Benchmarking algorithms for single-cell multi-omics prediction and integration.

The development of single-cell multi-omics technology has greatly enhanced our understanding of biology, and in parallel, numerous algorithms have been proposed to predict the protein abundance and/or chromatin accessibility of cells from single-cell transcriptomic information and to integrate various types of single-cell multi-omics data. However, few studies have systematically compared and evaluated the performance of these algorithms. Here, we present a benchmark study of 14 protein abundance/chromatin accessibility prediction algorithms and 18 single-cell multi-omics integration algorithms using 47 single-cell multi-omics datasets. Our benchmark study showed overall totalVI and scArches outperformed the other algorithms for predicting protein abundance, and LS_Lab was the top-performing algorithm for the prediction of chromatin accessibility in most cases. Seurat, MOJITOO and scAI emerge as leading algorithms for vertical integration, whereas totalVI and UINMF excel beyond their counterparts in both horizontal and mosaic integration scenarios. Additionally, we provide a pipeline to assist researchers in selecting the optimal multi-omics prediction and integration algorithm.

Free water in gray matter linked to gut microbiota changes with decreased butyrate producers in Alzheimer's disease and mild cognitive impairment.

Neuroinflammation contributes to the pathology and progression of Alzheimer's disease (AD), and it can be observed even with mild cognitive impairment (MCI), a prodromal phase of AD. Free water (FW) imaging estimates the extracellular water content and has been used to study neuroinflammation across several neurological diseases including AD. Recently, the role of gut microbiota has been implicated in the pathogenesis of AD. The relationship between FW imaging and gut microbiota was examined in patients with AD and MCI. Fifty-six participants underwent neuropsychological assessments, FW imaging, and gut microbiota analysis targeting the bacterial 16S rRNA gene. They were categorized into the cognitively normal control (NC) (n = 19), MCI (n = 19), and AD (n = 18) groups according to the neuropsychological assessments. The correlations of FW values, neuropsychological assessment scores, and the relative abundance of gut microbiota were analyzed. FW was higher in several white matter tracts and in gray matter regions, predominantly the frontal, temporal, limbic and paralimbic regions in the AD/MCI group than in the NC group. In the AD/MCI group, higher FW values in the temporal (superior temporal and temporal pole), limbic and paralimbic (insula, hippocampus and amygdala) regions were the most associated with worse neuropsychological assessment scores. In the AD/MCI group, FW values in these regions were negatively correlated with the relative abundances of butyrate-producing genera Anaerostipes, Lachnospiraceae UCG-004, and [Ruminococcus] gnavus group, which showed a significant decreasing trend in the order of the NC, MCI, and AD groups. The present study showed that increased FW in the gray matter regions related to cognitive impairment was associated with low abundances of butyrate producers in the AD/MCI group. These findings suggest an association between neuroinflammation and decreased levels of the short-chain fatty acid butyrate that is one of the major gut microbial metabolites having a potentially beneficial role in brain homeostasis.

Clinical characteristics and pathophysiological properties of newly discovered LRRK2 variants associated with Parkinson's disease.

Leucine-rich repeat kinase 2 (LRRK2) is the most common gene responsible for familial Parkinson's disease (PD). The gene product of LRRK2 contains multiple protein domains, including armadillo repeat, ankyrin repeat, leucine-rich repeat (LRR), Ras-of-complex (ROC), C-terminal of ROC (COR), kinase, and WD40 domains. In this study, we performed genetic screening of LRRK2 in our PD cohort, detecting sixteen LRRK2 rare variants. Among them, we selected seven variants that are likely to be familial and characterized them in terms of LRRK2 protein function, along with clinical information and one pathological analysis. The seven variants were S1120P and N1221K in the LRR domain; I1339M, S1403R, and V1447M in the ROC domain; and I1658F and D1873H in the COR domain. The kinase activity of the LRRK2 variants N1221K, S1403R, V1447M, and I1658F toward Rab10, a well-known phosphorylation substrate, was higher than that of wild-type LRRK2. LRRK2 D1873H showed enhanced self-association activity, whereas LRRK2 S1403R and D1873H showed reduced microtubule-binding activity. Pathological analysis of a patient with the LRRK2 V1447M variant was also performed, which revealed Lewy pathology in the brainstem. No functional alterations in terms of kinase activity, self-association activity, and microtubule-binding activity were detected in LRRK2 S1120P and I1339M variants. However, the patient with PD carrying LRRK2 S1120P variant also had a heterozygous Glucosylceramidase beta 1 (GBA1) L444P variant. In conclusion, we characterized seven LRRK2 variants potentially associated with PD. Five of the seven variants in different LRRK2 domains exhibited altered properties in kinase activity, self-association, and microtubule-binding activity, suggesting that each domain variant may contribute to disease progression in different ways.

