A transcriptomic atlas of mouse cerebellar cortex comprehensively defines cell types.

The cerebellar cortex is a well-studied brain structure with diverse roles in motor learning, coordination, cognition and autonomic regulation. However,  a complete inventory of cerebellar cell types is currently lacking. Here, using recent advances in high-throughput transcriptional profiling1-3, we molecularly define cell types across individual lobules of the adult mouse cerebellum. Purkinje neurons showed considerable regional specialization, with the greatest diversity occurring in the posterior lobules. For several types of cerebellar interneuron, the molecular variation within each type was more continuous, rather than discrete. In particular, for the unipolar brush cells-an interneuron population previously subdivided into discrete populations-the continuous variation in gene expression was associated with a graded continuum of electrophysiological properties. Notably, we found that molecular layer interneurons were composed of two molecularly and functionally distinct types. Both types show a continuum of morphological variation through the thickness of the molecular layer, but electrophysiological recordings revealed marked differences between the two types in spontaneous firing, excitability and electrical coupling. Together, these findings provide a comprehensive cellular atlas of the cerebellar cortex, and outline a methodological and conceptual framework for the integration of molecular, morphological and physiological ontologies for defining brain cell types.

Identification of potential causal metabolites associated with atopic dermatitis.

Atopic dermatitis is a chronically recurrent dermatologic disease affected by complex pathophysiology with limited therapeutic options. To identify promising biomarkers for atopic dermatitis, we conducted a Mendelian randomization (MR) study to systematically screen blood metabolome for potential causal mediators of atopic dermatitis and further predict target-mediated side effects. We selected 128 unique blood metabolites from three European-descent metabolome genome-wide association studies (GWASs) with a total of 147 827 participants. Atopic dermatitis dataset originated from a large-scale GWAS including 10 788 cases and 30 047 controls of European ancestry. MR analyses were performed to estimate the associations of blood metabolites with atopic dermatitis. We then applied a phenome-wide MR analysis to ascertain potential on-target side effects of metabolite intervention. Three metabolites were identified as potential causal mediators for atopic dermatitis, including docosahexaenoic acid (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.81-0.94; P = 3.45 × 10-4), arachidonate (OR, 0.30; 95% CI, 0.17-0.53; P = 4.09 × 10-5) and 1-arachidonoylglycerophosphoethanolamine (1-arachidonoyl-GPE) (OR, 0.25; 95% CI, 0.12-0.53; P = 2.58 × 10-4). In the phenome-wide MR analysis, docosahexaenoic acid and arachidonate were also identified to have beneficial or detrimental effects on multiple diseases beyond atopic dermatitis, respectively. No adverse side effects were found for 1-arachidonoyl-GPE. In this systematic MR study, docosahexaenoic acid, arachidonate and 1-arachidonoyl-GPE were identified as potential causal and beneficial mediators in the development of atopic dermatitis. Side-effect profiles were characterized to help inform drug target prioritization, and 1-arachidonoyl-GPE was a promising target for prevention and treatment of atopic dermatitis with no predicted adverse side effects.

Genetic analyses identify brain imaging-derived phenotypes associated with the risk of amyotrophic lateral sclerosis.

Brain imaging-derived phenotypes have been suggested to be associated with amyotrophic lateral sclerosis in observational studies, but whether these associations are causal remains unclear. We aimed to assess the potential bidirectional causal associations between imaging-derived phenotypes and amyotrophic lateral sclerosis using bidirectional 2-sample Mendelian randomization analyses. Summary statistics for 469 imaging-derived phenotypes (33,224 individuals) and amyotrophic lateral sclerosis (20,806 cases and 59,804 controls) were obtained from 2 large-scale genome-wide association studies of European ancestry. We used the inverse-variance weighted Mendelian randomization method in the main analysis to assess the bidirectional associations between imaging-derived phenotypes and amyotrophic lateral sclerosis, followed by several sensitivity analyses for robustness validation. In the forward Mendelian randomization analyses, we found that genetically determined high orientation dispersion index in the right cerebral peduncle was associated with the increased risk of amyotrophic lateral sclerosis (odds ratio = 1.30, 95% confidence interval = 1.16-1.45, P = 2.26 × 10-6). In addition, the reverse Mendelian randomization analysis indicated that amyotrophic lateral sclerosis had no effect on 469 imaging-derived phenotypes. Mendelian randomization-Egger regression analysis showed no directional pleiotropy for the association between high orientation dispersion index in the right cerebral peduncle and amyotrophic lateral sclerosis, and sensitivity analyses with different Mendelian randomization models further confirmed these findings. The present systematic bidirectional Mendelian randomization analysis showed that high orientation dispersion index in the right cerebral peduncle might be the potential causal mediator of amyotrophic lateral sclerosis, which may provide predictive guidance for the prevention of amyotrophic lateral sclerosis. Further studies are warranted to replicate our findings and clarify the underlying mechanisms.

