Understanding the dynamics of TKI-induced changes in the tumor immune microenvironment for improved therapeutic effect.

BACKGROUND: The dynamic interplay between tyrosine kinase inhibitors (TKIs) and the tumor immune microenvironment (TME) plays a crucial role in the therapeutic trajectory of non-small cell lung cancer (NSCLC). Understanding the functional dynamics and resistance mechanisms of TKIs is essential for advancing the treatment of NSCLC. METHODS: This study assessed the effects of short-term and long-term TKI treatments on the TME in NSCLC, particularly targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations. We analyzed changes in immune cell composition, cytokine profiles, and key proteins involved in immune evasion, such as laminin subunit γ-2 (LAMC2). We also explored the use of aspirin as an adjunct therapy to modulate the TME and counteract TKI resistance. RESULTS: Short-term TKI treatment enhanced T cell-mediated tumor clearance, reduced immunosuppressive M2 macrophage infiltration, and downregulated LAMC2 expression. Conversely, long-term TKI treatment fostered an immunosuppressive TME, contributing to drug resistance and promoting immune escape. Differential responses were observed among various oncogenic mutations, with ALK-targeted therapies eliciting a stronger antitumor immune response compared with EGFR-targeted therapies. Notably, we found that aspirin has potential in overcoming TKI resistance by modulating the TME and enhancing T cell-mediated tumor clearance. CONCLUSIONS: These findings offer new insights into the dynamics of TKI-induced changes in the TME, improving our understanding of NSCLC challenges. The study underscores the critical role of the TME in TKI resistance and suggests that adjunct therapies, like aspirin, may provide new strategies to enhance TKI efficacy and overcome resistance.

Distinct effects of first-episode and recurrent major depressive disorder on brain changes related to suicidal ideation: Evidence from the REST-meta-MDD Project.

BACKGROUND: Significant differences in clinical manifestations between first-episode and recurrent major depression disorder (FE-MDD/R-MDD) have been demonstrated in previous studies, including the degree of suicide attempt. However, the potential brain mechanism underlying the effect of depressive episode frequency on suicidal ideation (SI) remains unclear. METHODS: In this study, 102 patients with FE-MDD (SI/non-SI: N = 70/32) and 71 matched normal controls (NCs), as well as 75 patients with R-MDD (SI/non-SI: N = 37/38) and 49 matched NCs were screened from the Chinese REST-meta-MDD consortium. T1-weighted and resting-state fMRI images were used to calculate gray matter volume (GMV) and fractional amplitude of low-frequency fluctuations (fALFF), respectively. RESULTS: Group comparisons revealed that FE-MDD showed changes only in GMV, while R-MDD showed changes in both GMV and fALFF compared to NCs. SI-specific GMV decreases were observed in the right cerebellum, superior marginal gyrus, and left middle temporal gyrus in FE-MDD patients, while SI-specific fALFF decreases in bilateral superior frontal gyrus and increases in bilateral cerebellum and left parahippocampal gyrus were obserevd in R-MDD patients. Moreover, a negative correlation was found between GMV value in right cerebellum and HAMD score. CONCLUSIONS: These findings suggest that first-episode and recurrent MDD show different effects on brain structure and function in patients with SI, providing a potential explanation for the distinct clinical manifestations of MDD patients from a brain mechanisms perspective.

Relationship between family function, self-perceived burden and loneliness in patients with type 2 diabetes mellitus: a cross-lagged analysis.

AIMS: To explore the inter-predictive role and causal relationship between family functioning, self-perceived burden and loneliness in people with type 2 diabetes. METHODS: In this study, patients with type 2 diabetes admitted to two tertiary care hospitals in China were selected for an 8-month follow-up, and the patients' scores on the Family Functioning, Self-perceived Burden, and Loneliness scales were measured repeatedly at three time periods: during hospitalisation (T1), 1 month after discharge (T2), and 3 months after discharge (T3). RESULTS: The results showed that family function at the T1 time point had a negative predictive effect on self-perceived burden at the T2 time point, ß = - 0.43, P = 0.005. Loneliness at the T1 time point had a positive predictive effect on self-perceived burden at the T2 time point, ß = 0.08, P = 0.021. Unlike the pathway at time point T1, family functioning at time point T2 negatively predicted loneliness at time point T3, ß = - 0.32, P = 0.013. Loneliness at time point T2 positively predicted family functioning at time point T3, ß = 0.025, P = 0.013. Loneliness at time point T2 negatively predicted self-perceived burden at time point T3 (P = 0.011). CONCLUSIONS: The results of the cross-lagged analysis show that there is a mutually predictive and moderating relationship between family functioning and loneliness in patients with type 2 diabetes. Loneliness can predict the level of self-perceived burden at the next time point.

