Exploring potential plasma drug targets for cholelithiasis through multiancestry Mendelian randomization.

BACKGROUND: Cholelithiasis poses significant health and economic burdens, necessitating novel pharmacological targets to enhance treatment efficacy. METHOD: Based on genome-wide association analysis (GWAS) studies, we performed two-sample Mendelian randomization (MR) analysis based on plasma proteomics to explore potential drug targets in European (nCase=40,191 and nControl=361,641) and Asian (nCase=9,305 and nControl=168,253) populations. We confirmed the directionality and robust correlation of the drug targets with the results through reverse MR analysis, Steiger filtering, Bayesian colocalization, phenotype scanning and replication in multiple databases. Further exploration of the safety and possible mechanisms of action of phenome-wide MR analysis and protein‒protein interactions (PPIs) as individual drug targets was performed. RESULTS: Our proteomics-based MR analyses suggested that FUT3 (OR=0.87; 95% CI, 0.84-0.89; P=4.70×10-32), NOE1 (OR=0.58; 95% CI, 0.52-0.66; P=4.21×10-23), UGT1A6 (OR=0.68; 95% CI, 0.64-0.73; P=9.58×10-30) and FKBP52 (OR=1.75; 95% CI, 1.37-2.24; P=8.61×10-6) were potential drug targets in Europeans, whereas KLB (OR=1.11; 95% CI, 1.07-1.16; P=7.59×10-7) and FGFR4 (OR=0.94; 95% CI, 0.91-0.96; P=4.07×10-6) were valid targets in East Asians. There was no reverse causality for these drug targets. Evidence from Bayesian colocalization analyses supported that exposure and outcome shared consistent genetic variables. Phenome-wide MR analysis suggested the potential deleterious effects of NOE1 and FGFR4. PPI analysis confirmed the pathways associated with the potential targets involved in bile acid metabolism. CONCLUSIONS: Genetically predicted levels of the plasma proteins FUT3, NOE1, UGT1A6 and FKBP52 have potential as prospective targets in Europeans. Moreover, the plasma levels of KLB and FGFR4 may serve as potential targets for the treatment of cholelithiasis in East Asians.

Association of lipid-lowering drugs with gut microbiota: A Mendelian randomization study.

BACKGROUND: The gut microbiota can be influenced by lipid metabolism. We aimed to evaluate the impact of lipid-lowering medications, such as proproteinconvertase subtilisin/kexin type 9 (PCSK9) inhibitors, Niemann-Pick C1-like protein (NPC1L1) inhibitors, and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitors, on gut microbiota through drug target Mendelian randomization (MR) investigation. METHODS: We used genetic variants that were associated with low-density lipoprotein cholesterol (LDL-C) in genome-wide association studies and located within or near drug target genes as proxies for lipid-lowering drug exposure. In addition, expression trait loci in drug target genes were used as complementary genetic tools. We used effect estimates calculated using inverse variance weighted MR (IVW-MR) and summary data-based MR (SMR). Multiple sensitivity analyses were performed. RESULTS: Genetic proxies for lipid-lowering drugs broadly affected the abundance of gut microbiota. High expression of NPC1L1 was significantly associated with an increase in the genus Eggerthella (ß = 1.357, SE = 0.337, P = 5.615 × 10-5). An HMGCR-mediated increase in LDL-C was significantly associated with the order Pasteurellales (ß = 0.489, SE = 0.123, P = 6.955 × 10-5) and the genus Haemophilus (ß = 0.491, SE = 0.125, P = 8.379 × 10-5), whereas a PCSK9-mediated increase in LDL-C was associated with the genus Terrisporobacter (ß = 0.666, SE = 0.127, P = 1.649 × 10-5). No pleiotropy was detected. CONCLUSIONS: This drug target MR highlighted the potential interventional effects of lipid-lowering drugs on the gut microbiota and separately revealed the possible effects of different types of lipid-lowering drugs on specific gut microbiota.

Associations of hearing loss and structural changes in specific cortical regions: a Mendelian randomization study.

