Plasma fatty acids and attention deficit hyperactivity disorder: a Mendelian randomization investigation.

Background: Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood, and pathogenesis is not fully understood. Observational studies suggest an association between fatty acids abnormalities and ADHD, but there are contradictions and differences between these findings. To address this uncertainty, we employed a two-sample bidirectional Mendelian Randomization (MR) analysis to investigate the causal relationship between fatty acids and ADHD. Methods: We conducted a two-sample Mendelian Randomization (MR) study, selecting single nucleotide polymorphisms (SNPs) highly correlated with fatty acid levels from the CHARGE Consortium as our instruments. The outcome data were sourced from the Psychiatric Genomics Consortium (PGC) dataset on ADHD, comprising 225,534 individuals, with 162,384 cases and 65,693 controls. Inverse variance weighting, MR-Egger, and weighted median methods were employed to estimate the causal relationship between fatty acids and ADHD. Cochran's Q-test was used to quantify heterogeneity of instrumental variables. Sensitivity analyses included MR-Egger intercept tests, leave-one-out analyses, and funnel plots. Results: The MR analysis revealed no significant associations between genetically predicted levels of various saturated, monounsaturated, and polyunsaturated fatty acids (including omega-3 and omega-6) and ADHD risk in the CHARGE and PGC cohorts. Notably, an initial association with Dihomo-gamma-linolenic acid (DGLA) (OR = 1.009, p = 0.032 by IVW) did not persist after correction for multiple testing (adjusted p-value = 0.286). Sensitivity analysis supported our findings, indicating robustness. Moreover, there was a lack of evidence supporting a causal link from ADHD to fatty acids. Conclusion: While our study on the basis of genetic data does not provide evidence to support the causal role of fatty acids in ADHD, it does not preclude their potential involvement in reducing the risk of ADHD. Further research is needed to explore this possibility.

Fractal and first-passage properties of a class of self-similar networks.

A class of self-similar networks, obtained by recursively replacing each edge of the current network with a well-designed structure (generator) and known as edge-iteration networks, has garnered considerable attention owing to its role in presenting rich network models to mimic real objects with self-similar structures. The generator dominates the structural and dynamic properties of edge-iteration networks. However, the general relationships between these networks' structural and dynamic properties and their generators remain unclear. We study the fractal and first-passage properties, such as the fractal dimension, walk dimension, resistance exponent, spectral dimension, and global mean first-passage time, which is the mean time for a walker, starting from a randomly selected node and reaching the fixed target node for the first time. We disclose the properties of the generators that dominate the fractal and first-passage properties of general edge-iteration networks. A clear relationship between the fractal and first-passage properties of the edge-iteration networks and the related properties of the generators are presented. The upper and lower bounds of these quantities are also discussed. Thus, networks can be customized to meet the requirements of fractal and dynamic properties by selecting an appropriate generator and tuning their structural parameters. The results obtained here shed light on the design and optimization of network structures.

Effect of Time Window on Endovascular Thrombectomy with or without Intravenous Thrombolysis in Acute Ischemic Stroke: Results from DIRECT-MT.

INTRODUCTION: Whether time window affects the intravenous thrombolysis (IVT) effect before endovascular thrombectomy (EVT) is uncertain. We aimed to investigate the effect of different time windows (0-3 h and >3-4.5 h from stroke onset to randomization) on clinical outcomes of EVT with or without IVT in a subgroup analysis of DIRECT-MT. METHODS: The primary outcome was the 90-day modified Rankin Scale (mRS) according to time window. Logistic regression models were used to analyze the effect of different treatments (EVT with or without IVT) on outcomes within 0-3 h or >3-4.5 h. RESULTS: Among 656 patients who were included in the analysis, 282 (43.0%) were randomized within >3-4.5 h after stroke onset (125 without IVT and 157 with IVT), and 374 (57.0%) were randomized within 0-3 h (202 without IVT and 172 with IVT). We noted no significant difference in the thrombectomy-alone effect between the time window subgroups according to 90-day ordinal mRS (adjusted common odds ratio [acOR] in patients within 0-3 h: 1.06 [95% CI: 0.73-1.52], acOR in patients within >3-4.5 h: 1.19 [95% CI: 0.78-1.82]) and 90-day functional independence. Thrombectomy alone resulted in an increased proportion of patients with 90-day mRS 0-3 treated within >3-4.5 h (62.90 vs. 48.72%) but not within 0-3 h (65.84 vs. 63.95%). However, there was no interaction effect regarding all outcomes after the Bonferroni correction. CONCLUSIONS: Our results did not support thrombectomy-alone administration within 3-4.5 h in patients with acute ischemic stroke from large-vessel occlusion in the subgroup analysis of DIRECT-MT.

