Intranasal LAG3 antibody infusion induces a rapid antidepressant effect via the hippocampal ERK1/2-BDNF signaling pathway in chronically stressed mice.

The decline of microglia in the dentate gyrus is a new phenomenon that may explain the pathogenesis of depression, and reversing this decline has an antidepressant effect. The development of strategies that restore the function of dentate gyrus microglia in under stressful conditions is becoming a new focus. Lymphocyte-activating gene-3 (LAG3) is an immune checkpoint expressed by immune cells including microglia. One of its functions is to suppress the expansion of immune cells. In a recent study, chronic systemic administration of a LAG3 antibody that readily penetrates the brain was reported to reverse chronic stress-induced hippocampal microglia decline and depression-like behaviors. We showed here that a single intranasal infusion of a LAG3 antibody (In-LAG3 Ab) reversed chronic unpredictable stress (CUS)-induced depression-like behaviors in a dose-dependent manner, which was accompanied by an increase in brain-derived neurotrophic factor (BDNF) in the dentate gyrus. Infusion of an anti-BDNF antibody into the dentate gyrus, construction of knock-in mice with the BDNF Val68Met allele, or treatment with the BDNF receptor antagonist K252a abolished the antidepressant effect of In-LAG3 Ab. Activation of extracellular signal-regulated kinase1/2 (ERK1/2) is required for the reversal effect of In-LAG3 Ab on CUS-induced depression-like behaviors and BDNF decrease in the dentate gyrus. Moreover, both inhibition and depletion of microglia prevented the reversal effect of In-LAG3 Ab on CUS-induced depression-like behaviors and impairment of ERK1/2-BDNF signaling in the dentate gyrus. These results suggest that In-LAG3 Ab exhibits an antidepressant effect through microglia-mediated activation of ERK1/2 and synthesis of BDNF in the dentate gyrus.

Liver damage and lipid metabolic dysregulation in adult zebrafish (Danio rerio) induced by spirotetramat.

Spirotetramat, an insecticide derived from cycloketone and extensively utilized in agricultural production, has been reported to be toxic to an array of aquatic organisms. Previous studies have indicated that spirotetramat can cause toxicity such as impaired ovarian development and apoptosis in zebrafish, but its toxicological effects on lipid metabolism and liver health in zebrafish remain unclear. In this study, we explored the effects of spirotetramat exposure on zebrafish (Danio rerio) by examining key markers of lipid metabolism, alterations in gene expression related to this process, and histological characteristics of the liver. Spirotetramat significantly reduced the condition factor, triglycerides and low-density lipoprotein cholesterol levels at 2 mg/L. The expression of genes related to fatty acid synthesis (acacb), ß-oxidation (acox1, pparda) and pro-inflammatory cytokines (tnf-α, il-1ß) was downregulated. However, the expression of genes related to lipid transport and uptake (cd36, ppara) and output (apob) was upregulated. The activity of alanine aminotransferase was significantly inhibited. Histopathology results showed that spirotetramat exposure led to liver cell vacuolation and necrosis. In addition, molecular docking results of spirotetramat and lipid transport related protein (ACC, ApoB) in both zebrafish and human showed the binding energy of human proteins is lower than that for zebrafish, and that the number of hydrogen bonds formed was higher. It is speculated that spirotetramat may also pose a significant potential hazard to humans, potentially affecting human lipid metabolism and health. This study expunge shed light on the ecological toxicity of spirotetramat by showing how it disrupts lipid metabolism and causes tissue damage specifically in zebrafish liver, contributing to a deeper understanding of its harmful effects in aquatic environment.

Exploring the Maintaining Period and the Differentially Expressed Genes between the Yellow and Black Stripes of the Juvenile Stripe in the Offspring of Wild Boar and Duroc.

