Magnetic resonance imaging-based prediction models for differentiating intraspinal schwannomas from meningiomas: classification and regression tree and random forest analysis.

Background: Due to the variations in surgical approaches and prognosis between intraspinal schwannomas and meningiomas, it is crucial to accurately differentiate between the two prior to surgery. Currently, there is limited research exploring the implementation of machine learning (ML) methods for distinguishing between these two types of tumors. This study aimed to establish a classification and regression tree (CART) model and a random forest (RF) model for distinguishing schwannomas from meningiomas. Methods: We retrospectively collected 88 schwannomas (52 males and 36 females) and 51 meningiomas (10 males and 41 females) who underwent magnetic resonance imaging (MRI) examinations prior to the surgery. Simple clinical data and MRI imaging features, including age, sex, tumor location and size, T1-weighted images (T1WI) and T2-weighted images (T2WI) signal characteristics, degree and pattern of enhancement, dural tail sign, ginkgo leaf sign, and intervertebral foramen widening (IFW), were reviewed. Finally, a CART model and RF model were established based on the aforementioned features to evaluate their effectiveness in differentiating between the two types of tumors. Meanwhile, we also compared the performance of the ML models to the radiologists. The receiver operating characteristic (ROC) curve, accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were used to evaluate the models and clinicians' discrimination performance. Results: Our investigation reveals significant variations in ten out of 11 variables in the training group and five out of 11 variables in the test group when comparing schwannomas and meningiomas (P<0.05). Ultimately, the CART model incorporated five variables: enhancement pattern, the presence of IFW, tumor location, maximum diameter, and T2WI signal intensity (SI). The RF model combined all 11 variables. The CART model, RF model, radiologist 1, and radiologist 2 achieved an area under the curve (AUC) of 0.890, 0.956, 0.681, and 0.723 in the training group, and 0.838, 0.922, 0.580, and 0.659 in the test group, respectively. Conclusions: The RF prediction model exhibits more exceptional performance than an experienced radiologist in discriminating intraspinal schwannomas from meningiomas. The RF model seems to be better in discriminating the two tumors than the CART model.

[Mechanism of Chaijin Jieyu Anshen Tablets in regulating abnormal ACC-vHPC glutaminergic neural circuit to alleviate synaptic remodeling of ventral hippocampal neurons in depressed rats].

This study aims to reveal the molecular mechanism of Chaijin Jieyu Anshen Tablets(CJJYAS) in regulating the abnormal anterior cingulate cortex(ACC)-ventral hippocampus(vHPC) glutaminergic neural circuit to alleviate synaptic remodeling of ventral hippocampal neurons in depressed rats. Firstly, the study used chemogenetics to localize glutaminergic adeno-associated virus(AAV) into the ACC brain region of rats. The model of depressed rats was established by chronic unpredictable mild stress(CUMS) combined with independent feeding. The rats were randomly divided into control group, model group, AAV empty group, AAV group, AAV+ glucocorticoid receptors(GR) blocker group, AAV+chemokine receptor 1(CX3CR1) blocker group, and AAV+CJJYAS group. Depressive-like behaviors of rats were evaluated by open-field, forced-swimming, and Morris water maze tests, combined with an animal behavior analysis system. The morphological and structural changes of ACC and vHPC neurons in rats were observed by hematoxylin-eosin(HE) staining. Immunofluorescence and nuclear phosphoprotein(c-Fos) were used to detect glutaminergic neural circuit activation of ACC-vHPC in rats. The changes in dendrites, synaptic spines, and synaptic submicrostructure of vHPC neurons were observed by Golgi staining and transmission electron microscopy, respectively. The expressions of synaptic remodeling-related proteins N-methyl-D-asprtate receptor 2A(GRIN2A), N-methyl-D-asprtate receptor 2B(GRIN2B), Ca~(2+)/calmodulin-dependent protein kinase Ⅱ(CaMKⅡ), mitogen-activated protein kinase-activated protein kinase 2(MK2), and a ubiquitous actin-binding protein(cofilin) in vHPC glutaminergic neurons of rats were detected by immunofluorescence and Western blot, respectively. The results indicated that the activated glutaminergic AAV aggravated the depressive-like behaviors phenotype of rats in the model group and deteriorated the damage of morphology and structure of ACC and vHPC neurons and synaptic ultrastructure. However, both GR and CX3CR1 bloc-kers could reverse the abnormal changes to varying degrees, suggesting that the abnormal activation of ACC-vHPC glutaminergic neural circuit mediated by GR/CX3CR1 signals in gliocytes in the ACC brain region may be closely related to the occurrence and development of depression. Interestingly, CJJYAS significantly inhibited the activation of the ACC-vHPC glutaminergic neural circuit induced by AAV and the elevated Glu level. Furthermore, CJJYAS could also effectively reverse the aggravation of depressive-like behaviors and synaptic remodeling of vHPC neurons of rats in the model group induced by the activated AAV. Additionally, the findings suggested that the molecular mechanism of CJJYAS in improving synaptic damage of vHPC neurons might be related to the regulation of synaptic remodeling-related signals such as NR/CaMKⅡ and MK2/cofilin. In conclusion, this research confirms that CJJYAS effectively regulates the abnormal ACC-vHPC glutaminergic neural circuit and alleviates the synaptic remodeling of vHPC glutaminergic neurons in depressed rats, and the molecular mechanism might be associated with the regulation of synapse-related NR/CaMKⅡ and MK2/cofilin signaling pathways, which may be the crucial mechanism of its antidepressant effect.

