Uncovering novel drug targets for bipolar disorder: a Mendelian randomization analysis of brain, cerebrospinal fluid, and plasma proteomes.

BACKGROUND: There is a clear demand for innovative therapeutics for bipolar disorder (BD). METHODS: We integrated the largest BD genome-wide association study (GWAS) dataset (NCase = 41 917, NControl = 371 549) with protein quantitative trait loci from brain, cerebrospinal fluid, and plasma. Using a range of integrative analyses, including Mendelian randomization (MR), Steiger filter analysis, Bayesian colocalization, and phenome-wide MR analysis, we prioritized novel drug targets for BD. Additionally, we incorporated data from the UK Biobank (NCase = 1064, NControl = 365 476) and the FinnGen study (NCase = 7006, NControl = 329 192) for robust biological validation. RESULTS: Through MR analysis, we found that in the brain, downregulation of DNM3, MCTP1, ABCB8 and elevation of DFNA5 and PDF were risk factors for BD. In cerebrospinal fluid, increased BD risk was associated with increased levels of FRZB, AGRP, and IL36A and decreased CTSF and LRP8. Plasma analysis revealed that decreased LMAN2L, CX3CL1, PI3, NCAM1, and TIMP4 correlated with increased BD risk, but ITIH1 did not. All these proteins passed Steiger filtering, and Bayesian colocalization confirmed that 12 proteins were colocalized with BD. Phenome-wide MR analysis revealed no significant side effects for potential drug targets, except for LRP8. External validation further underscored the concordance between the primary and validation cohorts, confirming MCTP1, DNM3, PDF, CTSF, AGRP, FRZB, LMAN2L, NCAM1, and TIMP4 are intriguing targets for BD. CONCLUSIONS: Our study identified druggable proteins for BD, including MCTP1, DNM3, and PDF in the brain; CTSF, AGRP, and FRZB in cerebrospinal fluid; and LMAN2L, NCAM1, and TIMP4 in plasma, delineating promising avenues to development of novel therapies.

Enhanced removal strategy towards organic matter with low coagulability: Immediate entrapment and complexation of oxidized intermediates by the hybrid ozonation-coagulation process.

The existence of dissolved organic matter (DOM) with low coagulability poses great challenges for conventional coagulation (CC) in water treatment. As a kind of typical organochlorine pesticide, 2,4-dichlorophenoxyacetic acid (2,4-D) cannot be efficiently removed by CC. To enhance the 2,4-D removal, ozonation was applied with coagulation. The hybrid ozonation-coagulation (HOC) achieved 60.61% DOC removal efficiency, which was obviously higher than pre-ozonation coagulation (POC) (45.83%). Synchronous fluorescence spectroscopy revealed stronger complexation between modified 2,4-D and coagulants during the HOC than that in subsequent coagulation of the POC process. During the HOC process, ozone promoted the formation of polymeric Al species, such as Alb. To investigate the 2,4-D removal mechanism, γ-Al2O3/O3 process with the same oxidation ability as the HOC was established. 2,4-D was oxidized step-by-step to 2,4-dichlorophenol, 4,6-dichlororesorcin, 3,5-dichlorocatechol, 2-chlorohydroquinone, 4-chlorocatechol, 1,2,4,5-tetrahydroxybenzene, pentahydroxybenzene and oxalic acid in γ-Al2O3/O3 process. However, during the HOC process, these oxidized intermediates were readily complexed by coagulants and accumulated in flocs. Especially 1,2,4,5-tetrahydroxybenzene and pentahydroxybenzene, completely complexed by AlCl3•6H2O hydrolysates as soon as being formed. Immediate entrapment and complexation between coagulant hydrolysates and 2,4-D oxidized intermediates inhibited the generation of small-molecular-weight organics such as oxalic acid, which enhanced the removal of organics with low coagulability.

Unraveling the over-oxidation inhibition mechanism during the hybrid ozonation-coagulation process: Immediate entrapment and complexation between intermediate organic matter and coagulants.

Pre-ozonation coagulation process had a very low and narrow range of ozone dosages for enhancing the dissolved organic matter (DOC) removal efficiency, in which over-oxidation may occur if the ozone dosage was not strictly controlled. In contrast, the proposed hybrid ozonation-coagulation (HOC) process with higher oxidation ability notably inhibited over-oxidation in this study, and exhibited improved DOC removal efficiency compared with coagulation at a much wider range of ozone dosages at different initial pH for the treatment of WWTP effluent. The HOC process also had a higher DOC removal efficiency than pre-ozonation coagulation. According to zeta potential analysis, a rising trend indicated that complexation between organic matter and metal coagulants persisted throughout the HOC process. However, the zeta potential remained almost unchanged during subsequent coagulation after pre-ozonation at high ozone dosages. Synchronous fluorescence spectroscopy analysis revealed that immediate entrapment and complexation between hydrolysed coagulants and oxidized intermediate organic matter occurred in the HOC process. Furthermore, FT-IR analysis showed that more oxygen-containing functional groups were generated, which were effectively trapped by metal coagulants and readily flocculated. To further prove the immediate entrapment and complexation during the HOC process, UPLC-Q-TOF-MS was applied to analyze the intermediate organic matter in the supernatant and flocs. The results implied that C21- organic matter was oxidized and decomposed into C11-C20, and C11-C20 intermediate organic matter was trapped and complexed by metal coagulants once formed, which led to the increase of C11-C20 in the flocs. Nevertheless, the catalytic ozonation process (γ-Al2O3/O3) with the same oxidation ability as the HOC process decomposed the organic matter into C1-C10. XPS analysis further confirmed the immediate entrapment and removal of aliphatic/aromatic carbon and oxygen-containing functional groups during the HOC process. Therefore, over-oxidation can be effectively inhibited, and wide range of ozone dosages was obtained during the HOC process, which facilitate the application of the HOC process.

