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
Background
The impacts of chronic airway diseases on coronavirus disease 2019 (COVID‐19) are far from understood.
Objective
To explore the influence of asthma and chronic obstructive pulmonary ...disease (COPD) comorbidity on disease expression and outcomes, and the potential underlying mechanisms in COVID‐19 patients.
Methods
A total of 961 hospitalized COVID‐19 patients with a definite clinical outcome (death or discharge) were retrospectively enrolled. Demographic and clinical information were extracted from the medical records. Lung tissue sections from patients suffering from lung cancer were used for immunohistochemistry study of angiotensin‐converting enzyme II (ACE2) expression. BEAS‐2B cell line was stimulated with various cytokines.
Results
In this cohort, 21 subjects (2.2%) had COPD and 22 (2.3%) had asthma. After adjusting for confounding factors, COPD patients had higher risk of developing severe illness (OR: 23.433; 95% CI 1.525‐360.135; P < .01) and acute respiratory distress syndrome (OR: 19.762; 95% CI 1.461‐267.369; P = .025) than asthmatics. COPD patients, particularly those with severe COVID‐19, had lower counts of CD4+ T and CD8+ T cells and B cells and higher levels of TNF‐α, IL‐2 receptor, IL‐10, IL‐8, and IL‐6 than asthmatics. COPD patients had increased, whereas asthmatics had decreased ACE2 protein expression in lower airways, compared with that in control subjects without asthma and COPD. IL‐4 and IL‐13 downregulated, but TNF‐α, IL‐12, and IL‐17A upregulated ACE2 expression in BEAS‐2B cells.
Conclusion
Patients with asthma and COPD likely have different risk of severe COVID‐19, which may be associated with different ACE2 expression.
After adjusting for confounding factors, COVID‐19 patients with COPD have higher risks of developing severe illness and acute respiratory distress syndrome than COVID‐19 patients with asthma. COPD patients have increased, whereas asthmatics have decreased ACE2 protein expression in lower airways, compared with that in control subjects without asthma and COPD. IL‐17A, TNF‐α, and IL‐12 promote, while IL‐4 and IL‐13 suppress ACE2 expression in airway BEAS‐2B cells. Abbreviations: ACE2, angiotensin‐converting enzyme II; ARDS, acute respiratory distress syndrome; BEAS‐2B, adenovirus‐12 SV40 hybrid virus transformed bronchial epithelial cells; COPD, chronic obstructive pulmonary disease; COVID‐19, coronavirus disease 2019.
Exosomes are lipid-bilayer enclosed nano-sized vesicles that transfer functional cellular proteins, mRNA and miRNAs. Mesenchymal stem cells (MSCs) derived exosomes have been demonstrated to prevent ...memory deficits in the animal model of Alzheimer's disease (AD). However, the intravenously injected exosomes could be abundantly tracked in other organs except for the targeted regions in the brain. Here, we proposed the use of central nervous system-specific rabies viral glycoprotein (RVG) peptide to target intravenously-infused exosomes derived from MSCs (MSC-Exo) to the brain of transgenic APP/PS1 mice. MSC-Exo were conjugated with RVG through a DOPE-NHS linker.
RVG-tagged MSC-Exo exhibited improved targeting to the cortex and hippocampus after being administered intravenously. Compared with the group administered MSC-Exo, in the group administered RVG-conjugated MSC-Exo (MSC-RVG-Exo) plaque deposition and Aβ levels were sharply decreased and activation of astrocytes was obviously reduced. The brain targeted exosomes derived from MSCs was better than unmodified exosomes to improve cognitive function in APP/PS1 mice according to Morris water maze test. Additionally, although MSC-Exo injected intravenously reduced the expression of pro-inflammatory mediators TNF-α, IL-β, and IL-6, but the changes of anti-inflammatory factors IL-10 and IL-13 were not obvious. However, administration of MSC-RVG-Exo significantly reduced the levels of TNF-α, IL-β, and IL-6 while significantly raised the levels of IL-10, IL-4 and IL-13.
Taken together, our results demonstrated a novel method for increasing delivery of exosomes for treatment of AD. By targeting exosomes to the cortex and hippocampus of AD mouse, there was a significant improvement in learning and memory capabilities with reduced plaque deposition and Aβ levels, and normalized levels of inflammatory cytokines.
