Statistical methods for assessing the effects of de novo variants on birth defects.

With the development of next-generation sequencing technology, de novo variants (DNVs) with deleterious effects can be identified and investigated for their effects on birth defects such as congenital heart disease (CHD). However, statistical power is still limited for such studies because of the small sample size due to the high cost of recruiting and sequencing samples and the low occurrence of DNVs. DNV analysis is further complicated by genetic heterogeneity across diseased individuals. Therefore, it is critical to jointly analyze DNVs with other types of genomic/biological information to improve statistical power to identify genes associated with birth defects. In this review, we discuss the general workflow, recent developments in statistical methods, and future directions for DNV analysis.

Network assisted analysis of de novo variants using protein-protein interaction information identified 46 candidate genes for congenital heart disease.

De novo variants (DNVs) with deleterious effects have proved informative in identifying risk genes for early-onset diseases such as congenital heart disease (CHD). A number of statistical methods have been proposed for family-based studies or case/control studies to identify risk genes by screening genes with more DNVs than expected by chance in Whole Exome Sequencing (WES) studies. However, the statistical power is still limited for cohorts with thousands of subjects. Under the hypothesis that connected genes in protein-protein interaction (PPI) networks are more likely to share similar disease association status, we developed a Markov Random Field model that can leverage information from publicly available PPI databases to increase power in identifying risk genes. We identified 46 candidate genes with at least 1 DNV in the CHD study cohort, including 18 known human CHD genes and 35 highly expressed genes in mouse developing heart. Our results may shed new insight on the shared protein functionality among risk genes for CHD.

P2X7 receptor antagonists modulate experimental autoimmune neuritis via regulation of NLRP3 inflammasome activation and Th17 and Th1 cell differentiation.

BACKGROUND: Guillain-Barré syndrome (GBS), a post-infectious, immune-mediated, acute demyelinating disease of the peripheral nerves and nerve roots, represents the most prevalent and severe acute paralyzing neuropathy. Purinergic P2X7 receptors (P2X7R) play a crucial role in central nervous system inflammation. However, little is known about their role in the immune-inflammatory response within the peripheral nervous system. METHODS: Initially, we assessed the expression of purinergic P2X7R in the peripheral blood of patients with GBS using flow cytometry and qRT-PCR. Next, we explored the expression of P2 X7R in CD4+ T cells, CD8+ T cells, and macrophages within the sciatic nerves and spleens of rats using immunofluorescence labeling and flow cytometry. The P2X7R antagonist brilliant blue G (BBG) was employed to examine its therapeutic impact on rats with experimental autoimmune neuritis (EAN) induced by immunization with the P0180 - 199 peptide. We analyzed CD4+ T cell differentiation in splenic mononuclear cells using flow cytometry, assessed Th17 cell differentiation in the sciatic nerve through immunofluorescence staining, and examined the expression of pro-inflammatory cytokine mRNA using RT-PCR. Additionally, we performed protein blotting to assess the expression of P2X7R and NLRP3-related inflammatory proteins within the sciatic nerve. Lastly, we utilized flow cytometry and immunofluorescence labeling to examine the expression of NLRP3 on CD4+ T cells in rats with EAN. RESULTS: P2X7R expression was elevated not only in the peripheral blood of patients with GBS but also in rats with EAN. In rats with EAN, inhibiting P2X7R with BBG alleviated neurological symptoms, reduced demyelination, decreased inflammatory cell infiltration of the peripheral nerves, and improved nerve conduction. BBG also limited the production of pro-inflammatory molecules, down-regulated the expression of P2X7R and NLRP3, and suppressed the differentiation of Th1 and Th17 cells, thus protecting against EAN. These effects collectively contribute to modifying the inflammatory environment and enhancing outcomes in EAN rats. CONCLUSIONS: Suppression of P2X7R relieved EAN manifestation by regulating CD4+ T cell differentiation and NLRP3 inflammasome activation. This finding underscores the potential significance of P2X7R as a target for anti-inflammatory treatments, advancing research and management of GBS.

Attenuated neural activity in processing decision-making feedback in uncertain conditions in patients with mild cognitive impairment.

