Interpretation of 10 years of Alzheimer's disease genetic findings in the perspective of statistical heterogeneity.

Common genetic variants and susceptibility loci associated with Alzheimer's disease (AD) have been discovered through large-scale genome-wide association studies (GWAS), GWAS by proxy (GWAX) and meta-analysis of GWAS and GWAX (GWAS+GWAX). However, due to the very low repeatability of AD susceptibility loci and the low heritability of AD, these AD genetic findings have been questioned. We summarize AD genetic findings from the past 10 years and provide a new interpretation of these findings in the context of statistical heterogeneity. We discovered that only 17% of AD risk loci demonstrated reproducibility with a genome-wide significance of P < 5.00E-08 across all AD GWAS and GWAS+GWAX datasets. We highlighted that the AD GWAS+GWAX with the largest sample size failed to identify the most significant signals, the maximum number of genome-wide significant genetic variants or maximum heritability. Additionally, we identified widespread statistical heterogeneity in AD GWAS+GWAX datasets, but not in AD GWAS datasets. We consider that statistical heterogeneity may have attenuated the statistical power in AD GWAS+GWAX and may contribute to explaining the low repeatability (17%) of genome-wide significant AD susceptibility loci and the decreased AD heritability (40-2%) as the sample size increased. Importantly, evidence supports the idea that a decrease in statistical heterogeneity facilitates the identification of genome-wide significant genetic loci and contributes to an increase in AD heritability. Collectively, current AD GWAX and GWAS+GWAX findings should be meticulously assessed and warrant additional investigation, and AD GWAS+GWAX should employ multiple meta-analysis methods, such as random-effects inverse variance-weighted meta-analysis, which is designed specifically for statistical heterogeneity.

Genetic Insights into Glycine's Protective Role Against CAD - European and East Asia, 2015 and 2020.

Introduction: The purpose of this study is to examine the potential causal relationship between levels of circulating glycine and coronary artery disease (CAD) using a two-step Mendelian randomization (MR) analysis. Methods: We analyzed data from genome-wide association studies (GWAS) conducted on European and East Asian populations. To assess the causal effects of circulating glycine levels on the risk of CAD. We used the inverse-variance weighting (IVW), weighted median (WM), MR-Egger, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) methods. Furthermore, we conducted mediation analysis to investigate the contribution of blood pressure and other cardiovascular disease-related traits. Results: The two-step Mendelian randomization analysis revealed that higher levels of glycine in the blood were associated with a reduced risk of CAD in Europeans [odds ratio ( OR)=0.84, 95% confidence interval ( CI): 0.72, -0.98; P=0.029] and East Asians: ( OR=0.76, 95% CI: 0.66, -0.89; P=3.57×10 -4). Sensitivity analysis confirmed the robustness of these findings. Additionally, our results suggest that about 6.06% of the observed causal effect is mediated through genetically predicted systolic blood pressure (SBP) in the European population. Discussion: Our results contribute to the current knowledge regarding the involvement of glycine in the progression of CAD, and provide valuable methodological insights for the prevention and treatment of this condition.

Adversarial learning-based domain adaptation algorithm for intracranial artery stenosis detection on multi-source datasets.

Intracranial arterial stenosis (ICAS) is characterized by the pathological narrowing or occlusion of the inner lumen of intracranial blood vessels. However, the retina can indirectly react to cerebrovascular disease. Therefore, retinal fundus images (RFI) serve as valuable noninvasive and easily accessible screening tools for early detection and diagnosis of ICAS. This paper introduces an adversarial learning-based domain adaptation algorithm (ALDA) specifically designed for ICAS detection in multi-source datasets. The primary objective is to achieve accurate detection and enhanced generalization of ICAS based on RFI. Given the limitations of traditional algorithms in meeting the accuracy and generalization requirements, ALDA overcomes these challenges by leveraging RFI datasets from multiple sources and employing the concept of adversarial learning to facilitate feature representation sharing and distinguishability learning. In order to evaluate the performance of the ALDA algorithm, we conducted experimental validation on multi-source datasets. We compared its results with those obtained from other deep learning algorithms in the ICAS detection task. Furthermore, we validated the potential of ALDA for detecting diabetic retinopathy. The experimental results clearly demonstrate the significant improvements achieved by the ALDA algorithm. By leveraging information from diverse datasets, ALDA learns feature representations that exhibit enhanced generalizability and robustness. This makes it a reliable auxiliary diagnostic tool for clinicians, thereby facilitating the prevention and treatment of cerebrovascular diseases.