[Clinical characteristics and genetic analysis of a child with Char syndrome caused by TFAP2B gene variant].

OBJECTIVE: To explore the clinical features and genetic etiology of a child with Char syndrome. METHODS: A child who was presented at the Department of Child Health, Henan Children's Hospital in February 2022 was selected as the study subject. Clinical data of the child was collected, and peripheral blood samples of the child and her parents were collected for the extraction of genomic DNA. Whole exome sequencing was carried out, and candidate variants were verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child had mainly manifested facial dysmorphism, patent ductus arteriosus, growth retardation, curving of fifth fingers and middle toes. Whole exome sequencing revealed that she has harbored a heterozygous c.944A>C (p.Glu315Ala) variant of the TFAP2B gene, which was verified to be de novo by Sanger sequencing. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated to be likely pathogenic (PM1+PM2_Supporting+PM6+PP3). CONCLUSION: The heterozygous c.944A>C (p.Glu315Ala) variant of the TFAP2B gene probably underlay the Char syndrome in this child. Above finding has expanded the mutational and phenotypic spectra of the TFAP2B gene, which has facilitated early identification and diagnosis of Char syndrome.

[Risk factors for embolism in children with refractory Mycoplasmapneumoniae pneumonia and construction of a nomogram model for prediction of embolism]. / éš¾æ²»æ€§è‚ºç‚Žæ”¯åŽŸä½“è‚ºç‚Žæ‚£å„¿åˆå¹¶æ “å¡žçš„å±é™©å› ç´ åˆ†æžåŠåˆ—çº¿å›¾é¢„æµ‹æ¨¡åž‹çš„æž„å»º.

OBJECTIVES: To study the risk factors for embolism in children with refractory Mycoplasma pneumoniae pneumonia (RMPP) and to construct a nomogram model for prediction of embolism. METHODS: This retrospective study included 175 children diagnosed with RMPP at Children's Hospital Affiliated toZhengzhou University from January 2019 to October 2023. They were divided into two groups based on the presence of embolism: the embolism group (n=62) and the non-embolism group (n=113). Multivariate logistic regression analysis was used to screen for risk factors of embolism in children with RMPP, and the R software was applied to construct the nomogram model for prediction of embolism. RESULTS: Multivariate logistic regression analysis indicated that higher levels of D-dimer, interleukin-6 (IL-6) and neutrophil to lymphocyte ratio (NLR), lung necrosis, and pleural effusion were risk factors for embolism in children with RMPP (P<0.05). The area under the curve of the nomogram model for prediction of embolism constructed based on the aforementioned risk factors was 0.912 (95%CI: 0.871-0.952, P<0.05). The Hosmer-Lemeshow goodness-of-fit test showed that the model had a good fit with the actual situation (P<0.05). Calibration and decision curve analysis indicated that the model had high predictive efficacy and clinical applicability. CONCLUSIONS: Higher levels of D-dimer, IL-6 and NLR, lung necrosis, and pleural effusion are risk factors for embolism in children with RMPP. The nomogram model based on these risk factors has high clinical value for predicting embolism in children with RMPP.

Molecular genetics of Parkinson's disease: Contributions and global trends.

Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized by motor dysfunction. Aging is the greatest risk factor for developing PD. Recent molecular genetic studies have revealed that genetic factors, in addition to aging and environmental factors, play an important role in the development of the disorder. Studies of familial PD have identified approximately 20 different causative genes. PRKN is the most frequently detected causative gene in Japan. The PRKN gene is located at a common fragile site, and both copy number variants as well as single nucleotide variants are frequently detected. The location and variety of variant types makes an accurate genetic diagnosis difficult with conventional genetic testing. In sporadic PD, genome-wide association studies have revealed more than 200 genes that are potential drivers for the development of PD. Many of these studies have been conducted in Caucasian populations alone, which has limited the identification of all genetic risk factors for sporadic PD, particularly as genetic backgrounds vary widely by race. The Global Parkinson's Genetics Program is a global undertaking meant to address the issue of regional differences in genetic studies of PD.