Coloration is a crucial trait that allows species to adapt and survive in different environments. Wild boars exhibit alternating black (dark) and yellow (light) longitudinal stripes on their back during their infancy (juvenile stripes), and as adults, they transform into uniform wild-type coat color. Aiming to record the procedure of juvenile stripes disappearing, piglets (WD) with juvenile stripes were produced by crossing a wild boar with Duroc sows, and photos of their coat color were taken from 20 d to 220 d. The pigments in the hairs from the black and yellow stripes were determined. Furthermore, the differentially expressed genes between the black and yellow stripes were investigated in 5 WD with the age of 30 d using whole-transcriptome sequencing to explore the genetic mechanism of the juvenile stripes. The juvenile stripes started to disappear at about 70 d, and stripes were not distinguished with the naked eye at about 160 d; that is, the juvenile stripe completely disappeared. A hotspot of a differentially expressing (DE) region was found on chromosome 13, containing/covering 2 of 13 DE genes and 8 of 10 DE lncRNAs in this region. A network among ZIC4, ssc-miR-532-3p, and ENSSSCG00000056225 might regulate the formation of juvenile stripes. Altogether, this study provides new insights into spatiotemporal coat color pattern.

Bismuth: An Epitaxy-like Conversion Mechanism Enabled by Intercalation-Conversion Chemistry for Stable Aqueous Chloride-Ion Storage.

The exploitation of new anion battery systems based on high-abundance oceanic elements (e.g., F-, Cl-, and Br-) is a strong supplement to the current metal cation (e.g., Li+, Na+) battery technologies. Bismuth (Bi), the rare anion-specific anode species nearest to practical application for chloride ion storage, is plagued by volume expansion and structure collapse due to limited control of its conversion behavior. Here, we reveal that a unique epitaxy-like conversion mechanism in the monocrystalline Bi nanospheres (R3m group) can drastically inhibit grain pulverization and capacity fading, which is enabled by Cl- intercalation in their interlayer space. The Bi nanosphere anode can self-evolve and transform into a rigid BiOCl nanosheet-interlaced structure after the initial conversion reaction. With this epitaxy-like conversion mechanism, the Bi anode exhibits a record-high capacity of 249 mAh g-1 (∼1.2 mAh cm-2) at 0.25 C and sustains more than 1400 h with 20% capacity loss. Pairing this anode with a Prussian blue cathode, the full battery can deliver an ultrahigh desalination capacity of 127.1 m gCl gBi-1. Our study milestones the understanding of conversion-type anode structures, which is an essential step toward the commercialization of aqueous batteries.

A popcorn-inspired strategy for compounding graphene@NiFe2O4 flexible films for strong electromagnetic interference shielding and absorption.

Compounding functional nanoparticles with highly conductive and porous carbon scaffolds is a basic pathway for engineering many important functional devices. However, enabling uniform spatial distribution of functional particles within a massively conjugated, monolithic and mesoporous structure remains challenging, as the high processing temperature for graphitization can arouse nanoparticle ripening, agglomerations and compositional changes. Herein, we report a unique "popcorn-making-mimic" strategy for preparing a highly conjugated and uniformly compounded graphene@NiFe2O4 composite film through a laser-assisted instantaneous compounding method in ambient condition. It can successfully inhibit the unwanted structural disintegration and mass loss during the laser treatment by avoiding oxidation, bursting, and inhomogeneous heat accumulations, thus achieving a highly integrated composite structure with superior electrical conductivity and high saturated magnetization. Such a single-sided film exhibits an absolute shielding effectiveness of up to 20906 dB cm2 g-1 with 75% absorption rate, superior mechanical flexibility and excellent temperature/humidity aging reliability. These performance indexes signify a substantial advance in EMI absorption capability, fabrication universality, small form-factor and device reliability toward commercial applications. Our method provides a paradigm for fabricating sophisticated composite materials for versatile applications.

Apoptosis-induced decline in hippocampal microglia mediates the development of depression-like behaviors in adult mice triggered by unpredictable stress during adolescence.

