Disrupted resting-state interhemispheric functional connectivity in systemic lupus erythematosus patients with and without neuropsychiatric lupus.

PURPOSE: The aim of the study is to explore interhemispheric homotopic functional connectivity alterations in systemic lupus erythematosus (SLE) patients with and without neuropsychiatric lupus (NPSLE and non-NPSLE, respectively) and their potential correlations with clinical characteristics and neuropsychological performance. METHODS: Based on resting-state functional MRI (rs-fMRI) data collected from SLE patients and matched healthy controls (HCs), the voxel-mirrored homotopic connectivity (VMHC) analysis was conducted to measure functional homotopy. Subsequently, correlations between altered functional homotopy and clinical/neuropsychological data were analyzed. RESULTS: Compared with the HC group, both NPSLE and non-NPSLE groups showed attenuated homotopic connectivity in middle temporal gyrus (MTG), cuneus (CUN), middle occipital gyrus (MOG), angular gyrus (ANG), and postcentral gyrus (PoCG). NPSLE patients also exhibited decreased homotopic connectivity in inferior parietal gyrus (IPG) and middle frontal gyrus (MFG). Compared with non-NPSLE patients, NPSLE patients showed weaker interhemispheric homotopic functional connectivity in MOG. Decreased homotopic functional connectivity in PoCG, IPG, and MOG were associated with the anxiety state of SLE patients. CONCLUSIONS: Our findings revealed attenuated functional homotopy in both NPSLE and non-NPSLE groups compared to the HC group, which appeared to be more severe in patients with comorbid neuropsychiatric lupus. Interhemispheric homotopy dysconnectivity may participate in the neuropathology of anxiety symptoms in SLE.

Comparative study of striatum GABA concentrations and magnetic resonance spectroscopic imaging in Parkinson's disease monkeys.

BACKGROUND: Parkinson's disease is a progressive degenerative nervous system disease. Recent studies have shown that secondary changes in the GABA system play directly affect the pathogenesis of PD. There is still much debate about GABA concentrations because currently, GABA concentrations in the brain tissue are obtained indirectly by measuring its concentration in the blood and cerebrospinal fluid. These results are unreliable. Magnetic resonance spectroscopy (MRS) is the only noninvasive method for evaluating the concentration of metabolites in living brain tissue and has been widely applied in research and clinical practice. In addition, combining MEGA-PRESS technology with LCModel software for quantitative GABA measurements is largely recognized. At present, the PD monkeys model in primates has been increasingly proficient. Primates are more similar to humans in terms of brain structure and function than other animals. However, 3.0 T MRS studies involving the PD monkey model to measure metabolites in living subjects with PD are still rare. The study was performed at 3.0 T MRI with control monkeys and PD monkeys that were injected methyl-phenyl-tetrahydropyridine (MPTP) in one side of common carotid artery before and 3 months after successful model establishment to measure GABA concentrations in the bilateral striatum. Behavioral observations were performed for all animals, and the behavioral score was recorded. After 3 months, the GABA concentration in the bilateral striatum was measured in both groups by high-performance liquid chromatography (HPLC). The data obtained from magnetic resonance spectroscopy (MRS) were compared with the actual measured GABA concentrations in tissues isolated from the corresponding regions, and their correlations with the behavior score were analyzed. The research objectives are to investigate the changes of γ-aminobutyric acid (GABA) concentration in the bilateral striatum of monkeys with Parkinson's disease (PD) and the value of quantitatively measuring its concentration by noninvasive 3.0 T spectroscopy. RESULTS: (1) The MRS results showed that the GABA concentration in the injured side of the striatum of the PD monkeys was higher than in the contralateral side, but the difference was not statistically significant (P = 0.154). Compared with that the blank control group, the GABA concentration in the striatum of the PD monkeys increased, but there was no difference between the groups (P = 0.381; P = 0.425). (2) The GABA concentration that determined from the isolated specimens by HPLC in the injured side of the striatum of the PD monkeys was significantly higher than that in the contralateral side (P < 0.01). Compared with the blank control group, the PD monkeys had higher GABA concentrations in both sides of the striatum, and there was a significant difference in the lesion side (P = 0.004), while there was a non-significant difference in the contralateral side (P = 0.475). (3) The mean GABA concentration in the injured striatum of PD monkeys determined by MRS was not significantly correlated with the behavioral score (r = 0.146, P = 0.688). The mean GABA concentration in the injured striatum determined from the isolated specimens was positively correlated with the behavioral score in the same period (r = 0.444, P = 0.038). CONCLUSION: The GABA concentration in the injured striatum of PD monkeys is increased and positively correlated with behavioral changes. Validity of noninvasive 3.0 T MRS to detect PD neurotransmitter changes is limited.

