Mitochondrial dynamics and lipid mediators regulate immune responses of macrophage to Mycobacterium tuberculosis

Tuberculosis (TB), caused by the ancient pathogen Mycobacterium tuberculosis (M.tb), is a highly infectious disease. Alveolar macrophages, as a residing niche for M.tb, exert immuno-modulatory and microbicidal effects. In the macrophage, M.tb can adapt to the environment, to achieve the goal of longer survival and dissemination of the bacteria in the surrounding environment. A better understanding of the host-mycobacteria interactions is necessary for the discovery of new immunotherapeutic targets and the establishment of effective host-direct therapies (HDT). Elongated mitochondria and enhanced mitochondrial interconnectivity were found in M.tb-infected macrophages. These changes of dynamics were achieved by increased expression of mitofusin 1 (MFN1) and accompanied by enhanced mitochondrial oxidative phosphorylation (OXPHOS) and ATP production, which are required for the autophagy process and suppression of intracellular bacterial growth. A comprehensive lipid mediators (LM) profile of M.tb-conditioned medium (MTB-CM)-stimulated M1-macrophages was analyzed by UPLC-MS/MS. Decreased expression of cycloxygenase 2 (COX-2) and prostaglandin E2 (PGE2) were proposed as the reasons for the resolving and potential microbicidal activity of sulfasalazine (SASP). As one of the highly expressed prostaglandins (PGs) in MTB-CM-stimulated M1-macrophages, prostaglandin J2 (PGJ2) was found to suppress pro-inflammatory cytokines expression and inhibit COX-2 expression via a negative feedback loop. PGJ2 also decreased the mycobacterial phagocytosis ability of macrophages and increased intracellular bacterial survival rate. Taken together, the findings presented in this thesis provide new insights into how M.tb modulates macrophage reactions within the immune system. The interactions between M.tb and host including mitochondrial dynamics regulation and LM biosynthesis might be promising targets for the development of HDT strategies against TB

Weibull analysis of the tensile behavior of fibers with geometrical irregularities

This paper further develops the conventional Weibull/weakest-link model by incorporating the within-fiber diameter variation. This is necessary for fibers with considerable geometrical irregularities, such as the wool and other animal fibers. The strength of wool fibers has been verified to follow this modified Weibull/weakest-link distribution. In addition, the modified Weibull model can predict the gauge length effect more accurately than the conventional model

A Memetic Differential Evolution Algorithm Based on Dynamic Preference for Constrained Optimization Problems

The constrained optimization problem (COP) is converted into a biobjective optimization problem first, and then a new memetic differential evolution algorithm with dynamic preference is proposed for solving the converted problem. In the memetic algorithm, the global search, which uses differential evolution (DE) as the search scheme, is guided by a novel fitness function based on achievement scalarizing function (ASF). The novel fitness function constructed by a reference point and a weighting vector adjusts preference dynamically towards different objectives during evolution, in which the reference point and weighting vector are determined adapting to the current population. In the local search procedure, simplex crossover (SPX) is used as the search engine, which concentrates on the neighborhood embraced by both the best feasible and infeasible individuals and guides the search approaching the optimal solution from both sides of the boundary of the feasible region. As a result, the search can efficiently explore and exploit the search space. Numerical experiments on 22 well-known benchmark functions are executed, and comparisons with five state-of-the-art algorithms are made. The results illustrate that the proposed algorithm is competitive with and in some cases superior to the compared ones in terms of the quality, efficiency, and the robustness of the obtained results

Decreased Peripheral BDNF Levels and Cognitive Impairment in Late-Life Schizophrenia

Objectives: There are relatively few studies on mechanisms of cognitive deficits in late-life schizophrenia (LLS). Brain-derived neurotrophic factor (BDNF), as an important neuroplastic molecule, has been reported to be involved in neurocognitive impairment in schizophrenia. This study aimed to examine whether peripheral BDNF levels were associated with cognitive deficits in LLS, which has not been explored yet.Methods: Forty-eight LLS patients and 45 age-matched elderly controls were recruited. We measured all participants on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) for cognition and serum BDNF levels. Psychopathological symptoms in patients were assessed by the Positive and Negative Syndrome Scale (PANSS).Results: The levels of BDNF in LLS patients were significantly lower than those in healthy controls (8.80 ± 2.30 vs. 12.63 ± 5.08 ng/ml, p < 0.001). The cognitive performance of LLS patients was worse than that of the controls on RBANS total score and scores of immediate memory, attention, language, and delayed memory (all p ≤ 0.005). BDNF was positively associated with attention in LLS patients (r = 0.338, p = 0.019).Conclusion: Our findings suggest that older patients with schizophrenia exhibit lower BDNF levels and more cognitive deficits than older controls, supporting the accelerated aging hypothesis of schizophrenia. Moreover, decreased BDNF is related to attention deficits, indicating that BDNF might be a candidate biomarker of cognitive impairments in LLS patients

