Suppression of excitatory synaptic transmission in the centrolateral amygdala via presynaptic histamine H3 heteroreceptors.

The central histaminergic system has a pivotal role in emotional regulation and psychiatric disorders, including anxiety, depression and schizophrenia. However, the effect of histamine on neuronal activity of the centrolateral amygdala (CeL), an essential node for fear and anxiety processing, remains unknown. Here, using immunostaining and whole-cell patch clamp recording combined with optogenetic manipulation of histaminergic terminals in CeL slices prepared from histidine decarboxylase (HDC)-Cre rats, we show that histamine selectively suppresses excitatory synaptic transmissions, including glutamatergic transmission from the basolateral amygdala, on both PKC-δ- and SOM-positive CeL neurons. The histamine-induced effect is mediated by H3 receptors expressed on VGLUT1-/VGLUT2-positive presynaptic terminals in CeL. Furthermore, optoactivation of histaminergic afferent terminals from the hypothalamic tuberomammillary nucleus (TMN) also significantly suppresses glutamatergic transmissions in CeL via H3 receptors. Histamine neither modulates inhibitory synaptic transmission by presynaptic H3 receptors nor directly excites CeL neurons by postsynaptic H1, H2 or H4 receptors. These results suggest that histaminergic afferent inputs and presynaptic H3 heteroreceptors may hold a critical position in balancing excitatory and inhibitory synaptic transmissions in CeL by selective modulation of glutamatergic drive, which may not only account for the pathophysiology of psychiatric disorders but also provide potential psychotherapeutic targets. KEY POINTS: Histamine selectively suppresses the excitatory, rather than inhibitory, synaptic transmissions on both PKC-δ- and SOM-positive neurons in the centrolateral amygdala (CeL). H3 receptors expressed on VGLUT1- or VGLUT2-positive afferent terminals mediate the suppression of histamine on glutamatergic synaptic transmission in CeL. Optogenetic activation of hypothalamic tuberomammillary nucleus (TMN)-CeL histaminergic projections inhibits glutamatergic transmission in CeL via H3 receptors.

Unveiling potential roles of earthworms in mitigating the presence of virulence factor genes in terrestrial ecosystems.

Earthworms can redistribute soil microbiota, and thus might affect the profile of virulence factor genes (VFGs) which are carried by pathogens in soils. Nevertheless, the knowledge of VFG profile in the earthworm guts and its interaction with earthworm gut microbiome is still lacking. Herein, we characterized earthworm gut and soil microbiome and VFG profiles in natural and agricultural ecosystems at a national scale using metagenomics. VFG profiles in the earthworm guts significantly differed from those in the surrounding soils, which was mainly driven by variations of bacterial communities. Furthermore, the total abundance of different types of VFGs in the earthworm guts was about 20-fold lower than that in the soils due to the dramatic decline (also by approximately 20-fold) of VFG-carrying bacterial pathogens in the earthworm guts. Additionally, five VFGs related to nutritional/metabolic factors and stress survival were identified as keystones merely in the microbe-VFG network in the earthworm guts, implying their pivotal roles in facilitating pathogen colonization in earthworm gut microhabitats. These findings suggest the potential roles of earthworms in reducing risks related to the presence of VFGs in soils, providing novel insights into earthworm-based bioremediation of VFG contamination in terrestrial ecosystems.

Application of predictive model based on CT radiomics and machine learning in diagnosis for occult locally advanced esophageal squamous cell carcinoma before treatment: A two-center study.

