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Abstract Autonomic nervous system disorders play a pivotal role in the pathophysiology of cardiovascular diseases. Regulating it is essential for preventing and treating acute ventricular arrhythmias (VAs). Photothermal neuromodulation is a nonimplanted technique, but the response temperature ranges of transient receptor potential vanilloid 1 (TRPV1) and TWIK-related K+ Channel 1 (TREK1) exhibit differences while being closely aligned, and the acute nature of VAs require that it must be rapid and precise. However, the low photothermal conversion efficiency (PCE) still poses limitations in achieving rapid and precise treatment. Here, we achieve a nearly perfect blackbody absorption and a high PCE in the second near infrared (NIR-II) window (73.7% at 1064 nm) via a Pt nanoparticle shell (PtNP-shell). By precisely manipulating the photothermal effect, we successfully achieve rapid and precise multimodal neuromodulation encompassing neural activation (41.0–42.9 °C) and inhibition (45.0–46.9 °C) in a male canine model. The NIR-II photothermal modulation additionally achieves multimodal reversible autonomic modulation and confers protection against acute VAs associated with myocardial ischemia and reperfusion injury in interventional therapy.

ABSTRACT Metagenomic next-generation sequencing (mNGS) is an unbiased and rapid method for detecting pathogens. This study enrolled 145 suspected severe pneumonia patients who were admitted to the Affiliated Hospital of Jining Medical University. This study primarily aimed to determine the diagnostic performance of mNGS and conventional microbiological tests (CMTs) using bronchoalveolar lavage fluid samples for detecting pathogens. Our findings indicated that mNGS performed significantly higher sensitivity (97.54% vs 28.68%, P < 0.001), coincidence (90.34% vs 35.17%, P < 0.001), and negative predictive value (80.00% vs 13.21%, P < 0.001) but performed lower specificity than CMTs (52.17% vs 87.5%, P < 0.001). Streptococcus pneumoniae as the most common bacterial pathogen had the largest proportion (22.90%, 30/131) in this study. In addition to bacteria, fungi, and virus, mNGS can detect a variety of atypical pathogens such as Mycobacterium tuberculosis and non-tuberculous. Mixed infections were common in patients with severe pneumonia, and bacterial-fungal-viral-atypical pathogens were the most complicated infection. After adjustments of antibiotics based on mNGS and CMTs, the clinical manifestation improved in 139 (95.86%, 139/145) patients. Our data demonstrated that mNGS had significant advantage in diagnosing respiratory tract infections, especially atypical pathogens and fungal infections. Pathogens were detected timely and comprehensively, contributing to the adjustments of antibiotic treatments timely and accurately, improving patient prognosis and decreasing mortality potentially.IMPORTANCEMetagenomic next-generation sequencing using bronchoalveolar lavage fluid can provide more comprehensive and accurate pathogens for respiratory tract infections, especially when considering the previous usage of empirical antibiotics before admission or complicated clinical presentation. This technology is expected to play an important role in the precise application of antimicrobial drugs in the future.

Objectives: Celastrol has widespread therapeutic applications in various pathological conditions, including chronic inflammation. Previous studies have demonstrated the potent cardioprotective effects of celastrol. Nevertheless, limited attention has been given to its potential in reducing ventricular arrhythmias (VAs) following myocardial infarction (MI). Hence, this study aimed to elucidate the potential mechanisms underlying the regulatory effects of celastrol on VAs and cardiac electrophysiological parameters in rats after MI. Methods: Sprague-Dawley rats were divided at random: the sham, MI, and MI + celastrol groups. The left coronary artery was occluded in the MI and MI + Cel groups. Electrocardiogram, heart rate variability (HRV), ventricular electrophysiological parameters analysis, histology staining of ventricles, Enzyme-linked immunosorbent assay (ELISA), western blotting and Quantitative real-time polymerase chain reaction (qRT-PCR) were performed to elucidate the underlying mechanism of celastrol. Besides, H9c2 cells were subjected to hypoxic conditions to create an in vitro model of MI and then treated with celastrol for 24 hours. Nigericin was used to activate the NLRP3 inflammasome. Results: Compared with that MI group, cardiac electrophysiology instability was significantly alleviated in the MI + celastrol group. Additionally, celastrol improved HRV, upregulated the levels of Cx43, Kv.4.2, Kv4.3 and Cav1.2, mitigated myocardial fibrosis, and inhibited the NLRP3 inflammasome pathway. In vitro conditions also supported the regulatory effects of celastrol on the NLRP3 inflammasome pathway. Conclusions: Celastrol could alleviate the adverse effects of VAs after MI partially by promoting autonomic nerve remodeling, ventricular electrical reconstruction and ion channel remodeling, and alleviating ventricular fibrosis and inflammatory responses partly by through inhibiting the NLRP3/Caspase-1/IL-1β pathway.