A simple and precise alignment calibration method for cone-beam computed tomography with the verifications.

Cone-beam Computed Tomography (CBCT) is widely used in dental imaging, small animal imaging, radiotherapy, and non-destructive industrial inspection. The quality of CBCT images depends on the precise knowledge of the CBCT system's alignment. We introduce a distinct procedure, "precision alignment loop (PAL)", to calibrate any CBCT system with a circular trajectory. We describe the calibration procedure by using a line-beads phantom, and how PAL determines the misalignments from a CBCT system. PAL also yields the uncertainties in the simulated calibration to give an estimate of the errors in the misalignments. From the analytical simulations, PAL can precisely obtain the source-to-rotation axis distance (SRD), and the geometric center G, "the point in z-axis meets the detector", where the z-axis is coincident with the line from the X-ray source that intersects the axis of the rotation (AOR) orthogonally. The uncertainties of three misalignment angles of the detector are within ±0.05°, which is close to ±0.04° for the results of Yang et al. [18], but our method is easy and simple to implement. Our distinct procedure, on the other hand, yields the calibration of a micro-CT system and an example of reconstructed images, showing our calibration method for the CBCT system to be simple, precise, and accurate.

Genome-wide DNA methylation analysis identifies potent CpG signature for temzolomide response in non-G-CIMP glioblastomas with unmethylated MGMT promoter: MGMT-dependent roles of GPR81.

PURPOSES: To identify potent DNA methylation candidates that could predict response to temozolomide (TMZ) in glioblastomas (GBMs) that do not have glioma-CpGs island methylator phenotype (G-CIMP) but have an unmethylated promoter of O-6-methylguanine-DNA methyltransferase (unMGMT). METHODS: The discovery-validation approach was planned incorporating a series of G-CIMP-/unMGMT GBM cohorts with DNA methylation microarray data and clinical information, to construct multi-CpG prediction models. Different bioinformatic and experimental analyses were performed for biological exploration. RESULTS: By analyzing discovery sets with radiotherapy (RT) plus TMZ versus RT alone, we identified a panel of 64 TMZ efficacy-related CpGs, from which a 10-CpG risk signature was further constructed. Both the 64-CpG panel and the 10-CpG risk signature were validated showing significant correlations with overall survival of G-CIMP-/unMGMT GBMs when treated with RT/TMZ, rather than RT alone. The 10-CpG risk signature was further observed for aiding TMZ choice by distinguishing differential outcomes to RT/TMZ versus RT within each risk subgroup. Functional studies on GPR81, the gene harboring one of the 10 CpGs, indicated its distinct impacts on TMZ resistance in GBM cells, which may be dependent on the status of MGMT expression. CONCLUSIONS: The 64 TMZ efficacy-related CpGs and in particular the 10-CpG risk signature may serve as promising predictive biomarker candidates for guiding optimal usage of TMZ in G-CIMP-/unMGMT GBMs.

[Neuroprotective effect and mechanism of Zuogui Jiangtang Jieyu Formula on diabetes mellitus complicated with depression model rats based on CX3CL1-CX3CR1 axis].

Based on the CX3C chemokine ligand 1(CX3CL1)-CX3C chemokine receptor 1(CX3CR1) axis, this study explored the potential mechanism by which Zuogui Jiangtang Jieyu Formula(ZGJTJY) improved neuroinflammation and enhanced neuroprotective effect in a rat model of diabetes mellitus complicated with depression(DD). The DD rat model was established by feeding a high-fat diet combined with streptozotocin(STZ) intraperitoneal injection for four weeks and chronic unpredictable mild stress(CUMS) combined with isolated cage rearing for five weeks. The rats were divided into a control group, a model group, a positive control group, an inhibitor group, and a ZGJTJY group. The open field test and forced swimming test were used to assess the depression-like behaviors of the rats. Enzyme-linked immunosorbent assay(ELISA) was performed to measure the expression levels of the pro-inflammatory cytokines interleukin-1ß(IL-1ß) and tumor necrosis factor-α(TNF-α) in plasma. Immunofluorescence staining was used to detect the expression of ionized calcium-binding adapter molecule 1(Iba1), postsynaptic density protein-95(PSD95), and synapsin-1(SYN1) in the hippocampus. Hematoxylin-eosin(HE) staining, Nissl staining, and TdT-mediated dUTP nick end labeling(TUNEL) fluorescence staining were performed to assess hippocampal neuronal damage. Western blot was used to measure the expression levels of CX3CL1, CX3CR1, A2A adenosine receptor(A2AR), glutamate receptor 2A(NR2A), glutamate receptor 2B(NR2B), and brain-derived neurotrophic factor(BDNF) in the hippocampus. Compared with the model group, the ZGJTJY group showed improved depression-like behaviors in DD rats, enhanced neuroprotective effect, increased expression of PSD95, SYN1, and BDNF(P<0.01), and decreased expression of Iba1, IL-1ß, and TNF-α(P<0.01), as well as the expression of CX3CL1, CX3CR1, A2AR, NR2A, and NR2B(P<0.01). These results suggest that ZGJTJY may exert its neuroprotective effect by inhibiting the CX3CL1-CX3CR1 axis and activation of hippocampal microglia, thereby improving neuroinflammation and abnormal activation of N-methyl-D-aspartate receptor(NMDAR) subunits, and ultimately enhancing the expression of synaptic-related proteins PSD95, SYN1, and BDNF in the hippocampus.