Analysis of LIN28A variants in patients with Parkinson's disease.

A heterozygous loss-of-function variant in lin-28 homolog A (LIN28A) was recently reported as a novel pathogenic gene in patients with PD from Korea. Two patients harboring LIN28A variants had early- or middle-aged-onset PD with good responses to levodopa. In the current study, we aimed to identify the prevalence of LIN28A variants among PD patients of Japanese origin. We performed genetic sequencing of 284 patients with early-onset PD. We then estimated the frequency and functional effect of each variant using prediction tools. We identified three different rare variants in LIN28A (rs4623750, c.228 + 49 C > T; rs199541048, c.*7 A > G; and rs4659441, c.*43 C > T). The frequency of each variant in the PD patients did not differ from that of the general population. No variants were identified in the amino acid-coding regions. Our results do not support a strong association of LIN28A with early-onset PD among Japanese patients.

Silver nanoparticle-induced enhancement of light extraction in two-dimensional light-emitting diodes.

Monolayer transition metal dichalcogenides (TMDCs) with direct bandgaps are considered promising candidates for building light-emitting diodes (LEDs). One crucial indicator of their performance is the brightness of electroluminescence (EL). In this study, we fabricate WS2-based LEDs that make full use of the assistance of effective transient-mode charge injection. By introducing self-assembled silver nanoparticles (NPs) on top of the LED, the extraction efficiency is significantly improved, with a 2.9-fold EL enhancement observed in the experiment. Full-wave simulations further confirm that the improvement comes from the scattering capability of silver NPs, with results qualitatively fitting the experiment. This approach, with its compatibility with van der Waals heterostructures, can be further promoted to enhance the brightness of 2D monolayer TMDC-based LEDs.

Value of Radiomic Analysis Combined With Diffusion Tensor Imaging in Early Diagnosis of HIV-Associated Neurocognitive Disorders.

BACKGROUND: The combination of radiomics and diffusion tensor imaging (DTI) may have potential clinical value in the early stage of HIV-associated neurocognitive disorders (HAND). PURPOSE: To investigate the value of DTI-based radiomics in the early stage of HAND in people living with HIV (PLWH). STUDY TYPE: Retrospective. POPULATION: A total of 138 male PLWH were included, including 68 with intact cognition (IC) and 70 with asymptomatic neurocognitive impairment (ANI). Seventy healthy controls (HCs) were recruited for tract-based spatial statistics (TBSS) analysis. All PLWHs were randomly divided into training and validation cohorts at a 7:3 ratio. FIELD STRENGTH/SEQUENCE: A 3 T, single-shot spin-echo echo planar imaging (EPI). ASSESSMENT: The differences between the PLWH groups were compared using TBSS and region of interest (ROI) analysis. Radiomic features were extracted from the corpus callosum (CC) on DTI postprocessed images, including fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD). The performance of the radiomic signatures was evaluated by ROC curve analysis. The radiomic signature with the highest area under the curve (AUC) was combined with clinical characteristics to construct a nomogram. Decision curve analysis (DCA) was performed to evaluate the ability of different methods in discriminating ANI. STATISTICAL TESTS: Chi-square test, independent-samples t test, Kruskal-Wallis test, Mann-Whitney U test, threshold-free cluster enhancement (TFCE), ROC curve analysis, DCA, multivariate logistic regression analysis, Hosmer-Lemeshow test. P < 0.05 with TFCE corrected and P < 0.0001 without TFCE corrected were considered statistically significant. RESULTS: The ANI group showed lower FA and higher AD than the IC group. In the validation cohort, the AUCs of the FA-, AD-, MD- and RD-based radiomic signatures and the clinicoradiomic nomogram were 0.829, 0.779, 0.790, 0.864, and 0.874, respectively. DCA revealed that the nomogram was of greater clinical value than TBSS analysis, the clinical models, and the RD-based radiomic signature. DATA CONCLUSION: The combination of DTI and radiomics is correlated with early stage of HAND in PLWH. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 2.

Significantly Affected Lubrication Behavior of Silicone Oil Lubricated Si3N4/Glass Contact after Cleaning with Different Solvents.

