Integrative multi-omics analysis identifies genetically supported druggable targets and immune cell specificity for myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by fluctuating muscle weakness. Despite the availability of established therapies, the management of MG symptoms remains suboptimal, partially attributed to lack of efficacy or intolerable side-effects. Therefore, new effective drugs are warranted for treatment of MG. METHODS: By employing an analytical framework that combines Mendelian randomization (MR) and colocalization analysis, we estimate the causal effects of blood druggable expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs) on the susceptibility of MG. We subsequently investigated whether potential genetic effects exhibit cell-type specificity by utilizing genetic colocalization analysis to assess the interplay between immune-cell-specific eQTLs and MG risk. RESULTS: We identified significant MR results for four genes (CDC42BPB, CD226, PRSS36, and TNFSF12) using cis-eQTL genetic instruments and three proteins (CTSH, PRSS8, and CPN2) using cis-pQTL genetic instruments. Six of these loci demonstrated evidence of colocalization with MG susceptibility (posterior probability > 0.80). We next undertook genetic colocalization to investigate cell-type-specific effects at these loci. Notably, we identified robust evidence of colocalization, with a posterior probability of 0.854, linking CTSH expression in TH2 cells and MG risk. CONCLUSIONS: This study provides crucial insights into the genetic and molecular factors associated with MG susceptibility, singling out CTSH as a potential candidate for in-depth investigation and clinical consideration. It additionally sheds light on the immune-cell regulatory mechanisms related to the disease. However, further research is imperative to validate these targets and evaluate their feasibility for drug development.

Treatment of Persistent Idiopathic Dentoalveolar Pain with Venlafaxine: A Multicentric Retrospective Study on Its Effectiveness and Safety.

Purpose: To determine the effectiveness and safety of venlafaxine in treating persistent idiopathic dentoalveolar pain (PIDP). Patients and Methods: A retrospective analysis was conducted on a cohort comprising 129 patients with a definite diagnosis of PIDP, who were treated with venlafaxine between May 2020 and December 2022 at three different institutions. Baseline characteristics were statistically described, and visual analog scale (VAS) scores before and during treatment were collected. The percentage of pain relief was calculated. Differences in baseline characteristics between responsive and unresponsive patients were evaluated. Additionally, side effects experienced during treatment were also summarized. Results: Among the included patients, 4 suffered immediate side effects following the initial dose of venlafaxine and the treatment was discontinued. 104 (80.6%) patients achieved pain relief. VAS scores of responsive patients at weeks 2, and months 1, 2, and 3 were significantly lower than baseline (p<0.001). Duration of pain was the only factor related to responsiveness (Wilcoxon rank sum test p<0.001, logistic regression p=0.001). 64 patients (49.6%) suffered from mild side effects. No serious side effects were observed during the study. Conclusion: Venlafaxine is potentially effective and safe in the management of PIDP. Early application of venlafaxine following the diagnoses of PIDP can result in a higher possibility of pain relief.

Pyridine Functionalized Carbon Nanotubes: Unveiling the Role of External Pyridinic Nitrogen Sites for Oxygen Reduction Reaction.

Pyridinic nitrogen has been recognized as the primary active site in nitrogen-doped carbon electrocatalysts for the oxygen reduction reaction (ORR), which is a critical process in many renewable energy devices. However, the preparation of nitrogen-doped carbon catalysts comprised of exclusively pyridinic nitrogen remains challenging, as well as understanding the precise ORR mechanisms on the catalyst. Herein, a novel process is developed using pyridyne reactive intermediates to functionalize carbon nanotubes (CNTs) exclusively with pyridine rings for ORR electrocatalysis. The relationship between the structure and ORR performance of the prepared materials is studied in combination with density functional theory calculations to probe the ORR mechanism on the catalyst. Pyridinic nitrogen can contribute to a more efficient 4-electron reaction pathway, while high level of pyridyne functionalization result in negative structural effects, such as poor electrical conductivity, reduced surface area, and small pore diameters, that suppressed the ORR performance. This study provides insights into pyridine-doped CNTs-functionalized for the first time via pyridyne intermediates-as applied in the ORR and is expected to serve as valuable inspiration in designing high-performance electrocatalysts for energy applications.