Summary: Doxorubicin (Dox) poses a considerable threat to patients owing to its cardiotoxicity, thus limiting its clinical utility. Optimal cardioprotective intervention strategies are needed to suppress tumor growth but also minimize cardiac side effects. Here, we showed that tragus vagus nerve stimulation (tVNS) improved the imbalanced autonomic tone, ameliorated impaired cardiac function and fibrosis, attenuated myocyte apoptosis, and mitochondrial dysfunction compared to those in the Dox group. The beneficial effects were attenuated by methyllycaconitine citrate (MLA). The transcript profile revealed that there were 312 differentially expressed genes and the protection of tVNS and retardation of MLA were related to inflammatory response and NADPH oxidase activity. In addition, tVNS synergizing with Dox inhibited tumor growth and lung metastasis and promoted apoptosis of tumor cells in an anti-tumor immunity manner. These results indicated that non-invasive neuromodulation can play a dual role in preventing Dox-induced cardiotoxicity and suppressing tumor growth through inflammation and oxidative stress.

Regarding the issue of information freshness in systems that aid in data collection using unmanned aerial vehicles (UAVs), a data collection algorithm that is based on freshness and UAV assistance is proposed. Under the limitations of wireless sensor node communication distance and UAV parameters, the optimization problem of minimizing the average spatial correlation age of information (SCAoI) of all nodes in the area is set up. This problem is solved by optimizing the number of clusters, UAV flight trajectories, and the order of data collection from cluster member nodes. The maximum communication distance of the nodes is used as the cluster formation radius, and the maximum-minimum distance clustering algorithm is used to cluster the nodes in the region to obtain the minimum number of clusters. After it has been proven that the trajectory optimization problem in this study is NP-hard, the ant colony algorithm is applied to obtain the minimum flight time and the corresponding trajectory. By using the greedy algorithm to determine the member nodes in the sequence of data collection for a cluster, the instantaneous SCAoI of the UAV arriving at the cluster head is solved. Simulation results show that the proposed algorithm in this paper can effectively improve the freshness of data and reduce the average SCAoI of the system compared with the algorithm in the comparative literature, reducing the average SCAoI by about 61%.

Abstract 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.

BackgroundThe advantages of multimodal digitally transformed mobile health management for patients diagnosed with mild to moderate hypertension are not yet established. ObjectiveWe aim to evaluate the therapeutic benefits of a novel WeChat-based multimodal digital transforming management model in mobile health blood pressure (BP) management. MethodsThis randomized controlled clinical trial included 175 individuals with new-onset mild to moderate hypertension who were admitted to our center between September and October 2022. The patients were randomly assigned to either the multimodal intervention group (n=88) or the usual care group (n=87). The primary composite outcome was home and office BP differences after 6 months. The major secondary outcomes were 6-month quality-of-life scores, including the self-rating anxiety scale, self-rating depression scale, and Pittsburgh Sleep Quality Index. ResultsThe mean home BP decreased from 151.74 (SD 8.02)/94.22 (SD 9.32) to 126.19 (SD 8.45)/82.28 (SD 9.26) mm Hg in the multimodal intervention group and from 150.78 (SD 7.87)/91.53 (SD 9.78) to 133.48 (SD 10.86)/84.45 (SD 9.19) mm Hg in the usual care group, with a mean difference in systolic blood pressure and diastolic blood pressure of –8.25 mm Hg (95% CI –11.71 to –4.78 mm Hg; P

