rTMS concurrent with cognitive training rewires AD brain by enhancing GM-WM functional connectivity: a preliminary study.

Repetitive transcranial magnetic stimulation (rTMS) and cognitive training for patients with Alzheimer's disease (AD) can change functional connectivity (FC) within gray matter (GM). However, the role of white matter (WM) and changes of GM-WM FC under these therapies are still unclear. To clarify this problem, we applied 40 Hz rTMS over angular gyrus (AG) concurrent with cognitive training to 15 mild-moderate AD patients and analyzed the resting-state functional magnetic resonance imaging before and after treatment. Through AG-based FC analysis, corona radiata and superior longitudinal fasciculus (SLF) were identified as activated WM tracts. Compared with the GM results with AG as seed, more GM regions were found with activated WM tracts as seeds. The averaged FC, fractional amplitude of low-frequency fluctuation (fALFF), and regional homogeneity (ReHo) of the above GM regions had stronger clinical correlations (r/P = 0.363/0.048 vs 0.299/0.108, 0.351/0.057 vs 0.267/0.153, 0.420/0.021 vs 0.408/0.025, for FC/fALFF/ReHo, respectively) and better classification performance to distinguish pre-/post-treatment groups (AUC = 0.91 vs 0.88, 0.65 vs 0.63, 0.87 vs 0.82, for FC/fALFF/ReHo, respectively). Our results indicated that rTMS concurrent with cognitive training could rewire brain network by enhancing GM-WM FC in AD, and corona radiata and SLF played an important role in this process.

Best practices for managing malodorous and infected wounds in advanced cervical cancer.

This cross-sectional study was conducted to examine the most effective strategies for managing malodorous and infected wounds in patients who have been diagnosed with advanced cervical cancer. The research was conducted in Liupanshui, China. The study specifically examined demographic profiles, wound characteristics and effectiveness of wound management approaches. The study incorporated the heterogeneous sample of 289 participants who fulfilled the inclusion criteria. Data collection was conducted via structured questionnaires and medical record evaluations. Descriptive statistics and statistical analyses, such as regression analysis, were utilized to evaluate demographic attributes, wound profiles and effects of different approaches to wound management. The findings unveiled the heterogeneous demographic composition of patients, encompassing differences in socioeconomic standing, educational attainment and age. A wide range of wound characteristics were observed, as 65.7% of lesions during the acute phase with diameter between 2 and 5 centimetres, while 41.5% of lesions had this range. The most prevalent types of infections were those caused by fungi (48.4%), followed by bacterial infections lacking resistance (38.1%). A moderate degree of odour intensity was prevalent, affecting 45.0% of the cases. With maximal odour reduction of 80%, a mean healing time of 25 days and patient satisfaction rating of 4.5 out of 5, Negative Pressure Wound Therapy demonstrated itself to be the most efficacious treatment method. Additional approaches, such as photodynamic therapy and topical antibiotic therapy, demonstrated significant effectiveness, as evidenced by odour reductions of 70% and 75%, respectively, and patient satisfaction ratings of 4.3 and 4.2. Thus, the study determined challenges associated with management of malodorous and infected lesions among patients with advanced cervical cancer. The results underscored the significance of individualized care approaches, drew attention to efficacious wound management techniques and identified critical determinants that impacted patient recuperation. The findings of this study hold potential for advancing palliative care for individuals diagnosed with advanced cervical cancer.

A metabolism-functional connectome sparse coupling method to reveal imaging markers for Alzheimer's disease based on simultaneous PET/MRI scans.