Mendelian randomization study supports the causal effects of air pollution on longevity via multiple age-related diseases.

Growing evidence suggests that exposure to fine particulate matter (PM2.5) may reduce life expectancy; however, the causal pathways of PM2.5 exposure affecting life expectancy remain unknown. Here, we assess the causal effects of genetically predicted PM2.5 concentration on common chronic diseases and longevity using a Mendelian randomization (MR) statistical framework based on large-scale genome-wide association studies (GWAS) (>400,000 participants). After adjusting for other types of air pollution and smoking, we find significant causal relationships between PM2.5 concentration and angina pectoris, hypercholesterolaemia and hypothyroidism, but no causal relationship with longevity. Mediation analysis shows that although the association between PM2.5 concentration and longevity is not significant, PM2.5 exposure indirectly affects longevity via diastolic blood pressure (DBP), hypertension, angina pectoris, hypercholesterolaemia and Alzheimer's disease, with a mediated proportion of 31.5, 70.9, 2.5, 100, and 24.7%, respectively. Our findings indicate that public health policies to control air pollution may help improve life expectancy.

Causal effect of lipoprotein-associated phospholipase A2 activity on ischemic stroke : a Mendelian randomization study.

Background The relationship between ischemic stroke (IS) and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity is still unclear, and there is a dearth of stratified research on the relationship between Lp-PLA2 activity and different IS subtypes. Therefore, Mendelian randomization was used in this study to examine the relationship between genetically proxied Lp-PLA2 activity and the risks of IS and its subtypes. Methods Based on information from a meta-analysis of GWAS, which included 13,664 European people, five single-nucleotide polymorphisms related to Lp-PLA2 activity were chosen as instrumental variables. Summary statistics information about MEGESTROKE consortium with the European group (40,585 cases and 406,111 controls) include any ischemic stroke (AIS) (n = 34,217); large-artery stroke (LAS, n=4,373), cardioembolic stroke (CES, n=7,193) and small vessel stroke (SVS, n=5,386). In order to determine the causal relationships between Lp-PLA2 activity and IS as well as its subtypes, the inverse variance weighted (IVW) approach was chosen as the primary analysis. Significant estimates were then tested by sensitivity analysis to rule out heterogeneity and pleiotropy. Results IVW showed Lp-PLA2 activity was causally associated with LAS (OR=3.25, 95% CI=1.65-6.41, p=0.0007), but not with other subtypes of stroke. Sensitivity analysis for causal estimates between Lp-PLA2 activity and LAS showed no significant heterogeneity or pleiotropy. Conclusions These MR analyses support a causal effect of Lp-PLA2 activity on LAS but not on AIS, CES or SVS, which suggests that serum Lp-PLA2 activity might be a biomarker for prediction of LAS.

rs56405341 Variant Associates with Expression of C4orf33 and C4orf33 Was Downregulated in Alzheimer's Disease and Progressive Supranuclear Palsy.

The first primary age-related tauopathy (PART) genome-wide association study confirmed significant associations of Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) genetic variants with PART, and highlighted a novel genetic variant rs56405341. Here, we perform a comprehensive analysis of rs56405341. We found that rs56405341 was significantly associated with C4orf33 mRNA expression, but not JADE1 mRNA expression in multiple brain tissues. C4orf33 was mainly expressed in cerebellar hemisphere and cerebellum, and JADE1 was mainly expressed in thyroid, and coronary artery. Meanwhile, we found significantly downregulated C4orf33 expression both AD and PSP compared with normal controls, respectively.

Genetic correlation, causal relationship, and shared loci between vitamin D and COVID-19: A genome-wide cross-trait analysis.