Risk Factors of Central Venous Catheter-Related Bloodstream Infection for Continuous Renal Replacement Therapy in Kidney Intensive Care Unit Patients.

BACKGROUND: The incidence of central venous catheter-related bloodstream infection (CRBSI) for continuous renal replacement therapy (CRRT) in kidney intensive care unit (ICU) patients is worthy of particular attention and recently, we analyzed clinical characteristics and risk factors of CRBSI for CRRT in our kidney ICU patients. METHODS: To be part of this retrospective study, 1,523 patients who had a central venous catheter (CVC) for CRRT during the period April 2010 to May 2015 in our centre were enrolled. The clinical features and pathogens of CRBSI patients were investigated. Patients who also had CRRT of kidney ICU hospitalization without CRBSI were enrolled in a 1: 2 ratio as control. Risk factors of the CRBSI were analyzed. RESULTS: A total of 57 patients had central venous CRBSI. The incidence of the infection was 3.7%. The mean rate of CRBSI was 3.9 per 1,000 catheter days, and the catheter median indwelling time was 14 (7-30) days. The most common pathogens were Gram-positive bacteria, which were noted in 29 cases (50.9%), followed by Gram-negative bacteria (36.8%). The most common pathogens causing CRBSI were Staphylococcus aureus (10 cases) and sewer enterobacteriaceae (10 cases) followed by Staphylococcus epidermidis (9 cases). CVC insertion sites included internal jugular vein (33 cases) and femoral vein (24 cases), accounting for 2.9% of internal jugular vein catheterization (1,140 cases) and 6.3% of femoral vein catheterization (383 cases) respectively. In total, 16, 20, 7 and 14 cases of CRBSI were noted in Spring, Summer, Autumn and Winter, accounting for 28.1, 35.1, 12.3 and 24.6% respectively. The most common infectious manifestations were chills (68.4%), fever (100%), and septic shock (49.1%). Multivariate analysis showed that catheterization of the femoral vein, long catheter indwelling time, low CD4+ lymphocytes and high acute physiology and chronic health evaluation (APACHE) II scores were independent factors associated with CRBSI. CONCLUSIONS: The incidence of CRBSI in our kidney ICU was 3.7%. Central venous CRBSI for CRRT was associated with catheterization of the femoral vein, long catheter indwelling time, compromised immune function and high APACHE II scores. Understanding pathogens and risk factors for central venous CRBSI in kidney ICU can help doctors prevent and treat CRBSI earlier.

Combinatorial metabolic pathway assembly in the yeast genome with RNA-guided Cas9.

The yeast Saccharomyces cerevisiae is an important industrial platform for the production of grain and cellulosic ethanol, isobutanol, butanediol, isoprenoids, and other chemicals. The construction of a successful production strain usually involves multiple gene knockouts and chromosomal integration of expression cassettes to redirect the metabolic fluxes for the conversion of sugars and other feed stocks into the desired product. RNA-guided Cas9 based genome editing has been demonstrated in many prokaryotic and eukaryotic hosts including S. cerevisiae, in which it has been additionally exploited as a tool for metabolic engineering. To extend the utilization of RNA-guided Cas9 as a metabolic pathway building tool, we demonstrated the direct assembly and chromosomal integration of up to 17 overlapping DNA fragments encoding the beta-carotene biosynthetic pathway. Furthermore, we generated a combinatorial strain library for the beta-carotene biosynthetic pathway, directly integrated into the yeast genome to create a diverse library of strains. This enabled the screening of combinatorial libraries in stable chromosomally integrated strains for rapid improvements of product titers. This combinatorial approach for pathway assembly will significantly accelerate the current speed of metabolic engineering for S. cerevisiae as an industrial platform, and increase the number of strains that can be simultaneously evaluated for enzyme screening, expression optimization and protein engineering to achieve the titer, rate and yield necessary for the commercialization of new industrial fermentation products.

[Reduction in hypoxia-derived neuroinflammation and dysfunctional glutamate transporters by minocycline may restore hypoxia-injured cognition of neonatal rat].

