Novel ATF6 homozygous variant in a Chinese patient with achromatopsia.

BACKGROUND: ATF6-associated Achromatopsia (ACHM) is a rare autosomal recessive disorder characterized by reduction of visual acuity, photophobia, nystagmus, and poor color vision. METHODS: Detailed ophthalmological examinations were performed in a Chinese patient with ACHM. Whole exome sequencing and Sanger sequencing were performed to detect the disease-causing gene in the patient. RESULTS: A 6-year-old girl presented photophobia, low vision and reduced color discrimination. Small yellow lesion in the macula of both eyes was observed. FAF demonstrated hypofluorescence in the macular fovea. OCT images revealed interruption of ellipsoid and interdigitation zone in the foveal area and a loss of the foveal pit. ERG showed relatively normal rod responses and unrecordable cone responses. Sequencing result identified a novel splicing variant c.354 + 6T>C in the ATF6 gene (NM_007348.4). CONCLUSIONS: We reported detailed clinical features and genetic analysis of a new Chinese ATF6-associated patient with ACHM.

Influence of Coal-Fired Fly Ash on Measurement Error of NO2 Electrochemical Sensors.

To overcome the limitations of NO2 electrochemical sensors, including their inaccurate measurements and short working life, when used around coal-fired power plants, we investigated the influence of coal-fired fly ash deposition on the measurement error of NO2 electrochemical sensors through experimental tests. The morphological characteristics and pellet diameter distribution of coal-fired fly ash pellets were determined via scanning electron microscopy. The sedimentation velocity of coal-fired fly ash pellets in the air was determined through theoretical calculations of aerodynamics and hydrodynamics. Additionally, the effect of the deposition of coal-fired fly ash on the measurement error of NO2 electrochemical sensors was determined through experimental tests. The test results show that the minimum and maximum measurement errors of the NO2 electrochemical gas sensor were 8.015% and 30.35%, respectively, after a deposition duration of 30 days with 30 mg/m3 coal-fired fly ash. This demonstrates that coal-fired fly ash deposition is the cause of the inaccurate measurements and short working life of these sensors. Coal-fired fly ash causes a decrease in the gas diffusion area of the sensor and the diffusion coefficient, thus increasing the sensor measurement error.

Visualized sensing of erythritol using a simple enzyme-free catechol-based hydrogel film.

Based on the versatile properties of bio-derived materials, non-enzymatic assays in combination with electronic devices have attracted increasing interest. Here, we report a novel enzyme-free visualization approach for the detection of erythritol, which is a zero-calorie natural sweetener and serves as an ideal sucrose substitute for diabetics or overweight people who need sugar control. The recognition element of the electrochemical biosensor was constructed by catechol modification on a chitosan-based hydrogel film. The signal transduction was achieved by the competitive binding assay of sweeteners. The results show that 2-fluorophenylboronic acid (FPBA) can form a cyclic boronate ester with the ortho-hydroxyls of both reduced catechol and oxidized quinone, impeding the electron transfer and leading to redox signal attenuation. The addition of sweeteners caused a competitive reaction resulting in bonding between the 1,2-diols and FPBA moieties, and in the recovery of the redox signals. Importantly, the pattern of redox signal changes of catechol can be detected optically, as the oxidized quinone state is darker in color than the reduced catechol state. Using a simple cell phone imaging application, we demonstrate that erythritol can be distinguished from other sweeteners in real samples using the oxidized catechol-Chit0/agarose hydrogel film. Thus, we envision that this method could allow diabetics and people who need to control their sugar intake to detect whether the product contains only erythritol in the field or at home. In addition, this work further illustrates the potential of bio-derived materials for performing redox-based functions and enzyme-free visualization assays.

Clinical and genetic characterization of a large cohort of Chinese patients with Bietti crystalline retinopathy.