Abnormal glucose metabolism and hemodynamic changes in the brain are closely related to cognitive function, providing complementary information from distinct biochemical and physiological processes. However, it remains unclear how to effectively integrate these two modalities across distinct brain regions. In this study, we developed a connectome-based sparse coupling method for hybrid PET/MRI imaging, which could effectively extract imaging markers of Alzheimer's disease (AD) in the early stage. The FDG-PET and resting-state fMRI data of 56 healthy controls (HC), 54 subjective cognitive decline (SCD), and 27 cognitive impairment (CI) participants due to AD were obtained from SILCODE project (NCT03370744). For each participant, the metabolic connectome (MC) was constructed by Kullback-Leibler divergence similarity estimation, and the functional connectome (FC) was constructed by Pearson correlation. Subsequently, we measured the coupling strength between MC and FC at various sparse levels, assessed its stability, and explored the abnormal coupling strength along the AD continuum. Results showed that the sparse MC-FC coupling index was stable in each brain network and consistent across subjects. It was more normally distributed than other traditional indexes and captured more SCD-related brain areas, especially in the limbic and default mode networks. Compared to other traditional indices, this index demonstrated best classification performance. The AUC values reached 0.748 (SCD/HC) and 0.992 (CI/HC). Notably, we found a significant correlation between abnormal coupling strength and neuropsychological scales (p < .05). This study provides a clinically relevant tool for hybrid PET/MRI imaging, allowing for exploring imaging markers in early stage of AD and better understanding the pathophysiology along the AD continuum.

Nanoscale metal-organic framework delivers rapamycin to induce tissue immunogenic cell death and potentiates cancer immunotherapy.

Rapamycin has great potential in the antitumor application, but its therapeutic effect is seriously affected by poor water solubility, targeting ability, and low bioavailability. Here, we constructed a novel composite nanomaterial with PCN-224 as a drug carrier and loaded rapamycin, named R@BP@HA. The nanoplate not only improves targeting, but also synergizes rapamycin with PCN-224 to effectively promote tumor cell apoptosis, which subsequently causes immunogenic cell death (ICD), and shows strong therapeutic effect in 4T1 breast cancer model. The treatment effect depends on three main points:(i)Proapoptotic effect of rapamycin on tumor cells;(ii)ROS production by PCN-224-mediated photodynamic therapy;(iii)ICD induced DC maturation, increased immune response and promoted T cell proliferation and differentiation. This nanoplate offers potential antitumor efficacy in combination with chemotherapy, photodynamic therapy, and immunotherapy.

Predicting physical exercise changes in Chinese rural adolescents: the application of the health action process approach model.

The purposes of the current study were to explore the applicability of the Health Action Process Approach (HAPA) model for interpreting changes in physical exercise behavior and to examine the key determinants of changes in physical exercise. The participants were 639 rural middle school students in Sichuan province, China, who did not perform physical exercise. Three surveys and two interventions were completed in the same participants within 1.5 years. The HAPA model elements and physical exercise were estimated by a self-reported questionnaire. The results showed that 158 students (24.7%) formed a habit of physical exercise. The structural equation model for the pre-intention stage and behavior stage showed acceptable goodness of fit. Outcome expectancies (ß=0.136, P=0.014) and action self-efficacy (ß=0.314, P=0.001) directly predicted intention of physical exercise, the latter directly predicted physical exerciseplanning (ß=0.537, P<0.001), andplanning subsequently predicted physical exercise (ß=0.324, P<0.001). Maintenance self-efficacy indirectly predicted physical exercise through planning (95%CI: 0.014, 0.053). The findings suggested that the HAPA model was a very useful tool for predicting changes in physical exercise behavior, as this model explains the process of changing physical exercise habits and reveals the weak link in such behavioral changes among Chinese rural adolescents.

[Influencing factors of depressive symptoms of rural middle school students in Zizhong County based on two-level Logistic regression model].

