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Severe sleep deprivation (SD) has been highly associated with systemic energy wasting, such as lipid loss and glycogen depletion. Despite immune dysregulation and neurotoxicity observed in SD animals, whether and how the gut-secreted hormones participate in SD-induced disruption of energy homeostasis remains largely unknown. Using Drosophila as a conserved model organism, we characterize that production of intestinal Allatostatin A (AstA), a major gut-peptide hormone, is robustly increased in adult flies bearing severe SD. Interestingly, the removal of AstA production in the gut using specific drivers significantly improves lipid loss and glycogen depletion in SD flies without affecting sleep homeostasis. We reveal the molecular mechanisms whereby gut AstA promotes the release of an adipokinetic hormone (Akh), an insulin counter-regulatory hormone functionally equivalent to mammalian glucagon, to mobilize systemic energy reserves by remotely targeting its receptor AstA-R2 in Akh-producing cells. Similar regulation of glucagon secretion and energy wasting by AstA/galanin is also observed in SD mice. Further, integrating single-cell RNA sequencing and genetic validation, we uncover that severe SD results in ROS accumulation in the gut to augment AstA production via TrpA1. Altogether, our results demonstrate the essential roles of the gut-peptide hormone AstA in mediating SD-associated energy wasting.

Protein structure affects allergenicity, and critical structural elements, especially conformational epitopes that determine allergenicity, have attracted a great deal of interest. In this study, we aimed to identify the localized structure that affects the potential allergenicity of protein by making targeted modifications of Ara h 2 and comparing the structure and allergenicity of mutants with those of the wide-type allergen. The structures of the allergen and its mutants were characterized by circular dichroism and ultraviolet absorption spectroscopy and simulated by molecular dynamics. The allergenicity was assessed by Western blotting, an indirect competitive enzyme-linked immunosorbent assay, a cell model, and a mouse model. Then, the structures that affect allergenicity were analyzed and screened. Our results showed that mutations in amino acids changed the nearby localized structure and the overall structures. The structural changes affected the IgE binding capacity of the allergen and reduced its potential allergenicity. The solvent accessible surface area (SASA) of aromatic residues was positively correlated with the IgE binding capacity. The integrity of the disulfide bond is also critical for the binding of IgE to allergens. Interestingly, different mutations induced similar electrostatic potential and allergenicity changes, such as localized structure R

BackgroundDisruption of the autonomic nervous system (ANS) can lead to acute coronary syndrome (ACS). We developed a nomogram model using heart rate variability (HRV) and other data to predict major adverse cardiovascular events (MACEs) following emergency coronary angiography in patients with ACS.MethodsACS patients admitted from January 2018 to June 2020 were examined. Holter monitors were used to collect HRV data for 24 h. Coronary angiograms, clinical data, and MACEs were recorded. A nomogram was developed using the results of Cox regression analysis.ResultsThere were 439 patients in a development cohort and 241 in a validation cohort, and the mean follow-up time was 22.80 months. The nomogram considered low-frequency/high-frequency ratio, age, diabetes, previous myocardial infarction, and current smoking. The area-under-the-curve (AUC) values for 1-year MACE-free survival were 0.790 (95% CI: 0.702–0.877) in the development cohort and 0.894 (95% CI: 0.820–0.967) in the external validation cohort. The AUCs for 2-year MACE-free survival were 0.802 (95% CI: 0.739–0.866) in the development cohort and 0.798 (95% CI: 0.693–0.902) in the external validation cohort. Development and validation were adequately calibrated and their predictions correlated with the observed outcome. Decision curve analysis (DCA) showed the model had good discriminative ability in predicting MACEs.ConclusionOur validated nomogram was based on non-invasive ANS assessment and traditional risk factors, and indicated reliable prediction of MACEs in patients with ACS. This approach has potential for use as a method for non-invasive monitoring of health that enables provision of individualized treatment strategies.

Clinical outcomes following myocardial ischemia-reperfusion (I/R) injury are strongly related to the intensity and duration of inflammation. The splenic nerve (SpN) is indispensable for the anti-inflammatory reflex. This study aimed to investigate whether splenic nerve stimulation (SpNS) plays a cardioprotective role in myocardial I/R injury and the potential underlying mechanism.Sprague-Dawley rats were randomly divided into four groups: sham group, I/R group, SpNS group, and I/R plus SpNS group. The highest SpNS intensity that did not influence heart rate was identified, and SpNS at this intensity was used as the subthreshold stimulus. Continuous subthreshold SpNS was applied for 1 h before ligation of the left coronary artery for 45 min. After 72 h of reperfusion, samples were collected for analysis.SpN activity and splenic concentrations of cholinergic anti-inflammatory pathway (CAP)-related neurotransmitters were significantly increased by SpNS. The infarct size, oxidative stress, sympathetic tone, and the levels of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, were significantly reduced in rats subjected to subthreshold SpNS after myocardial I/R injury compared with those subjected to I/R injury alone.Subthreshold SpNS ameliorates myocardial damage, the inflammatory response, and cardiac remodelling induced by myocardial I/R injury via neuroimmunomodulation of proinflammatory factor levels. SpNS is a potential therapeutic strategy for the treatment of myocardial I/R injury.