Canadine inhibits epithelial mesenchymal transformation of HPV-negative cervical cancer.

Although the majority of the population will be protected due to the advent and widespread use of the HPV vaccine, the treatment of cervical cancer for all causes, including HPV-negative cervical cancer, is still worthy of further research. The focal point of this study was Canadine's inhibition of epithelial-mesenchymal transformation (EMT) in cervical cancer. Immunoblotting, wound healing and tumor invasion experiments showed that low concentration of Canadine could inhibit the EMT process, proliferation and migration of HT-3 cells (HPV-negative cell line). Combined with GEO database, it was found that the expression levels of several genes highly expressed in cervical tumor tissues could be inhibited by Canadine, especially MAGEA3. Further experiments confirmed that the inhibition of Canadine on MAGEA3 protein increased with time. The small interference and overexpression plasmid of MAGEA3 were designed and verified. In HT-3 cells, when MAGEA3 levels were directly decreased, mesenchymal phenotypic markers were decreased and epithelial phenotypic markers were increased. The opposite result was obtained by overexpression of MAGEA3. In addition, the inhibition of EMT due to the reduction of endogenous MAGEA3 by Canadine was also offset by the overexpression of exogenous MAGEA3. The study concludes that Canadine inhibits EMT of cervical cancer by inhibiting MAGEA3.

A whole transcriptome profiling analysis for antidepressant mechanism of Xiaoyaosan mediated synapse loss via BDNF/trkB/PI3K signal axis in CUMS rats.

BACKGROUND: Depression is a neuropsychiatric disease resulting from deteriorations of molecular networks and synaptic injury induced by stress. Traditional Chinese formula Xiaoyaosan (XYS) exert antidepressant effect, which was demonstrated by a great many of clinical and basic investigation. However, the exact mechanism of XYS has not yet been fully elucidated. METHODS: In this study, chronic unpredictable mild stress (CUMS) rats were used as a model of depression. Behavioral test and HE staining were used to detect the anti-depressant effects of XYS. Furthermore, whole transcriptome sequencing was employed to establish the microRNA (miRNA), long non-coding RNA (lncRNA), circular RNA (circRNA), and mRNA profiles. The biological functions and potential mechanisms of XYS for depression were gathered from the GO and KEGG pathway. Then, constructed the competing endogenous RNA (ceRNA) networks to illustrate the regulatory relationship between non-coding RNA (ncRNA) and mRNA. Additionally, longest dendrite length, total length of dendrites, number of intersections, and density of dendritic spines were detected by Golgi staining. MAP2, PSD-95, SYN were detected by immunofluorescence respectively. BDNF, TrkB, p-TrkB, PI3K, Akt, p-Akt were measured by Western Blotting. RESULTS: The results showed that XYS could increase the locomotor activity and sugar preference, decreased swimming immobility time as well as attenuate hippocampal pathological damage. A total of 753 differentially expressed lncRNAs (DElncRNAs), 28 circRNAs (DEcircRNAs), 101 miRNAs (DEmiRNAs), and 477 mRNAs (DEmRNAs) were identified after the treatment of XYS in whole transcriptome sequencing analysis. Enrichment results revealed that XYS could regulate multiple aspects of depression through different synapse or synaptic associated signal, such as neurotrophin signaling and PI3K/Akt signaling pathways. Then, vivo experiments indicated that XYS could promote length, density, intersections of synapses and also increase the expression of MAP2 in hippocampal CA1, CA3 regions. Meanwhile, XYS could increase the expression of PSD-95, SYN in the CA1, CA3 regions of hippocampal by regulating the BDNF/trkB/PI3K signal axis. CONCLUSION: The possible mechanism on synapse of XYS in depression was successfully predicted. BDNF/trkB/PI3K signal axis were the potential mechanism of XYS on synapse loss for its antidepressant. Collectively, our results provided novel information about the molecular basis of XYS in treating depression.

Prenatal Exposure to Air Pollution and Pre-Labor Rupture of Membranes in a Prospective Cohort Study: The Role of Maternal Hemoglobin and Iron Supplementation.