Research Progress in Diffusion Spectrum Imaging.

Studies have demonstrated that many regions in the human brain include multidirectional fiber tracts, in which the diffusion of water molecules within image voxels does not follow a Gaussian distribution. Therefore, the conventional diffusion tensor imaging (DTI) that hypothesizes a single fiber orientation within a voxel is intrinsically incapable of revealing the complex microstructures of brain tissues. Diffusion spectrum imaging (DSI) employs a pulse sequence with different b-values along multiple gradient directions to sample the diffusion information of water molecules in the entire q-space and then quantitatively estimates the diffusion profile using a probability density function with a high angular resolution. Studies have suggested that DSI can reliably observe the multidirectional fibers within each voxel and allow fiber tracking along different directions, which can improve fiber reconstruction reflecting the true but complicated brain structures that were not observed in the previous DTI studies. Moreover, with increasing angular resolution, DSI is able to reveal new neuroimaging biomarkers used for disease diagnosis and the prediction of disorder progression. However, so far, this method has not been used widely in clinical studies, due to its overly long scanning time and difficult post-processing. Within this context, the current paper aims to conduct a comprehensive review of DSI research, including the fundamental principles, methodology, and application progress of DSI tractography. By summarizing the DSI studies in recent years, we propose potential solutions towards the existing problem in the methodology and applications of DSI technology as follows: (1) using compressed sensing to undersample data and to reconstruct the diffusion signal may be an efficient and promising method for reducing scanning time; (2) the probability density function includes more information than the orientation distribution function, and it should be extended in application studies; and (3) large-sample study is encouraged to confirm the reliability and reproducibility of findings in clinical diseases. These findings may help deepen the understanding of the DSI method and promote its development in clinical applications.

Identification of factors associated with fear of hypoglycemia using the capability, opportunity, motivation and behavior model in people with type 2 diabetes mellitus: a cross-sectional study.

AIMS: To examined the relationship between fear of hypoglycemia and certain variables in people with type 2 diabetes mellitus (T2DM) based on the Capability, Opportunity, Motivation, and Behavior model, combined with the context unique to people with diabetes to provide a basis for developing targeted nursing interventions. METHODS: In this cross-sectional study, 212 people with T2DM were recruited from February 2021 to July 2021. Data were collected using the Hypoglycaemia Fear Survey, Gold score, Patient Assessment of Chronic Illness Care (PACIC) scale and Diabetic Self-Management Attitudes Scale. Multiple linear regression analysis was performed to determine the predictors of fear of hypoglycemia using SPSS 26.0. RESULTS: The mean fear of hypoglycemia score was 74.88 ± 18.28 (range: 37.00-132.00). In people with T2DM, the frequency of blood glucose monitoring, the frequency of hypoglycemia in the past half-year, degree of understanding of hypoglycemia, impaired awareness of hypoglycemia, PACIC, and self-management attitude of diabetes were the influencing factors of fear of hypoglycemia (adjusted R2 = 0.560, F[21,190] = 13.800, P < 0.001). These variables explained 56.0% of the variance in the fear of hypoglycemia. CONCLUSIONS: The level of fear of hypoglycemia in people with T2DM was relatively high. In addition to paying attention to the disease characteristics of people with T2DM, medical staff should also pay attention to patients' own perception and handling ability of disease and hypoglycemia, attitude toward self-management behavior and external environment support, all of which have a positive effect on improving the fear of hypoglycemia in people with T2DM, optimizing the self-management level and improving quality of life.

ß-Glucan alleviates goal-directed behavioral deficits in mice infected with Toxoplasma gondii.