Aims The clinical use of antitumor agent doxorubicin (DOX) is hampered by its dose-dependent cardiotoxicity. Development of highly efficient and safe adjuvant intervention for preventing DOX-induced adverse cardiac events is urgently needed. We aimed to investigate whether transcutaneous vagal nerve stimulation (tVNS) plays a cardio-protective role in DOX-induced cardiotoxicity. Methods and results Healthy male adult Sprague Dawley rats were used in the experiment and were randomly divided into four groups including control, DOX, tVNS and DOX+tVNS groups. A cumulative dose of 15 mg/kg DOX was intraperitoneally injected into rats to generate cardiotoxicity. Non-invasive tVNS was conducted for 6 weeks (30 min/day). After six-week intervention, the indices from the echocardiography revealed that tVNS significantly improved left ventricular function compared to the DOX group. The increased malondialdehyde (MDA) and Interleukin-1β (IL-1β), and decreased superoxide dismutase (SOD) were observed in the DOX group, while tVNS significantly prevented these changes. From cardiac histopathological analysis, the DOX+tVNS group showed a mild myocardial damage, and decreases in cardiac fibrosis and myocardial apoptosis compared to the DOX group. Heart rate variability (HRV) analysis showed that tVNS significantly inhibited DOX-induced sympathetic hyperactivity compared to the DOX group. Additionally, the results of RNA-sequencing analysis showed that there were 245 differentially expressed genes in the DOX group compared to the control group, among which 39 genes were downregulated by tVNS and most of these genes were involved in immune system. Moreover, tVNS significantly downregulated the relative mRNA expressions of chemokine-related genes and macrophages recruitment compared to the DOX group. Conclusion These results suggest that tVNS prevented DOX-induced cardiotoxicity by rebalancing autonomic tone, ameliorating cardiac dysfunction and remodeling. Notably, crosstalk between autonomic neuromodulation and innate immune cells macrophages mediated by chemokines might be involved in the underlying mechanisms. A translational perspective Non-invasive tVNS has been identified an effective neuromodulation strategy exerting beneficial effects on rebalancing autonomic tone and cardiac pathological conditions. The present study provided direct evidence for a beneficial role of tVNS in preventing DOX-induced autonomic dysfunction and cardiotoxicity in vivo. Additionally, recent studies revealed the importance of sympathetic nerve fibers involving in tumorigenesis and the benefits of higher vagal tone for tumor prognosis either in animal or human trials. Together, tVNS may not only become a novel, nonpharmacological adjuvant therapy for preventing doxorubicin-induced cardiotoxicity, but also may be beneficial for prognosis of cancer patients during chemotherapy. In our future study, we would investigate the effect of tVNS on both combined chemotherapy-induced cardiotoxicity and the antitumor efficacy of DOX in tumor models.

Many nutrition delivery systems (NDSs) have been developed for the encapsulation, protection, and delivery of bioactive compounds, such as β-carotene. Most of those systems were prepared in solution, which is inconvenient for transportation and storage in the food industry. In the present work, we constructed an environmentally friendly dry NDS based on defatted soybean particles (DSPs) by milling a β-carotene-DSP mixture. The loading efficiency of the NDS reached 89.0%, and the cumulative release rate decreased from 15.1% (free β-carotene) to 6.0% within 8 h. The stability of β-carotene in the dry NDS was found to have increased in a thermogravimetric analysis. Stored for 14 days at 55 °C or under UV irradiation, the retaining rates of β-carotene in the NDS increased to 50.7% and 63.6%, respectively, while they were 24.2% and 54.6% for the free samples. The bioavailability of β-carotene was improved by the NDS too. The apparent permeability coefficient of the NDS reached 1.37 × 10−6 cm/s, which is 12 times that of free β-carotene (0.11 × 10−6 cm/s). Besides being environmentally friendly, the dry NDS can facilitate carriage, transportation, or storage in the food industry, and similar to other NDSs, it improves the stability and bioavailability of nutrients.

Background Children and older adults with coronavirus disease 2019 (COVID-19) display a distinct spectrum of disease severity yet the risk factors aren’t well understood. We sought to examine the expression pattern of angiotensin-converting enzyme 2 (ACE2), the cell-entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the role of lung progenitor cells in children and older patients. Methods We retrospectively analyzed clinical features in a cohort of 299 patients with COVID-19. The expression and distribution of ACE2 and lung progenitor cells were systematically examined using a combination of public single-cell RNA-seq data sets, lung biopsies, and ex vivo infection of lung tissues with SARS-CoV-2 pseudovirus in children and older adults. We also followed up patients who had recovered from COVID-19. Results Compared with children, older patients (>50 years.) were more likely to develop into serious pneumonia with reduced lymphocytes and aberrant inflammatory response (P = .001). The expression level of ACE2 and lung progenitor cell markers were generally decreased in older patients. Notably, ACE2 positive cells were mainly distributed in the alveolar region, including SFTPC positive cells, but rarely in airway regions in the older adults (P < .01). The follow-up of discharged patients revealed a prolonged recovery from pneumonia in the older (P < .025). Conclusions Compared to children, ACE2 positive cells are generally decreased in older adults and mainly presented in the lower pulmonary tract. The lung progenitor cells are also decreased. These risk factors may impact disease severity and recovery from pneumonia caused by SARS-Cov-2 infection in older patients.

Surface integrals of vector fields play an important role in the solutions of natural science and physical science. The Gauss theorem reduces the difficulty of directly computing surface integrals of vector fields. This paper introduces an approach for the computation of integral surfaces in vector fields and obtains a generalized mathematical expression based on Gauss theorem. Moreover, the computation time is investigated by two classical examples.