PURPOSE: Development and validation of a radiomics model for predicting occult locally advanced esophageal squamous cell carcinoma (LA-ESCC) on computed tomography (CT) radiomic features before implementation of treatment. METHODS: The study retrospectively collected 574 patients with esophageal squamous cell carcinoma (ESCC) from two medical centers, which were divided into three cohorts for training, internal and external validation. After delineating volume of interest (VOI), radiomics features were extracted and subjected to feature selection using three robust methods. Subsequently, 10 machine learning models were constructed, among which the optimal model was utilized to establish a radiomics signature. Furthermore, a predictive nomogram incorporating both clinical and radiomics signatures was developed. The performance of these models was evaluated through receiver operating characteristic curves, calibration curves, decision curve analysis as well as measures including accuracy, sensitivity, and specificity. RESULTS: A total of 19 radiomics features were selected. The multilayer perceptron (MLP), which was found to be optimal, achieved an AUC of 0.919, 0.864 and 0.882 in the training, internal and external validation cohorts, respectively. Similarly, MLP showed good accuracy in distinguish occult LA-ESCC in subgroup of cT1-2N0M0 diagnosed by clinicians with 0.803 and 0.789 in two validation cohorts respectively. By incorporating the radiomics signature with clinical signature, a predictive nomogram demonstrated superior prediction performance with an AUC of 0.877 and accuracy of 0.85 in external validation cohort. CONCLUSION: The radiomics and machine learning model can offers improved accuracy in prediction of occult LA-ESCC, providing valuable assistance to clinicians when choosing treatment plans.

LncRNA 4930581F22Rik promotes myogenic differentiation by regulating the ERK/MAPK signaling pathway.

The skeletal muscle is the largest organ in mammals and is the primary motor function organ of the body. Our previous research has shown that long non-coding RNAs (lncRNAs) are significant in the epigenetic control of skeletal muscle development. Here, we observed progressive upregulation of lncRNA 4930581F22Rik expression during skeletal muscle differentiation. Knockdown of lncRNA 4930581F22Rik hindered skeletal muscle differentiation and resulted in the inhibition of the myogenic markers MyHC and MEF2C. Furthermore, we found that lncRNA 4930581F22Rik regulates myogenesis via the ERK/MAPK signaling pathway, and this effect could be attenuated by the ERK-specific inhibitor PD0325901. Additionally, in vivo mice injury model results revealed that lncRNA 4930581F22Rik is involved in skeletal muscle regeneration. These results establish a theoretical basis for understanding the contribution of lncRNAs in skeletal muscle development and regeneration.

Advancements in Stimulus-Responsive Co-Delivery Nanocarriers for Enhanced Cancer Immunotherapy.

Cancer immunotherapy has emerged as a novel therapeutic approach against tumors, with immune checkpoint inhibitors (ICIs) making significant clinical practice. The traditional ICIs, PD-1 and PD-L1, augment the cytotoxic function of T cells through the inhibition of tumor immune evasion pathways, ultimately leading to the initiation of an antitumor immune response. However, the clinical implementation of ICIs encounters obstacles stemming from the existence of an immunosuppressive tumor microenvironment and inadequate infiltration of CD8+T cells. Considerable attention has been directed towards advancing immunogenic cell death (ICD) as a potential solution to counteract tumor cell infiltration and the immunosuppressive tumor microenvironment. This approach holds promise in transforming "cold" tumors into "hot" tumors that exhibit responsiveness to antitumor. By combining ICD with ICIs, a synergistic immune response against tumors can be achieved. However, the combination of ICD inducers and PD-1/PD-L1 inhibitors is hindered by issues such as poor targeting and uncontrolled drug release. An advantageous solution presented by stimulus-responsive nanocarrier is integrating the physicochemical properties of ICD inducers and PD-1/PD-L1 inhibitors, facilitating precise delivery to specific tissues for optimal combination therapy. Moreover, these nanocarriers leverage the distinct features of the tumor microenvironment to accomplish controlled drug release and regulate the kinetics of drug delivery. This article aims to investigate the advancement of stimulus-responsive co-delivery nanocarriers utilizing ICD and PD-1/PD-L1 inhibitors. Special focus is dedicated to exploring the advantages and recent advancements of this system in enabling the combination of ICIs and ICD inducers. The molecular mechanisms of ICD and ICIs are concisely summarized. In conclusion, we examine the potential research prospects and challenges that could greatly enhance immunotherapeutic approaches for cancer treatment.