BACKGROUND: Exposure to air pollution in prenatal period is associated with prelabor rupture of membranes (PROM). However, the sensitive exposure time windows and the possible biological mechanisms underlying this association remain unclear. OBJECTIVE: We aimed to identify the sensitive time windows of exposure to air pollution for PROM risk. Further, we examined whether maternal hemoglobin levels mediate the association between exposure to air pollution and PROM, as well as investigated the potential effect of iron supplementation on this association. METHOD: From 2015 to 2021, 6,824 mother-newborn pairs were enrolled in the study from three hospitals in Hefei, China. We obtained air pollutant data [particulate matter (PM) with aerodynamic diameter ≤2.5µm (PM2.5), PM with aerodynamic diameter ≤10µm (PM10), sulfur dioxide (SO2), and carbon monoxide (CO)] from the Hefei City Ecology and Environment Bureau. Information on maternal hemoglobin levels, gestational anemia, iron supplementation, and PROM was obtained from medical records. Logistic regression models with distributed lags were used to identify the sensitive time window for the effect of prenatal exposure to air pollutant on PROM. Mediation analysis estimated the mediated effect of maternal hemoglobin in the third trimester, linking prenatal air pollution with PROM. Stratified analysis was used to investigate the potential effect of iron supplementation on PROM risk. RESULTS: We found significant association between prenatal exposure to air pollution and increased PROM risk after adjusting for confounders, and the critical exposure windows of PM2.5, PM10, SO2 and CO were the 21th to 24th weeks of pregnancy. Every 10-µg/m3 increase in PM2.5 and PM10, 5-µg/m3 increase in SO2, and 0.1-mg/m3 increase in CO was associated with low maternal hemoglobin levels [-0.94g/L (95% confidence interval (CI): -1.15, -0.73), -1.31g/L (95% CI: -1.55, -1.07), -2.96g/L (95% CI: -3.32, -2.61), and -1.11g/L (95% CI: -1.31, -0.92), respectively] in the third trimester. The proportion of the association between air pollution and PROM risk mediated by hemoglobin levels was 20.61% [average mediation effect (95% CI): 0.02 (0.01, 0.05); average direct effect (95%): 0.08 (0.02, 0.14)]. The PROM risk associated with exposure to low-medium air pollution could be attenuated by maternal iron supplementation in women with gestational anemia. CONCLUSIONS: Prenatal exposure to air pollution, especially in the 21st to 24th weeks of pregnancy, is associated with PROM risk, which is partly mediated by maternal hemoglobin levels. Iron supplementation in anemia pregnancies may have protective effects against PROM risk associated with exposure to low-medium air pollution. https://doi.org/10.1289/EHP11134.

Gender differences in clinical characteristics of patients with non-cystic fibrosis bronchiectasis in different age groups in northern China.

INTRODUCTION: Patient gender has clinical and prognostic implications in non-cystic fibrosis bronchiectasis, yet the potential effect of gender on clinical characteristics of patients with non-cystic fibrosis bronchiectasis is still unclear. OBJECTIVES: This study aimed to investigate the gender differences in clinical characteristics of patients with bronchiectasis in different age groups in northern China. METHODS: A total of 777 patients diagnosed with bronchiectasis were retrospectively included in Beijing Chaoyang Hospital and divided into two groups by gender: the male group and the female group. Each group was then subdivided into two according to their age (≤65 and >65 years). Gender differences in clinical characteristics were compared in all patients with bronchiectasis in the two age groups, respectively. RESULTS: A total of 777 bronchiectasis patients were included. Of these patients, the prevalence of female non-smokers was substantially higher than that of male non-smokers (94.0% vs. 36.8%). There were gender differences in etiology of bronchiectasis, with more post-measles and connective tissue disease in females (p = 0.006 and 0.002 separately) and more chronic obstructive pulmonary disease (COPD) in males (p < 0.001). The male group had a significantly higher C-reactive protein (CRP) on admission (p = 0.03). Female patients showed a higher forced expiratory volume in 1 s as percentage of predicted volume (FEV1%pred) and forced vital capacity rate of 1 s (FEV1/FVC) (p < 0.001), lower partial pressure of carbon dioxide (PaCO2 ) (p = 0.04) and hospital costs (p = 0.02) than males, and a higher prevalence of infection with Pseudomonas aeruginosa in >65-year-old group (p = 0.019). CONCLUSIONS: There were many differences between male and female patients in smoking status, etiology, lung function, blood gas analysis, and hospital costs in all patients or different age groups.

Safety profile of 0.0015% tafluprost eye drops in China: a post-marketing observational study.

