The Phenotypic and Genotypic Spectrum of CSF1R-Related Disorder in China.

BACKGROUND: Colony-stimulating factor 1 receptor (CSF1R)-related disorder (CRD) is a rare autosomal dominant disease. The clinical and genetic characteristics of Chinese patients have not been elucidated. OBJECTIVE: The objective of the study is to clarify the core features and influence factors of CRD patients in China. METHODS: Clinical and genetic-related data of CRD patients in China were collected. Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Sundal MRI Severity Score were evaluated. Whole exome sequencing was used to analyze the CSF1R mutation status. Patients were compared between different sexes, mutation types, or mutation locations. RESULTS: A total of 103 patients were included, with a male-to-female ratio of 1:1.51. The average age of onset was (40.75 ± 8.58). Cognitive impairment (85.1%, 86/101) and parkinsonism (76.2%, 77/101) were the main clinical symptoms. The most common imaging feature was bilateral asymmetric white matter changes (100.0%). A total of 66 CSF1R gene mutants (22 novel mutations) were found, and 15 of 92 probands carried c.2381 T > C/p.I794T (16.30%). The MMSE and MoCA scores (17.0 [9.0], 11.90 ± 7.16) of female patients were significantly lower than those of male patients (23.0 [10.0], 16.36 ± 7.89), and the white matter severity score (20.19 ± 8.47) of female patients was significantly higher than that of male patients (16.00 ± 7.62). There is no statistical difference in age of onset between male and female patients. CONCLUSIONS: The core manifestations of Chinese CRD patients are progressive cognitive decline, parkinsonism, and bilateral asymmetric white matter changes. Compared to men, women have more severe cognitive impairment and imaging changes. c.2381 T > C/p.I794T is a hotspot mutation in Chinese patients. © 2024 International Parkinson and Movement Disorder Society.

Episodic Neurological Dysfunction in X-Linked Charcot-Marie-Tooth Disease: Expansion of the Phenotypic and Genetic Spectrum.

BACKGROUND AND PURPOSE: X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is characterized by peripheral neuropathy with or without episodic neurological dysfunction. We performed clinical, neuropathological, and genetic investigations of a series of patients with mutations of the gap-junction beta-1 gene (GJB1) to extend the phenotypic and genetic description of CMTX1. METHODS: Detailed clinical evaluations, sural nerve biopsy, and genetic analysis were applied to patients with CMTX1. RESULTS: We collected 27 patients with CMTX1 with GJB1 mutations from 14 unrelated families. The age at onset (AAO) was 20.9±12.2 years (mean±standard deviation; range, 2-45 years). Walking difficulties, weakness in the legs, and pes cavus were common initial symptoms. Compared with female patients, males tended to have a younger AAO (males vs. females=15.4±9.6 vs. 32.0±8.8 years, p=0.002), a longer disease course (16.8±16.1 vs. 5.5±3.8 years, p=0.034), and more-severe electrophysiological results. Besides peripheral neuropathy, six of the patients had special episodic central nervous system (CNS) evidence from symptoms, signs, and/or reversible white-matter lesions. Neuropathology revealed the loss of large myelinated fibers, increased number of regenerated axon clusters with abnormally thin myelin sheaths, and excessively folded myelin. Genetic analysis identified 14 GJB1 variants, 6 of which were novel. CONCLUSIONS: These findings expand the phenotypic and genetic spectrum of CMTX1. Although CMTX1 was found to have high phenotypic and CNS involvement variabilities, detailed neurological examinations and nerve conduction studies will provide critical clues for accurate diagnoses. Further exploration of the underlying mechanisms of connexin 32 involvement in neuropathy or CNS dysfunction is warranted to develop promising therapies.

Adult-onset neuronal intranuclear inclusion disease related retinal degeneration: a Chinese case series.