Genetic mitochondrial cardiomyopathy (MCM) is a myocardial condition characterized by abnormal cardiac structure and function secondary to genetic defects. Severity can vary from asymptomatic to severe with manifestations that include heart failure, arrhythmias, and sudden cardiac death. The heterogeneity of gene mutation-provoked mitochondrial dysfunction and a variety of manifestations hamper the development of effective therapeutics. In this review, we present the common pathogenesis of mitochondrial cardiomyopathies, and the most recent promising novel therapeutic strategies for cardiac repair including use of cells or stem cells, adeno-associated virus (AAV)-based gene therapies, mitochondrial-based therapy, pharmaceutical compounds, dietary supplementation, and exercise. We discuss their respective advantages and limitations that may aid their broader clinical application. Some novel treatments remain a long way from achieving safe and effective clinical therapeutic effects.

Abstract Lithium–sulfur (Li–S) batteries are promising alternatives of conventional Li‐ion batteries attributed to their remarkable energy densities and high sustainability. However, the practical applications of Li–S batteries are hindered by the shuttling effect of lithium polysulfides (LiPSs) on cathode and the Li dendrite formation on anode, which together leads to inferior rate capability and cycling stability. Here, an advanced N‐doped carbon microreactors embedded with abundant Co3O4/ZnO heterojunctions (CZO/HNC) are designed as dual‐functional hosts for synergistic optimization of both S cathode and Li metal anode. Electrochemical characterization and theoretical calculations confirm that CZO/HNC exhibits an optimized band structure that effectively facilitates ion diffusion and promotes bidirectional LiPSs conversion. In addition, the lithiophilic nitrogen dopants and Co3O4/ZnO sites together regulate dendrite‐free Li deposition. The S@CZO/HNC cathode exhibits excellent cycling stability at 2 C with only 0.039% capacity fading per cycle over 1400 cycles, and the symmetrical Li@CZO/HNC cell enables stable Li plating/striping behavior for 400 h. Remarkably, Li‐S full cell using CZO/HNC as both cathode and anode hosts shows an impressive cycle life of over 1000 cycles. This work provides an exemplification of designing high‐performance heterojunctions for simultaneous protection of two electrodes, and will inspire the applications of practical Li–S batteries.

Abstract 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

Abstract 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.

Model systems to study SARS-CoV-2 infection are required to better understand the immune response. Here the authors use a lung and macrophage co-culture system by differentiation of human pluripotent stem cells to better understand the phenotype and gene expression changes in host lung cells and macrophages after SARS-CoV-2 infection in vitro.

Abstract Autonomic imbalance is an important characteristic of patients after myocardial infarction (MI) and adversely contributes to post‐MI cardiac remodeling and ventricular arrhythmias (VAs). A previous study proved that optogenetic modulation could precisely inhibit cardiac sympathetic hyperactivity and prevent acute ischemia‐induced VAs. Here, a wireless self‐powered optogenetic modulation system is introduced, which achieves long‐term precise cardiac neuromodulation in ambulatory canines. The wireless self‐powered optical system based on a triboelectric nanogenerator is powered by energy harvested from body motion and realized the effective optical illumination that is required for optogenetic neuromodulation (ON). It is further demonstrated that long‐term ON significantly mitigates MI‐induced sympathetic remodeling and hyperactivity, and improves a variety of clinically relevant outcomes such as improves ventricular dysfunction, reduces infarct size, increases electrophysiological stability, and reduces susceptibility to VAs. These novel insights suggest that wireless ON holds translational potential for the clinical treatment of arrhythmia and other cardiovascular diseases related to sympathetic hyperactivity. Moreover, this innovative self‐powered optical system may provide an opportunity to develop implantable/wearable and self‐controllable devices for long‐term optogenetic therapy.

