Severity of depressive and anxious symptoms and its association with birth outcomes among pregnant women during the COVID-19 pandemic: a prospective case-control study.

AIM: Comparing the anxiety and depression severity and their impact on subsequent birth outcomes in pregnant women before and during Omicron wave in Shanghai in 2022. METHODS: The depression-anxiety symptoms networks were compared between the pregnant women during the outbreak period (outbreak group; n = 783) and a matched control group of pregnant women before the outbreak (pre-outbreak group; n = 783). The impact of baseline mental state on follow-up pregnancy and neonatal outcomes was also explored by logistic regression. FINDINGS: Levels of depression and anxiety between the two groups were not significant different. Network analysis showed that central symptom "trouble relaxing" and bridge symptom "depressed mood" shared by both groups. Different symptom associations in different periods of the pandemic. Total scores and sub-symptom scores of prenatal depressive and anxious severities increased the odds ratios of maternal and neonatal syndromes. The influence of mental state on gestational and neonatal outcomes differed across different pandemic periods. CONCLUSION: The Omicron wave did not have a significant negative impact on the depressive and anxious mood in pregnant women. Targeting central and bridge symptoms intervention may be effective in reducing their adverse effects on co-occurring of anxious and depressive mood and birth outcomes.

Choline metabolism reprogramming mediates an immunosuppressive microenvironment in non-small cell lung cancer (NSCLC) by promoting tumor-associated macrophage functional polarization and endothelial cell proliferation.

INTRODUCTION: Lung cancer is a prevalent malignancy globally, and immunotherapy has revolutionized its treatment. However, resistance to immunotherapy remains a challenge. Abnormal cholinesterase (ChE) activity and choline metabolism are associated with tumor oncogenesis, progression, and poor prognosis in multiple cancers. Yet, the precise mechanism underlying the relationship between ChE, choline metabolism and tumor immune microenvironment in lung cancer, and the response and resistance of immunotherapy still unclear. METHODS: Firstly, 277 advanced non-small cell lung cancer (NSCLC) patients receiving first-line immunotherapy in Sun Yat-sen University Cancer Center were enrolled in the study. Pretreatment and the alteration of ChE after 2 courses of immunotherapy and survival outcomes were collected. Kaplan-Meier survival and cox regression analysis were performed, and nomogram was conducted to identify the prognostic and predicted values. Secondly, choline metabolism-related genes were screened using Cox regression, and a prognostic model was constructed. Functional enrichment analysis and immune microenvironment analysis were also conducted. Lastly, to gain further insights into potential mechanisms, single-cell analysis was performed. RESULTS: Firstly, baseline high level ChE and the elevation of ChE after immunotherapy were significantly associated with better survival outcomes for advanced NSCLC. Constructed nomogram based on the significant variables from the multivariate Cox analysis performed well in discrimination and calibration. Secondly, 4 choline metabolism-related genes (MTHFD1, PDGFB, PIK3R3, CHKB) were screened and developed a risk signature that was found to be related to a poorer prognosis. Further analysis revealed that the choline metabolism-related genes signature was associated with immunosuppressive tumor microenvironment, immune escape and metabolic reprogramming. scRNA-seq showed that MTHFD1 was specifically distributed in tumor-associated macrophages (TAMs), mediating the differentiation and immunosuppressive functions of macrophages, which may potentially impact endothelial cell proliferation and tumor angiogenesis. CONCLUSION: Our study highlights the discovery of ChE as a prognostic marker in advanced NSCLC, suggesting its potential for identifying patients who may benefit from immunotherapy. Additionally, we developed a prognostic signature based on choline metabolism-related genes, revealing the correlation with the immunosuppressive microenvironment and uncovering the role of MTHFD1 in macrophage differentiation and endothelial cell proliferation, providing insights into the intricate workings of choline metabolism in NSCLC pathogenesis.

Safety and efficacy of a low-dose combination of midazolam, alfentanil, and propofol for deep sedation of elderly patients undergoing ERCP.