BACKGROUND: Toxoplasma gondii (T. gondii) is a neuroinvasive parasite causing neuroinflammation, which in turn is associated with a higher risk for several psycho-behavioral disorders. There is an urgent need to identify drugs capable of improving cognitive deficits induced by T. gondii infection. ß-Glucan, an active ingredient in mushrooms, could significantly enhance immunity. However, the effects of ß-glucan against neuroinflammation and cognitive decline induced by T. gondii infection remain unknown. The present study aimed to investigate the neuroprotective effect of ß-glucan on goal-directed behavior of mice chronically infected by T. gondii Wh6 strain. METHODS: A mice model of chronic T. gondii Wh6 infection was established by infecting mice by oral gavage with 10 cysts of T. gondii Wh6. Intraperitoneal injection of ß-glucan was manipulated 2 weeks before T. gondii infection. Performance of the infected mice on the Y-maze test and temporal order memory (TOM) test was used to assess the goal-directed behavior. Golgi-Cox staining, transmission electron microscopy, immunofluorescence, real-time PCR and western blot assays were used to detect prefrontal cortex-associated pathological change and neuroinflammation. RESULTS: The administration of ß-glucan significantly prevented T. gondii Wh6-induced goal-directed behavioral impairment as assessed behaviorally by the Y-maze test and TOM test. In the prefrontal cortex, ß-glucan was able to counter T. gondii Wh6-induced degeneration of neurites, impairment of synaptic ultrastructure and decrease of pre- and postsynaptic protein levels. Also, ß-glucan significantly prevented the hyperactivation of pro-inflammatory microglia and astrocytes, as well as the upregulation of proinflammatory cytokines caused by chronic T. gondii Wh6 infection. CONCLUSIONS: This study revealed that ß-glucan prevents goal-directed behavioral impairment induced by chronic T. gondii infection in mice. These findings suggest that ß-glucan may be an effective drug candidate to prevent T. gondii-associated psycho-behavioral disorders including goal-directed behavioral injury.

Polyene phosphatidylcholine ameliorates synovial inflammation: involvement of PTEN elevation and glycolysis suppression.

BACKGROUND: Synovial inflammation, characterized by the activation of synovial fibroblasts (SFs), is a crucial factor to drive the progression of rheumatoid arthritis (RA). Polyene phosphatidylcholine (PPC), the classic hepatoprotective drug, has been reported to ameliorate arthritis in animals. However, the molecular mechanism remains poorly understood. METHODS AND RESULTS: Using in vitro primary synovial fibroblast (SFs) culture system, we revealed that phosphatase and tension homolog deleted on chromosome 10 (PTEN), a tumor suppressor, mediates the anti-inflammatory effect of PPC in lipopolysaccharide (LPS)-stimulated primary SFs. PPC decreased the production of TNF-α and IL-6 production while elevating the level of IL-10 and TGF-ß. Furthermore, PPC up-regulated the expression of PTEN, but inhibited the expression of p-AKT (ser473) and PI3K-p85α. Moreover, pre-treatment of SF1670 (the inhibitor of PTEN) or 740Y-P (the agonist of AKT/PI3K pathways) partially abrogated the anti-inflammatory effect of PPC. In addition, PPC could inhibit the expression of GLUT4, a key transporter of glucose that fuels the glycolysis, which is accompanied by the expression downregualtion of glycolytic enzymes PFKFB3 and PKM2. Furthermore, PPC could reduce ROS production and mitochondrial membrane potential in LPS-stimulated SFs and MH7A cell line. CONCLUSION: The present study supported that PPC can alleviate synovial inflammation, which involves in the elevation of PTEN and blockage of glycolysis.

Abnormal gray matter structure in children and adolescents with high-functioning autism spectrum disorder.

