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To comprehensively investigate the effects of antioxidant nutrients on muscle mass, strength and function in chronic obstructive pulmonary disease (COPD) patients. PubMed, Embase, Cochrane Library, and Web of Science were comprehensively searched from the inception to January 3, 2024. The quality of randomized controlled trials (RCTs) was measured using the Jadad scale. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were used as the effect size for measurement data. Further, subgroup analysis was conducted based on whether patients participated in lung rehabilitation plans while receiving nutritional interventions. Sensitivity analysis was performed on all outcomes. A total of 12 studies involving 595 patients with COPD were included, with 11 studies had high quality, and one study had low quality. For muscle mass, patients receiving antioxidant nutrients had a significantly increased lean body mass index compared with those not receiving antioxidant nutrients (pooled WMD: 0.903, 95% CI: 0.264, 1.541, P = 0.006). For patients who did not participate in lung rehabilitation plan while receiving nutritional interventions, antioxidant nutrients brought about a significantly higher lean body mass index (pooled WMD: 1.360, 95% CI: 0.560, 2.160, P = 0.001). For muscle strength, patients in the antioxidant nutrient intervention group had significantly higher hand grip strength (HGS) than those in the non-antioxidant nutrient intervention group (pooled WMD: 1.976, 95% CI: 1.337, 2.615, P < 0.001). Patients receiving antioxidant nutrients had significantly greater inspiratory muscle strength (MIP) than those not receiving antioxidant nutrients (pooled WMD: 8.127, 95% CI: 2.677, 13.577, P = 0.003). Antioxidant nutrient intervention significantly improved HGS, MIP and lean body mass index in COPD. Clinicians should consider increasing food intake or supplementation rich in antioxidants in the treatment plan of patients with COPD.

Background Despite its identification as a key checkpoint regulator of microglial activation in Alzheimer’s disease, the overarching role of CX3CR1 signaling in modulating mechanisms of Aβ driven neurodegeneration, including accumulation of hyperphosphorylated tau is not well understood. Methodology Accumulation of soluble and insoluble Aβ species, microglial activation, synaptic dysregulation, and neurodegeneration is investigated in 4- and 6-month old 5xFAD; Cx3cr1 + / + and 5xFAD; Cx3cr1 −/− mice using immunohistochemistry, western blotting, transcriptomic and quantitative real time PCR analyses of purified microglia. Flow cytometry based, in-vivo Aβ uptake assays are used for characterization of the effects of CX3CR1-signaling on microglial phagocytosis and lysosomal acidification as indicators of clearance of methoxy-X-04 + fibrillar Aβ. Lastly, we use Y-maze testing to analyze the effects of Cx3cr1 deficiency on working memory. Results Disease progression in 5xFAD; Cx3cr1 −/− mice is characterized by increased deposition of filamentous plaques that display defective microglial plaque engagement. Microglial Aβ phagocytosis and lysosomal acidification in 5xFAD; Cx3cr1 −/− mice is impaired in-vivo . Interestingly, Cx3cr1 deficiency results in heighted accumulation of neurotoxic, oligomeric Aβ, along with severe neuritic dystrophy, preferential loss of post-synaptic densities, exacerbated tau pathology, neuronal loss and cognitive impairment. Transcriptomic analyses using cortical RNA, coupled with qRT-PCR using purified microglia from 6 month-old mice indicate dysregulated TGFβ-signaling and heightened ROS metabolism in 5xFAD; Cx3cr1 −/− mice. Lastly, microglia in 6 month-old 5xFAD; Cx3cr1 −/− mice express a ‘degenerative’ phenotype characterized by increased levels of Ccl2 , Ccl5 , Il-1β , Pten and Cybb along with reduced Tnf , Il-6 and Tgfβ1 mRNA. Conclusions Cx3cr1 deficiency impairs microglial uptake and degradation of fibrillar Aβ, thereby triggering increased accumulation of neurotoxic Aβ species. Furthermore, loss of Cx3cr1 results in microglial dysfunction typified by dampened TGFβ-signaling, increased oxidative stress responses and dysregulated pro-inflammatory activation. Our results indicate that Aβ-driven microglial dysfunction in Cx3cr1 −/− mice aggravates tau hyperphosphorylation, neurodegeneration, synaptic dysregulation and impairs working memory.