Genetic analyses identify brain imaging-derived phenotypes associated with the risk of intracerebral hemorrhage.

Previous observational studies have reported associations between brain imaging-derived phenotypes (IDPs) and intracerebral hemorrhage (ICH), but the causality between them remains uncertain. We aimed to investigate the potential causal relationship between IDPs and ICH by a two-sample Mendelian randomization (MR) study. We selected genetic instruments for 363 IDPs from a genome-wide association study (GWASs) based on the UK Biobank (n = 33,224). Summary-level data on ICH was derived from a European-descent GWAS with 1,545 cases and 1,481 controls. Inverse variance weighted MR method was applied in the main analysis to investigate the associations between IDPs and ICH. Reverse MR analyses were performed for significant IDPs to examine the reverse causation for the identified associations. Among the 363 IDPs, isotropic or free water volume fraction (ISOVF) in the anterior limb of the left internal capsule was identified to be associated with the risk of ICH (OR per 1-SD increase, 4.62 [95% CI, 2.18-9.81], P = 6.63 × 10-5). In addition, the reverse MR analysis indicated that ICH had no effect on ISOVF in the anterior limb of the left internal capsule (beta, 0.010 [95% CI, -0.010-0.030], P = 0.33). MR-Egger regression analysis showed no directional pleiotropy for the association between ISOVF and ICH, and sensitivity analyses with different MR models further confirmed these findings. ISOVF in the anterior limb of the left internal capsule might be a potential causal mediator of ICH, which may provide predictive guidance for the prevention of ICH. Further studies are warranted to replicate our findings and clarify the underlying mechanisms.

Secondhand Smoke Exposure and Risk of Dementia in Nonsmokers: A Population-Based Cohort Study.

BACKGROUND: Large population-based prospective studies are necessary to provide clarification on the associations of panoramic secondhand smoking burden, including prenatal and postnatal secondhand smoke (SHS) exposure, with the risk of developing dementia. METHODS: Our study comprised a sample of 353,756 dementia-free individuals from the UK Biobank who were nonsmokers had data on the exposure of maternal smoking as well as SHS exposure in daily life, which was quantified in terms of hours per week (h/week) and whether they lived with household smokers. Multivariable Cox regression models were utilized to analyze the independent and joint associations of maternal smoking and daily life SHS exposure with dementia risk. RESULTS: During a median follow-up of 11.8 years, 4,113 participants developed dementia. Compared with those who lived in the environment without smokers, multivariable-adjusted hazard ratios (HRs) (95% CIs) were 1.11 (1.02, 1.20) and 1.31 (1.13, 1.52) for those who exposed to SHS for >0 but ≤4 h/week and >4 h/week, respectively, and was 1.25 (1.13, 1.39) for those who lived with smokers in the household. A positive history of maternal smoking was associated with a modestly higher risk of dementia (HR = 1.07; 95% CI: 1.01, 1.15). Furthermore, compared with participants with neither history of maternal smoking nor exposure to SHS, a particularly higher risk of dementia was observed among those with both exposures (HR = 1.48; 95% CI: 1.18, 1.86). Additionally, the HR (95% CI) was 1.32 (1.10, 1.59) when comparing participants with a history of maternal smoking who lived with smokers in their households with those who had neither exposures. CONCLUSIONS: Having a history of maternal smoking, longer exposure to SHS, and living with smokers in the household were each associated with an increased risk of developing dementia. Individuals who were simultaneously exposed to maternal smoking and SHS or lived with household smokers had a particularly higher dementia risk.

Physical activity and sleep pattern in relation to incident Parkinson's disease: a cohort study.

