Depletion of microglia with PLX3397 attenuates MK-801-induced hyperactivity associated with regulating inflammation-related genes in the brain

Acute administration of MK-801(dizocilpine),an N-methyl-D-aspartate receptor(NMDAR)antagonist,can establish animal models of psychiatric disorders.However,the roles of microglia and inflammation-related genes in these animal models of psychiatric disorders remain unknown.Here,we found rapid elimination of microglia in the prefrontal cortex(PFC)and hippocampus(HPC)of mice following administration of the dual colony-stimulating factor 1 receptor(CSF1R)/c-Kit kinase inhibitor PLX3397(pexidartinib)in drinking water.Single administration of MK-801 induced hyperactivity in the open-field test(OFT).Importantly,PLX3397-induced depletion of microglia prevented the hyperactivity and schizophrenia-like behaviors induced by MK-801.However,neither repopulation of microglia nor inhibition of microglial activation by minocycline affected MK-801-induced hyperactivity.Importantly,microglial density in the PFC and HPC was significantly correlated with behavioral changes.In addition,common and distinct glutamate-,GABA-,and inflammation-related gene(116 genes)expression patterns were observed in the brains of PLX3397-and/or MK-801-treated mice.Moreover,10 common inflammation-related genes(CD68,CD163,CD206,TMEM119,CSF3R,CX3CR1,TREM2,CD11b,CSF1R,and F4/80)with very strong correlations were identified in the brain using hierarchical clustering analysis.Further correlation analysis demonstrated that the behavioral changes in the OFT were most significantly associated with the expression of inflammation-related genes(NLRP3,CD163,CD206,F4/80,TMEM119,and TMEM176a),but not glutamate-or GABA-related genes in PLX3397-and MK-801-treated mice.Thus,our results suggest that microglial depletion via a CSF1R/c-Kit kinase inhibitor can ameliorate the hyperactivity induced by an NMDAR antagonist,which is associated with modulation of immune-related genes in the brain.

Application of ablative therapy for intrahepatic recurrent hepatocellular carcinoma following hepatectomy

The post-hepatectomy recurrence rate of hepatocellular carcinoma(HCC)is persistently high,affecting the prognosis of patients.An effective therapeutic option is crucial for achieving long-term survival in patients with postoperative recurrences.Local ablative therapy has been established as a treatment option for resectable and unresectable HCCs,and it is also a feasible approach for recurrent HCC(RHCC)due to less trauma,shorter operation times,fewer complications,and faster recovery.This review focused on ablation techniques,description of potential candidates,and therapeutic and prognostic implications of ablation for guiding its application in treating intrahepatic RHCC.