Characteristics of dissolved ozone flotation for the enhanced treatment of bio-treated drilling wastewater from a gas field.

Working fluid preparation using treated drilling wastewater is of great potential for drilling wastewater reuse, especially in water-deficient and ecologically fragile areas, which require low levels of organic matter and suspended solids (SS). This study established the dissolved ozone flotation (DOF) process as the advanced treatment process to replace the original electrocatalytic system (ECS) which exhibited low organic and suspended solids removal efficiency. Higher and more stable organic matter, suspended solids and turbidity removal efficiency were obtained for the DOF process. Consequently, the lower fouling potential and higher water production rate of treated water from DOF process was observed for the following reverse osmosis (RO) system. In addition, brine drilling fluids can be successfully prepared using DOF effluent directly, which exhibited promising practical implications in the advanced drilling wastewater treatment. Based on organic matter fractionation and redundancy analysis (RDA), the hydrophobic acid (HOA), hydrophobic neutral (HON) and hydrophilic fraction (HI) contents significantly impacted brine drilling fluid preparation. Based on X-ray photoelectron spectroscopy (XPS) analysis, the aromatic carbon species in the HOA, HON and HI fractions were found to be the critical factors deteriorating the brine drilling fluid preparation. However, oxygen-containing groups played a positive role. The favorable brine drilling fluid preparation performance using DOF effluent directly can be ascribed to the removal of HOA, HON and HI fractions and enhanced generation of oxygen-containing groups in ozone flotation zone.

Electro-dissolved ozone flotation (E-DOF) integrated anoxic/oxic membrane reactor for leachate treatment from a waste transfer station.

With high organics and ammonia, leachate from waste transfer stations (WTSs) is among the most complex wastewater that cannot be easily disposed by signal biological processes. In this study, an electro-dissolved ozone flotation (E-DOF) was established, in which dissolved ozone flotation (DOF) and electro-coagulation (EC) occurred concurrently in one unit and integrated with anoxic/oxic membrane bioreactor (A/O-MBR) to dispose leachate from a WTS. In the integrated reactor, E-DOF acted as pretreatment and advanced treatment unit. A/O-MBR acted as secondary treatment unit. The E-DOF pretreatment achieved 34.48% COD and 16.96% NH3-N removal efficiency through synergistic effect between EC and DOF. BOD5/COD of leachate was increased from 0.32 to 0.51 after E-DOF pretreatment, indicating the enhancement of biodegradability. Molecular weight distribution (MWD) and three-dimensional excitation-emission matrix (3D-EEM) analysis demonstrate that the reduction of molecular weight and elimination of refractory organics through EC, ozone, and their interacted product (•OH) are attributed to biodegradability enhancement in lechate. Microbial community analysis proved that chemoheterotrophy and oxic chemoheterotrophy functions, mainly provided by Truepera, Aquamicrobium, Saprospiraceae, and Lentimicrobiaceae, ensured the efficient degradation of organic in the secondary processes. E-DOF advanced treatment effectively disposed residual contaminant in MBR effluent. The E-DOF advanced treatment mainly disposed residual contaminant in MBR effluent. High removal efficiency of COD (98.59 ± 0.27%), NH3-N (95.59 ± 0.50%), TN (95.37 ± 0.73%), and TP (96.75 ± 1.66%) were observed in the integrated reactor, and final effluent met the discharge standards for inclusion in the sewage pipe network in China.

[Genetic diversity and antibacterial activity of endophytic fungi from Zanthoxylum nitidum].