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.

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.

Abstract Mesenchymal stem cell (MSC)-based therapy has emerged as a novel strategy to treat many degenerative diseases. Accumulating evidence shows that the function of MSCs declines with age, thus limiting their regenerative capacity. Nonetheless, the underlying mechanisms that control MSC ageing are not well understood. We show that compared with bone marrow-MSCs (BM-MSCs) isolated from young and aged samples, NADH dehydrogenase (ubiquinone) iron-sulfur protein 6 (Ndufs6) is depressed in aged MSCs. Similar to that of Ndufs6 knockout (Ndufs6−/−) mice, MSCs exhibited a reduced self-renewal and differentiation capacity with a tendency to senescence in the presence of an increased p53/p21 level. Downregulation of Ndufs6 by siRNA also accelerated progression of wild-type BM-MSCs to an aged state. In contrast, replenishment of Ndufs6 in Ndufs6−/−-BM-MSCs significantly rejuvenated senescent cells and restored their proliferative ability. Compared with BM-MSCs, Ndufs6−/−-BM-MSCs displayed increased intracellular and mitochondrial reactive oxygen species (ROS), and decreased mitochondrial membrane potential. Treatment of Ndufs6−/−-BM-MSCs with mitochondrial ROS inhibitor Mito-TEMPO notably reversed the cellular senescence and reduced the increased p53/p21 level. We provide direct evidence that impairment of mitochondrial Ndufs6 is a putative accelerator of adult stem cell ageing that is associated with excessive ROS accumulation and upregulation of p53/p21. It also indicates that manipulation of mitochondrial function is critical and can effectively protect adult stem cells against senescence.

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.

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.

Background: The ventromedial hypothalamus (VMH) is an important nuclei in responding to emotional stress, and emotional stress is a risk factor for cardiovascular diseases. However, the role of the VMH in cardiovascular diseases remains unknown. This study aimed to investigate the effects and underlying mechanisms of VMH activation on hypertension related cardiac remodeling in two-kidney-one-clip (2K1C) hypertension (HTN) rats.Methods: Eighteen male Sprague-Dawley rats were injected with AAV-hSyn-hM3D(Gq) into the VMH at 0 weeks and then randomly divided into three groups: (1) sham group (sham 2K1C + saline i.p. injection); (2) HTN group (2K1C + saline i.p. injection); (3) HTN+VMH activation group (2K1C + clozapine-N-oxide i.p. injection). One week later, rats were subjected to a sham or 2K1C operation, and 2 weeks later rats were injected with clozapine-N-oxide or saline for 2 weeks.Results: In the HTN+VMH activation group, FosB expression was significantly increased in VMH sections compared with those of the other two groups. Compared to the HTN group, the HTN+VMH activation group showed significant: (1) increases in systolic blood pressure (SBP); (2) exacerbation of cardiac remodeling; and (3) increases in serum norepinephrine levels and sympathetic indices of heart rate variability. Additionally, myocardial RNA-sequencing analysis showed that VMH activation might regulate the HIF-1 and PPAR signal pathway and fatty acid metabolism. qPCR results confirmed that the relative mRNA expression of HIF-1α was increased and the PPARα and CPT-1 mRNA expression were decreased in the HTN+VMH activation group compared to the HTN group.Conclusions: VMH activation could increase SBP and aggravate cardiac remodeling possibly by sympathetic nerve activation and the HIF-1α/PPARα/CPT-1 signaling pathway might be the underlying mechanism.