BACKGROUND: Proper sedation of patients, particularly elderly individuals, who are more susceptible to sedation-related complications, is of significant importance in endoscopic retrograde cholangiopancreatography (ERCP). This study aims to assess the safety and efficacy of a low-dose combination of midazolam, alfentanil, and propofol for deep sedation in elderly patients undergoing ERCP, compared to a group of middle-aged patients. METHODS: The medical records of 610 patients with common bile duct stones who underwent elective ERCP under deep sedation with a three-drug regimen, including midazolam, alfentanil, and propofol at Shandong Provincial Third Hospital from January 2023 to September 2023 were retrospectively reviewed in this study. Patients were categorized into three groups: middle-aged (50-64 years, n = 202), elderly (65-79 years, n = 216), and very elderly (≥ 80 years, n = 192). Intraoperative vital signs and complications were compared among these groups. RESULTS: The three groups showed no significant difference in terms of intraoperative variation of systolic blood pressure (P = 0.291), diastolic blood pressure (P = 0.737), heart rate (P = 0.107), peripheral oxygen saturation (P = 0.188), bispectral index (P = 0.158), and the occurrence of sedation-related adverse events including hypotension (P = 0.170) and hypoxemia (P = 0.423). CONCLUSION: The results suggest that a low-dose three-drug regimen consisting of midazolam, alfentanil, and propofol seems safe and effective for deep sedation of elderly and very elderly patients undergoing ERCP procedures. However, further studies are required to verify these findings and clarify the benefits and risks of this method.

Comparing sedation protocols for endoscopic retrograde cholangiopancreatography (ERCP): A retrospective study.

Background: Endoscopic retrograde cholangiopancreatography (ERCP) is a widely used diagnostic and therapeutic procedure. Effective sedation is crucial to enhance patient comfort and optimize endoscopist performance. Various sedation protocols, including Propofol and Dexmedetomidine (Pro-Dex), Ketamine and Propofol (Keto-Fol), Propofol and Midazolam (Pro-Mid), and Propofol alone, have been utilized during ERCP. This retrospective study aims to compare the safety and efficacy of these four sedation protocols. Methods: A retrospective analysis was conducted on data from 600 patients who underwent ERCP between 2018 and 2021, with each patient receiving one of the four sedation protocols. Protocol assignment was based on the endoscopist's preference. Data on hemodynamic parameters, sedation level, recovery time, and procedure-related complications were collected. Results: Baseline data showed no significant differences among the groups pre-procedure. The Pro-Dex group exhibited significantly lower mean total propofol dose, shorter recovery time, and faster achievement of Ramsay Sedation Scale (RSS) score 3-4 compared to the other groups. The Pro-group demonstrated significantly longer hospital stay than the other three groups (median, 4.19 ± 1.1 vs. 3.48 ± 1.2 days in the KP groups, p = 0.042). There were no significant variations in the incidence of respiratory depression, hypotension, or bradycardia among the four groups. Additionally, notable trends were found for hemodynamic measures, total propofol dosage, time to reach the desired level of sedation (as measured by the Ramsay Sedation Scale), and hospital stay based on BMI categories, indicating that higher BMI is linked to more serious outcomes. Conclusion: Our retrospective study demonstrates that the Pro-Dex protocol offers superior sedation quality, faster recovery, and fewer complications compared to the other protocols during ERCP. However, the incidence of ERCP-related adverse events did not significantly differ among the four sedation protocols. These findings can aid clinicians in selecting the most appropriate sedation protocol for ERCP, considering patient and endoscopist preferences.

Polystyrene microplastics induce anxiety via HRAS derived PERK-NF-κB pathway.

Exposure to environmentally hazardous substances is recognized as a significant risk factor for neurological associated disorders. Among these substances, polystyrene microplastics (PS-MPs), widely utilized in various consumer products, have been reported to exhibit neurotoxicity. However, the potential association of PS-MPs with abnormal anxiety behaviors, along with the underlying molecular mechanisms and key proteins involved, remains insufficiently explored. Here, we delineated the potential mechanisms of PS-MPs-induced anxiety through proteomics and molecular investigations. We characterized the PS-MPs, observed their accumulation in the brain, leading to anxiety-like behavior in mice, which is correlated with microglia activation and pro-inflammatory response. Consistent with these findings, our studies on BV2 microglia cells showed that PS-MPs activated NF-κB-mediated inflammation resulting in the upregulation of pro-inflammatory cytokines such as TNFα and IL-1ß. Of particular significance, HRAS was identified as a key factor in the PS-MPs induced pro-inflammatory response through whole proteomics analysis, and knockdown of H-ras effectively inhibited PS-MPs induced PERK-NF-κB activation and associated pro-inflammatory response in microglia cells. Collectively, our findings highlight that PS-MPs induce anxiety of mice via the activation of the HRAS-derived PERK-NF-κB pathway in microlglia. Our results contribute valuable insights into the molecular mechanisms of PS-MPs-induced anxiety, and may offer implications for addressing neurotoxicity and prevention the adverse effects of environmentally hazardous substances, including microplastics.