Background Genetic variants of the T riggering R eceptor E xpressed on M yeloid Cells- 2 (TREM2) confer increased risk of developing late-onset Alzheimer’s Disease (LOAD) and other neurodegenerative disorders. Recent studies provided insight into the multifaceted roles of TREM2 in regulating extracellular β-amyloid (Aβ) pathology, myeloid cell accumulation, and inflammation observed in AD, yet little is known regarding the role of TREM2 in regulating intracellular microtubule associated protein tau (MAPT; tau) pathology in neurodegenerative diseases and in AD, in particular. Results Here we report that TREM2 deficiency leads to accelerated and exacerbated hyperphosphorylation and aggregation of tau in a humanized mouse model of tauopathy. TREM2 deficiency also results, indirectly, in dramatic widespread dysregulation of neuronal stress kinase pathways. Conclusions Our results suggest that deficiency of microglial TREM2 leads to heightened tau pathology coupled with widespread increases in activated neuronal stress kinases. These findings offer new insight into the complex, multiple roles of TREM2 in regulating Aβ and tau pathologies.

To investigate the clinical features of active tuberculosis (TB) infection due to immune checkpoint inhibitors (ICIs) treatment in patients with advanced cancer. We report the diagnosis and treatment of a case of pulmonary malignancy (squamous cell carcinoma, cT4N3M0 IIIC), secondary to active TB infection following ICIs therapy. Moreover, we summarize and analyze other related cases collected from the China National Knowledge Infrastructure (CNKI), Wanfang Database, PubMed, the Web of Science, and EMBASE (up to October 2021). A total of 23 patients, including 20 males and 3 females who were aged 49-87 years with a median age of 65 years, were included in the study. Twenty-two patients were diagnosed by Mycobacterium tuberculosis culture or DNA polymerase chain reaction (PCR), while the remaining patient was diagnosed by tuberculin purified protein derivative and pleural biopsy. One case had an interferon-gamma release assay (IGRA) to rule out latent TB infection prior to the application of ICI. Fifteen patients received an anti-tuberculosis regimen. Among the 20 patients with a description of clinical regression, 13 improved and 7 died. Seven of the patients who improved were treated with ICI again and four of them did not experience a recurrence or worsening of TB. The case diagnosed in our hospital also improved after receiving anti-TB treatment after stopping ICI therapy, and continued chemotherapy on the basis of anti-TB treatment, and his condition is relatively stable at present. Due to the lack of specificity of TB infection following ICIs therapy, patients should be followed for fever and respiratory symptoms for 6.3 months after drug administration. It is recommended that IGRA should be performed before ICIs therapy and the development of TB during immunotherapy in patients who are positive in IGRA should be closely monitored. The symptoms of TB in most patients can be improved with ICIs withdrawal and anti-TB treatment, but there is still a need to be alert to the potentially fatal risk of TB.

Background The R47H variant of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) confers greatly increased risk for Alzheimer’s disease (AD), reflective of a central role for myeloid cells in neurodegeneration. Understanding how this variant confers AD risk promises to provide important insights into how myeloid cells contribute to AD pathogenesis and progression. Methods In order to investigate this mechanism, CRISPR/Cas9 was used to generate a mouse model of AD harboring one copy of the single nucleotide polymorphism (SNP) encoding the R47H variant in murine Trem2 . TREM2 expression, myeloid cell responses to amyloid deposition, plaque burden, and neuritic dystrophy were assessed at 4 months of age. Results AD mice heterozygous for the Trem2 R47H allele exhibited reduced total Trem2 mRNA expression, reduced TREM2 expression around plaques, and reduced association of myeloid cells with plaques. These results were comparable to AD mice lacking one copy of Trem2 . AD mice heterozygous for the Trem2 R47H allele also showed reduced myeloid cell responses to amyloid deposition, including a reduction in proliferation and a reduction in CD45 expression around plaques. Expression of the Trem2 R47H variant also reduced dense core plaque number but increased plaque-associated neuritic dystrophy. Conclusions These data suggest that the AD-associated TREM2 R47H variant increases risk for AD by conferring a loss of TREM2 function and enhancing neuritic dystrophy around plaques.

Background Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia. Methods To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2 Y38C/Y38C and Trem2 −/− mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches. Results While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2 −/− mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2 Y38C/Y38C and Trem2 −/− mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia.