The aim of the present study was to investigate the effects of minocycline on cognitive functions in neonatal rat after hypoxia exposure and the underlying mechanism. A model of hypoxic brain damage (HBD) was developed by exposing postnatal 1 day (P1) rats to systemic hypoxia. The rats were intraperitoneally injected with normal saline (Hy group) or minocycline (Hy + M group) 2 h after hypoxia exposure. Some other P1 rats that were not subjected to systemic hypoxia were used as normal control (NG group). The Y-maze test was used to evaluate learning and memory ability on postnatal day 30. Inflammatory mediators (Iba-1, IL-1ß, TNF-α and TGF-ß1), glutamate transporters (EAAT1 and EAAT2), total Tau and phosphorylated Tau (phosphorylation sites: Tyr18, Thr205, Thr231, Ser396 and Ser404) protein expressions in the hippocampus were detected by Western blot 7 d after hypoxic exposure. The results showed that hypoxia induced learning and memory impairments of the neonatal rats, and minocycline administration could reverse the effects of hypoxia. The protein expression levels of Iba-1, IL-1ß, TNF-α, EAAT2 and Tau phosphorylated at T231 were increased, but the total Tau expression was decreased in the hippocampus of the rats from Hy group 7 d after hypoxia exposure. In the hypoxia-treated rats, minocycline down-regulated Iba-1, IL-1ß, TNF-α and EAAT2 protein expressions significantly, but did not affect total Tau and phosphorylated Tau protein expressions. Our results suggest that minocycline can prevent cognitive deficits of rats with hypoxia exposure, and the underlying mechanism may involve the inhibition of neuroinflammation and dysfunctional glutamate transporters but not the regulation of the Tau hyperphosphorylation.

Identification of key modules in metabolic syndrome induced by second-generation antipsychotics based on co-expression network analysis.

Background: Second-generation antipsychotics (SGAs) frequently cause metabolic syndrome (MetS), which raises the risk of heart disease, type 2 diabetes, morbid obesity, atherosclerosis, and hypertension. MetS also impairs cognitive function in patients with schizophrenia. However, the fundamental reasons of MetS caused by SGAs are not yet fully understood. Thus, we aimed to identify potential therapeutic targets for MetS induced by SGAs. Methods: The serum biochemical parameters and the RNA-sequencing of peripheral blood mononuclear cells were measured in three groups (healthy controls and patients with schizophrenia with and without MetS taking SGAs). The study of the weighted gene co-expression network was utilized to pinpoint modules that were significantly connected to clinical markers. Results: Statistical analysis showed significant differences in triglyceride and high-density lipoprotein among the three groups. The TNF signaling pathway, TGF-ß signaling pathway, fatty acid metabolism, NF-kappa B signaling pathway, MAPK signaling pathway, and Toll-like receptor signaling pathway were the pathways that were primarily enriched in the two unique co-expression network modules that were found. Finally, five specific genes (TNF, CXCL8, IL1B, TIMP1, and ESR1) associated with metabolism and immunity pathways were identified. Conclusions: This study indicated that SGAs differentially induced MetS of patients with schizophrenia through metabolic and inflammation-related pathways. Therefore, the potential side effects of drugs on inflammatory processes need to be considered when using SGAs for the treatment of schizophrenia.

Does clinical experience affect the bracket bonding accuracy of guided bonding devices in vitro?

OBJECTIVES: To study whether and how the clinical experience of the operator affects the accuracy of bracket placement using guided bonding devices (GBDs) in vitro. MATERIALS AND METHODS: Five resin models were bonded virtually with brackets, and the corresponding GBDs were generated and three-dimensionally printed. Nine operators, which included three dental students, three orthodontic students, and three orthodontists, bonded the brackets on the resin models using GBDs on a dental mannequin. After being bonded with brackets, the models were scanned, and the actual and designed positions of the brackets were compared. RESULTS: There was no immediate debonding. The orthodontists spent a significantly shorter time (22.36 minutes) in bracket bonding than the dental students (24.62 minutes; P < .05). The brackets tended to deviate to the buccal side in the dental student group. Linear deviations tended to be smallest in the orthodontic student group, but no significant difference was found among operators with different clinical experience (P > .5). All linear and angular deviations in each group were under 0.5 mm and 2°, respectively. CONCLUSIONS: Clinical experience was positively related to the bonding accuracy using GBDs, especially in the buccolingual dimension. Inexperience also led to longer bonding duration. However, bonding accuracy was clinically acceptable in general.

Characterizing defective lipid metabolism in the lateral septum of mice treated with olanzapine: implications for its side effects.