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Background Diabetic foot ulcer (DFU) is a serious chronic complication of diabetes mellitus that contributes to 85% of nontraumatic lower extremity amputations in diabetic patients. Preliminary clinical benefits have been shown in treatments based on mesenchymal stem cells for patients with DFU or peripheral arterial disease (PAD). However, the long-term safety and benefits are unclear for patients with both DFU and PAD who are not amenable to surgical revascularization. Methods In this phase I pilot study, 14 patients with PAD and incurable DFU were enrolled to assess the safety and efficacy of human umbilical cord mesenchymal stem cell (hUC-MSC) administration based on conservative treatments. All patients received topical and intravenous administrations of hUC-MSCs at a dosage of 2 × 105 cells/kg with an upper limit of 1 × 107 cells for each dose. The adverse events during treatment and follow-up were documented for safety assessments. The therapeutic efficacy was assessed by ulcer healing status, recurrence rate, and 3-year amputation-free rate in the follow-up phase. Results The safety profiles were favorable. Only 2 cases of transient fever were observed within 3 days after transfusion and considered possibly related to hUC-MSC administration intravenously. Ulcer disclosure was achieved for more than 95% of the lesion area for all patients within 1.5 months after treatment. The symptoms of chronic limb ischaemia were alleviated along with a decrease in Wagner scores, Rutherford grades, and visual analogue scale scores. No direct evidence was observed to indicate the alleviation of the obstruction in the main vessels of target limbs based on computed tomography angiography. The duration of rehospitalization for DFU was 2.0 ± 0.6 years. All of the patients survived without amputation due to the recurrence of DFU within 3 years after treatments. Conclusions Based on the current pilot study, the preliminary clinical benefits of hUC-MSCs on DFU healing were shown, including good tolerance, a shortened healing time to 1.5 months and a favorable 3-year amputation-free survival rate. The clinical evidence in the current study suggested a further phase I/II study with a larger patient population and a more rigorous design to explore the efficacy and mechanism of hUC-MSCs on DFU healing. Trial registration: The current study was registered retrospectively on 22 Jan 2022 with the Chinese Clinical Trial Registry (ChiCTR2200055885), http://www.chictr.org.cn/showproj.aspx?proj=135888 Graphical Abstract

In this paper, a new class of skew multimodal distributions with more flexible than alpha skew normal distribution and alpha-beta skew normal distribution is proposed, which makes some important distributions become its special cases. The statistical properties of the new distribution are studied in detail, its moment generating function, skewness coefficient, kurtosis coefficient, Fisher information matrix, maximum likelihood estimators are derived. Moreover, a random simulation study is carried out for test the performance of the estimators, the simulation results show that with the increase of sample size, the mean value of maximum likelihood estimators tends to the true value. The new distribution family provides a better fit compared with other known skew distributions through the analysis of a real data set.

Exploring specific electrode active materials with excellent kinetic properties is important for the development of high performance supercapacitors. Herein, a novel nickel-cobalt fluoride (Ni1-xCoxF2) with a porous nanoprism structure is synthesized via step-wise recrystallization and ion-exchange reactions with a morphology control agent, namely polyvinyl pyrrolidone (PVP). The synergistic effect between the bimetallic redox centers promotes the reconstruction of the electronic coordination, leading to apparent discrepancies in the microstructure and morphology of Ni1-xCoxF2 with different stoichiometric ratios of Ni/Co. The micro-porous structure also provides sufficient interfaces and active sites for efficient electrolyte penetration and ion diffusion, thus improving its electrochemical performance. Among the as-synthesized samples, Ni0.5Co0.5F2, with an Ni/Co ratio of 1 : 1, achieved the highest specific capacity of 1979.6 F g-1 at 1.0 A g-1 and a remarkable long-term cycling stability of 900 F g-1 residual after 30 000 cycles at 20 A g-1. The supercapacitor with Ni0.5Co0.5F2 and activated carbon as the positive and negative electrodes, respectively, delivers a high specific capacitance of 107.3 F g-1 at 1 A g-1, outstanding cycling stability of 90.07% capacity retention after 30 000 cycles, and a maximum energy density of 48.3 W h kg-1 at a power density of 952.9 W kg-1. A flexible asymmetric all-solid-state supercapacitor based on a PVA/KOH gel electrolyte was assembled, which delivered a specific capacitance of 41.0 F g-1 at 1 A g-1 and showed promising applications in flexible electronic devices.

Mesenchymal stem cells (MSCs) can be widely isolated from various tissues including bone marrow, umbilical cord, and adipose tissue, with the potential for self-renewal and multipotent differentiation. There is compelling evidence that the therapeutic effect of MSCs mainly depends on their paracrine action. Extracellular vesicles (EVs) are fundamental paracrine effectors of MSCs and play a crucial role in intercellular communication, existing in various body fluids and cell supernatants. Since MSC-derived EVs retain the function of protocells and have lower immunogenicity, they have a wide range of prospective therapeutic applications with advantages over cell therapy. We describe some characteristics of MSC-EVs, and discuss their role in immune regulation and regeneration, with emphasis on the molecular mechanism and application of MSC-EVs in the treatment of fibrosis and support tissue repair. We also highlight current challenges in the clinical application of MSC-EVs and potential ways to overcome the problem of quality heterogeneity.

Peanut allergy is the leading pediatric food allergy. Many attempts have been made to reduce its allergenicity by processing. After roasting, Ara h 2 and its derivatives in the matrix were isolated by immunoaffinity chromatography (IAC). The structure and allergenicity of Ara h 2 were analyzed by circular dichroism, mass spectrometry (MS), western blotting, the enzyme-linked immunoassay, and cell modeling. Our results showed that a large portion of Ara h 2 was fragmented and cross-linked. Ara h 2 monomers accounted for only 13% of the total proteins after IAC purification. In addition, the structure of Ara h 2 changed after roasting. In addition to methylation and oxidation modification, the disulfide bonds of Ara h 2 were found to be rearranged after roasting. In the conformational structure of Ara h 2, the content of the α-helix decreased from 27.1 to 21.6% after roasting, while the content of the random coil increased from 29.1 to 34.3%. Six cleavage sites of trypsin were exposed, while three were covered. In terms of allergenicity, most of the cross-linking products were not recognized by patients' sera. Only one faint band around 40 kDa was observed in our blotting. For Ara h 2 monomers, roasting enhanced their IgE binding capacity and ability to stimulate the degranulation of basophils. The potential allergenicity increase of Ara h 2 monomers did not reflect the allergenicity change of Ara h 2 in the matrix due to the amount and property of its derivatives after roasting.