Purpose: To evaluate adult-onset neuronal intranuclear inclusion disease (NIID)-related retinopathy with guanine-guanine-cytosine repeat expansions in NOTCH2NLC. Materials and methods: Neuro-ophthalmic evaluations, including best-corrected visual acuity, slit-lamp biomicroscopy, intraocular pressure (IOP), ultrasound biomicroscopy, pupillometry, fundus photography, fundus autofluorescence (FAF), optical coherence tomography (OCT), Humphrey visual field, full-field electroretinography (ERG), and multifocal ERG (mf-ERG) were performed in patients with gene-proven NIID. Results: Nine patients (18 eyes) were evaluated, with a median age of 62 years (55-68) and only one man was included in our study. Six patients presented with decreased visual acuity or night blindness, whereas the other three were asymptomatic. The visual acuity was measured from 20/200 to 20/20. Miosis was present in eight patients, four of whom had ciliary process hypertrophy and pronation, and three of whom had shallow anterior chambers. Fundus photography, FAF, and OCT showed consistent structural abnormalities mainly started from peripapillary areas and localized in the outer layer of photoreceptors and inner ganglion cell layer. ERG and mf-ERG also revealed retinal dysfunction in the corresponding regions. Conclusion: Patients with NIID showed both structural and functional retinopathies which were unique and different from common cone-rod dystrophy or retinitis pigmentosa. Patients with miosis may have a potential risk of an angle-closure glaucoma attack. Neuro-ophthalmic evaluations is essential for evaluating patients with NIID, even without visual symptom.

Safety, pharmacokinetics and pharmacodynamics of HRS-7535, a novel oral small molecule glucagon-like peptide-1 receptor agonist, in healthy participants: A phase 1, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, and food effect trial.

AIM: To assess the safety, tolerability, pharmacokinetics (PKs) and pharmacodynamics of HRS-7535, a novel glucagon-like peptide-1 receptor agonist (GLP-1RA), in healthy participants. MATERIALS AND METHODS: This phase 1 trial consisted of single-ascending dose (SAD), food effect (FE) and multiple-ascending dose (MAD) parts. In the SAD part, participants were randomized (6:2) to receive HRS-7535 (at doses of 15, 60 and 120 mg; administered orally once daily) or placebo. In the FE part, participants were randomized (8:2) to receive a single dose of 90-mg HRS-7535 or placebo, in both fed and fasted states. In the MAD part, participants were randomized (18:6) to receive daily HRS-7535 (120 mg [30/60/90/120-mg titration scheme]) or placebo for 28 days. The primary endpoints were safety and tolerability. RESULTS: Nausea and vomiting were the most frequently reported AEs across all three parts. In the SAD part, the median Tmax was 5.98-5.99 hours and the geometric mean t1/2 was 5.28-9.08 hours across the HRS-7535 dosing range. In the MAD part, the median Tmax was 5.98-10.98 hours and the geometric mean t1/2 was 6.48-8.42 hours on day 28 in participants on HRS-7535. PKs were approximately dose-proportional. On day 29 in the MAD part, the mean (percentage) reduction in body weight from baseline was 4.38 kg (6.63%) for participants who received HRS-7535, compared with 0.8 kg (1.18%) for those participants who received a placebo. CONCLUSIONS: HRS-7535 exhibited a safety and tolerability profile consistent with other GLP-1RAs and showed PKs suitable for once-daily dosing. These findings support further clinical development of HRS-7535 for type 2 diabetes.

Relationship between mental health, sleep status and screen time among university students during the COVID-19 pandemic: a cross-sectional study.