AIM: To investigate the treatment pattern and safety of tafluprost for glaucoma and ocular hypertension (OH) in clinical practice in China. METHODS: This post-marketing observational study included patients who received tafluprost to lower intraocular pressure (IOP) within 30d between September 2017 and March 2020 in 20 hospitals in China. Adverse drug reactions (ADRs) during tafluprost treatment and within 30d after the treatment were collected. RESULTS: A total of 2544 patients were included in this study, of them 58.5% (1488/2544) had primary open angle glaucoma (POAG), 21.9% (556/2544) had OH and 19.7% (500/2544) used tafluprost for other reasons. Of 359 ADRs occurred in 10.1% (258/2544) patients, and no serious adverse event occurred. The most common ADR was conjunctival hyperemia (128 ADRs in 124 patients, 4.9%). Totally 1670 participants (65.6%) combined tafluprost with carbonic anhydrase inhibitors (CAIs; 37.1%, 620/1670), sympathomimetics (33.5%, 559/1670), ß-blockers (33.2%, 555/1670), other prostaglandin analogs (PGAs; 15.6%, 260/1670) and other eye drops (15.1%, 253/1670). The highest incidence of conjunctival hyperemia was noted in patients who received tafluprost in combination with other PGAs (23 ADRs in 23 patients, 8.8%, 23/260) and the lowest was in combination with CAIs (16 ADRs in 16 patients, 2.6%, 16/620). Tafluprost was applied in primary angle-closure glaucoma (41.6%, 208/500), after glaucoma surgery (17.8%, 89/500) and after non-glaucoma surgery (15.8%, 79/500). CONCLUSION: Tafluprost is safe for POAG and OH, and tolerable when combined with other eye drops and under various clinical circumstances.

Sleep deprivation leads to further impairment of hippocampal synaptic plasticity by suppressing melatonin secretion in the pineal gland of chronically unpredictable stress rats.

There has been ample research showing that insomnia is a potential trigger of depression as well as a symptom of depression. These two factors contribute to behavioural problems and are closely related to the plasticity of hippocampal synapses. Although depression and insomnia impair hippocampal synaptic plasticity, the mechanism by which this happens remains a mystery. This study aimed to investigate the pathogenesis of insomnia comorbidity in depression and the regulatory effect of venlafaxine combined with melatonin on hippocampal synaptic plasticity in chronic unpredictable mild stress (CUMS) with sleep deprivation (SD) rats. Thus, rats were subjected to 14 days of chronic mild unpredictable stress, gradually acclimated to sleep deprivation on days 12-14. Followed by 21 consecutive days of sleep deprivation, 18 h per day, with daily gavage of venlafaxine (13.5 mg/kg) + melatonin (72 mg/kg) on days 15-36. Venlafaxine + melatonin treatment improves depression-like behaviour, pentobarbital sodium experimental sleep latency, and sleep duration in CUMS +SD rats. In addition to improving depressive-like behaviors, sleep deprivation also upregulates the expression of caspase-specific cysteine protein 3 (Caspase 3) in the pineal glial cells of chronic mild rats, as well as in hippocampal microglia. Expression of ionic calcium-binding adaptor 1 (iba-1), downregulates the secretion of several synaptic plasticity-related proteins, notably cAMP response element binding protein (CREB), glial cell line-derived neurotrophic factor (GDNF), and the synaptic scaffolding protein Spinophiline (Spinophiline). Hematoxylin-eosin staining showed that the structure of the pineal gland and hippocampus was damaged, and Golgi staining showed that the dendrites and spines in the DG area of the hippocampus were destroyed, vaguely aggregated or even disappeared, and the connection network could not be established. Western blot analysis further revealed a positive correlation between low melatonin levels and reduced Spinophiline protein. Interestingly, venlafaxine + melatonin reversed these events by promoting hippocampal synaptic plasticity by regulating melatonin secretion from the pineal gland. Therefore, it exerted an antidepressant effect in sleep deprivation combined with CUMS model rats. Overall, the results of this study suggest that the pathophysiology of depressive insomnia comorbidity is mediated by impaired pineal melatonin secretion and impaired hippocampal synaptic plasticity. In addition, these responses are associated with melatonin secretion from the pineal gland.

Feasibility of utilizing ultra-low-dose contrast medium for pancreatic artery depiction using the combination of advanced virtual monoenergetic imaging and high-concentration contrast medium: an intra-patient study.

OBJECTIVES: The least amount of contrast medium (CM) should be used under the premise of adequate diagnosis. The purpose of this study is to evaluate the feasibility of utilizing ultra-low-dose (224 mgI/kg) CM for pancreatic artery depiction using the combination of advanced virtual monoenergetic imaging (VMI+) and high-concentration (400 mgI/mL) CM. MATERIALS AND METHODS: 41 patients who underwent both normal dose CM (ND-CM, 320 mgI/kg) and low dose CM (LD-CM, 224 mgI/kg) thoracoabdominal enhanced CT for tumor follow-up were prospectively included. The VMI+ at the energy level of 40-kev for LD-CM images was reconstructed. CT attenuation, signal-to-noise ratios (SNRs), and contrast-to-noise ratios (CNRs) of the abdominal artery, celiac artery, and superior mesenteric artery (SMA) and qualitative scores of pancreatic arteries depiction were recorded and compared among the three groups (ND-CM, LD-CM, and VMI+ LD-CM images). ANOVA and Friedman tests were used for statistical analysis. RESULTS: All quantitative and qualitative parameters on LD-CM images were lower than that on ND-CM images (all p < 0.01). There were no significant differences of all arteries' qualitative scores between ND-CM and VMI+ LD-CM images (all p > 0.05). VMI+ LD-CM images had the highest mean CT and CNR values of all arteries (all p < 0.0001). The CM volume was 52.6 ± 9.4 mL for the ND-CM group and 37.0 ± 6.7 mL for the LD-CM group. CONCLUSION: Ultra-low-dose CM (224 mgI/kg) was feasible for depicting pancreatic arteries. Inferior angiographic image quality could be successfully compensated by VMI+ and high-concentration CM.