Optimizing search processes with stochastic resetting on the pseudofractal scale-free web.

The pseudofractal scale-free web (PSFW) is a well-known model for a scale-free network with small-world characteristics. Understanding the dynamic properties of this network can provide valuable insights into dynamic processes occurring in general scale-free and small-world networks. In this study we investigate search processes using discrete-time random walks on the PSFW to reveal the impact of the resetting position on optimizing search efficiency, as measured by the mean first-passage time (MFPT). At each step the walker has two options: with a probability of 1-γ, it moves to one of the neighboring sites, and with a probability of γ, it resets to the predefined resetting position. We explore various choices for the resetting position, present rigorous results for the MFPT to a given node of the network, determine the optimal resetting probability γ^{*} where the MFPT reaches its minimum, and evaluate the ratio of the minimum for MFPT to the MFPT without resetting for each case. Results show that, in large PSFWs, both the degree of the resetting position and the distance between the target and the resetting position significantly affect the search efficiency. A higher degree of the resetting position leads to a slower convergence of the walker to the target, while a greater distance between the target and the resetting position also results in a slower convergence. Additionally, we observe that resetting to a vertex randomly selected from the stationary distribution can significantly expedite the process of the walker reaching the target. The findings presented in this study shed light on optimizing stochastic search processes on large networks, offering valuable insights into improving search efficiency in real-world applications, where the target node's location is unknown.

Remote self-administration of digital cognitive tests using the Brief Assessment of Cognition: Feasibility, reliability, and sensitivity to subjective cognitive decline.

Cognitive impairment is a common and pervasive feature of etiologically diverse disorders of the central nervous system, and a target indication for a growing number of symptomatic and disease modifying drugs. Remotely acquired digital endpoints have been recognized for their potential in providing frequent, real-time monitoring of cognition, but their ultimate value will be determined by the reliability and sensitivity of measurement in the populations of interest. To this end, we describe initial validation of remote self-administration of cognitive tests within a regulatorily compliant tablet-based platform. Participants were 61 older adults (age 55+), including 20 individuals with subjective cognitive decline (SCD). To allow comparison between remote (in-home) and site-based testing, participants completed 2 testing sessions 1 week apart. Results for three of four cognitive domains assessed demonstrated equivalence between remote and site-based tests, with high cross-modality ICCs (absolute agreement) for Symbol Coding (ICC = 0.75), Visuospatial Working Memory (ICC = 0.70) and Verbal Fluency (ICC > 0.73). Group differences in these domains were significant and reflected sensitivity to objective cognitive impairment in the SCD group for both remote and site-based testing (p < 0.05). In contrast, performance on tests of verbal episodic memory suggested inflated performance during unmonitored testing and indicate reliable use of remote cognitive assessments may depend on the construct, as well as the population being tested.

High-frequency repetitive transcranial magnetic stimulation (rTMS) protects against ischemic stroke by inhibiting M1 microglia polarization through let-7b-5p/HMGA2/NF-κB signaling pathway.

