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

Superconductivity and Charge Density Wave in ZrTe3−x_{3-x}Sex_{x}

Charge density wave (CDW), the periodic modulation of the electronic charge density, will open a gap on the Fermi surface that commonly leads to decreased or vanishing conductivity. On the other hand superconductivity, a commonly believed competing order, features a Fermi surface gap that results in infinite conductivity. Here we report that superconductivity emerges upon Se doping in CDW conductor ZrTe$_{3}$ when the long range CDW order is gradually suppressed. Superconducting critical temperature $T_c(x)$ in ZrTe$_{3-x}$Se$_x$ (${0\leq}x\leq0.1$) increases up to 4 K plateau for $0.04$$\leq$$x$$\leq$$0.07$. Further increase in Se content results in diminishing $T_{c}$ and filametary superconductivity. The CDW modes from Raman spectra are observed in $x$ = 0.04 and 0.1 crystals, where signature of ZrTe$_{3}$ CDW order in resistivity vanishes. The electronic-scattering for high $T_{c}$ crystals is dominated by local CDW fluctuations at high temperures, the resistivity is linear up to highest measured $T=300K$ and contributes to substantial in-plane anisotropy.Comment: 15 pages, 4 figure

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

Deferoxamine regulates neuroinflammation and iron homeostasis in a mouse model of postoperative cognitive dysfunction

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after surgery, especially amongst elderly patients. Neuroinflammation and iron homeostasis are key hallmarks of several neurological disorders. In this study, we investigated the role of deferoxamine (DFO), a clinically used iron chelator, in a mouse model of surgery-induced cognitive dysfunction and assessed its neuroprotective effects on neuroinflammation, oxidative stress, and memory function. METHODS: A model of laparotomy under general anesthesia and analgesia was used to study POCD. Twelve to 14 months C57BL/6J male mice were treated with DFO, and changes in iron signaling, microglia activity, oxidative stress, inflammatory cytokines, and neurotrophic factors were assessed in the hippocampus on postoperative days 3, 7, and 14. Memory function was evaluated using fear conditioning and Morris water maze tests. BV2 microglia cells were used to test the anti-inflammatory and neuroprotective effects of DFO. RESULTS: Peripheral surgical trauma triggered changes in hippocampal iron homeostasis including ferric iron deposition, increase in hepcidin and divalent metal transporter-1, reduction in ferroportin and ferritin, and oxidative stress. Microglia activation, inflammatory cytokines, brain-derived neurotropic factor impairments, and cognitive dysfunction were found up to day 14 after surgery. Treatment with DFO significantly reduced neuroinflammation and improved cognitive decline by modulating p38 MAPK signaling, reactive oxygen species, and pro-inflammatory cytokines release. CONCLUSIONS: Iron imbalance represents a novel mechanism underlying surgery-induced neuroinflammation and cognitive decline. DFO treatment regulates neuroinflammation and microglia activity after surgery

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

A novel porcine reproductive and respiratory syndrome virus vector system that stably expresses enhanced green fluorescent protein as a separate transcription unit

Abstract Here we report the rescue of a recombinant porcine reproductive and respiratory syndrome virus (PRRSV) carrying an enhanced green fluorescent protein (EGFP) reporter gene as a separate transcription unit. A copy of the transcription regulatory sequence for ORF6 (TRS6) was inserted between the N protein and 3′-UTR to drive the transcription of the EGFP gene and yield a general purpose expression vector. Successful recovery of PRRSV was obtained using an RNA polymerase II promoter to drive transcription of the full-length virus genome, which was assembled in a bacterial artificial chromosome (BAC). The recombinant virus showed growth replication characteristics similar to those of the wild-type virus in the infected cells. In addition, the recombinant virus stably expressed EGFP for at least 10 passages. EGFP expression was detected at approximately 10 h post infection by live-cell imaging to follow the virus spread in real time and the infection of neighbouring cells occurred predominantly through cell-to-cell-contact. Finally, the recombinant virus generated was found to be an excellent tool for neutralising antibodies and antiviral compound screening. The newly established reverse genetics system for PRRSV could be a useful tool not only to monitor virus spread and screen for neutralising antibodies and antiviral compounds, but also for fundamental research on the biology of the virus.This study was funded by grants from the National Natural Science Foundation of China (U0931003/L01) and the National High-Tech R&D Program of China (2011AA10A208) to EMZ, the National Natural Science Foundation of China (31302103) to WCB, the European Community’s Seventh Frame-work Programme (PoRRSCon, FP7-KBBE-2009-3-245141) and the Ministry of Science and Innovation of Spain (MCINN) (BIO2010-16075) to FA and LE.Peer Reviewe

High strength polymer/silicon nitride composites for dental restorations

Objectives To fabricate polymer-infiltrated silicon nitride composite (PISNC) and evaluate the potential of PISNC in dental application. Methods Porous silicon nitride (Si3N4) ceramics were fabricated through gelcasting and pressureless sintering. Polymer infiltrating was carried out then and composites were obtained after curing of polymer. Flexural strength and microstructures of porous ceramic scaffolds and polymer-infiltrated composites were obtained by three-point bending and SEM, respectively. Phase distributions of polymer-infiltrated ceramics were observed by EDS. Human gingival fibroblast cells (HGFs) were used to evaluate the cytocompatibility and IL-6 release. The cell morphology were observed by SEM. The amount of released IL-6 was investigated using ELISA test system. Results Porosity and mechanical strength of porous ceramics ranged from 45.1 to 49.3% and 171.8–262.3 MPa, respectively. The bicontinuous structure of polymer-infiltrated composites possessed them with excellent mechanical properties. Porosity and mechanical strength of polymer-infiltrated Si3N4 composites ranged from 1.94 to 2.28% and 273–385.3 MPa, respectively. Additionally, the PISNC enhanced the initial adhesion and spreading activity of HGFs compared with PMMA. The PISNC showed similar IL-6 release performance with PMMA samples.acceptedVersion© 2019. This is the authors’ accepted and refereed manuscript to the article. Locked until 12.6.2021 due to copyright restrictions. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0

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

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