The present study aimed to explore the brain structural mechanisms underlying clinical dysfunction in patients with ASD using magnetic resonance imaging (MRI). After screening T1 structural images from the Autism Brain Imaging Data Exchange (ABIDE) database, 111 children and adolescents with high-functioning ASD and 151 typically developing (TD) subjects matched were included in this study. We first compared the differences in gray matter volume (GMV) and gray matter density (GMD) between the two groups. Then, the relationships between GMV/GMD and clinical assessments in ASD patients were evaluated. We found that compared with the TD group, the ASD group showed increased GMV/GMD in the precuneus, thalamus, hippocampus and cingulate gyrus. Moreover, in the ASD group, social interaction was negatively correlated with GMD in the bilateral superior temporal gyrus and limbic system; communication was positively correlated with GMD in the right middle temporal gyrus, inferior frontal gyrus, and anterior cingulate gyrus; and repetitive behavior was positively correlated with GMD in the cerebellum and negatively correlated with GMV in the prefrontal cortex. In conclusion, the gray matter structure in children and adolescents with ASD was abnormal, and different clinical dysfunctions in ASD patients were related to structural abnormalities in specific regions.

Altered cerebellar functional connectivity in chronic subcortical stroke patients.

Background: Previous studies demonstrated that cerebellar subregions are involved in different functions. Especially the cerebellar anterior lobe (CAL) and cerebellar posterior lobe (CPL) have been postulated to primarily account for sensorimotor and cognitive function, respectively. However, the functional connectivity (FC) alterations of CAL and CPL, and their relationships with behavior performance in chronic stroke participants are unclear so far. Materials and methods: The present study collected resting-state fMRI data from thirty-six subcortical chronic stroke participants and thirty-eight well-matched healthy controls (HCs). We performed the FC analysis with bilateral CAL and CPL as seeds for each participant. Then, we detected the FC difference between the two groups by using a two-sample t-test and evaluated the relationship between the FC and scores of motor and cognitive assessments across all post-stroke participants by using partial correlation analysis. Results: The CAL showed increased FCs in the prefrontal cortex, superior/inferior temporal gyrus, and lingual gyrus, while the CPL showed increased FCs in the inferior parietal lobule, precuneus, and cingulum gyrus in the stroke participants compared with HCs. Moreover, the FC alteration in the right CAL and the right CPL were negatively correlated with executive and memory functions across stroke participants, respectively. Conclusion: These findings shed light on the different increased FC alteration patterns of CAL and CPL that help understand the neuro-mechanisms underlying behavior performance in chronic stroke survivors.

Transcriptomic Profiles of Splenic CD19+ B Cells in Mice Chronically Infected With the Larval Echinococcus granulosus.

Background: We previously reported that the larval Echinococcus granulosus (E. granulosus) infection can expand the population of regulatory B cells in mice, thereby inhibiting the anti-infective immunity. However, the underlying mechanism is still largely unknown. This study further investigated the holistic transcriptomic profiles of total splenic B cells following the chronic infection of the parasite. Methods: The infection model of larval E. granulosus was established by intraperitoneal inoculation with 2000 protoscolexes. Magnetic-Activated Cell Separation (MACS) was used to isolate the total splenic B cells. RNA sequencing was performed to screen the differentially expressed genes (DEGs) after infection. The expression of selected DEGs was verified using qRT-PCR. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Co-expression network analysis were applied to predict these DEGs' underlying biological processes, pathways, and interactions respectively. Results: A total of 413 DEGs were identified in larval E. granulosus infected B cells, including 303 up- and 110 down-regulated genes. Notably, most DEGs related to inflammation and chemotaxis were significantly upregulated after infection. In line with these changes, significant expression upregulation of DEGs associated with fatty acid oxidation, lipid synthesis, lipolysis, lipid transport, and cholesterol biosynthesis, were observed in infected B cells. Co-expression network analysis showed an intimate interaction between these DEGs associated with immune and metabolism. Conclusions: The present study revealed that the larval E. granulosus infection induces metabolic reprogramming of B cells, which provides a novel clue to clarify the immunoregulatory mechanism of B cells in parasitic infection.

Polyene Phosphatidylcholine Ameliorates High Fat Diet-Induced Non-alcoholic Fatty Liver Disease via Remodeling Metabolism and Inflammation.