BACKGROUND: Microglia assume opposite phenotypes in response to ischemic brain injury, exerting neurotoxic and neuroprotective effects under different ischemic stages. Modulating M1/M2 polarization is a potential therapy for treating ischemic stroke. Repetitive transcranial magnetic stimulation (rTMS) held the capacity to regulate neuroinflammation and astrocytic polarization, but little is known about rTMS effects on microglia. Therefore, the present study aimed to examine the rTMS influence on microglia polarization and the underlying possible molecular mechanisms in ischemic stroke models. METHODS: Previously reported 10 Hz rTMS protocol that regulated astrocytic polarization was used to stimulate transient middle cerebral artery occlusion (MCAO) rats and oxygen and glucose deprivation/reoxygenation (OGD/R) injured BV2 cells. Specific expression levels of M1 marker iNOS and M2 marker CD206 were measured by western blotting and immunofluorescence. MicroRNA expression changes detected by high-throughput second-generation sequencing were validated by RT-PCR and fluorescence in situ hybridization (FISH) analysis. Dual-luciferase report assay and miRNA knock-down were applied to verify the possible mechanisms regulated by rTMS. Microglia culture medium (MCM) from different groups were collected to measure the TNF-α and IL-10 concentrations, and detect the influence on neuronal survival. Finally, TTC staining and modified Neurological Severity Score (mNSS) were used to determine the effects of MCM on ischemic stroke volume and neurological functions. RESULTS: The 10 Hz rTMS inhibited ischemia/reperfusion induced M1 microglia and significantly increased let-7b-5p level in microglia. HMGA2 was predicted and proved to be the target protein of let-7b-5p. HMGA2 and its downstream NF-κB signaling pathway were inhibited by rTMS. Microglia culture medium (MCM) collected from rTMS treated microglia contained lower TNF-α concentration but higher IL-10 concentration than no rTMS treated MCM, reducing ischemic volumes and neurological deficits of MCAO mice. However, knockdown of let-7b-5p by antagomir reversed rTMS effects on microglia phenotype and associated HMGA/NF-κB activation and neurological recovery. CONCLUSION: High-frequency rTMS could alleviate ischemic stroke injury through inhibiting M1 microglia polarization via regulating let-7b-5p/HMGA2/NF-κB signaling pathway in MCAO models.

Associations of risk genes with onset age and plasma biomarkers of Alzheimer's disease: a large case-control study in mainland China.

Most genetic studies concerning risk genes in Alzheimer's disease (AD) are from Caucasian populations, whereas the data remain limited in the Chinese population. In this study, we systematically explored the relationship between AD and risk genes in mainland China. We sequenced 33 risk genes previously reported to be associated with AD in a total of 3604 individuals in the mainland Chinese population. Common variant (MAF ≥ 0.01) based association analysis and gene-based (MAF < 0.01) association test were performed by PLINK 1.9 and Sequence Kernel Association Test-Optimal, respectively. Polygenic risk score (PRS) was calculated, and receiver operating characteristic curve (AUC) was computed. Plasma Aß42, Aß40, total tau (T-tau), and neurofilament light chain (NFL) were tested in a subgroup, and their associations with PRS were conducted using the Spearman correlation test. Six common variants varied significantly between AD patients and cognitively normal controls after the adjustment of age, gender, and APOE ε4 status, including variants in ABCA7 (n = 5) and APOE (n = 1). Among them, four variants were novel and two were reported previously. The AUC of PRS was 0.71. The high PRS was significantly associated with an earlier age at onset (P = 4.30 × 10-4). PRS was correlated with plasma Aß42, Aß42/Aß40 ratio, T-tau, and NFL levels. Gene-based association test revealed that ABCA7 and UNC5C reached statistical significance. The common variants in APOE and ABCA7, as well as rare variants in ABCA7 and UNC5C, may contribute to the etiology of AD. Moreover, the PRS, to some extent, could predict the risk, onset age, and biological changes of AD.

First encounters on Watts-Strogatz networks and Barabási-Albert networks.

The Watts-Strogatz networks are important models that interpolate between regular lattices and random graphs, and Barabási-Albert networks are famous models that explain the origin of the scale-free networks. Here, we consider the first encounters between two particles (e.g., prey A and predator B) embedded in the Watts-Strogatz networks and the Barabási-Albert networks. We address numerically the mean first-encounter time (MFET) while the two particles are moving and the mean first-passage time (MFPT) while the prey is fixed, aiming at uncovering the impact of the prey's motion on the encounter time, and the conditions where the motion of the prey would accelerate (or slow) the encounter between the two particles. Different initial conditions are considered. In the case where the two particles start independently from sites that are selected randomly from the stationary distribution, on the Barabási-Albert networks, the MFET is far less than the MFPT, and the impact of prey's motion on the encounter time is enormous, whereas, on the Watts-Strogatz networks (including Erdos-Rényi random networks), the MFET is about 0.5-1 times the MFPT, and the impact of prey's motion on the encounter time is relatively small. We also consider the case where prey A starts from a fixed site and the predator starts from a randomly drawn site and present the conditions where the motion of the prey would accelerate (or slow) the encounter between the two particles. The relation between the MFET (or MFPT) and the average path length is also discussed.

Effects of flotation and acid treatment on unburned carbon recovery from atmospheric circulating fluidized bed coal gasification fine ash and application evaluation of residual carbon.