Objective: Butyrate, a short-chain fatty acid (SCFA) produced by the intestinal microbiota, plays a protective role in cardiovascular diseases (CVDs), but the mechanisms involved in this process remain unelucidated. We aimed to explore the effect of butyrate on myocardial ischemia/reperfusion (I/R) injury through the gut-brain neural circuit.Methods: Rats were randomly divided into four groups: sham group (sham), I/R group (I/R), I/R+ butyrate group (butyrate), and I/R+ butyrate+ vagotomy group (vagotomy). The rats were treated with sodium butyrate for 4 weeks, and the gut-brain neural circuit was investigated by subdiaphragmatic vagotomy.Results: Butyrate treatment significantly reduced the infarct size and decreased the expression of creatine kinase (CK), creatine kinase myocardial isoenzyme (CK-MB), and lactate dehydrogenase (LDH) compared with the values found for the I/R group. In addition, the I/R-induced increases in inflammation, oxidative stress, and apoptosis were attenuated by butyrate. However, the above-mentioned protective effects were diminished by subdiaphragmatic vagotomy. The RNA sequencing results also revealed that the butyrate-induced protective changes at the cardiac transcription level were reversed by vagotomy. An analysis of the heart rate variability (HRV) and the detection of norepinephrine (NE) showed that butyrate significantly inhibited the I/R-induced autonomic imbalance, but this inhibition was not observed in the vagotomy group. Butyrate treatment also suppressed the neural activity of the paraventricular nucleus (PVN) and superior cervical ganglion (SCG), and both of these effects were lost after vagotomy.Conclusions: Butyrate treatment significantly improves myocardial I/R injury via a gut-brain neural circuit, and this cardioprotective effect is likely mediated by suppression of the sympathetic nervous system.

Background: We previously demonstrated the gut microbes-derived metabolite trimethylamine N-oxide (TMAO) could activate the atrial autonomic ganglion plexus and promote atrial arrhythmia. The cardiac sympathetic nervous system (CSNS) play important roles in modulating ventricular arrhythmia (VA). Methods: Part 1: To test whether TMAO can directly activate the CSNS, we performed local injection of TMAO into the left stellate ganglion (LSG). Part 2: To test whether TMAO can indirectly activate the CSNS through the central nervous system, we performed intravenous injection of TMAO. Ventricular electrophysiology and LSG function and neural activity were measured before and after TMAO administration. Then, the left anterior descending coronary artery was ligated, and electrocardiograms were recorded for 1 h. At the end of the experiment, LSG and paraventricular nucleus (PVN) tissues were excised for molecular analyses. Findings: Compared with the control, both intravenous and local TMAO administration significantly increased LSG function and activity, shortened effective refractory period, and aggravated ischemia-induced VA. Proinflammatory markers and c-fos in the LSG were also significantly upregulated in both TMAO-treated groups. Particularly, c-fos expression in PVN was significantly increased in the systemic TMAO administration group but not the local TMAO administration group. Interpretation: The gut microbe-derived metabolite TMAO can activate the CSNS and aggravate ischemia-induced VA via the direct pathway through the LSG and the indirect pathway through central autonomic activation. Fund: This work was supported by the National Key R&D Program of China [2017YFC1307800], and the National Natural Science Foundation of China [81530011, 81770364, 81570463, 81871486, 81600395, 81600367 and 81700444]. Keywords: Gut microbes, Trimethylamine N-oxide, Cardiac autonomic nervous system, Left stellate ganglion, Ventricular arrhythmia

Background: Circadian rhythms have a considerable impact on the daily physiology of the heart, and their disruption causes pathology. Several studies have revealed that circadian disruption impaired cardiac remodeling after myocardial infarction (MI); however, the underlying brain-heart mechanisms remain unknown. We aim to discuss whether circadian disruption facilitates cardiac remodeling after MI by activating sympathetic nervous system.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 pseudorabies virus (PRV) injections for trans-synaptic retrograde tracing; rats were randomly divided into two groups: MI+ circadian disruption + Empty Vector+ clozapine N-oxide (CNO) (Empty Vector), and MI+ circadian disruption + hM4D(Gi)+ CNO [hM4D(Gi)].Results: Circadian disruption significantly facilitated cardiac remodeling after MI with lower systolic function, larger left ventricular volume, and aggravated cardiac fibrosis. Cardiac sympathetic remodeling makers and serum norepinephrine levels were also significantly increased by circadian disruption. PRV virus-labeled neurons were identified in the superior cervical ganglion (SCG), paraventricular nucleus (PVN), and suprachiasmatic nucleus (SCN) regions. Ganglionic blockade via designer receptors exclusively activated by designer drugs (DREADD) technique suppressed the activity of sympathetic nervous system and significantly alleviated the disruption-related cardiac dysfunction.Conclusion: Circadian disruption adversely affected cardiac remodeling after MI possibly by activating sympathetic nervous system, and suppressing sympathetic activity can attenuate this disruption-related cardiac dysfunction.