BACKGROUND: How physical activity (PA) and different sleep traits and overall sleep pattern interact in the development of Parkinson's disease (PD) remain unknown. OBJECTIVE: To prospectively investigate the joint associations of PA and sleep pattern with risk of PD. METHODS: Included were 339,666 PD-free participants from the UK Biobank. Baseline PA levels were grouped into low (< 600 MET-mins/week), medium (600 to < 3000 MET-mins/week) and high (≥ 3000 MET-mins/week) according to the instructions of the UK Biobank. Healthy sleep traits (chronotype, sleep duration, insomnia, snoring, and daytime sleepiness) were scored from 0 to 5 and were categorized into "ideal sleep pattern" (≥ 3 sleep scores) and "poor sleep pattern" (0-2 sleep scores). Hazard ratios (HRs) and 95% confidence intervals (CIs) of PD were estimated by Cox proportional hazards models. RESULTS: During a median of 11.8 years of follow-up, 1,966 PD events were identified. The PD risk was lower in participants with high PA (HR = 0.73; 95% CI: 0.64, 0.84), compared to those with low PA; and participants with ideal sleep pattern also had a lower risk of PD (HR = 0.78; 95% CI: 0.69, 0.87), compared to those with poor sleep pattern. When jointly investigating the combined effect, participants with both high PA and ideal sleep pattern had the lowest risk of incident PD (HR = 0.55; 95% CI: 0.44, 0.69), compared to those with low PA and poor sleep pattern; notably, participants with high PA but poor sleep pattern also gained benefit on PD risk reduction (HR = 0.74; 95% CI: 0.55, 0.99). CONCLUSIONS: Both high PA and ideal sleep pattern were independently associated with lower risk of developing PD, and those with both high PA level and ideal sleep pattern had the lowest risk. Our results suggest that improving PA levels and sleep quality may be promising intervention targets for the prevention of PD.

Mendelian randomization analysis implicates bidirectional associations between brain imaging-derived phenotypes and ischemic stroke.

Brian imaging-derived phenotypes (IDPs) have been suggested to be associated with ischemic stroke, but the causality between them remains unclear. In this bidirectional two-sample Mendelian randomization (MR) study, we explored the potential causal relationship between 461 imaging-derived phenotypes (n = 33,224, UK Biobank) and ischemic stroke (n = 34,217 cases/406,111 controls, Multiancestry Genome-Wide Association Study of Stroke). Forward MR analyses identified five IDPs associated with ischemic stroke, including mean diffusivity (MD) in the right superior fronto-occipital fasciculus (1.22 [95% CI, 1.11-1.34]), MD in the left superior fronto-occipital fasciculus (1.30 [1.17-1.44]), MD in the anterior limb of the right internal capsule (1.36 [1.22-1.51]), MD in the right anterior thalamic radiation (1.17 [1.09-1.26]), and MD in the right superior thalamic radiation (1.23 [1.11-1.35]). In the reverse MR analyses, ischemic stroke was identified to be associated with three IDPs, including high isotropic or free water volume fraction in the body of corpus callosum (beta, 0.189 [95% confidence interval, 0.107-0.271]), orientation dispersion index in the pontine crossing tract (0.175 [0.093-0.257]), and volume of the third ventricle (0.219 [0.138-0.301]). This bidirectional two-sample MR study suggested five predictors and three diagnostic markers for ischemic stroke at the brain-imaging level. Further studies are warranted to replicate our findings and clarify underlying mechanisms.

Association of phthalate exposure with all-cause mortality across renal function status: The U.S. National Health and Nutrition Examination Survey, 2005-2018.