PURPOSE: To investigate the clinical and genetic characteristics for a large cohort of Chinese patients with Bietti crystalline retinopathy (BCR). METHODS: A total of 208 Chinese BCR patients from 175 families were recruited. Comprehensive clinical evaluations and genetic analysis were performed. Genotype-phenotype correlations were evaluated through statistical analysis. RESULTS: The patients' median age was 37 years (range, 20-76 years). The median best corrected visual acuity (BCVA) was 0.8 LogMAR unit (range, 2.8 to -0.12). A significant decline of BCVA was revealed in patients over 40 years old (P<0.001). Two clinical types were observed: peripheral type (type P) and central type (type C). Significantly more type C patients had a worse central visual acuity, but a more preserved retinal function (P<0.05). Molecular screening detected biallelic CYP4V2 pathogenic variants in 98.3% (172/175) of the families, including 19 novel ones. The most frequent pathogenic variant was c.802-8_810del17insGC, with the allele frequency of 55.7% (195/350), followed by c.992A>C (28/350, 8%) and c.1091-2A>G (23/350, 6.6%). BCR patients with one c.802-8_810del17insGC and one truncating variant (IVS6-8/Tru) had BCVA>1.3 LogMAR unit (Snellen equivalent<20/400) at a younger age than those with homozygous c.802-8_810del17insGC variants (homo IVS6-8) (P=0.031). CONCLUSIONS: BCR patients preserved relatively good vision before 40 years old. Two distinct clinical types of BCR were observed. BCR patients with IVS6-8/Tru had an earlier decline in visual acuity than those with homo IVS6-8. Our findings enhance the knowledge of BCR and will be helpful in patient selection for gene therapy.

A Causal Role of Right Temporoparietal Junction in Prosocial Learning: A Transcranial Direct Current Stimulation Study.

Prosocial behavior is a common and important aspect of everyday social life. To behave prosocially, we need to learn the consequences of our actions for other people, known as prosocial learning. Previous studies have identified the right temporoparietal junction (rTPJ) as the critical neurological substrate for prosocial behavior. However, little is known about the causal role of the rTPJ in prosocial learning. To clarify the role of the rTPJ in prosocial learning, we used a reinforcement learning paradigm and transcranial direct current stimulation (tDCS). A total of 75 participants were recruited and randomly assigned to the anodal or sham tDCS group. While receiving tDCS stimulation over the rTPJ, participants were instructed to choose between different stimuli that were probabilistically associated with rewards for themselves in the self-learning condition or for another person in the prosocial-learning condition. Participants were able to learn to obtain rewards for themselves or others, and learning performance in the self-learning condition was better than that in the prosocial-learning condition. However, anodal tDCS over the rTPJ significantly improved learning performance in the prosocial-learning condition. These results indicate that the rTPJ plays a causal role in prosocial learning.

Effects of Intestinal M Cells on Intestinal Barrier and Neuropathological Properties in an AD Mouse Model.

Intestinal microfold cells (M cells) play a critical role in the immune response of the intestinal mucosa by actively taking up antigens, facilitating antigen presentation to immune cells, and promoting the production of secretory immunoglobulin A by B cells. Despite their known important functions in the gut, the effect of M cells on the central nervous system remains unclear. We investigated the expression of M cell-related factor genes and protein levels in Peyer's patches (PPs) of 3-month-old and 9-month-old APP/PS1 mice, as well as the expression of intestinal barrier proteins in the ileum and colon of these mice. Furthermore, we employed intestinal M cell conditional ablation mice (i.e., RankΔIEC mice) to assess the influence of M cells on the intestinal barrier and Alzheimer's disease (AD)-like behavioral and pathological features. Our findings revealed that compared to wild-type mice, APP/PS1 mice showed altered M cell-related genes and disrupted intestinal barriers. In addition, there is a significant decrease in glycoprotein 2 (GP2) mRNA levels in the PPs of 3-month-old APP/PS1 mice, with the relative expression of GP2 mRNA tending to zero. Parameters related to the intestinal barrier (IgA, MUC2, Claudin-5, ZO-1) were significantly downregulated in both 3-month-old and 9-month-old APP/PS1 mice compared to wild-type controls, and the differences were more pronounced in the 9-month-old mice. Moreover, M cell ablation in APP/PS1 mice (i.e., APP/PS1ΔMC mice) resulted in more severe intestinal barrier destruction. Notably, we observed through water maze experiments that APP/PS1ΔMC mice at 6 months of age exhibited significantly poorer spatial learning memory compared to APP/PS1 mice. And the neuropathological alterations were also observed in APP/PS1ΔMC mice at 6 months of age that when intestinal M cells are damaged in APP/PS1 mice, brain microglia are activated, Tau phosphorylation is exacerbated, and the number of neurons is reduced. Our results suggest for the first time that the absence of intestinal M cells might further aggravate intestinal leakage, lead to neuropathological damage, and subsequently cause the impairment of learning memory ability in AD mice. Our research highlights the impact of intestinal M cells on the intestinal barrier and AD neuropathogenesis in AD mouse model.