Insights into the Microscopic Oil-Water Flow Characteristics and Displacement Mechanisms during Waterflooding in Sandstone Reservoir Rock Based on Micro-CT Technology: A Pore-Scale Numerical Simulation Study.

The low oil recovery rate observed in current oil fields is largely attributed to the presence of remaining oil trapped in the pores of porous media during waterflooding. To improve the recovery rate, it is imperative to gain an understanding of the oil-water flow characteristics and displacement mechanisms during waterflooding, as well as to elucidate the underlying mobilization mechanisms of residual oil at the pore scale. In this paper, we explore these issues in depth by numerically investigating the influence of factors such as water injection velocities, oil-water viscosity ratios, and wettability conditions on pore-scale oil-water flow characteristics and oil recovery rate. To this end, we employ a direct numerical simulation (DNS) method in conjunction with the volume of fluid (VOF) method to study the microscopic displacement mechanisms of waterflooding in a reconstructed two-dimensional digital rock core based on micro-CT technology. In addition, the particle tracing method is adopted to identify the flow path and dominant areas during waterflooding in order to mobilize the residual oil within the pores. The findings indicate that the oil-water flow characteristics in porous media are determined by the interplay between capillary and viscous forces. Furthermore, the oil recovery rate is 10.6% and 24.7% lower under strong water-wet and oil-wet conditions than that (32.36%) under intermediate wettability conditions, and the final oil recovery rate is higher under water-wet conditions than under oil-wet conditions. The seepage path and the dominant areas are directly linked to the capillarity formed during waterflooding. The findings of this study are significant in terms of enhancing the recovery rate of residual oil and provide a novel perspective for understanding the waterflooding process.

Microglia/macrophages require vitamin D signaling to restrain neuroinflammation and brain injury in a murine ischemic stroke model.

Vitamin D deficiency is associated with worse clinical outcomes after ischemic stroke; nevertheless, the pathophysiological mechanisms remain largely unexplored. In this study, we characterized the molecular mechanisms of how vitamin D signaling modulated stroke progression in male mouse ischemia-reperfusion stroke models. We found that vitamin D receptor (VDR) exhibited a predominant upregulation in peri-infarct microglia/macrophages following cerebral ischemia. Conditional Vdr inactivation in microglia/macrophages markedly augmented infarct volumes and neurological deficits. VDR-deficient microglia/macrophages exhibited a more primed proinflammatory phenotype with substantial secretion of TNF-α and IFN-γ. These inflammatory cytokines further enhanced CXCL10 release from endothelial cells and blood-brain barrier disruption, and ultimately infiltration of peripheral T lymphocytes. Notably, blocking TNF-α and IFN-γ significantly ameliorated stroke phenotypes in Vdr conditional knockout mice. Collectively, VDR signaling in microglia/macrophages plays a crucial role in restraining ischemia-elicited neuroinflammation and stroke progression. Our findings delineate a novel mechanism underlying the association between vitamin D deficiency and poor stroke outcomes, and underline the significance of maintaining a functional vitamin D signaling in the management of acute ischemic stroke.

Dual interfacial engineering of a Chevrel phase electrode material for stable hydrogen evolution at 2500 mA cm-2.

Constructing stable electrodes which function over long timescales at large current density is essential for the industrial realization and implementation of water electrolysis. However, rapid gas bubble detachment at large current density usually results in peeling-off of electrocatalysts and performance degradation, especially for long term operations. Here we construct a mechanically-stable, all-metal, and highly active CuMo6S8/Cu electrode by in-situ reaction between MoS2 and Cu. The Chevrel phase electrode exhibits strong binding at the electrocatalyst-support interface with weak adhesion at electrocatalyst-bubble interface, in addition to fast hydrogen evolution and charge transfer kinetics. These features facilitate the achievement of large current density of 2500 mA cm-2 at a small overpotential of 334 mV which operate stably at 2500 mA cm-2 for over 100 h. In-situ total internal reflection imaging at micrometer level and mechanical tests disclose the relationships of two interfacial forces and performance of electrocatalysts. This dual interfacial engineering strategy can be extended to construct stable and high-performance electrodes for other gas-involving reactions.