The present study aimed to explore the potential neural correlates during feedback evaluation during decision-making under risk and ambiguity in MCI. Nineteen individuals with MCI and twenty age-matched HCs were enrolled. Decision-making performance under risk and ambiguity was examined with the modified game of dice task (GDT) and an Iowa gambling task (IGT). Using task-related EEG data, reward positivity (RewP) and feedback P3 (fb-P3) were used to characterize participants' motivation and allocation of cognitive resources. Also, response time and event-related oscillation (ERO) were used to evaluate information processing speed, and the potent of post-feedback information integration and behavioral modulation. MCI patients had lower RewP (p = 0.022) and fb-P3 (p = 0.045) amplitudes in the GDT than HCs. Moreover, the amount and valence of feedback modulated the RewP (p = 0.008; p = 0.017) and fb-P3 (p < 0.001; p < 0.001). In the IGT, in addition to the significantly reduced fb-P3 observed in MCI patients (p = 0.010), the amount and valence of feedback modulated the RewP (p = 0.002; p = 0.020). Furthermore, MCI patients took longer to make decisions (t = 2.15, p = 0.041). The ERO analysis revealed that delta power was reduced in MCI (GDT: p = 0.045; p = 0.011). The findings suggest that, during feedback evaluation when making risky and ambiguous decisions, motivation, allocation of cognitive resources, information processing and neuronal excitability were attenuated in MCI. It implies that neural activity related to decision making was compromised in MCI.

M-DATA: A statistical approach to jointly analyzing de novo mutations for multiple traits.

Recent studies have demonstrated that multiple early-onset diseases have shared risk genes, based on findings from de novo mutations (DNMs). Therefore, we may leverage information from one trait to improve statistical power to identify genes for another trait. However, there are few methods that can jointly analyze DNMs from multiple traits. In this study, we develop a framework called M-DATA (Multi-trait framework for De novo mutation Association Test with Annotations) to increase the statistical power of association analysis by integrating data from multiple correlated traits and their functional annotations. Using the number of DNMs from multiple diseases, we develop a method based on an Expectation-Maximization algorithm to both infer the degree of association between two diseases as well as to estimate the gene association probability for each disease. We apply our method to a case study of jointly analyzing data from congenital heart disease (CHD) and autism. Our method was able to identify 23 genes for CHD from joint analysis, including 12 novel genes, which is substantially more than single-trait analysis, leading to novel insights into CHD disease etiology.

Whole-Exome Sequencing Analyses Support a Role of Vitamin D Metabolism in Ischemic Stroke.

BACKGROUND: Ischemic stroke (IS) is a highly heritable trait, and genome-wide association studies have identified several commonly occurring susceptibility risk loci for this condition. However, there are limited data on the contribution of rare genetic variation to IS. METHODS: We conducted an exome-wide study using whole-exome sequencing data from 152 058 UK Biobank participants, including 1777 IS cases. We performed single-variant analyses for rare variants and gene-based analyses for loss-of-function and deleterious missense rare variants. We validated these results through (1) gene-based testing using summary statistics from MEGASTROKE-a genome-wide association study of IS that included 67 162 IS cases and 454 450 controls, (2) gene-based testing using individual-level data from 1706 IS survivors, including 142 recurrent IS cases, enrolled in the VISP trial (Vitamin Intervention for Stroke Prevention); and (3) gene-based testing against neuroimaging phenotypes related to cerebrovascular disease using summary-level data from 42 310 UK Biobank participants with available magnetic resonance imaging data. RESULTS: In single-variant association analyses, none of the evaluated variants were associated with IS at genome-wide significance levels (P<5×10-8). In the gene-based analysis focused on loss-of-function and deleterious missense variants, rare genetic variation at CYP2R1 was significantly associated with IS risk (P=2.6×10-6), exceeding the Bonferroni-corrected threshold for 16 074 tests (P<3.1×10-6). Validations analyses indicated that CYP2R1 was associated with IS risk in MEGASTROKE (gene-based test, P=0.003), with IS recurrence in the VISP trial (gene-based test, P=0.001) and with neuroimaging traits (white matter hyperintensity, mean diffusivity, and fractional anisotropy) in the UK Biobank neuroimaging study (all gene-based tests, P<0.05). CONCLUSIONS: Because CYP2R1 plays an important role in vitamin D metabolism and existing observational evidence suggests an association between vitamin D levels and cerebrovascular disease, our results support a role of this pathway in the occurrence of IS.