Cdc42-driven endosomal cholesterol transport promotes collateral resistance in HER2-positive gastric cancer.

Resistance to trastuzumab and the poor efficacy of subsequent chemotherapy have become major challenges for HER2-positive gastric cancer (GC). As resistance evolves, tumor cells may acquire a new drug susceptibility profile, profoundly impacting the subsequent treatment selection and patient survival. However, the interplay between trastuzumab and other types of drugs in HER2-positive GC remains elusive. In our study, we utilized resistant cell lines and tissue specimens to map the drug susceptibility profile of trastuzumab-resistant GC, discovering that resistance to trastuzumab induces collateral resistance to commonly used chemotherapeutic agents. Additionally, patients with collateral resistance distinguished by a 13-gene scoring model in HER2-positive GC cohorts are predicted to have a poor prognosis and may be sensitive to cholesterol-lowering drugs. Mechanistically, endosomal cholesterol transport is further confirmed to enrich cholesterol in the plasma membrane, contributing to collateral resistance through the Hedgehog-ABCB1 axis. As a driver for cholesterol, Cdc42 is activated by the formation of the NPC1-TßRI-Cdc42 complex to facilitate endosomal cholesterol transport. We demonstrated that inhibiting Cdc42 activation with ZCL278 reduces cholesterol levels in the plasma membrane and reverses collateral resistance between trastuzumab and chemotherapy in vitro and in vivo. Collectively, our findings verify the phenomena and mechanism of collateral resistance between trastuzumab and chemotherapy, and propose a potential therapeutic target and strategy in the second-line treatment for trastuzumab-resistant HER2-positive GC.

Mirabegron Add-On Tamsulosin for Men with Overactive Bladder Symptoms: A Pooled Analysis of Four Randomized Controlled Trials.

INTRODUCTION: Overactive bladder symptoms (OABSs) affect patients' quality of life (QOL) worldwide. This pooled analysis compared the efficacy and safety of mirabegron add-on tamsulosin with those of tamsulosin add-on placebo in OABS treatment. METHODS: PubMed, Embase, MEDLINE, and the Cochrane Controlled Trial Register databases were searched for randomized controlled trials (RCTs) examining the efficacy of mirabegron add-on therapy to tamsulosin in the treatment of OABS. Moreover, references from the selected studies were screened. Review Manager 5.4 was used to analyze data. RESULTS: Four RCTs involving 1,397 patients with OABS were selected. Of the total, 697 patients receiving mirabegron add-on tamsulosin constituted the experimental group, and 700 patients receiving tamsulosin add-on placebo constituted the control group. The efficacy endpoints were as follows: mean number of micturition per day (mean difference [MD] = -0.26, 95% confidence interval [CI] = -0.41 to -0.10, p = 0.0001), urgency episodes per day (MD = -0.67, 95% CI = -1.02 to -0.32, p = 0.0002), urgency urinary incontinence (UUI) episodes per day (MD = -0.42, 95% CI = -0.66 to -0.19, p = 0.0005), mean volume voided/micturition (MD = 10.84, 95% CI = 4.97-16.71, p = 0.0003), total International Prostate Symptom Score (IPSS) (MD = -2.01, 95% CI = -4.02 to -0.01, p = 0.05), and IPSS QOL index (MD = -0.65, 95% CI = -0.94 to -0.35, p < 0.0001). Mirabegron therapy, an add-on therapy to tamsulosin, was effective in treating patients with OABS. Moreover, mirabegron might reduce the total IPSS (MD = -2.01, 95% CI = -4.02 to -0.01, p = 0.05). The safety endpoint, treatment-emergent adverse events (odds ratio = 0.94, 95% CI = 0.78-1.13, p = 0.49), suggested that although mirabegron was well-tolerated, it possibly increased the post-void residual urine volume (MD = 10.28, 95% CI = 1.82-18.75, p = 0.02). CONCLUSION: Combination therapy using mirabegron and tamsulosin may be effective in treating patients with non-neurogenic OABS in terms of UUI episodes, total IPSS, and IPSS QOL index. However, its effectiveness must be verified by analyzing additional factors for OABS through further RCTs.

