUCTION: Older adults with multimorbidity are at high risk of cognitive impairment development. There is a lack of research on the associations between different multimorbidity measures and cognitive function among older Chinese adults living in the community. METHODS: We used the Chinese Longitudinal Healthy Longevity Survey from 2002 to 2018 and included data on dementia-free participants aged ≥65 years. Multimorbidity measures included condition counts, multimorbidity patterns, and trajectories. The association of multimorbidity measures with cognitive function was examined by generalized estimating equation and linear and logistic regression models. RESULTS: Among 14,093 participants at baseline, 43.2% had multimorbidity. Multimorbidity patterns were grouped into cancer-inflammatory, cardiometabolic, and sensory patterns. Multimorbidity trajectories were classified as "onset-condition," "newly developing," and "severe condition." The Mini-Mental State Examination scores were significantly lower for participants with more chronic conditions, with cancer-inflammatory/cardiometabolic/sensory patterns, and with developing multimorbidity trajectories. DISCUSSION: Condition counts, sensory pattern, cardiometabolic pattern, cancer-inflammatory pattern, and multimorbidity developmental trajectories were prospectively associated with cognitive function. HIGHLIGHTS: Elderly individuals with a higher number of chronic conditions were associated with lower MMSE scores in the Chinese Longitudinal Healthy Longevity Survey data. MMSE scores were significantly lower for participants with specific multimorbidity patterns. Individuals with developing trajectories of multimorbidity were associated with lower MMSE scores and a higher risk of mild cognitive impairment.

Fenofibrate-promoted hepatomegaly and liver regeneration are PPARα-dependent and partially related to the YAP pathway.

Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, is widely prescribed for hyperlipidemia management. Recent studies also showed that it has therapeutic potential in various liver diseases. However, its effects on hepatomegaly and liver regeneration and the involved mechanisms remain unclear. Here, the study showed that fenofibrate significantly promoted liver enlargement and regeneration post-partial hepatectomy in mice, which was dependent on hepatocyte-expressed PPARα. Yes-associated protein (YAP) is pivotal in manipulating liver growth and regeneration. We further identified that fenofibrate activated YAP signaling by suppressing its K48-linked ubiquitination, promoting its K63-linked ubiquitination, and enhancing the interaction and transcriptional activity of the YAP-TEAD complex. Pharmacological inhibition of YAP-TEAD interaction using verteporfin or suppression of YAP using AAV Yap shRNA in mice significantly attenuated fenofibrate-induced hepatomegaly. Other factors, such as MYC, KRT23, RAS, and RHOA, might also participate in fenofibrate-promoted hepatomegaly and liver regeneration. These studies demonstrate that fenofibrate-promoted liver enlargement and regeneration are PPARα-dependent and partially through activating the YAP signaling, with clinical implications of fenofibrate as a novel therapeutic agent for promoting liver regeneration.

Development of a new environmentally friendly and efficient centrifugal variable diameter metering device.

Introduction: The design of the maize metering device involves centrifugal variable diameter pneumatic and cleaning mechanisms, aiming to enhance the performance and power efficiency of pneumatic maize metering devices. Leveraging the impact of changes in centrifugal diameter and the guidance and positioning of airflow, we optimize the hole insert, seeding plate, seed limit board, and integrated front shell. This optimization facilitates the adjustment of both the quantity and posture of seed filling. As a result, seeds can form a uniform flow within the annular cavity, reducing the wind pressure necessary for regular operation and decreasing power consumption. Methods: A quadratic regression orthogonal rotation combination experiment is conducted using a self-made experiment bench, considering ground speed, wind pressure, and seeding rate as the experiment factors. Furthermore, a comparative experiment involving a novel centrifugal variable-diameter type metering device. Results: The results indicate optimal seeding performance when the ground speed is 13.2 km/h, the wind pressure is 1.2 kPa, and the feeding rate is 25 seeds/s. Under these conditions, the quality of feed index reaches 95.20%, the multi-index is 3.87%, and the miss index is 0.93%. Findings reveal that the developed seed metering device achieved a quality of feed index exceeding 93.00% across varying speeds of 12~18 km/h, aligning with the production requirements. Moreover, the actual power consumption of Type B and C is about 85.00% and 98.00% lower than Type A, standing at only 32.90 W at 18 km/h. The COP of Type C is about 86 times and 12 times that of Type A and B, respectively, meeting the demands for efficient production of maize seed metering devices. Discussion: In comparison to traditional design and structural parameter optimization methods for maize seed metering device, this study is helpful to the sustainable development of maize industry and reduce environmental pollution.

Exploring the pharmacokinetics and tolerability of cyclooxygenase inhibitor ampiroxicam: a phase I study on single and multiple oral doses.