Tumor-induced host wasting and mortality are general phenomena across species. Many groups have previously demonstrated endocrinal impacts of malignant tumors on host wasting in rodents and Drosophila. Whether and how environmental factors and host immune response contribute to tumor-associated host wasting and survival, however, are largely unknown. Here, we report that flies bearing malignant yki

Beta-thalassemia (BT) is a hereditary disease caused by abnormal hemoglobin synthesis with consequent ineffective erythropoiesis. Patients with thalassemia major are dependent on long-term blood transfusions with associated long-term complications such as iron overload (IO). This excess iron can result in tissue damage, impaired organ function, and increased morbidity. Growing evidence has demonstrated that IO contributes to impairment of the bone marrow (BM) microenvironment that largely impacts the function of BM mesenchymal stem cells, hematopoietic stem cells, and endothelial cells. In this article, we review recent progress in the understanding of iron metabolism and the perniciousness induced by IO. We highlight the importance of understanding the cross-talk between BM stem cells and the BM microenvironment, particularly the pathological effect of IO on BM stem cells and BT-associated complications. We also provide an update on recent novel therapies to cure transfusion-dependent beta-thalassemia and iron overload-induced complications for their future clinical application.

Three-dimensional P-doped Co9S8/CoO (denoted as Co–S–P) nanoflowers are designed and synthesized via a phosphor doping method. Because of the novel structures and the ultrathin nanosheets, the electrode materials supply rapid charge transmission rate, shortened ion diffusion length, and large electroactive specific area, resulting in outstanding electrochemical performance. As a supercapacitor electrode active material, the Co–S–P exhibits outstanding pseudocapacitive performance with a specific capacitance of 969.5 F g–1 at 1 A g–1 and 775 F g–1 at 20 A g–1 and approximately 105% capacity retention after 30 000 cycles at 20 A g–1. As expected, an asymmetric supercapacitor was configured on the basis of the obtained Co–S–P and activated carbon electrode, which showed a high energy density of 17.9 Wh kg–1 at 266 W kg–1 and remained 97.9% of initial specific capacitance after 10 000 cycles.

Gallic acid or its alkyl ester was added in combination with α-tocopherol in the oil-in-water (O/W) emulsion to investigate their interaction in emulsions. Results showed that all the tested gallat...

Background It is reported interleukin (IL)-17A, a classical proinflammatory cytokine, is implicated in neuroimmune-associated remodeling in neural plasticity and pathological conditions. However, the effect of IL-17A on left stellate ganglion (LSG) remodeling remains unclear. Objective This study was performed to determine whether exogenous IL-17A promotes LSG remodeling and destabilize ventricular electrophysiological properties (EPs) in normal canines. Methods 24 beagles were randomly allocated into three groups. In the first group, animals were subjected to 0.1 ml phosphate buffer saline (PBS) microinjection of into LSG (n = 8), an equivalent IL-17A was administrated in the second group (n = 8), and an equivalent anti-IL-17A mAb plus IL-17A was administrated in the third group (n = 8). The ventricular EPs, neural function and activity of the LSG were determined at baseline and 30 min after administration. In the end, LSG tissues were collected. Results Compared with the control group, the experimental group had a significantly shorter effective refractory period (ERP) and action potential duration (APD)90, an increased ERP, APD90, Smax dispersion, and APD alternans cycle length; and steepened APD restitution curves. In addition, IL-17A enhanced the neural function and activity of the LSG, upregulated the expressions of neuropeptides and proinflammatory cytokines and cells. And all these effects were attenuated by anti-IL-17A mAb. Importantly, IL-17 receptor A (IL-17R-A) was detected in sympathetic neurons in the LSG. Conclusion IL-17A promoted LSG remodeling by regulating the neural inflammation response. It did so by binding to IL-17R-A, resulting in unstable ventricular electrophysiology in normal structural hearts.

Duck Tembusu virus disease, caused by the duck Tembusu virus (DTMUV), can lead to a severe reduction in egg production and growth retardation in laying ducks and ducklings, respectively. In this study, we engineered a novel recombinant adenovirus expressing the E protein of DTMUV (rAd-E) in AAV-293 cells (analyzed by western blot and indirect immunofluorescence assays). Intramuscular immunization of Cherry Valley ducks with rAd-E was performed to evaluate host cellular and humoral immune responses. Compared to the phosphate-buffered saline administered group and the negative control wild-type adenovirus (wtAd) group, the rAd-E vaccinated group showed increased cellular and humoral responses. The results from the cytokine release and lymphocyte proliferation assays showed that rAd-E induced a stronger cellular immune response than the control group (P

Heterostructures have been extensively developed with remarkable improvement on the electrochemical properties due to their intriguing synergetic effects. Herein, novel heterostructure of CoSe 2 and Mo2 C nanoparticles confined into porous carbon nanofibers (CoSe 2/Mo2C/C NFs) is rationally designed and controllably synthesized through a facile hydrothermal approach, followed by the annealing treatment and selenization process. The resultant CoSe2/Mo2C/C NFs show around 10 μm in length and 250 nm in diameter. And the CoSe2 and Mo2 C nanoparticles derived from Co-Mo compound as precursor provide high possibility of constructing their sufficient heterointerfaces, which could facilitate the electron transfer during electrochemical process and boost the surface reaction kinetics because of the heterointerface effect. Furthermore, the CoSe 2 and Mo2C nanoparticles are conformally confined into the porous carbon nanofibers, which could alleviate the volume change effectively durng charging and discharging process in LIBs. As a result, the CoSe2/Mo2C/C NFs electrode possesses high reversible capacities (929.6 mAh g−1 during 100th cycle at a current density of 0.1 A g−1) and superior rate capability (376.2 mAh g−1 at 10 A g−1) as anodes for LIBs. Furthermore, the CoSe2/Mo2C/C NFs also show good sodium storage properties. A high specific capacity of 530.7 mAh g−1 after 100 cycles at 0.1 A g−1, and good rate performance (193.8 mAh g−1 at 8 A g−1) can be achieved in Na ion batteries. The unique hetero-architectures and synergistic effect are significantly responsible for the fascinating electrochemical performance.