Depression triggered by harmful stress during adolescence is a common problem that can affect mental health. To date, the mechanisms underlying this type of depression remain unclear. One mechanism for the promotion of depression by chronic stress in adulthood is the loss of hippocampal microglia. Since deleterious stress in adolescence also activates microglia, we investigated the dynamic changes of microglia in the hippocampus in mice exposed to chronic unpredictable stress (CUS) in adolescence. Our results showed that 12 days of CUS stimulation in adolescence induced typical depression-like behaviors in adult mice, which were accompanied by a significant decrease and dystrophy of microglia in the dentate gyrus of the hippocampus. Further analysis showed that this decrease in microglia was mediated by the initial response of microglia to unpredictable stress in the dentate gyrus of the hippocampus and their subsequent apoptosis. Blocking the initial response of microglia to unpredictable stress by pretreatment with minocycline was able to prevent apoptosis and microglial decline as well as the development of depression-like behaviors in adult mice induced by adolescent CUS. Moreover, administration of lipopolysaccharide (LPS) or macrophage-colony stimulatory factor (M-CSF), two drugs that reversed microglia decline in the dentate gyrus, ameliorated the depression-like behaviors induced by CUS stimulation in adolescence. These findings reveal a novel mechanism for the development of depression-like behaviors in animals triggered by deleterious stress in adolescence and suggest that reversing microglial decline in the hippocampus may be a hopeful strategy for the treatment of depression triggered by deleterious stress in adolescence.

Differential Bioactivation Profiles of Different GS-441524 Prodrugs in Cell and Mouse Models: ProTide Prodrugs with High Cell Permeability and Susceptibility to Cathepsin A Are More Efficient in Delivering Antiviral Active Metabolites to the Lung.

We assessed factors that determine the tissue-specific bioactivation of ProTide prodrugs by comparing the disposition and activation of remdesivir (RDV), its methylpropyl and isopropyl ester analogues (MeRDV and IsoRDV, respectively), the oral prodrug GS-621763, and the parent nucleotide GS-441524 (Nuc). RDV and MeRDV yielded more active metabolite remdesivir-triphosphate (RDV-TP) than IsoRDV, GS-621763, and Nuc in human lung cell models due to superior cell permeability and higher susceptivity to cathepsin A. Intravenous administration to mice showed that RDV and MeRDV delivered significantly more RDV-TP to the lung than other compounds. Nevertheless, all four ester prodrugs exhibited very low oral bioavailability (<2%), with Nuc being the predominant metabolite in blood. In conclusion, ProTides prodrugs, such as RDV and MeRDV, are more efficient in delivering active metabolites to the lung than Nuc, driven by high cell permeability and susceptivity to cathepsin A. Optimizing ProTides' ester structures is an effective strategy for enhancing prodrug activation in the lung.

Regulation of human hydrolases and its implications in pharmacokinetics and pharmacodynamics.

Hydrolases represent an essential class of enzymes indispensable for the metabolism of various clinically essential medications. Individuals exhibit marked differences in the expression and activation of hydrolases, resulting in significant variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs metabolized by these enzymes. The regulation of hydrolase expression and activity involves both genetic polymorphisms and nongenetic factors. This review examines the current understanding of genetic and nongenetic regulators of six clinically significant hydrolases, including Carboxylesterase 1 (CES1), Carboxylesterase 2 (CES2), Arylacetamide Deacetylase (AADAC), Paraoxonase 1 (PON1), Paraoxonase 3 (PON3), and Cathepsin A (CTSA). We explore genetic variants linked to the expression and activity of the hydrolases and their effects on the PK and PD of their substrate drugs. Regarding nongenetic regulators, we focus on the inhibitors and inducers of these enzymes. Additionally, we examine the developmental expression patterns and gender differences in the hydrolases when pertinent information was available. Many genetic and nongenetic regulators were found to be associated with the expression and activity of the hydrolases and PK and PD. However, hydrolases remain generally understudied compared to other drug-metabolizing enzymes, such as cytochrome P450s. The clinical significance of genetic and nongenetic regulators has not yet been firmly established for the majority of hydrolases. Comprehending the mechanisms that underpin the regulation of these enzymes holds the potential to refine therapeutic regimens, thereby enhancing the efficacy and safety of drugs metabolized by the hydrolases. Significance Statement Hydrolases play a crucial role in the metabolism of numerous clinically important medications. Genetic polymorphisms and nongenetic regulators can affect hydrolases' expression and activity, consequently influencing the exposure and clinical outcomes of hydrolase substrate drugs. A comprehensive understanding of hydrolase regulation can refine therapeutic regimens, ultimately enhancing the efficacy and safety of drugs metabolized by the enzymes.

