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Abstract Background Chronic hypoxia and skeletal muscle atrophy commonly coexist in patients with COPD and CHF, yet the underlying physio‐pathological mechanisms remain elusive. Muscle regeneration, driven by muscle stem cells (MuSCs), holds therapeutic potential for mitigating muscle atrophy. This study endeavours to investigate the influence of chronic hypoxia on muscle regeneration, unravel key molecular mechanisms, and explore potential therapeutic interventions. Methods Experimental mice were exposed to prolonged normobaric hypoxic air (15% pO2, 1 atm, 2 weeks) to establish a chronic hypoxia model. The impact of chronic hypoxia on body composition, muscle mass, muscle strength, and the expression levels of hypoxia‐inducible factors HIF‐1α and HIF‐2α in MuSC was examined. The influence of chronic hypoxia on muscle regeneration, MuSC proliferation, and the recovery of muscle mass and strength following cardiotoxin‐induced injury were assessed. The muscle regeneration capacities under chronic hypoxia were compared between wildtype mice, MuSC‐specific HIF‐2α knockout mice, and mice treated with HIF‐2α inhibitor PT2385, and angiotensin converting enzyme (ACE) inhibitor lisinopril. Transcriptomic analysis was performed to identify hypoxia‐ and HIF‐2α‐dependent molecular mechanisms. Statistical significance was determined using analysis of variance (ANOVA) and Mann–Whitney U tests. Results Chronic hypoxia led to limb muscle atrophy (EDL: 17.7%, P

Exosomes are found in various tissues of the body and carry abundant contents including nucleic acids, proteins, and metabolites, which continuously flow between cells of various tissues and mediate important intercellular communication. In addition, exosomes from different cellular sources possess different physiopathological immunomodulatory effects, which are closely related to the immune regeneration of normal or abnormal organs and tissues. Here, we focus on the mechanistic interactions between exosomes and the human immune system, introduce the immuno-regenerative therapeutic potential of exosomes in common clinical immune-related diseases, such as infectious diseases, autoimmune diseases, and tumors, and reveal the safety and efficacy of exosomes as a novel cell-free immune regenerative therapy.

Exosomes are small disk-shaped extracellular vesicles (EVs) that are naturally released into the environment by different types of cells. Exosomes range from 30-150 nm in size and contain complex RNA and proteins. They are widely found in body fluids such as blood, saliva, urine and breast milk and participate in cell communication by functioning as cell messengers. Almost all cell types can transmit information and exchange substances through the production and release of exosomes to regulate proliferation, differentiation, apoptosis, the immune response, inflammation, and other biological functions. Because exosomes exist widely in various body fluids, they are easy to obtain and detect and have the potential for use in disease diagnosis and prognosis detection. Exosomes can be genetically fused with targeted proteins, enhancing their biocompatibility and immunogenicity. Therefore, exosomes are the preferred vector tools for vaccines. In this review, we describe the characteristics of exosomes and discuss their unique and ambiguous functions in the immune microenvironment after infection. In this regard, we explored the ability of exosomes to carry immunogenic virus antigens and to establish adaptive immune responses. Exosomes can provide an interesting platform for antigen presentation and since vaccines are a powerful method for the prevention of infectious diseases, we further review the advantages and disadvantages of the use of exosomes in vaccine preparation. Overall, exosomes are emerging as a promising avenue for vaccine development.

Abstract T cells engineered to express chimeric antigen receptors (CARs) with specificity toward tumor cells have led to promising outcomes in patients with hematological malignancies. Nevertheless, the application of CAR‐T cell therapy in solid tumors encounters several obstacles. These include tumor heterogeneity and immune escape, T cell exhaustion and restricted infiltration into the tumors that affect the therapeutic efficacy of CAR‐T cells, as well as “on‐target, off‐tumor” toxicities that can lead to severe and even fatal adverse events. In recent years, clinical trials and new approaches of CAR‐T cell therapy for solid tumors have made certain progress. Here, we update the outcomes of related clinical trials and summarize engineered strategies aiming to improve the efficacy and therapeutic safety of CAR‐T cells based on experimental and clinical studies.

