Mendelian randomization analysis of the brain, cerebrospinal fluid, and plasma proteome identifies potential drug targets for attention deficit hyperactivity disorder.

BACKGROUND: The need for new therapeutics for attention deficit hyperactivity disorder (ADHD) is evident. Brain, cerebrospinal fluid (CSF), and plasma protein biomarkers with causal genetic evidence could represent potential drug targets. However, a comprehensive screen of the proteome has not yet been conducted. METHODS: We employed a three-pronged approach using Mendelian Randomization (MR) and Bayesian colocalization analysis. Firstly, we studied 608 brains, 214 CSF, and 612 plasma proteins as potential causal mediators of ADHD using MR analysis. Secondly, we analysed the consistency of the discovered biomarkers across three distinct subtypes of ADHD: childhood, persistent, and late-diagnosed ADHD. Finally, we extended our analysis to examine the correlation between identified biomarkers and Tourette syndrome and pervasive autism spectrum disorder (ASD), conditions often linked with ADHD. To validate the MR findings, we conducted sensitivity analysis. Additionally, we performed cell type analysis on the human brain to identify risk genes that are notably enriched in various brain cell types. FINDINGS: After applying Bonferroni correction, we found that the risk of ADHD was increased by brain proteins GMPPB, NAA80, HYI, CISD2, and HYI, TIE1 in CSF and plasma. Proteins GMPPB, NAA80, ICA1L, CISD2, TIE1, and RMDN1 showed overlapped loci with ADHD risk through Bayesian colocalization. Overexpression of GMPPB protein was linked to an increase in the risk for all three ADHD subtypes. While ICA1L provided protection against both ASD and ADHD, CISD2 increased the probability of both disorders. Cell-specific studies revealed that GMPPB, NAA80, ICA1L, and CISD2 were predominantly present on the surface of excitatory-inhibitory neurons. INTERPRETATION: Our comprehensive MR investigation of the brain, CSF, and plasma proteomes revealed seven proteins with causal connections to ADHD. Particularly, GMPPB and TIE1 emerged as intriguing targets for potential ADHD therapy. FUNDING: This work was partly funded by the Key R & D Program of Zhejiang (T.L. 2022C03096); the National Natural Science Foundation of China Project (C.Z. 82001413); Postdoctoral Foundation of West China Hospital (C.Z. 2020HXBH163).

Unraveling NEK4 as a Potential Drug Target in Schizophrenia and Bipolar I Disorder: A Proteomic and Genomic Approach.

BACKGROUND AND HYPOTHESIS: Investigating the shared brain protein and genetic components of schizophrenia (SCZ) and bipolar I disorder (BD-I) presents a unique opportunity to understand the underlying pathophysiological processes and pinpoint potential drug targets. STUDY DESIGN: To identify overlapping susceptibility brain proteins in SCZ and BD-I, we carried out proteome-wide association studies (PWAS) and Mendelian Randomization (MR) by integrating human brain protein quantitative trait loci with large-scale genome-wide association studies for both disorders. We utilized transcriptome-wide association studies (TWAS) to determine the consistency of mRNA-protein dysregulation in both disorders. We applied pleiotropy-informed conditional false discovery rate (pleioFDR) analysis to identify common risk genetic loci for SCZ and BD-I. Additionally, we performed a cell-type-specific analysis in the human brain to detect risk genes notably enriched in distinct brain cell types. The impact of risk gene overexpression on dendritic arborization and axon length in neurons was also examined. STUDY RESULTS: Our PWAS identified 42 proteins associated with SCZ and 14 with BD-I, among which NEK4, HARS2, SUGP1, and DUS2 were common to both conditions. TWAS and MR analysis verified the significant risk gene NEK4 for both SCZ and BD-I. PleioFDR analysis further supported genetic risk loci associated with NEK4 for both conditions. The cell-type specificity analysis revealed that NEK4 is expressed on the surface of glutamatergic neurons, and its overexpression enhances dendritic arborization and axon length in cultured primary neurons. CONCLUSIONS: These findings underscore a shared genetic origin for SCZ and BD-I, offering novel insights for potential therapeutic target identification.

Rapid and Green Fabrication of Nanozyme with Geminal CuN3O Configuration for Efficient Catecholase-Mimicking.