Observational studies have shown that vitamin D supplementation reduces the risk of COVID-19 infection, yet little is known about the shared genomic architectures between them. Leveraging large-scale genome-wide association study (GWAS) summary statistics, we investigated the genetic correlation and causal relationship between genetically determined vitamin D and COVID-19 using linkage disequilibrium score regression and Mendelian randomization (MR) analyses, and conducted a cross-trait GWAS meta-analysis to identify the overlapping susceptibility loci of them. We observed a significant genetic correlation between genetically predicted vitamin D and COVID-19 (rg = -0.143, p = 0.011), and the risk of COVID-19 infection would decrease by 6% for every 0.76 nmol L-1 increase of serum 25 hydroxyvitamin D (25OHD) concentrations in generalized MR (OR = 0.94, 95% CI: 0.89-0.99, p = 0.019). We identified rs4971066 (EFNA1) as a risk locus for the joint phenotype of vitamin D and COVID-19. In conclusion, genetically determined vitamin D is associated with COVID-19. Increased levels of serum 25OHD concentration may benefit the prevention and treatment of COVID-19.

Potential of Secondary Metabolites of Diaporthe Species Associated with Terrestrial and Marine Origins.

Diaporthe species produce versatile secondary metabolites (SMs), including terpenoids, fatty acids, polyketides, steroids, and alkaloids. These structurally diverse SMs exhibit a wide range of biological activities, including cytotoxic, antifungal, antibacterial, antiviral, antioxidant, anti-inflammatory, and phytotoxic activities, which could be exploited in the medical, agricultural, and other modern industries. This review comprehensively covers the production and biological potencies of isolated natural products from the genus Diaporthe associated with terrestrial and marine origins. A total of 275 SMs have been summarized from terrestrial (153; 55%) and marine (110; 41%) origins during the last twelve years, and 12 (4%) compounds are common to both environments. All secondary metabolites are categorized predominantly on the basis of their bioactivities (cytotoxic, antibacterial, antifungal, and miscellaneous activity). Overall, 134 bioactive compounds were isolated from terrestrial (92; 55%) and marine (42; 34%) origins, but about half the compounds did not report any kind of activity. The antiSMASH results suggested that Diaporthe strains are capable of encoding a wide range of SMs and have tremendous biosynthetic potential for new SMs. This study will be useful for future research on drug discovery from terrestrial and marine natural products.

Heterologous Expression, Purification and Characterization of an Alkalic Thermophilic ß-Mannanase CcMan5C from Coprinopsis cinerea.

A endo-1,4-ß-mannanase (CcMan5C) gene was cloned from Coprinopsis cinerea and heterologously expressed in Pichia pastoris, and the recombinant enzyme was purified by Ni-affinity chromatography and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF-MS). CcMan5C hydrolyzed only locust bean gum galactomannan (LBG) but not α-mannan from S. cerevisiae or Avicel cellulose, oat spelt xylan, or laminarin from Laminaria digitata. CcMan5C exhibited distinctive catalytic features that were different from previously reported ß-mannanases. (1) CcMan5C is the first reported fungal ß-mannase with an optimal alkalic pH of 8.0-9.0 for hydrolytic activity under assay conditions. (2) CcMan5C is the first reported alkalic fungal ß-mannase with an optimal temperature of 70 °C for hydrolytic activity under assay conditions. (3) The organic solvents methanol, ethanol, isopropanol, and acetone at concentrations of 10% or 20% did not inhibit CcMan5C activity, while 10% or 20% isopropanol and acetone even enhanced CcMan5C activity by 9.20-34.98%. Furthermore, CcMan5C tolerated detergents such as Tween 20 and Triton X-100, and its activity was even enhanced to 26.2-45.6% by 1% or 10% Tween 20 and Triton X-100. (4) CcMan5C solution or lyophilized CcMan5C exhibited unchanged activity and even increasing activity after being stored at -20 °C or -80 °C for 12 months and retained above 50% activity after being stored at 4 °C for 12 months. These features make CcMan5C a suitable candidate for the detergent industry and paper and pulp industry.

Branched-chain amino acids and risk of stroke: A Mendelian randomization study.