Structural variants involved in high-altitude adaptation detected using single-molecule long-read sequencing.

Structural variants (SVs), accounting for a larger fraction of the genome than SNPs/InDels, are an important pool of genetic variation, enabling environmental adaptations. Here, we perform long-read sequencing data of 320 Tibetan and Han samples and show that SVs are highly involved in high-altitude adaptation. We expand the landscape of global SVs, apply robust models of selection and population differentiation combining SVs, SNPs and InDels, and use epigenomic analyses to predict enhancers, target genes and biological functions. We reveal diverse Tibetan-specific SVs affecting the regulatory circuitry of biological functions, including the hypoxia response, energy metabolism and pulmonary function. We find a Tibetan-specific deletion disrupts a super-enhancer and downregulates EPAS1 using enhancer reporter, cellular knock-out and DNA pull-down assays. Our study expands the global SV landscape, reveals the role of gene-regulatory circuitry rewiring in human adaptation, and illustrates the diverse functional roles of SVs in human biology.

Anomaly Detection of Wind Turbine Driveline Based on Sequence Decomposition Interactive Network.

Aimed at identifying the health state of wind turbines (WTs) accurately by using the comprehensive spatio and temporal information from the supervisory control and data acquisition (SCADA) data, a novel anomaly-detection method called decomposed sequence interactive network (DSI-Net) is proposed in this paper. Firstly, a DSI-Net model is trained using preprocessed data from a healthy state. Subsequences of trend and seasonality are obtained by DSI-Net, which can dig out underlying features both in spatio and temporal dimensions through the interactive learning process. Subsequently, the trained model processes the online data and calculates the residual between true values and predicted values. To identify anomalies of the WTs, the residual and root mean square error (RMSE) are calculated and processed by exponential weighted moving average (EWMA). The proposed method is validated to be more effective than the existing models according to the control experiments.

Intestinal Barrier Function and Neurodegenerative Disease.

Neurodegenerative diseases are caused by the loss of neurons and/or their myelin sheaths, which deteriorate over time and become dysfunctional. Alzheimer's disease, Parkinson's disease, and multiple sclerosis are among the most prominent neurodegenerative diseases that affect millions of older adults worldwide. Despite extensive research over several decades, controversies still surround the etiology of neurodegenerative diseases, and many of them remain incurable. Meanwhile, an increasing number of new mechanistic studies related to the microbiota-gut-brain axis have emerged, among which the relationship between the function of the intestinal barrier and neurodegenerative diseases has received widespread attention. As one of the first lines of defense between the body and the external environment, the impaired function of the intestinal barrier is closely related to the development of neurodegenerative pathologies. Among them, the microbiota-gut-brain axis disorder characterized by intestinal barrier disruption mainly includes impaired function of the intestinal microbial barrier, chemical barrier, mechanical barrier, and immune barrier. This review focuses on the structure and molecular mechanisms of the various layers of the intestinal barrier as well as their relationship with neurodegenerative lesions. In recent years, intestinal barrier repair therapies have provided new ideas for the studied disease treatment modalities. We believe that a better understanding of the role of the intestinal barrier in neurodegenerative diseases would provide new insights for the development of viable therapeutic strategies for patients.

Increased neural activity of right temporo-parietal junction causes different effect on altruism in situations of advantageous and disadvantageous inequity.