Elevated homocysteine levels, white matter abnormalities and cognitive impairment in patients with late-life depression

BackgroundCognitive impairment in late−life depression (LLD) is considered to be caused by neurodegenerative changes. Elevated homocysteine (Hcy) levels may be linked to cognitive abnormalities associated with LLD. The important role of white matter (WM) damage in cognitive impairment and pathogenesis in patients with LLD has been widely reported. However, no research has explored the interrelationships of these features in patients with LLD.ObjectiveThe goal of the study was to examine the interrelationship between Hcy levels, cognition, and variations in WM microstructure detected by diffusion tensor imaging (DTI) in patients with LLD.MethodsWe recruited 89 healthy controls (HCs) and 113 patients with LLD; then, we measured the plasma Hcy levels of participants in both groups. All individuals performed a battery of neuropsychological tests to measure cognitive ability. Seventy-four patients with LLD and 68 HCs experienced a DTI magnetic resonance imaging (MRI) scan.ResultsPatients with LLD showed significantly lower fractional anisotropy (FA) values in the bilateral inferior longitudinal fasciculus than those of healthy participants. Only in LLD patients was Hcy concentration inversely associated to FA values in the forceps minor. Finally, multiple regression analyses showed that an interaction between Hcy levels and FA values in the right cingulum of the cingulate cortex and right inferior longitudinal fasciculus were independent contributors to the executive function of patients with LLD.ConclusionOur results highlight the complex interplay between elevated homocysteine levels and WM abnormalities in the pathophysiology of LLD-related cognitive impairment, consistent with the neurodegeneration hypothesis

The core inflammatory factors in patients with major depressive disorder: a network analysis

IntroductionThe symptoms of major depressive disorder (MDD) vary widely. Psycho-neuro-inflammation has shown that MDD’s inflammatory factors can accelerate or slow disease progression. This network analysis study examined the complex interactions between depressed symptoms and inflammatory factors in MDD prevention and treatment.MeasuresWe gathered participants’ inflammatory factor levels, used the Hamilton Depression Scale (HAMD-17), and network analysis was used to analyzed the data. Network analysis revealed the core inflammatory (nodes) and their interactions (edges). Stability and accuracy tests assessed these centrality measures’ network robustness. Cluster analysis was used to group persons with similar dimension depressive symptoms and examine their networks.ResultsInterleukin-1β (IL-1β) is the core inflammatory factor in the overall sample, and IL-1β—interleukin-4 (IL-4) is the strongest correlation. Network precision and stability passed. Network analysis showed significant differences between Cluster 1 (with more severe anxiety/somatization and sleep disruption) and Cluster 3 (with more severe retardation and cognitive disorders), as well as between Cluster 2 (with more severe anxiety/somatization, sleep disruption and body weight) and Cluster 3. IL-1β is the core inflammatory factor in Cluster 1 and Cluster 2, while tumor necrosis factor alpha (TNF-α) in Cluster 3.ConclusionIL-1β is the central inflammatory factor in the network, and there is heterogeneity in the core inflammatory factor of MDD with specific depressive dimension symptoms as the main manifestation. In conclusion, inflammatory factors and their links should be prioritized in future theoretical models of MDD and may provide new research targets for MDD intervention and treatment

Hippocampal region metabolites and cognitive impairment in patients with general paresis: based on 1H-proton magnetic resonance spectroscopy

Background:This study utilizes Hydrogen proton magnetic resonance spectroscopy (1H-MRS) to investigate metabolite concentrations in the bilateral hippocampus of general paresis (GP) patients.Methods:A total of 80 GP patients and 57 normal controls (NCs) were enrolled. Metabolite ratios in the bilateral hippocampus were measured using 1H-MRS. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Based on MMSE scores, participants were categorized into normal control, mild cognitive impairment, and moderate-severe dementia groups. Metabolite ratios (N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/creatine (Cr), N-acetylaspartate (NAA)/choline (Cho), myoinositol (MI)/creatine (Cr), choline (Cho)/N-acetylaspartate (NAA)) were compared between groups, and correlations between metabolite ratios and cognitive performance were examined.Results:MMSE scores progressively decreased in the normal, mild cognitive impairment, and moderate-severe dementia groups (p < 0.001). The moderate-severe dementia group showed significantly lower NAA/Cr ratios in the left hippocampus region (L-NAA/Cr ratios) (p < 0.001) and higher Cho/NAA ratios in the left hippocampus region (L-Cho/NAA ratios) (p < 0.05) compared to the other groups. However, differences in L-NAA/Cr and L-Cho/NAA ratios between the mild cognitive impairment group and the NC group were not significant in the hippocampus region (p > 0.05). NAA/Cho and NAA/Cr ratios in the right hippocampus region (R-NAA/Cho and R-NAA/Cr ratios) in the moderate-severe dementia group were lower than those in the control group (p < 0.05). No correlation was found between metabolite ratios and MMSE scores in bilateral hippocampus regions.Conclusion:There are distinctive metabolic characteristics in the hippocampus of GP patients. GP patients exhibited lower NAA/Cr and NAA/Cho ratios in the bilateral hippocampus, indicating neuron loss in these areas, which may become more pronounced as the disease progresses