Schizophrenia significantly impacts cognitive and behavioral functions and is primarily treated with second-generation antipsychotics (SGAs) such as olanzapine. Despite their efficacy, these drugs are linked to serious metabolic side effects which can diminish patient compliance, worsen psychiatric symptoms and increase cardiovascular disease risk. This study explores the hypothesis that SGAs affect the molecular determinants of synaptic plasticity and brain activity, particularly focusing on the lateral septum (LS) and its interactions within hypothalamic circuits that regulate feeding and energy expenditure. Utilizing functional ultrasound imaging, RNA sequencing, and weighted gene co-expression network analysis, we identified significant alterations in the functional connection between the hypothalamus and LS, along with changes in gene expression in the LS of mice following prolonged olanzapine exposure. Our analysis revealed a module closely linked to increases in body weight and adiposity, featuring genes primarily involved in lipid metabolism pathways, notably Apoa1, Apoc3, and Apoh. These findings suggest that olanzapine may influence body weight and adiposity through its impact on lipid metabolism-related genes in the LS. Therefore, the neural circuits connecting the LS and LH, along with the accompanying alterations in lipid metabolism, are likely crucial factors contributing to the weight gain and metabolic side effects associated with olanzapine treatment.

Potential predictive value of IVIM MR for xerostomia in nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: Xerostomia, caused by radiation-induced parotid damage, is the most commonly reported radiotherapy (RT) complication for nasopharyngeal carcinoma (NPC). The purpose of this study was to evaluate the value of intravoxel incoherent motion (IVIM) MR in monitoring radiation-induced parotid gland damage and predicting the risk of xerostomia. METHODS: Fifty-four NPC patients were enrolled and underwent at least three IVIM MR scans: before (pre-RT), after 5 fractions of (5th-RT), halfway through (mid-RT), and after RT (post-RT). The degree of xerostomia patients was assessed before each MR examination. Furthermore, the time when patients first reported xerostomia symptoms was recorded. The changes in IVIM parameters throughout RT, as well as the relationships between IVIM parameters and xerostomia, were analysed. RESULT: All IVIM parameters increased significantly from pre-RT to post-RT (p < 0.001). The rates of D, D* and f increase increased significantly from pre-RT to mid-RT (p < 0.001), indicating that cell necrosis mainly occurs in the first half of RT. In multivariate analysis, N3 (p = 0.014), pre-D (p = 0.007) and pre-D* (p = 0.003) were independent factors influencing xerostomia. D and f were significantly higher at 5th-RT than at pre-RT (both p < 0.05). IVIM detected parotid gland injury at 5th-RT at an average scanning time of 6.18 ± 1.07 days, earlier than the 11.94 ± 2.61 days when the patient first complained of xerostomia according to the RTOG scale (p < 0.001). CONCLUSIONS: IVIM MR can dynamically monitor radiation-induced parotid gland damage and assess it earlier and more objectively than RTOG toxicity. Moreover, IVIM can screen people at risk of more severe xerostomia early.

Andrographolide exhibits antinociceptive effects in neuropathic rats via inhibiting class â ¡ MHC associated response and regulating synaptic plasticity.

BACKGROUND: Neuropathic pain (NP) due to nerve injury, disrupts neural plasticity by triggering the release of inflammatory mediators. Alongside the hypothesis that neuro-inflammation contributes to this disruption, Andrographolide (Andro), a traditional bioactive compound derived from Andrographis paniculata, has garnered attention for its potent anti-inflammatory properties. However, whether Andro could ameliorate NP by regulating neuroinflammation remains unknown. PURPOSE: This study aimed to investigate whether and how Andro regulates neuroinflammation and alleviates NP. METHODS: The analgesic effects of Andro on NP were evaluated using both the spinal nerve ligation (SNL) and formalin rat models. A combination of network pharmacology, RNA sequencing, and experimental validation was employed to elucidate the underlying mechanism behind Andro's analgesic effects. Additionally, various techniques such as functional ultrasound, immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR), patch clamp, and electron microscopy were employed to investigate the specific neural cell types, neural functions, and changes in neural plasticity influenced by Andro. RESULTS: Network pharmacology analysis unveiled the crucial roles played by shared targets of Andro and pain in regulating pain-related inflammation, including microglia activation, neuroinflammation, immune modulation, and synaptic transmission. Furthermore, we confirmed Andro's superior efficacy in pain relief compared to the traditional analgesic drug, Gabapentin. In these models, Andro was observed to modulate the haemodynamic response triggered by SNL. Transcriptome analysis and molecular docking studies indicated the involvement of major histocompatibility complex class II (MHCII) genes (Db1, Da, and Bb). Electron microscopy revealed improvements in synaptic ultrastructure, and electrophysiological investigations showed a selective reduction in glutamatergic transmission in neuropathic rats after following Andro treatment. The integration of systems pharmacology analysis and biological validation collectively demonstrated that the mechanism of pain relief involves immune modulation, enhancement of synaptic plasticity, and precise regulation of excitatory neurotransmission. CONCLUSION: In conclusion, this study has demonstrated that Andro, by targeting MHCII genes, may serve as a promising therapeutic candidate for neuropathic pain.