OBJECTIVE: To understand the prevalence of depressive symptoms of middle school students in rural areas of Zizhong County, and to analyze its main influencing factors. METHODS: In October 2015, two rural middle schools in Zizhong County, Sichuan Province, were selected to conduct a self-administered questionnaire survey(general demographic characteristics, the center for epidemiological studies depression scale(CES-D), self-esteem scale(SES) and connor-davidson resilience scale(CD-RICS)) on all the students(there were 2744 effective persons, including 1308 boys and 1436 girls, 554 middle school students and 2190 high school students), and then carried out a follow-up survey every semester. RESULTS: The prevalence of depressive symptoms was 30. 5%(in the baseline survey, it was 26. 7%, the third 35. 7% and the fifth 29. 8%), and the rate of female students was 30. 3%, higher than that of male students 22. 9%(χ~2=19. 72, P<0. 05). The main influencing factors of depressive symptoms of rural middle school students in Sichuan were gender(ß=0. 201, P=0. 001), be aware of whether teacher liked or not(ß=0. 228, P=0. 005), be aware of whether classmates liked or not(ß=0. 488, P<0. 001), be aware of the relationship with parents(ß=0. 201, P=0. 001), the power of the psychological resilience(ß=0. 046, P<0. 001) and the optimism of the psychological resilience(ß=-0. 030, P=0. 038), self-esteem(ß=-0. 140, P<0. 001). CONCLUSION: The depression symptoms of adolescents are related to many factors. The self-conscious teachers and classmates do not like himself(herself), and the bad relationship with parents are positively related to the depression symptoms of adolescents, while the psychological resilience and self-esteem are negatively related. The multi-level Model of repeated measurement is suitable for the analysis of the influencing factors and their changing rules in the longitudinal study of depression symptoms.

[Analysis of reciprocity between mental health status and academic achievement under the protective effect of psychological resilience in junior school students in earthquake-hit area].

OBJECTIVE: To verify the reciprocity between mental health status and academic achievement and the protection of psychological resilience. METHODS: An approximate sampling method was adopted in October, 2010. Two junior high schools were selected from the severely earthquake-hit area( Mianzhu City, Sichuan Province) andthe slight earthquake-hit area( a suburban county of Chengdu City, Sichuan Province), respectively, and conducted the survey by using a self-report questionnaire( including general demographic characteristics, middle school students ' mental health scale and resilience scale). Then, the follow-up surveys were conducted every half year. The data were analyzed by repeated measurement variance analysis, Pearson product moment correlation analysis and non-recursive structural equation model. RESULTS: 1015 participants were included in this study who participated 5 surveys, of whom 49. 3% were male and 57. 9% in the slight disaster areas. The average age in the baseline survey was( 12. 72 ± 0. 50) years old, with a range of 11-15 years old. In the non-recursive structural equation model, the better the mental health status was, the higher academic achievement was( ß =-0. 037, P < 0. 001), vice versa( ß =-0. 199, P < 0. 001). The psychological resilience was protective factor for academic achievement( ß = 0. 199, P <0. 001) and mental health( ß =-0. 282, P < 0. 001). The 95% CI of the two intermediate effects( " psychological resilience→ mental health→academic achievement" and " psychological resilience→ academic achievement→mental health") were( 0. 008-0. 017) and(-0. 062--0. 025), with 5. 7% and 13. 0% of total effect, respectively. CONCLUSION: Mental health status and academic achievement are mutual influence. The effect of academic performance on mental health status is greater than that of mental health status on academic performance. Psychological resilience is an important protective factor of mental health and academic performance.

[Physical exercise impact on the life satisfaction among rural adolescents in Zizhong County].

OBJECTIVE: To explore the direct effect of physical exercise impacting on life satisfaction and the mediating role of mental health status and resilience between the relationship of physical exercise and life satisfaction in rural adolescents. METHODS: A total of 2282 of grade 7 and grade 10 of two rural middle school students( 15. 21± 0. 74 years, range 11-18 years) were surveyed in Zizhong County, Sichuan Province, chosen by typical sampling and cluster sampling using a self-report structured questionnaire, including demographic characteristics, physical exercise, Resilience Scale( CD-RISC) and mental health scale( MMHI-60), life satisfaction scale. A structural equation model was used for statistical analysis. RESULTS: The fitting indices of multiple mediating role of structural equation model showed good fitting: χ~2/DF = 4. 528, GFI = 0. 935, AGFI = 0. 906, RMSEA = 0. 039. Physicalexercise was a direct protective determination for life satisfaction, the standardized coefficient was 0. 056( P < 0. 05). Physical exercise indirectly impacted on life satisfaction through the mediating variables of resilience and mental health status, and the 90 % CI of the mediating effect were( 0. 331-0. 557) and( 0. 051-0. 178), respectively. The mediating effect accounted for 67. 1 % of total effect. CONCLUSION: Physical exercise exerts a direct and indirect positive effect on life satisfaction. Resilience and mental health status have mediating effects on the relationship between physical exercise and life satisfaction.