In order to reveal the distribution and population characteristics of endophytic fungi from Zanthoxylum nitidum and the antibacterial potential,this study performed molecular identification and analyzed the genetic diversity and antibacterial activity of endophytic fungi from Z. nitidum in Guangxi. Through culture and molecular identification,35 strains,belonging to 15 genera,12 families,10 orders,4 classes,and 2 phyla,were isolated from various tissues of Z. nitidum,of which Colletotrichum and Fusarium were the dominant genera,respectively accounting for 20% of total strains. The diversity of endophytic fungi was significantly different among roots,stems,and leaves,as manifested by the significantly higher Shannon index( H') in stems( 1. 678) than in roots( 0. 882 1) and leaves( 0. 515 4). The antimicrobial activity analysis showed that 14. 28% of endophytic fungi inhibited at least one indicator pathogen. Among them,Fusarium sp. ZN-34 and Fusarium sp. ZN-26 separately demonstrated the strongest inhibitory effect on Escherichia coli and Staphylococcus aureus. In general,Fusarium sp. ZN-26 and Phialemoniopsis plurioloculosa ZN-35 were advantageous in suppressing the two bacteria owing to the broad spectrum and strong efficacy. In summary,Z. nitidum in Guangxi boasts rich endophytic fungi with the majority showing strong antibacterial activity,which can be used as candidates for the extraction and separation of basic antibacterial substances and the development of natural antibacterial agents.

Behaviour of ozone in the hybrid ozonation-coagulation (HOC) process for ibuprofen removal: Reaction selectivity and effects on coagulant hydrolysis.

Simultaneous ozonation and coagulation can be realized in one unit in the developed hybrid ozonation-coagulation (HOC) process. To reveal the reaction sequence within the HOC process, the ibuprofen (IBP) removal efficiency of the ozonation only, HOC and HOC-PO43- (inhibition of the reactions between ozone and metal coagulant) processes at pH 5 and different ozone dosages were investigated. The removal efficiency is almost the same for the three processes at a low ozone dosage (4.8 mg/L), and higher removal performance can be achieved by the HOC process with increasing ozone dosage. It can be implied that ozone preferentially reacts with OH- to generate OH which react with IBP in the HOC process, and subsequently reacts with the surface hydroxyl groups of hydrolysed Al species to enhance OH generation. Moreover, based on the kinetics, X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FT-IR) analyses, the synergistic reactions between ozone and the metal coagulants (SOC) started to take effect from ozone dosage of 9.6 mg/L, which further verified that ozone will be involved in the IBP ozonation prior to the SOC reactions. The subsequent SOC reactions also resulted in the increased generation of polymeric Al species and more abundant intermediates in the HOC process.

Enhanced complexation of humic acids: Homogenization of protonated groups in the hybrid ozonation-coagulation process.

In this study, we compared dissolved organic carbon (DOC) and UV254 removal efficiencies of the hybrid ozonation-coagulation (HOC) and pre-ozonation-coagulation (POC) processes for humic acid (HA) at pH 5 with AlCl3•6H2O as the coagulant. The DOC and UV254 removal efficiencies of the HOC process were higher than those of the POC process at ozone dosages less than 2.0 mg O3 (mg DOC)-1. The ozone dosage was optimized at 0.3 and 0.1 mg O3 (mg DOC)-1 for the HOC and POC processes, respectively, implying a more rigorous ozone dosage for the POC process. During the POC process, pre-ozonation was observed to increase the binding sites of HA (e.g., hydroxyl and carboxyl groups), improving the complexation of dissolved organic matter. For the HOC process, in addition to its role in the oxidation of organic matter, ozone also reacted with coagulants. The reaction between ozone and coagulants can facilitate the formation of Al13. Moreover, the oxidation of •OH and ozone can increase the charge density of the HA binding sites, homogenizing the binding sites of HA and enhancing the complexation with Al13.

Paternal cytoplasmic transmission in Chinese pine (Pinus tabulaeformis).

In this paper, the stages of normal sexual reproduction between pollen tube penetration of the archegonium and early embryo formation in Pinus tabulaeformis are described, emphasizing the transmission of parental cytoplasm, especially the DNA-containing organelles--plastids and mitochondria. The pollen tube growing in the nucellus contained an irregular tube nucleus followed by a pair of sperm cells. The tube cytoplasm contained abundant organelles, including starch-containing plastids and mitochondria. The two sperm cells differed in their volume of cytoplasm. The leading sperm, with more cytoplasm, contained abundant plastids and mitochondria, while the trailing one, with a thin layer of cytoplasm, had very few organelles. The mature egg cell contained a great number of mitochondria, whereas it lacked normal plastids. At fertilization, the pollen tube penetrated into the egg cell at the micropylar end and released all of its contents, including the two sperms. One of the sperm nuclei fused with the egg nucleus, whereas the other one was retained by the receptive vacuole. Very few plastids and mitochondria of male origin were observed around the fusing sperm and egg nuclei, while the retained sperm nucleus was surrounded by a large amount of male cytoplasm. The discharged tube cytoplasm occupied a large micropylar area in the egg cell. In the free nuclear proembryo, organelles of maternal and paternal origins intermingled in the neocytoplasm around the free nuclei. Most of the mitochondria had the same features as those of the egg cell, but some appeared to be from sperm cells and tube cytoplasm. Plastids were obviously of male origin, with an appearance similar to those of the sperm or tube cells. After cellularization of the proembryo, maternal mitochondria became more abundant than the paternal ones and the plastids enlarged and began to accumulate starch. The results reveal the cytological mechanism for paternal inheritance of plastids and biparental inheritance of mitochondria in Chinese pine.