The carbon dioxide (CO2) capture and utilization has attracted a great attention in organic synthesis. Herein, an unpresented transient stabilization effect (TSE) of CO2 is disclosed and well applied ...to the electrochemical hydrogenation of azo compounds to hydrazine derivatives. Mechanistic experiments and computational studies imply that CO2 can capture azo radical anion intermediates to protect the hydrogenation from potential degradation reactions, and is finally released through decarboxylation. The promotion effect of CO2 was further demonstrated to work in the preliminary study of electrochemical reductive coupling of α‐ketoesters to vicinal diol derivatives. For the electrochemical reductive reactions mentioned above, CO2 is indispensable. The presented results shed light on a different usage of CO2 and could inspire novel experimental design by using CO2 as a transient protecting group.
A new transient stabilization effect (TSE) of CO2 is identified and applied to the electrochemical hydrogenation of azo compounds and the reductive coupling of α‐ketoesters. The TSE influence of CO2 means that overactive intermediates can be captured by CO2 to prevent their decomposition or side reaction to complete the synthesis that is difficult to achieve by direct means. The CO2 can be released later through a decarboxylation process.
Systems with non-Hermitian skin effects are very sensitive to the imposed boundary conditions and lattice size, and thus an important question is whether non-Hermitian skin effects can survive when ...deviating from the open boundary condition. To unveil the origin of boundary sensitivity, we present exact solutions for one-dimensional non-Hermitian models with generalized boundary conditions and study rigorously the interplay effect of lattice size and boundary terms. Besides the open boundary condition, we identify the existence of non-Hermitian skin effect when one of the boundary hopping terms vanishes. Apart from this critical line on the boundary parameter space, we find that the skin effect is fragile under any tiny boundary perturbation in the thermodynamic limit, although it can survive in a finite size system. Moreover, we demonstrate that the non-Hermitian Su-Schreieffer-Heeger model exhibits a new phase diagram in the boundary critical line, which is different from either open or periodical boundary case.
Defective spectral degeneracy, known as exceptional point (EP), lies at the heart of various intriguing phenomena in optics, acoustics, and other nonconservative systems. Despite extensive studies in ...the past two decades, the collective behaviors (e.g., annihilation, coalescence, braiding, etc.) involving multiple exceptional points or lines and their interplay have been rarely understood. Here we put forward a universal non-Abelian conservation rule governing these collective behaviors in generic multiband non-Hermitian systems and uncover several counterintuitive phenomena. We demonstrate that two EPs with opposite charges (even the pairwise created) do not necessarily annihilate, depending on how they approach each other. Furthermore, we unveil that the conservation rule imposes strict constraints on the permissible exceptional-line configurations. It excludes structures like Hopf link yet permits novel staggered rings composed of noncommutative exceptional lines. These intriguing phenomena are illustrated by concrete models which could be readily implemented in platforms like coupled acoustic cavities, optical waveguides, and ring resonators. Our findings lay the cornerstone for a comprehensive understanding of the exceptional non-Abelian topology and shed light on the versatile manipulations and applications based on exceptional degeneracies in nonconservative systems.
Hadal trenches are the deepest and most remote regions of the ocean. The 11-kilometer deep Challenger Deep is the least explored due to the technical challenges of sampling hadal depths. It receives ...organic matter and heavy metals from the overlying water column that accumulate differently across its V-shaped topography. Here, we collected sediments across the slope and bottom-axis of the Challenger Deep that enable insights into its in situ microbial communities. Analyses of 586 metagenome-assembled genomes retrieved from 37 metagenomes show distinct diversity and metabolic capacities between bottom-axis and slope sites. 26% of prokaryotic 16S rDNA reads in metagenomes were novel, with novelty increasing with water and sediment depths. These predominantly heterotrophic microbes can recycle macromolecules and utilize simple and complex hydrocarbons as carbon sources. Metagenome and metatranscriptome data support reduction and biotransformation of arsenate for energy gain in sediments that present a two-fold greater accumulation of arsenic compared to non-hadal sites. Complete pathways for anaerobic ammonia oxidation are predominantly identified in genomes recovered from bottom-axis sediments compared to slope sites. Our results expand knowledge of microbially-mediated elemental cycling in hadal sediments, and reveal differences in distribution of processes involved in nitrogen loss across the trench.