High precision system modeling of liquid crystal adaptive optics systems.

In this paper, we present a heuristic method to simplify the liquid crystal adaptive optics system (LCAOS) into a single-input-single-output (SISO) system, then build the dynamic model of LCAOS based on subspace identification. Results show that the identified model could accurately describe the dynamical behavior of LCAOS (97% match), with extremely low complexity. The wonderful features of low complexity and high precision, make the identified model highly beneficial for model based controller design, system analysis and dynamical behavior simulation of liquid crystal adaptive optics systems.

Small cell lung cancer growth is inhibited by miR-342 through its effect of the target gene IA-2.

BACKGROUND: Small cell lung cancers (SCLC) are tumors of neuroendocrine origin. Previous in vitro studies from our laboratory showed that SCLC expresses high levels of the transmembrane dense core vesicle protein IA-2 (islet cell antigen-2) as compared to normal lung cells. IA-2, through its effect on dense core vesicles (DCVs), is known to be involved in the secretion of hormones and neurotransmitters. It is believed that the dysregulated release of the neurotransmitter Acetylcholine (ACh) by DCVs has an autocrine effect on SCLC cell growth. Recently, we found that IA-2 is a target of the microRNA miR-342 and that miR-342 mimics suppress the expression of IA-2. The present experiments were initiated to see whether IA-2 and/or miR-342 affect the growth of SCLC. METHODS: SCLC cell growth was evaluated following the knockdown of endogenous IA-2 with RNAi or by overexpressing miR-342 with a mimic. The secretion and content of ACh in SCLC cells was analyzed using a human acetylcholine ELISA (enzyme-linked immunosorbent assay) kit. RESULTS: The knockdown of endogenous IA-2 by RNAi reduced SCLC cell growth within 4 days by 40 % or more. Similar results were obtained when these cell lines were transfected with a miR-342 mimic. The knockdown of IA-2 by RNAi or miR-342 with a mimic also resulted in a significant decrease in the secretion of ACh, one of the autocrine hormones secreted by SCLC. Further studies revealed that the growth of SCLC cell lines that had been treated with the miR-342 mimic was restored to nearly normal levels by treatment with ACh. CONCLUSION: Our studies show for the first time that both miR-342 and its target gene IA-2 are involved in the growth process of SCLC cells and act by their effect on autocrine secretion. These findings point to possible new therapeutic approaches for the treatment of autocrine-induced tumor proliferation.

Analysis and reduction of errors caused by Poisson noise for phase diversity technique.

An effective method for reducing the sensitivity of phase diversity (PD) technique to Poisson noise is proposed. The denoising algorithm based on blocking-matching and 3D filtering is first introduced in the wavefront sensing field as a preprocessing stage. Then, the PD technique is applied to the denoised images. Results of the numerical simulations and experiments demonstrate that our approach is better than the traditional PD technique in terms of both the root-mean-square error (RMSE) of phase estimates and the structural similarity index metrics (SSIM). The RMSEs of phase estimates on synthetic data are decreased by approximately 40% across noise levels within the range of 58.7-18.8 dB in terms of peak signal-to-noise ratio (PSNR). Meanwhile, the overall decline range of SSIM is significantly decreased from 49% to 9%. The experiment and simulation results are in good agreement. The approach may be widely used in various domains, such as the measurements of intrinsic aberrations in optical systems and compensations for atmospheric turbulence.