Exosomes are small extracellular vesicles (sEVs) secreted by cells. With advances in the study of sEVs, they have shown great potential in the diagnosis and treatment of disease. However, sEV therapy usually requires a certain dose and purity of sEVs to achieve the therapeutic effect, but the existing sEV purification technology exists in the form of low yield, low purity, time-consuming, complex operation and many other problems, which greatly limits the application of sEVs. Therefore, how to obtain high-purity and high-quality sEVs quickly and efficiently, and make them realize large-scale production is a major problem in current sEV research. This paper discusses how to improve the purity and yield of sEVs from the whole production process of sEVs, including the upstream cell line selection and cell culture process, to the downstream isolation and purification, quality testing and the final storage technology.

Unlike most studies on urban innovation, which focus on the effects of land-use policies, this study investigates the effect of urban innovation (UI) on land finance dependence (LFD). In China, innovation-related policies are intended to create a shared business environment where new entrepreneurs can contribute to achieving sustainable economic growth. This study analyzes the spatiotemporal dynamics of LFD and UI from 2005 to 2019 using the spatial autocorrelation model and dynamic spatial Durbin model. It finds a positive spatial association between LFD and UI throughout the studied regions during the study period. It also reveals a significant inhibitory effect of UI on LFD and a negative impact on the LFD of neighbouring cities. Moreover, the inhibitory effects will increase over time. Lastly, this study shows varied impacts of UI on LFD in different regions, especially in eastern China. Important policy recommendations for high-quality development in China are provided.

Abstract Extracellular vesicles (EVs) facilitate the extracellular transfer of proteins, lipids, and nucleic acids and mediate intercellular communication among multiple cells in the tumour environment. Small extracellular vesicles (sEVs) are defined as EVs range in diameter from approximately 50 to 150 nm. Tumour-derived sEVs (TDsEVs) and immune cell-derived sEVs have significant immunological activities and participate in cancer progression and immune responses. Cancer-specific molecules have been identified on TDsEVs and can function as biomarkers for cancer diagnosis and prognosis, as well as allergens for TDsEVs-based vaccination. Various monocytes, including but not limited to dendritic cells (DCs), B cells, T cells, natural killer (NK) cells, macrophages, and myeloid-derived suppressor cells (MDSCs), secrete sEVs that regulate immune responses in the complex immune network with either protumour or antitumour effects. After engineered modification, sEVs from immune cells and other donor cells can provide improved targeting and biological effects. Combined with their naïve characteristics, these engineered sEVs hold great potential as drug carriers. When used in a variety of cancer therapies, they can adjunctly enhance the safety and antitumor efficacy of multiple therapeutics. In summary, both naïve sEVs in the tumour environment and engineered sEVs with effector cargoes are regarded as showing promising potential for use in cancer diagnostics and therapeutics.

IntroductionThe effect of elevated luteinizing hormone (LH) on the clinical outcomes of ovulation induction (OI) in infertile anovulatory patients with polycystic ovary syndrome (PCOS) remains controversial. This retrospective study included PCOS patients undergoing intrauterine insemination (IUI) following letrozole (LE) stimulation without OC pretreatment.Materials and methodsA retrospective cohort analysis was conducted in a single, academic ART center from January 2013 to May 2019. In total, 835 IUI cycles of PCOS patients treated with letrozole were collected for the analysis. Cohorts were separated based on the level of basal LH (bLH) and LH level after letrozole administration (LHle) during OI. OI response and reproductive outcomes were evaluated for each cohort.ResultsNo adverse effects of dysregulated levels of either bLH or LHle on ovulation rate or reproductive outcomes were observed. Furthermore, the cohort of individuals with normal bLH and high LHle levels, exclusive of LH surge, exhibited significantly higher rates of clinical pregnancy (30.3% vs. 17.3%, p = 0.002) and live birth (24.2% vs. 15.2%, p = 0.024) than those with normal bLH and normal LHle.ConclusionThese results indicated that high LH levels in PCOS are not solid evidence of poor prognosis of letrozole-induced ovulation, while elevated LHle may be a prospective predictor for better OI outcomes. It seems that preinhibition of LH secretion is not needed.