Computational Study of Dynamic Susceptibility and Phase-Matching Angle by Two-Photon Entangled Generation.

Two-photon entangled generation is used to produce an entangled photon source which is a key and core element concerning the technology applications of quantum computing, quantum communication, and quantum precision measurement. In this work, we have deduced the formulas of dynamic susceptibility and phase-matching angle of two-photon entangled generation in nonlinear optical crystals. The formulas are employed to compute the susceptibilities and phase-matching angles of these optical processes for uniaxial and biaxial crystals. The susceptibility magnitude and phase-matching condition of two-photon entangled generation affect the performance of the source. The calculated results by these formulas are employed to study properties and estimate the performance of an entangled photon source. In this way, we discuss the phase matching among waves and working wavelength in an entangled source that affects the efficiency of satellite communication with the ground during the day and night.

Long-term Outcomes of Pulsed Radiofrequency for Supraorbital Neuralgia: A Retrospective Multicentric Study.

BACKGROUND: Pulsed radiofrequency (PRF) is a percutaneous, micro-invasive, and micro-destructive neuromodulation technology. It has been reported to be useful in the treatment of supraorbital neuralgia (SN). However, the long-term effectiveness and safety of this technique in SN has not been reported yet. OBJECTIVES: To investigate the outcomes of PRF on supraorbital neuralgia (SN) in multi-centers and a long-term perspective. STUDY DESIGN: Retrospective case series. METHODS: Patients who underwent PRF for SN at 4 hospitals in Beijing between Jan 2007 and Jan 2021 were identified and reviewed for inclusion. Their demographic data and baseline conditions were statistically described, and their conditions of pain control were analyzed using Kaplan-Meier survival analyses. A survival curve was plotted, the cumulative proportion of pain-free at specific time points was determined, and the median pain-free time was estimated. Complications related to PRF treatment were summarized. The risk factors for initial pain control and pain-free survival were analyzed using logistic regression and Cox regression. RESULTS: A total of 116 patients were included; 91 (78.4%) patients got initial pain control with just one attempt of PRF. The maximum length of follow-up was 127 months, with a median of 18 months. During follow-up, 29 (31.9%) patients suffered from pain recurrence, and 11 (12.1%) were lost. The cumulative pain-free survival at 6 months, 1 year, 2 years, 3 years, 5 years, 8 years, and 10 years were estimated as 70%, 64%, 59%, 55%, 44%, 37%, and 37%, respectively. The median pain-free time was 52 months. No severe complications were observed or reported. Duration of disease could significantly influence initial pain control, while no risk factors for pain-free survival were recognized. LIMITATIONS: A retrospective study setting without a control group. CONCLUSION: The performance of PRF for the treatment of SN was confirmed to be favorable in a multicentric, relatively large scale, and long-term perspective.

Heusler alloy catalysts for electrochemical CO2 reduction.

Developing efficient catalysts for electrochemical CO2 reduction reaction (ECO2RR) to hydrocarbons is becoming increasingly important but still challenging due to their high overpotential and poor selectivity. Here, the famous Heusler alloys are investigated as ECO2RR catalysts for the first time by means of density functional theory calculations. The linear scaling relationship between the adsorption energies of CHO (and COOH) and CO intermediates is broken and, thus, the overpotential can be tuned regularly by chemically permuting different 3d, 4d, or 5d transition metals (TMs) in Heusler alloy Cu2TMAl. Cu2ZnAl shows the best activity among all the 30 Heusler alloys considered in the present study, with 41% improvement in energy efficiency compared to pure Cu electrode. Cu2PdAl, Cu2AgAl, Cu2PtAl, and Cu2AuAl are also good candidates. The calculations on the competition between hydrogen evolution reaction and CO2RR indicate that Cu2ZnAl is also the one having the best selectivity toward hydrocarbons. This work identifies the possibility of applying the Heusler alloy as an efficient ECO2RR catalyst. Since thousands of Heusler alloys have been found in experiments, the present study also encourages the search for more promising candidates in this broad research area.