OBJECTIVE: On 20 July 2021, after the outbreak of COVID-19 at Nanjing Lukou International Airport, several universities started closed management and online teaching. This had a large impact on students' daily life and study, which may lead to mental health problems. The purpose of this study is to study the effect of screen time on mental health status of university students and the possible mediating effect of sleep status. METHODS: This was a cross-sectional study. A web-based questionnaire survey was employed that included demographic characteristics, sleep status and mental health status (depression, anxiety and loneliness). The Pittsburgh Sleep Quality Index scale was used to assess sleep status, while the Centre for Epidemiologic Studies Depression (CES-D) scale, Generalised Anxiety Disorder-7 (GAD-7) scale and Emotional versus Social Loneliness Scale (ESLS) were used to assess depression, anxiety and loneliness, respectively. Linear and logistic regression models were developed and adjusted for confounding factors, and finally the mediating effects were tested using the Karlson-Holm-Breen method. RESULTS: Finally, 1070 valid questionnaires were included. Among these, 604 (56.45%) indicated depressive symptoms (CES-D score ≥16) and 902 (84.30%) indicated anxiety symptoms (GAD-7 score ≥10). The mean ESLS score (for loneliness) was 26.51±6.64. The relationship between screen time and depressive symptoms (OR 1.118, 95% CI 1.072 to 1.166) and anxiety symptoms (OR 1.079, 95% CI 1.023 to 1.138) remained significant after adjusting for confounding factors. Meanwhile, sleep status plays an intermediary role in screen time and mental health status (depression and anxiety) and accounts for 13.73% and 19.68% of the total effects, respectively. We did not find a significant association between screen time and loneliness. CONCLUSION: During the outbreak of COVID-19, screen time is inevitably prolonged among university students. There is a relationship between mental health and screen time, and sleep status plays a mediating role.

Nose-to-brain translocation and nervous system injury in response to indium tin oxide nanoparticles of long-term low-dose exposures.

Indium tin oxide (ITO) is a semiconductor nanomaterial with broad application in liquid crystal displays, solar cells, and electrochemical immune sensors. It is worth noting that, with the gradual increase in worker exposure opportunities, the exposure risk in occupational production cannot be ignored. At present, the toxicity of ITO mainly focuses on respiratory toxicity. ITO inhaled through the upper respiratory tract can cause pathological changes such as interstitial pneumonia and pulmonary fibrosis. Still, extrapulmonary toxicity after nanoscale ITO nanoparticle (ITO NPs) exposure, such as long-term effects on the central nervous system, should also be of concern. Therefore, we set up exposure dose experiments (0 mg·kg-1, 3.6 mg·kg-1, and 36 mg·kg-1) based on occupational exposure limits to treat C57BL/6 mice via nasal drops for 15 weeks. Moreover, we conducted a preliminary assessment of the neurotoxicity of ITO NPs (20-30 nm) in vivo. The results indicated that ITO NPs can cause diffuse inflammatory infiltrates in brain tissue, increased glial cell responsiveness, abnormal neuronal cell lineage transition, neuronal migration disorders, and neuronal apoptosis related to the oxidative stress induced by ITO NPs exposure. Hence, our findings provide useful information for the fuller risk assessment of ITO NPs after occupational exposure.

The Association between Circulating Lipids and Female Infertility Risk: A Univariable and Multivariable Mendelian Randomization Analysis.

BACKGROUND: Although observational studies have demonstrated that blood lipids are associated with female infertility, the causality of this association remains unclear. We performed a univariable and multivariable Mendelian randomization (MR) analysis to evaluate the causal relationship between blood lipids and female infertility. METHODS: Single-nucleotide polymorphisms associated with lipid traits in univariate analysis were obtained from the Million Veteran Program (MVP) and Global Lipids Genetics Consortium (GLGC), involving up to 215,551 and 188,577 European individuals, respectively. Blood lipids in multivariate analysis were obtained from the latest genome-wide association study meta-analysis with lipid levels in 73 studies encompassing >300,000 participants. Data on female infertility were obtained from the FinnGen Consortium R6 release, which included 6481 samples and 75,450 controls. Subsequently, MR analysis was performed using inverse variance-weighted (IVW), weighted median, weighted-mode, simple-mode and MR-Egger regression to demonstrate the causal relationship between lipids and female infertility. RESULTS: After controlling confounding factors including body mass index and age at menarche, two-sample MR demonstrated that genetically predicted LDL-C and TC were causally associated with the risk of female infertility (When the genetic instruments come from the MVP database, LDL-C and female infertility, IVW OR: 1.13, 95% CI: 1.001-1.269, p = 0.047; TC and female infertility, IVW OR: 1.16, 95% CI: 1.018-1.317, p = 0.025, and when the genetic instruments came from the GLGC database, LDL-C and female infertility, IVW OR: 1.10, 95% CI: 1.008-1.210, p = 0.033; TC and female infertility, IVW OR: 1.14, 95% CI: 1.024-1.258, p = 0.015). However, the IVW estimate showed that HDL-C was not significantly associated with the risk of female infertility (when the genetic instruments came from the MVP database, IVW OR: 1.00, 95% CI: 0.887-1.128, p = 0.999; when the genetic instruments came from the GLGC database, IVW OR: 1.00, 95% CI: 0.896-1.111, p = 0.968). The multivariable MR analysis also provided evidence that LDL-C (OR: 1.12, 95% CI: 1.006-1.243, p = 0.042) was significantly associated with the risk of female infertility after considering the correlation of all lipid-related traits. CONCLUSION: These findings support a causal relationship between increased LDL-cholesterol and increased female infertility risk. Furthermore, the association between lipid-related traits and female infertility risk merits more studies.