Links between life-course SES and frailty trajectory moderated by community environment resources: Person-environment Fit perspective.

INTRODUCTION: Drawing from the life course and person-environment fit perspectives, this study examined whether life-course SES disadvantages during childhood, adulthood and old- age influence frailty development in late- life and how community environment resources moderated the association between life-course SES disadvantages and frailty trajectories over a seven-year follow-up period. METHODS: Data from 11,675 participants aged ≥ 50 years at baseline who participated in the four waves (2011-2018) of the China Health and Retirement Longitudinal Survey (CHARLS) were used. Life-course SES disadvantages were self-reported, and community environment resources (basic infrastructure and voluntary organizations) were ascertained from informed officials in the community. Frailty development was measured at each wave by the Frailty Index (FI) based on 39 potential deficits. Multilevel growth modeling was used to examine the interactive effect of life-course SES disadvantages and community environment resources on frailty development. RESULTS: Life-course SES disadvantage exerted cumulatively negative effects on frailty trajectory, and individuals with SES disadvantages in two or three life stages reported higher initial levels of and faster increases in frailty scores. Community environmental resources (basic infrastructure and voluntary organizations) had a protective effect on frailty development and buffered the negative effects of SES vulnerability experiences accumulated over the life course. Community basic infrastructure resources played an important role in slowing the progression of frailty for individuals with cumulative SES disadvantage and downward mobility. DISCUSSION: Our findings provided new evidence of person-environmental docility among older adults, documenting the role of community resources in buffering SES disparities in health during later-life.

Evaluation of the accuracy of implant placement by using implant positional guide versus freehand: a prospective clinical study.

PURPOSE: The aim of this study is to examine and compare the accuracy of implant placement using implant positional guide and freehand. METHODS: 48 implants were placed in patients with single tooth loss with implant positional guide and freehand, respectively. The accuracy of implant placement was assessed by comparing the actual and planned position, including four parameters: coronal deviation, apical deviation, angular deviation, and vertical deviation. RESULTS: Comparing all the variables, it has been found that the implant positional guide is more accurate than the freehand. All parameters describing in the deviation were significantly lower in the implant positional guide group than the freehand. CONCLUSIONS: The implant positional guide can act as a practicable tool for dental implant surgery. It is a promising technology that guarantees low cost and high precision in implant surgery. However, based on the restricted evidence from clinical studies, longer follow-up periods, larger population studies, and standardized experimental studies are required. Trial registration CHICTR, ChiCTR2300071024. Registered 28 April 2023-CHICTR, ChiCTR2300071024. Registered 28 April 2023-Retrospectively registered, https://www.chictr.org.cn/showproj.html?proj=195424 .

Inhibition of abnormal C/EBPß/α-Syn signaling pathway through activation of Nrf2 ameliorates Parkinson's disease-like pathology.

Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs) in the brain. These LBs are primarily composed of α-Synuclein (α-Syn), which has aggregated. A recent report proposes that CCAAT/enhancer-binding proteins ß (C/EBPß) may act as an age-dependent transcription factor for α-Syn, thereby initiating PD pathologies by regulating its transcription. Potential therapeutic approaches to address PD could involve targeting the regulation of α-Syn by C/EBPß. This study has revealed that Nrf2, also known as nuclear factor (erythroid-derived 2)-like 2 (NFE2L2), suppresses the transcription of C/EBPß in SH-SY5Y cells when treated with MPP+ . To activate Nrf2, sulforaphane, an Nrf2 activator, was administered. Additionally, C/EBPß was silenced using C/EBPß-DNA/RNA heteroduplex oligonucleotide (HDO). Both approaches successfully reduced abnormal α-Syn expression in primary neurons treated with MPP+ . Furthermore, sustained activation of Nrf2 via its activator or inhibition of C/EBPß using C/EBPß-HDO resulted in a reduction of aberrant α-Syn expression, thus leading to an improvement in the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) in mouse models induced by 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) and those treated with preformed fibrils (PFFs). The data presented in this study illustrate that the activation of Nrf2 may provide a potential therapeutic strategy for PD by inhibiting the abnormal C/EBPß/α-Syn signaling pathway.

MRI-based radiomics models for the early prediction of radiation-induced temporal lobe injury in nasopharyngeal carcinoma.