Background: The causality between plasma branched-chain amino acids (BCAAs) levels and stroke remains uncertain and the stratified research on the association between BCAAs levels and subtypes of stroke is not well studied. Therefore, the association of genetically proxied circulating BCAA levels with the risks of stroke and its subtypes was explored by Mendelian randomization (MR) in this study. Methods: Summary-level data derived from the published genome-wide association studies (GWAS) were employed for analyses. Data for plasma BCAA levels (n = 16,596) were obtained from a meta-analysis of GWAS. The MEGASTROKE consortium provided data for ischemic stroke (n = 440,328) and its subtypes and data for hemorrhagic stroke were available from 2 meta-analyses of GWAS of European-ancestry groups (intracerebral hemorrhage, n = 3,026; subarachnoid hemorrhage, n = 77,074). The inverse variance weighted (IVW) method was selected as the primary MR analysis. Supplementary analysis used included the weighted median, MR-Egger regression, Cochran's Q statistic, MR Pleiotropy Residual Sum and Outlier global test, and leave-one-out analysis method. Results: According to IVW analysis, 1-SD increment in genetically determined circulating isoleucine was associated with increased risks of cardioembolic stroke (CES) (OR: 1.56, 95% CI: 1.21-2.20, P = 0.0007), but not with risks of other stroke subtypes. We could not discover any proof that leucine and valine levels could increase risk of any stroke subtype. All heterogeneity tests produced stable findings, and there was no concrete evidence to indicate the perturbation of horizontal multiplicity. Conclusion: Increasing plasma isoleucine level had a causal effect on the risk of CES but not on the risk of other stroke subtypes. Further research is needed to identify the mechanisms of the causal associations between BCAAs and stroke subtypes.

Chemical Investigation of Endophytic Diaporthe unshiuensis YSP3 Reveals New Antibacterial and Cytotoxic Agents.

Chemical investigation of the plant-derived endophytic fungus Diaporthe unshiuensis YSP3 led to the isolation of four new compounds (1-4), including two new xanthones (phomopthane A and B, 1 and 2), one new alternariol methyl ether derivative (3) and one α-pyrone derivative (phomopyrone B, 4), together with eight known compounds (5-12). The structures of new compounds were interpreted on the basis of spectroscopic data and single-crystal X-ray diffraction analysis. All new compounds were assessed for their antimicrobial and cytotoxic potential. Compound 1 showed cytotoxic activity against HeLa and MCF-7 cells with IC50 values of 5.92 µM and 7.50 µM, respectively, while compound 3 has an antibacterial effect on Bacillus subtilis (MIC value 16 µg/mL).

Causal association of genetically determined circulating vitamin D metabolites and calcium with multiple sclerosis in participants of European descent.

BACKGROUND: Vitamin D is an important regulator of calcium. Mendelian randomization (MR) studies exclusively focused on the circulating total 25-hydroxyvitamin D (25(OH)D) as a biomarker of vitamin D status, and have found the causal association between 25(OH)D and the risk of multiple sclerosis (MS). However, it currently remains unclear about the causal association of the 25(OH)D subtypes including 25(OH)D3 and C3-epi-25(OH)D3, as well as calcium with the risk of MS. METHODS: We performed a two-sample MR study to evaluate the causal association of circulating total 25(OH)D, 25(OH)D3, C3-epi-25(OH)D3, and calcium with the risk of MS using large-scale genome-wide association studies (GWAS) datasets from total 25(OH)D (n = 417,580), 25(OH)D3 (n = 40,562), C3-epi-25(OH)D3 (n = 40,562), calcium (n = 305,349), and MS (14,802 MS and 26,703 controls). We selected five MR methods including inverse-variance weighted (IVW), simple median, weighted median, MR-Egger, MR-PRESSO (Mendelian Randomization Pleiotropy Residual Sum and Outlier), and contamination mixture method. RESULTS: IVW showed that the genetically increased circulating 25(OH)D level (OR = 0.81, 95% CI: 0.70-0.94, P = 4.00E-03), circulating 25(OH)D3 level (OR = 0.85, 95% CI: 0.76-0.95, P = 5.00E-03), and circulating C3-epi-25(OH)D3 level (OR = 0.85, 95% CI: 0.74-0.98, P = 2.30E-02) were causally associated with reduced risk of MS. However, IVW showed no causal association between circulating calcium level and the risk of MS with OR = 2.85, 95% CI: 0.42-19.53, P = 2.85E-01. CONCLUSIONS: Our current findings together with evidence from other MR studies support the use of vitamin D but not calcium supplementation for the prevention of MS.