Shearing-enhanced mechanical exfoliation with mild-temperature pretreatment for cathode active material recovery from spent LIBs.

The conventional approaches for recovering valuable metals from spent lithium-ion batteries (LIBs) suffer from heavy dependence on chemical reagents, high energy consumption, and low recovery efficiencies. In this study, we developed a shearing-enhanced mechanical exfoliation combined with mild-temperature pretreatment (SMEMP) method. The method achieves high-efficiency exfoliation of the cathode active materials that remain strongly adhered to polyvinylidene fluoride after it melts during mild pretreatment. The pretreatment temperature was decreased from 500-550 °C to 250 °C, the duration was decreased to 1/4-1/6 of the traditional pretreatment duration, and the exfoliation efficiency and product purity reached 96.88% and 99.93%, respectively. Despite the weakening thermal stress, the cathode materials could be exfoliated by strengthened shear forces. Compared with other traditional methods, the superiority of this method in temperature reduction and energy saving was established. The proposed SMEMP method is environmentally friendly and economical, and it offers a new route for the recovery of cathode active materials from spent LIBs.

Elevated serum uric acid is associated with infertility in women living in America.

Excessive uric acid levels may affect several organs and systems in the body. There is limited evidence of the effects of high serum uric acid levels on the female reproductive system. This study used the National Health and Nutrition Examination Survey (NHANES) database to explore the relationship between serum uric acid and female infertility. This cross-sectional study included a total of 2197 eligible subjects using data from NHANES 2013-March 2020 pre-pandemic data. Self-reported infertility (ever experiencing an inability to conceive after 12 months of trying to become pregnant) was the main outcome. Logistic regression models and restricted cubic spline were used to analyze the relationship between serum uric acid and female infertility, and stratified analysis was carried out. A total of 295 women self-reported infertility (13.43%). The median uric acid level for all study subjects was 4.4 mg/dL (interquartile range [IQR]: 3.7, 5.1). Serum uric acid levels were higher in the infertility group than in the control group (4.7 mg/dL [IQR: 4.0, 5.3] vs. 4.4 mg/dL [IQR: 3.7, 5.1], P < 0.001). After adjusting for age, race, marital status, smoking, alcohol, history of pregnancy, history of diabetes, history of hypertension, fasting glucose, total cholesterol, creatinine in refrigerated serum, low-density lipoprotein cholesterol, direct high-density lipoprotein cholesterol, glycohemoglobin, and body mass index confounders, women with serum uric acid levels at Q3 (4.4-5.1 mg/dL) had a 73% (odds ratio [OR] = 1.73, 95% confidence interval [CI] 1.18, 2.54, P = 0.005) higher risk of infertility, and women with uric acid levels at Q4 (5.1-18.0 mg/dL) had an 83% (OR = 1.83, 95% CI 1.22, 2.75, P = 0.003) increased risk of infertility compared to women at Q1 (1.6-3.7 mg/dL). The restricted cubic spline also showed that when serum uric acid levels exceeded the reference value, the risk of infertility gradually increased. We also performed a sensitivity analysis based on the complete dataset and found that the results were robust. Higher serum uric acid levels were significantly associated with an increased risk of female infertility. Women planning a pregnancy should have increased serum uric acid monitoring.