BACKGROUND: Wide phthalate exposure has been associated with both declines in renal function and an elevated risk of mortality. Whether phthalate-associated risk of premature mortality differs by renal function status remains unclear. METHODS: This study included 9605 adults from the U.S. National Health and Nutrition Examination Survey. Urinary concentrations of 11 phthalate metabolites were assessed using high-performance liquid chromatography-electrospray ionization tandem mass spectrometry. According to estimated glomerular filtration rate (eGFR), participants were grouped as having normal or modestly declined renal functions, or chronic kidney disease (CKD). Multivariable Cox regression models estimated all-cause mortality associated with phthalate exposure, overall and by renal function status. RESULTS: Overall, Mono-n-butyl phthalate (MnBP), Mono-benzyl phthalate (MBzP), Mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and Mono-(2-ethyl-5-carbox-ypentyl) phthalate (MECPP) were associated with an elevated risk of mortality (P-trend across tertile <0.05). Moreover, significant interactions were observed between eGFR and MEHHP, MEOHP, MECPP, DEHP in the whole population (P for interactions <0.05). After stratification by renal function, total Di (2-ethylhexyl) phthalate (DEHP) was additionally found to be associated with mortality risk in the CKD group (HR = 1.12; 95% CI: 1.01, 1.25). Co-exposure to the 11 phthalate metabolites was associated with a higher risk of all-cause mortality in the CKD (HR = 1.47; 95% CI: 1.18, 1.84) and modestly declined renal function group (HR = 1.25; 95% CI: 1.09, 1.44). CONCLUSIONS: The associations between phthalate exposure and risk of all-cause mortality were primarily observed in CKD patients, reinforcing the need for monitoring phthalate exposure in this patient population.

A Vision/Inertial Navigation/Global Navigation Satellite Integrated System for Relative and Absolute Localization in Land Vehicles.

This paper presents an enhanced ground vehicle localization method designed to address the challenges associated with state estimation for autonomous vehicles operating in diverse environments. The focus is specifically on the precise localization of position and orientation in both local and global coordinate systems. The proposed approach integrates local estimates generated by existing visual-inertial odometry (VIO) methods into global position information obtained from the Global Navigation Satellite System (GNSS). This integration is achieved through optimizing fusion in a pose graph, ensuring precise local estimation and drift-free global position estimation. Considering the inherent complexities in autonomous driving scenarios, such as the potential failures of a visual-inertial navigation system (VINS) and restrictions on GNSS signals in urban canyons, leading to disruptions in localization outcomes, we introduce an adaptive fusion mechanism. This mechanism allows seamless switching between three modes: utilizing only VINS, using only GNSS, and normal fusion. The effectiveness of the proposed algorithm is demonstrated through rigorous testing in the Carla simulation environment and challenging UrbanNav scenarios. The evaluation includes both qualitative and quantitative analyses, revealing that the method exhibits robustness and accuracy.

RBS and ABS Coordinated Control Strategy Based on Explicit Model Predictive Control.

During the braking process of electric vehicles, both the regenerative braking system (RBS) and anti-lock braking system (ABS) modulate the hydraulic braking force, leading to control conflict that impacts the effectiveness and real-time capability of coordinated control. Aiming to enhance the coordinated control effectiveness of RBS and ABS within the electro-hydraulic composite braking system, this paper proposes a coordinated control strategy based on explicit model predictive control (eMPC-CCS). Initially, a comprehensive braking control framework is established, combining offline adaptive control law generation, online optimized control law application, and state compensation to effectively coordinate braking force through the electro-hydraulic system. During offline processing, eMPC generates a real-time-oriented state feedback control law based on real-world micro trip segments, improving the adaptiveness of the braking strategy across different driving conditions. In the online implementation, the developed three-dimensional eMPC control laws, corresponding to current driving conditions, are invoked, thereby enhancing the potential for real-time braking strategy implementation. Moreover, the state error compensator is integrated into eMPC-CCS, yielding a state gain matrix that optimizes the vehicle braking status and ensures robustness across diverse braking conditions. Lastly, simulation evaluation and hardware-in-the-loop (HIL) testing manifest that the proposed eMPC-CCS effectively coordinates the regenerative and hydraulic braking systems, outperforming other CCSs in terms of braking energy recovery and real-time capability.

Intrinsic RNA Targeting Triggers Indiscriminate DNase Activity of CRISPR-Cas12a.