Traumatic brain injury (TBI) promotes several Alzheimer’s disease-like pathological features, including microtubule-associated protein tau (MAPT) accumulation within neurons. Macrophage activation in the injured hTau mouse model of tauopathy raises the question whether there is a relationship between MAPT pathology and alterations in macrophage activation following TBI. Triggering receptor expressed on myeloid cells 2 (TREM2) is a critical regulator of microglia and macrophage phenotype, but its mechanisms on TBI remain unclear. To address the association with TREM2 in TBI and MAPT pathology, we studied TREM2 deficiency in hTau mice ( hTau;Trem2 -/- ) 3 (acute phase) and 120 (chronic phase) days after experimental TBI. At three days following injury, hTau;Trem2 -/- mice exhibited reduced macrophage activation both in the cortex and hippocampus. However, to our surprise, hTau;Trem2 -/- mice exposed to TBI augments macrophage accumulation in the corpus callosum and white matter near the site of tissue damage in a chronic phase, which results in exacerbated axonal injury, tau aggregation, and impaired neurogenesis. We further demonstrate that TREM2 deficiency in hTau injured mice promotes neuronal dystrophy in the white matter due to impaired phagocytosis of apoptotic cells. Remarkably, hTau;Trem2 -/- exposed to TBI failed to restore blood-brain barrier integrity. These findings imply that TREM2 deficiency accelerates inflammation and neurodegeneration, accompanied by attenuated microglial phagocytosis and continuous blood-brain barrier (BBB) leakage, thus exacerbating tauopathy in hTau TBI mice.

Garnet‐type oxide Li6.4La3Zr1.4Ta0.6O12 (LLZTO) features superior ionic conductivity and good stability toward lithium (Li) metal, but requires high‐temperature sintering (≈1200 °C) that induces high fabrication cost, poor mechanical processability, and high interface resistance. Here, a novel high‐performance tricomponent composite solid electrolyte (CSE) comprising LLZTO−4LiBH4/xLi3BN2H8 is reported, which is prepared by ball milling the LLZTO−4LiBH4 mixture followed by hand milling with Li3BN2H8. Green pellets fabricated by heating the cold‐pressed CSE powders at 120 °C offer ultrafast room‐temperature ionic conductivity (≈1.73 × 10−3 S cm−1 at 30 °C) and ultrahigh Li‐ion transference number (≈0.9999), which enable the Li|Li symmetrical cells to cycle over 1600 h at 30 °C with only 30 mV of overpotential. Moreover, the Li|CSE|TiS2 full cells deliver 201 mAh g−1 of capacity with long cyclability. These outstanding performances are due to the low open porosity in the electrolyte pellets as well as the high intrinsic ionic conductivity and easy deformability of Li3BN2H8. Synergized tricomponent all‐inorganics solid electrolyte comprising LLZTO−4LiBH4/xLi3BN2H8 offers ultrafast room‐temperature ionic conductivity (≈1.73 × 10−3 S cm−1 at 30 °C) and ultrahigh Li‐ion transference number (≈0.9999), thus enabling the Li|Li symmetrical cells to cycle over 1600 h at 30 °C with only 30 mV of overpotential. Moreover, the Li|CSE|TiS2 full cells (CSE: composite solid electrolyte) deliver 201 mAh g−1 with long cyclability.

Background Fractalkine (CX 3 CL1) and its receptor (CX 3 CR1) play an important role in regulating microglial function. We have previously shown that Cx 3 cr1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CX 3 CL1 is essential in regulating neuronal tau pathology. Methods We used transgenic mice lacking endogenous Cx 3 cl 1 ( Cx 3 cl1 −/− ) and expressing only obligatory soluble form (with only chemokine domain) and lacking the mucin stalk of CX 3 CL1 (referred to as Cx 3 cl1 105Δ mice) to assess tau pathology and behavioral function in both lipopolysaccharide (LPS) and genetic (hTau) mouse models of tauopathy. Results First, increased basal tau levels accompanied microglial activation in Cx 3 cl1 105Δ mice compared to control groups. Second, increased CD45 + and F4/80 + neuroinflammation and tau phosphorylation were observed in LPS, hTau/ Cx 3 cl1 −/− , and hTau/ Cx 3 cl1 105Δ mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CX 3 CR1 was reduced in Cx 3 cl1 105Δ mice, suggesting enhanced fractalkine receptor internalization (mimicking Cx 3 cr1 deletion), which likely contributes to the elevated tau pathology. Conclusions Collectively, our data suggest that overexpression of only chemokine domain of CX 3 CL1 does not protect against tau pathology.