TNF-α contributes to sarcopenia through caspase-8/caspase-3/GSDME-mediated pyroptosis.

Sarcopenia has become a leading cause of disability and mortality in the elderly. It has been reported that programmed cell death (PCD) is associated with the development of sarcopenia that is characterized by reduction of muscle fiber size and number. TNF-α is also validated to play a prominent role in sarcopenia through its complex signaling pathways including cell death signaling. However, it is still unclear whether TNF-α contributes to sarcopenia by mediating pyroptosis, one type of PCD. Here, we first established naturally aged mice with sarcopenia model and confirmed an inflammatory state represented by TNF-α in aged mice. Evidence of GSDME-mediated pyroptosis and activation of apoptotic caspase-8/-3 were also found in skeletal muscle cells of aged mice with sarcopenia. We demonstrated that TNF-α triggered GSDME-mediated pyroptosis in myotubes through activating caspase-8 and caspase-3 by using caspase-8 and caspase-3 inhibitors. Comparing the activation of caspase-8 and GSDME expression between TNF Complex IIa and TNF Complex IIb, TNF-α was found to be more inclined to assemble TNF Complex IIb in activating caspase-8 and triggering pyroptosis. Moreover, pyroptotic myotubes were validated to result in decreased expression of MHC1 and finally loss of myotubes by knockdown of GSDME. Our work reveals a novel mechanism that TNF-ɑ/caspase-8/caspase-3/GSDME signaling-mediated pyroptosis contributes to the development of sarcopenia. Caspase-3/GSDME signaling-mediated pyroptosis may be a promising therapeutic target for sarcopenia.

LC-MS/MS determination of HY072808, a novel candidate for treating atopic dermatitis, and its active metabolite: Application to a first-in-human pharmacokinetic study.

HY072808 is a novel phosphodiesterase 4 inhibitor currently under clinical development to treat atopic dermatitis. The first step is to address the pharmacokinetics and safety after topical administration of HY072808 ointments in healthy humans. In this study, we developed a highly sensitive liquid chromatography-tandem mass spectrometry method to determine plasma HY072808 and its active metabolite, ZZ24, in tiny amounts. The plasma samples were prepared using a simple liquid-liquid extraction method. Liquid chromatographic separation was achieved by gradient elution. The MS/MS quantification was performed in positive ion mode via multiple reaction monitoring. The method showed satisfactory linearity from 10 to 4,000 pg/ml for HY072808 and ZZ24. There was no significant interference from blank plasma. The method was validated for accuracy and precision, matrix effect and extraction recovery, dilution integrity, injection carryover and stability according to the related guidelines of the regulatory authorities. The HY072808 and ZZ24 concentrations in human plasma from a clinical trial were determined using this method. In conclusion, the validated method was robust and could be utilized to support the clinical development of HY072808.

The effects of perfluoroalkyl and polyfluoroalkyl substances on female fertility: A systematic review and meta-analysis.