INTRODUCTION: Previous studies have suggested a correlation between hearing loss (HL) and cortical alterations, but the specific brain regions that may be affected are unknown. METHODS: Genome-wide association study (GWAS) data for 3 subtypes of HL phenotypes, sensorineural hearing loss (SNHL), conductive hearing loss, and mixed hearing loss, were selected as exposures, and GWAS data for brain structure-related traits were selected as outcomes. The inverse variance weighted method was used as the main estimation method. RESULTS: Negative associations were identified between genetically predicted SNHL and brain morphometric indicators (cortical surface area, cortical thickness, or volume of subcortical structures) in specific brain regions, including the bankssts (ß = -0.006 mm, P = 0.016), entorhinal cortex (ß = -4.856 mm2, P = 0.029), and hippocampus (ß = -24.819 cm3, P = 0.045), as well as in brain regions functionally associated with visual perception, including the pericalcarine (ß = -10.009 cm3, P = 0.013). CONCLUSION: Adaptive changes and functional remodeling of brain structures occur in patients with genetically predicted HL. Brain regions functionally associated with auditory perception, visual perception, and memory function are the main brain regions vulnerable in HL.

Association of gut microbiota with cerebral cortical thickness: A Mendelian randomization study.

BACKGROUND: The causal relationship between gut microbiota and cerebral cortex development remains unclear. We aimed to scrutinize the plausible causal impact of gut microbiota on cortical thickness via Mendelian randomization (MR) study. METHODS: Genome-wide association study (GWAS) data for 196 gut microbiota phenotypes (N = 18,340) were obtained as exposures, and GWAS data for cortical thickness-related traits (N = 51,665) were selected as outcomes. Inverse variance weighted was used as the main estimate method. A series of sensitivity analyses was used to test the robustness of the estimates including Cochran's Q test, MR-Egger intercept analysis, Steiger filtering, scatter plot funnel plot and leave-one-out analysis. RESULTS: Genetic prediction of high Bacillales (ß = 0.005, P = 0.032) and Lactobacillales (ß = 0.010, P = 0.012) abundance was associated with a potential increase in global cortical thickness. For specific functional brain subdivisions, genetically predicted order Lactobacillales would potentially increase the thickness of the fusiform (ß = 0.014, P = 0.016) and supramarginal (ß = 0.017, P = 0.003). Meanwhile, order Bacillales would increase the thickness of fusiform (ß = 0.007, P = 0.039), insula (ß = 0.011, P = 0.003), rostralanteriorcingulate (ß = 0.014, P = 0.002) and supramarginal (ß = 0.006, P = 0.043). No significant estimates of heterogeneity or pleiotropy were found. CONCLUSIONS: Through MR studies, we discovered genetic prediction of the Lactobacillales and Bacillales orders potentially linked to cortical thickness, affirming gut microbiota may enhance brain structure. Genetically predicted supramarginal and fusiform may be potential targets.

Causal relationships between type 1 diabetes mellitus and Alzheimer's disease and Parkinson's disease: a bidirectional two-sample Mendelian randomization study.

BACKGROUND: Previous compelling evidence suggests an association between Type 2 diabetes (T2D) and neurodegenerative diseases. However, it remains uncertain whether Type 1 diabetes mellitus (T1DM) exerts a causal influence on the risk of Alzheimer's disease (AD) and Parkinson's disease (PD). Consequently, this study employed a bidirectional two-sample Mendelian Randomization (MR) approach to investigate the causal relationship between T1DM and the genetic susceptibility to AD and PD. METHODS: We utilized large-scale cohorts derived from publicly available genome-wide association study datasets involving European populations to perform MR analyses. The primary analytical method employed was the inverse-variance weighted (IVW) approach. Furthermore, sensitivity analyses, including assessments of heterogeneity and horizontal pleiotropy, were carried out using Cochran's Q, MR-Egger intercept, and MR-PRESSO tests to enhance the robustness of our conclusions. RESULTS: Using the IVW-based method, the MR analysis indicated no significant association between genetically determined T1DM and AD (OR = 0.984, 95% CI: 0.958-1.011, p = 0.247). Conversely, T1DM appeared to be associated with a reduced risk of genetic susceptibility to PD (IVW: OR = 0.958, 95% CI: 0.928-0.989, p = 0.001). In the reverse direction, no evidence of reverse causality was observed between AD (OR = 1.010, 95% CI: 0.911-1.116, p = 0.881) or PD (OR = 1.164, 95% CI: 0.686-2.025, p = 0.5202) and T1DM. Additionally, our analysis found no indications of the results being influenced by horizontal pleiotropy. CONCLUSION: This MR study reveals that T1DM is associated with a reduced genetic susceptibility to PD, whereas no significant genetic susceptibility is observed between T1DM and AD. These findings suggest that T1DM may have a distinct role in the development of neurodegenerative diseases compared to T2D. Further investigations are warranted to elucidate the underlying mechanisms and provide a more comprehensive understanding of this relationship.