The CRISPR-Cas12a system has emerged as a powerful tool for next-generation nucleic acid-based molecular diagnostics. However, it has long been believed to be effective only on DNA targets. Here, we investigate the intrinsic RNA-enabled trans-cleavage activity of AsCas12a and LbCas12a and discover that they can be directly activated by full-size RNA targets, although LbCas12a exhibits weaker trans-cleavage activity than AsCas12a on both single-stranded DNA and RNA substrates. Remarkably, we find that the RNA-activated Cas12a possesses higher specificity in recognizing mutated target sequences compared to DNA activation. Based on these findings, we develop the "Universal Nuclease for Identification of Virus Empowered by RNA-Sensing" (UNIVERSE) assay for nucleic acid testing. We incorporate a T7 transcription step into this assay, thereby eliminating the requirement for a protospacer adjacent motif (PAM) sequence in the target. Additionally, we successfully detect multiple PAM-less targets in HIV clinical samples that are undetectable by the conventional Cas12a assay based on double-stranded DNA activation, demonstrating unrestricted target selection with the UNIVERSE assay. We further validate the clinical utility of the UNIVERSE assay by testing both HIV RNA and HPV 16 DNA in clinical samples. We envision that the intrinsic RNA targeting capability may bring a paradigm shift in Cas12a-based nucleic acid detection and further enhance the understanding of CRISPR-Cas biochemistry.

Lipoprotein(a), family history of cardiovascular disease, and incidence of heart failure.

Lipoprotein(a) (Lp(a)) is a largely genetically determined biomarker for cardiovascular disease (CVD), while its potential interplay with family history (FHx) of CVD, a measure of both genetic and environmental exposures, remains unclear. We examined the associations of Lp(a) in terms of circulating concentration or polygenetic risk score (PRS), and FHx of CVD with risk of incident heart failure (HF). Included were 299,158 adults from the UK Biobank without known HF and CVD at baseline. Hazards ratios (HRs) and 95% Cls were estimated by Cox regression models adjusted for traditional risk factors defined by the Atherosclerosis Risk in Communities study HF risk score. During the 11.8-year follow-up, 5,502 incidents of HF occurred. Higher levels of circulating Lp(a), Lp(a) PRS, and positive FHx of CVD were associated with higher risks of HF. Compared with individuals who had lower circulating Lp(a) and no FHx, HRs (95% CIs) of HF were 1.36 (1.25, 1.49), 1.31 (1.19, 1.43), and 1.42 (1.22, 1.67) for those with higher Lp(a) and a positive history of CVD for all family members, parents, and siblings, respectively; similar results were observed by using Lp(a) PRS. The risk estimates for HF associated with elevated Lp(a) and positive FHx were attenuated after excluding those with incident myocardial infarction (MI) during follow-up. Lp(a) and FHx of CVD were independent risk factors for incident HF, and the highest risk of HF was observed among individuals with both risk factors. The association may be partly mediated by myocardial infarction.

Association between human blood metabolome and the risk of breast cancer.

BACKGROUND: Breast cancer is the most common cancer among women with limited treatment options. To identify promising drug targets for breast cancer, we conducted a systematical Mendelian randomization (MR) study to screen blood metabolome for potential causal mediators of breast cancer and further predict target-mediated side effects. METHODS: We selected 112 unique blood metabolites from 3 large-scale European ancestry-based genome-wide association studies (GWASs) with a total of 147,827 participants. Breast cancer data were obtained from a GWAS in the Breast Cancer Association Consortium (BCAC), involving 122,977 cases and 105,974 controls of European ancestry. We conducted MR analyses to systematically assess the associations of blood metabolites with breast cancer, and a phenome-wide MR analysis was further applied to ascertain the potential on-target side effects of metabolite interventions. RESULTS: Two blood metabolites were identified as the potential causal mediators for breast cancer, including high-density lipoprotein cholesterol (HDL-C) (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.06-1.12; P = 9.67 × 10-10) and acetate (OR, 1.24; 95% CI, 1.13-1.37; P = 1.35 × 10-5). In the phenome-wide MR analysis, lowering HDL-C might have deleterious effects on the risk of the circulatory system and foreign body injury, while lowering acetate had deleterious effects on mental disorders disease. CONCLUSIONS: The present systematic MR analysis revealed that HDL-C and acetate may be the causal mediators in the risk of developing breast cancer. Side-effect profiles were characterized to help inform drug target prioritization for breast cancer prevention. HDL-C and acetate might be promising drug targets for preventing breast cancer, but they should be applied under weighting advantages and disadvantages.

Trends in cognitive function before and after stroke in China.