OBJECTIVE: The reproductive toxicity of perfluoroalkyl and polyfluoroalkyl substances (PFAS) has been verified in both animal and in vitro experiments, however, the association between PFAS and female fertility remains contradictory in population studies. Therefore, in this systematic review and meta-analysis, we evaluated the effects of PFAS on female fertility based on population evidence. METHODS: Electronic searches of the Web of Science, PubMed, The Cochrane Library, and Embase databases were conducted (from inception to March 2022) to collect observational studies related to PFAS and female fertility. Two evaluators independently screened the literature, extracted information and evaluated the risk of bias for the included studies, meta-analysis was performed using R software. RESULTS: A total of 5468 records were searched and 13 articles fully met the inclusion criteria. Meta-analysis showed that perfluorooctanoic acid (PFOA) exposure was negatively associated with the female fecundability odds ratio (FOR = 0.88, 95% confidence interval (Cl) [0.78; 0.98]) and positively associated with the odds ratio for infertility (OR = 1.33, 95%Cl [1.03; 1.73]). Perfluorooctane sulfonate (PFOS) exposure was negatively associated with the fecundability odds ratio (FOR = 0.94, 95% CI [0.90; 0.98]). Pooled effect values for perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluorohexane sulfonate (PFHxS) exposure did not find sufficient evidence for an association with female fertility. CONCLUSION: Based on the evidence provided by the current study, increased levels of PFAS exposure are associated with reduced fertility in women, this was characterized by a reduction in fecundability odds ratio and an increase in odds ratio for infertility. This finding could partially explain the decline in female fertility and provide insight into risk assessment when manufacturing products containing PFAS.

Trends and prospects in graphene and its derivatives toxicity research: A bibliometric analysis.

The purpose of this paper is to explore the current research status, hot topics, and future prospects in the field of graphene and its derivatives toxicity. In the article, the Web of Science Core Collection database was used as the data source, and the CiteSpace and VOSviewer were used to conduct a visual analysis of the last 10 years of research on graphene and its derivatives toxicity. A total of 8573 articles were included, and we analyzed the literature characteristics of the research results in the field of graphene and its derivatives toxicity, as well as the distribution of authors and co-cited authors; the distribution of countries and institutions; the situation of co-cited references; and the distribution of journals and categories. The most prolific countries, institutions, journals, and authors are China, the Chinese Academy of Sciences, RSC Advances, and Wang, Dayong, respectively. The co-cited author with the most citations was Akhavan, Omid. The five research hotspot keywords in the field of graphene and its derivatives toxicity were "nanomaterials," "exposure," "biocompatibility," "adsorption," and "detection." Frontier topics were "facile synthesis," "antibacterial activity," and "carbon dots." Our study provides perspectives for the study of graphene and its derivatives toxicity and yields valuable information and suggestions for the development of graphene and its derivatives toxicity research in the future.

Effects of physical activity and sleep duration on fertility: A systematic review and meta-analysis based on prospective cohort studies.

Objective: Subfertility is a common problem for couples in modern society. Many studies have confirmed that lifestyle factors can affect fertility although there are conflicting conclusions relating to the effects of physical activity and sleep duration on fertility. In this study, we aimed to summarize and analyze the available evidence. Methods: PubMed, Web of Science, Cochrane, and Embase databases (as of October 14, 2022) were systematically searched for eligible prospective cohort studies. Data were extracted and effect values were combined. We also performed methodological quality and bias risk assessments for all the included studies. Results: A total of 10 eligible articles were included in our analysis; seven investigated the relationship between physical activity and fertility, and three investigated the effect of sleep duration on fertility. Compared with the lowest level of physical activity, high intensity physical activity (the highest levels of physical activity) was negatively correlated with fertility [odds ratio (OR) = 0.84; 95% confidence interval (CI): 0.70, 1.00, I 2 = 64%]. However, we did not find an association between moderate intensity physical activity and fertility (OR = 1.09; 95% CI: 0.98, 1.22, I 2 = 60%). We observed an inverse association between limited sleep duration (≤ 7 h) and fertility (OR = 0.92; 95% CI: 0.84, 1.00, I 2 = 0%) compared with 8 h of sleep. The relationship between long sleep duration (≥9 h) and fertility was not statistically significant (OR = 0.85; 95% CI: 0.60, 1.21, I 2 = 83%). According to the Newcastle-Ottawa Scale score, the overall quality of the research articles included was ranked as medium to high (6-9). Through GRADE system, the quality of evidence for the impact of high intensity physical activity and limited sleep duration on fertility was moderate, while the quality of evidence for the impact of moderate intensity physical activity and long sleep duration on fertility was low. Conclusion: The current evidence shows that high intensity physical activity and limited sleep time are negatively related to fertility. But there was great heterogeneity among studies, and the quality of research evidence was low to median. Thus, further high-quality research is needed to confirm this conclusion. PROSPERO registration number: CRD42022298137.