Multiple microRNAs within the 14q32 cluster target the mRNAs of major type 1 diabetes autoantigens IA-2, IA-2ß, and GAD65.

Islet antigen (IA)-2, IA-2ß, and glutamate decarboxylase (GAD65) are major autoantigens in type 1 diabetes (T1D). Autoantibodies to these autoantigens appear years before disease onset and are widely used as predictive markers. Little is known, however, about what regulates the expression of these autoantigens. The present experiments were initiated to test the hypothesis that microRNAs (miRNAs) can target and affect the levels of these autoantigens. Bioinformatics was used to identify miRNAs predicted to target the mRNAs coding IA-2, IA-2ß, and GAD65. RNA interference for the miRNA processing enzyme Dicer1 and individual miRNA mimics and inhibitors were used to confirm the effect in mouse islets and MIN6 cells. We show that the imprinted 14q32 miRNA cluster contains 56 miRNAs, 32 of which are predicted to target the mRNAs of T1D autoantigens and 12 of which are glucose-sensitive. Using miRNA mimics and inhibitors, we confirmed that at least 7 of these miRNAs modulate the mRNA levels of the T1D autoantigens. Dicer1 knockdown significantly reduced the mRNA levels of all 3 autoantigens, further confirming the importance of miRNAs in this regulation. We conclude that miRNAs are involved in regulating the expression of the major T1D autoantigens.

The Ia-2ß intronic miRNA, miR-153, is a negative regulator of insulin and dopamine secretion through its effect on the Cacna1c gene in mice.

AIMS/HYPOTHESIS: miR-153 is an intronic miRNA embedded in the genes that encode IA-2 (also known as PTPRN) and IA-2ß (also known as PTPRN2). Islet antigen (IA)-2 and IA-2ß are major autoantigens in type 1 diabetes and are important transmembrane proteins in dense core and synaptic vesicles. miR-153 and its host genes are co-regulated in pancreas and brain. The present experiments were initiated to decipher the regulatory network between miR-153 and its host gene Ia-2ß (also known as Ptprn2). METHODS: Insulin secretion was determined by ELISA. Identification of miRNA targets was assessed using luciferase assays and by quantitative real-time PCR and western blots in vitro and in vivo. Target protector was also employed to evaluate miRNA target function. RESULTS: Functional studies revealed that miR-153 mimic suppresses both glucose- and potassium-induced insulin secretion (GSIS and PSIS, respectively), whereas miR-153 inhibitor enhances both GSIS and PSIS. A similar effect on dopamine secretion also was observed. Using miRNA target prediction software, we found that miR-153 is predicted to target the 3'UTR region of the calcium channel gene, Cacna1c. Further studies confirmed that Cacna1c mRNA and protein are downregulated by miR-153 mimics and upregulated by miR-153 inhibitors in insulin-secreting freshly isolated mouse islets, in the insulin-secreting mouse cell line MIN6 and in the dopamine-secreting cell line PC12. CONCLUSIONS/INTERPRETATION: miR-153 is a negative regulator of both insulin and dopamine secretion through its effect on Cacna1c expression, which suggests that IA-2ß and miR-153 have opposite functional effects on the secretory pathway.

Wavefront detection method of a single-sensor based adaptive optics system.

In adaptive optics system (AOS) for optical telescopes, the reported wavefront sensing strategy consists of two parts: a specific sensor for tip-tilt (TT) detection and another wavefront sensor for other distortions detection. Thus, a part of incident light has to be used for TT detection, which decreases the light energy used by wavefront sensor and eventually reduces the precision of wavefront correction. In this paper, a single Shack-Hartmann wavefront sensor based wavefront measurement method is presented for both large amplitude TT and other distortions' measurement. Experiments were performed for testing the presented wavefront method and validating the wavefront detection and correction ability of the single-sensor based AOS. With adaptive correction, the root-mean-square of residual TT was less than 0.2 λ, and a clear image was obtained in the lab. Equipped on a 1.23-meter optical telescope, the binary stars with angle distance of 0.6″ were clearly resolved using the AOS. This wavefront measurement method removes the separate TT sensor, which not only simplifies the AOS but also saves light energy for subsequent wavefront sensing and imaging, and eventually improves the detection and imaging capability of the AOS.