Fabrication of nanozyme with catecholase-like catalytic activity faces the great challenge of merging outstanding activity with low cost as well as simple, rapid, and low-energy-consumed production, restricting its industrial applications. Herein, an inexpensive yet robust nanozyme (i.e., DT-Cu) via simple one-step coordination between diaminotriazole (DT) and CuSO4 within 1 h in water at room temperature is constructed. The asymmetric dicopper site with CuN3O configuration for each copper as well as Cu─O bond length of ≈1.83 Å and Cu···Cu distance of ≈3.5 Å in DT-Cu resemble those in catechol oxidase (CO), which ensure its prominent intrinsic activity, outperforming most CO-mimicking nanozymes and artificial homogeneous catalysts. The use of inexpensive DT/CuSO4 in this one-pot strategy endows DT-Cu with only ≈20% cost of natural CO per activity unit. During catalysis, O2 experienced a 4e-dominated reduction process accompanied by the formation of 1O2 and H2O2 intermediates and the product of H2O. Benefiting from the low cost as well as the distinctive structure and superior intrinsic activity, DT-Cu presents potential applications ranging from biocatalysis to analytical detection of biomolecules such as epinephrine and beyond.

Novel α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) potentiator LT-102: A promising therapeutic agent for treating cognitive impairment associated with schizophrenia.

AIMS: We aimed to evaluate the potential of a novel selective α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) potentiator, LT-102, in treating cognitive impairments associated with schizophrenia (CIAS) and elucidating its mechanism of action. METHODS: The activity of LT-102 was examined by Ca2+ influx assays and patch-clamp in rat primary hippocampal neurons. The structure of the complex was determined by X-ray crystallography. The selectivity of LT-102 was evaluated by hERG tail current recording and kinase-inhibition assays. The electrophysiological characterization of LT-102 was characterized by patch-clamp recording in mouse hippocampal slices. The expression and phosphorylation levels of proteins were examined by Western blotting. Cognitive function was assessed using the Morris water maze and novel object recognition tests. RESULTS: LT-102 is a novel and selective AMPAR potentiator with little agonistic effect, which binds to the allosteric site formed by the intradimer interface of AMPAR's GluA2 subunit. Treatment with LT-102 facilitated long-term potentiation in mouse hippocampal slices and reversed cognitive deficits in a phencyclidine-induced mouse model. Additionally, LT-102 treatment increased the protein level of brain-derived neurotrophic factor and the phosphorylation of GluA1 in primary neurons and hippocampal tissues. CONCLUSION: We conclude that LT-102 ameliorates cognitive impairments in a phencyclidine-induced model of schizophrenia by enhancing synaptic function, which could make it a potential therapeutic candidate for CIAS.

Understanding the dependence of biochar properties on different types of biomass.

Owing to the diversity of biomasses and many variables in pyrolysis process, the property of biochar from varied biomass feedstock or even same biomass could differ significantly. Since the property of biochar governs the further application of biochar, this review paid particular attention to the correlation between the nature of biomass feedstock and the specifications of biochar in terms of yield, elemental composition, pH, functionalities, heating value, pore structures, morphologies, etc. The property of the biochar from the pyrolysis of cellulose, hemicellulose, lignin, woody biomass (pine, mallee, poplar, acacia, oak, eucalyptus and beech), bark of woody biomass, leaves of woody biomass, straw, algae, fruit peels, tea waste was compared and summarized. In addition, the differences of the biochar of these varied origins were also analyzed. The remaining questions, about the correlation of biomass nature with biochar characteristics, to be further investigated are analyzed in detail. The deduced information about the relationship of the nature of biochar and biomass feedstock as well as key pyrolysis parameters is of importance for further development of the methods for tailoring or production of the biochar of desirable properties. The results from this study could be interesting technically and commercially for the technology developer using biochar as the source of carbon in different applications.

Type B3 thymoma complicated with Chlamydia psittaci pneumonia with rare features: A case report.

The case of a patient with type B3 thymomacomorbid with Chlamydia psittaci (C. psittaci) pneumonia exhibiting rare features is presented in the current report. The patient was admitted at the Second Affiliated Hospital of Jiaxing University (Jiaxing, China) with a history of direct contact with poultry. Clinical manifestations included fever, shivers, cough, fatigue and poor appetite. Chest computed tomography (CT) indicated right lung pneumonia, while metagenomics next-generation sequencing using bronchoalveolar lavage fluid confirmed infection with C. psittaci. Additionally, positron emission tomography-CT suggested the presence of thymoma. After surgery and treatment with doxycycline and imipenem cilastatin, the patient was discharged showing signs of improvement.

Iodine-Doped Hollow Carbon Nanocages without Templates Strategy for Boosting Zinc-Ion Storage by Nucleophilicity.