Alterations of Audiovisual Integration in Alzheimer's Disease.

Audiovisual integration is a vital information process involved in cognition and is closely correlated with aging and Alzheimer's disease (AD). In this review, we evaluated the altered audiovisual integrative behavioral symptoms in AD. We further analyzed the relationships between AD pathologies and audiovisual integration alterations bidirectionally and suggested the possible mechanisms of audiovisual integration alterations underlying AD, including the imbalance between energy demand and supply, activity-dependent degeneration, disrupted brain networks, and cognitive resource overloading. Then, based on the clinical characteristics including electrophysiological and imaging data related to audiovisual integration, we emphasized the value of audiovisual integration alterations as potential biomarkers for the early diagnosis and progression of AD. We also highlighted that treatments targeted audiovisual integration contributed to widespread pathological improvements in AD animal models and cognitive improvements in AD patients. Moreover, investigation into audiovisual integration alterations in AD also provided new insights and comprehension about sensory information processes.

Causal effects of COVID-19 on structural changes in specific brain regions: a Mendelian randomization study.

BACKGROUND: Previous studies have found a correlation between coronavirus disease 2019 (COVID-19) and changes in brain structure and cognitive function, but it remains unclear whether COVID-19 causes brain structural changes and which specific brain regions are affected. Herein, we conducted a Mendelian randomization (MR) study to investigate this causal relationship and to identify specific brain regions vulnerable to COVID-19. METHODS: Genome-wide association study (GWAS) data for COVID-19 phenotypes (28,900 COVID-19 cases and 3,251,161 controls) were selected as exposures, and GWAS data for brain structural traits (cortical thickness and surface area from 51,665 participants and volume of subcortical structures from 30,717 participants) were selected as outcomes. Inverse-variance weighted method was used as the main estimate method. The weighted median, MR-Egger, MR-PRESSO global test, and Cochran's Q statistic were used to detect heterogeneity and pleiotropy. RESULTS: The genetically predicted COVID-19 infection phenotype was nominally associated with reduced cortical thickness in the caudal middle frontal gyrus (ß = - 0.0044, p = 0.0412). The hospitalized COVID-19 phenotype was nominally associated with reduced cortical thickness in the lateral orbitofrontal gyrus (ß = - 0.0049, p = 0.0328) and rostral middle frontal gyrus (ß = - 0.0022, p = 0.0032) as well as with reduced cortical surface area of the middle temporal gyrus (ß = - 10.8855, p = 0.0266). These causal relationships were also identified in the severe COVID-19 phenotype. Additionally, the severe COVID-19 phenotype was nominally associated with reduced cortical thickness in the cuneus (ß = - 0.0024, p = 0.0168); reduced cortical surface area of the pericalcarine (ß = - 2.6628, p = 0.0492), superior parietal gyrus (ß = - 5.6310, p = 0.0408), and parahippocampal gyrus (ß = - 0.1473, p = 0.0297); and reduced volume in the hippocampus (ß = - 15.9130, p = 0.0024). CONCLUSIONS: Our study indicates a suggestively significant association between genetic predisposition to COVID-19 and atrophy in specific functional regions of the human brain. Patients with COVID-19 and cognitive impairment should be actively managed to alleviate neurocognitive symptoms and minimize long-term effects.