SARS coronavirus 2 (SARS-CoV-2) invades the human body by binding to major receptors such as ACE2 via its S-spike protein, so the interaction of receptor-binding sites has been a hot topic in the development of coronavirus drugs. At present, the clinical progress in monoclonal antibody therapy that occurred early in the pandemic is gradually showing signs of slowing. While recombinant soluble ACE2, as an alternative therapy, has been modified by many engineering methods, both the safety and functional aspects are approaching maturity, and this therapy shows great potential for broadly neutralizing coronaviruses, but its progress in clinical development remains stalled. Therefore, there are still several key problems to be considered and solved for recombinant soluble ACE2 to be approved as a clinical treatment as soon as possible.

Abstract The world is experiencing one of the most difficult moments in history with COVID‐19, which has rapidly developed into a worldwide pandemic with a significant health and economic burden. Efforts to fight the virus, including prevention and treatment, have never stopped. However, no specific drugs or treatments have yet been found. Antibody drugs have never been absent in epidemics such as SARS, MERS, HIV, Ebola, and so on in the past two decades. At present, while research on the SARS‐CoV‐2 vaccine is in full swing, antibody drugs are also receiving widespread attention. Several antibody drugs have successfully entered clinical trials and achieved impressive therapeutic effects. Here, we summarize the therapeutic antibodies against SARS‐CoV‐2, as well as the research using ACE2 recombinant protein or ACE2‐Ig fusion protein.

Compared with traditional roofing, green roofs (GRs) have quantifiable environmental and economic benefits, yet limited research exists on GR plant survival, maintenance practices, and costs related to plant performance. The objective of this study was to assess plant cover, site conditions, and maintenance practices on 10 extensive GRs in the Research Triangle Area of North Carolina. Green roof maintenance professionals were surveyed to assess plant performance, maintenance practices, and maintenance costs. Vegetation cover on each site was characterized. Relationships among plant performance and environmental and physical site characteristics, and maintenance practices were evaluated. Survey respondents ranked weed control as the most problematic maintenance task, followed by irrigation, pruning, and debris removal. No single design or maintenance factor was highly correlated with increased plant cover. Green roof age, substrate organic matter, and modular planting methods were not correlated with greater plant cover. Results showed a trend that irrigation increased plant cover. Plants persisting on GRs included several species of stonecrop (Sedum sp.), but flame flower (Talium calycinum) and ice plant (Delosperma basuticum) were also present in high populations on at least one roof each. Green roof maintenance costs ranged from $0.13/ft2 to $3.45/ft2 per year, and were greater on sites with more weeds and frequent hand watering.

SARS-CoV-2 uses ACE2 as the entry receptor. Here, the authors show that an ACE2-Ig fusion protein inhibits entry of virus pseudotyped with the SARS-CoV-2 spike protein, show differential binding kinetics of SARS-CoV and SARSCoV-2 spike proteins to ACE2, and determine pharmakocinetic parameters of ACE2-Ig in mice.

Abstract Methods and experiments In this study, a functionalized multiwalled carbon nanotube (MWCNT)-coated solid-phase microextraction (SPME) fiber was developed for concentrating analytes in aqueous samples. Sodium deoxycholate (NaDC) was used as a dispersing agent for non-covalent modification of MWCNTs. The coating showed porous structure and large adsorption capacity. To investigate the capability of this MWCNTs/NaDC SPME fiber, it was applied to the analysis of phenols in aqueous solution. After extraction, the analytes were desorbed in an acetonitrile–water solution and analyzed using high-performance liquid chromatography. Results The MWCNTs/NaDC fiber exhibited good analytical performance, and fine preparation reproducibility was obtained with the relative standard deviations (RSDs) ranging from 4.9% to 10.2% (n = 6) in one batch, from 5.7% to 11.9% (n = 3) among different batches. Under the optimum extraction conditions, the detection limits were 0.15–0.30 ng/mL(S/N = 3), the linear detection ranges were 1–100 ng/mL (R2 ≥ 0.9997) for these analytes, and good recoveries (80.3–95.4%) were obtained for the spiked samples. Conclusion This is a simple and accurate pretreatment method for the analysis of phenols in aqueous samples.