Altruism is defined as the performance of "costly acts that confer economic benefits on other individuals", which is one of the major puzzles in the behavioural sciences today. Altruistic behaviour not only facilitates interpersonal adaptation and harmony but also enhances social welfare and social responsibility. The right temporo-parietal junction (rTPJ) has been proposed as playing a key role in guiding human altruistic behaviour, but its precise functional contribution to altruistic behaviour in situations of advantageous and disadvantageous inequity remains unclear. The purpose of this study was to modulate the activation of the rTPJ through transcranial direct current stimulation (tDCS) in order to clarify the causal role of the rTPJ in altruistic behaviour in situations of advantageous and disadvantageous inequity. A total of 106 participants were randomly assigned to one of three stimulation conditions: anodal tDCS stimulation on the rTPJ; sham tDCS stimulation on the rTPJ and anodal tDCS stimulation on the primary visual cortex (VC)as the control group, and. After 20 min of stimulation, participants undertook a modified dictator game that measured altruistic behaviour. Mixed-effect logistic regressions were applied to statistical analyses in this study. The results indicated that anodal tDCS over the rTPJ increased participants' altruistic tendency by increasing their tendency to choose altruistic options in trials with higher cost, as well as their tendency to behave altruistically in situations of advantageous but not disadvantageous inequity. These results suggested that increased neural activity of the rTPJ leads to different impacts on altruism in these two different inequity situations.

Molecular dynamics study on thermal conductance between a nanotip and a substrate under vertical forces and horizontal sliding.

The heat transfer between a nanotip and its substrate is extremely complex but is a key factor in determining the measurement accuracy in tip-assisted nanomanufacturing and thermometry. In this work, the heat transfer from the nanotip to the substrate during sliding is investigated using molecular dynamics simulations. Interfacial interaction and bond formation are analyzed during the sliding process. The results show that the increase of vertical force would greatly improve the interface thermal conductance between the nanotip and the substrate. It is found that more bonds are formed and there are larger contact areas at the interface. In addition, we found that the thermal conductivity of the nanotip is another obstacle for heat transfer between the tip and substrate and it is greatly limited by the nanotip diameter near contact which is close to or even smaller than the phonon mean free path. Meanwhile, the dynamic formation and breakage of the covalent bonds during the sliding could gradually smoothen the tip apex and enhance the thermal transport at the interface. This work provides guidance for the thermal design of a nanotip-substrate system for nanoscale thermal transport measurements.

Chitosan-Based Hydrogels for Bioelectronic Sensing: Recent Advances and Applications in Biomedicine and Food Safety.

Due to the lack of efficient bioelectronic interfaces, the communication between biology and electronics has become a great challenge, especially in constructing bioelectronic sensing. As natural polysaccharide biomaterials, chitosan-based hydrogels exhibit the advantages of flexibility, biocompatibility, mechanical tunability, and stimuli sensitivity, and could serve as an excellent interface for bioelectronic sensors. Based on the fabrication approaches, interaction mechanisms, and bioelectronic communication modalities, this review divided chitosan-based hydrogels into four types, including electrode-based hydrogels, conductive materials conjugated hydrogels, ionically conductive hydrogels, and redox-based hydrogels. To introduce the enhanced performance of bioelectronic sensors, as a complementary alternative, the incorporation of nanoparticles and redox species in chitosan-based hydrogels was discussed. In addition, the multifunctional properties of chitosan-based composite hydrogels enable their applications in biomedicine (e.g., smart skin patches, wood healing, disease diagnosis) and food safety (e.g., electrochemical sensing, smart sensing, artificial bioelectronic tongue, fluorescence sensors, surface-enhanced Raman scattering). We believe that this review will shed light on the future development of chitosan-based biosensing hydrogels for micro-implantable devices and human-machine interactions, as well as potential applications in medicine, food, agriculture, and other fields.

Genetic analysis and clinical features of three Chinese patients with Oguchi disease.