Conventional methyl silicone oils have poor lubricating properties in boundary lubrication regions, particularly for ceramic/oxide point contact lubrication. In this study, the residues of various organic solvents on the surfaces of Si3N4 spheres/glass disks were used to determine their effect on the lubricating properties of silicone oil 200. The minute ethanol residues significantly enhanced the antifriction and antiwear properties of silicone oil. Compared to the blank sample, the coefficient of friction (COF) and wear volume of silicone oil 200 with the residual ethanol friction pair were reduced by >40% and >98%, respectively. Being immiscible with silicone oil, the minute ethanol residues also removed impurities from the glass surface and maintained a clean interface, thus effectively blocking direct interactions between the friction pair interfaces. In addition, the residual ethanol reduced the atomic force microscope probe-to-glass surface adhesive force in the silicone oil 200 environment, thus allowing it to maintain low COF and wear rates over a broader range of speeds, loads, and times. In contrast to previous work, this study is the first to effectively regulate the lubrication properties of silicone oil using a residual organic solvent. The findings further verified that the adsorption of vapor molecules can significantly alter the surface forces between interfaces. Thus, adjusting the adhesion force through trace amounts of organic solvent residues may provide novel research inputs, thereby guiding the expansion and scope of silicone oil lubrication applications.

Motor neuron TDP-43 proteinopathy in progressive supranuclear palsy and corticobasal degeneration.

TDP-43 is mislocalized from the nucleus and aggregates within the cytoplasm of affected neurons in cases of amyotrophic lateral sclerosis. TDP-43 pathology has also been found in brain tissues under non-amyotrophic lateral sclerosis conditions, suggesting mechanistic links between TDP-43-related amyotrophic lateral sclerosis and various neurological disorders. This study aimed to assess TDP-43 pathology in the spinal cord motor neurons of tauopathies. We examined 106 spinal cords from consecutively autopsied cases with progressive supranuclear palsy (n = 26), corticobasal degeneration (n = 12), globular glial tauopathy (n = 5), Alzheimer's disease (n = 21) or Pick's disease (n = 6) and neurologically healthy controls (n = 36). Ten of the progressive supranuclear palsy cases (38%) and seven of the corticobasal degeneration cases (58%) showed mislocalization and cytoplasmic aggregation of TDP-43 in spinal cord motor neurons, which was prominent in the cervical cord. TDP-43 aggregates were found to be skein-like, round-shaped, granular or dot-like and contained insoluble C-terminal fragments showing blotting pattern of amyotrophic lateral sclerosis or frontotemporal lobar degeneration. The lower motor neurons also showed cystatin-C aggregates, although Bunina bodies were absent in haematoxylin-eosin staining. The spinal cord TDP-43 pathology was often associated with TDP-43 pathology of the primary motor cortex. Positive correlations were shown between the severities of TDP-43 and four-repeat (4R)-tau aggregates in the cervical cord. TDP-43 and 4R-tau aggregates burdens positively correlated with microglial burden in anterior horn. TDP-43 pathology of spinal cord motor neuron did not develop in an age-dependent manner and was not found in the Alzheimer's disease, Pick's disease, globular glial tauopathy and control groups. Next, we assessed SFPQ expression in spinal cord motor neurons; SFPQ is a recently identified regulator of amyotrophic lateral sclerosis/frontotemporal lobar degeneration pathogenesis, and it is also reported that interaction between SFPQ and FUS regulates splicing of MAPT exon 10. Immunofluorescent and proximity-ligation assays revealed altered SFPQ/FUS-interactions in the neuronal nuclei of progressive supranuclear palsy, corticobasal degeneration and amyotrophic lateral sclerosis-TDP cases but not in Alzheimer's disease, Pick's disease and globular glial tauopathy cases. Moreover, SFPQ expression was depleted in neurons containing TDP-43 or 4R-tau aggregates of progressive supranuclear palsy and corticobasal degeneration cases. Our results indicate that progressive supranuclear palsy and corticobasal degeneration may have properties of systematic motor neuron TDP-43 proteinopathy, suggesting mechanistic links with amyotrophic lateral sclerosis-TDP. SFPQ dysfunction, arising from altered interaction with FUS, may be a candidate of the common pathway.