Modulating Electronic Structure of PtCo-Ptrich Nanowires with Ru atoms for Boosted Hydrogen Evolution Catalysis.

Rational design and development of highly efficient hydrogen evolution reaction (HER) electrocatalysts is of great significance for the development of green water electrolysis hydrogen production technology. Ru-engineered 1D PtCo-Ptrich nanowires (Ru-Ptrich Co NWs) are fabricated by a facile electrodeposition method. The rich Pt surface on 1D Pt3 Co contributes to the fully exposed active sites and enhanced intrinsic catalytic activity (co-engineered by Ru and Co atoms) for HER. The incorporation of Ru atoms can not only accelerate the water dissociation in alkaline condition to provide sufficient H* but also modulate the electronic structure of Pt to achieve optimized H* adsorption energy. As a result, Ru-Ptrich Co NWs have exhibited ultralow HER overpotentials (η) of 8 and 112 mV to achieve current densities of 10 and 100 mA cm-2 in 1 m KOH, respectively, which far exceed those of commercial Pt/C catalyst (η10  = 29 mV, η100  = 206 mV). Density functional theory (DFT) calculations further demonstrate that the incorporated Ru atoms possess strong water adsorption capacity (-0.52 vs -0.12 eV for Pt), facilitating water dissociation. The Pt atoms in the outermost Pt-rich skin of Ru-Ptrich Co NWs achieve optimized H* adsorption free energy (ΔGH* ) of -0.08 eV, boosting hydrogen generation.

Direct Oxygen-Oxygen Cleavage through Optimizing Interatomic Distances in Dual Single-atom Electrocatalysts for Efficient Oxygen Reduction Reaction.

The oxygen reduction reaction (ORR) on transition single-atom catalysts (SACs) is sustainable in energy-conversion devices. However, the atomically controllable fabrication of single-atom sites and the sluggish kinetics of ORR have remained challenging. Here, we accelerate the kinetics of acid ORR through a direct O-O cleavage pathway through using a bi-functional ligand-assisted strategy to pre-control the distance of hetero-metal atoms. Concretely, the as-synthesized Fe-Zn diatomic pairs on carbon substrates exhibited an outstanding ORR performance with the ultrahigh half-wave potential of 0.86 V vs. RHE in acid electrolyte. Experimental evidence and density functional theory calculations confirmed that the Fe-Zn diatomic pairs with a specific distance range of around 3 Å, which is the key to their ultrahigh activity, average the interaction between hetero-diatomic active sites and oxygen molecules. This work offers new insight into atomically controllable SACs synthesis and addresses the limitations of the ORR dissociative mechanism.

A novel transcriptional risk score for risk prediction of complex human diseases.

Recently polygenetic risk score (PRS) has been successfully used in the risk prediction of complex human diseases. Many studies incorporated internal information, such as effect size distribution, or external information, such as linkage disequilibrium, functional annotation, and pleiotropy among multiple diseases, to optimize the performance of PRS. To leverage on multiomics datasets, we developed a novel flexible transcriptional risk score (TRS), in which messenger RNA expression levels were imputed and weighted for risk prediction. In simulation studies, we demonstrated that single-tissue TRS has greater prediction power than LDpred, especially when there is a large effect of gene expression on the phenotype. Multitissue TRS improves prediction accuracy when there are multiple tissues with independent contributions to disease risk. We applied our method to complex traits, including Crohn's disease, type 2 diabetes, and so on. The single-tissue TRS method outperformed LDpred and AnnoPred across the tested traits. The performance of multitissue TRS is trait-dependent. Moreover, our method can easily incorporate information from epigenomic and proteomic data upon the availability of reference datasets.

Constructing Atomic Heterometallic Sites in Ultrathin Nickel-Incorporated Cobalt Phosphide Nanosheets via a Boron-Assisted Strategy for Highly Efficient Water Splitting.