With the development of computer science technology, theory and method of image segmentation are widely used in fish discrimination, which plays an important role in improving the efficiency of fisheries sorting and biodiversity studying. However, the existing methods of fish images segmentation are less accurate and inefficient, which is worthy of in-depth exploration. Therefore, this paper proposes an atrous pyramid GAN segmentation network aimed at increasing accuracy and efficiency. This paper introduces an atrous pyramid structure, and the GAN module is added before the CNN backbone in order to augment the dataset. The Atrous pyramid structure first fuses the input and output of the dilated convolutional layer with a small sampling rate and then feeds the fused features into the subsequent dilated convolutional layer with a large sampling rate to obtain dense multiscale contextual information. Thus, by capturing richer contextual information, this structure improves the accuracy of segmentation results. In addition to the aforementioned innovation, various data enhancement methods, such as MixUp, Mosaic, CutMix, and CutOut, are used in this paper to enhance the model’s robustness. This paper also improves the loss function and uses the label smoothing method to prevent model overfitting. The improvement is also tested by extensive ablation experiments. As a result, our model’s F1-score, GA, and MIoU were tested on the validation dataset, reaching 0.961, 0.981, and 0.973, respectively. This experimental result demonstrates that the proposed model outperforms all the other contrast models. Moreover, in order to accelerate the deployment of the encapsulated model on hardware, this paper optimizes the execution time of the matrix multiplication method on Hbird E203 based on Strassen’s algorithm to ensure the efficient operation of the model on this hardware platform.

Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19), with macrophages as one of the main cell types involved. It is urgent to understand the interactions among permissive cells, macrophages, and the SARS-CoV-2 virus, thereby offering important insights into effective therapeutic strategies. Here, we establish a lung and macrophage co-culture system derived from human pluripotent stem cells (hPSCs), modeling the host-pathogen interaction in SARS-CoV-2 infection. We find that both classically polarized macrophages (M1) and alternatively polarized macrophages (M2) have inhibitory effects on SARS-CoV-2 infection. However, M1 and non-activated (M0) macrophages, but not M2 macrophages, significantly up-regulate inflammatory factors upon viral infection. Moreover, M1 macrophages suppress the growth and enhance apoptosis of lung cells. Inhibition of viral entry using an ACE2 blocking antibody substantially enhances the activity of M2 macrophages. Our studies indicate differential immune response patterns in distinct macrophage phenotypes, which could lead to a range of COVID-19 disease severity.

Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19) from mild to severe stages including fatality, with pro-inflammatory macrophages as one of the main mediators of lung hyper-inflammation. Therefore, there is an urgent need to better understand the interactions among SARS-CoV-2 permissive cells, macrophage, and the SARS-CoV-2 virus, thereby offering important insights into new therapeutic strategies. Here, we used directed differentiation of human pluripotent stem cells (hPSCs) to establish a lung and macrophage co-culture system and model the host-pathogen interaction and immune response caused by SARS-CoV-2 infection. Among the hPSC-derived lung cells, alveolar type II and ciliated cells are the major cell populations expressing the viral receptor ACE2 and co-effector TMPRSS2, and both were highly permissive to viral infection. We found that alternatively polarized macrophages (M2) and classically polarized macrophages (M1) had similar inhibitory effects on SARS-CoV-2 infection. However, only M1 macrophages significantly up-regulated inflammatory factors including IL-6 and IL-18, inhibiting growth and enhancing apoptosis of lung cells. Inhibiting viral entry into target cells using an ACE2 blocking antibody enhanced the activity of M2 macrophages, resulting in nearly complete clearance of virus and protection of lung cells. These results suggest a potential therapeutic strategy, in that by blocking viral entrance to target cells while boosting anti-inflammatory action of macrophages at an early stage of infection, M2 macrophages can eliminate SARS-CoV-2, while sparing lung cells and suppressing the dysfunctional hyper-inflammatory response mediated by M1 macrophages.

BackgroundThe outbreak of COVID-2019 is becoming a global public health emergency. Although its basic clinical features have been reported, the dynamic characteristics of immune system in COVID-2019 patients, especially those critical patients with refractory hypoxemia, are not yet well understood. We aim to describe the dynamic characteristics of immune system in 3 critical patients with refractory hypoxemia, and discuss the relationship between hypoxemia severity and immune cell levels, and the changes of gut microbes of COVID-2019 patient.MethodsThis is a retrospective study from 3 patients with 2019-nCoV infection admitted to Renmin Hospital of Wuhan University, a COVID-2019 designated hospital in Wuhan, from January 31 to February 6, 2020. All patients were diagnosed and classified based on the Diagnosis and Treatment of New Coronavirus Pneumonia (6th edition) published by the National Health Commission of China4. We recorded the epidemiological history, demographic features, clinical characteristics, symptoms and signs, treatment and clinical outcome in detail. Blood samples were collected and we determined the expression levels of immune cells (CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD16+56+ NK cells) in different time points. Nanopore Targeted Sequencing was used to determine the alterations of gut microbiota homeostasis.ResultsApart from the clinical features described previously4, we found that four patients had decreased immune cells and refractory hypoxemia during the hospitalization, and the severity of hypoxemia was strongly correlated to the expression levels of immune cells. Additionally, we found that the proportion of probiotics was significantly reduced, such as Bifidobacterium, Lactobacillus, and Eubacterium, and the proportion of conditioned pathogenic bacteria was significantly increased, such as Corynebacterium of Actinobacteria and Ruthenibacterium of Firmicutes. Notably, all patients died.ConclusionsWe discussed the dynamic characteristics of host immune system and the imbalance of gut microbiota in 3 critical patients with COVID-2019. Hypoxemia severity was closely related with host immune cell levels, and the vicious circle between immune disorder and gut microbiota imbalance may be a high risk of fatal pneumonia. To the best of our knowledge, this is the first study which revealing that immunodepletion with refractory hypoxemia is a potential high risk subtype of COVID-2019 and the vicious circle between immune disorder and gut dysbiosis may be a high risk of fatal pneumonia.