Regulation of carboxylesterases and its impact on pharmacokinetics and pharmacodynamics: an up-to-date review.

INTRODUCTION: Carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) are among the most abundant hydrolases in humans, catalyzing the metabolism of numerous clinically important medications, such as methylphenidate and clopidogrel. The large interindividual variability in the expression and activity of CES1 and CES2 affects the pharmacokinetics (PK) and pharmacodynamics (PD) of substrate drugs. AREAS COVERED: This review provides an up-to-date overview of CES expression and activity regulations and examines their impact on the PK and PD of CES substrate drugs. The literature search was conducted on PubMed from inception to January 2024. EXPERT OPINION: Current research revealed modest associations of CES genetic polymorphisms with drug exposure and response. Beyond genomic polymorphisms, transcriptional and posttranslational regulations can also significantly affect CES expression and activity and consequently alter PK and PD. Recent advances in plasma biomarkers of drug-metabolizing enzymes encourage the research of plasma protein and metabolite biomarkers for CES1 and CES2, which could lead to the establishment of precision pharmacotherapy regimens for drugs metabolized by CESs. Moreover, our understanding of tissue-specific expression and substrate selectivity of CES1 and CES2 has shed light on improving the design of CES1- and CES2-activated prodrugs.

Immunization with a low dose of zymosan A confers resistance to depression-like behavior and neuroinflammatory responses in chronically stressed mice.

Stimulation of the innate immune system prior to stress exposure is a possible strategy to prevent depression under stressful conditions. Based on the innate immune system stimulating activities of zymosan A, we hypothesize that zymosan A may prevent the development of chronic stress-induced depression-like behavior. Our results showed that a single injection of zymosan A 1 day before stress exposure at a dose of 2 or 4 mg/kg, but not at a dose of 1 mg/kg, prevented the development of depression-like behaviors in mice treated with chronic social defeat stress (CSDS). The prophylactic effect of a single zymosan A injection (2 mg/kg) on CSDS-induced depression-like behaviors disappeared when the time interval between zymosan A and stress exposure was extended from 1 day or 5 days to 10 days, which was rescued by a second zymosan A injection 10 days after the first zymosan A injection and 4 days (4×, once daily) of zymosan A injections 10 days before stress exposure. Further analysis showed that a single zymosan A injection (2 mg/kg) 1 day before stress exposure could prevent the CSDS-induced increase in pro-inflammatory cytokines in the hippocampus and prefrontal cortex. Inhibition of the innate immune system by pretreatment with minocycline (40 mg/kg) abolished the preventive effect of zymosan A on CSDS-induced depression-like behaviors and CSDS-induced increase in pro-inflammatory cytokines in the brain. These results suggest that activation of the innate immune system triggered by zymosan A prevents the depression-like behaviors and neuroinflammatory responses in the brain induced by chronic stress.

NSC689857, an inhibitor of Skp2, produces antidepressant-like effects in mice.