Development and in vitro study of a bi-specific magnetic resonance imaging molecular probe for hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma(HCC)ranks second in terms of cancer mortality worldwide.Molecular magnetic resonance imaging(MRI)targeting HCC biomarkers such as alpha-fetoprotein(AFP)or glypican-3(GPC3)offers new strategies to enhance specificity and help early diagnosis of HCC.However,the existing iron oxide nanoparticle-based MR molecular probes singly target AFP or GPC3,which may hinder their efficiency to detect heterogeneous micro malignant HCC tumors<1 cm(MHCC).We hypothesized that the strategy of double antibody-conjugated iron oxide nanoparticles which simultaneously target AFP and GPC3 antigens may potentially be used to overcome the tumor heterogeneity and enhance the detection rate for MRI-based MHCC diagnosis.AIM To synthesize an AFP/GPC3 double antibody-labeled iron oxide MRI molecular probe and to assess its impact on MRI specificity and sensitivity at the cellular level.METHODS A double antigen-targeted MRI probe for MHCC anti-AFP-USPIO-anti-GPC3(UAG)was developed by simultaneously conjugating AFP andGPC3 antibodies to a 5 nm ultra-small superparamagnetic iron oxide nanoparticle(USPIO).At the same time,the singly labeled probes of anti-AFP-USPIO(UA)and anti-GPC3-USPIO(UG)and non-targeted USPIO(U)were also prepared for comparison.The physical characterization including morphology(transmission electron microscopy),hydrodynamic size,and zeta potential(dynamic light scattering)was conducted for each of the probes.The antigen targeting and MRI ability for these four kinds of USPIO probes were studied in the GPC3-expressing murine hepatoma cell line Hepa1-6/GPC3.First,AFP and GPC3 antigen expression in Hepa1-6/GPC3 cells was confirmed by flow cytometry and immunocytochemistry.Then,the cellular uptake of USPIO probes was investigated by Prussian blue staining assay and in vitro MRI(T2-weighted and T2-map)with a 3.0 Tesla clinical MR scanner.RESULTS Our data showed that the double antibody-conjugated probe UAG had the best specificity in targeting Hepa1-6/GPC3 cells expressing AFP and GPC3 antigens compared with single antibody-conjugated and unconjugated USPIO probes.The iron Prussian blue staining and quantitative T2-map MRI analysis showed that,compared with UA,UG,and U,the uptake of double antigen-targeted UAG probe demonstrated a 23.3%(vs UA),15.4%(vs UG),and 57.3%(vs U)increased Prussian stained cell percentage and a 14.93%(vs UA),9.38%(vs UG),and 15.3%(vs U)reduction of T2 relaxation time,respectively.Such bi-specific probe might have the potential to overcome tumor heterogeneity.Meanwhile,the coupling of two antibodies did not influence the magnetic performance of USPIO,and the relatively small hydrodynamic size(59.60±1.87 nm)of double antibodyconjugated USPIO probe makes it a viable candidate for use in MHCC MRI in vivo,as they are slowly phagocytosed by macrophages.CONCLUSION The bi-specific probe presents enhanced targeting efficiency and MRI sensitivity to HCC cells than singly-or non-targeted USPIO,paving the way for in vivo translation to further evaluate its clinical potential.

Application of artificial intelligence in preoperative imaging of hepatocellular carcinoma:Current status and future perspectives

Hepatocellular carcinoma(HCC)is the most common primary malignant liver tumor in China.Preoperative diagnosis of HCC is challenging because of atypical imaging manifestations and the diversity of focal liver lesions.Artificial intelligence(AI),such as machine learning(ML)and deep learning,has recently gained attention for its capability to reveal quantitative information on images.Currently,AI is used throughout the entire radiomics process and plays a critical role in multiple fields of medicine.This review summarizes the applications of AI in various aspects of preoperative imaging of HCC,including segmentation,differential diagnosis,prediction of histo-pathology,early detection of recurrence after curative treatment,and evaluation of treatment response.We also review the limitations of previous studies and discuss future directions for diagnostic imaging of HCC.

Social avoidance behavior in male tree shrews and prosocial behavior in male mice toward unfamiliar conspecifics in the laboratory

Adult male tree shrews vigorously defend against intruding male conspecifics. However, the characteristics of social behavior have not been entirely explored in these males. In this study, male wild-type tree shrews(Tupaia belangeri chinensis)and C57 BL/6 J mice were first allowed to familiarize themselves with an open-field apparatus. The tree shrews exhibited a short duration of movement(moving) in the novel environment, whereas the mice exhibited a long duration of movement. In the 30 min social preference-avoidance test, target animals significantly decreased the time spent by the experimental tree shrews in the social interaction(SI)zone, whereas experimental male mice exhibited the opposite. In addition, experimental tree shrews displayed a significantly longer latency to enter the SI zone in the second 15 min session(targetpresent) than in the first 15 min session(targetabsent), which was different from that found in mice.Distinct behavioral patterns in response to a conspecific male were also observed in male tree shrews and mice in the first, second, and third 5 min periods. Thus, social behaviors in tree shrews and mice appeared to be time dependent. In summary,our study provides results of a modified social preference-avoidance test designed for the assessment of social behavior in tree shrews. Our findings demonstrate the existence of social avoidance behavior in male tree shrews and prosocial behavior in male mice toward unfamiliar conspecifics. The tree shrew may be a new animal model, which differs from mice, for the study of social avoidance and prosocial behaviors.

Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway

Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder(BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex(mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase(PI3K)-protein kinase B(AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206(40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania.Furthermore, selective knockdown of AKT via AAVAKT-sh RNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly,pharmacological activation of AKT signaling by SC79(40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002(25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin(mTOR)signaling with rapamycin(10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.