Causal relationship between gastroesophageal reflux disease, Barrett's esophagus, and epilepsy: A bidirectional Mendelian randomization study.

BACKGROUND: The incidence of gastroesophageal reflux disease (GERD) has been shown to be elevated in individuals with epilepsy. Traditional observational studies have led to a limited understanding of the effects of GERD and BE on epilepsy due to the interference of reverse causation and potential confounders. METHODS: We conducted a bidirectional two-sample Mendelian randomization (MR) analysis to determine whether GERD and BE can increase the risk of epilepsy. Genome-wide association study data on epilepsy and its subgroups were obtained from the International League Against Epilepsy consortium for primary analysis using three MR approaches and the FinnGen consortium for replication and meta-analysis. We calculated causal estimates between the two esophageal diseases and epilepsy using the inverse-variance weighted method. Sensitivity analysis was conducted to detect heterogeneity and pleiotropy. RESULTS: We found a potential effect of genetically predicted GERD on the risk of epilepsy (odds ratio [OR] = 1.078; 95% confidence interval [CI], 1.014-1.146, p = .016). Specifically, GERD showed an effect on the risk of generalized epilepsy (OR = 1.163; 95% CI, 1.048-1.290, p = .004) but not focal epilepsy (OR = 1.059, 95% CI, 0.992-1.131, p = .084). Notably, BE did not show a significant causal relationship with the risks of generalized and focal epilepsy. CONCLUSIONS: Under MR assumptions, our findings suggest a potential risk-increasing effect of GERD on epilepsy, especially generalized epilepsy. Considering the exploratory nature of our study, the association between GERD and epilepsy needs to be confirmed by future prospective studies.

Efficacy and Safety of Long-Pulsed 755-nm Alexandrite Laser for Keratosis Pilaris: A Split-Body Randomized Clinical Trial.

INTRODUCTION: Keratosis pilaris (KP) is a disfiguring disease and is resistant to treatment. Several treatment methods are available, but the efficacy is limited. This prospective, rater-blinded, split-body comparative study investigated the efficacy and safety of long-pulsed 755-nm alexandrite laser in the treatment of KP. METHODS: Twenty-two patients with KP of bilateral arms were enrolled in this study. All participants were randomized and treated with a long-pulsed 755-nm alexandrite laser on the left or right arm in four sessions held 3 weeks apart. The unified moisturizing lotion was applied on both left and right arms once a day. Physicians' assessment scores and patients' self-assessment scores were recorded, and skin imaging changes in dermoscopy, high-frequency ultrasound, and skin biopsy were obtained at baseline and 4 weeks after the fourth treatment. RESULTS: Of the 21 patients who completed the study, 15 were women and 6 were men. At 4 weeks after the fourth treatment, the laser side showed significantly lower total (2.0 versus 4.5), roughness (1.0 versus 2.0), and redness (1.0 versus 2.0) scores according to physicians' assessment (all P < 0.05). Furthermore, the laser side showed significantly lower total (2.0 versus 4.0), roughness (1.0 versus 2.0), and redness scores (1.0 versus 2.0) according to the patients' self-assessment (all P < 0.05). The proportions of patients who achieved dermoscopically and ultrasonographically showed excellent improvements in follicular plugs (57.1% versus 14.3%), perifollicular erythema (52.4% versus 9.5%), perifollicular hyperpigmentation (47.6% versus 14.3%), and the number of epidermal bulges (57.1% versus 19.1%) in the laser side was significantly higher than those who achieved such improvements in the control side (all P < 0.05). Histopathology showed that the follicular plugs and inflammatory cell infiltration were improved at the final visit. Three patients exhibited reversible postinflammatory hyperpigmentation. CONCLUSION: Long-pulsed 755-nm alexandrite laser treatment is effective and safe in treating both skin roughness and redness in KP. TRIAL REGISTRATION NUMBER: ChiCTR2100054489.

Effect of rhodamine 6G dye molecular interactions on counterintuitive self-assembly of noble metal nanorods.