Zn-ion hybrid supercapacitors (ZHCs) combining merits of battery-type and capacitive electrodes are considered to be a prospective candidate in energy storage systems. Tailor-made carbon cathodes with high zincophilicity and abundant physi/chemisorption sites are critical but it remains a great challenge to achieve both features by a sustainable means. Herein, a hydrogen-bonding interaction-guided self-assembly strategy is presented to prepare iodine-doped carbon nanocages without templates for boosting zinc-ion storage by nucleophilicity. The biomass ellagic acid contains extensional hydroxy and acyloxy groups with electron-donating ability, which interact with melamine and ammonium iodide to form organic supermolecules. The organic supermolecules further self-assemble into a nanocage-like structure with cavities under hydrothermal processes via hydrogen-bonding and π-π stacking. The carbon nanocages as ZHCs cathodes enable the high approachability of zincophilic sites and low ion migration resistance resulting from the interconnected conductive network and nanoscale architecture. The experimental analyses and theoretical simulations reveal the pivotal role of iodine dopants. The I5-/I3- doping anions in carbon cathodes have a nucleophilicity to preferentially adsorb the Zn2+ cation by the formation of C+-I5--Zn2+ and C+-I3--Zn2+. Of these, the C+-I3- shows stronger bonding with Zn2+ than C+-I5-. As a result, the iodine-doped carbon nanocages produced via this template-free strategy deliver a high capacity of 134.2 mAh/g at 1 A/g and a maximum energy and power density of 114.1 Wh/kg and 42.5 kW/kg.

Retraction: The lncRNA XIST/miR-29b-3p/COL3A1 axis regulates central carbon metabolism in head and neck squamous cell carcinoma and is associated with poor tumor prognosis.

[This retracts the article DOI: 10.21037/atm-23-30.].

Artificial LiF-Rich Interface Enabled by In situ Electrochemical Fluorination for Stable Lithium-Metal Batteries.

Lithium (Li)-metal batteries are promising next-generation energy storage systems. One drawback of uncontrollable electrolyte degradation is the ability to form a fragile and nonuniform solid electrolyte interface (SEI). In this study, we propose the use of a fluorinated carbon nanotube (CNT) macrofilm (CMF) on Li metal as a hybrid anode, which can regulate the redox state at the anode/electrolyte interface. Due to the favorable reaction energy between the plated Li and fluorinated CNTs, the metal can be fluorinated directly to a LiF-rich SEI during the charging process, leading to a high Young's modulus (~2.0 GPa) and fast ionic transfer (~2.59×10-7  S cm-1 ). The obtained SEI can guide the homogeneous plating/stripping of Li during electrochemical processes while suppressing dendrite growth. In particular, the hybrid of endowed full cells with substantially enhanced cyclability allows for high capacity retention (~99.3 %) and remarkable rate capacity. This work can extend fluorination technology into a platform to control artificial SEI formation in Li-metal batteries, increasing the stability and long-term performance of the resulting material.

W-N heteroatom-interface in melon carbon nitride/N-doped tungsten oxide Z-Scheme photocatalyst toward improved photocatalytic hydrogen generation activity.

The construction of heterointerface in photocatalyst is an efficient approach to boost the separation and utilization efficiency of charge carriers, which is challenging and crucial in photocatalysis. Here, the construction of melon-structured carbon nitride/N-doped WO3 (MCN/NWx) heterojunction photocatalyst was achieved by a method of prealcoholysis combined with thermal polymerization, where N-doping of WO3 was achieved in-situ in the formation of heterojunction. The promoted charge separation efficiency was realized through the charge transfer from the conduction band of N-doped WO3 to the valence band of the MCN. Density functional theory calculation results showed that the formation of the W-N heteroatom-interface led to the increase of density of states at the heterointerface and decrease of the band gap. The MCN/NWx nanocomposite featured a metallic band structure of the nanocomposite photocatalysts, resulting in the enhanced photocatalytic activity. The photocatalytic hydrogen evolution activity of the MCN/NW2 was enhanced about 2.5 times than that of MCN. This research provides a novel insight into the construction of a novel heteroatom-junction that boosts the separation efficiency of charge carriers, and thereby improves the photocatalytic activity.

Enhanced light extraction efficiency of GaN-based green micro-LED modulating by a thickness-tunable SiO2 passivation structure.