The difference in the elderly's visual impact assessment of pocket park landscape.

As an important part of urban public open space, pocket parks have become an important activity place for the elderly in the context of the aging society in China. With the pocket parks in Nanjing, Jiangsu province, China as research object, this paper set six landscape features to be studied, namely, Height of trees, Green color richness, Stratification of green landscapes, Green space ratio, Leisure facilities, and Water landscape. The elderly respondents with different demographic characteristics, such as age, gender, education level and residential type, were subjected to the picture stimulation experiment whose results were then statistically analyzed. The results indicate that gender and residential type exert certain influence on the elderly's visual impact assessment of pocket park landscape. To be specific, the male elderly prefer the pocket park landscape with 3-6 m high trees, medium green space ratio, and more leisure facilities; the female elderly are in greater favor of pocket park landscapes with 0-3 m high trees, five or more colors, three or more layers; the elderly who live with their families prefer pocket park landscapes with medium green space ratio and more leisure facilities; to the elderly who live alone, pocket park landscapes with trees which are 0-3 m high, five or more colors, and medium leisure facilities are more attractive. This study can provide valuable reference for pocket park design in China.

Multitrack and multianchor point screw technique combined with the Wiltse approach for lesion debridement for lumbar tuberculosis.

BACKGROUND: The incidence of lumbar tuberculosis is high worldwide, and effective treatment is a continuing problem. AIM: To study the safety and efficacy of the multitrack and multianchor point screw technique combined with the contralateral Wiltse approach for lesion debridement to treat lumbar tuberculosis. METHODS: The C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), visual analogue scale (VAS) score, oswestry disability index (ODI) and American Spinal Injury Association (ASIA) grade were recorded and analysed pre- and postoperatively. RESULTS: The CRP level and ESR returned to normal, and the VAS score and ODI were decreased at 3 mo postoperatively, with significant differences compared with the preoperative values (P < 0.01). Neurological dysfunction was relieved, and the ASIA grade increased, with no adverse events. CONCLUSION: The multitrack, multianchor point screw fixation technique combined with the contralateral Wiltse approach for debridement is an effective and safe method for the treatment of lumbar tuberculosis.

Screening of Candidate Effectors from Magnaporthe oryzae by In Vitro Secretomic Analysis.

Magnaporthe oryzae is the causal agent of rice blast, one of the most serious diseases of rice worldwide. Secreted proteins play essential roles during a M. oryzae-rice interaction. Although much progress has been made in recent decades, it is still necessary to systematically explore M. oryzae-secreted proteins and to analyze their functions. This study employs a shotgun-based proteomic analysis to investigate the in vitro secretome of M. oryzae by spraying fungus conidia onto the PVDF membrane to mimic the early stages of infection, during which 3315 non-redundant secreted proteins were identified. Among these proteins, 9.6% (319) and 24.7% (818) are classified as classically or non-classically secreted proteins, while the remaining 1988 proteins (60.0%) are secreted through currently unknown secretory pathway. Functional characteristics analysis show that 257 (7.8%) and 90 (2.7%) secreted proteins are annotated as CAZymes and candidate effectors, respectively. Eighteen candidate effectors are selected for further experimental validation. All 18 genes encoding candidate effectors are significantly up- or down-regulated during the early infection process. Sixteen of the eighteen candidate effectors cause the suppression of BAX-mediated cell death in Nicotiana benthamiana by using an Agrobacterium-mediated transient expression assay, suggesting their involvement in pathogenicity related to secretion effectors. Our results provide high-quality experimental secretome data of M. oryzae and will expand our knowledge on the molecular mechanisms of M. oryzae pathogenesis.