Identification of active sites for highly efficient catalysts at the atomic scale for water splitting is still a great challenge. Herein, we fabricate ultrathin nickel-incorporated cobalt phosphide porous nanosheets (Ni-CoP) featuring an atomic heterometallic site (NiCo16-xP6) via a boron-assisted method. The presence of boron induces a release-and-oxidation mechanism, resulting in the gradual exfoliation of hydroxide nanosheets. After a subsequent phosphorization process, the resultant Ni-CoP nanosheets are implanted with unsaturated atomic heterometallic NiCo16-xP6 sites (with Co vacancies) for alkaline hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). The optimized Ni-CoP exhibits a low overpotential of 88 and 290 mV at 10 mA cm-2 for alkaline HER and OER, respectively. This can be attributed to reduced free energy barriers, owing to the direct influence of center Ni atoms to the adjacent Co/P atoms in NiCo16-xP6 sites. These provide fundamental insights on the correlation between atomic structures and catalytic activity.

Anti-LINGO-1 antibody ameliorates cognitive impairment, promotes adult hippocampal neurogenesis, and increases the abundance of CB1R-rich CCK-GABAergic interneurons in AD mice.

In view of the negative regulatory effect of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) on neurons, an antibody against LINGO-1 (anti-LINGO-1 antibody) was herein administered to 10-month-old APP/PS1 transgenic Alzheimer's disease (AD) mice for 2 months as an experimental intervention. Behavioral, stereology, immunohistochemistry and immunofluorescence analyses revealed that the anti-LINGO-1 antibody significantly improved the cognitive abilities, promoted adult hippocampal neurogenesis (AHN), decreased the amyloid beta (Aß) deposition, enlarged the hippocampal volume, and increased the numbers of total neurons and GABAergic interneurons, including GABAergic and CCK-GABAergic interneurons rich in cannabinoid type 1 receptor (CB1R), in the hippocampus of AD mice. In contrast, this intervention significantly reduced the number of GABAergic interneurons expressing LINGO-1 and CB1R in the hippocampus of AD mice. More importantly, we also found a negative correlation between LINGO-1 and CB1R on GABAergic interneurons in the hippocampus of AD mice, while the anti-LINGO-1 antibody reversed this relationship. These results indicated that LINGO-1 plays an important role in the process of hippocampal neuron loss in AD mice and that antagonizing LINGO-1 can effectively prevent hippocampal neuron loss and promote AHN. The improvement in cognitive abilities may be attributed to the improvement in AHN, and in the numbers of GABAergic interneurons and CCK-GABAergic interneurons rich in CB1Rs in the hippocampus of AD mice induced by the anti-LINGO-1 antibody. Collectively, the double target effect (LINGO-1 and CB1R) initiated by the anti-LINGO-1 antibody may provide an important basis for the study of drugs for the prevention and treatment of AD in the future.

Difficult removal of an endoscopic nasobiliary drainage tube after laparoendoscopic rendezvous surgery.

A 52-year-old female patient came to our hospital with upper abdominal pain over more than four days. Magnetic resonance cholangiopancreatography confirmed gallstones, common bile duct dilatation, and suspected choledocholithiasis. After the recommended preoperative preparation, the patient underwent laparoscopic cholecystectomy and intraoperative endoscopic retrograde cholangiopancreatography (ERCP), also called laparoendoscopic rendezvous surgery (LERV). During surgery sand-like stones were successfully removed from the common bile duct.

Thermoplastic Dielectric Elastomer of Triblock Copolymer with High Electromechanical Performance.

Dielectric elastomer (DE) actuators have been shown to have promising applications as soft electromechanical transducers in many emerging technologies. The DE actuators, which are capable of large actuation strain over a wide range of excitation frequencies, are highly desirable. Here, the first single-component DE of a triblock copolymer with attractive electromechanical performance is reported. Symmetric poly(styrene-b-butyl acrylate-b-styrene) (SBAS) is designed and synthesized. The SBAS actuator exhibits about 100% static actuation area strain and excellent dynamic performance, as evidenced by a wide half bandwidth of 300 Hz and a very high specific power of 1.2 W g-1 within the excitation frequency range of 300-800 Hz.

Children who are deaf or hard of hearing in inclusive educational settings: a literature review on interactions with peers.