Regional transcriptional vulnerability to basal forebrain functional dysconnectivity in mild cognitive impairment patients.

Nucleus basalis of Meynert (NbM), one of the earliest targets of Alzheimer's disease (AD), may act as a seed for pathological spreading to its connected regions. However, the underlying basis of regional vulnerability to NbM dysconnectivity remains unclear. NbM functional dysconnectivity was assessed using resting-state fMRI data of health controls and mild cognitive impairment (MCI) patients from the Alzheimer's disease Neuroimaging Initiative (ADNI2/GO phase). Transcriptional correlates of NbM dysconnectivity was explored by leveraging public intrinsic and differential post-mortem brain-wide gene expression datasets from Allen Human Brain Atlas (AHBA) and Mount Sinai Brain Bank (MSBB). By constructing an individual-level tissue-specific gene set risk score (TGRS), we evaluated the contribution of NbM dysconnectivity-correlated gene sets to change rate of cerebral spinal fluid (CSF) biomarkers during preclinical stage of AD, as well as to MCI onset age. An independent cohort of health controls and MCI patients from ADNI3 was used to validate our main findings. Between-group comparison revealed significant connectivity reduction between the right NbM and right middle temporal gyrus in MCI. This regional vulnerability to NbM dysconnectivity correlated with intrinsic expression of genes enriched in protein and immune functions, as well as with differential expression of genes enriched in cholinergic receptors, immune, vascular and energy metabolism functions. TGRS of these NbM dysconnectivity-correlated gene sets are associated with longitudinal amyloid-beta change at preclinical stages of AD, and contributed to MCI onset age independent of traditional AD risks. Our findings revealed the transcriptional vulnerability to NbM dysconnectivity and their crucial role in explaining preclinical amyloid-beta change and MCI onset age, which offer new insights into the early AD pathology and encourage more investigation and clinical trials targeting NbM.

Preserving cognitive function in patients with Alzheimer's disease: The Alzheimer's disease neuroprotection research initiative (ADNRI).

The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease (AD) and associated socioeconomic burdens. Abnormal metabolism of amyloid-ß (Aß) has been proposed as a significant pathomechanism in AD, supported by results of recent clinical trials using anti-Aß antibodies. Nonetheless, the cognitive benefits of the current treatments are limited. The etiology of AD is multifactorial, encompassing Aß and tau accumulation, neuroinflammation, demyelination, vascular dysfunction, and comorbidities, which collectively lead to widespread neurodegeneration in the brain and cognitive impairment. Hence, solely removing Aß from the brain may be insufficient to combat neurodegeneration and preserve cognition. To attain effective treatment for AD, it is necessary to (1) conduct extensive research on various mechanisms that cause neurodegeneration, including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level; (2) identify neuroprotective intervention targets against different neurodegeneration mechanisms; and (3) discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients. The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated, multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD. The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD, with the goal of halting or even reversing cognitive decline.

Single-Cell RNA-Seq Reveals a Population of Smooth Muscle Cells Responsible for Atherogenesis.

Understanding the regional propensity differences of atherosclerosis (AS) development is hindered by the lack of animal models suitable for the study of the disease process. In this paper, we used 3S-ASCVD dogs, an ideal large animal human-like models for AS, to interrogate the heterogeneity of AS-prone and AS-resistant arteries; and at the single-cell level, identify the dominant cells involved in AS development. Here we present data from 3S-ASCVD dogs which reliably mimic human AS pathophysiology, predilection for lesion sites, and endpoint events. Our analysis combined bulk RNA-seq with single-cell RNA-seq to depict the transcriptomic profiles and cellular atlas of AS-prone and AS-resistant arteries in 3S-ASCVD dogs. Our results revealed the integral role of smooth muscle cells (SMCs) in regional propensity for AS. Notably, TNC+ SMCs were major contributors to AS development in 3S-ASCVD dogs, indicating enhanced extracellular matrix remodeling and transition to myofibroblasts during the AS process. Moreover, TNC+ SMCs were also present in human AS-prone carotid plaques, suggesting a potential origin of myofibroblasts and supporting the relevance of our findings. Our study provides a promising large animal model for pre-clinical studies of ASCVD and add novel insights surrounding the regional propensity of AS development in humans, which may lead to interventions that delay or prevent lesion progression and adverse clinical events.