Changes of factors associated with vaccine hesitancy in Chinese residents: A qualitative study.

Introduction: There is an urgent need to address vaccine hesitancy to achieve booster vaccination. This study aimed to reveal the factors associated with vaccine hesitancy (including COVID-19 vaccine) among Chinese residents, address modifications of the factors since the previous year, and propose vaccination rate improvement measures. Materials and methods: This qualitative return visit study was performed between January and mid-February 2022, following the last interview conducted between February and March 2021. According to an outline designed in advance, 60 Chinese residents from 12 provinces participated in semi-structured interviews. Results: Vaccine safety was the biggest concern raised by respondents, followed by self-immunity and vaccine effectiveness, eliciting concern since the interview last year. Notably, online media accounted for a more significant portion of suggestion sources than before, and fear of pain was a novel factor affecting vaccine hesitancy. Moreover, unlike other areas, those from provinces with a per capita gross domestic product of 3-5 (RMB 10,000) reported less concern about vaccine price and effectiveness. They tended to seek advice via online media less and were greatly influenced by vaccination policies. Conclusions: Influential factors of vaccine hesitancy among Chinese residents are changing dynamically. Monitoring these trends is essential for public health measures and higher vaccination levels.

DNA hypermethylation of NOTCH2NLC in neuronal intranuclear inclusion disease: a case-control study.

BACKGROUND: GGC repeat expansions in NOTCH2NLC gene have been recently proposed to cause neuronal intranuclear inclusion disease (NIID) via prevailing gain-of-function mechanism (protein and RNA toxicity). Nevertheless, increasing evidences suggest that epigenetics can also play a role in the pathogenesis of repeat-mediated disorders. METHODS: In this study, using MethylTarget sequencing, we performed a quantitative analysis of the methylation status of 68 CpG sites located around the NOTCH2NLC promoter in 25 NIID patients and 25 age- and gender-matched healthy controls. We further explored the correlation of DNA methylation (DNAm) status with disease features and performed receiver operating characteristic (ROC) analysis. RESULTS: DNAm levels of GGC repeats and adjacent CpG islands were higher in the NIID patients than in controls, independent of gender and family history. DNAm levels at 4 CpG sites (CpG_207, CpG_421, GpG_473 and CpG_523) were negatively correlated with age at onset, and DNAm levels at 7 CpG sites (CpG_25, CpG_298, CpG_336, CpG_374, CpG_411, CpG_421 and CpG_473) were positively correlated with GGC repeats. NIID patients had concomitant system symptoms besides nervous system symptoms, and negative correlations between NOTCH2NLC DNAm levels and the number of multi-systemic involvement were observed in the study. The area under the ROC curve at NOTCH2NLC DNAm level reached to 0.733 for the best cutoff point of 0.012. CONCLUSIONS: Our findings suggested the aberrant DNAm status of the NOTCH2NLC promoter in NIID, and we explored the link between DNAm levels and disease features quantitatively for the first time, which may help to further explore pathogenic mechanism.

Altered intrinsic brain activity in patients with CSF1R-related leukoencephalopathy.