HYPOTHESIS: Self-assembled nanostructures with highly ordered and diversified patterns can be obtained by adding additives that directionally control the interparticle interactions. However, due to the complex non-covalent weak interactions in the self-assembly process, the active mechanism of additives is not fully understood, resulting in the limitation of obtaining the nano-superstructures. The introduction of rhodamine 6G (R6G) enables gold nanorods (GNRs) self-assembled into a counterintuitive tetragonal superlattice, during which the exploration of the influence of R6G molecular interactions on the GNRs self-assembly is of importance. EXPERIMENTS: We present the detailed investigations of spacial configuration, binding modes, and aggregated degree of R6G molecule on formation of the tetragonal GNRs superlattices by combining the experimental and simulated results. FINDINGS: By analyzing the peak position and peak intensity in the fluorescent spectra of assembled samples and pure R6G samples, H-dimer is verified as the main cause for inducing the tetragonal superstructures. Molecular dynamics simulations reveal that 2-3 H-dimers adsorbed obliquely in a zigzag chain manner on the surface of GNRs is the most stable state of the self-assembly. This work would contribute to a deeper understanding of the complex colloidal nanoparticle self-assemblies and push forward the development of the bottom-up nanoscale superstructures.

Morphological and Orientational Controls of Self-Assembly of Gold Nanorods Directed by Evaporative Microflows.

Evaporative self-assembly of noble metal nanoparticles into ordered structures holds great promise for fabricating optical and plasmonic devices by virtue of its low cost, high efficiency, and ease of operation. However, poor control of Marangoni flows is one of the challenges accounting for realizing a well-defined assembly. Herein, based on the theoretical analysis of the influence of evaporative intensity on the assembly, two simple but reliable flow-field-confinement platforms are designed to control the evaporative microflows and to work concurrently with depletion forces to enable the regulated self-assembly of gold nanorods. Orientationally ordered assemblies are realized by the designed strong unidirectional microflow in a capillary, and a device-scale assembly of monolayer membrane is obtained by the created weak convection in homemade glass cells. Morphologically diversified superstructure assemblies, such as spherulite-like, boundary-twisted, chiral spiral assemblies, and merging membranes with a π-twisted domain wall, are obtained due to the spontaneous symmetry breaking or in the presence of defects, such as surface steps and screw dislocations. Optical anisotropy and polarization-dependent behaviors of these assemblies are further revealed, implying the potential applications in plasmonic coupling devices and optoelectronic components. An understanding of the entropy-driven assembly behaviors and control of evaporative microflows to guide the self-assembly of gold nanorods provides insights into the general bottom-up approach that is helpful for constructing complex yet robust nanosuperstructures.

Depletion-Mediated Uniform Deposition of Nanorods with Patterned, Multiplexed Assembly.

Device-scale, uniform, and controllable deposition of nanoparticles on various substrates is fundamentally important not only for the fabrication of thin-film devices but also for the large sample statistics of single-particle performances. However, it is challenging to obtain such predefined depositions using a simple and efficient method. Here, we present a novel strategy for obtaining the uniform and particle density/spacing-tunable deposition of nanorods on a linker-free substrate. The deposition is driven by the tailored particle-substrate depletion attraction owing to the size-matched design of the substrate roughness and the nanorod diameter. Both gold nanorods and upconversion nanorods were applied to demonstrate the generality of the method. The high particle density of more than 21 per µm2 and correspondingly the small particle spacing of fewer than 0.3 µm were achieved on a scalable substrate template. On this basis, orientational ordering and pattern-selective deposition of nanorods were realized by controlling the liquid flow rate and employing the substrate with patterned roughness areas, respectively. With the roughness-directed density-tunable depositions of nanorods integrated onto a single platform, multiplexed gold nanorod assembly and programmable surface-enhanced Raman mapping were achieved, with a promising prospect in information encoding by using the Raman signals as the translation units. The thermal stability and related transition temperature of about 160 °C of gold nanorods were also revealed as an application of single-particle statistics. This practical method could be extended to wide ranges of potential applications in plasmonic coupling devices, cryptography, or single-particle performance statistics with the feature of the high-throughput, low-cost, and scalable fabrication.