Circadian misalignment on submarines and other non-24-h environments – from research to application

Circadian clocks have important physiological and behavioral functions in humans and other organisms, which enable organisms to anticipate and respond to periodic environmental changes. Disturbances in circadian rhythms impair sleep, metabolism, and behavior. People with jet lag, night workers and shift workers are vulnerable to circadian misalignment. In addition, non-24-h cycles influence circadian rhythms and cause misalignment and disorders in different species, since these periods are beyond the entrainment ranges. In certain special conditions, e.g., on submarines and commercial ships, non-24-h watch schedules are often employed, which have also been demonstrated to be deleterious to circadian rhythms. Personnel working under such conditions suffer from circadian misalignment with their on-watch hours, leading to increased health risks and decreased cognitive performance. In this review, we summarize the research progress and knowledge concerning circadian rhythms on submarines and other environments in which non-24-h watch schedules are employed.

Bi-specific T1 positive-contrast-enhanced magnetic resonance imaging molecular probe for hepatocellular carcinoma in an orthotopic mouse model

BACKGROUND Hepatocellular carcinoma(HCC)is the second leading cause of cancer-related mortality.HCC-targeted magnetic resonance imaging(MRI)is an effective noninvasive diagnostic method that involves targeting clinically-related HCC biomarkers,such as alpha-fetoprotein(AFP)or glypican-3(GPC3),with iron oxide nanoparticles.However,in vivo studies of HCC-targeted MRI utilize single-target iron oxide nanoprobes as negative(T2)contrast agents,which might weaken their future clinical applications due to tumor heterogeneity and negative MRI contrast.Ultra-small superparamagnetic iron oxide(USPIO)nanoparticles(approximately 5 nm)are potential optimal positive(T1)contrast agents.We previously verified the efficiency of AFP/GPC3-double-antibody-labeled iron oxide MR molecular probe in vitro.AIM To validate the effectiveness of a bi-specific probe in vivo for enhancing T1-weighted positive contrast to diagnose the early-stage HCC.METHODS The single-and double-antibody-conjugated 5-nm USPIO probes,including antiAFP-USPIO(UA),anti-GPC3-USPIO(UG),and anti-AFP-USPIO-anti-GPC3(UAG),were synthesized.T1-and T2-weighted MRI were performed on day 10 after establishment of the orthotopic HCC mouse model.Following intravenous injection of U,UA,UG,and UAG probes,T1-and T2-weighted images were obtained at 12,12,and 32 h post-injection.At the end of scanning,mice were euthanized,and a histologic analysis was performed on tumor samples.RESULTS T1-and T2-weighted MRI showed that absolute tumor-to-background ratios in UAG-treated HCC mice peaked at 24 h post-injection,with the T1-and T2-weighted signals increasing by 46.7%and decreasing by 11.1%,respectively,relative to pre-injection levels.Additionally,T1-weighted contrast in the UAG-treated group at 24 h post-injection was enhanced 1.52-,2.64-,and 4.38-fold compared to those observed for single-targeted anti-GPC3-USPIO,anti-AFP-USPIO,and nontargeted USPIO probes,respectively.Comparison of U-,UA-,UG-,and UAG-treated tumor sections revealed that UAG-treated mice exhibited increased stained regions compared to those observed in UG-or UA-treated mice.CONCLUSION The bi-specific T1-positive contrast-enhanced MRI probe(UAG)for HCC demonstrated increased specificity and sensitivity to diagnose early-stage HCC irrespective of tumor size and/or heterogeneity.

A Silver Cluster-Assembled Material Showing Luminescent Mechanochromism and Thermochromism

Silver chalcogenolate clusters(SCCs)[1]are a new category of materials with attractive photophysical properties.However,the notorious instability and the low emission quantum yield of SCCs hindered the profound investigation.

Reversible Wide-Range Tuneable Luminescence of a Dual-Stimuli- Responsive Silver Cluster-Assembled Material

Background and Originality Content In recent years,the construction of atomically precise noble metal nanoclusters has been extensively studied[1] owing to their favorable photophysical properties and promising applications in photoluminescent materials,optical sensors,catalysis,and biological labelling.[2,3] As a distinct family of noble metal clusters,silver chalcogenolate clusters(SCCs)[4]are a new category of materials with many unusual properties.