The high carbon content (20-60%) in coal gasification fine ash (CGFA) makes CGFA unable to be directly used in the building materials and ceramic industries, and can only be dissipated in landfills, which brings serious environmental safety problems. This paper uses physical (flotation method) and chemical (multi-stage pickling method) methods to treat CGFA, analyze the separated carbon, and evaluate its application. The carbon content of the filter cake ash (FCA) residual carbon recovered by the flotation method is slightly increased, and the carbon ash separation effect for the water-containing CGFA is poor. The carbon content of dry ash (DA) recovered carbon in acid treatment increased from 16.33% to 89.97%. The specific surface area of the acid-washed recovered carbon is 6-34 times that of the original sample, and the specific surface area of dry ash-HCl/HF/HCl (DA-CFC) is as high as 425.31 m2/g, and its pore structure network is more developed than before deashing. After pickling treatment, the microcrystalline structure changes, the carbon skeleton becomes looser, the degree of crosslinking decreases, and the reaction activity increases. The relative content of CC in the acid-washed recovered carbon increased by 6.4-46.3%, and the relative content of functional group CH bonds increased by 48.5-89.5%. Compared with the activation energy of the original sample, the activation energy E of the sample after flotation and acid treatment is reduced, and the reaction activity is enhanced. Flotation and pickling methods can improve the grade of fuel, and multi-stage pickling methods to obtain high specific surface area carbon can be used as a precursor for the preparation of activated carbon. Carbon-ash separation of DA by flotation method can be applied to fuel combustion, fine chemical industry, and road filling. However, for FCA, it is necessary to use a pickling scheme for carbon-ash separation to realize resource utilization and harmlessness.

The role of frontotemporal dementia associated genes in patients with Alzheimer's disease.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) overlap clinically and pathologically. However, the role of FTD-associated genes in patients with AD remained unclear. To explore the relationship between FTD-associated genes and AD risk, we investigated 14 FTD-associated genes via targeted next-generation sequencing panel or whole-genome sequencing in a total of 721 AD patients and 1391 controls. Common variant-based association analysis and gene-based association test of rare variants were performed by PLINK 1.9 and Sequence Kernel Association Test-Optimal (SKAT-O test) respectively. As a result, 2 common variants, UBQLN1 rs1044175 (p value = 2.76 × 10-4) and MAPT rs2258689 (p value = 5.71 × 10-4), differed significantly between AD patients and controls. Additionally, gene-based analysis aggregating rare variants demonstrated that HNRNPA1 reached statistical significance in the SKAT-O test (p value = 2.24 × 10-3). Protein-protein interaction analysis showed that UBQLN1, MAPT, and HNRNPA1 interacted with proteins encoded by well-recognized AD-associated genes. Our study indicated that UBQLN1, MAPT, and HNRNPA1 are implicated in the pathogenesis of AD in the mainland Chinese population.

The role of NOTCH3 variants in Alzheimer's disease and subcortical vascular dementia in the Chinese population.

AIMS: NOTCH3 gene mutations predominantly cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a common etiology of subcortical vascular dementia (SVaD). Besides, there may be a pathogenic link between NOTCH3 variants and Alzheimer's disease (AD). We aimed to study the role of NOTCH3 variants in AD and SVaD patients. METHODS: We recruited 763 patients with dementia (667 AD and 96 SVaD) and 365 healthy controls from the Southern Han Chinese population. Targeted capture sequencing was performed on NOTCH3 coding and adjacent intron regions to detect the pathogenic variants in AD and SVaD. The relationship between common or rare NOTCH3 variants and AD was further analyzed using Plink1.9. RESULTS: Five known pathogenic variants (p.R182C, p.C201S, p.R544C, p.R607C, and p.R1006C) and two novel likely pathogenic variants (p.C201F and p.C1061F) were detected in 16 SVaD patients. Additionally, no pathogenic or likely pathogenic variants were found in AD patients. NOTCH3 was not associated with AD in either single-variant association analysis or gene-based association analysis. CONCLUSION: Our findings broaden the mutational spectrum of NOTCH3 and validate the pathogenic role of NOTCH3 mutations in SVaD, but do not support the notion that NOTCH3 variation influences the risk of AD.

GPCards: An integrated database of genotype-phenotype correlations in human genetic diseases.