Objective: This study was conducted to develop and validate a radiomics-clinics combined model-based magnetic resonance imaging (MRI) radiomics and clinical features for the early prediction of radiation-induced temporal lobe injury (RTLI) in patients with nasopharyngeal carcinoma (NPC). Methods: This retrospective study was conducted using data from 130 patients with NPC (80 patients with and 50 patients without RTLI) who received radiotherapy. Cases were assigned randomly to training (n = 91) and testing (n = 39) datasets. Data on 168 medial temporal lobe texture features were extracted from T1WI, T2WI, and T1WI-CE MRI sequences obtained at the end of radiotherapy courses. Clinics, radiomics, and radiomics-clinics combined models (based on selected radiomics signatures and clinical factors) were constructed using machine learning software. Univariate logistic regression analysis was performed to identify independent clinical factors. The area under the ROC curve (AUC) was performed to evaluate the performance of three models. A nomogram, decision curves, and calibration curves were used to assess the performance of the combined model. Results: Six texture features and three independent clinical factors associated significantly with RTLI were used to build the combined model. The AUCs for the combined and radiomics models were 0.962 [95% confidence interval (CI), 0.9306-0.9939] and 0.904 (95% CI, 0.8431-0.9651), respectively, for the training cohort and 0.947 (95% CI, 0.8841-1.0000) and 0.891 (95% CI, 0.7903-0.9930), respectively, for the testing cohort. All of these values exceeded those for the clinics model (AUC = 0.809 and 0.713 for the training and testing cohorts, respectively). Decision curve analysis showed that the combined model had a good corrective effect. Conclusion: The radiomics-clinics combined model developed in this study showed good performance for predicting RTLI in patients with NPC.

Performance of Pretreatment MRI-Based Radiomics in Recombinant Human Endostatin Plus Concurrent Chemoradiotherapy Response Prediction in Nasopharyngeal Carcinoma: A Retrospective Study.

PURPOSE: To investigate the capability of an Magnetic resonance imaging (MRI) radiomics model based on pretreatment texture features in predicting the short-term efficacy of recombinant human endostatin (RHES) plus concurrent chemoradiotherapy (CCRT) for nasopharyngeal carcinoma (NPC). METHODS: We retrospectively enrolled 65 patients newly diagnosed as having NPC and treated with RHES + CCRT. A total of 144 texture features were extracted from the MRI before RHES + CCRT treatment of all the NPC patients. The maximum relevance minimum redundancy (mRMR) method was used to remove redundant, irrelevant texture features, and calculate the Rad score of the primary tumor. Multivariable logistic regression was used to select the most predictive features subset, and prediction models were constructed. The performance of the 3 models in predicting the early response of RHES + CCRT for NPC was explored. RESULTS: The diagnostic efficiency of combined model and radiomics model in distinguishing between the effective and the ineffective groups of patients was found to be moderate. The area under the ROC curve (AUC) of the combined model and radiomics model was 0.74 (95% confidence interval [CI]: 0.62-0.86) and 0.71 (95% CI: 0.58-0.84), respectively, with both being higher than the AUC of the clinics model (0.63, 95% CI: 0.49-0.78). Compared with the radiomics model, the combined model showed marginally improved diagnostic performance in predicting RHES + CCRT treatment response. The accuracy of combined model and radiomics model for RHES + CCRT response assessment in NPC were higher than those of the clinics model (0.723, 0.723 vs 0.677). CONCLUSION: The pretreatment MRI-based radiomics may be a noninvasive and effective method for the prediction of RHES + CCRT early response in patients with NPC.

p55γ degrades RIP3 via MG53 to suppress ischaemia-induced myocardial necroptosis and mediates cardioprotection of preconditioning.