IL-12-Overexpressed Nanoparticles Suppress the Proliferation of Melanoma Through Inducing ICD and Activating DC, CD8+ T, and CD4+ T Cells.

Purpose: The drug resistance and low response rates of immunotherapy limit its application. This study aimed to construct a new nanoparticle (CaCO3-polydopamine-polyethylenimine, CPP) to effectively deliver interleukin-12 (IL-12) and suppress cancer progress through immunotherapy. Methods: The size distribution of CPP and its zeta potential were measured using a Malvern Zetasizer Nano-ZS90. The morphology and electrophoresis tentative delay of CPP were analyzed using a JEM-1400 transmission electron microscope and an ultraviolet spectrophotometer, respectively. Cell proliferation was analyzed by MTT assay. Proteins were analyzed by Western blot. IL-12 and HMGB1 levels were estimated by ELISA kits. Live/dead staining assay was performed using a Calcein-AM/PI kit. ATP production was detected using an ATP assay kit. The xenografts in vivo were estimated in C57BL/6 mice. The levels of CD80+/CD86+, CD3+/CD4+ and CD3+/CD8+ were analyzed by flow cytometry. Results: CPP could effectively express EGFP or IL-12 and increase ROS levels. Laser treatment promoted CPP-IL-12 induced the number of dead or apoptotic cell. CPP-IL-12 and laser could further enhance CALR levels and extracellular HMGB1 levels and decrease intracellular HMGB1 and ATP levels, indicating that it may induce immunogenic cell death (ICD). The tumors and weights of xenografts in CPP-IL-12 or laser-treated mice were significantly reduced than in controls. The IL-12 expression, the CD80+/CD86+ expression of DC from lymph glands, and the number of CD3+/CD8+T or CD3+/CD4+T cells from the spleen increased in CPP-IL-12-treated or laser-treated xenografts compared with controls. The levels of granzyme B, IFN-γ, and TNF-α in the serum of CPP-IL-12-treated mice increased. Interestingly, CPP-IL-12 treatment in local xenografts in the back of mice could effectively inhibit the growth of the distant untreated tumor. Conclusion: The novel CPP-IL-12 could overexpress IL-12 in melanoma cells and achieve immunotherapy to melanoma through inducing ICD, activating CD4+ T cell, and enhancing the function of tumor-reactive CD8+ T cells.

[Corrigendum] Induction of microRNA­let­7a inhibits lung adeno-carcinoma cell growth by regulating cyclin D1.

After the publication of the article, an interested reader drew to the authors' attention that, in the western blots shown in Fig. 5C and D, a pair of data panels were inadvertently duplicated comparing between panels (C) and (D); in addition, the cell migration data shown in Fig. 7F on p. 1852 were selected incorrectly. The authors have examined their original data, and realize that these errors arose inadvertently as a consequence of their mishandling of their data. The revised versions of Figs. 5 and 7, featuring the corrected data for the caspase-8 experiment in Fig. 5C and alternative data for the cell migration assay experiments in Fig. 7F, are shown on the next two pages. The revised data shown for these Figures do not affect the overall conclusions reported in the paper. All the authors agree to the publication of this corrigendum, and are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish this. Furthermore, the authors apologize to the readership for any inconvenience caused. [Oncology Reports 40: 1843-1854, 2018; DOI: 10.3892/or.2018.6593].

A role for the cerebellum in motor-triggered alleviation of anxiety.

Physical exercise is known to reduce anxiety, but the underlying brain mechanisms remain unclear. Here, we explore a hypothalamo-cerebello-amygdalar circuit that may mediate motor-dependent alleviation of anxiety. This three-neuron loop, in which the cerebellar dentate nucleus takes center stage, bridges the motor system with the emotional system. Subjecting animals to a constant rotarod engages glutamatergic cerebellar dentate neurons that drive PKCδ+ amygdalar neurons to elicit an anxiolytic effect. Moreover, challenging animals on an accelerated rather than a constant rotarod engages hypothalamic neurons that provide a superimposed anxiolytic effect via an orexinergic projection to the dentate neurons that activate the amygdala. Our findings reveal a cerebello-limbic pathway that may contribute to motor-triggered alleviation of anxiety and that may be optimally exploited during challenging physical exercise.

m6A-methylated KCTD21-AS1 regulates macrophage phagocytosis through CD47 and cell autophagy through TIPR.