Electroconvulsive therapy for agitation in schizophrenia: Meta-analysis of randomized controlled trials

Background: Agitation poses a significant challenge in the treatment of schizophrenia. Electroconvulsive therapy (ECT) is a fast, effective and safe treatment for a variety of psychiatric disorders, but no meta-analysis of ECT treatment for agitation in schizophrenia has yet been reported. Aims: To systematically evaluate the efficacy and safety of ECT alone or ECT-antipsychotics (APs) combination for agitation in schizophrenia. Methods: Systematic literature search of randomized controlled trials (RCTs) was performed. Two independent evaluators selected studies, extracted data about outcomes and safety with available data, conducted quality assessment and data synthesis. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) was used to judge the level of the overall evidence of main outcomes. Results: Seven RCTs from China, including ECT alone (4 RCTs with 5 treatment arms, n=240) and ECT-APs combination (3 RCTs, n=240), were identified. Participants in the studies were on average 34.3(4.5) years of age and lasted an average of 4.3(3.1) weeks of treatment duration. All 7 RCTs were non-blinded, and were rated as low quality based on Jadad scale. Meta-analysis of the pooled sample found no significant difference in the improvement of the agitation sub-score of the Positive and Negative Syndrome Scale (PANSS) when ECT alone (weighted mean difference=-0.90, (95% confidence interval (CI): -2.91, 1.11), p=0.38) or ECT-APs combination (WMD=-1.34, (95%CI: -4.07, 1.39), p=0.33) compared with APs monotherapy. However, ECT alone was superior to APs monotherapy regarding PANSS total score (WMD=-7.13, I2=0%, p=0.004) and its excitement sub-score (WMD=-1.97, pI2=0%, p=0.004) and its excitement sub-score at 7 and 14 days (WMD=-1.97 to -1.92, p=0.002 to 0.0001) after ECT. The ECT-APs combination was superior to APs monotherapy with respect to the PANSS total score at treatment endpoint (WMD=-10.40, p=0.03) and 7 days (WMD=-5.01, p=0.02). Headache ( number-needed-to-harm (NNH)=3, 95%CI=2-4) was more frequent in the ECT alone group compared to AP monotherapy. According to the GRADE approach, the evidence levels of main outcomes were rated as ‘‘very low’’ (37.5%) and “low” (50%). Conclusion: Pooling of the data based on 7 RCTs from China found no advantage of ECT alone or ECT-APs combination in the treatment of agitation related outcomes in schizophrenia patients. However, ECT alone or ECT-APs combination were associated with significant reduction in the PANSS total score. High-quality RCTs are needed to confirm the current interpretations. Review registration number: CRD4201400668

7-Piperazinethylchrysin inhibits melanoma cell proliferation by targeting Mek 1/2 kinase activity

Purpose: To investigate the growth-inhibitory effect of 7-piperazinethylchrysin (PEC) on melanoma cell lines.Methods: Cell viability was analyzed by trypan blue exclusion assays and the cell cycle by flow cytometry using ModFit LT software. Specifically, cells were stained with propidium iodide (0.5 mg/mL) supplemented with RNase A (50 mg/mL), and analyzed using flow cytometry and ModFit LT software.Results: In A375 and B16F10 cell cultures, proliferation was reduced to 79 and 72 %, respectively, on treatment with 30 μM PEC. PEC increased the proportion of A375 cells in G1/G0 phase to 71.23 %, versus 42.76 % in untreated cells. In B16F10 and A375 cells, treatment with PEC caused the inhibition of Mek 1/2 kinase activity and suppressed Erk 1/2 phosphorylation. The level of cAMP-response element binding protein was increased by PEC. The expression of microphthalmia-linked transcription factor was also increased by PEC treatment. Marked enhancement was observed in the level of tyrosinase in melanoma cells on treatment with PEC. Analysis of PBG-D expression showed a marked increase in B16F10 and A375 cells on the addition of PEC to cell cultures at 72 h. The level of PBG D expression was increased by 9- and 8.5-fold in B16F10 and A375 cells, respectively, on incubation with 30 μM PEC. The addition of a Mek 1/2 inhibitor (U0126) to the cultures promoted PEC-mediated growth inhibition.Conclusion: PEC inhibited melanoma cell proliferation, apparently by blocking the cell cycle at G0/G1 and downregulating the Ras/Raf/Mek/Erk pathway.Keywords: Tyrosinase, Kinase, Microphthalmia, Phosphorylation, 7-Piperazinethylchrysi