Targeted therapeutics for the treatment of coronavirus disease 2019 (COVID-19), especially severe cases, are currently lacking. As macrophages have unique effector functions as a first-line defense against invading pathogens, we genetically armed human macrophages with chimeric antigen receptors (CARs) to reprogram their phagocytic activity against SARS-CoV-2. After investigation of CAR constructs with different intracellular receptor domains, we found that although cytosolic domains from MERTK (CARMERTK) did not trigger antigen-specific cellular phagocytosis or killing effects, unlike those from MEGF10, FcRγ and CD3ζ did, these CARs all mediated similar SARS-CoV-2 clearance in vitro. Notably, we showed that CARMERTK macrophages reduced the virion load without upregulation of proinflammatory cytokine expression. These results suggest that CARMERTK drives an ‘immunologically silent’ scavenger effect in macrophages and pave the way for further investigation of CARs for the treatment of individuals with COVID-19, particularly those with severe cases at a high risk of hyperinflammation.

Genetically engineered T cells expressing a chimeric antigen receptor (CAR-T cells) are a promising new treatment for cancer, but are associated with unique toxicities. Here, the authors test CAR-T-cell-derived exosomes as a surrogate for CAR-T cells and show that they can elicit a potent antitumour immune response in preclinical models of breast cancer with reduced signs of cytokine release syndrome compared with CAR-T therapy.

The perfect synchronization of maternal immune-endocrine mechanisms and those of the fetus is necessary for a successful pregnancy. In this report, decidual immune cells at the maternal-fetal interface were detected that expressed TIGIT (T cell immunoreceptor with Ig and ITIM domains), which is a co-inhibitory receptor that triggers immunological tolerance. We generated recombinant TIGIT-Fc fusion proteins by linking the extracellular domain of TIGIT and silent Fc fragments. The treatment with TIGIT-Fc of human decidual antigen presenting cells (APCs), the decidual dendritic cells (dDCs), and decidual macrophages (dMϕs) increased the production of interleukin 10 and induced the decidua APCs to powerfully polarize the decidual CD4+ T cells toward a classic TH2 phenotype. We further proposed that Notch signaling shows a pivotal effect on the transcriptional regulation in decidual immune cell subsets. Moreover, the administration of TIGIT-Fc to CBA/J pregnant mice at preimplantation induced CD4+ forkhead box P3+ (Foxp3+) regulatory T cells and tolerogenic dendritic cells and increased pregnancy rates in an abortion-prone animal model stress. The results suggested the therapeutic potential of the TIGIT-Fc fusion protein in reinstating immune tolerance in failing pregnancies.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multiple autoantibody production and often affects the kidneys, known as lupus nephritis. However, the mechanism underlying lupus nephritis development is unclear. Biofilms that protect bacteria from stress are ubiquitous in almost every environment. Here, we identified that a conserved peptide (HU1) derived from DNABII proteins, one of major bacterial biofilm components, was specifically recognized by sera from about 47% patients with SLE. Moreover, the serum anti-HU1 levels showed a significant positive correlation with lupus nephritis occurrence. Presence of antibodies against HU1 in pristane-induced mice aggravated lupus nephritis, although these antibodies also attenuated bacterial biofilm formation. We further identified that antibodies against HU1 cross-recognized protein disulfide isomerase (P4HB) located on the renal cell surface and inhibited the activities of this enzyme. Our findings reveal a novel mechanism underlying the development of lupus nephritis triggered by bacterial biofilms.

Stem cells have the unique capacity to differentiate into many cell types during embryonic development and postnatal growth. Through coordinated cellular behaviors (self-renewal, proliferation, and differentiation), stem cells are also pivotal to the homeostasis, repair, and regeneration of many adult tissues/organs and thus of great importance in regenerative medicine. Emerging evidence indicates that mitochondria are actively involved in the regulation of stem cell behaviors. Mitochondria undergo specific dynamics (biogenesis, fission, fusion, and mitophagy) during stem cell self-renewal, proliferation, and differentiation. The alteration of mitochondrial dynamics, fine-tuned by stem cell niche factors and stress signaling, has considerable impacts on stem cell behaviors. Here, we summarize the recent research progress on (1) how mitochondrial dynamics controls stem cell behaviors, (2) intrinsic and extrinsic factors that regulate mitochondrial dynamics, and (3) pharmacological regulators of mitochondrial dynamics and their therapeutic potential. This review emphasizes the metabolic control of stemness and differentiation and may shed light on potential new applications in stem cell-based therapy.