Psychological support for public-funded normal students engaged in teaching profession.

Among primary and secondary school teachers in China, 70% of teachers believe that they are facing greater occupational pressure. 63.8% of teachers clearly stated that occupational pressure has caused a great or great impact on themselves. And this has had negative effects on them such as mental, physical and personal development. This article studies the group of public-funded normal students from the perspective of psychological support. This article uses the SCL-90 form to investigate the professional psychology of teachers for the psychological support of public-funded normal students engaged in the teaching profession. And it conducts a survey on the curriculum setting and satisfaction of the public-funded normal students during their study stage. The experimental results of this article show that only 11.9% of public-funded normal students are very willing to take root and serve township education. Moreover, the psychological pressure of teachers at different educational stages is quite different.

The Application of Virtual Reality Technology in Sports Psychology: Theory, Practice, and Prospect.

Once virtual reality technology (Virtual Reality, VR) came out, it has received a lot of attention; in recent years, it has been widely used in the study of psychology. Because it can improve the ecological validity of experimental research, the level of conditional control, reproducibility, and avoid the dangers of field operations, it has been introduced into the field of psychology by many researchers. Compared with traditional sports psychology research methods, virtual reality technology has the characteristics of multiperception, immersion, interaction, and imagination to get a better, more realistic feel and increase people's interest in sports. Taking the application of virtual reality technology in table tennis teaching in colleges and universities as an example, this study aims to review the application of virtual reality technology in sports psychology; summarize the theory, practice, and prospect of the application of virtual reality technology in sports psychology; and add new content to the research of sports psychology. It aims to review the principles, characteristics, and application of virtual reality technology in sports psychology; summarize the advantages and disadvantages of the application of virtual reality technology in sports and point out the problems that need to be paid attention to when using this method; explore the application of virtual reality technology in sports psychology; and add new content to the research of sports psychology.

Rational design of a topological polymeric solid electrolyte for high-performance all-solid-state alkali metal batteries.

Poly(ethylene oxide)-based solid-state electrolytes are widely considered promising candidates for the next generation of lithium and sodium metal batteries. However, several challenges, including low oxidation resistance and low cation transference number, hinder poly(ethylene oxide)-based electrolytes for broad applications. To circumvent these issues, here, we propose the design, synthesis and application of a fluoropolymer, i.e., poly(2,2,2-trifluoroethyl methacrylate). This polymer, when introduced into a poly(ethylene oxide)-based solid electrolyte, improves the electrochemical window stability and transference number. Via multiple physicochemical and theoretical characterizations, we identify the presence of tailored supramolecular bonds and peculiar morphological structures as the main factors responsible for the improved electrochemical performances. The polymeric solid electrolyte is also investigated in full lithium and sodium metal lab-scale cells. Interestingly, when tested in a single-layer pouch cell configuration in combination with a Li metal negative electrode and a LiMn0.6Fe0.4PO4-based positive electrode, the polymeric solid-state electrolyte enables 200 cycles at 42 mA·g-1 and 70 °C with a stable discharge capacity of approximately 2.5 mAh when an external pressure of 0.28 MPa is applied.

Space-Confined One-Step Growth of 2D MoO2 /MoS2 Vertical Heterostructures for Superior Hydrogen Evolution in Alkaline Electrolytes.