CSF1R-related leukoencephalopathy is an adult-onset white matter disease with high disability and mortality, while little is known about its pathogenesis. This study introduced amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) based on resting-state functional magnetic resonance imaging(rsfMRI) to compare the spontaneous brain activities of patients and healthy controls, aiming to enhance our understanding of the disease. RsfMRI was performed on 16 patients and 23 healthy controls, and preprocessed for calculation of ALFF and ReHo. Permutation tests with threshold free cluster enhancement (TFCE) was applied for comparison (number of permutations = 5,000). The TFCE significance threshold was set at [Formula: see text] < 0.05. In addition, 10 was set as the minimum cluster size. Compared to healthy controls, the patient group showed decreased ALFF in right paracentral lobule, and increased ALFF in bilateral insula, hippocampus, thalamus, supramarginal and precentral gyrus, right inferior, middle and superior frontal gyrus, right superior and middle occipital gyrus, as well as left parahippocampal gyrus, fusiform, middle occipital gyrus and angular gyrus. ReHo was decreased in right supplementary motor area, paracentral lobule and precentral gyrus, while increased in right superior occipital gyrus and supramarginal gyrus, left parahippocampal gyrus, hippocampus, fusiform, middle occipital gyrus and angular gyrus, as well as bilateral middle occipital gyrus and midbrain. These results revealed altered spontaneous brain activities in CSF1R-related leukoencephalopathy, especially in limbic system and motor cortex, which may shed light on underlying mechanisms.

Synthesis and bioactivities evaluation of oleanolic acid oxime ester derivatives as α-glucosidase and α-amylase inhibitors.

Different oleanolic acid (OA) oxime ester derivatives (3a-3t) were designed and synthesised to develop inhibitors against α-glucosidase and α-amylase. All the synthesised OA derivatives were evaluated against α-glucosidase and α-amylase in vitro. Among them, compound 3a showed the highest α-glucosidase inhibition with an IC50 of 0.35 µM, which was ∼1900 times stronger than that of acarbose, meanwhile compound 3f exhibited the highest α-amylase inhibitory with an IC50 of 3.80 µM that was ∼26 times higher than that of acarbose. The inhibition kinetic studies showed that the inhibitory mechanism of compounds 3a and 3f were reversible and mixed types towards α-glucosidase and α-amylase, respectively. Molecular docking studies analysed the interaction between compound and two enzymes, respectively. Furthermore, cytotoxicity evaluation assay demonstrated a high level of safety profile of compounds 3a and 3f against 3T3-L1 and HepG2 cells.HighlightsOleanolic acid oxime ester derivatives (3a-3t) were synthesised and screened against α-glucosidase and α-amylase.Compound 3a showed the highest α-glucosidase inhibitory with IC50 of 0.35 µM.Compound 3f presented the highest α-amylase inhibitory with IC50 of 3.80 µM.Kinetic studies and in silico studies analysed the binding between compounds and α-glucosidase or α-amylase.

Expanding the clinical spectrum of adult-onset neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a heterogeneous neurodegenerative disease with multiple clinical subtypes. Recent breakthroughs on neuroimaging, skin biopsy and genetic testing have facilitated the diagnosis. We aim to investigate the clinical characteristics of Chinese NIID patients to further refine the spectrum. We analyzed the clinical features of 25 NIID patients from 24 unrelated families and performed skin biopsy and/or sural nerve biopsy on 24 probands. Repeat-primed PCR and fluorescence amplicon length PCR were conducted to detect GGC repeats of NOTCH2NLC. Onset age ranged from 24 to 72 years old, and the disease duration ranged from 12 h to 25 years with the mode of onset characterized as acute, recurrent or chronic progressive type. Tremor was a common phenotype, often observed in the early stages, next to dementia and paroxysmal encephalopathy. Symptoms infrequently reported such as oromandibular dystonia, recurrent vomiting, dizziness and headache of unknown origin, as well as pure peripheral neuropathy were also suggestive of NIID. Reversible leukoencephalopathy following encephalitic episodes and the absence of apparent DWI abnormality were noticed. Two genetically confirmed NIID patients failed to be identified intranuclear inclusions, and one patient was simultaneously found significant mitochondrial swelling and fingerprint profiles depositing in lysosomes. All the patients were identified abnormal GGC repeats of NOTCH2NLC. We identify some atypical clinicopathological features and consider that pathological examinations combined with genetic testing is the gold standard for diagnosis. Whether lysosomal and mitochondrial dysfunction is involved in the pathogenesis of NIID deserves further study.