We have previously reported that two inhibitors of an E3 ligase S-phase kinase-associated protein 2 (Skp2), SMIP004 and C1, have an antidepressant-like effect in non-stressed and chronically stressed mice. This prompted us to ask whether other Skp2 inhibitors could also have an antidepressant effect. Here, we used NSC689857, another Skp2 inhibitor, to investigate this hypothesis. The results showed that administration of NSC689857 (5 mg/kg) produced an antidepressant-like effect in a time-dependent manner in non-stressed male mice, which started 8 days after drug administration. Dose-dependent analysis showed that administration of 5 and 10 mg/kg, but not 1 mg/kg, of NSC689857 produced antidepressant-like effects in both non-stressed male and female mice. Administration of NSC689857 (5 mg/kg) also induced antidepressant-like effects in non-stressed male mice when administered three times within 24 h (24, 5, and 1 h before testing) but not when administered acutely (1 h before testing). In addition, NSC689857 and fluoxetine coadministration produced additive antidepressant-like effects in non-stressed male mice. These effects of NSC689857 were not associated with the changes in locomotor activity. Administration of NSC689857 (5 mg/kg) also attenuated depression-like behaviors in male mice induced by chronic social defeat stress, suggesting therapeutic potential of NSC689857 in depression. Overall, these results suggest that NSC689857 is capable of exerting antidepressant-like effects in both non-stressed and chronically stressed mice.

Comparisons of long-term clinical outcomes with left bundle branch pacing, left ventricular septal pacing, and biventricular pacing for cardiac resynchronization therapy.

BACKGROUND: Left bundle branch pacing (LBBP) and left ventricular septal pacing (LVSP) are referred to as left bundle branch area pacing. OBJECTIVE: This study investigated whether long-term clinical outcomes differ in patients undergoing LBBP, LVSP, and biventricular pacing (BiVP) for cardiac resynchronization therapy (CRT). METHODS: Consecutive patients with reduced left ventricular ejection fraction (LVEF <50%) undergoing CRT were prospectively enrolled if they underwent successful LBBP, LVSP, or BiVP. The primary composite end point was all-cause mortality or heart failure hospitalization. Secondary end points included all-cause mortality, heart failure hospitalization, and echocardiographic measures of reverse remodeling. RESULTS: A total of 259 patients (68 LBBP, 38 LVSP, and 153 BiVP) were observed for a mean duration of 28.8 ± 15.8 months. LBBP was associated with a significantly reduced risk of the primary end point by 78% compared with both BiVP (7.4% vs 41.2%; adjusted hazard ratio [aHR], 0.22 [0.08-0.57]; P = .002) and LVSP (7.4% vs 47.4%; aHR, 0.22 [0.08-0.63]; P = .004]. The adjusted risk of all-cause mortality was significantly higher in LVSP than in BiVP (31.6% vs 7.2%; aHR, 3.19 [1.38-7.39]; P = .007) but comparable between LBBP and BiVP (2.9% vs 7.2%; aHR, 0.33 [0.07-1.52], P = .155). Propensity score adjustment also obtained similar results. LBBP showed a higher rate of echocardiographic response (ΔLVEF ≥10%: 60.0% vs 36.2% vs 16.1%; P < .001) than BiVP or LVSP. CONCLUSION: LBBP yielded long-term clinical outcomes superior to those of BiVP and LVSP. The role of LVSP for CRT needs to be reevaluated because of its high mortality risk.

Customizing catalyst surface/interface structures for electrochemical CO2 reduction.

Electrochemical CO2 reduction reaction (CO2RR) provides a promising route to converting CO2 into value-added chemicals and to neutralizing the greenhouse gas emission. For the industrial application of CO2RR, high-performance electrocatalysts featuring high activities and selectivities are essential. It has been demonstrated that customizing the catalyst surface/interface structures allows for high-precision control over the microenvironment for catalysis as well as the adsorption/desorption behaviors of key reaction intermediates in CO2RR, thereby elevating the activity, selectivity and stability of the electrocatalysts. In this paper, we review the progress in customizing the surface/interface structures for CO2RR electrocatalysts (including atomic-site catalysts, metal catalysts, and metal/oxide catalysts). From the perspectives of coordination engineering, atomic interface design, surface modification, and hetero-interface construction, we delineate the resulting specific alterations in surface/interface structures, and their effect on the CO2RR process. At the end of this review, we present a brief discussion and outlook on the current challenges and future directions for achieving high-efficiency CO2RR via surface/interface engineering.

CT radiomics analysis discriminates pulmonary lesions in patients with pulmonary MALT lymphoma and non-pulmonary MALT lymphoma.