Blocking immune checkpoint CD47/SIRPα is a useful strategy to engineer macrophages for cancer immunotherapy. However, the roles of CD47-related noncoding RNA in regulating macrophage phagocytosis for lung cancer therapy remain unclear. This study aims to investigate the effects of long noncoding RNA (lncRNA) on the phagocytosis of macrophage via CD47 and the proliferation of non-small cell lung cancer (NSCLC) via TIPRL. Our results demonstrate that lncRNA KCTD21-AS1 increases in NSCLC tissues and is associated with poor survival of patients. KCTD21-AS1 and its m6A modification by Mettl14 promote NSCLC cell proliferation. miR-519d-5p gain suppresses the proliferation and metastasis of NSCLC cells by regulating CD47 and TIPRL. Through ceRNA with miR-519d-5p, KCTD21-AS1 regulates the expression of CD47 and TIPRL, which further regulates macrophage phagocytosis and cancer cell autophagy. Low miR-519d-5p in patients with NSCLC corresponds with poor survival. High TIPRL or CD47 levels in patients with NSCLC corresponds with poor survival. In conclusion, we demonstrate that KCTD21-AS1 and its m6A modification promote NSCLC cell proliferation, whereas miR-519d-5p inhibits this process by regulating CD47 and TIPRL expression, which further affects macrophage phagocytosis and cell autophagy. This study provides a strategy through miR-519-5p gain or KCTD21-AS1 depletion for NSCLC therapy by regulating CD47 and TIPRL.

Adjuvant therapy provides no additional recurrence-free benefit for esophageal squamous cell carcinoma patients after neoadjuvant chemoimmunotherapy and surgery: a multi-center propensity score match study.

Purpose: The need for adjuvant therapy (AT) following neoadjuvant chemoimmunotherapy (nICT) and surgery in esophageal squamous cell cancer (ESCC) remains uncertain. This study aims to investigate whether AT offers additional benefits in terms of recurrence-free survival (RFS) for ESCC patients after nICT and surgery. Methods: Retrospective analysis was conducted between January 2019 and December 2022 from three centers. Eligible patients were divided into two groups: the AT group and the non-AT group. Survival analyses comparing different modalities of AT (including adjuvant chemotherapy and adjuvant chemoimmunotherapy) with non-AT were performed. The primary endpoint was RFS. Propensity score matching(PSM) was used to mitigate inter-group patient heterogeneity. Kaplan-Meier survival curves and Cox regression analysis were employed for recurrence-free survival analysis. Results: A total of 155 nICT patients were included, with 26 patients experiencing recurrence. According to Cox analysis, receipt of adjuvant therapy emerged as an independent risk factor(HR:2.621, 95%CI:[1.089,6.310], P=0.032), and there was statistically significant difference in the Kaplan-Meier survival curves between non-AT and receipt of AT in matched pairs (p=0.026). Stratified analysis revealed AT bring no survival benefit to patients with pathological complete response(p= 0.149) and residual tumor cell(p=0.062). Subgroup analysis showed no significant difference in recurrence-free survival between non-AT and adjuvant chemoimmunotherapy patients(P=0.108). However, patients receiving adjuvant chemotherapy exhibited poorer recurrence survival compared to non-AT patients (p= 0.016). Conclusion: In terms of recurrence-free survival for ESCC patients after nICT and surgery, the necessity of adjuvant therapy especially the adjuvant chemotherapy, can be mitigated.

[Effects of metal materials for oral fixation and restoration on magnetic resonance imaging artifacts and the health of tissues around dental implants].