Simple and robust algorithm to extend the dynamic range of tip-tilt for a Shack-Hartmann sensor.

We propose an algorithm to extend the dynamic range of tip-tilt (TT) for a Shack-Hartmann wave-front sensor. With this method, the dynamic range of TT is determined by the size of the whole CCD pixel array rather than the size of the sub-aperture. Thus the separate TT sensor in adaptive optics (AO) systems for optical telescope can be saved, which will simplify the systems and enhance the light energy efficiency. The proposed algorithm is computationally effective and appropriate for the real-time TT computation of AO systems. The simulated and experimental results show that the algorithm is robust to realistic scintillation and photon noise and can work well under poor observing conditions. For the given condition with r0 of 5 cm at 550 nm and average flux of 100 photons per sub-aperture, the ultimate measurement accuracy of TT is about 5% pixels (peak-to-valley value).

Time delay compensation method for tip-tilt control in adaptive optics system.

The time delay engendered by wavefront sampling and data processing inevitability exists in almost all the wavefront sensor (WFS) based adaptive optics (AO) systems. Also, when WFS is used for tip-tilt aberration detection, the time delay significantly reduces the tip-tilt correction performance of the AO system. In this paper, we focus on researching time delay in a tip-tilt (TT) control system and introduce a predicted signal compensation method (PSCM) to compensate the time delay by modifying the WFS detected signals. Based on a precise model of a TT dynamic control system, the detection delay of TT corrections included in a WFS detected signal can be compensated. Experiments are conducted in the lab: the pure integrator (I), proportional and integral (PI) wavefront TT controllers, and these controllers with PSCM are compared to test the efficiency of the PSCM for TT corrections. For the PI controller, the rejection bandwidth increases from 52 to 62 Hz by using PCSM; meanwhile, the open-loop phase margin increases from 45 to 60 deg. In addition, astronomical observation results are also given based on the PI wavefront TT controller. The PSCM improves the Strehl ratio by a factor of 1.3. The new method is proven to improve the AO system closed-loop performance not only for increasing the closed-loop rejection bandwidth but also in favor of the error attenuation at low frequency. Furthermore, the method does not introduce more noise to the system.

Hepatitis E virus causes apoptosis of ovarian cells in hens and resulting in a decrease in egg production.

Previous studies have shown that avian hepatitis E virus (HEV) decreases egg production by 10-40% in laying hens, but have not fully elucidated the mechanism of there. In this study, we evaluated the replication of avian HEV in the ovaries of laying hens and the mechanism underlying the decrease in egg production. Forty 150-days-old commercial laying hens were randomly divided into 2 groups of 20 hens each. A total of 1 mL (104GE) of avian HEV stock was inoculated intravenously into each chicken in the experimental group, with 20 chickens in the other group serving as negative controls. Five chickens from each group were necropsied weekly for histopathological examination. The pathogenicity of avian HEV has been characterized by seroconversion, viremia, fecal virus shedding, ovarian lesions, and decreased egg production. Both positive and negative-strand avian HEV RNA, and ORF2 antigens can be detected in the ovaries, suggesting that avian HEV can replicate in the ovaries and serve as an important extrahepatic replication site. The ovaries of laying hens underwent apoptosis after avian HEV infection. These results indicate that avian HEV infection and replication in ovarian tissues cause structural damage to the cells, leading to decreased egg production.

Unlocking the enigma: unraveling multiple cognitive dysfunction linked to glymphatic impairment in early Alzheimer's disease.