Recent years have witnessed a rise in the morbidity of non-alcoholic fatty liver disease (NAFLD), in line with the global outbreak of obesity. However, effective intervention strategy against NAFLD is still unavailable. The present study sought to investigate the effect and mechanism of polyene phosphatidylcholine (PPC), a classic hepatoprotective drug, on NAFLD induced by high fat diet (HFD). We found that PPC intervention reduced the mass of liver, subcutaneous, epididymal, and brown fats in HFD mice. Furthermore, PPC supplementation significantly mitigated liver steatosis and improved glucose tolerance and insulin sensitivity in HFD mice, which was accompanied by declined levels of hepatic triglyceride, serum triglyceride, low density lipoprotein, aspartate aminotransferase, and alanine aminotransferase. Using transcriptome analysis, there were 1,789 differentially expressed genes (| fold change | ≥ 2, P < 0.05) including 893 upregulated genes and 896 downregulated genes in the HFD group compared to LC group. A total of 1,114 upregulated genes and 1,337 downregulated genes in HFD + PPC group were identified in comparison to HFD group. With the help of Gene Ontology (GO) analysis, these differentially expressed genes between HFD+PPC and HFD group were discovered related to "lipid metabolic process (GO: 0006629)," "lipid modification (GO: 0030258)," and "lipid homeostasis (GO: 0055088)". Though Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we found pathways associated with hepatic homeostasis of metabolism and inflammation. Notably, the pathway "Non-alcoholic fatty liver disease (mmu04932)" (P-value = 0.00698) was authenticated in the study, which may inspire the potential mechanism of PPC to ameliorate NAFLD. The study also found that lipolysis, fatty acid oxidation, and lipid export associated genes were upregulated, while the genes in uptake of lipids and cholesterol synthesis were downregulated in the liver of HFD mice after PPC supplementation. Interestingly, PPC attenuated the metabolic inflammation via inhibiting pro-inflammatory macrophage in the livers of mice fed by HFD. In summary, this study demonstrates that PPC can ameliorate HFD-induced liver steatosis via reprogramming metabolic and inflammatory processes, which inspire clues for further clarifying the intervention mechanism of PPC against NAFLD.

Polyene Phosphatidylcholine Interacting with TLR-2 Prevents the Synovial Inflammation via Inactivation of MAPK and NF-κB Pathways.

Rheumatoid arthritis (RA) is a chronic autoimmune joint disease that causes cartilage and bone damage or even disability, seriously endangering human health. Chronic synovial inflammation has been shown to play a vital role in disease sustainability. Therefore, downregulation of synovial inflammation is considered to be an effective discipline for RA therapy. Polyene phosphatidylcholine (PPC) is a hepatoprotective agent, which was observed to inhibit inflammation in macrophages and prevent collagen-induced arthritis (CIA) of rats in our previous study. However, the underlying mechanism remains unclear. The present study further reported that PPC can inhibit synovial inflammation. In lipopolysaccharide (LPS)-stimulated primary synovial fibroblasts (SFs) of mice, PPC significantly decreased pro-inflammatory cytokines production while increasing anti-inflammatory cytokines level. In this process, PPC downregulated the expression of TLR-2 and their downstream signaling molecules such as MyD88, p-ERK1/2, p-JNK1/2, and p-P38 in MAPK pathway and p-IκBα and NF-κB-p65 in NF-κB pathway. Moreover, the inhibitory effect of PPC on the above molecules and cytokines was weakened after pre-treatment with TLR-2 agonist Pam3CSK4. In addition, PPC lost its anti-inflammatory effect and its suppressing capability on MAPK and NF-κB pathways in TLR-2-/- primary SFs after exposure to LPS. Collectively, this study demonstrated that PPC can alleviate synovial inflammation through TLR-2-mediated MAPK and NF-κB pathways, which can be proposed to be a potential drug candidate for RA prevention.

Relationship between gray matter structure and age in children and adolescents with high-functioning autism spectrum disorder.

Objective: The present study used magnetic resonance imaging to investigate the difference in the relationship between gray matter structure and age in children and adolescents with autism spectrum disorder (ASD) and typically developing (TD) subjects. Methods: After screening T1 structural images from the Autism Brain Imaging Data Exchange (ABIDE) database, 111 children and adolescents (7-18 years old) with high-functioning ASD and 151 TD subjects matched for age, sex and full IQ were included in the current study. By using the voxel-based morphological analysis method, gray matter volume/density (GMV/GMD) maps were obtained for each participant. Then, a multiple regression analysis was performed for ASD and TD groups, respectively to estimate the relationship between GMV/GMD and age with gender, education, site, and IQ scores as covariates. Furthermore, a z-test was used to compare such relationship difference between the groups. Results: Results showed that compared with TD, the GMD of ASD showed stronger positive correlations with age in the prefrontal cortex, and a stronger negative correlation in the left inferior parietal lobule, and a weaker positive correlation in the right inferior parietal lobule. The GMV of ASD displayed stronger positive correlations with age in the prefrontal cortex and cerebellum. Conclusion: These findings may provide evidence to support that the brain structure abnormalities underlying ASD during childhood and adolescence may differ from each other.