PURPOSE: To investigate the effects of metal materials for oral fixation and restoration on magnetic resonance imaging artifacts and the health of tissues around dental implants. METHODS: A total of 153 patients undergoing fixed oral restoration were selected from May 2018 to June 2020. They were divided according to the random number table method into group A (cobalt-chromium alloy, n=31), group B (nickel-chromium alloy, n=32), group C (titanium alloy, n=28), group D (pure titanium, n=29) and group E (gold alloy, n=33). The largest area of metal crown artifacts and the number of layers of the 5 groups were compared. The probing depth(PD), modified plaque index(mPLI), modified sulcus bleeding index(mSBI) and papilla index(PI) 6 months after restoration were evaluated.The data were statistically analyzed with SPSS 22.0 software package. RESULTS: One-way ANOVA showed that the largest area of metal crown artifacts and the number of layers involved in the 5 groups had significant differences(P＜0.05). Pairwise comparison showed that the largest area of metal crown artifacts, and the number of involved layers in group E were significantly lower than those in groups A, B, C, and D(P＜0.05). One-way ANOVA showed that there was no significant difference in PD, mPLI, mSBI and PI among 5 groups (P＞0.05). Pairwise comparison showed that there was no significant difference in PD, mPLI, mSBI and PI between group A and group B,C,D and E (P＞0.05). CONCLUSIONS: The artifacts produced by metal materials for oral fixation and restoration are closely related to the types of metal materials. Among them, cobalt-chromium alloys produce the largest artifacts, and gold alloys produce the smallest artifacts. The use of metal materials for oral fixation and restoration will not affect the health of tissues around dental implants.

Pseudouridine synthase 1 promotes hepatocellular carcinoma through mRNA pseudouridylation to enhance the translation of oncogenic mRNAs.

BACKGROUND AND AIMS: Pseudouridine is a prevalent RNA modification and is highly present in the serum and urine of patients with HCC. However, the role of pseudouridylation and its modifiers in HCC remains unknown. We investigated the function and underlying mechanism of pseudouridine synthase 1 (PUS1) in HCC. APPROACH AND RESULTS: By analyzing the TCGA data set, PUS1 was found to be significantly upregulated in human HCC specimens and positively correlated with tumor grade and poor prognosis of HCC. Knockdown of PUS1 inhibited cell proliferation and the growth of tumors in a subcutaneous xenograft mouse model. Accordingly, increased cell proliferation and tumor growth were observed in PUS1-overexpressing cells. Furthermore, overexpression of PUS1 significantly accelerates tumor formation in a mouse HCC model established by hydrodynamic tail vein injection, while knockout of PUS1 decreases it. Additionally, PUS1 catalytic activity is required for HCC tumorigenesis. Mechanistically, we profiled the mRNA targets of PUS1 by utilizing surveying targets by apolipoprotein B mRNA-editing enzyme 1 (APOBEC1)-mediated profiling and found that PUS1 incorporated pseudouridine into mRNAs of a set of oncogenes, thereby endowing them with greater translation capacity. CONCLUSIONS: Our study highlights the critical role of PUS1 and pseudouridylation in HCC development, and provides new insight that PUS1 enhances the protein levels of a set of oncogenes, including insulin receptor substrate 1 (IRS1) and c-MYC, by means of pseudouridylation-mediated mRNA translation.

Magnetic Resonance Deep Learning Radiomic Model Based on Distinct Metastatic Vascular Patterns for Evaluating Recurrence-Free Survival in Hepatocellular Carcinoma.