Electromagnetic fields ameliorate hepatic lipid accumulation and oxidative stress: potential role of CaMKKß/AMPK/SREBP-1c and Nrf2 pathways.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and is related to disturbed lipid metabolism and redox homeostasis. However, a definitive drug treatment has not been approved for this disease. Studies have found that electromagnetic fields (EMF) can ameliorate hepatic steatosis and oxidative stress. Nevertheless, the mechanism remains unclear. METHODS: NAFLD models were established by feeding mice a high-fat diet. Simultaneously, EMF exposure is performed. The effects of the EMF on hepatic lipid deposition and oxidative stress were investigated. Additionally, the AMPK and Nrf2 pathways were analysed to confirm whether they were activated by the EMF. RESULTS: Exposure to EMF decreased the body weight, liver weight and serum triglyceride (TG) levels and restrained the excessive hepatic lipid accumulation caused by feeding the HFD. The EMF boosted CaMKKß protein expression, activated AMPK phosphorylation and suppressed mature SREBP-1c protein expression. Meanwhile, the activity of GSH-Px was enhanced following an increase in nuclear Nrf2 protein expression by PEMF. However, no change was observed in the activities of SOD and CAT. Consequently, EMF reduced hepatic reactive oxygen species (ROS) and MDA levels, which means that EMF relieved liver damage caused by oxidative stress in HFD-fed mice. CONCLUSIONS: EMF may activate the CaMKKß/AMPK/SREBP-1c and Nrf2 pathways to control hepatic lipid deposition and oxidative stress. This investigation indicates that EMF may be a novel therapeutic method for NAFLD.

Alterations in the gut microbiome and metabolome profiles of septic rats treated with aminophylline.

The treatment of sepsis remains a major challenge worldwide. Aminophylline has been shown to have anti-inflammatory effects; however, the role of aminophylline in sepsis, a disease characterized by immune dysregulation, is unknown. In this study, we combined microbiome sequencing and metabolomic assays to investigate the effect of aminophylline administration on the intestinal flora and metabolites in septic rats. Sixty SD rats were randomly divided into three groups: a sham-operated (SC) group, a sepsis model (CLP) group and a CLP + aminophylline treatment (Amino) group. The intestinal flora and metabolic profile of rats in the CLP group were significantly different than those of the SC group, while aminophylline administration resulted in a return to a state similar to healthy rats. Differential abundance analysis showed that aminophylline significantly back-regulated the abundance of Firmicutes, unidentified_Bacteria, Proteobacteria, Lactobacillus, Escherichia-Shigella and other dominant bacteria (P < 0.05) and altered chenodeoxycholic acid, isolithocholic acid and a total of 26 metabolites (variable importance in the projection (VIP) > 1, P < 0.05). In addition, we found that there were significant correlations between differential metabolites and bacterial genera of the Amino and CLP groups. For example, Escherichia-Shigella was associated with 12 metabolites, and Lactobacillus was associated with two metabolites (P < 0.05), suggesting that differences in the metabolic profiles caused by aminophylline were partly dependent on its influence on the gutmicrobiome. In conclusion, this study identified a novel protective mechanism whereby aminophylline could regulate disordered intestinal flora and metabolites in septic rats.

CT-based radiomics for differentiating intracranial contrast extravasation from intraparenchymal haemorrhage after mechanical thrombectomy.

OBJECTIVE: To develop a nonenhanced CT-based radiomic signature for the differentiation of iodinated contrast extravasation from intraparenchymal haemorrhage (IPH) following mechanical thrombectomy. METHODS: Patients diagnosed with acute ischaemic stroke who underwent mechanical thrombectomy in 4 institutions from December 2017 to June 2020 were included in this retrospective study. The study population was divided into a training cohort and a validation cohort. The nonenhanced CT images taken after mechanical thrombectomy were used to extract radiomic features. The maximum relevance minimum redundancy (mRMR) algorithm was used to eliminate confounding variables. Afterwards, least absolute shrinkage and selection operator (LASSO) logistic regression was used to generate the radiomic signature. The diagnostic performance of the radiomic signature was evaluated by the area under the curve (AUC), accuracy, specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: A total of 166 intraparenchymal areas of hyperattenuation from 101 patients were used. The areas of hyperattenuation were randomly allocated to the training and validation cohorts at a ratio of 7:3. The AUC of the radiomic signature was 0.848 (95% confidence interval (CI) 0.780-0.917) in the training cohort and 0.826 (95% CI 0.705-0.948) in the validation cohort. The accuracy of the radiomic signature was 77.6%, with a sensitivity of 76.7%, a specificity of 78.9%, a PPV of 85.2%, and a NPV of 68.2% in the validation cohort. CONCLUSIONS: The radiomic signature constructed based on initial post-operative nonenhanced CT after mechanical thrombectomy can effectively differentiate IPH from iodinated contrast extravasation. KEY POINTS: • Radiomic features were extracted from intraparenchymal areas of hyperattenuation on initial post-operative CT scans after mechanical thrombectomy. • The nonenhanced CT-based radiomic signature can differentiate IPH from iodinated contrast extravasation early. • The radiomic signature may help prevent unnecessary rescanning after mechanical thrombectomy, especially in cases where contrast extravasation is highly suggestive.