The non-oral infection of larval Echinococcus granulosus induces immune and metabolic reprogramming in the colon of mice.

Background: The intestinal tract serves as a critical regulator for nutrient absorption and overall health. However, its involvement in anti-parasitic infection and immunity has been largely neglected, especially when a parasite is not transmitted orally. The present study investigated the colonic histopathology and functional reprogramming in mice with intraperitoneal infection of the larval Echinococcus granulosus (E. granulosus). Results: Compared with the control group, the E. granulosus-infected mice exhibited deteriorated secreted mucus, shortened length, decreased expression of tight junction proteins zonula occludens-1 (ZO-1), and occludin in the colon. Moreover, RNA sequencing was employed to characterize colonic gene expression after infection. In total, 3,019 differentially expressed genes (1,346 upregulated and 1,673 downregulated genes) were identified in the colon of infected mice. KEGG pathway and GO enrichment analysis revealed that differentially expressed genes involved in intestinal immune responses, infectious disease-associated pathways, metabolism, or focal adhesion were significantly enriched. Among these, 18 tight junction-relative genes, 44 immune response-associated genes, and 23 metabolic genes were annotated. Furthermore, mebendazole treatment could reverse the colonic histopathology induced by E. granulosus infection. Conclusions: Intraperitoneal infection with E. granulosus induced the pathological changes and functional reprogramming in the colon of mice, and mebendazole administration alleviated above alternations, highlighting the significance of the colon as a protective barrier against parasitic infection. The findings provide a novel perspective on host-parasite interplay and propose intestine as a possible target for treating parasitic diseases that are not transmitted orally.

Parasite-Derived Excretory-Secretory Products Alleviate Gut Microbiota Dysbiosis and Improve Cognitive Impairment Induced by a High-Fat Diet.

High-fat (HF) diet-induced neuroinflammation and cognitive decline in humans and animals have been associated with microbiota dysbiosis via the gut-brain axis. Our previous studies revealed that excretory-secretory products (ESPs) derived from the larval Echinococcus granulosus (E. granulosus) function as immunomodulators to reduce the inflammatory response, while the parasitic infection alleviates metabolic disorders in the host. However, whether ESPs can improve cognitive impairment under obese conditions remain unknown. This study aimed to investigate the effects of E. granulosus-derived ESPs on cognitive function and the microbiota-gut-brain axis in obese mice. We demonstrated that ESPs supplementation prevented HF diet-induced cognitive impairment, which was assessed behaviorally by nest building, object location, novel object recognition, temporal order memory, and Y-maze memory tests. In the hippocampus (HIP) and prefrontal cortex (PFC), ESPs suppressed neuroinflammation and HF diet-induced activation of the microglia and astrocytes. Moreover, ESPs supplementation improved the synaptic ultrastructural impairments and increased both pre- and postsynaptic protein levels in the HIP and PFC compared to the HF diet-treated group. In the colon, ESPs reversed the HF diet-induced gut barrier dysfunction, increased the thickness of colonic mucus, upregulated the expression of zonula occludens-1 (ZO-1), attenuated the translocation of bacterial endotoxins, and decreased the colon inflammation. Notably, ESPs supplementation alleviated the HF diet-induced microbiota dysbiosis. After clarifying the role of antibiotics in obese mice, we found that broad-spectrum antibiotic intervention abrogated the effects of ESPs on improving the gut microbiota dysbiosis and cognitive decline. Overall, the present study revealed for the first time that the parasite-derived ESPs alleviate gut microbiota dysbiosis and improve cognitive impairment induced by a high-fat diet. This finding suggests that parasite-derived molecules may be used to explore novel drug candidates against obesity-associated neurodegenerative diseases.

Heterogeneous alterations in thalamic subfields in major depression disorder.