Morphological changes in gray matter volume correlate with catechol-O-methyl transferase gene Val158Met polymorphism in first-episode treatment-nave patients with schizophrenia

The catechol-O-methyltransferase（COMT） gene is a schizophrenia susceptibility gene. A common functional polymorphism of this gene,Val158/158 Met,has been proposed to influence gray matter volume（GMV）. However,the effects of this polymorphism on cortical thickness/surface area in schizophrenic patients are less clear. In this study,we explored the relationship between the Val158 Met polymorphism of the COMT gene and the GMV/ cortical thickness/cortical surface area in 150 firstepisode treatment-nave patients with schizophrenia and 100 healthy controls. Main effects of diagnosis were found for GMV in the cerebellum and the visual,medial temporal,parietal,and middle frontal cortex. Patients with schizophrenia showed reduced GMVs in these regions. And main effects of genotype were detected for GMV in the left superior frontal gyrus. Moreover,a diagnosis × genotype interaction was found for the GMV of the left precuneus,and the effect of the COMT gene on GMV was due mainly to cortical thickness rather than cortical surface area. In addition,a pattern ofincreased GMV in the precuneus with increasing Met dose found in healthy controls was lost in patients with schizophrenia. These findings suggest that the COMTMet variant is associated with the disruption of dopaminergic influence on gray matter in schizophrenia,and the effect of the COMT gene on GMV in schizophrenia is mainly due to changes in cortical thickness rather than in cortical surface area.

Layer-by-layer alloying of NIR-Ⅱ emissive M50(Au/Ag/Cu)superatomic nanocluster

The intermetallic synergy plays a critical role in exploring the chemical-physical properties of metal nanoclusters.However,the controlled doping or layer-by-layer alloying of atom-precise metal nanoclusters(NCs)has long been a challenging pursuit.In this work,two novel alloy nanoclusters[PPh_(4)]_(4)[Ag_(32)Cu_(18)(PFBT)_(36)]((AgCu)_(50))and[PPh_(4)]_(4)[Au_(12)Ag_(20)Cu_(18)(PFBT)_(36)](Au_(12)(AgCu)_(38)),where PFBT is pentafluorobenzenethiolate,with shell-by-shell configuration of M_(12)@Ag_(20)@Cu_(18)(PFBT)_(36)(M=Ag/Au)were synthesized by a facile one-pot co-reduction method.Notably,a fingerprint library of[Ag_(50)−xCux(PFBT)_(36)]^(4−)(x=0 to 50)from Ag_(50)to Cu_(50)has been successfully established as revealed by electrospray ionization mass spectrometry.Single-crystal X-ray diffraction analysis of trimetallic Au_(12)(AgCu)_(38)confirmed the layer-by-layer alloying under reducing conditions.What is more,(AgCu)_(50)and Au12(AgCu)_(38)both show broad photoluminescence(PL)peak in the second near-infrared(NIR-II)window,and the Au doping in the innermost shell considerably enhances the photoluminescence intensity.This work not only offers an insight in the process of metal cluster alloying but also provides a platform to study the doping-directed PL properties in the multimetallic cluster system.

Apolipoprotein E gene polymorphisms associated with processing speed and executive functions in healthy Han Chinese

Dear Editor,A few studies have focused on exploring APOE gene- related effects on cognitive functions and brain activities in healthy populations. Bondi et aL found that ε4 carriers perform significantly worse on the California Verbal Learning Test than non-carriers in non-demented old subjects （mean age, 72 years）ε11. But the results are not entirely consistent. For example, Scarmeas et aL found no effect of the E4 allele on neuropsychological performance[2] in young adults, and Jochemsen et al. found that the ε4 allele is associated with age-related cognitive decline[3]. Furthermore, protective and negative effects of the E2 allele on cognition are inconsistent[4＇ s]. APOE E2 is thought to be a protective allele for AD in the elderly population due to its role in the superior cognitive performance of ε2 carriers compared to E3 or E4 carriers[5]. However, the ε2 allele has also been found to have a negative effect on AD pathology[4].