The gastrointestinal (GI) tract in both vertebrates and invertebrates is now recognized as a major source of signals modulating, via gut-peptide hormones, the metabolic activities of peripheral organs, and carbo-lipid balance. Key advances in the understanding of metabolic functions of gut-peptide hormones and their mediated interorgan communication have been made using Drosophila as a model organism, given its powerful genetic tools and conserved metabolic regulation. Here, we summarize recent studies exploring peptide hormones that are involved in the communication between the midgut and other peripheral organs/tissues during feeding conditions. We also highlight the emerging impacts of fly gut-peptide hormones on stress sensing and carbo-lipid metabolism in various disease models, such as energy overload, pathogen infection, and tumor progression. Due to the functional similarity of intestine and its derived peptide hormones between Drosophila and mammals, it can be anticipated that findings obtained in the fly system will have important implications for the understanding of human physiology and pathology.

The melt content is significant characteristic for the low velocity layer, so it is very necessary to set up the quantitative relationship between the low velocity anomaly and the melt fraction. We describe the computational methods for melt volume fractions and discussed the parameter selections for the theoretical computations. • We discuss the seismic wave velocity characteristics and the equilibrium geometry model in the partial melting system. • Equations for computing the elastic properties atop the LVL are presented. • Parameter selection of the equilibrium geometry model is shown.

Maize leaf disease detection is an essential project in the maize planting stage. This paper proposes the convolutional neural network optimized by a Multi-Activation Function (MAF) module to detect maize leaf disease, aiming to increase the accuracy of traditional artificial intelligence methods. Since the disease dataset was insufficient, this paper adopts image pre-processing methods to extend and augment the disease samples. This paper uses transfer learning and warm-up method to accelerate the training. As a result, three kinds of maize diseases, including maculopathy, rust, and blight, could be detected efficiently and accurately. The accuracy of the proposed method in the validation set reached 97.41%. This paper carried out a baseline test to verify the effectiveness of the proposed method. First, three groups of CNNs with the best performance were selected. Then, ablation experiments were conducted on five CNNs. The results indicated that the performances of CNNs have been improved by adding the MAF module. In addition, the combination of Sigmoid, ReLU, and Mish showed the best performance on ResNet50. The accuracy can be improved by 2.33%, proving that the model proposed in this paper can be well applied to agricultural production.

Abstract Left stellate ganglion (LSG) hyperactivity promotes ischemia induced ventricular arrhythmia (VA). Blocking the Nav1.8 channel decreases neuron activity. Therefore, the present study aimed to investigate whether blocking the Nav1.8 channel with its specific blocker A-803467 in the LSG reduces sympathetic activity and exerts anti-arrhythmic effects. Forty canines were divided into dimethylsulfoxide (DMSO) group and 10 mM, 15 mM, and 20 mM A-803467 groups. A volume of 0.1 ml of A-803467 or DMSO was injected into the LSG. The ventricular electrophysiological parameters, LSG function were measured before and 30 min after the injection. VA was assessed for 60 min after ischemia and then LSG tissues were collected for molecular biological experiments. Compared with DMSO, concentration-dependent prolonged action potential duration and effective refractory period, decreased LSG function were identified after A-803467 treatment. Moreover, the severity of ischemia induced VA was decreased in A-803467 groups. Furthermore, decreased nerve growth factor, decreased c-fos and increased sympathetic neuron apoptosis were found in the LSG after A-803467 injection. In conclusion, blocking the Nav1.8 channel could significantly attenuate ischemia-induced VA, primarily by suppressing LSG activity.