Mutations in CHCHD2 cause α-synuclein aggregation.

Mutations in CHCHD2 are linked to a familial, autosomal dominant form of Parkinson's disease (PD). The gene product may regulate mitochondrial respiratory function. However, whether mitochondrial dysfunction induced by CHCHD2 mutations further yields α-synuclein pathology is unclear. Here, we provide compelling genetic evidence that mitochondrial dysfunction induced by PD-linked CHCHD2 T61I mutation promotes α-synuclein aggregation using brain autopsy, induced pluripotent stem cells (iPSCs) and Drosophila genetics. An autopsy of an individual with CHCHD2 T61I revealed widespread Lewy pathology with both amyloid plaques and neurofibrillary tangles that appeared in the brain stem, limbic regions and neocortex. A prominent accumulation of sarkosyl-insoluble α-synuclein aggregates, the extent of which was comparable to that of a case with α-synuclein (SNCA) duplication, was observed in CHCHD2 T61I brain tissue. The prion-like activity and morphology of α-synuclein fibrils from the CHCHD2 T61I brain tissue were similar to those of fibrils from SNCA duplication and sporadic PD brain tissues. α-Synuclein insolubilization was reproduced in dopaminergic neuron cultures from CHCHD2 T61I iPSCs and Drosophila lacking the CHCHD2 ortholog or expressing the human CHCHD2 T61I. Moreover, the combination of ectopic α-synuclein expression and CHCHD2 null or T61I enhanced the toxicity in Drosophila dopaminergic neurons, altering the proteolysis pathways. Furthermore, CHCHD2 T61I lost its mitochondrial localization by α-synuclein in Drosophila. The mislocalization of CHCHD2 T61I was also observed in the patient brain. Our study suggests that CHCHD2 is a significant mitochondrial factor that determines α-synuclein stability in the etiology of PD.

Effects of Abrasive Particles on Liquid Superlubricity and Mechanisms for Their Removal.

Liquid superlubricity results in a near-frictionless lubrication state, which can greatly reduce friction and wear under aqueous conditions. However, during the running-in process, a large number of abrasive particles are generated, and because these may lead to a breakdown in superlubricity performance, they should be effectively removed. In this paper, the morphology, size, and composition of abrasive particles were verified using scanning electron microscopy with energy-dispersive X-ray spectroscopy, and their influence on liquid superlubricity was explored through friction tests. Subsequently, different solvents were used to remove the abrasive particles, and the optimal cleaning process was determined by macroscopic tribo-tests and microscopic analysis. Finally, droplet-spreading experiments and a force-curve analysis were carried out to understand the abrasive-particle removal mechanism by different solvents. We found that SiO2 was the main component in the abrasive particles, and micron-sized SiO2 particles resulted in random "wave peaks" in the coefficient of friction and, thus, the superlubricity. Absolute ethanol + ultrapure water was determined to be the optimal solvent for effectively removing abrasive particles from friction-pair surfaces and helped the lubricant in exhibiting an ultralow friction coefficient for long periods of time. We proposed a "wedge" and "wrap" model to explain the abrasive-particle removal mechanism of different solvents. The SiO2 removal mechanism outlined in this study can be applied under aqueous conditions to improve the stability and durability of liquid superlubricity in practical engineering applications.

Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with polyneuropathy.