Background: Circadian rhythms have a considerable impact on the daily physiology of the heart, and their disruption causes pathology. Sympathetic nervous system is essential for transmitting circadian information from central clock to peripheral organs. The role of cardiac sympathetic ganglion, a key target of cardiac sympathetic outflow, in circadian disruption-related cardiovascular diseases is not completely understood. Thereby, we aim todiscuss whether cardiac sympathetic ganglion plays an important role in the development of cardiac remodeling after myocardial infarction (MI)in a circadian disruption model. Methods: Rats were randomly divided into three groups: Sham group (Sham), MI group (MI), and MI+ circadian disruption group (MI+Dis); rats were treated with PRV injections for trans-synaptic retrograde tracing; rats were randomly divided into two groups: MI+ circadian disruption+ Empty Vector+ CNO (Empty Vector) and MI+ circadian disruption+ hM4D(Gi)+ CNO (hM4D(Gi)). Findings: Circadian disruption significantly facilitated cardiac remodeling after MI with lower systolic function, larger left ventricular volume, increased infarct size and aggravated cardiac fibrosis. Serum norepinephrine levels and cardiac sympathetic remodeling makers were also significantly increased by disruption. PRV virus-labeled neurons were identified in the SCG, PVN, and SCN regions. Ganglionic blockade via DREADD technique suppressed the cardiac sympathetic outflow and significantly alleviated the disruption-related cardiac dysfunction. Interpretation: Circadian disruption adversely affected cardiac remodeling after MI, possibly by increasing the cardiac sympathetic outflow, and cardiac sympathetic ganglionic blockade canattenuatethis disruption-related cardiac dysfunction. Funding Statement: National Key R&D Program of China, and National Natural Science Foundation of China. Declaration of Interests: None. Ethics Approval Statement: Experimental protocols were conducted under the guidelines of the National Institutes of Health and were approved by the Animal Care and Use Committees of Renmin Hospital of Wuhan University.

Herein, nickel carbide (Ni3C) nanoparticles were controlled synthesized by decomposing nickel acetylacetonate in oleylamine and oleic acid solvent at a comparatively low temperature of 280 °C. The resultant Ni3C nanoparticles with an average size of 18 nm exhibited large specific surface area and excellent electrical conductivity. And the charge transport during the Li+ intercalation and deintercalation processes can be effectively facilitated by this kind of unique structure. Serving as an anode material in lithium-ion batteries, the Ni3C nanoparticles presented a high stable specific capacity of 390.1 mAh g−1 during 100 cycles at a current density of 0.1 A g−1 and excellent rate performance (e.g. 152.1 mAh g−1 at 5 A g−1). This phenomenon attributed to the advantages of the high intrinsic electrical conductivity and chemical stability of Ni3C. The effective nanostructure of transition metal carbides provides a promising approach to synthesis stable electrode materials for energy and environmental related applications.

Transition metal silicates as anode materials for LIBs have drawn increasing attention because of their high theoretical capacity, abundance in nature, thermal stability and non-toxicity. Among them, Co2SiO4 is particularly promising. Herein, hierarchical amorphous Co2SiO4 nanosheets coated with nanoparticles were prepared by a template-free one-pot hydrothermal method. Co2SiO4 nanoparticles (~20 nm) are uniformly deposited on ultrathin Co2SiO4 nanosheets. The method avoids prefabricating template compared with hydrothermal method, the nanostructure obtained is also superior that obtained through the traditional high temperature sintering approach. As lithium ion battery anode, the hierarchical Co2SiO4 electrode delivers a high capacity of about 1410 mAh g-1 after 100 cycles (current density: 100 mA g-1). Even at 5 A g-1, a specific capacity of 670 mAh g-1 can be maintained after 1500 cycles. The excellent battery performance may be attributed to the synergistic effect between the nanoparticles and nanosh...

Objective Blood pressure elevation in response to transient renal nerve stimulation (RNS) has been used to determine the ablation target and endpoint of renal denervation. This study aimed to evaluate the safety of transient RNS in canines with normal or ischaemic hearts. Methods In ten normal (Group 1) and six healed myocardial infarction (HMI) (Group 2) canines, a large-tip catheter was inserted into the left or right renal artery to perform transient RNS. The left stellate ganglion neural activity (LSGNA) and ventricular electrophysiological parameters were measured at baseline and during transient RNS. In another 20 acute myocardial infarction (AMI) canines, RNS (Group 3, n = 10) or sham RNS (Group 4, n = 10) was intermittently (1 min ON and 4 min OFF) performed for 1 h following AMI induction. The LSGNA and AMI-induced ventricular arrhythmias were analysed. Results In normal and HMI canines, although transient RNS significantly increased the LSGNA and facilitated the action potential duration (APD) alternans, it did not induce any ventricular arrhythmias and did not change the ventricular effective refractory period, APD or maximum slope of the APD restitution curve. In AMI canines, transient RNS significantly exacerbated LSG activation and promoted the incidence of ventricular arrhythmias. Conclusion Transient RNS did not increase the risk of ventricular arrhythmias in normal or HMI hearts, but it significantly promoted the occurrence of ventricular arrhythmias in AMI hearts. Therefore, electrical stimulation-based renal nerve mapping may be unsafe in AMI patients and in patients with a high risk for malignant ventricular arrhythmias.

The concept of vibratory energy harvesting has flourished in recent years as a possible alternative to provide a continuous power supply. Most work focusing on changing the configuration of piezoelectric energy harvester has concentrated on cantilevered beams at resonance using harmonic excitation. This work is mainly devoted to obtain the effects of changing PZT length on output characteristics for doubly-clamped piezoelectric energy harvester with different beam shapes under stochastic excitation. Firstly, analytical expressions of output characteristics of random excited doubly-clamped piezoelectric energy harvester are derived. Subsequently, the trends between factors that affect output characteristics and the change of beam shape or PZT length are calculated and analyzed. Finally, effects of changing PZT length on output characteristics varying with load resistance and acceleration’s spectral density for doubly-clamped piezoelectric energy harvester with different beam shapes are compared and discussed. Monte Carlo simulation and experimental results exhibit qualitative agreement with Fokker–Planck theory, showing that changing PZT length could improve output characteristics of random excited doubly-clamped piezoelectric energy harvester considerably. Besides, it also demonstrates that doubly-clamped trapezoidal piezoelectric energy harvesters under random excitation are superior to their rectangular counterparts.