The production of cellulases in plants is an economical method for the conversion of lignocellulosic biomass into fuels. Herein we report the expressions of two thermostable Acidothermus cellulolyticus cellulases, endo-1,4-β-D-glucanase (E1) and exoglucanase (Gux1), in tobacco and rice. To evaluate the expression of these recombinant cellulases, we expressed the full-length E1, the catalytic domains of E1 (E1cd) and Gux1 (Gux1cd), as well as an E1–Gux1cd fusion enzyme in various subcellular compartments. In the case of tobacco, transgenic plants that expressed apoplast-localized E1 showed the highest level of activity, about three times higher than those that expressed the cytosolic E1. In the case of rice, the level of cellulase-specific activity in the transgenic plants ranged from 11 to 20 nmol 4-methylumbelliferone min−1 mg−1 total soluble protein. The recombinant cellulases exhibited good thermostability below 70 °C. Furthermore, transgenic rice leaves that were stored at room temperature for a month lost about 20% of the initial cellulase activity. Taken together, the results suggested that heterologous expression of thermostable cellulases in plants may be a viable option for biomass conversion.

Objective: Renal ischemia reperfusion (I/R) is not an isolated event; however, it results in remote organ dysfunction. Vagus nerve stimulation (VNS) has shown protective effects against renal I/R injury via an anti-inflammatory mechanism. This study aimed to investigate whether VNS could attenuate liver injury induced by renal I/R and identify the underlying mechanisms. Methods: Eighteen healthy male Sprague-Dawley rats (200–250 g) were equally divided into three groups: sham group (sham surgery without I/R or VNS), I/R group (renal I/R) and VNS group (renal I/R plus VNS). The I/R model was established by excising the right kidney and then clamping the left renal pedicle with an occlusive nontraumatic microaneurysm clamp for 45 min followed by a 6-h reperfusion. The rats in the VNS group received spontaneous left cervical VNS with renal ischemia and reperfusion. At the end of the experiment, blood and liver tissues were collected to detect liver function, oxidative stress and inflammatory parameters. Additionally, TUNEL staining, real-time PCR, western blotting and hematoxylin and eosin staining of liver tissues were performed to assess liver injury and the underlying mechanisms. Results: Kidney and liver function was severely damaged in the I/R group compared to the sham group. However, VNS significantly protected kidney and liver function. Rats treated with VNS revealed decreases in oxidative enzymes, apoptosis and levels of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) in serum and liver compared with rats in the I/R group. Rats in the VNS group also showed increased antioxidant stress responses compared to rats in the I/R group. Conclusion: VNS exerts protective effects against liver injury from renal I/R via inhibiting oxidative stress and apoptosis, downregulating inflammatory cytokines and enhancing antioxidative capability in the liver, and may become a promising adjuvant therapeutic strategy for treating liver injury induced by acute renal injury.

Background: The NRG1/ErbB4 signaling mechanism has been widely studied in the central nervous system for many years. However, the role of this pathway in modulating the intrinsic cardiac nervous system is largely unknown.Objective: The present study investigated whether the NRG1/ErbB4 signaling system affects the activity of major atrial ganglionated plexi (GP) in a paroxysmal atrial fibrillation (AF) model by 6-h rapid atrial pacing (RAP).Methods: Twenty-four dogs were randomly divided into (1) a control group (saline microinjections into GP), (2) RAP group (saline microinjections into GP plus 6 h-RAP), (3) NRG1 group (microinjections of neuregulin-1 into GP plus 6 h-RAP) and (4) NRG1 + ERA group (microinjections of neuregulin-1 and ErbB4 receptor antagonist-ERA into GP plus 6 h-RAP). The effective refractory period (ERP), window of vulnerability (WOV), anterior right GP (ARGP) function and neural activity were measured. ARGP tissues were excised for histological study and western blotting.Results: When compared to the control group, 6 h-RAP produced a significant (1) decrease in ERP, an increase in ΣWOV, (2) an increase in ARGP neural activity and neural function, and (3) an increase in c-fos and nerve growth factor protein expression in the ARGP. However, microinjection of NRG1 into the ARGP prior to RAP prevented ERP shortening and AGRP activity enhancement and inhibited the expression of c-Fos and NGF proteins. Furthermore, these changes were significantly attenuated by pretreatment with an ErbB4 receptor antagonist.Conclusion: The NRG1/ErbB4 signaling pathway may exist in the GP, and activation of this pathway suppressed RAP-induced GP activation, atrial electrical remodeling and AF.