Programmable Ultralight Magnets via Orientational Arrangement of Ferromagnetic Nanoparticles within Aerogel Hosts.

The actuation and levitation of air-suspended objects by a magnetic field, due to its noncontact and holonomic manipulation modes, are important technological capabilities for device applications. However, owing to a higher density of conventional ferromagnets or nanoparticle-containing polymers and strong magnetic fields required for actuation, fabricating lightweight materials with a sensitive magnetic response for weight critical applications is challenging. Here, we report ultralight aerogel-based magnets (aero-magnets) comprising assembled ferromagnetic nanomaterials with highly magnetic anisotropy where the magnetic domains can be programmed by external predesigned fields. To demonstrate the breadth of manufacturing methods for this breed of aero-magnet composites, both silica/nanocellulose aerogel hosts and ferromagnetic nanorod/nanoplatelet guests have been explored. Single and double domains with out-of-plane magnetization are programmed into the aero-magnets and characterized by magnetic force microscopy. The levitation and actuation of the aero-magnets are realized while exposed to a small external magnetic field of 11 mT and introduced to a switching circuit. Furthermore, the elastic moduli of the aero-magnets are estimated by dynamic magnetic responses of the ferromagnetic nanoparticles tightly tethered in the aerogel hosts under rapid cyclic fields. These programmable aero-magnets could serve as monolithic magnetic actuator units in the fields of tiny robots and aerospace components.

Evaluation and correction on quinones' quantification errors: Derived from the coexistence of different quinone species and pH-sensitive feature.

Quinones are becoming an essential tool for refractory organics treatment, while their quantification may be not well-considered. In this paper, two kinds of potential errors in quantification were evaluated in multiple pH conditions. They were derived from the coexistence of oxidized/reduced quinone species (Type I) and pH-sensitive feature (Type II), respectively. These errors would remarkably influence the accuracy of quantification while they haven't been emphasized. Thus, to elaborate the relationship between the two types of errors and the absorbance or pH conditions, three typical quinones [Anthraquinone-1-sulfonate (α-AQS), anthraquinone-2,6-disulfonate (AQDS) and lawsone] were selected and their acid dissociation coefficients (pKa) as well as UV-Vis spectra were determined. Results revealed that, for Type I, the relative error (RE) of α-AQS concentration would exceed the limit (5%) when reduced α-AQS was below 48% of total α-AQS. Similar results were found for lawsone. However, the RE can be eliminated by the equation established in this paper. For Type II, the pH-sensitive feature was related to the pKa values of quinones. Absorbances of α-AQS and lawsone would change remarkably with pH variation. Therefore, a model for correction was established. Analog data showed high consistency with experimental data [r = 0.995 (n = 25, p < 0.01) and r = 0.997 (n = 36, p < 0.01), for lawsone and α-AQS respectively]. Especially, the determination of AQDS concentrations was noticed to be pH-independent at 437 nm under pH 4.00 to 9.18 conditions. Based on these features, a comprehensive data solution was proposed for handling these errors.

Enhanced dyes adsorption from wastewater via Fe3O4 nanoparticles functionalized activated carbon.

Fe3O4 nanoparticles functionalized activated carbon (Fe3O4/AC) as an adsorbent was prepared and used for fast and effectively removing rhodamine B (RhB) and methyl orange (MO) from aqueous solution. Its physical and chemical properties characterized indicate that the adsorbent possesses abundant surface functional groups, sensitive magnetic response and enhanced specific surface area. Batch experiments were carried out to investigate the adsorption capacity and mechanisms. The obtained experimental data fitted well with the general-order kinetic equation and Liu's isotherm model with a maximum adsorption capacity of 182.48 mg g-1 for RhB and 150.35 mg g-1 for MO, respectively. The thermodynamic parameter was analyzed further and it showed an exothermic and spontaneous adsorption process. This composite with high adsorption efficiency and rapid magnetic separation can be a promising and recyclable adsorbent for practical wastewater treatment and purification processes.