BACKGROUND: It is well known that the thalamus is not a unitary and homogeneous entity but a complex and highly connected archeocortical structure. Although many neuroimaging studies have reported alterations in the thalamus in major depressive disorder (MDD), the structural alterations in thalamic subfields remain unclear. This study aimed to investigate changes in gray matter volume (GMV) in thalamic subfields in MDD patients. METHODS: The present study included structural images of 848 MDD patients and 794 age-matched normal controls (NC) from 17 study sites of the REST-meta-MDD consortium. We performed voxel-based morphometric analyses to calculate the GMV in the entire thalamus and its subfields using three different automated anatomical labeling atlases and subsequently compared the differences between first-episode drug-naïve major depressive disorder (FEDN), recurrent major depressive disorder (RMDD), and NC groups. We also evaluated the relationships between thalamic GMV and clinical symptoms in MDD patients. RESULTS: Compared to NC, the FEDN patients showed increased GMV in thalamic subfields but not in the entire thalamus, while RMDD patients showed no significant alterations in GMV in the entire thalamus and its subfields. Moreover, the mean GMV in the right anterior thalamus and left anteroventral thalamus in RMDD patients were mildly positively correlated with the Hamilton Anxiety Rating Scale scores. LIMITATIONS: The main limitations are a single-modal analysis based on T1-weighted MR images and a cross-sectional design. CONCLUSIONS: Our findings suggest that FEDN and RMDD patients show heterogeneous alterations across thalamic subfields, which may help us understand the pathophysiological mechanisms of MDD.

Metabolomics Analysis of Splenic CD19+ B Cells in Mice Chronically Infected With Echinococcus granulosus sensu lato Protoscoleces.

Background: The larval stages of Echinococcus granulosus sensu lato (E. granulosus s.l) infection can alter B cell function and affect host anti-infective immunity, but the underlying mechanism remains unclear. The newly emerging immunometabolism highlights that several metabolites are key factors in determining the fate of immune cells, which provides a new insight for exploring how larval E. granulosus s.l. infection remodels B cell function. This study investigated the metabolomic profiles of B cells in mice infected with E. granulosus s.l. protoscoleces (PSC). Results:Total CD19+ B cells, purified from the spleen of infected mice, showed significantly increased production of IL-6, TNF-α, and IL-10 after exposure to LPS in vitro. Moreover, the mRNA expression of metabolism related enzymes in B cells was remarkably disordered post infection. In addition, differential metabolites were identified in B cells after infection. There were 340 differential metabolites (83 upregulated and 257 downregulated metabolites) identified in the positive ion model, and 216 differential metabolites (97 upregulated and 119 downregulated metabolites) identified in the negative ion mode. Among these, 64 differential metabolites were annotated and involved in 68 metabolic pathways, including thyroid hormone synthesis, the metabolic processes of glutathione, fructose, mannose, and glycerophospholipid. Furthermore, several differential metabolites such as glutathione, taurine, and inosine were validated to regulate the cytokine production in LPS stimulated B cells. Conclusion:Infection with the larval E. granulosus s.l. causes metabolic reprogramming in the intrinsic B cells of mice, which provides the first evidence for understanding the role and mechanism of B cells in parasite anti-infective immunity from the viewpoint of immunometabolism.

Personalized Variable vs Fixed-Dose Systemic Corticosteroid Therapy in Hospitalized Patients With Acute Exacerbations of COPD: A Prospective, Multicenter, Randomized, Open-Label Clinical Trial.