Two new sesquiterpene derivatives, dendocarbin B and bisaborosaol C with antifungal activity from the endophytic fungus Nigrospora chinensis GGY-3.

Two novel sesquiterpene derivatives, dendocarbin B (1), bisaborosaol C (2), and nine known compounds (3-11), were isolated from Nigrospora chinensis GGY-3 derived from Ilex cornuta. The structures of new compounds were elucidated using HR-ESI-MS, 1 D and 2 D NMR spectra, X-ray diffraction analysis as well as ECD calculation and comparison. Compound 1 showed moderate antifungal activities against Rhizoctonia solani and Botrytis cinerea. Compounds 5 and 6 exhibited significant inhibitory activity against Phytophthora capsici, Magnaporthe oryzae and R. solani with EC50 values ranging from 13.91 to 29.49 µg/mL. Compounds 10 and 11 displayed moderate antibacterial effects on Bacillus subtilis and Xanthomonas oryzae pv. oryzae (Xoo), with MIC values of 16-64 µg/mL. Particularly, 11 presented strong antibacterial activity against Staphylococcus aureus with an MIC value of 4 µg/mL (2 µg/mL for streptomycin sulfate). In addition, compound 11 also possessed DPPH radical scavenging capability with an IC50 value of 14.80 µg/mL.

White blood cell count and chronic obstructive pulmonary disease: A Mendelian Randomization study.

Blood leukocyte counts (e.g., eosinophil count) are important biomarkers for the onset, classification, and exacerbation of chronic obstructive pulmonary disease (COPD). The causal relationships between them are necessary for the development of COPD treatment strategy, but remain unclear. Here, we implement two-sample bi-directional univariable Mendelian Randomization (MR) and multivariable MR to investigate the causal relationships. Univariable MR find that elevated blood eosinophil count significantly increases the risk of COPD (odds ratio (OR) = 1.22, 95% confidence interval (CI): 1.14-1.30, P = 1.54 × 10-09) and COPD-related hospitalization (OR = 1.44, 95% CI: 1.15-1.80, P = 1.36 × 10-03). Besides, it also significantly decreases the ratio of forced expiratory volume in the first second over forced vital capacity (FEV1/FVC ratio) (OR = 0.942, 95% CI: 0.914-0.971, P = 1.02 × 10-04). These findings are fully supported by multivariate MR results. Interestingly, univariable MR reveals a weak causal relationship between elevated blood eosinophil count and COPD risk in younger people (<65 years) (OR = 1.39, 95% CI: 1.10-1.75, P = 5.52 × 10-03), but not older individuals (OR = 1.20, 95% CI: 0.926-1.55, P = 0.17). Finally, reverse univariable MR reveals the onset of COPD and the decreased FEV1/FVC ratio both lead to increased blood neutrophil count (OR = 1.03, 95% CI: 1.01-1.05, P = 3.40 × 10-03 and OR = 0.947, 95% CI: 0.91-0.986, P = 8.75 × 10-03 respectively). In summary, this MR study demonstrates that high blood eosinophil count is an independent causal mediator of COPD risk, FEV1/FVC decline, and COPD-related hospitalization. The increase in neutrophil count is induced by COPD onset or FEV1/FVC decline. This suggests eosinophil, but not neutrophil, may be used as a therapeutic target for preventing the onset and exacerbation of COPD and FEV1/FVC decline. Therefore, a non-neutrophil-targeted therapeutic strategy for neutrophilic COPD is required in the future.

An updated analysis of the association between CD2-associated protein gene rs9349407 polymorphism and Alzheimer's disease in Chinese population.