Decreased hemodynamic response to fearful faces relative to neutral faces in the medial frontal cortex of first-episode drug-naïve major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a disabling disease with impaired recognition of emotional facial expressions. However, the evidence is heterogeneous, regarding the mechanism of emotional processing in MDD. Focusing on patients with first-episode drug-naïve MDD, we used functional near-infrared spectroscopy (fNIRS) to investigate whether MDD have characteristic patterns in cerebral activation under facial emotion recognition task (FERT). METHODS: Thirty-five patients with first-episode drug-naïve MDD and 39 healthy controls (HCs) underwent fNIRS measure to evaluate cerebral hemodynamic response in the frontal and temporal cortex during FERT. The 17-item Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale and Inventory of Depressive Symptomatology-Self Report were applied to assess the symptoms of the patients. Cognitive functions were assessed using THINC-integrated tool. RESULTS: Hypoactivation in the medial frontal was observed in patients with MDD during recognition of fearful faces relative to neutral faces (F-N faces). Specifically, we found more right lateralized activation in the medial frontal cortex among patients with MDD compared to HCs. Further, the medial frontal activation under the condition of F-N faces was positively correlated to scores of digit symbol substitution test, and negatively relative to severity of depressive symptoms in MDD group. LIMITATIONS: Our study is cross-sectional designed, and has a relatively small sample size. CONCLUSIONS: We found abnormal patterns in the medial frontal activation of patients with first-episode drug-naïve MDD in recognition of F-N faces, which correlates with performance in cognitive function and depressive symptoms.

Circularly polarized luminescence and performance modulation of chiral europium-titanium (Eu2Ti4)-oxo clusters.

The designed synthesis of chiral luminescent molecules with excellent circularly polarized luminescence (CPL) performance and high quantum yield (QY) levels has attracted great interest but remains very challenging. Herein, we report three pairs of chiral europium-titanium-oxo clusters featuring both modest CPL characteristics and high QY levels (up to 79%), which can be regulated by switching between different ligand substituents.

Effect evaluation of various nanofiltration systems for filtering intravenous human immunoglobulin / 中国生物制品学杂志

@#Abstract： Objective To evaluate the filtration effects of various nanofiltration systems on intravenous human immunog⁃ lobulin（IVIG）in order to screen the optimal nanofiltration system. Methods Various nanofilters were used for IVIG filtration to determine the best one and then various prefilters were selected to combine with the optimal nanofilter for IVIG filtration to determine the optimal nanofiltration system. Results The tangential flow（cross flow）nanofilter showed better filtering effect than dead end（direct current）nanofilter，and nanofilter C was the best one. The effect of deep filtration prefilter was better than that of absolute filtration prefilter，and prefilter Y1 in series with nanofilter C was the optimal nanofiltration system. Conclusion The optimal nanofiltration system was determined through the effect evaluation of various nanofiltration systems filtering for IVIG.

A novel elicitor MoVcpo is necessary for the virulence of Magnaporthe oryzae and triggers rice defense responses.

Rice blast caused by Magnaporthe oryzae is one of the most important diseases of rice. Elicitors secreted by M. oryzae play important roles in the interaction with rice to facilitate fungal infection and disease development. In recent years, several elicitor proteins have been identified in M. oryzae, and their functions and importance are increasingly appreciated. In this study, we purified a novel elicitor-activity protein from M. oryzae, which was further identified as a vanadium chloroperoxidase (MoVcpo) by MAIDL TOF/TOF MS. The purified MoVcpo induced reactive oxygen species (ROS) accumulation in host cells, up-regulated the expression of multiple defense-related genes, thus significantly enhancing rice resistance against M. oryzae. These results suggested that MoVcpo functions as a pathogen-associated molecular pattern (PAMP) to trigger rice immunity. Furthermore, MoVcpo was highly expressed in the early stage of M. oryzae infection. Deletion of MoVcpo affected spore formation, conidia germination, cell wall integrity, and sensitivity to osmotic stress, but not fungal growth. Interestingly, compared with the wild-type, inoculation with MoVcpo deletion mutant on rice led to markedly induced ROS accumulation, increased expression of defense-related genes, but also lower disease severity, suggesting that MoVcpo acts as both an elicitor activating plant immune responses and a virulence factor facilitating fungal infection. These findings reveal a novel role for vanadium chloroperoxidase in fungal pathogenesis and deepen our understanding of M. oryzae-rice interactions.