PURPOSE: The aim of this study is to create and validate a radiomics model based on CT scans, enabling the distinction between pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma and other pulmonary lesion causes. METHODS: Patients diagnosed with primary pulmonary MALT lymphoma and lung infections at Fuzhou Pulmonary Hospital were randomly assigned to either a training group or a validation group. Meanwhile, individuals diagnosed with primary pulmonary MALT lymphoma and lung infections at Fujian Provincial Cancer Hospital were chosen as the external test group. We employed ITK-SNAP software for delineating the Region of Interest (ROI) within the images. Subsequently, we extracted radiomics features and convolutional neural networks using PyRadiomics, a component of the Onekey AI software suite. Relevant radiomic features were selected to build an intelligent diagnostic prediction model utilizing CT images, and the model's efficacy was assessed in both the validation group and the external test group. RESULTS: Leveraging radiomics, ten distinct features were carefully chosen for analysis. Subsequently, this study employed the machine learning techniques of Logistic Regression (LR), Support Vector Machine (SVM), and k-Nearest Neighbors (KNN) to construct models using these ten selected radiomics features within the training groups. Among these, SVM exhibited the highest performance, achieving an accuracy of 0.868, 0.870, and 0.90 on the training, validation, and external testing groups, respectively. For LR, the accuracy was 0.837, 0.863, and 0.90 on the training, validation, and external testing groups, respectively. For KNN, the accuracy was 0.884, 0.859, and 0.790 on the training, validation, and external testing groups, respectively. CONCLUSION: We established a noninvasive radiomics model utilizing CT imaging to diagnose pulmonary MALT lymphoma associated with pulmonary lesions. This model presents a promising adjunct tool to enhance diagnostic specificity for pulmonary MALT lymphoma, particularly in populations where pulmonary lesion changes may be attributed to other causes.

Liquid Metal Loaded Molecular Sieve: Specialized Lithium Dendrite Blocking Filler for Polymeric Solid-State Electrolyte.

All-solid-state lithium metal batteries (LMBs) are currently one of the best candidates for realizing the yearning high-energy-density batteries with high safety. However, even polyethylene oxide (PEO), the most popular polymeric solid-state electrolyte (SSE) with the largest ionic conductivity in the category so far, has significant challenges due to the safety issues of lithium dendrites, and the insufficient ionic conductivity. Herein, molecular sieve (MS) is integrated into the PEO as an inert filler with the liquid metal (LM) as a functional module, forming an "LM-MS-PEO" composite as both SSE with enhanced ionic conductivity, and protection layer against lithium dendrites. As demonstrated by theoretical and experimental investigations, LM released from MS can be uniformly and efficiently distributed in PEO, which could avoid agglomeration, enable the effective blocking of lithium dendrites, and regulate the mass transport of Li ions, thus achieving even deposition of lithium during charge/discharge. Moreover, MS could reduce the crystallinity of PEO, improve lithium-ion conductivity, and reduce operating temperature. Benefiting from the introduction of the functional MS/LM, the LM-MS-PEO electrolyte exhibits fourfold higher lithium ionic conductivity than the pristine PEO at 40 °C, while the as-assembled all-solid-state LMBs have four to five times longer stable cycle life.

Mineralization and residue characteristics of chloramphenicol in aerobic soils: evidence from a carbon-14 study.

Chloramphenicol, a broad-spectrum antibiotic employed for controlling bacterial infections, presents an intriguing aspect in terms of its environmental fate in soils. 14C-labeled chloramphenicol was used to explore its mineralization and residue characteristics in three distinct agricultural soils in China. The findings revealed a nuanced pattern in the fate of 14C-chloramphenicol, with notable variations among the different soils under investigation. The chloramphenicol extract residue exhibited a reduction of 18.04% in sandy clay soil, 23.04% in clay loam soil, and 21.73% in loamy clay soil. Notably, the mineralization rate in sandy clay soil was 25.22% surpassed that in the other two soils, particularly during the initial stages of incubation. Over time, the diminishing extract residue underwent conversion into minerals and bound residue. The formation rate of bound residue was increased from 44.59 to 53.65% after adding 10% manure, suggesting that chloramphenicol easily binds with soils rich in organic matter. The bound residue is predominantly localized in the humin fraction across all soils. Additionally, the sterilized soil experiments indicated the pivotal role of microorganisms in influencing the fate of chloramphenicol under the specified experimental conditions. In conclusion, this study offers valuable insights into the environmental dynamics of chloramphenicol in soils, emphasizing the importance of soil composition, organic matter content, and microbial activity. The findings contribute to a scientific understanding of the environmental safety implications associated with chloramphenicol usage.