Green micro-light emitting diodes (micro-LEDs) is one of the three primary color light sources as full-color display, which serves as a key research object in the field of micro-LED display. As the micro-LED size decreases, the surface-area-to-volume ratio of the device increases, leading to more serious damage on the sidewall by inductively coupled plasma (ICP) etching. The passivation process of SiO2 provides an effective method to reduce sidewall damage caused by ICP etching. In this work, green rectangular micro-LEDs with passivation layer thickness of 0∼600 nm was designed using the finite-difference time-domain (FDTD) simulation. In order to verify the simulation results, the micro-LED array was fabricated by parallel laser micro-lens array (MLA) lithography in high speed and large area. The effect of the SiO2 passivation layer thickness on the performance of the green micro-LED was analyzed, which shows that the passivation layer thickness-light extraction efficiency curve fluctuates periodically. For the sample with 90 nm thickness of SiO2 passivation layer, there exists a small leakage current and higher operating current density, and the maximum external quantum efficiency (EQE) is 2.8 times higher than micro-LED without SiO2 passivation layer.

Multiple Spontaneous Vertebral Fractures in a Younger Post-menopausal Woman Upon Stopping Denosumab Therapy.

Denosumab is a widely used medication for the treatment of osteoporosis. It has been observed in recent years that abruptly stopping denosumab leads to an increase in bone turnover markers, a decrease in bone mineral density, and a higher incidence of vertebral fractures. We present the case of a 53-year-old woman with few comorbidities and no prior fragility fractures who experienced 4 spontaneous and severely debilitating vertebral fractures 5-months post denosumab discontinuation. At the time of her fractures, she was found to have markedly elevated bone turnover markers, despite bone mineral density that was not significantly changed from measurements done while on denosumab treatment. She went on to be treated with an alternative antiresorptive agent, risedronate, and had substantial declines in her bone turnover markers, along with clinical improvement in her back pain. She experienced no further fractures while on treatment. Abrupt discontinuation of denosumab without starting an alternative antiresorptive agent can lead to spontaneous vertebral fractures. These fractures can occur in young patients with no prior history of fragility fractures and can be severely debilitating. An alternative antiresorptive agent should be started in the case of denosumab discontinuation.

B-Site Super-Excess Design Sr2V0.4Fe0.9Mo0.7O6-δ-Ni0.4 as a Highly Active and Redox-Stable Solid Oxide Fuel Cell Anode.

In-situ exsolution type perovskites as solid oxide fuel cell (SOFCs) anode materials have received widespread attention because of their excellent catalytic activity. In this study, excessive NiO is introduced to the Sr2V0.4Fe0.9Mo0.7O6-δ (SVFMO) perovskite with the B-site excess design, and in-situ growth of FeNi3 alloy nanoparticles is induced in the reducing atmosphere to form the Sr2V0.4Fe0.9Mo0.7O6-δ-Ni0.4 (SVFMO-Ni0.4) composite anode. Here, with H2 or CH4 as SOFCs fuel gas, the formation of FeNi3 nanoparticles further enhances the catalytic ability. Compared with SVFMO, the maximum power density (Pmax) of Sr2V0.4Fe0.9Mo0.7O6-δ-Ni0.4 (SVFMO-Ni0.4) increases from 538 to 828 mW cm-2 at 850 °C with hydrogen as the fuel gas, and the total polarization resistance (RP) decreases from 0.23 to 0.17 Ω cm2. In addition, the long-term operational stability of the SVFMO-Ni0.4 anode shows no apparent performance degradation for more than 300 h. Compared with SVFMO, the Pmax of SVFMO-Ni0.4 increases from 138 to 464 mW cm-2 with methane as fuel gas, and the RP decreases from 1.21 to 0.29 Ω cm2.

Biochar assisted cultivation of Chlorella protothecoides for adsorption of tetracycline and electrochemical study on self-cultured Chlorella protothecoides.

Microalgae present a viable mechanism for purifying aquatic environments through the absorption of organic pollutants. In this paper, Chlorella protothecoides was cultured in a tetracycline environment, and biochar was added during the cultivation process. Compared with conventionally cultured Chlorella protothecoides, the addition of biochar for cultivation under a tetracycline environment increased the biomass of Chlorella protothecoides by 13.26 %. Moreover, the adsorption of tetracycline by biochar alone was not complete, but when mixed with Chlorella protothecoides, tetracycline was completely removed, which proved the biosorption of Chlorella protothecoides for low concentrations of tetracycline. Finally, the cultured Chlorella protothecoides was used further to prepare electrode materials, and it was found that the specific capacitance of the material reached 233.15F/g at a current density of 1 A/g. In this study, the use of biochar and Chlorella protothecoides to jointly adsorb tetracycline is of great significance for environmental protection and microalgae cultivation.

Hallmark guided identification and characterization of a novel immune-relevant signature for prognostication of recurrence in stage I-III lung adenocarcinoma.