This review is conducted to describe how children who are deaf or hard of hearing (D/HH) interact with hearing peers in inclusive settings, illustrate the difficulties and challenges faced by them in interacting with peers, and identify effective interventions that promote their social interaction in inclusive education. A systematic search of databases and journals identified 21 papers that met the inclusion criteria. Two broad themes emerged from an analysis of the literatures, which included processes and outcomes of interactions with peers and intervention programs. The research indicates that children who are D/HH face great difficulties in communicating, initiating/entering, and maintaining interactions with hearing peers in inclusive settings. The co-enrollment and social skills training programs are considered to be effective interventions for their social interaction. Communication abilities and social skills of children who are D/HH, responses of children with normal hearing, and the effect of environment are highlighted as crucial aspects of social interactions. In addition, future research is needed to study the interaction between children who are D/HH and hearing peers in natural settings, at different stages of school life, as well as improving social interaction and establishing an inclusive classroom climate for children who are D/HH.

Construction of core-shell CoSe2/ZnIn2S4 heterostructures for efficient visible-light-driven photocatalytic hydrogen evolution.

The use of photocatalysts based on semiconductor heterostructures for hydrogen evolution is a prospective tactic for converting solar energy. Herein, visible-light-responsive three-dimensional core-shell CoSe2/ZnIn2S4 heterostructures were successfully fabricated via in situ growth of ZnIn2S4 ultrathin nanosheets on spherical CoSe2. Without any noble metal co-catalysts, the as-prepared CoSe2/ZnIn2S4 composite achieved attractive photocatalytic hydrogen evolution activity under visible light illumination. Optimal CoSe2/ZnIn2S4 achieved a hydrogen evolution rate of 2199 µmol g-1 h-1, which was 7 times higher than that of pristine ZnIn2S4 and even exceeded that of ZnIn2S4 loaded with platinum. In this distinctive core-shell heterostructure, the presence of CoSe2 could considerably improve the ability to harvest light, quicken the charge transfer kinetics, and avoid the agglomeration of ZnIn2S4 nanosheets. Meanwhile, the experimental results demonstrated that the strong interaction between CoSe2 and ZnIn2S4 at the compact interface could appropriately boost the photogenerated electron-hole pair migration and relieve charge recombination, thus improving photocatalytic hydrogen evolution activity. This work has bright prospects in constructing noble-metal-free core-shell heterostructures for solar energy conversion.

Music training influences online temporal order processing during reading comprehension.

Numerous studies have demonstrated the influence of musical expertise on spoken language processing; however, its effects on reading comprehension remain largely unexplored. This study aims to investigate the role of musical expertise in sentence comprehension, particularly concerning the processing of temporal order. Using two self-paced reading experiments, we examined individuals' responses to two-clause sentences connected by the temporal connectives "before" or "after". "After" sentences consistently presented events in their actual order of temporal occurrence, while "before" sentences described events in reverse temporal order. In both experiments, our analyses of reading times consistently uncovered a significant temporal order effect, with words immediately following the temporal connectives being processed slower in "before" sentences compared to "after" sentences. This suggests the presence of immediate online processing costs associated with "before" sentences. Notably, these processing costs were found to be attenuated in individuals with musical expertise compared to those without. However, analyses of comprehension accuracy showed no advantage of musicians over non-musicians. Specifically, in Experiment 1, the two groups showed no difference in comprehension accuracy, while in Experiment 2, musicians exhibited lower accuracy rates compared to non-musicians in both "before" and "after" sentences. These results suggest that musical expertise may attenuate online processing costs associated with complex linguistic constructs, but could not promote reading accuracy. We concluded that music training is associated with a restricted effect on written sentence comprehension.

Determination of 90Sr and 210Pb in food samples by liquid scintillation counting after sequential separation with an extraction chromatographic column.

90Sr and 210Pb are considered to be key radionuclides in internal exposure resulting from dietary intake, however, the established methods employed for their detection are time-comsuming. A method for the sequential separation of 90Sr and 210Pb using a Sr·spec resin by LSC measurement is developed, which is highly suitable for food safety monitoring as its minimal sample requirements. The sequential separation of Sr and Pb from the sample was using 0.05 mol/L HNO3 and 0.05 mol/L C6H5O7(NH4)3. The chemical recoveries of Sr and Pb measured using ICP-OES were 72-83% and 80-88%, respectively. The minimum detectable activities of 90Sr and 210Pb in the food sample were 36.2 mBq/kg and 28.6 mBq/kg, respectively, obtained from a 0.1 kg fresh sample and 300 min counting time. The method was validated using reference materials and compared with other methods. The feasibility of the developed method for other highly complex food matrices needs further investigation.