Background Increased inflammation was found in the left stellate ganglion (LSG) in patients with malignant ventricular arrhythmia (VA). However, the role of inflammation in LSG remodeling is unknown. This study aimed to investigate whether exogenous interleukin-1β (IL-1β) could aggravate VA through regulating LSG remodeling. Methods Twenty-four canines who received saline (Control, n=8), IL-1β injection into the LSG (n=8) or IL-1 receptor antagonist (IL-Ra) pre-injection plus IL-1β injection (n=8) were included. Ventricular electrophysiology parameters, heart rate variability (HRV), LSG activity were measured at different time points. VA was recorded for 60min after ischemia and then LSG tissues were collected for molecular detection. Results Compared with the control group, IL-1β injection decreased the effective refractory period, action potential duration (APD) 90 and increased the maximal slope of the restitution curve in normal hearts. Besides, the occurrence of VA was significantly increased in the IL-1β group. Additionally, IL-1β injection increased the sympathetic indices of HRV and LSG activity in normal and ischemic hearts. Mechanically, the mRNA expression of pro-inflammatory cytokines and protein expression of c-fos, nerve growth factor and neuropeptide Y in LSG were increased, whereas the expression of neuronal nitric oxide synthase was decreased in the IL-1β group. More importantly, all these effects induced by IL-1β were attenuated by IL-1Ra pre-injection. Conclusion Increased inflammation induced by IL-1β injection aggravates ischemia induced VA through regulating the neuronal remodeling of the LSG. Inflammation induced neuroplasticity may be a novel mechanism and therapeutic target for VA.

Background Studies have shown that left stellate ganglion (LSG) suppression protects against ventricular arrhythmias (VAs). Optogenetics is a novel technique to reversibly regulate the activity of the targeted neurons. Objectives This study aimed to investigate whether an optogenetically silenced LSG could protect against VAs induced by myocardial ischemia. Methods Adeno-associated virus (AAV) was used as the vector to deliver ArchT, an inhibitory light-sensitive opsin, to the LSG neurons. Twenty male beagles were randomized into the optogenetics group (n = 10, AAV2/9-CAG-ArchT-GFP microinjected into LSG) and control group (n = 10, AAV2/9-CAG-GFP microinjected into LSG). After 4 weeks, the LSG function and neural activity, heart rate variability, ventricular action potential duration, and effective refractory period were measured in the absence or presence of a light-emitting diode illumination (565 nm). Myocardial ischemia was induced by left anterior coronary artery ligation and 1 h of electrocardiography was recorded for VAs analysis. Results ArchT was successfully expressed in all dogs. Transient light-emitting diode illumination significantly suppressed the LSG function, LSG neural activity, and sympathetic nerve indices of heart rate variability as well as prolonged left ventricular effective refractory period and APD90 only in the optogenetics group. Thirty-minute illumination further enhanced these changes in the optogenetics group. Importantly, all of these changes returned to baseline within 2 h after illumination was turned off. Moreover, the ischemia-induced VAs were significantly suppressed by illumination only in the optogenetics group. Conclusions Optogenetic modulation could reversibly inhibit the neural activity of LSG, thereby increasing electrophysiological stability and protecting against myocardial ischemia–induced VAs.

X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder associated with mutations of the ABCD1 gene that encodes a peroxisomal transmembrane protein. It results in accumulation of very long chain fatty acids in tissues and body fluid. Along with other factors such as epigenetic and environmental involvement, ABCD1 mutation-provoked disorders can present different phenotypes including cerebral adrenoleukodystrophy (cALD), adrenomyeloneuropathy (AMN), and peripheral neuropathy. cALD is the most severe form that causes death in young childhood. Bone marrow transplantation and hematopoietic stem cell gene therapy are only effective when performed at an early stage of onsets in cALD. Nonetheless, current research and development of novel therapies are hampered by a lack of in-depth understanding disease pathophysiology and a lack of reliable cALD models. The Abcd1 and Abcd1/Abcd2 knock-out mouse models as well as the deficiency of Abcd1 rabbit models created in our lab, do not develop cALD phenotypes observed in human beings. In this review, we summarize the clinical and biochemical features of X-ALD, the progress of pre-clinical and clinical studies. Challenges and perspectives for future X-ALD studies are also discussed.

Objectives The aim of this study was to investigate whether low-level tragus stimulation (LL-TS) treatment could reduce myocardial ischemia-reperfusion injury in patients with ST-segment elevation myocardial infarction (STEMI). Background The authors’ previous studies suggested that LL-TS could reduce the size of myocardial injury induced by ischemia. Methods Patients who presented with STEMI within 12 h of symptom onset, treated with primary percutaneous coronary intervention, were randomized to the LL-TS group (n = 47) or the control group (with sham stimulation [n = 48]). LL-TS, 50% lower than the electric current that slowed the sinus rate, was delivered to the right tragus once the patients arrived in the catheterization room and lasted for 2 h after balloon dilatation (reperfusion). All patients were followed for 7 days. The occurrence of reperfusion-related arrhythmia, blood levels of creatine kinase-MB, myoglobin, N-terminal pro–B-type natriuretic peptide and inflammatory markers, and echocardiographic characteristics were evaluated. Results The incidence of reperfusion-related ventricular arrhythmia during the first 24 h was significantly attenuated by LL-TS. In addition, the area under the curve for creatine kinase-MB and myoglobin over 72 h was smaller in the LL-TS group than the control group. Furthermore, blood levels of inflammatory markers were decreased by LL-TS. Cardiac function, as demonstrated by the level of N-terminal pro–B-type natriuretic peptide, the left ventricular ejection fraction, and the wall motion index, was markedly improved by LL-TS. Conclusions LL-TS reduces myocardial ischemia-reperfusion injury in patients with STEMI. This proof-of-concept study raises the possibility that this noninvasive strategy may be used to treat patients with STEMI undergoing primary percutaneous coronary intervention.

