Administration of exosomes derived from mesenchymal stromal cells (MSCs) could improve some neurologic conditions by transferring functional biomolecules to recipient cells. Furthermore, exosomes ...from hypoxic progenitor cells exerted better therapeutic effects in organ injury through specific cargoes. However, there are no related reports about whether exosomes derived from MSCs or hypoxia‐preconditioned MSCs (PC‐MSCs) could prevent memory deficits in Alzheimer disease (AD). In this study, the exosomes derived from MSCs or PC‐MSCs were systemically administered to transgenic APP/PS1 mice. The expression of miR‐21 in MSCs was significantly increased after hypoxic treatment. Injection of exosomes from normoxic MSCs could rescue cognition and memory impairment according to results of the Morris water maze test, reduced plaque deposition, and Aβ levels in the brain; could decrease the activation of astrocytes and microglia; could down‐regulate proinflammatory cytokines (TNF‐α and IL‐1β); and could up‐regulate anti‐inflammatory cytokines (IL‐4 and ‐10) in AD mice, as well as reduce the activation of signal transducer and activator of transcription 3 (STAT3) and NF‐κB. Compared to the group administered exosomes from normoxic MSCs, in the group administered exosomes from PC‐MSCs, learning and memory capabilities were significantly improved; the plaque deposition and Aβ levels were lower, and expression of growth‐associated protein 43, synapsin 1, and IL‐10 was increased; and the levels of glial fibrillary acidic protein, ionized calcium‐binding adaptor molecule 1, TNF‐α, IL‐1β, and activation of STAT3 and NF‐κB were sharply decreased. More importantly, exosomes from PC‐MSCs effectively increased the level of miR‐21 in the brain of AD mice. Additionally, replenishment of miR‐21 restored the cognitive deficits in APP/PS1 mice and prevented pathologic features. Taken together, these findings suggest that exosomes from PC‐MSCs could improve the learning and memory capabilities of APP/PS1 mice, and that the underlying mechanism may lie in the restoration of synaptic dysfunction and regulation of inflammatory responses through regulation of miR‐21.—Cui, G.‐H., Wu, J., Mou, F.‐F., Xie, W.‐H., Wang, F.‐B., Wang, Q.‐L., Fang, J., Xu, Y.‐W., Dong, Y.‐R., Liu, J.‐R., Guo, H.‐D. Exosomes derived from hypoxia‐preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice. FASEB J. 32, 654–668 (2018). www.fasebj.org
An X-ray plateau followed by a steep decay ("internal plateau") has been observed in both long and short gamma-ray burst (GRBs), implying that a millisecond magnetar operates in some GRBs. The sharp ...decay at the end of the plateau, marking the abrupt cessation of the magnetar's central engine, has been considered the collapse of a supra-massive magnetar into a black hole (BH) when it spins down. If this "internal plateau" is indeed evidence of a magnetar central engine, the natural expectation in some candidates would be a signature from the newborn BH. In this work, we find that GRB 070110 is a particular case which shows a small X-ray bump following its "internal plateau." We interpret the plateau as a spin-down supra-massive magnetar and the X-ray bump as fallback BH accretion. This indicates that a newborn BH is likely active in some GRBs. Therefore, GRB 070110-like events may provide further support to the magnetar central engine model and enable us to investigate the properties of the magnetar as well as the newborn BH.
Metal binding to microbial extracellular polymeric substances (EPS) greatly influences the distribution of heavy metals in microbial aggregates, soil and aquatic systems in nature. In this work, the ...thermodynamic characteristics of the binding between aqueous metals (with copper ion as an example) and EPS of activated sludge were investigated. Isothermal titration calorimetry was employed to estimate the thermodynamic parameters for the binding of Cu2+ onto EPS, while three-dimensional excitation-emission matrix (EEM) fluorescence spectroscopy with parallel factor analysis was used for quantifying the complexation of Cu2+ with the EPS. The binding mechanisms were further explored by X-ray absorption fine structure (XAFS) and Fourier transform infrared (FTIR) spectroscopy analysis. The results show that the proteins and humic substances in EPS were both strong ligands for Cu2+. The binding capacity N, binding constant K, binding enthalpy ΔH were calculated as 5.74 × 10−2 mmol/g, 2.18 × 105 L/mol, and −11.30 kJ/mol, respectively, implying that such a binding process was exothermic and thermodynamically favorable. The binding process was found to be driven mainly by the entropy change of the reaction. A further investigation shows that Cu2+ bound with the oxygen atom in the carboxyl groups in the EPS molecules of activated sludge. This study facilitates a better understanding about the roles of EPS in protecting microbes against heavy metals.