Truncation of the Cytoplasmic Tail of Equine Infectious Anemia Virus Increases Virion Production by Improving Env Cleavage and Plasma Membrane Localization.

Envelope glycoproteins (Envs) of lentiviruses harbor unusually long cytoplasmic tails (CTs). Natural CT truncations always occur in vitro and are accompanied by attenuated virulence, but their effects on viral replication have not been fully elucidated. The Env in equine infectious anemia virus (EIAV) harbors the longest CT in the lentiviral family, and a truncated CT was observed in a live attenuated vaccine. This study demonstrates that CT truncation significantly increased EIAV production, as determined by comparing the virion yields from EIAV infectious clones in the presence and absence of the CT. A significant increase in a cleaved product from the CT-truncated Env precursor, but not the full-length Env, was observed. We further confirmed that the presence of the CT inhibited the cleavage of the Env precursor and found that a functional domain located at the C terminus was responsible for this function. Moreover, CT-truncated Env was mainly localized at the plasma membrane (PM), while full-length Env was mainly localized in the cytoplasm. The CT truncation caused a dramatic reduction in the endocytosis of Env. These results suggest that the CT can modulate the processing and trafficking of EIAV Env and thus regulate EIAV replication. IMPORTANCE The mature lentivirus envelope glycoprotein (Env) is composed of a surface unit (SU) and a transmembrane unit (TM), which are cleaved products of the Env precursor. After mature Env is heterodimerically formed from the cleavage of the Env precursor, it is trafficked to the plasma membrane (PM) for incorporation and virion assembly. Env harbors a long cytoplasmic tail (CT), which has been increasingly found to play multiple roles in the Env biological cycle. Here, we revealed for the first time that the CT of equine infectious anemia virus (EIAV) Env inhibits cleavage of the Env precursor. Simultaneously, the CT promoted Env endocytosis, resulting in weakened Env localization at the PM. We also validated that the CT could significantly decrease EIAV production. These findings suggest that the CT regulates the processing and trafficking of EIAV Env to balance virion production.

[Identifying Molecular Subtypes of Whole-Slide Image in Colorectal Cancer via Deep Learning].

OBJECTIVE: To establish an artificial intelligence-assisted diagnosis system for molecular subtyping of colorectal cancer (CRC). METHODS: 812 whole-slide images (WSIs) of 422 patients were selected from the database of The Cancer Genome Atlas (TCGA) and were put into the training set (75%) and the test set (25%). The slides were stored in the www.paiwsit.com database. We preprocessed and segmented the slides based on the labelling results of experienced pathologists to generate a training set of more than 4 million labeled samples. Finally, deep learning models were adopted for training. RESULTS: After training with several convolutional neural network models, we tested the performance of the trained deep learning model on the test set of 203 WSIs from 110 patients, and our model achieved an accuracy of 53.04% at patch-level and 51.72% at slide-level, while the accuracy of CMS2 (one of a consensus of four subtypes for CRC) at slide-level was as high as 75.00%. CONCLUSION: This study is of great significance to the promotion of colorectal cancer screening and precision treatment.

GR/NF-κB signaling pathway regulates hippocampal inflammatory responses in diabetic rats with chronic unpredictable mild stress.

Clinical studies have shown that diabetes can present with underlying depression, and a combination of the two can lead to emotional, memory and cognitive disorders, closely associated with hippocampal neuroinflammation. However, the mechanism underlying the development of hippocampal neuroinflammation under the above condition remains elusive. The aims of this study were to explore the pathogenesis of diabetes combined with depression, and the effect of dexamethasone (Dex), a glucocorticoid receptor (GR) agonist, on hippocampal neuroinflammation in diabetic rats with chronic unpredictable mild stress (CUMS). Therefore, rats were intragastrically fed on a high-fat diet (10% cholesterol 10 ml/kg) for 14 days and thereafter injected with 38 mg/kg of streptozotocin on the 15th day to induce diabetes. Dex treatment of the diabetic and CUMS rats ameliorated the depression-associated behavior in the respective rats. Apart from enhanced depressive behavior, diabetes-depressed condition also up-regulated the expression of hippocampus microglia chemokine Ⅰ receptor (CX3CR1) and secretion of several pro-inflammatory factors, in particular, interleukin 1ß (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor - α (TNF-α). Hematoxylin-eosin staining revealed inflammatory damages in the hippocampus. Western blot analysis further revealed repression of GR proteins converse to the nuclear factor kappa-B (NF-κB) proteins, which were up-regulated. Intriguingly, Dex reversed the above events by inhibiting inflammatory reactions in the hippocampus. Consequently, played an antidepressant effect in diabetic and CUMS model rats. Overall, findings of this research suggest that the physiopathology of diabetes with stress cormobity are mediated by inflammatory reactions in the hippocampus. In particular, the responses are associated with regulation of GR/NF-κB signaling pathway.