FoCupin1, a Cupin_1 domain-containing protein, is necessary for the virulence of Fusarium oxysporum f. sp. cubense tropical race 4.

Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4) is an important soilborne fungal pathogen that causes the most devastating banana disease. Effectors secreted by microbes contribute to pathogen virulence on host plants in plant-microbe interactions. However, functions of Foc TR4 effectors remain largely unexplored. In this study, we characterized a novel cupin_1 domain-containing protein (FoCupin1) from Foc TR4. Sequence analysis indicated that the homologous proteins of FoCupin1 in phytopathogenic fungi were evolutionarily conserved. Furthermore, FoCupin1 could suppress BAX-mediated cell death and significantly downregulate the expression of defense-related genes in tobacco by using the Agrobacterium-mediated transient expression system. FoCupin1 was highly induced in the early stage of Foc TR4 infection. The deletion of FoCupin1 gene did not affect Foc TR4 growth and conidiation. However, FoCupin1 deletion significantly reduced Foc TR4 virulence on banana plants, which was further confirmed by biomass assay. The expression of the defense-related genes in banana was significantly induced after inoculation with FoCupin1 mutants. These results collectively indicate FoCupin1 is a putative effector protein that plays an essential role in Foc TR4 pathogenicity. These findings suggest a novel role for cupin_1 domain-containing proteins and deepen our understanding of effector-mediated Foc TR4 pathogenesis.

[Chinese Expert Consensus on Management of Special Adverse Effects 
Associated with Lorlatinib].

Anaplastic lymphoma kinase (ALK) fusions represent the second most common oncogenic driver mutation in non-small cell lung cancer (NSCLC). As the new class of 3rd generation of ALK tyrosine kinase inhibitor (TKI), lorlatinib has shown robust potency and brain-penetrant clinical activity against a wide spectrum of multiple resistance mutations within the ALK domain detected during crizotinib and 2nd generation ALK TKI treatment. Lorlatinib is generally well-tolerated with unique adverse drug reaction/adverse event, including hyperlipidemia and central nervous system effects, which are mostly mild to moderate severity and manageable through dosage modifications and/or standard medical intervention. For advanced NSCLC with ALK positivity, patients should be evaluated for baseline characteristics and pre-existing medication, informed of the potential toxicities, and periodically monitored to balance benefits and risks. Moreover, a multidisciplinary group of experts is essential to establish a comprehensive diagnostic and therapeutic strategy.
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Induction of A Disintegrin and Metalloproteinase with Thrombospondin motifs 1 by a rare variant or cognitive activities reduces hippocampal amyloid-ß and consequent Alzheimer's disease risk.

Amyloid-ß (Aß) derived from amyloid precursor protein (APP) hydrolysis is acknowledged as the predominant hallmark of Alzheimer's disease (AD) that especially correlates to genetics and daily activities. In 2019, meta-analysis of AD has discovered five new risk loci among which A Disintegrin and Metalloproteinase with Thrombospondin motifs 1 (ADAMTS1) has been further suggested in 2021 and 2022. To verify the association, we re-sequenced ADAMTS1 of clinical AD samples and subsequently identified a novel rare variant c.-2067A > C with watchable relevance (whereas the P-value was not significant after adjustment). Dual-luciferase assay showed that the variant sharply stimulated ADAMTS1 expression. In addition, ADAMTS1 was also clearly induced by pentylenetetrazol-ignited neuronal activity and enriched environment (EE). Inspired by the above findings, we investigated ADAMTS1's role in APP metabolism in vitro and in vivo. Results showed that ADAMTS1 participated in APP hydrolysis and consequently decreased Aß generation through inhibiting ß-secretase-mediated cleavage. In addition, we also verified that the hippocampal amyloid load of AD mouse model was alleviated by the introduction of ADAMTS1, and thus spatial cognition was restored as well. This study revealed the contribution of ADAMTS1 to the connection of genetic and acquired factors with APP metabolism, and its potential in reducing hippocampal amyloid and consequent risk of AD.

Pharmacological induction of AMFR increases functional EAAT2 oligomer levels and reduces epileptic seizures in mice.