For indoor mobile robots, many localization systems based on wireless sensor network have been reported. Received signal strength indicator is often used for distance measurement. However, the value of received signal strength indicator always has large fluctuation because radio signal is easily influenced by environmental factors. This will bring adverse effect on the distance measurement and deteriorate the performance of robot localization. In this article, the measured data are dealt with weighted recursive filter, which can depress the measurement noise effectively. In the linearization procedure, the least square method often causes additional error because it seriously relies on anchor nodes. Therefore, a minimum residual localization algorithm based on particle swarm optimization is proposed for a mobile robot running in indoor environment. With continuous optimization and update of particle swarm, the position that gets the best solution of objective function can be adopted as the final estimated position. Experiment results show that the proposed algorithm, compared with traditional algorithms, can attain better localization accuracy and is closer to Cramer–Rao lower bound.

In pertinence to the application of multidimensional scaling (MDS) methods in ranging-based positioning systems, an analysis is firstly conducted by the classical MDS algorithm. Modified MDS algorithm and subspace method are presented in localization application. We also depicted the unified framework and general solutions of MDS methods. However, the least square solutions under this framework are not optimal. Their performance is still related to selection of coordinate reference points. To address this problem, a minimum residual MDS algorithm based on particle swarm optimization (PSO) is proposed to derive a new solution for indoor robot localization under the unified framework. The result of analysis indicates that the performance of minimum residual MDS method is immune to selection of reference points. Furthermore, the localization accuracy for indoor robot has been enhanced by 41% as compared with the classical MDS algorithm.

With the development of the wireless communication technology and intelligent mobile phone, the positioning services based on Wi-Fi and mobile phone are increasingly demanded. In this paper, a Wi-Fi fingerprint localization method is proposed on the basis of important access points (IAP). For the Wi-Fi fingerprint, Wi-Fi access point with the highest received signal strength (RSS) is denoted as the important access point. At the localization stage, the fingerprints are chosen with the same IAP as the estimated fingerprint from the database. Then, the distance and the AP repetition of the fingerprints are used to calculate the similarity degree. The location of the fingerprint which matches the estimated fingerprint well can be regarded as the estimated location. Experimental results show that the proposed algorithm can achieve high accuracy in indoor environment.

In recent years, collinearity theory is widely used in large-scale sensor network. When the anchor nodes are located at almost a straight line, the collinearity phenomenon will happen and usually cause negative influence on positioning accuracy. From detailed analysis of the relation between DV-Hop localization error and the collinearity, we proposed to select the anchor nodes which can meet the condition of hop count threshold and collinearity to participate in the localization procedure. Since there is uncertain situation that the anchor node's region is hard to be decided for the sensor nodes in one hop area, Voronoi diagram is adopted to divide the sensor network into several regions. Then, we can get the anchor node information in each Voronoi polygon. With this information and the collinearity condition, we can estimate the unknown node's position with relatively higher accuracy. Compared with the traditional DV-Hop and collinearity algorithm, our proposed algorithm can get better positioning accuracy in both homogeneous network and anisotropic network.

In wireless sensor networks (WSN), the geometric distribution of anchor nodes has a significant influence on the positioning accuracy. Geometric dilution of precision (GDOP) can be used to measure the positioning precision of the localization system. In order to select the optimal node combination, traditional algorithms based on GDOP need to spend much time on calculating every possible combination of nodes. This paper proposes GDOP assisted nodes selection (GANS) algorithm to calculate GDOP value of the current geometric distribution. Sensor node's contribution to the overall GDOP value is adopted as the evaluation criteria. The nodes whose contribution value is greater than the threshold will be selected. The anchor nodes subset, which participates in the positioning, will be real-time determined. Simulation results show that the GANS algorithm can effectively reduce the energy consumption of the system, while the positioning accuracy has no obvious loss. Meanwhile, computational complexity is also obviously decreased.