BACKGROUND: While cognitive impairment after stroke is common, cognitive trends before stroke are poorly understood, especially among the Chinese population who have a relatively high stroke burden. We aimed to model the trajectories of cognitive function before and after new-onset stroke among Chinese. METHODS: A total of 13,311 Chinese participants aged ≥ 45 years and without a history of stroke were assessed at baseline between June 2011 and March 2012 and in at least one cognitive test between 2013 (wave 2) and 2018 (wave 4). Cognitive function was assessed using a global cognition score, which included episodic memory, visuospatial abilities, and a 10-item Telephone Interview of Cognitive Status (TICS-10) test to reflect calculation, attention, and orientation abilities. RESULTS: During the 7-year follow-up, 610 (4.6%) participants experienced a first stroke. Both stroke and non-stroke groups showed declined cognitive function during follow-up. After adjustment for covariates, there was no significant difference in pre-stroke cognitive trajectories between stroke patients and stroke-free participants. The stroke group showed an acute decline in episodic memory (- 0.123 SD), visuospatial abilities (- 0.169 SD), and global cognition (- 0.135 SD) after stroke onset. In the years following stroke, the decline rate of the TICS-10 test was higher than the rate before stroke (- 0.045 SD/year). CONCLUSIONS: Chinese stroke patients had not experienced steeper declines in cognition before stroke compared with stroke-free individuals. Incident stroke was associated with acute declines in global cognition, episodic memory, visuospatial abilities, and accelerated declines in calculation, attention, and orientation abilities.

Clay-Originated Two-Dimensional Holey Silica Separator for Dendrite-Free Lithium Metal Anode.

Lithium metal anode is the ultimate choice to obtain next-generation high-energy-density lithium batteries, while the dendritic lithium growth owing to the unstable lithium anode/electrolyte interface largely limits its practical application. Separator is an important component in batteries and separator engineering is believed to be a tractable and effective way to address the above issue. Separators can play the role of ion redistributors to guide the transport of lithium ions and regulate the uniform electrodeposition of Li. The electrolyte wettability, thermal shrinkage resistance, and mechanical strength are of importance for separators. Here, clay-originated two-dimensional (2D) holey amorphous silica nanosheets (ASN) to develop a low-cost and eco-friendly inorganic separator is directly adopted. The ASN-based separator has higher porosity, better electrolyte wettability, much higher thermal resistance, larger lithium transference number, and ionic conductivity compared with commercial separator. The large amounts of holes and rich surface oxygen groups on the ASN guide the uniform distribution of lithium-ion flux. Consequently, the Li//Li cell with this separator shows stable lithium plating/stripping, and the corresponding Li//LiFePO4 , Li//LiCoO2, and Li//NCM523 full cells also show high capacity, excellent rate performance, and outstanding cycling stability, which is much superior to that using the commercial separator.

Association between Human Blood Metabolome and the Risk of Alzheimer's Disease.

OBJECTIVE: Alzheimer's disease (AD) is the most common degenerative neurological disorder with limited therapeutic options. Therefore, it is particularly important to explore the potential biomarkers implicated in the occurrence and progression of AD prior to clinical testing. METHODS: We selected 119 unique blood metabolites from 3 metabolome genome-wide association studies (GWASs) with 147,827 European participants. Summary data about AD were obtained from a GWAS meta-analysis with 63,926 European individuals from the International Genomics of Alzheimer's Project. MR analyses were performed to assess the associations of blood metabolites with AD, and a phenome-wide MR analysis was further applied to ascertain the potential on-target side effects of metabolite interventions. RESULTS: Four metabolites were identified as causal mediators for AD, including epiandrosterone sulfate (odds ratio [OR] per SD increase: 0.60; 95% confidence interval [CI]: 0.51-0.71; p = 6.14 × 10-9 ), 5alpha-androstan-3beta-17beta-diol disulfate (OR per SD increase: 0.69; 95% CI: 0.57-0.84; p = 1.98 × 10-4 ), sphingomyelin (OR per SD increase: 2.53; 95% CI: 1.78-3.59; p = 2.10 × 10-7 ), and glutamine (OR per SD increase: 0.83; 95% CI: 0.77-0.89; p = 2.09 × 10-6 ). Phenome-wide MR analysis showed that epiandrosterone sulfate, 5alpha-androstan-3beta-17beta-diol disulfate and sphingomyelin mediated the risk of multiple diseases, and glutamine had beneficial effects on the risk of 4 diseases. INTERPRETATION: Genetically predicted increased epiandrosterone sulfate, 5alpha-androstan-3beta-17beta-diol disulfate, and glutamine might be associated with a decreased risk of AD, while sphingomyelin was associated with an increased risk. Side-effect profiles were characterized to help inform drug target prioritization, and glutamine might be a promising target for the prevention and treatment of AD with no predicted detrimental side effects. ANN NEUROL 2022;92:756-767.