Dynamically Adaptive Bubbling for Upgrading Oxygen Evolution Reaction Using Lamellar Fern-Like Alloy Aerogel Self-Standing Electrodes.

Adopting renewable electricity to produce "green" hydrogen has been a critical challenge because at a high current density the mass transfer capability of most catalytic electrodes deteriorates significantly. Herein, a unique lamellar fern-like alloy aerogel (LFA) electrode, showing a unique dynamically adaptive bubbling capability and can effectively avoid stress concentration caused by bubble aggregation is reported. The LFA electrode is intrinsically highly catalytic-active and shows a highly porous, resilient, hierarchically ordered, and well-percolated conductive network. It not only shows superior gas evacuation capability but also exhibits significantly improved stability at high current densities, showing the record lowest oxygen evolution reaction (OER) overpotential of 244 mV at 1000 mA cm-2 and stably over 6000 h. With the merits of mechanical robustness, excellent electron transport, and efficient bubble evacuation, LFA can be self-standing catalytic electrode and gas diffusion layers in anion-exchange-membrane water electrolysis (AEMWE), which can achieve 3000 mA cm-2 at a low voltage of 1.88 V and can sustain stable electrolysis at 2000 mA cm-2 for over 1300 h. This strategy can be extended to various gas evolution reactions as a general design rule for multiphase catalysis applications.

Novel Independent Trans- and Cis-Genetic Variants Associated with CYP2D6 Expression and Activity in Human Livers.

Cytochrome P450 2D6 (CYP2D6) is a critical hepatic drug-metabolizing enzyme in humans, responsible for metabolizing approximately 20%-25% of commonly used medications such as codeine, desipramine, fluvoxamine, paroxetine, and tamoxifen. The CYP2D6 gene is highly polymorphic, resulting in substantial interindividual variability in its catalytic function and the pharmacokinetics and therapeutic outcomes of its substrate drugs. Although many functional CYP2D6 variants have been discovered and validated, a significant portion of the variability in the expression and activity of CYP2D6 remains unexplained. In this study, we performed a genome-wide association study (GWAS) to identify novel variants associated with CYP2D6 protein expression in individual human livers, followed by a conditional analysis to control for the effect of functional CYP2D6 star alleles. We also examined their impact on hepatic CYP2D6 activity. Genotyping on a genome-wide scale was achieved using the Illumina Multi-Ethnic Genotyping Array (MEGA). A data-independent acquisition (DIA)-based proteomics method was used to quantify CYP2D6 protein concentrations. CYP2D6 activity was determined by measuring the dextromethorphan O-demethylation in individual human liver s9 fractions. The GWAS identified 44 single nuclear polymorphisms (SNPs) that are significantly associated with CYP2D6 protein expressions with a P value threshold of 5.0 × 10-7 After the conditional analysis, five SNPs, including the cis-variants rs1807493 and rs1062753 and the trans-variants rs4073010, rs729559, and rs80274432, emerged as independent variants significantly correlated with hepatic CYP2D6 protein expressions. Notably, four of these SNPs, except for rs80274432, also exhibited a significant association with CYP2D6 activities in human livers, suggesting their potential as novel and independent cis- and trans-variants regulating CYP2D6. SIGNIFICANT STATEMENT: Using individual human livers, we identified four novel cis- and trans-pQTLs/aQTLs (protein quantitative trait loci/activity quantitative trait loci) of Cytochrome P450 2D6 (CYP2D6) that are independent from known functional CYP2D6 star alleles. This study connects the CYP2D6 gene expression and activity, enhancing our understanding of the genetic variants associated with CYP2D6 protein expression and activity, potentially advancing our insight into the interindividual variability in CYP2D6 substrate medication response.