BACKGROUND: Oguchi disease is a rare autosomal recessive form of congenital stationary night blindness caused by disease-causing variants in the rhodopsin kinase gene (GRK1) or the arrestin gene (SAG). Our study aims to describe the clinical features and identify the genetic defects for three Chinese patients with Oguchi disease. METHODS: We conducted detailed ophthalmologic examinations for three patients from three unrelated non-consanguineous Chinese families. Targeted next-generation sequencing (targeted NGS) and copy number variations (CNVs) analysis were applied to screen pathogenic variants. Sanger sequencing validation, quantitative real-time PCR (qPCR), and segregation analysis were further performed for confirmation. Subsequently, a combined genetic and structural biology approach was used to infer the likely functional consequences of novel variants. RESULTS: All three patients presented with typical clinical features of Oguchi disease, including night blindness, characteristic fundus appearance (Mizuo-Nakamura phenomenon), attenuated rod responses, and negative ERG waveforms. Their visual acuity and visual field were normal. Genetic analysis revealed two pathogenic variants in SAG and four pathogenic variants in GRK1. Patient 1 was identified to harbor compound heterozygous SAG variants c.874C > T (p.R292*) and exon2 deletion. Compound heterozygous GRK1 variants c.55C > T (p.R19*) and c.1412delC (p.P471Lfs*52) were found in patient 2. In patient 3, compound heterozygous GRK1 variants c.946C > A (p.R316S) and c.1388 T > C (p. L463P) were detected. CONCLUSIONS: We reported the first two Chinese Oguchi patients with novel GRK1 pathogenic variants (P471Lfs*52, R316S, L463P) and one Oguchi case with SAG, indicating both GRK1 and SAG are important causative genes in Chinese Oguchi patients.

Modulating the Activity of the Right Dorsolateral Prefrontal Cortex Alters Altruism in Situations of Advantageous Inequity.

Altruism is highly valued and cherished by human society. However, human preferences and behavior are sensitive to inequality considerations. Currently, remarkably little is known about the neurobiological mechanisms underlying the process of altruistic acts in inequity situations. Therefore, to clarify the causal role of the right dorsolateral prefrontal cortex (rDLPFC) in altruism during situations of advantageous and disadvantageous inequity, we applied transcranial direct current stimulation (tDCS) to demonstrate the involvement of the rDLPFC in altruism in situations of inequity. A total of 71 participants (38 female and 33 male) received anodal tDCS at 1.5 mA over the rDLPFC (n = 38) or the primary visual cortex (n = 33) and subsequently participated in a modified dictator game that measures altruism. We found that anodal tDCS over the rDLPFC decreased subjects' sensitivity to altruistic efficiency and cost in situations of advantageous inequity. Our results suggested that the rDLPFC plays an important role in overriding self-interest to enforce altruism in situations of advantageous inequity.

Distinct roles of the medial prefrontal cortex in advantageous and disadvantageous inequity aversion.

Human beings have a strong preference for the fair distribution of resources in situations of both advantageous and disadvantageous inequity. Neuroimaging studies have shown that the process of advantageous and disadvantageous inequity aversion involves distinct brain regions. However, little is known about the causal roles of the dorsal medial prefrontal cortex (dmPFC) in these two types of inequity aversion. To clarify the roles of the dmPFC in both types of inequity aversion, 70 subjects were recruited and randomly assigned to two anodal transcranial direct current stimulation (tDCS) groups: tDCS over the dmPFC and tDCS over the primary visual cortex. Participants then completed a dictator game, which was used to measure the aversion to inequity. This study found that tDCS over the dmPFC decreased the aversion to disadvantageous inequity, but not that to advantageous inequity, and the treatment effect was modulated by equity cost. These results show that the dmPFC plays different roles in these two types of inequity aversion.

Excretion of Amyloid-ß in the Gastrointestinal Tract and Regulation by the Gut Microbiota.