BACKGROUND: Systemic corticosteroids for the treatment of COPD exacerbations decrease treatment failure and shorten the length of hospitalization. However, the optimal dose is unclear. RESEARCH QUESTION: Is personalized-dose corticosteroid administered according to a dosing scale more effective than fixed-dose corticosteroid administration in hospitalized patients with COPD with exacerbations? STUDY DESIGN AND METHODS: This was a prospective, randomized, open-label trial. In-hospital patients with COPD with exacerbations were randomly assigned at a 1:1 ratio to either the fixed-dose group (receiving the equivalent of 40 mg of prednisolone) or the personalized-dose group for 5 days. The primary end point was a composite measure of treatment failure that included in-hospital treatment failure and medium-term (postdischarge) failure. Secondary end points were length of stay and cost. RESULTS: A total of 248 patients were randomly assigned to the fixed-dose group (n = 124) or personalized-dose group (n = 124). One patient in each group was not included in the intention-to-treat population because of incorrect initial COPD diagnosis. Failure of therapy occurred in 27.6% in the personalized-dose group, compared with 48.8% in the fixed-dose group (relative risk, 0.40; 95% CI, 0.24-0.68; P = .001). The in-hospital failure of therapy was significantly lower in the personalized-dose group (10.6% vs 24.4%; P = .005), whereas the medium-term failure rate, adverse event rate, hospital length of stay, and costs were similar between the two groups. After treatment failure, a lower additional dose of corticosteroids and a shorter duration of treatment were needed in the personalized-dose group to achieve control of the exacerbation. In the personalized-dose cohort, those receiving 40 mg or less had an average failure rate of 44.4%, compared with 22.9% among those receiving more than 40 mg (P = .027). INTERPRETATION: Personalized dosing of corticosteroids reduces the risk of failure because more patients were provided with a higher initial dose, especially > 60 mg, whereas 40 mg or less was too low in either group. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02147015; URL: www.clinicaltrials.gov.

Schistosoma japonicum Infection Leads to the Reprogramming of Glucose and Lipid Metabolism in the Colon of Mice.

The deposition of Schistosoma japonicum (S. japonicum) eggs commonly induces inflammation, fibrosis, hyperplasia, ulceration, and polyposis in the colon, which poses a serious threat to human health. However, the underlying mechanism is largely neglected. Recently, the disorder of glucose and lipid metabolism was reported to participate in the liver fibrosis induced by the parasite, which provides a novel clue for studying the underlying mechanism of the intestinal pathology of the disease. This study focused on the metabolic reprogramming profiles of glucose and lipid in the colon of mice infected by S. japonicum. We found that S. japonicum infection shortened the colonic length, impaired intestinal integrity, induced egg-granuloma formation, and increased colonic inflammation. The expression of key enzymes involved in the pathways regulating glucose and lipid metabolism was upregulated in the colon of infected mice. Conversely, phosphatase and tensin homolog deleted on chromosome ten (PTEN) and its downstream signaling targets were significantly inhibited after infection. In line with these results, in vitro stimulation with soluble egg antigens (SEA) downregulated the expression of PTEN in CT-26 cells and induced metabolic alterations similar to that observed under in vivo results. Moreover, PTEN over-expression prevented the reprogramming of glucose and lipid metabolism induced by SEA in CT-26 cells. Overall, the present study showed that S. japonicum infection induces the reprogramming of glucose and lipid metabolism in the colon of mice, and PTEN may play a vital role in mediating this metabolic reprogramming. These findings provide a novel insight into the pathogenicity of S. japonicum in hosts.

Abnormal dynamic functional network connectivity of the mirror neuron system network and the mentalizing network in patients with adolescent-onset, first-episode, drug-naïve schizophrenia.

Previous studies based on an assumption of connectivity stationarity reported disconnections in mirror neuron system (MNS) and mentalizing networks of schizophrenic brains with social cognitive disruptions. However, recent studies demonstrated that functional brain connections are dynamic, and static connectivity metrics fail to capture time-varying properties of functional connections. The present study used a dynamic functional connectivity (dFC) method to test whether alterations of functional connectivity in the two networks are time-varying in adolescent-onset schizophrenia (AOS) patients. We collected resting-state fMRI data from 28 patients with AOS and 22 matched healthy controls. Static functional connectivity and dFC were used to explore the connectivity difference in the MNS and mentalizing networks between the two groups, respectively. Then a Pearson's correlation analysis between the connectivity showing intergroup differences and clinical scores was conducted in the AOS group. Compared with static functional connectivity analyses, dFC revealed state-specific connectivity decreases within the MNS network in the AOS group. Additionally, the dFC between the left middle temporal gyrus and left V5 was negatively correlated with the item2 of PANSS negative scores across all the AOS patients. Our findings suggest that social dysfunctions in AOS patients may be associated with the altered integrity and interaction of the MNS and mentalizing networks, and the functional impairments in the MNS are dynamic over time.