Transplacental methadone exposure and risk of Neonatal Opioid Withdrawal Syndrome.

STUDY OBJECTIVE: Neonatal opioid withdrawal syndrome (NOWS) is a condition that often occurs in neonates born to mothers who received methadone treatment for opioid use disorder during pregnancy. Early identification and treatment of infants at risk of NOWS may improve clinical outcomes. The purpose of this study was to evaluate whether maternal and umbilical cord plasma concentrations of methadone and its metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), could predict the need for NOWS treatment. DESIGN: Single-center prospective study. SETTING: University of Michigan Neonatal Intensive Care Unit. PATIENTS: The study included 11 opioid-dependent mother-infant dyads, where the mothers were treated with methadone at 34 weeks' gestation or later. INTERVENTION: Maternal and cord blood samples were collected from the study participants. MEASUREMENTS AND MAIN RESULTS: Maternal and cord plasma concentrations of methadone and EDDP were determined. Six out of the 11 infants required treatment for NOWS. Maternal methadone plasma concentrations were comparable between infants requiring and not requiring NOWS treatment (329.1 ± 229.7 ng/mL vs. 413.2 ± 329.8 ng/mL). However, the average cord plasma methadone concentration in infants who did not require NOWS treatment was 2.9-fold higher than in those who required the treatment (120.0 ± 88.6 ng/mL vs. 40.9 ± 24.4 ng/mL), although the difference was not statistically significant. The ratios of maternal-to-cord methadone plasma concentrations were significantly higher in patients who required treatment for NOWS compared with those who did not (7.7 ± 1.9 vs. 3.5 ± 1.6, p = 0.003). Maternal and cord plasma EDDP concentrations and the maternal-to-cord plasma EDDP concentration ratios did not differ between patients who required and did not require treatment for NOWS. CONCLUSIONS: The results suggest that methadone permeability across the blood-placental barrier may affect in utero exposure to methadone, and the maternal-to-cord methadone plasma concentration ratio could be a potential biomarker for predicting the need for NOWS treatment.

Mobilization of the innate immune response by a specific immunostimulant ß-glucan confers resistance to chronic stress-induced depression-like behavior by preventing neuroinflammatory responses.

Pre-stimulation of the innate immune response is an effective strategy to prevent depression-like phenotypes in animals. However, the use of conventional immunostimulants may cause adverse effects. Therefore, the search for agents that stimulate the innate immune response but do not induce a pro-inflammatory response could be a new research direction for the prevention of depression. ß-glucan is a polysaccharide from Saccharomyces cerevisiae with unique immunomodulatory activity in microglia without eliciting a pro-inflammatory response that could lead to tissue damage. This suggests that ß-glucan may be a suitable drug that can be used to prevent depression-like phenotypes. Our results showed that a single injection of ß-glucan 1 day before stress exposure at a dose of 10 or 20 mg/kg, but notat a dose of 5 mg/kg, prevented depression-like behavior in mice treated with chronic unpredictable stress (CUS). This effect of ß-glucan disappeared when the time interval between ß-glucan and stress was extended from 1 day or 5 days to 10 days, which was rescued by a second injection 10 days after the first injection or by a repeated injection (4×, once daily) 10 days before stress exposure. A single ß-glucan injection (20 mg/kg) 1 day before stress exposure prevented the CUS-induced increase in brain pro-inflammatory cytokines, and inhibition of the innate immune response by minocycline (40 mg/kg) abolished the preventive effect of ß-glucan on CUS-induced depression-like behaviors and neuroinflammatory responses. These results suggest that ß-glucan may prevent chronic stress-induced depression-like phenotypes and neuroinflammatory responses by stimulating the innate immune response.