2D material-based heterostructures are constructed by stacking or spicing individual 2D layers to create an interface between them, which have exotic properties. Here, a new strategy for the in situ growth of large numbers of 2D heterostructures on the centimeter-scale substrate is developed. In the method, large numbers of 2D MoS2 , MoO2 , or their heterostructures of MoO2 /MoS2 are controllably grown in the same setup by simply tuning the gap distance between metal precursor and growth substrate, which changes the concentration of metal precursors feed. A lateral force microscope is used first to identify the locations of each material in the heterostructures, which have MoO2 on the top of MoS2 . Noteworthy, the creation of a clean interface between atomic thin MoO2 (metallic) and MoS2 (semiconducting) results in a different electronic structure compared with pure MoO2 and MoS2 . Theoretical calculations show that the charge redistribution at such an interface results in an improved HER performance on the MoO2 /MoS2 heterostructures, showing an overpotential of 60 mV at 10 mA cm-2 and a Tafel slope of 47 mV dec-1 . This work reports a new strategy for the in situ growth of heterostructures on large-scale substrates and provides platforms to exploit their applications.

Recent progress of Bi-based electrocatalysts for electrocatalytic CO2 reduction.

To mitigate excessively accumulated carbon dioxide (CO2) in the atmosphere and tackle the associated environmental concerns, green and effective approaches are necessary. The electrocatalytic CO2 reduction reaction (CO2RR) using sustainable electricity under benign reaction conditions represents a viable way to produce value-added and profitable chemicals. In this minireview, recent studies regarding unary Bi electrocatalysts and binary BiSn electrocatalysts are symmetrically categorized and reviewed, as they disclose high faradaic efficiencies toward the production of formate/formic acid, which has a relatively higher value of up to 0.50 $·per kg and has been widely used in the chemical and pharmaceutical industry. In particular, the preparation methodologies, electrocatalyst morphologies, catalytic performances and the corresponding mechanisms are comprehensively presented. The use of solid-state electrolytes showing high economic prospects for directly obtaining high-purity formic acid is highlighted. Finally, the remaining questions and challenges for CO2RR exploitations using Bi-related electrocatalysts are proposed, while perspectives and the corresponding strategies aiming to enhance their entire catalytic functionalities and boost their performance are provided.

Somatic mosaicism reveals clonal distributions of neocortical development.

The structure of the human neocortex underlies species-specific traits and reflects intricate developmental programs. Here we sought to reconstruct processes that occur during early development by sampling adult human tissues. We analysed neocortical clones in a post-mortem human brain through a comprehensive assessment of brain somatic mosaicism, acting as neutral lineage recorders1,2. We combined the sampling of 25 distinct anatomic locations with deep whole-genome sequencing in a neurotypical deceased individual and confirmed results with 5 samples collected from each of three additional donors. We identified 259 bona fide mosaic variants from the index case, then deconvolved distinct geographical, cell-type and clade organizations across the brain and other organs. We found that clones derived after the accumulation of 90-200 progenitors in the cerebral cortex tended to respect the midline axis, well before the anterior-posterior or ventral-dorsal axes, representing a secondary hierarchy following the overall patterning of forebrain and hindbrain domains. Clones across neocortically derived cells were consistent with a dual origin from both dorsal and ventral cellular populations, similar to rodents, whereas the microglia lineage appeared distinct from other resident brain cells. Our data provide a comprehensive analysis of brain somatic mosaicism across the neocortex and demonstrate cellular origins and progenitor distribution patterns within the human brain.

Biallelic FRA10AC1 variants cause a neurodevelopmental disorder with growth retardation.

The major spliceosome mediates pre-mRNA splicing by recognizing the highly conserved sequences at the 5' and 3' splice sites and the branch point. More than 150 proteins participate in the splicing process and are organized in the spliceosomal A, B, and C complexes. FRA10AC1 is a peripheral protein of the spliceosomal C complex and its ortholog in the green alga facilitates recognition or interaction with splice sites. We identified biallelic pathogenic variants in FRA10AC1 in five individuals from three consanguineous families. The two unrelated Patients 1 and 2 with loss-of-function variants showed developmental delay, intellectual disability, and no speech, while three siblings with the c.494_496delAAG (p.Glu165del) variant had borderline to mild intellectual disability. All patients had microcephaly, hypoplasia or agenesis of the corpus callosum, growth retardation, and craniofacial dysmorphism. FRA10AC1 transcripts and proteins were drastically reduced or absent in fibroblasts of Patients 1 and 2. In a heterologous expression system, the p.Glu165del variant impacts intrinsic stability of FRA10AC1 but does not affect its nuclear localization. By co-immunoprecipitation, we found ectopically expressed HA-FRA10AC1 in complex with endogenous DGCR14, another component of the spliceosomal C complex, while the splice factors CHERP, NKAP, RED, and SF3B2 could not be co-immunoprecipitated. Using an in vitro splicing reporter assay, we did not obtain evidence for FRA10AC1 deficiency to suppress missplicing events caused by mutations in the highly conserved dinucleotides of 5' and 3' splice sites in an in vitro splicing assay in patient-derived fibroblasts. Our data highlight the importance of specific peripheral spliceosomal C complex proteins for neurodevelopment. It remains possible that FRA10AC1 may have other and/or additional cellular functions, such as coupling of transcription and splicing reactions.