BACKGROUND: The metastatic vascular patterns of hepatocellular carcinoma (HCC) are mainly microvascular invasion (MVI) and vessels encapsulating tumor clusters (VETC). However, most existing VETC-related radiological studies still focus on the prediction of VETC status. PURPOSE: This study aimed to build and compare VETC-MVI related models (clinical, radiomics, and deep learning) associated with recurrence-free survival of HCC patients. STUDY TYPE: Retrospective. POPULATION: 398 HCC patients (349 male, 49 female; median age 51.7 years, and age range: 22-80 years) who underwent resection from five hospitals in China. The patients were randomly divided into training cohort (n = 358) and test cohort (n = 40). FIELD STRENGTH/SEQUENCE: 3-T, pre-contrast T1-weighted imaging spoiled gradient recalled echo (T1WI SPGR), T2-weighted imaging fast spin echo (T2WI FSE), and contrast enhanced arterial phase (AP), delay phase (DP). ASSESSMENT: Two radiologists performed the segmentation of HCC on T1WI, T2WI, AP, and DP images, from which radiomic features were extracted. The RFS related clinical characteristics (VETC, MVI, Barcelona stage, tumor maximum diameter, and alpha fetoprotein) and radiomic features were used to build the clinical model, clinical-radiomic (CR) nomogram, deep learning model. The follow-up process was done 1 month after resection, and every 3 months subsequently. The RFS was defined as the date of resection to the date of recurrence confirmed by radiology or the last follow-up. Patients were followed up until December 31, 2022. STATISTICAL TESTS: Univariate COX regression, least absolute shrinkage and selection operator (LASSO), Kaplan-Meier curves, log-rank test, C-index, and area under the curve (AUC). P < 0.05 was considered statistically significant. RESULTS: The C-index of deep learning model achieved 0.830 in test cohort compared with CR nomogram (0.731), radiomic signature (0.707), and clinical model (0.702). The average RFS of the overall patients was 26.77 months (range 1-80 months). DATA CONCLUSION: MR deep learning model based on VETC and MVI provides a potential tool for survival assessment. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

[Corrigendum] Knockdown of HOXA10 reverses the multidrug resistance of human chronic mylogenous leukemia K562/ADM cells by downregulating P­gp and MRP­1.

Following the publication of the above article, an interested reader drew to the authors' attention that, in Fig. 2 on p. 1408, the microscopic images shown for the light scope images (upper row) and the green fluorescence images (lower row) appeared to be overlapping, such that these images appeared to have been derived from the same original sources even though they were intended to portray the results from differently performed experiments. After having re­examined their figures, the authors realized that this figure was assembled incorrectly. The revised version of Fig. 2, showing the correct data for all four experimental panels, is shown below. Note that the errors made during the assembly of these figures did not affect the overall conclusions reported in the paper. All the authors agree with the publication of this corrigendum, and are grateful to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this. They also apologize to the readership for any inconvenience caused. [International Journal of Molecular Medicine 37: 1405­1411, 2016; DOI: 10.3892/ijmm.2016.2539].

RNA-binding protein CCDC137 activates AKT signaling and promotes hepatocellular carcinoma through a novel non-canonical role of DGCR8 in mRNA localization.

BACKGROUND: RNA binding proteins (RBPs)-regulated gene expression play a vital role in various pathological processes, including the progression of cancer. However, the role of RBP in hepatocellular carcinoma (HCC) remains much unknown. In this study, we aimed to explore the contribution of RBP CCDC137 in HCC development. METHODS: We analyzed the altered expression level and clinical significance of CCDC137 in database and HCC specimens. In vitro cell assays and in vivo spontaneous mouse models were used to assess the function of CCDC137. Finally, the molecular mechanisms of how CCDC137 regulates gene expression and promotes HCC was explored. RESULTS: CCDC137 is aberrantly upregulated in HCC and correlates with poor clinical outcomes in HCC patients. CCDC137 markedly promoted HCC proliferation and progression in vitro and in vivo. Mechanistically, CCDC137 binds with FOXM1, JTV1, LASP1 and FLOT2 mRNAs, which was revealed by APOBEC1-mediated profiling, to increase their cytoplasmic localization and thus enhance their protein expressions. Upregulation of FOXM1, JTV1, LASP1 and FLOT2 subsequently synergistically activate AKT signaling and promote HCC. Interestingly, we found that CCDC137 binds with the microprocessor protein DGCR8 and DGCR8 has a novel non-canonical function in mRNA subcellular localization, which mediates the cytoplasmic distribution of mRNAs regulated by CCDC137. CONCLUSIONS: Our results identify a critical proliferation-related role of CCDC137 and reveal a novel CCDC137/DGCR8/mRNA localization/AKT axis in HCC progression, which provide a potential target for HCC therapy.