BACKGROUND: Amyloid-ß (Aß) is important in the etiology of Alzheimer's disease (AD). Removal of Aß from the brain is a major strategy for the prevention and treatment of AD. OBJECTIVE: To clarify whether Aß42 can be cleared by intestinal excretion and whether the gut microbiota (GM) can affect the excretory clearance of Aß42 in the peripheral blood and intestines. METHODS: Male 8-month-old C57BL6 mice were maintained on either normal chow or received broad-spectrum antibiotics in their drinking water for one week. Sterile saline, fluorescein isothiocyanate (FITC), or FITC-Aß42 (fluorescein isothiocyanate-labeled amyloid-ß42 peptides) was injected 1 h before sampling. Related changes of Aß42 before and after injection were evaluated. RESULTS: FITC-Aß42 was injected into mice through the tail vein and could later be detected in feces. Furthermore, the fecal concentrations of FITC-Aß42 were higher in mice that had been fed antibiotics to alter their GM than in normal mice. However, the FITC-Aß42 concentrations in blood showed the opposite pattern. CONCLUSION: Aß42 can be excreted into the intestinal lumen and is regulated by the GM.

[Expression of zinc transporter 8 in Saccharomyces cerevisiae and its antigenicity analysis].

Zinc transporter 8 (ZnT8) is an important candidate antigen for type Ⅰ diabetes. The autoantibody detection kit based on ZnT8 can be used to help diagnose type Ⅰ diabetes, and the related products have been launched in Europe and the United States. Since the recombinant production system of active ZnT8 has not been established in China, this key raw material is heavily dependent on imports. We used Saccharomyces cerevisiae to carry out the recombinant expression of ZnT8. First, multiple antigenic forms of ZnT8 were designed as C-terminal haploid (C), C-terminal diploid (C-C), and N-terminal and C-terminal concatemers (N-C). The proteins were expressed, purified and tested for antigenicity by bridging-type ELISA. The serum of 13 patients with type Ⅰ diabetes and the serum of 16 healthy volunteers were detected. C, N-C, and C-C proteins had similar detection rates, which were 53.8% (7/13), 61.5% (8/13) and 53.8% (7/13). The specificity of the three groups was 100% (16/16). The detection value on positive samples P3, P4, and P8 increased by more than 90%, indicating better serum antibody recognition ability. Finally, N-C protein was selected for further serum sample testing, and the test results were characterized by receiver operating characteristic (ROC) curve for sensitivity and specificity. Compared with imported gold standard antigen, the sensitivity was 76.9% (10/13) and the specificity was 87.5% (14/16). There was no significant difference in the sensitivity of the method, but the specificity needed to be improved. In conclusion, the ZnT8 N-terminal and C-terminal concatemer protein developed based on S. cerevisiae expression system is expected to be a key alternative raw material in the development of in vitro diagnostic reagents for type Ⅰ diabetes.

Generation of a human induced pluripotent stem cell line PUMCHi019-A from a dominant optic atrophy patient with an OPA1 mutation.

Dominant optic atrophy (DOA) is one of the most common type of hereditary optic atrophy. Here, we describe the generation and characterization of a human induced pluripotent stem cell (hiPSC) line of DOA patient with an OPA1 mutation. The reprogramming of this iPSC line was performed from peripheral blood mononuclear cells (PBMCs) using the non-integrative Sendai virus. The established hiPSC line retained the disease-associated mutation and showed normal karyotype, pluripotency, and differentiation capacity.

Generation of a human induced pluripotent stem cell line PUMCHi017-A from a Choroideremia patient with CHM mutation.

Choroideremia (CHM) is a rare monogenic, X-linked recessive inherited chorioretinal dystrophy caused by loss of function variants in the CHM gene. We successfully generated a novel human induced pluripotent stem cell (hiPSC) line from a CHM patient with CHM variant using the Sendai-virus based approach. These cells will provide a disease model for further studies on the disease pathogenesis and potential interventions.

Generation of a human induced pluripotent stem cell line (PUMCHi018-A) from an early-onset severe retinal dystrophy patient with RDH12 mutations.

RDH12 mutations have been identified in patients diagnosed with severe early-onset retinal dystrophy, including Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD). Here, we describe the generation and characterization of a human induced pluripotent stem cell (hiPSC) line of a patient with RDH12 mutations. Blood sample was obtained, and peripheral blood mononuclear cells (PBMCs) were reprogrammed using the non-integrative Sendai virus to generate the iPSC line. The hiPSCs were characterized according to standard protocols including karyotyping, pluripotency marker expression and differentiation towards the three germ layers.