Genotype-phenotype correlations are the basis of precision medicine of human genetic diseases. However, it remains a challenge for clinicians and researchers to conveniently access detailed individual-level clinical phenotypic features of patients with various genetic variants. To address this urgent need, we manually searched for genetic studies in PubMed and catalogued 8,309 genetic variants in 1,288 genes from 17,738 patients with detailed clinical phenotypic features from 1,855 publications. Based on genotype-phenotype correlations in this dataset, we developed an user-friendly online database called GPCards (http://genemed.tech/gpcards/), which not only provided the association between genetic diseases and disease genes, but also the prevalence of various clinical phenotypes related to disease genes and the patient-level mapping between these clinical phenotypes and genetic variants. To accelerate the interpretation of genetic variants, we integrated 62 well-known variant-level and gene-level genomic data sources, including functional predictions, allele frequencies in different populations, and disease-related information. Furthermore, GPCards enables automatic analyses of users' own genetic data, comprehensive annotation, prioritization of candidate functional variants, and identification of genotype-phenotype correlations using custom parameters. In conclusion, GPCards is expected to accelerate the interpretation of genotype-phenotype correlations, subtype classification, and candidate gene prioritisation in human genetic diseases.

Subdural Hemorrhage in Asymptomatic Neonates: Neurodevelopmental Outcomes and MRI Findings at 2 Years.

Background Subdural hemorrhage (SDH) is thought to have a benign course in asymptomatic neonates. However, effects on neurodevelopmental outcomes have not been established. Purpose To evaluate neurodevelopmental outcomes, gray matter volumes, and MRI findings in asymptomatic neonates with SDH compared with control neonates. Materials and Methods This retrospective analysis was conducted between 2003 and 2016 and was based on data from the University of North Carolina Early Brain Development Study. Neurodevelopmental outcomes were evaluated at 2 years of age by using the Mullen Scales of Early Learning (MSEL). All infants were imaged with 3.0-T MRI machines and were evaluated for SDH at baseline (neonates) and at ages 1 and 2 years. Volumetric MRI for brain segmentation was performed at ages 1 and 2 years. A secondary analysis was performed in neonates matched 1:1 with control neonates. Differences in categorical variables were measured by using the Fisher exact test, and the t test was used for continuous variables. Results A total of 311 neonates (mean gestational age ± standard deviation, 39.3 weeks ± 1.5), including 57 with SDH (mean gestational age, 39.5 weeks ± 1.2), were evaluated. The subgroup included 55 neonates with SDH (mean gestational age, 39.6 weeks ± 1.2) and 55 matched control neonates (mean gestational age, 39.7 weeks ± 1.2). Fifty-five of 57 neonates with SDH (97%; 95% CI: 92, 100) were delivered vaginally compared with 157 of 254 control neonates (62%, 95% CI: 56, 68; P < .001). Otherwise, there were no differences in perinatal, maternal, or obstetric parameters. There were no differences in composite MSEL scores (115 ± 15 and 109 ± 16 at 2 years, respectively; P = .05) or gray matter volumes between the neonatal SDH group and control neonates (730 cm3 ± 85 and 742 cm3 ± 76 at 2 years, respectively; P = .70). There was no evidence of rebleeding at follow-up MRI. Conclusion Neurodevelopmental scores and gray matter volumes at age 2 years did not differ between asymptomatic neonates with subdural hemorrhage and control neonates. © RSNA, 2020 Online supplemental material is available for this article.

Association of Genes Involved in the Metabolic Pathways of Amyloid-ß and Tau Proteins With Sporadic Late-Onset Alzheimer's Disease in the Southern Han Chinese Population.

The genes involved in the metabolic pathways of amyloid-ß (Aß) and tau proteins significantly influence the etiology of Alzheimer's disease (AD). Various studies have explored the associations between some of these genes and AD in the Caucasian population; however, researches regarding these associations remain limited in the Chinese population. To systematically evaluate the associations of these genes with AD, we investigated 19 genes involved in the metabolism of Aß and tau based on previous studies selected using the PubMed database. This study included 372 patients with sporadic late-onset AD (sLOAD) and 345 cognitively healthy individuals from southern China. The results were replicated in the International Genomics of Alzheimer's Project (IGAP). Protein-protein interactions were determined using the STRING v11 database. We found that a single-nucleotide polymorphism, rs11682128, of BIN1 conferred susceptibility to sLOAD after adjusting for age, sex, and APOE ε4 status and performing the Bonferroni correction {corrected P = 0.000153, odds ratio (OR) [95% confidence interval (CI)] = 1.403 (1.079-1.824)}, which was replicated in the IGAP. Protein-protein interactions indicated that BIN1 was correlated with MAPT. Moreover, rare variants of NEP and FERMT2 (0.0026 < corrected P < 0.05), and the Aß degradation, tau pathology, and tau phosphatase pathways (0.01 < corrected P < 0.05), were nominally significantly associated with sLOAD. This study suggested that the genes involved in the metabolic pathways of Aß and tau contributed to the etiology of sLOAD in the southern Han Chinese population.