Dual Stimuli-Responsive Micelles for Imaging-Guided Mitochondrion-Targeted Photothermal/Photodynamic/Chemo Combination Therapy-Induced Immunogenic Cell Death.

Introduction: As the special modality of cell death, immunogenic cell death (ICD) could activate immune response. Phototherapy in combination with chemotherapy (CT) is a particularly efficient tumor ICD inducing method that could overcome the defects of monotherapies. Methods: In this study, new dual stimuli-responsive micelles were designed and prepared for imaging-guided mitochondrion-targeted photothermal/photodynamic/CT combination therapy through inducing ICD. A dual-sensitive methoxy-polyethylene glycol-SS-poly(L-γ-glutamylglutamine)-SS-IR780 (mPEG-SS-PGG-SS-IR780) polymer was synthesized by grafting IR780 with biodegradable di-carboxyl PGG as the backbone, and mPEG-SS-PGG-SS-IR780/paclitaxel micelles (mPEG-SS-PGG-SS-IR780/PTXL MCs) were synthesized by encapsulating PTXL in the hydrophobic core. Results: In-vivo and -vitro results demonstrated that the three-mode combination micelles inhibited tumor growth and enhanced the therapeutic efficacy of immunotherapy. The dual stimuli-responsive mPEG-SS-PGG-SS-IR780/PTXL MCs were able to facilitate tumor cell endocytosis of nanoparticles. They were also capable of promoting micelles disintegration and accelerating PTXL release. The mPEG-SS-PGG-SS-IR780/PTXL MCs induced mitochondrial dysfunction by directly targeting the mitochondria, considering the thermo- and reactive oxygen species (ROS) sensitivity of the mitochondria. Furthermore, the mPEG-SS-PGG-SS-IR780/PTXL MCs could play the diagnostic and therapeutic roles via imaging capabilities. Conclusion: In summary, this study formulated a high-efficiency nanoscale platform with great potential in combined therapy for tumors through ICD.

The Conserved LncRNA DIO3OS Restricts Hepatocellular Carcinoma Stemness by Interfering with NONO-Mediated Nuclear Export of ZEB1 mRNA.

Hepatocellular carcinoma (HCC) is an aggressive and fatal disease caused by a subset of cancer stem cells (CSCs). It is estimated that there are approximately 100 000 long noncoding RNAs (lncRNAs) in humans. However, the mechanisms by which lncRNAs affect tumor stemness remain poorly understood. In the present study, it is found that DIO3OS is a conserved lncRNA that is generally downregulated in multiple cancers, including HCC, and its low expression correlates with poor clinical outcomes in HCC. In in vitro cancer cell lines and an in vivo spontaneous HCC mouse model, DIO3OS markedly represses tumor development via its suppressive role in CSCs through downregulation of zinc finger E-box binding homeobox 1 (ZEB1). Interestingly, DIO3OS represses ZEB1 post-transcriptionally without affecting its mRNA levels. Subsequent experiments show that DIO3OS interacts with the NONO protein and restricts NONO-mediated nuclear export of ZEB1 mRNA. Overall, these findings demonstrate that the DIO3OS-NONO-ZEB1 axis restricts HCC development and offers a valuable candidate for CSC-targeted therapeutics for HCC.

Serotonin and dopamine depletion in distinct brain regions may cause anxiety in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice as a model of early Parkinson's disease.