Parkinson's disease is a neurodegenerative disorder with a multifactorial aetiology. Nevertheless, the genetic predisposition in many families with multi-incidence disease remains unknown. This study aimed to identify novel genes that cause familial Parkinson's disease. Whole exome sequencing was performed in three affected members of the index family with a late-onset autosomal-dominant parkinsonism and polyneuropathy. We identified a novel heterozygous substitution c.941A>C (p.Tyr314Ser) in the mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene, which co-segregates with disease within the family. Additional analysis of 699 unrelated Parkinson's disease probands with autosomal-dominant Parkinson's disease and 1934 patients with sporadic Parkinson's disease revealed another two variants in UQCRC1 in the probands with familial Parkinson's disease, c.931A>C (p.Ile311Leu) and an allele with concomitant splicing mutation (c.70-1G>A) and a frameshift insertion (c.73_74insG, p.Ala25Glyfs*27). All substitutions were absent in 1077 controls and the Taiwan Biobank exome database from healthy participants (n = 1517 exomes). We then assayed the pathogenicity of the identified rare variants using CRISPR/Cas9-based knock-in human dopaminergic SH-SY5Y cell lines, Drosophila and mouse models. Mutant UQCRC1 expression leads to neurite degeneration and mitochondrial respiratory chain dysfunction in SH-SY5Y cells. UQCRC1 p.Tyr314Ser knock-in Drosophila and mouse models exhibit age-dependent locomotor defects, dopaminergic neuronal loss, peripheral neuropathy, impaired respiratory chain complex III activity and aberrant mitochondrial ultrastructures in nigral neurons. Furthermore, intraperitoneal injection of levodopa could significantly improve the motor dysfunction in UQCRC1 p.Tyr314Ser mutant knock-in mice. Taken together, our in vitro and in vivo studies support the functional pathogenicity of rare UQCRC1 variants in familial parkinsonism. Our findings expand an additional link of mitochondrial complex III dysfunction in Parkinson's disease.

Variants in saposin D domain of prosaposin gene linked to Parkinson's disease.

Recently, the genetic variability in lysosomal storage disorders has been implicated in the pathogenesis of Parkinson's disease. Here, we found that variants in prosaposin (PSAP), a rare causative gene of various types of lysosomal storage disorders, are linked to Parkinson's disease. Genetic mutation screening revealed three pathogenic mutations in the saposin D domain of PSAP from three families with autosomal dominant Parkinson's disease. Whole-exome sequencing revealed no other variants in previously identified Parkinson's disease-causing or lysosomal storage disorder-causing genes. A case-control association study found two variants in the intronic regions of the PSAP saposin D domain (rs4747203 and rs885828) in sporadic Parkinson's disease had significantly higher allele frequencies in a combined cohort of Japan and Taiwan. We found the abnormal accumulation of autophagic vacuoles, impaired autophagic flux, altered intracellular localization of prosaposin, and an aggregation of α-synuclein in patient-derived skin fibroblasts or induced pluripotent stem cell-derived dopaminergic neurons. In mice, a Psap saposin D mutation caused progressive motor decline and dopaminergic neurodegeneration. Our data provide novel genetic evidence for the involvement of the PSAP saposin D domain in Parkinson's disease.

A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson's Disease Affects LRRK2 Protein Levels.

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson's disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant-p.G2294R-located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient's peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.

Clinical characterization of patients with leucine-rich repeat kinase 2 genetic variants in Japan.

Variants of leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of familial Parkinson's disease (PD). We aimed to investigate the genetic and clinical features of patients with PD and LRRK2 variants in Japan by screening for LRRK2 variants in three exons (31, 41, and 48), which include the following pathogenic mutations: p.R1441C, p.R1441G, p.R1441H, p.G2019S, and p.I2020T. Herein, we obtained data containing LRRK2 variants derived from 1402 patients with PD (653 with sporadic PD and 749 with familial PD). As a result, we successfully detected pathogenic variants (four with p.R1441G, five with p.R1441H, seven with p.G2019S, and seven with p.I2020T) and other rare variants (two with p.V1447M, one with p.V1450I, one with p.T1491delT, and one with p.H2391Q). Two risk variants, p.P1446L and p.G2385R, were found in 10 and 146 patients, respectively. Most of the patients presented the symptoms resembling a common type of PD, such as middle-aged onset, tremor, akinesia, rigidity, and gait disturbance. Dysautonomia, cognitive decline, and psychosis were rarely observed. Each known pathogenic variant had a different founder in our cohort proven by haplotype analysis. The generation study revealed that the LRRK2 variants p.G2019S and p.I2020T were derived 3500 and 1300 years ago, respectively. Our findings present overviews of the prevalence and distribution of LRRK2 variants in Japanese cohorts.