A Han Chinese Family With Early-Onset Parkinson's Disease Carrying Novel Frameshift Mutation and Compound Heterozygous Mutation of PRKN Appearing Incompatible With MDS Clinical Diagnostic Criteria.

Around 15% of patients with Parkinson's disease (PD) have a family history, and 5-10% have confirmed genetic causes. PRKN is the most common gene responsible for early-onset Parkinson's disease (EOPD), while rare variants of PLA2G6 likely raise PD susceptibility in the Chinese population. We investigated the genetic information of 13 members of a Han Chinese family with known EOPD by whole-exome sequencing and Sanger sequencing, and analyzed the clinical history, physical examination, blood laboratory test, and brain imaging data of the patients. Two members, including the proband, were suspected of having EOPD. A novel homozygous frameshift mutation, c.856delT, and a compound heterozygous mutation, c.1321T>C/c.856delT of PRKN, were identified, as well as two single nucleotide variants of PLA2G6 and TENM4. The proband exhibited a rare symmetrical resting tremor limited to her lower limbs and never exhibited signs of rigidity. 18F-DOPA PET/CT scan indicated a symmetrical reduced signaling in the striatum. The novel frameshift mutation and compound heterozygous mutation of PRKN are likely to be the genetic causes of EOPD in this family.

Association of rare variants in neurodegenerative genes with familial Alzheimer's disease.

OBJECTIVE: To investigate the impact of rare variants underlying neurodegenerative-related genes to familial Alzheimer's disease (AD). METHODS: We performed targeted sequencing of 277 neurodegenerative-related genes on probands from 75 Chinese AD families non-carrying causative mutation of dementia genes. Rare coding variants segregated in families were tested for association in an independent cohort of 506 patients with sporadic AD and 498 cognitively normal controls. East Asians data from the Exome Aggregation Consortium (ExAC) were used as a reference control. RESULTS: A novel rare variant, P410S of PLD3 was found in an early-onset AD family. LRRK2 I2012T, a causative mutation of Parkinson's disease, was identified in another early-onset AD family. Missense variants in ABCA7 (P143S and A1507T) and CR1(T239M) were significantly associated with familial AD (P = 0.005437, 0.001383, 0.000549), a missense variant in TREM2(S183C) was significantly associated with AD (P = 0.000396) when compared with the East Asian controls in ExAC database. A non-frameshift variant in FUS (G223del) was frequent in AD cases and significantly associated with familial AD (P = 0.008). INTERPRETATION: Multiple rare coding variants of causal and risk neurodegenerative genes were presented in clinically diagnosed AD families that may confer risk of AD. Our data supported that the clinical, pathological, and genetic architectures of AD, PD, and FTD/ALS may overlapping. We propose that targeted sequencing on neurodegenerative-related genes is necessary for genetically unclear AD families.

Identification of expanded repeats in NOTCH2NLC in neurodegenerative dementias.

Recently, the (GGC)n repeat expansion in the NOTCH2NLC gene has been identified to be associated with neuronal intranuclear inclusion disease (NIID). Given the clinical overlap of dementia-dominant NIID with neurodegenerative dementia, we therefore hypothesized that the NOTCH2NLC repeat expansion might also contribute to these diseases. In the present study, repeat primed polymerase chain reaction (RP-PCR) and GC-rich PCR were conducted to detect the repeats of NOTCH2NLC in a cohort of 1004 patients with neurodegenerative dementias from mainland China. As a result, 4 sporadic patients were found to carry the NOTCH2NLC repeats expansion, totally accounting for 0.4% of all dementia individuals, and the accurate repeated sizes were 110, 133,120 and 76 respectively. Of 4 mutation carriers, three and one were clinically diagnosed Alzheimer's disease (AD) and frontotemporal dementia (FTD) respectively. In addition, 3 out of them revealed leukoencephalopathy in T2-Flair imaging. This study revealed that although rare, the NOTCH2NLC repeat expansions may be associated with AD or FTD-like phenotype as well as leukoencephalopathy.