The prevalence of potential pathogens in ballast water and sediments of oceangoing vessels and implications for management.

Ballast water and sediments can serve as prominent vectors for the widespread dispersal of pathogens between geographically distant areas. However, information regarding the diversity and distribution of the bacterial pathogens in ballast water and sediments is highly limited. In this study, using high-throughput sequencing and quantitative PCR, we investigated the composition and abundance of potential pathogens, and their associations with indicator microorganisms. We accordingly detected 48 potential bacterial pathogens in the assessed ballast water and sediments, among which there were significant differences in the compositions and abundances of pathogenic bacterial communities characterizing ballast water and sediments. Rhodococcus erythropolis, Bacteroides vulgatus, and Vibrio campbellii were identified as predominant pathogens in ballast water, whereas Pseudomonas stutzeri, Mycobacterium paragordonae, and Bacillus anthracis predominated in ballast sediments. Bacteroidetes, Vibrio alginolyticus, Vibrio parahaemolyticus, and Escherichia coli were generally detected with median values of 8.54 × 103-1.22 × 107 gene copies (GC)/100 mL and 1.16 × 107-3.97 × 109 GC/100 g in ballast water and sediments, respectively. Notably, the concentrations of Shigella sp., Staphylococcus aureus, and V. alginolyticus were significantly higher in ballast sediments than in the water. In addition, our findings tend to confirm that the indicator species specified by the International Maritime Organization (IMO) might underestimate the pathogen risk in the ballast water and sediments, as these bacteria were unable to predict some potential pathogens assessed in this study. In summary, this study provides a comprehensive insight into the spectrum of the potential pathogens that transferred by ship ballast tanks and emphasizes the need for the implementation of IMO convention on ballast sediment management.

Middle Meningeal Artery Embolization Combined With Endoscopic Treatment for Chronic Subdural Hematoma.

OBJECTIVE: To explore the clinical feasibility of middle meningeal artery (MMA) embolization combined with endoscopic treatment for new or recurrent chronic subdural hematoma (CSDH). METHODS: Twenty patients with CSDH treated in the Binzhou Medical University Hospital from June 2020 to October 2022 were analyzed retrospectively. The clinical information, prognosis, imaging results, and surgical results of the patients were collected and analyzed. The authors first performed MMA embolization, and then endoscopic treatment of CSDH was performed after successful embolization of MMA. Results: All 20 patients with CSDH were successfully treated with MMA embolization combined with endoscope-assisted evacuation. The symptoms of all patients were relieved, no surgical complications occurred, and no rebleeding and recurrence were found in follow-up computed tomography. CONCLUSION: Middle meningeal artery embolization combined with endoscopic treatment of CSDH has a good clinical effect, and it may prevent postoperative recurrence.

Intelligent Vehicle Decision-Making and Trajectory Planning Method Based on Deep Reinforcement Learning in the Frenet Space.

The complexity inherent in navigating intricate traffic environments poses substantial hurdles for intelligent driving technology. The continual progress in mapping and sensor technologies has equipped vehicles with the capability to intricately perceive their exact position and the intricate interplay among surrounding traffic elements. Building upon this foundation, this paper introduces a deep reinforcement learning method to solve the decision-making and trajectory planning problem of intelligent vehicles. The method employs a deep learning framework for feature extraction, utilizing a grid map generated from a blend of static environmental markers such as road centerlines and lane demarcations, in addition to dynamic environmental cues including vehicle positions across varied lanes, all harmonized within the Frenet coordinate system. The grid map serves as the input for the state space, and the input for the action space comprises a vector encompassing lane change timing, velocity, and vertical displacement at the lane change endpoint. To optimize the action strategy, a reinforcement learning approach is employed. The feasibility, stability, and efficiency of the proposed method are substantiated via experiments conducted in the CARLA simulator across diverse driving scenarios, and the proposed method can increase the average success rate of lane change by 6.8% and 13.1% compared with the traditional planning control algorithm and the simple reinforcement learning method.