AIMS: Regulated necrosis (necroptosis) and apoptosis are important biological features of myocardial infarction, ischaemia-reperfusion (I/R) injury, and heart failure. However, the molecular mechanisms underlying myocardial necroptosis remain elusive. Ischaemic preconditioning (IPC) is the most powerful intrinsic cardioprotection against myocardial I/R injury. In this study, we aimed to determine whether IPC suppresses I/R-induced necroptosis and the underlying molecular mechanisms. METHODS AND RESULTS: We generated p55γ transgenic and knockout mice and used ligation of left anterior descending coronary artery to produce an in vivo I/R model. The effects of p55γ and its downstream molecules were subsequently identified using mass spectroscopy and co-immunoprecipitation and pulldown assays. We found that p55γ expression was down-regulated in failing human myocardium caused by coronary heart disease as well as in I/R mouse hearts. Cardiac-specific p55γ overexpression ameliorated the I/R-induced necroptosis. In striking contrast, p55γ deficiency (p55γ-/-) and cardiac-specific deletion of p55γ (p55γc-KO) worsened I/R-induced injury. IPC up-regulated p55γ expression in vitro and in vivo. Using reporter and chromatin immunoprecipitation assays, we found that Hif1α transcriptionally regulated p55γ expression and mediated the cardioprotection of IPC. IPC-mediated suppression of necroptosis was attenuated in p55γ-/- and p55γc-KO hearts. Mechanistically, p55γ overexpression decreased the protein levels of RIP3 rather than the mRNA levels, while p55γ deficiency increased the protein abundance of RIP3. IPC attenuated the I/R-induced up-regulation of RIP3, which was abolished in p55γ-deficient mice. Up-regulation of RIP3 attenuated the p55γ- or IPC-induced inhibition of necroptosis in vivo. Importantly, p55γ directly bound and degraded RIP3 in a ubiquitin-dependent manner. We identified MG53 as the E3 ligase that mediated the p55γ-induced degradation of RIP3. In addition, we also found that p55γ activated the RISK pathway during IPC. CONCLUSIONS: Our findings reveal that activation of the MG53-RIP3 signal pathway by p55γ protects the heart against I/R-induced necroptosis and underlies IPC-induced cardioprotection.

The role of BDNF transcription in the antidepressant-like effects of 18ß-glycyrrhetinic acid in a chronic social defeat stress model.

BACKGROUND: Xiaoyaosan (XYS), a traditional Chinese medicine formulation, has been used in the treatment of depression. However, no studies have yet identified the active compounds responsible for its antidepressant effects in the brain. STUDY DESIGN: We investigated the antidepressants effects of XYS and identified 18ß-glycyrrhetinic acid (18ß-GA) as the primary compound present in the brain following XYS injection. Furthermore, we explored the molecular mechanisms underlying the antidepressant-like effects of both XYS and 18ß-GA. METHODS: To investigate the antidepressant-like effects of XYS and elucidate the associated molecular mechanisms, we employed various methodologies, including cell cultures, the chronic social defeat stress (CSDS) model, behavioral tests, immunoprecipitation, quantitative PCR (qPCR) assays, Western blotting assays, luciferase assays, chromatin immunoprecipitation (ChIP) assays, immunofluorescence staining, and dendritic spine analysis. RESULTS: We identified 18ß-GA as the primary compound in the brain following XYS injection. In vitro, 18ß-GA was found to bind with ERK (extracellular signal-regulated kinase), subsequently activating ERK kinase activity toward both c-Jun and cAMP response element binding protein (CREB). Moreover, 18ß-GA activated brain-derived neurotrophic factor (BDNF) transcription by stimulating nuclear factor-erythroid factor 2-related factor 2 (Nrf2), c-Jun, and CREB, while also inhibiting methyl CpG binding protein 2 (MeCP2) both in vitro and in vivo. Chronic intraperitoneal (i.p.) administration of 18ß-GA exhibited prophylactic antidepressant-like effects in a CSDS model, primarily by activating BDNF transcription in the medial prefrontal cortex (mPFC). Interestingly, a single i.p. injection of 18ß-GA produced rapid and sustained antidepressant-like effects in CSDS-susceptible mice by engaging the BDNF-tropomyosin receptor kinase B (TrkB) signaling pathway in the mPFC. CONCLUSION: These findings suggest that the activation of BDNF transcription in the mPFC underlies the antidepressant-like effects of 18ß-GA, a key component of XYS in the brain.

The role of MeCP2 and the BDNF/TrkB signaling pathway in the stress resilience of mice subjected to CSDS.