In this study, we aimed to evaluate the association of early anxious behavior with serotonin, dopamine, and their metabolites in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson's disease. Forty C57BL/6 male mice were randomly divided into the control group (n = 20) and the model group (n = 20). Mice in the model group were injected intraperitoneally with MPTP. The light-dark box (LDB) and elevated plus-maze were used to monitor anxious behavior. The association of early anxious behavior with neurotransmitters in the prefrontal cortex, hippocampus, and striatum was evaluated. In our murine model, MPTP induced a decreased level of 5-hydroxytryptamine and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the prefrontal cortex, hippocampus, and striatum (all P < 0.05); however, it only induced a decreased level of dopamine and its metabolite homovanillic acid (HVA) in the striatum (both P < 0.001), with a negative correlation in the hippocampus and a positive correlation in the cortex and striatum. In the LDB, 5-hydroxytryptamine levels in the cortex and dopamine and HVA levels in the striatum were negatively correlated with anxious behavior. Moreover, in the elevate plus-maze, 5-hydroxytryptamine and 5-HIAA in the cortex and dopamine and HVA in the striatum were positively correlated with the ratio of the time spent in open arms. In the murine model of early Parkinson's disease, the balance between dopamine and 5-hydroxytryptamine systems varied among brain regions. The depletion of 5-hydroxytryptamine in the cortex and dopamine in the striatum may be associated with anxiety behaviors in MPTP-treated mice.

Development of subdural empyema from subdural effusion after suppurative encephalitis: A case report.

BACKGROUND: Chronic subdural effusion is very common in the cranial imaging of middle-aged and older people. Herein, we report a patient misdiagnosed with subdural effusion, who was eventually diagnosed with chronic subdural empyema (SDE) caused by Streptococcus pneumoniae. CASE SUMMARY: A 63-year-old man was brought to our emergency room with a headache, vomiting, and disturbed consciousness. Computed tomography (CT) revealed a bilateral subdural effusion at the top left side of the frontal lobe. Cerebrospinal fluid examination after lumbar puncture indicated suppurative meningitis, which improved after anti-infective therapy. However, the patient then presented with acute cognitive dysfunction and right limb paralysis. Repeat CT showed an increase in left frontoparietal subdural effusion, disappearance of the left lateral ventricle, and a shift of the midline to the right. Urgent burr hole drainage showed SDE that was culture-positive for Streptococcus pneumoniae. His condition improved after adequate drainage and antibiotic treatment. CONCLUSION: Patients with unexplained subdural effusion, especially asymmetric subdural effusion with intracranial infection, should be assessed for chronic SDE. Early surgical treatment may be beneficial.

Proinflammatory activation of microglia in the cerebellum hyperexcites Purkinje cells to trigger ataxia.

Specific medications to combat cerebellar ataxias, a group of debilitating movement disorders characterized by difficulty with walking, balance and coordination, are still lacking. Notably, cerebellar microglial activation appears to be a common feature in different types of ataxic patients and rodent models. However, direct evidence that cerebellar microglial activation in vivo is sufficient to induce ataxia is still lacking. Here, by employing chemogenetic approaches to manipulate cerebellar microglia selectively and directly, we found that specific chemogenetic activation of microglia in the cerebellar vermis directly leads to ataxia symptoms in wild-type mice and aggravated ataxic motor deficits in 3-acetylpyridine (3-AP) mice, a classic mouse model of cerebellar ataxia. Mechanistically, cerebellar microglial proinflammatory activation induced by either chemogenetic M3D(Gq) stimulation or 3-AP modeling hyperexcites Purkinje cells (PCs), which consequently triggers ataxia. Blockade of microglia-derived TNF-α, one of the most important proinflammatory cytokines, attenuates the hyperactivity of PCs driven by microglia. Moreover, chemogenetic inhibition of cerebellar microglial activation or suppression of cerebellar microglial activation by PLX3397 and minocycline reduces the production of proinflammatory cytokines, including TNF-α, to effectively restore the overactivation of PCs and alleviate motor deficits in 3-AP mice. These results suggest that cerebellar microglial activation may aggravate the neuroinflammatory response and subsequently induce dysfunction of PCs, which in turn triggers ataxic motor deficits. Our findings thus reveal a causal relationship between proinflammatory activation of cerebellar microglia and ataxic motor symptoms, which may offer novel evidence for therapeutic intervention for cerebellar ataxias by targeting microglia and microglia-derived inflammatory mediators.