MiR-19-3p Induces Tumor Cell Apoptosis via Targeting FAS in Rectal Cancer Cells.

MicroRNAs are reported as a vital important factor in cancer cell initiation and progression processes. MicroRNA-19-3p has drawn the attention of many researchers in recent years because of its wide expression and its key role in serious kinds of tumor cells. However, the detailed mechanism of microRNA-19a-3p in these tumors is still poorly understood. So, in the present study, we aimed to explore the biological function and potential molecular mechanism of microRNA-19a-3p in different cancer cells. We first detect the relative level of miR-19a-3p in cancer cell lines and tumor tissues compared to normal cells and tissues. Results indicated the messenger RNA expression of microRNA-19a-3p existing in an aberrant low level in cancer cells and tissues. The overexpression of microRNA-19a-3p significantly reduced the cell proliferation, migration, and invasion ability in HCT116 cells. In addition to this, increased microRNA-19a-3p could induce cell apoptosis via promoting reactive oxygen species (ROS) accumulation, whereas inhibition of microRNA-19a-3p exhibited an opposite effect. Moreover, we predicated the target genes and the binding sites of microRNA-19a-3p and confirmed FAS as the targeting of microRNA-19a-3p through luciferase activity assay. Taken together, these results indicated that microRNA-19a-3p overexpression inhibited HCT116 cell proliferation, migration and invasion, induced cell apoptosis, and ROS accumulation via FAS targeting effect. It was conceivable that microRNA-19a-3p might serve as a potential molecular target for breast and liver cancer treatment.

[Effects of ELK-1/JNK/c-Fos on apoptosis of rat hippocampal neurons cultured in vitro with Zuogui Jiangtang Jieyu Formula in simulated diabetes mellitus complicated with depression].

OBJECTIVE: To study the effects of Zuogui Jiangtang Jieyu Formula (ZGJTJYF, the Chinese Medicine) on hippocampal neuron apoptosis in diabetes mellitus complicated with depression (DD). METHODS: The primary cultured hippocampal neurons were treated with high glucose (150 mmol/L) and corticosterone (200 micromol/L) to establish the cell model of DD in vitro. The cultured hippocampal neurons were randomly divided into five groups: blank serum group, normal group, Zuogui Jiangtang Jieyu recipe drug-containing serum group, positive drug (metformin + fluoxetine) drug-containing serum group and model group (three compound holes in each group). The model group and the normal group were given the same amount of culture medium, and the other groups were given the corresponding serum with 10% volume fraction for 18 hours. Hoechst staining, high content cell imaging and RT-PCR were used to detect the apoptosis of hippocampal neurons and the expressions of apoptosis-related ETS-like 1 transcription factor(ELK-1), C-Jun N-terminal kinase(JNK) and c-Fos proteins and genes. RESULTS: Compared with the blank group, the apoptotic number of hippocampal neurons in the model group was increased significantly, and the expression levels of ELK-1, JNK and c-Fos were increased significantly (P＜0.05). Compared with the model group, the local bright spots of hippocampal neurons in the Zuogui Jiangtang Jieyu recipe-containing serum group and the positive drug-containing serum group were decreased significantly, and the number of apoptotic cells was decreased significantly. The expressions of JNK, c-fos protein and mRNA were down-regulated significantly (P＜ 0.05), and the neural network and dendritic junction were improved significantly. CONCLUSION: Zuo Gui Jiang Tang Jie Yu Formula can reverse the expressions of ELK-1, JNK and c-Fos signals in hippocampal neurons under DD environment and play an anti-apoptotic effect.

Analgesic and anti-inflammatory effects and molecular mechanisms of Kadsura heteroclita stems, an anti-arthritic Chinese Tujia ethnomedicinal herb.

ETHNOPHARMACOLOGICAL RELEVANCE: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by failure of spontaneous resolution of inflammation. The stem of Kadsura heteroclite (KHS) is a well-known anti-arthritic Tujia ethnomedicinal plant, which named Xuetong in folk, has long been used for the prevention and treatment of rheumatic and arthritic diseases. AIM OF THE STUDY: The analgesic and anti-inflammatory effects and the potential mechanisms behind such effects of KHS would be investigated by using different animal models. MATERIALS AND METHODS: The abdominal writhing episodes of mice induced by intraperitoneal injection of acetic acid and the tail-flick response induced by radiant heat stimulation were used to evaluate the analgesic effect of KHS. The number of abdominal writhing episodes of mice and the latency of tail-flick in rats were measured and recorded. In acute inflammatory models, the ear edema of mice was induced by applying xylene on the ear surface, while the paw edema of male and female rats was induced by subcutaneous injection of carrageenan into the right hind paws of animals. The carrageenan-induced paw swelling in rats were selected as an anti-acute inflammatory mechanism of KHS. Serum levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor (TNF-α) were measured by ELISA, and protein expression of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were detected by Western blot. RESULTS: The maximal tolerated single dose of KHS was determined to be 26 g/kg in both sexes of mice. Pharmacological studies showed that KHS at the dose of 200 mg/kg significantly prolonged the reaction time of rats to radiant heat stimulation and suppressed abdominal writhing episodes of mice induced by intraperitoneal injection of acetic acid. KHS at the dose of 200, 400, and 800 mg/kg, showed dose-dependent inhibition of xylene-induced ear swelling in mice. KHS at the dose of 100, 200, 400, and 800 mg/kg demonstrated dose- and time-dependent suppression of paw edema induced by subcutaneous injection of carrageenan in both all rats. Mechanistic studies revealed that the anti-inflammatory effect of KHS was associated with inhibition of the production of pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α and effectively decreased the expression of COX and iNOS proteins in the carrageenan-injected rat serum, paw tissues and inflammatory exudates. The positive reference drug, rotundine at a dosage of 100 mg/kg and indomethacin at a dosage of 10 mg/kg were used in both mice and rat models. CONCLUSION: These results suggested that KHS has significant effects on analgesia and anti-inflammation with decreasing the pro-inflammation cytokines of IL-1ß, IL-6, and TNF-α and inhibiting the proteins expression of COX-2 and iNOS.