Introduction: Ampiroxicam is a long-acting, non-steroidal anti-inflammatory drug that selectively inhibits human cyclooxygenase, effectively mitigating fever, pain, and inflammation. This study evaluated the drug's tolerability and pharmacokinetics to support personalized dosing strategies. Methods: The study involved healthy participants and focused on the pharmacokinetics of ampiroxicam. Plasma levels of piroxicam, a key metabolite of ampiroxicam, were measured using ultra-performance liquid chromatography. Piroxicam was chosen due to its integral role in ampiroxicam's metabolic pathway. The analytical method underwent rigorous validation to ensure precision and accuracy, addressing potential interference from endogenous plasma substances. Results: Participants received ampiroxicam in single doses (low, medium, and high) and multiple doses. Pharmacokinetic parameters, including AUC0-216, AUC0-∞, and Cmax, exhibited a dose-dependent increase. No significant differences were noted across the dosage groups, and sex-specific differences were minimal, with the exception of mean residence time (MRT) in the multiple-dose group, which appeared influenced by body weight variations. Discussion: The findings affirm the safety and efficacy of ampiroxicam across different dosing regimens, validating its clinical utility and potential for personalized medicine in the treatment of pain and inflammation.

Epigenetic molecular underpinnings of brain structural-functional connectivity decoupling in patients with major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is progressively recognized as a stress-related disorder characterized by aberrant brain network dynamics, encompassing both structural and functional domains. Yet, the intricate interplay between these dynamic networks and their molecular underpinnings remains predominantly unexplored. METHODS: Both structural and functional networks were constructed using multimodal neuroimaging data from 183 MDD patients and 300 age- and gender-matched healthy controls (HC). structural-functional connectivity (SC-FC) coupling was evaluated at both the connectome- and nodal-levels. Methylation data of five HPA axis key genes, including NR3C1, FKBP5, CRHBP, CRHR1, and CRHR2, were analyzed using Illumina Infinium Methylation EPIC BeadChip. RESULTS: We observed a significant reduction in SC-FC coupling at the connectome-level in patients with MDD compared to HC. At the nodal level, we found an imbalance in SC-FC coupling, with reduced coupling in cortical regions and increased coupling in subcortical regions. Furthermore, we identified 23 differentially methylated CpG sites on the HPA axis, following adjustment for multiple comparisons and control of age, gender, and medication status. Notably, three CpG sites on NR3C1 (cg01294526, cg19457823, and cg23430507), one CpG site on FKBP5 (cg25563198), one CpG site on CRHR1 (cg26656751), and one CpG site on CRHR2 (cg18351440) exhibited significant associations with SC-FC coupling in MDD patients. CONCLUSIONS: These findings provide valuable insights into the connection between micro-scale epigenetic changes in the HPA axis and SC-FC coupling at macro-scale connectomes. They unveil the mechanisms underlying increased susceptibility to MDD resulting from chronic stress and may suggest potential pharmacological targets within the HPA-axis for MDD treatment.

The YY1-CPT1C signaling axis modulates the proliferation and metabolism of pancreatic tumor cells under hypoxia.

Carnitine palmitoyltransferase 1C (CPT1C) is an enzyme that regulates tumor cell proliferation and metabolism by modulating mitochondrial function and lipid metabolism. Hypoxia, commonly observed in solid tumors, promotes the proliferation and progression of pancreatic cancer by regulating the metabolic reprogramming of tumor cells. So far, the metabolic regulation of hypoxic tumor cells by CPT1C and the upstream mechanisms of CPT1C remain poorly understood. Yin Yang 1 (YY1) is a crucial oncogene for pancreatic tumorigenesis and acts as a transcription factor that is involved in multiple metabolic processes. This study aimed to elucidate the relationship between YY1 and CPT1C under hypoxic conditions and explore their roles in hypoxia-induced proliferation and metabolic alterations of tumor cells. The results showed enhancements in the proliferation and metabolism of PANC-1 cells under hypoxia, as evidenced by increased cell growth, cellular ATP levels, up-regulation of mitochondrial membrane potential, and decreased lipid content. Interestingly, knockdown of YY1 or CPT1C inhibited hypoxia-induced rapid cell proliferation and vigorous cell metabolism. Importantly, for the first time, we reported that YY1 directly activated the transcription of CPT1C and clarified that CPT1C was a novel target gene of YY1. Moreover, the YY1 and CPT1C were found to synergistically regulate the proliferation and metabolism of hypoxic cells through transfection with YY1 siRNA to CRISPR/Cas9-CPT1C knockout PANC-1 cells. Taken together, these results indicated that the YY1-CPT1C axis could be a new target for the intervention of pancreatic cancer proliferation and metabolism.

The Effect of Transverse Sinus Stenosis Caused by Arachnoid Granulation on Patients with Venous Pulsatile Tinnitus: A Multiphysics Interaction Simulation Investigation.