Ba4GeSb2Se11: An Infrared Nonlinear Optical Crystal with a V-Shaped Se32- Group Possessing a Large Contribution to the SHG Response.

The quaternary selenide Ba4GeSb2Se11 was prepared by a high-temperature solid state reaction method. Ba4GeSb2Se11 crystallizes in an acentric orthorhombic space group Cmc21 with the lattice constants a = 9.370(11) Å, b = 25.850(0) Å, and c = 8.798(10) Å. The compound is composed of a [SbSe3]3- trigonal pyramid, [GeSbSe5]3- dimers, V-shaped Se32-, and the adjacent Ba2+ ions. It has indirect band gap of 1.35 eV and exhibits a second harmonic generation intensity of about 0.2 times that of the benchmark compound AgGaS2 at the same particle size. Interestingly, theoretical analyses show that the central Se atom of Se32- has the largest contribution (8.1%) to d31 compared to that of other Se atoms, which may be due to its easy swing in the a-axis direction.

A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion.

BACKGROUND: Structural birth defects occur in approximately 3% of live births; most such defects lack defined genetic or environmental causes. Despite advances in surgical approaches, pharmacologic prevention remains largely out of reach. METHODS: We queried worldwide databases of 20,248 families that included children with neurodevelopmental disorders and that were enriched for parental consanguinity. Approximately one third of affected children in these families presented with structural birth defects or microcephaly. We performed exome or genome sequencing of samples obtained from the children, their parents, or both to identify genes with biallelic pathogenic or likely pathogenic mutations present in more than one family. After identifying disease-causing variants, we generated two mouse models, each with a pathogenic variant "knocked in," to study mechanisms and test candidate treatments. We administered a small-molecule Wnt agonist to pregnant animals and assessed their offspring. RESULTS: We identified homozygous mutations in WLS, which encodes the Wnt ligand secretion mediator (also known as Wntless or WLS) in 10 affected persons from 5 unrelated families. (The Wnt ligand secretion mediator is essential for the secretion of all Wnt proteins.) Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects. The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis. Administration of a pharmacologic Wnt agonist partially restored embryonic development. CONCLUSIONS: Genetic variations affecting a central Wnt regulator caused syndromic structural birth defects. Results from mouse models suggest that what we have named Zaki syndrome is a potentially preventable disorder. (Funded by the National Institutes of Health and others.).

Developmental and temporal characteristics of clonal sperm mosaicism.

Throughout development and aging, human cells accumulate mutations resulting in genomic mosaicism and genetic diversity at the cellular level. Mosaic mutations present in the gonads can affect both the individual and the offspring and subsequent generations. Here, we explore patterns and temporal stability of clonal mosaic mutations in male gonads by sequencing ejaculated sperm. Through 300× whole-genome sequencing of blood and sperm from healthy men, we find each ejaculate carries on average 33.3 ± 12.1 (mean ± SD) clonal mosaic variants, nearly all of which are detected in serial sampling, with the majority absent from sampled somal tissues. Their temporal stability and mutational signature suggest origins during embryonic development from a largely immutable stem cell niche. Clonal mosaicism likely contributes a transmissible, predicted pathogenic exonic variant for 1 in 15 men, representing a life-long threat of transmission for these individuals and a significant burden on human population health.