A nonlinear energy harvester combined piezoelectric (PE) and electromagnetic (EM) is studied for the low vibration frequency excitation, and its resonant frequency can be tuned by magnetic force. In the paper, analytical solutions of amplitude, output voltage, current and power under sinusoidal and stochastic excitations are derived by the methods of harmonic balance and Fokker–Planck theory respectively. The theoretical analysis is carried out, and output performance is tested by the experiment. It can be concluded that the resonant frequency and bandwidth of harvester can be adjusted through magnetic force, and nonlinear energy harvester can improve output power compared with the corresponding linear harvester. In addition, coupling effect of PE element has influence on stiffness and damping of harvester simultaneously, while EM element coupling effect mainly affects the damping. When the harvester excited at the resonant frequency and connected with optimal PE and EM load simultaneously, the output power and 3 dB bandwidth can reach the maximum. Furthermore, mean power is linearly proportional to spectral density of acceleration at random excitation. Through analysis results, the ways that can boost the output power at low frequency excitation are found

MicroRNAs (miRNAs) are highly conserved molecules that regulate protein levels post-transcriptionally. Aberrant miRNA expression presents in various musculoskeletal disorders, such as osteoporosis, osteoarthritis and rheumatoid arthritis. The expression levels of miRNAs are characterized by endogenous properties and tissue specificity. This raises the possibility that miRNAs could serve as useful clinical biomarkers in the diagnosis of certain diseases. Intervertebral disc degeneration (IDD) is one of the major causes of back pain, and a process characterized by a cascade of molecular, cellular, biochemical and structural changes. The presence of dysregulated miRNA expression in patients with disc degeneration diseases indicates that miRNAs may play a vital role in the pathogenesis of IDD. Here, we provide an introduction of the roles of miRNAs in the process of IDD, and the prospective application of miRNAs as biomarkers for IDD. Copyright © 2017 John Wiley & Sons, Ltd.

For the designed nonlinear hybrid piezoelectric (PE)---electromagnetic (EM) energy harvester, electromechanical coupling state equations are established at stochastic excitation, and vibration response, output mean power, voltage and current are derived by statistical linearization method. Then, effects of nonlinear strength, load resistance and excitation spectral density on vibration response and electric output of nonlinear hybrid energy harvester are studied by theoretical analysis, simulation and experimental test. It is obtained that mean power of nonlinear hybrid energy harvester increases linearly with acceleration spectral density; the bigger nonlinear strength, the bigger output power of energy harvester and the lower resonant frequency are; besides, mean amplitude of nonlinear hybrid energy harvester reaches the minimum at PE optimal load, but it increases with EM load increasing. Compared with linear hybrid energy harvester, the resonant frequency of nonlinear energy harvester can be decreased by 57%, while output power can be increased by 72%.

In this work, for an arbitrary shape (i.e. the width can be described by an arbitrary function) beam, analytical models for vibrations and electrical output are established. And experiments are conducted to verify the models. In fact, for a rectangular beam, it can be found both theoretically and experimentally that the total output charges are independent of the beam width. For an arbitrary shape beam, parameters, which could be sensitive for obtaining a satisfied energy harvesting, could be learned by means of the analytical model in this paper. At the same time, the optimal shapes presented by Ayed et al. (J Intell Mater Syst Struct 25(2):174–186, 2014) and Tabatabaei et al. (Microsyst Technol 22:2435–2446, 2016) have been proved and supported by the analytical model in this paper.

Background Previous studies indicated that inhibiting the cardiac autonomic nervous system (CANS) suppressed atrial fibrillation (AF). Clinical research revealed serum adiponectin (APN) exerted a beneficial influence on sympathetic and vagal tone in patients with type 2 diabetes. However, the effects of APN on CANS is unknown. This study aims to investigate whether APN could regulate CANS and suppress rapid atrial pacing (RAP)-induced AF. Methods Eighteen beagles were divided into the control group (saline plus sham RAP, N = 6), the RAP group (saline plus RAP, N = 6) and the APN + RAP group (APN plus RAP, N = 6). APN (10 μg, 0.1 μg/μL) or saline was microinjected into 4 major ganglionated plexi (GP) prior to RAP. Atrial electrophysiological parameters, anterior right GP (ARGP) function, neural activity and GP tissues were detected. Results Compared with the control treatment, RAP shortened effective refractory period (ERP) values at all sites and increased cumulative window of vulnerability (ΣWOV), ARGP function and neural activity, whereas APN injection reversed these changes. Mechanistically, APN ameliorated RAP-induced inflammatory response and down-regulated the expression of c-fos protein and nerve growth factor. Moreover, the APN receptors 1 and APN receptors 2 were detected both in neurons and in non-neuronal cells. APN pretreatment activated downstream adenosine monophosphate-activated protein kinase (AMPK) signaling, inhibited nuclear factor-kappa B signaling and promoted macrophage phenotype switching from proinflammatory to anti-inflammatory state. Conclusions This study demonstrates that administration of APN into GP can suppress RAP-induced AF by regulating the CANS. APN signaling may provide a potential therapeutic target to AF.

Most of people live in an community in their daily life. However, since the dark side of human nature exists in everyone’s mind, people living in an community can be deindividualized by triggering and flourishing the evil existing in people’s hearts, emphasizing obedience, and creating an “enemy” for community members. People would rationalize their immoral behaviors to escape from the feeling of guilt and regret. As a result, the savagery in human nature is triggered and normal people in a community are transformed to sociopath.

The ugly beauty standard is caused by the fashion industry as people tend to pay more attention to being skinny and achieving the perfect body. More and more people are sacrificing their health and choose to do plastic surgeries. The fashion industry can also take some measures to get rid of the beauty standard by spreading the different brands that design clothes for different body types, and making the brand that is inclusive for all body size. The future fashion industry should be inclusive and diverse, and help people find the beautiful side and love themselves.