Expansion of the phenotypic spectrum of X-linked Charcot-Marie-Tooth (CMT) disease.

Charcot-Marie-Tooth (CMT) disease is the most common hereditary peripheral neuropathy. X-linked Charcot-Marie-Tooth disease in the GJB1 gene is known as CMTX1. We report a 14 years-old young man with walked unstably, bilateral strephenopodia, severe alopecia and paroxysmal bilateral upper limbs tremor without obvious muscle atrophy. Diagnostic whole-exome sequencing revealed a hemizygote missense mutation c.278 T > A in exon 2 of the GJB1 gene, with lysine at position 93 of the mature protein (p.M93K). This is the first CMT case with alopecia areata reported in the world.

Long non-coding RNA BZRAP1-AS1 silencing suppresses tumor angiogenesis in hepatocellular carcinoma by mediating THBS1 methylation.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer associated with a high mortality. Long non-coding RNAs (lncRNAs) have recently emerged as regulators in the development and progression of several cancers, and therefore represent an opportunity to uncover new targets for therapy. In the present study, we aimed to investigate the potential effect of lncRNA BZRAP1-AS1 on the angiogenesis of HCC. METHODS: Microarray-based data analysis was initially employed to screen genes and lncRNAs that are differentially expressed in HCC and the candidate BZRAP1-AS1 was identified as a hit. The expression of BZRAP1-AS1 and thrombospondin-1 (THBS1) in HCC tissues and cells were then determined using RT-qPCR. The gene methylation level was measured by methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP) assays. Next, the interactions between BZRAP1-AS1, DNA methyltransferase 3B (DNMT3b), and THBS1 were assessed by RIP, RNA pull-down and ChIP assays. Finally, the roles of BZRAP1-AS1, DNMT3b and THBS1 in angiogenesis in vitro as well as tumorigenesis in vivo were evaluated by a battery of the gain- and loss-of function experiments. RESULTS: BZRAP1-AS1 was identified as a highly expressed lncRNA in HCC tissues and cells. Down-regulation of BZRAP1-AS1 in HCC cells inhibited HUVEC proliferation, migration and angiogenesis. By interacting with DNMT3b, BZRAP1-AS1 induced methylation of the THBS1 promoter and inhibited the transcription of THBS1, resulting in promoted angiogenesis of HUVECs. Moreover, silencing of BZRAP1-AS1 repressed the angiogenesis as well as the tumor growth of HCC in vivo via up-regulating THBS1. CONCLUSION: This study provides evidence that angiogenesis in HCC is hindered by silencing of BZRAP1-AS1. Thus, BZRAP1-AS1 may be a promising marker for the treatment of HCC.

Analysis of Salivary Microbiome in Patients with Alzheimer's Disease.

Recent studies found that poor oral hygiene was associated with increased risk of dementia, and the number of oral bacteria significantly increased in the brain tissues of patients with Alzheimer's disease (AD), suggesting that the oral microbiota may play an important role in the pathogenesis of AD. However, the actual composition of oral bacteria communities in patients with AD and whether these oral bacteria are associated with disease severity remain largely unknown. Also, the APOEɛ4 polymorphism is a strong risk factor for sporadic AD, and it would be pertinent to see if the bacterial flora was different in those patients who were APOEɛ4 positive. A total of 78 subjects were recruited in this study, including 39 patients with AD and 39 healthy controls. Saliva was collected from each subject. 16S ribosomal RNA (16S rRNA) sequencing was conducted to analyze the salivary microbiota, and Sanger sequencing was performed to analyze the APOE genotype. There was a significantly lower richness and diversity of saliva microbiota detected in AD patients than healthy controls. The relative abundance of Moraxella, Leptotrichia, and Sphaerochaeta in the saliva of AD patients greatly increased, whereas that of Rothia was significantly reduced. Compared with APOEɛ4 (-) patients, the level of Abiotrophia and Desulfomicrobium was comparatively abundant, while Actinobacillus and Actinomyces decreased significantly in patients carrying the APOEɛ4. No bacteria were found to be associated with the severity of AD. This is the first study to analyze the salivary microorganisms in patients with AD, and we discovered that the composition of salivary microbiome was altered in AD, providing further support for the role of the oral microbiome in AD development.