Background: Alzheimer's disease (AD) is one of the world's well-known neurodegenerative diseases, which is related to the balance mechanism of production and clearance of two proteins (amyloid-ß and tau) regulated by the glymphatic system. Latest studies have found that AD patients exhibit impairments to their glymphatic system. However, the alterations in the AD disease continuum, especially in the early stages, remain unclear. Moreover, the relationship between the glymphatic system and cognitive dysfunction is still worth exploring. Methods: A novel diffusion tensor image analysis method was applied to evaluate the activity of the glymphatic system by an index for diffusivity along the perivascular space (ALPS-index). Based on this method, the activity of the glymphatic system was noninvasively evaluated in 300 subjects, including 111 normal controls (NC), 120 subjects with mild cognitive impairment (MCI), and 69 subjects with AD. Partial correlation analysis was applied to explore the association between glymphatic system and cognitive impairment based on three domain-general scales and several domain-specific cognitive scales. Receiver operating characteristic curve analysis was used to evaluate the classification performance of ALPS-index along the AD continuum. Results: ALPS-index was significantly different among NC, MCI and AD groups, and ALPS-index decreased with cognitive decline. In addition, ALPS-index was significantly correlated with the scores of the clinical scales (p<0.05, FDR corrected), especially in left hemisphere. Furthermore, combination of ALPS and fractional anisotropy (FA) values achieved better classification results (NC vs. MCI: AUC = 0.6610, NC vs. AD: AUC = 0.8214). Conclusion: Here, we show that the glymphatic system is closely associated with multiple cognitive dysfunctions, and ALPS-index can be used as a biomarker for alterations along the AD continuum. This may provide new targets and strategies for the treatment of AD, and has the potential to assist clinical diagnosis.

2,6-diazaspiro[3.4]octan-7-one derivatives as potent sigma-1 receptor antagonists that enhanced the antinociceptive effect of morphine and rescued morphine tolerance.

Opioids are efficacious analgesics for pain treatments. However, their repeated use in large doses often leads to analgesic tolerance, which limits the clinical application. Sigma-1 receptor (σ1R) antagonists were reported to synergistically enhance the analgesic effect of mu opioid receptor (MOR) agonists without amplifying the adverse effects. Therefore, the σ1R is considered a promising drug target for pain management. Based on the recently elucidated co-crystal structure of σ1R with 4-IBP, we designed and developed a series of σ1R antagonists harboring the 2,6-diazaspiro[3.4]octan-7-one scaffold. Through a detailed structure-activity relationship study, we identified compound 32 as a potent σ1R antagonist, which significantly enhanced the antinociceptive effect of morphine and rescued morphine-induced analgesic tolerance. Our results support σ1R antagonism as a promising strategy to develop novel analgesics and highlight the therapeutic potential of compound 32 to prevent morphine tolerance.

S1P/S1PR1 axis promotes macrophage M1 polarization through NLRP3 inflammasome activation in Lupus nephritis.

Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE) as well as the leading cause of mortality in patients. Previous studies revealed that S1P level is elevated in plasma samples of SLE patients and murine lupus models. FTY720, targeting S1P receptors, exhibited therapeutic effects in improving the nephritis symptoms of lupus mouse models. However, few studies have discussed the potential relevance of S1P/S1PR to the pathogenesis of LN. Macrophages have been shown to be an important causative agent of renal inflammation, while the pro-inflammatory M1-type promotes kidney injury and inflammation during LN. Importantly, macrophages express various S1P receptors, and how they respond to S1P in the setting of LN remains unclear. Therefore, we examined the level of S1P in the lupus MRL/lpr mice and explored the ensuing interaction of macrophages and S1P. We found that S1P level was elevated in the MRL/lpr mice with a subsequent enhancement of the S1PR1 expression, and blocking S1PR1 by FTY720, the nephritis symptoms of MRL/lpr mice were improved. Mechanistically, we demonstrated that elevated S1P level increase the M1-type macrophage accumulation. And the in-vitro studies proved that S1P/S1PR1 was involved in the promotion of macrophage polarization towards M1 type through activation of NLRP3 inflammasome. These findings confer a novel role to macrophage S1PR1 and provide a new perspective for targeting S1P during LN.