Coronavirus disease 2019 (COVID-19) has spread rapidly in China and other overseas areas, which has aroused widespread concern. The sharp increase in the number of patients has led to great ...psychological pressure on health care workers. The purpose of this study was to understand their mental health status and needs, so as to provide a scientific basis for alleviating the psychological pressure of health care workers.
Using a cross-sectional study design, 540 health care workers were randomly selected from two designated tuberculosis medical institutions in Anhui Province. The basic situation, perceived social support, depression level, loneliness and COVID-19 related knowledge were collected and analyzed by questionnaire.
A total of 511 valid questionnaires were finally retrieved. There were 139 people in epidemic prevention and control positions (27.20%). Depression level: People in isolation ward, fever clinic and pre-check triage were at the level of mild to moderate depression. Female was higher than male; nurse was higher than doctor; middle and junior job titles were higher than senior titles; junior college degree or below were higher than bachelor's degree, master's degree and above; isolation ward, fever clinic and pre-check triage were significantly higher than those of non-prevention and control positions (p < 0.05). Loneliness scores: Doctors were higher than that of medical technicians, and isolation ward, fever clinic and pre-check triage were higher than those of other medical departments (p < 0.05). Social support: Doctors were lower than that of medical technicians, and isolation ward, fever clinic and pre-check triage were significantly lower than those of other departments (p < 0.05). The score of social support was negatively correlated with depression and loneliness (p < 0.001), while depression was positively correlated with loneliness (p < 0.001). Health care workers most want to receive one-to-one psychological counseling (29.75%), and provide crisis management (24.07%). The awareness rate of health care workers on COVID-19's knowledge was relatively high.
The psychological problems of health care workers, especially women, nurses with low educational background, low professional title, and staff in the epidemic prevention and control positions are relatively serious.
There are no global screening recommendations for esophageal squamous cell carcinoma (ESCC). Endoscopic screening has been investigated in areas of high incidence in China since the 1970s. This study ...aimed to evaluate whether an endoscopic screening and intervention program could reduce mortality caused by ESCC.
Residents age 40 to 69 years were recruited from communities with high rates of ESCC. Fourteen villages were selected as the intervention communities. Ten villages not geographically adjacent to intervention villages were selected for comparison. Participants in the intervention group were screened once by endoscopy with Lugol's iodine staining, and those with dysplasia or occult cancer were treated. All intervention participants and a sample consisting of one tenth of the control group completed questionnaires. We compared cumulative ESCC incidence and mortality between the two groups.
Three thousand three hundred nineteen volunteers (48.62%) from an eligible population of 6,827 were screened in the intervention group. Seven hundred ninety-seven volunteers from an eligible population of 6,200 in the control group were interviewed. Six hundred fifty-two incident and 542 fatal ESCCs were identified during the 10-year follow-up. A reduction in cumulative mortality in the intervention group versus the control group was apparent (3.35% v 5.05%, respectively; P < .001). Furthermore, the intervention group had a significantly lower cumulative incidence of ESCC versus the control group (4.17% v 5.92%, respectively; P < .001).
We showed that endoscopic screening and intervention significantly reduced mortality caused by esophageal cancer. Detection and treatment of preneoplastic lesions also led to a reduction in the incidence of this highly fatal cancer.
CRISPR/Cas system has become one of the most powerful techologies in biomedical research, and has showed great potentials in the gene related diseases. However, efficient delivery systems of ...CRISPR/Cas to target cells remains challenging. In recent years, nanoparticles have showned great potentials for the delivery of CRISPR/Cas systems. This paper mainly approaches the development and new strategies of CRISPR/Cas delivery systems, as well as their application in the clinical diseases. By summarizing the CRISPR/Cas systems delivery, new strategies are expected for the gene therapy.
Editorial space: The CRISPR/Cas gene editing system relies on a delivery system to enter the cell so that it can perform its editing function. The CRISPR/Cas9 system can be packaged into viral or non‐viral vectors, which can be expressed in host cells and exert gene editing functions. The combination of nanoparticles and different vectors can promote the delivery of gene editing machinery.
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