RATIONALE: There is accumulating evidence to support the idea that brain-derived neurotrophic factor (BDNF) is involved in stress resilience. However, the precise molecular mechanisms underlying resilience in major depressive disorder (MDD) remain unknown. OBJECTIVE: The objective of this study was to explore the role of methyl CpG binding protein 2 (MeCP2) and the BDNF/tropomyosin-receptor-kinase B (TrkB) signaling pathway in the stress resilience to chronic social defeat stress (CSDS) in mice. RESULTS: We found that the overexpression of MeCP2 inhibited BDNF transcription, resulting in BDNF mRNA and protein downregulation in neuro-2a cells. The overexpression of MeCP2 increased S80-MeCP2 and decreased S421-MeCP2, BDNF, the ratio of S133-cyclic AMP response element binding protein (CREB)/CREB and p-TrkB/TrkB expression in neuro-2a cells. In addition, using the CSDS mouse model, we found that MeCP2 mRNA levels were decreased in the medial prefrontal cortex (mPFC) of resilient mice and increased in the hippocampus of susceptible mice. BDNF exon IV promoter and BDNF mRNA levels were decreased in the mPFC and hippocampus of susceptible mice. Finally, MeCP2 and S80-MeCP2 protein levels were increased in the mPFC and hippocampus of susceptible mice, whereas the protein expression of S421-MeCP2 and BDNF, the ratio of S133-CREB/CREB, and the levels of p-TrkB/TrkB were decreased in susceptible mice. CONCLUSIONS: These data suggest that the overexpression of MeCP2 inhibits BDNF transcription in neuro-2a cells. The inhibition of MeCP2 expression and activation of the BDNF/TrkB signaling pathway may confer stress resilience in CSDS mice.

Nrf2 regulates the arginase 1+ microglia phenotype through the initiation of TREM2 transcription, ameliorating depression-like behavior in mice.

The expression of the triggering receptor on myeloid cell-2 (TREM2) knockdown in microglia from the lateral habenula (LHb) reportedly induces depression-like behaviors in mice. However, the key molecular mechanism that mediates major depressive disorder (MDD) pathogenesis remains elusive. We herein show that Nrf2 regulates TREM2 transcription and effects TREM2 mRNA and protein expression. The activation of Nrf2 by sulforaphane (Nrf2 activator) increases the microglial arginase 1+ phenotype by initiating TREM2 transcription in the medial prefrontal cortex (mPFC) and ameliorates depression-like behavior in CSDS mice. The knockout of Nrf2 decreases TREM2 and the microglial arginase 1+ phenotype in the mPFC of Nrf2 KO mice with depression-like behavior. Downregulating TREM2 expression decreases the microglial arginase 1+ phenotype in the mPFC, resulting in depression-like behavior in SFN-treated CSDS mice. Finally, the knockout of Nrf2 and downregulation of TREM2 expression decreases the microglial arginase 1+ phenotype in the mPFC of Nrf2 KO mice and SFN-treated CSDS mice were associated with the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling pathway. These data indicate that alterations in the interaction between Nrf2 and TREM2 may play a role in the pathophysiology of depression-like behavior in mice.

Altered Functional Brain Network in Systemic Lupus Erythematosus Patients Without Overt Neuropsychiatric Symptoms Based on Resting-State Functional Magnetic Resonance Imaging and Multivariate Pattern Analysis.

Objective: This study aims to investigate the alterations in functional brain network in systemic lupus erythematosus patients without overt neuropsychiatric symptoms [neuropsychiatric systemic lupus erythematosus (non-NPSLE)] from the perspective of degree centrality (DC) and functional connectivity (FC) using resting-state functional magnetic resonance imaging (MRI) and multivariate pattern analysis (MVPA) approach. Methods: DC analysis was performed based on the resting-state functional MRI data derived from 47 non-NPSLE patients and 47 healthy controls (HCs). Nodes with abnormal DC were utilized as seeds for further FC analysis. The correlation between MRI variables and clinical or neuropsychological data was analyzed using Pearson correlation analysis. Finally, MVPA classification based on DC was performed. Results: When compared with the HCs, the non-NPSLE patients exhibited remarkably higher DC in the bilateral hippocampus (HIP), right insula (INS), and lower DC in the left superior parietal gyrus. Furthermore, the patients displayed significantly higher FC between the left HIP and the left INS/left dorsolateral middle frontal gyrus/left supramarginal gyrus and higher FC between the right HIP and the right middle temporal gyrus/right dorsolateral middle frontal gyrus/right dorsolateral inferior frontal gyrus/right supramarginal gyrus (all imaging variables mentioned earlier underwent cluster-level false discovery rate corrections, the voxel threshold was p < 0.001, cluster threshold was p < 0.05). Correlation analysis revealed significantly negative correlations between DC values of the right INS and disease activity and the DC values of the right HIP and the Montreal Cognitive Assessment scores. The accuracy, sensitivity, and specificity of MVPA classification based on DC were 72.34, 63.83, and 80.85%, respectively. The most discriminative power brain regions were chiefly located within the temporal, parietal, and frontal regions. Conclusion: Patients with non-NPSLE exhibited abnormal DC and FC in the brain network. MVPA based on DC possessed commendable classification ability. Our study may provide a novel perspective on the neuropathological mechanisms underlying subclinical brain damage in non-NPSLE.