Background: Since 2011, three large-scale genome-wide association studies (GWAS) have confirmed that the CD2AP rs9349407 polymorphism is significantly connected with Alzheimer's disease (AD) in individuals of European descent. Subsequently, this association has been replicated in European populations, but is unclear whether it can be replicated in Chinese. Recently, the correlation between rs9349407 and AD in the Chinese population has become a research hotspot. Objective: To explore the association between rs9349407 polymorphism and AD in the Chinese population. Materials and methods: Firstly, based on the exclusion and inclusion criteria, we selected 11 independent studies from 8 articles exploring the correlation between rs9349407 variation and AD in Chinese. Secondly, we conducted a meta-analysis based on fixed and random effect models and conducted a heterogeneity test. Thirdly, we used the additive model, dominant model, and recessive model for subgroup analysis. Results: We demonstrated that the CD2AP rs9349407 polymorphism increases AD susceptibility in Chinese populations (OR = 1.33, 95% CI = 1.08-1.64, P = 7.45E-03), which is consistent with the effect observed in Caucasian populations. Additionally, subgroup analysis showed that rs9349407 under the additive model (GG + CC vs. GC, OR = 0.76, 95% CI = 0.61-0.97, P = 2.04E-02) and dominant model (GG + GC vs. CC, OR = 0.49, 95% CI = 0.32-0.74, P = 8.51E-04) were also significantly correlated with AD susceptibility, but not under the recessive model (GG vs. GC + CC, OR = 0.77, 95% CI = 0.58-1.03, P = 7.44E-02). Conclusion: These existing data suggest that rs9349307 is significantly correlated with the susceptibility to AD in the Chinese population, but future studies with large samples are needed to confirm our findings.

[High-density fermentation of Escherichia coli to express 4-hydroxyphenylacetate 3-hydroxylase and efficient biosynthesis of caffeic acid].

The 4-hydroxyphenylacetate 3-hydroxylase (4HPA3H), originated from Escherichia coli, converts p-coumaric acid to caffeic acid. In order to improve the efficiency of caffeic acid biosynthesis, we engineered E. coli for overexpression of 4HPA3H. The high-density fermentation of the engineered E. coli was conducted in a 5 L bioreactor. Subsequently, the conditions for whole-cell biocatalysis were optimized. The dry cell weight of the 4HPA3H-expressed strain reached 34.80 g/L. After incubated in the bioreactor for 6 h, 18.74 g/L (0.85 g/(L·OD600)) of caffeic acid was obtained, with a conversion rate of 78.81% achieved. To the best of our knowledge, the titer of caffeic acid is the highest reported to date. The high-density fermentation of E. coli for overexpression of 4HPA3H and the efficient biosynthesis of caffeic acid may facilitate future large-scale production of caffeic acid.

Evaluating the Bidirectional Causal Association Between Daytime Napping and Alzheimer's Disease Using Mendelian Randomization.

BACKGROUND: Until now, both cross-sectional and longitudinal studies have identified controversial findings about the association between daytime napping and Alzheimer's disease (AD) or cognitive decline. Therefore, it remains unclear about the causal association between daytime napping and AD or cognitive decline. OBJECTIVE: We aim to investigate the causal association between daytime napping and AD. METHODS: Here, we conduct a bidirectional Mendelian randomization (MR) analysis to investigate the causal association between daytime napping and AD using large-scale GWAS datasets from daytime napping including 452,633 individuals of European ancestry and AD including 35,274 AD and 59,163 controls of European ancestry. A total of five MR methods are selected including inverse-variance weighted (IVW), weighted median, MR-Egger, MR-PRESSO, and contamination mixture method. RESULTS: MR analysis highlights significant causal association of AD with daytime napping using IVW (beta = -0.006, 95% CI [-0.009, -0.002], p = 2.00E-03), but no significant causal association of daytime napping with AD using IVW (OR = 0.76, 95% CI 0.53-1.10, p = 1.40E-01). CONCLUSION: Our bidirectional MR analysis demonstrates the causal effect of AD on daytime napping. However, there is no causal effect of daytime napping on AD. Our current findings are consistent with recent evidence from other MR studies that highlight little evidence supporting a causal effect of sleep traits on AD and support the causal effect of AD on sleep traits.