Display omitted
► Thermodynamic characteristics of binding of Cu2+ to EPS are investigated. ► The binding process is exothermic and thermodynamically favorable. ► Cu2+ binds with the O atom in the carboxyl groups in EPS.
Background
High incidence of asymptomatic venous thromboembolism (VTE) has been observed in severe COVID‐19 patients, but the characteristics of symptomatic VTE in general COVID‐19 patients have not ...been described.
Objectives
To comprehensively explore the prevalence and reliable risk prediction for VTE in COVID‐19 patients.
Methods/Results
This retrospective study enrolled all COVID‐19 patients with a subsequent VTE in 16 centers in China from January 1 to March 31, 2020. A total of 2779 patients were confirmed with COVID‐19. In comparison to 23,434 non‐COVID‐19 medical inpatients, the odds ratios (ORs) for developing symptomatic VTE in severe and non‐severe hospitalized COVID‐19 patients were 5.94 (95% confidence interval CI 3.91–10.09) and 2.79 (95% CI 1.43–5.60), respectively. When 104 VTE cases and 208 non‐VTE cases were compared, pulmonary embolism cases had a higher rate for in‐hospital death (OR 6.74, 95% CI 2.18–20.81). VTE developed at a median of 21 days (interquartile range 13.25–31) since onset. Independent factors for VTE were advancing age, cancer, longer interval from symptom onset to admission, lower fibrinogen and higher D‐dimer on admission, and D‐dimer increment (DI) ≥1.5‐fold; of these, DI ≥1.5‐fold had the most significant association (OR 14.18, 95% CI 6.25–32.18, p = 2.23 × 10−10). A novel model consisting of three simple coagulation variables (fibrinogen and D‐dimer levels on admission, and DI ≥1.5‐fold) showed good prediction for symptomatic VTE (area under the curve 0.865, 95% CI 0.822–0.907, sensitivity 0.930, specificity 0.710).
Conclusions
There is an excess risk of VTE in hospitalized COVID‐19 patients. This novel model can aid early identification of patients who are at high risk for VTE.
Blood exosomes, which are extracellular vesicles secreted by living cells into the circulating blood, are regarded as a relatively noninvasive novel tool for monitoring brain physiology and disease ...states. An increasing number of blood cargo-loaded exosomes are emerging as potential biomarkers for preclinical and clinical Alzheimer's disease. Therefore, we conducted a meta-analysis and systematic review of molecular biomarkers derived from blood exosomes to comprehensively analyze their diagnostic performance in preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease. We performed a literature search in PubMed, Web of Science, Embase, and Cochrane Library from their inception to August 15, 2020. The research subjects mainly included Alzheimer's disease, mild cognitive impairment, and preclinical Alzheimer's disease. We identified 34 observational studies, of which 15 were included in the quantitative analysis (Newcastle-Ottawa Scale score 5.87 points) and 19 were used in the qualitative analysis. The meta-analysis results showed that core biomarkers including Aβ1-42, P-T181-tau, P-S396-tau, and T-tau were increased in blood neuron-derived exosomes of preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease patients. Molecules related to additional risk factors that are involved in neuroinflammation (C1q), metabolism disorder (P-S312-IRS-1), neurotrophic deficiency (HGF), vascular injury (VEGF-D), and autophagy-lysosomal system dysfunction (cathepsin D) were also increased. At the gene level, the differential expression of transcription-related factors (REST) and microRNAs (miR-132) also affects RNA splicing, transport, and translation. These pathological changes contribute to neural loss and synaptic dysfunction. The data confirm that the above-mentioned core molecules and additional risk-related factors in blood exosomes can serve as candidate biomarkers for preclinical and clinical Alzheimer's disease. These findings support further development of exosome biomarkers for a clinical blood test for Alzheimer's disease. This meta-analysis was registered at the International Prospective Register of Systematic Reviews (Registration No. CRD4200173498, 28/04/2020).