Dysregulation of excitatory amino acid transporter 2 (EAAT2) contributes to the development of temporal lobe epilepsy (TLE). Several strategies for increasing total EAAT2 levels have been proposed. However, the mechanism underlying the oligomeric assembly of EAAT2, impairment of which inhibits the formation of functional oligomers by EAAT2 monomers, is still poorly understood. In the present study, we identified E3 ubiquitin ligase AMFR as an EAAT2-interacting protein. AMFR specifically increased the level of EAAT2 oligomers rather than inducing protein degradation through K542-specific ubiquitination. By using tissues from humans with TLE and epilepsy model mice, we observed that AMFR and EAAT2 oligomer levels were simultaneously decreased in the hippocampus. Screening of 2386 FDA-approved drugs revealed that the most common analgesic/antipyretic medicine, acetaminophen (APAP), can induce AMFR transcriptional activation via transcription factor SP1. Administration of APAP protected against pentylenetetrazol-induced epileptogenesis. In mice with chronic epilepsy, APAP treatment partially reduced the occurrence of spontaneous seizures and greatly enhanced the antiepileptic effects of 17AAG, an Hsp90 inhibitor that upregulates total EAAT2 levels, when the 2 compounds were administered together. In summary, our studies reveal an essential role for AMFR in regulating the oligomeric state of EAAT2 and suggest that APAP can improve the efficacy of EAAT2-targeted antiepileptic treatments.

Photoluminescence of Lanthanide-Titanium-Oxo Clusters Eu9Ti2 and Tb9Ti2 Based on a ß-Diketone Ligand.

A series of acetylacetone-protected lanthanide-titanium-oxo clusters (LTOCs), formulated as [La6Ti(µ3-OH)8(acac)12(CH3O)2(CH3OH)6] (La6Ti; Hacac = acetylacetone) and [Ln9Ti2(µ4-O)(µ3-OH)14(acac)17(CH3O)2(CH3OH)3] [Ln = Eu (Eu9Ti2) and Tb (Tb9Ti2)], were synthesized through the reactions of LnCl3·6H2O (Ln = La, Eu, and Tb), Hacac, Ti(OiPr)4, and triethylamine in methanol. Crystal structural analysis shows that La6Ti exhibits an hourglass-like structure consisting of two La3Ti cubane subunits by sharing one Ti4+ ion, while Eu9Ti2 can be viewed as a combination of four Eu3Ti cubane subunits by sharing three corners and one side. The photoluminescence (PL) measurements show that Tb9Ti2 exhibits excellent PL properties with a high quantum yield (QY) of 34.8%, while Eu9Ti2 only has a QY of 1.4% because of the different photosensitizations of ligands to Eu3+ and Tb3+ ions in the photophysical process.

Thalamo-hippocampal dysconnectivity is associated with serum cholesterol level in drug-naïve patients with first-episode schizophrenia.

Hippocampal deficits and metabolic dysregulations such as dyslipidemia have been frequently reported in schizophrenia and are suggested to contribute to the pathophysiology of schizophrenia. Hippocampus is particularly susceptible to environmental challenges including metabolism and inflammation. However, evidence linking hippocampal alterations and metabolic dysregulations are quite sparse in drug-naïve schizophrenia. A total of 166 drug-naïve patients with first-episode schizophrenia (FES) and 78 healthy controls (HC) underwent measures for several serum metabolic markers, structural and resting-state functional magnetic resonance imaging (rs-fMRI), as well as diffusion tensor imaging (DTI). Seed-to-voxel functional connectivity (FC) and probabilistic tractography were performed to assess the functional and microstructural connectivity of the bilateral hippocampi. Clinical symptoms were evaluated with Positive and Negative Syndrome Scale (PANSS). Patients with FES showed significantly decreased total cholesterol (Chol) level. Patients showed elevated FC between the left hippocampus and bilateral thalami while showing decreased microstructural connectivity between the left hippocampus and bilateral thalami. Multiple regression analyses showed that FC from the left hippocampus to the right superior frontal gyrus (SFG), bilateral frontal pole (FP), and right thalamus were negatively associated with the Chol level, while no association was observed in the HC group. Our study validated alterations in both functional and microstructural thalamo-hippocampal connectivities, and abnormal cholesterol level in FES. Moreover, decreased cholesterol level is associated with elevated thalamo-hippocampal functional connectivity in patients with FES, suggesting that dyslipidemia may interact with the hippocampal dysfunction in FES.