This study aimed to investigate the effect of the transverse sinus (TS) stenosis (TSS) position caused by arachnoid granulation on patients with venous pulsatile tinnitus (VPT) and to further identify the types of TSS that are of therapeutic significance for patients. Multiphysics interaction models of six patients with moderate TSS caused by arachnoid granulation and virtual stent placement in TSS were reconstructed, including three patients with TSS located in the middle segment of the TS (group 1) and three patients with TTS in the middle and proximal involvement segment of the TS (group 2). The transient multiphysics interaction simulation method was applied to elucidate the differences in biomechanical and acoustic parameters between the two groups. The results revealed that the blood flow pattern at the TS and sigmoid sinus junction was significantly changed depending on the stenosis position. Preoperative patients had increased blood flow in the TSS region and TSS downstream where the blood flow impacted the vessel wall. In group 1, the postoperative blood flow pattern, average wall pressure, vessel wall vibration, and sound pressure level of the three patients were comparable to the preoperative state. However, the postoperative blood flow velocity decreased in group 2. The postoperative average wall pressure, vessel wall vibration, and sound pressure level of the three patients were significantly improved compared with the preoperative state. Intravascular intervention therapy should be considered for patients with moderate TSS caused by arachnoid granulations in the middle and proximal involvement segment of the TS. TSS might not be considered the cause of VPT symptoms in patients with moderate TSS caused by arachnoid granulation in the middle segment of the TS.

Associations of serum uric acid variability with neuroimaging metrics and cognitive decline: a population-based cohort study.

BACKGROUND: The relationship between variation in serum uric acid (SUA) levels and brain health is largely unknown. This study aimed to examine the associations of long-term variability in SUA levels with neuroimaging metrics and cognitive function. METHODS: This study recruited 1111 participants aged 25-83 years from a multicenter, community-based cohort study. The SUA concentrations were measured every two years from 2006 to 2018. We measured the intraindividual SUA variability, including the direction and magnitude of change by calculating the slope value. The associations of SUA variability with neuroimaging markers (brain macrostructural volume, microstructural integrity, white matter hyperintensity, and the presence of cerebral small vessel disease) and cognitive function were examined using generalized linear models. Mediation analyses were performed to assess whether neuroimaging markers mediate the relationship between SUA variation and cognitive function. RESULTS: Compared with the stable group, subjects with increased or decreased SUA levels were all featured by smaller brain white matter volume (beta = - 0.25, 95% confidence interval [CI] - 0.39 to - 0.11 and beta = - 0.15, 95% CI - 0.29 to - 0.02). Participants with progressively increased SUA exhibited widespread disrupted microstructural integrity, featured by lower global fractional anisotropy (beta = - 0.24, 95% CI - 0.38 to - 0.10), higher mean diffusivity (beta = 0.16, 95% CI 0.04 to 0.28) and radial diffusivity (beta = 0.19, 95% CI 0.06 to 0.31). Elevated SUA was also associated with cognitive decline (beta = - 0.18, 95% CI - 0.32 to - 0.04). White matter atrophy and impaired brain microstructural integrity mediated the impact of SUA increase on cognitive decline. CONCLUSIONS: It is the magnitude of SUA variation rather than the direction that plays a critical negative role in brain health, especially for participants with hyperuricemia. Smaller brain white matter volume and impaired microstructural integrity mediate the relationship between increased SUA level and cognitive function decline. Long-term stability of SUA level is recommended for maintaining brain health and preventing cognitive decline.

Gray matter volume mediates the association of long-term blood pressure variability with cognitive function in an adult population.

INTRODUCTION: We delineated the associations among long-term blood pressure variability (BPV), brain structure, and cognitive function. METHODS: We included 1254 adult participants from the Kailuan study. BPV was calculated from 2006 to 2020. Brain magnetic resonance imaging (MRI) and Montreal Cognitive Assessment (MoCA) were conducted in 2020. RESULTS: Higher systolic BPV (SBPV) and diastolic BPV (DBPV) were associated with lower total and frontal gray matter (GM) volume, and higher SBPV was associated with lower temporal GM volume. Elevated DBPV was associated with lower volume of total brain and parietal GM, and higher white matter hyperintensity (WMH) volume. Higher SBPV and DBPV were associated with lower MoCA scores. Decreased total and regional GM volume and increased WMH volume were associated with lower MoCA scores. The association between SBPV and cognitive function was mediated by total, frontal, and temporal GM volume. DISCUSSION: GM volume may play key roles in the association between SBPV and cognitive function. HIGHLIGHTS: SBPV and DBPV were negatively associated with total and regional brain volume. SBPV and DBPV were negatively associated with cognitive function. Decreased brain volume was associated with cognitive decline. GM volume mediated the negative association between SBPV and cognitive function.

Deep learning model to discriminate diverse infection types based on pairwise analysis of host gene expression.

Accurate detection of pathogens, particularly distinguishing between Gram-positive and Gram-negative bacteria, could improve disease treatment. Host gene expression can capture the immune system's response to infections caused by various pathogens. Here, we present a deep neural network model, bvnGPS2, which incorporates the attention mechanism based on a large-scale integrated host transcriptome dataset to precisely identify Gram-positive and Gram-negative bacterial infections as well as viral infections. We performed analysis of 4,949 blood samples across 40 cohorts from 10 countries using our previously designed omics data integration method, iPAGE, to select discriminant gene pairs and train the bvnGPS2. The performance of the model was evaluated on six independent cohorts comprising 374 samples. Overall, our deep neural network model shows robust capability to accurately identify specific infections, paving the way for precise medicine strategies in infection treatment and potentially also for identifying subtypes of other diseases.