The high risk of postoperative mortality in lung adenocarcinoma (LUAD) patients is principally driven by cancer recurrence and low response rates to adjuvant treatment. Here, A combined cohort containing 1,026 stage I-III patients was divided into the learning (n = 678) and validation datasets (n = 348). The former was used to establish a 16-mRNA risk signature for recurrence prediction with multiple statistical algorithms, which was verified in the validation set. Univariate and multivariate analyses confirmed it as an independent indicator for both recurrence-free survival (RFS) and overall survival (OS). Distinct molecular characteristics between the two groups including genomic alterations, and hallmark pathways were comprehensively analyzed. Remarkably, the classifier was tightly linked to immune infiltrations, highlighting the critical role of immune surveillance in prolonging survival for LUAD. Moreover, the classifier was a valuable predictor for therapeutic responses in patients, and the low-risk group was more likely to yield clinical benefits from immunotherapy. A transcription factor regulatory protein-protein interaction network (TF-PPI-network) was constructed via weighted gene co-expression network analysis (WGCNA) concerning the hub genes of the signature. The constructed multidimensional nomogram dramatically increased the predictive accuracy. Therefore, our signature provides a forceful basis for individualized LUAD management with promising potential implications.

Dense Crystalline/Amorphous Phosphides/Oxides Interfacial Sites for Enhanced Industrial-Level Large Current Density Seawater Oxidation.

Designing high-efficiency and low-cost catalysts with high current densities for the oxygen evolution reaction (OER) is critical for commercial seawater electrolysis. Here, we present a heterophase synthetic strategy for constructing an electrocatalyst with dense heterogeneous interfacial sites among crystalline Ni2P, Fe2P, CeO2, and amorphous NiFeCe oxides on nickel foam (NF). The synergistic effect of high-density crystalline and amorphous heterogeneous interfaces effectively promotes the redistribution of the charge density and optimizes the adsorbed oxygen intermediates, lowering the energy barrier and promoting the O2 desorption, thus enhancing the OER performance. The obtained NiFeO-CeO2/NF catalyst exhibited outstanding OER catalytic activity, with low overpotentials of 338 and 408 mV required to attain high current densities of 500 and 1000 mA cm-2, respectively, in alkaline natural seawater electrolytes. The solar-driven seawater electrolysis system presents a record-setting and stable solar-to-hydrogen conversion efficiency of 20.10%. This work provides directives for developing highly effective and stable catalysts for large-scale clean energy production.

Interaction of the lignin-/cellulose-derived char with volatiles of varied origin: Part of the process for evolution of products in pyrolysis.

The interaction between volatiles and homologous and/or heterologous char is almost inevitable during the transfer or diffusion of volatiles from inner core to outer surface of a biomass particle in pyrolysis. This shapes both composition of volatiles (bio-oil) and property of char. In this study, the potential interaction of lignin- and cellulose-derived volatiles with char of varied origin was investigated at 500 °C. The results indicated that both the lignin- and cellulose-char promoted polymerization of the lignin-derived phenolics, enhancing production of bio-oil by ca. 20%-30%, generating more heavy tar but suppressing gases formation, especially over cellulose-char. Conversely, the char catalysts, especially the heterologous lignin-char, promoted cracking of the cellulose-derivatives, producing more gases while less bio-oil and heavy organics. Additionally, the volatiles-char interaction also led to gasification of some organics and also aromatization of some organics on surface of char, resulting in enhanced crystallinity and thermostability of the used char catalyst, especially for the lignin-char. Moreover, the substance exchange and formation of carbon deposit also blocked pores and formed fragmented surface dotted with particulate matters in the used char catalysts.

Lactic acidosis switches cancer cells from dependence on glycolysis to OXPHOS and renders them highly sensitive to OXPHOS inhibitors.

Targeting oxidative phosphorylation (OXPHOS) has emerged as a strategy for cancer treatment. However, most tumor cells exhibit Warburg effect, they primarily rely on glycolysis to generate ATP, and hence they are resistant to OXPHOS inhibitors. Here, we report that lactic acidosis, a ubiquitous factor in the tumor microenvironment, increases the sensitivity of glycolysis-dependent cancer cells to OXPHOS inhibitors by 2-4 orders of magnitude. Lactic acidosis reduces glycolysis by 79-86% and increases OXPHOS by 177-218%, making the latter the main production pathway of ATP. In conclusion, we revealed that lactic acidosis renders cancer cells with typical Warburg effect phenotype highly sensitive to OXPHOS inhibitors, thereby greatly expanding the anti-cancer spectrum of OXPHOS inhibitors. In addition, as lactic acidosis is a ubiquitous factor of TME, it is a potential indicator to predict the efficacy of OXPHOS inhibitors in cancer treatment.