A hybrid photocatalytic assembly with Ni poly‐pyridine polymers binding on CdS quantum dots was developed via thiophene immobilization. The fabricated hybrid assembly facilitated efficient charge ...separation, and each component endowed great synergy. As a result, a high syngas production rate was achieved over 5500 μmol gcat−1 h−1 from photocatalytic CO2 reduction under visible‐light irradiation, accompanied by an adjustable H2/CO ratio ranging from 4 : 1 to 1 : 3. A novel hybrid assembly was described for syngas synthesis with boosted activity and controlled selectivity, which provides a profile to ingeniously understand molecular‐level design for photocatalysts.
CO2 to syngas: A hybrid photocatalyst is assembled by a Ni poly‐pyridine polymer binding on CdS substrate via vinyl‐thiophene towards photo‐reducing CO2 into syngas with tunable H2/CO ratio. Each component in the fabricated hybrid endows great synergy. It shows a robust activity, which is superior to reported results on semiconductor‐based photocatalysts.
DNA methylation (5-methylcytosine, 5-mC) is the best characterized epigenetic mark that has regulatory roles in diverse biological processes. Recent investigation of RNA modifications also raises the ...possible functions of RNA adenine and cytosine methylations on gene regulation in the form of “RNA epigenetics.” Previous studies demonstrated global DNA hypomethylation in tumor tissues compared to healthy controls. However, DNA and RNA methylation in circulating tumor cells (CTCs) that are derived from tumors are still a mystery due to the lack of proper analytical methods. In this respect, here we established an effective CTCs capture system conjugated with a combined strategy of sample preparation for the captured CTCs lysis, nucleic acids digestion, and nucleosides extraction in one tube. The resulting nucleosides were then further analyzed by liquid chromatography–electrospray ionization–tandem mass spectrometry (LC-ESI-MS/MS). With the developed method, we are able to detect DNA and RNA methylation (5-methyl-2′-deoxycytidine, 5-methylcytidine, and N 6-methyladenosine) in a single cell. We then further successfully determined DNA and RNA methylation in CTCs from lung cancer patients. Our results demonstrated, for the first time, a significant decrease of DNA methylation (5-methyl-2′-deoxycytidine) and increase of RNA adenine and cytosine methylations (N 6-methyladenosine and 5-methylcytidine) in CTCs compared with whole blood cells. The discovery of DNA hypomethylation and RNA hypermethylation in CTCs in the current study together with previous reports of global DNA hypomethylation in tumor tissues suggest that nucleic acid modifications play important roles in the formation and development of cancer cells. This work constitutes the first step for the investigation of DNA and RNA methylation in CTCs, which may facilitate uncovering the metastasis mechanism of cancers in the future.
Anoikis is a critical obstacle to cancer metastasis. Colorectal cancer (CRC) exhibits a high rate of metastasis, leading to death, and the mechanisms involved in anoikis resistance are still unclear. ...We identified that the fatty acid oxidation (FAO) pathway was activated in detached CRC cells. Multiple genes in the FAO pathway, specifically the rate-limiting enzyme CPT1A, were upregulated in CRC cells grown in suspension. Reactive oxygen species elimination mediated by CPT1A in CRC cells was vital to anoikis resistance. In vivo experiments showed that CPT1A-suppressed CRC cells colonized the lung at a much lower rate than normal CRC cells, suggesting that CPT1A-mediated FAO activation increased metastatic capacity. In clinical tissue specimens from CRC patients, elevated expression of CPT1A was observed in metastatic sites compared with primary sites. Our results demonstrate that CPT1A-mediated FAO activation induces CRC cells to resist anoikis, suggesting that CPT1A is an attractive target for treating metastatic CRC.
Abstract A supermassive black hole can launch a relativistic jet when it violently disrupts a star that passes too close. Such jetted tidal disruption events (TDEs) are rare and unique tools to ...investigate quiescent supermassive black holes, jet physics, and circumnuclear environments at high redshift. The newly discovered TDE AT2022cmc ( z ∼ 1.193), providing rich multiband (X-ray, UV, optical, submillimeter, and radio) data, has been interpreted as the fourth on-axis jetted TDE. In this work, we constrain the circumnuclear medium (CNM) density profile with both a closure relation test and detailed forward shock model fit with a Markov Chain Monte Carlo approach to the multiband (optical, submillimeter, and radio) data of AT2022cmc. We find that the CNM density profile of AT2022cmc is n ∝ R − k with k ∼ 1.68, implying a Bondi accretion in history. Furthermore, our model fit result suggests a two-component jet in AT2022cmc, indicating similar jet physics to well-studied jetted TDE Sw J1644+57.
PDF