Kadsura heteroclita stem suppresses the onset and progression of adjuvant-induced arthritis in rats.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune diseased state, characterized by hyperplasia of the synovial membrane, degradation of cartilage, and bone erosion of diarthrodial joints. Kadsura heteroclita (Roxb) Craib (Schizandraceae), a traditional Tujia ethnomedicine called Xue Tong in China, has been long used for the prevention and treatment of rheumatic and arthritic diseases, especially in the southern China. This study aimed to evaluate anti-arthritic effects of the ethanol extract of Kadsura heteroclita stems (KHS) on complete Freund's adjuvant (CFA)-induced arthritis (AIA) in rats, as well as to explore the underlying mechanisms of anti-arthritis. METHODS: AIA was established in male Sprague-Dawley (SD) rats as described previously, and animals were daily treated by gavage with KHS ethanol extract (200, 400, or 800 mg/kg) or vehicle (0.3% CMCNa) throughout the 30-day experiment. The incidence and severity of arthritis were evaluated using clinical parameters. At the end of experiments, tissue swelling and bone destruction of the hind paws were assessed by computed tomography (CT) and histopathological analyses. Serum levels of tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), IL-6, and IL-17A and IL-17F were measured by ELISA, and protein expression of matrix metalloproteinases-1 (MMP-1), MMP-3 and tissue inhibitor of MMP-1 (TIMP-1) were detected by Western blot. RESULTS: Treatment with KHS dose-dependently inhibited paw swelling and reduced arthritis scores of AIA rats. CT images displayed that KHS remarkably protected AIA rats from tissue swelling and bone erosion of joints. Histopathological analyses revealed that KHS markedly reduced inflammatory cell infiltration, synovial proliferation, and the formation of pannus in the ankle joints of AIA rats. KHS was found to significantly suppress the production of TNF-α, IL-1 ß, IL-6, IL-17A and IL-17F, inhibited the protein expression of MMP-1 and MMP-3, and elevated the protein expressions of TIMP-1. CONCLUSION: KHS demonstrates potential anti-arthritic effects via inhibiting pivotal mediators of inflammation and cartilage destruction. This study strongly supports identification and isolation of active fractions of KHS which would be a potential candidate for further investigation as a new anti-arthritic botanical drug.

Structural and functional damage to the hippocampal neurovascular unit in diabetes-related depression.

Previous studies have shown that models of depression exhibit structural and functional changes to the neurovascular unit. Thus, we hypothesized that diabetes-related depression might be associated with damage to the hippocampal neurovascular unit. To test this hypothesis, neurons, astrocytes and endothelial cells were isolated from the brain tissues of rat embryos and newborn rats. Hippocampal neurovascular unit co-cultures were produced using the Transwell chamber co-culture system. A model of diabetes-related depression was generated by adding 150 mM glucose and 200 µM corticosterone to the culture system and compared with the neuron + astrocyte and astrocyte + endothelial cell co-culture systems. Western blot assay was used to measure levels of structural proteins in the hippocampal neurovascular unit co-culture system. Levels of basic fibroblast growth factor, angiogenic factor 1, glial cell line-derived neurotrophic factor, transforming growth factor ß1, leukemia inhibitory factor and 5-hydroxytryptamine in the hippocampal neurovascular unit co-culture system were measured by enzyme-linked immunosorbent assay. Flow cytometry and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling staining was used to assess neuronal apoptosis in the hippocampal neurovascular unit. The neurovascular unit triple cell co-culture system had better barrier function and higher levels of structural and secretory proteins than the double cell co-culture systems. In comparison, in the model of diabetes-related depression, the neurovascular unit was damaged with decreased barrier function, poor structural integrity and impaired secretory function. Moreover, neuronal apoptosis was markedly increased, and 5-hydroxytryptamine levels were reduced. These results suggest that diabetes-related depression is associated with structural and functional damage to the neurovascular unit. Our findings provide a foundation for further studies on the pathogenesis of diabetes-related depression.