Sodium para-aminosalicylic acid attenuates combined manganese/iron-induced cortical synaptic damage in rats.

We established experimental models of manganese (Mn) and iron (Fe) exposure in vitro and in vivo, and addressed the effects of manganese and iron combined exposure on the synaptic function of pheochromocytoma derived cell line 12 (PC12) cells and rat cortex, respectively. We investigated the protective effect of sodium para-aminosalicylate (PAS-Na) on manganese and iron combined neurotoxicity, providing a scientific basis for the prevention and treatment of ferromanganese combined neurotoxicity. Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were performed to detect the expression levels of protein and mRNA related to synaptic damage. Y-maze novelty test and balance beam test were used to evaluate the motor and cognitive function of rats. Haematoxylin and eosin (H&E) and Nissl staining were performed to observe the cortical damage of rats. The results showed that the combined exposure of Mn and Fe in rats led to a synergistic effect, attenuating growth and development, and altering learning and memory as well as motor function. The combination of Mn and Fe also caused damage to the synaptic structure of PC12 cells, which is manifested as swelling of dendrites and axon terminals, and even lead to cell death. PAS-Na displayed some antagonistic effects against the Mn- and Fe-induced synaptic structural damage, growth, learning and memory impairment.

Veliparib exerts protective effects in intracerebral hemorrhage mice by inhibiting the inflammatory response and accelerating hematoma resolution.

Poly (ADP-ribose) polymerase (PARP) inhibitors have potent anti-inflammatory effects, including the suppression of brain microglial activation. Veliparib, a well-known PARP1/2 inhibitor, exhibits particularly high brain penetration, but its effects on stroke outcome is unknown. Here, the effects of veliparib on the short-term outcome of intracerebral hemorrhage (ICH), the most lethal type of stroke, were investigated. Collagenase-induced mice ICH model was applied, and the T2-weighted magnetic resonance imaging was performed to evaluate lesion volume. Motor function and hematoma volume were also measured. We further performed immunofluorescence, enzyme linked immunosorbent assay, flow cytometry, and blood-brain barrier assessment to explore the potential mechanisms. Our results demonstrated veliparib reduced the ICH lesion volume dose-dependently and at a dosage of 5 mg/kg, veliparib significantly improved mouse motor function and promoted hematoma resolution at days 3 and 7 post-ICH. Veliparib inhibited glial activation and downregulated the production of pro-inflammatory cytokines. Veliparib significantly decreased microglia counts and inhibited peripheral immune cell infiltration into the brain on day 3 after ICH. Veliparib improved blood-brain barrier integrity at day 3 after ICH. These findings demonstrate that veliparib improves ICH outcome by inhibiting inflammatory responses and may represent a promising novel therapy for ICH.

Treatment of manganese and lead poisoning with sodium para-aminosalicylic acid: A contemporary update.

Sodium para-aminosalicylic acid (PAS-Na) treatment for manganese (Mn) intoxication has shown efficacy in experimental and clinical studies, giving rise to additional studies on its efficacy for lead (Pb) neurotoxicity and its associated mechanisms of neuroprotection. The difference between PAS-Na and other metal complexing agents, such as edetate calcium sodium (CaNa2-EDTA), is firstly that PAS-Na can readily pass through the blood-brain barrier (BBB), and complex and facilitate the excretion of manganese and lead. Secondly, PAS-Na has anti-inflammatory effects. Recent studies have broadened the understanding on the mechanisms associated with efficacy of PAS-Na. The latter has been shown to modulate multifarious manganese- and lead- induced neurotoxicity, via its anti-apoptotic and anti-inflammatory effects, as well as its ability to inhibit pyroptosis, and regulate abnormal autophagic processes. These observations provide novel scientific bases and new concepts for the treatment of lead, mercury, copper, thallium, as well as other toxic encephalopathies, and implicate PAS-Na as a compound with greater prospects for clinical medical application.