BackgroundThe mechanisms of atrial fibrillation (AF) induced by obstructive sleep apnea (OSA) are not completely understood. This study investigated the roles of the intrinsic and extrinsic cardiac autonomic nervous system in OSA‐induced AF and provided noninvasive autonomic nervous modulation for the suppression of OSA‐induced AF by using low‐level transcutaneous electrical stimulation (LL‐TS) of the auricular branch of the vagus nerve at the tragus. Methods and ResultsEighteen dogs received tracheostomy under general anesthesia and were randomly divided into 3 groups: the OSA group (OSA was simulated via clamping of the endotracheal tube at end expiration for 1.5 minutes every 10 minutes, n=6), the LL‐TS + OSA group (simulated OSA plus LL‐TS, at 80% of the slowing sinus rate, n=6), and the control group (sham surgery without stimulation, n=6). The effective refractory period was significantly shortened after 1 hour of simulated OSA, and the window of vulnerability and plasma norepinephrine levels were both markedly increased in the OSA group. OSA dramatically increased the neural function and activity of the intrinsic and extrinsic cardiac autonomic nervous system, including the superior left ganglionated plexus, the left stellate ganglion, and the left renal sympathetic nerve. OSA also significantly upregulated the expression levels of c‐fos and nerve growth factor in the superior left ganglionated plexus and the left stellate ganglion. However, LL‐TS markedly improved these parameters. ConclusionsThese findings suggest that the intrinsic and extrinsic cardiac autonomic nervous system plays crucial roles in the acute stage of OSA‐induced AF. Noninvasive LL‐TS suppressed shortening of atrial refractoriness and autonomic remodeling, which prevented OSA‐induced AF.

Background Recent studies have demonstrated that there is a high variability of renal sympathetic nerve density distribution from proximal to distal renal artery segments. The aim of our study was to investigate the roles of renal sympathetic nerve stimulation (RSS) on atrial fibrillation and cardiac autonomic nervous activity. Methods and Results Twenty‐eight dogs were randomly assigned to the proximal RSS group (P‐RSS, N=7), middle RSS group (M‐RSS, N=7), distal RSS group (D‐RSS, N=7), and the control group (sham RSS, N=7). RSS was performed using electrical stimulation on the bilateral renal arteries for 3 hours. Effective refractory period and the window of vulnerability were measured at atrial and pulmonary veins sites. Superior left ganglionated plexi (SLGP) and left stellate ganglion (LSG) function and neural activity were determined. C‐fos and nerve growth factor protein expression in the SLGP and LSG were examined. Only P‐RSS (1) caused pronounced blood pressure rises, induced a significant decrease in effective refractory period, and generated a marked increase in cumulative window of vulnerability and effective refractory period dispersion; (2) increased the frequency and amplitude of the neural activity in the SLGP and LSG; (3) increased SLGP and LSG function; and (4) upregulated the level of c‐fos and nerve growth factor expression in the SLGP and LSG. Conclusions This study demonstrated that renal sympathetic nerve activation induced by 3 hours of P‐RSS facilitated atrial fibrillation inducibility by upregulating cardiac autonomic nervous activity, suggesting a potential autonomic cross talk between kidney and heart.

Lanthanum sulfadiazine (LaSD) was synthesized from sulfadiazine and lanthanum nitrate using water as solvent under alkaline conditions, and was used as a novel rare earth thermal stabilizer to stabilize poly(vinyl chloride) (PVC). The structure of LaSD was characterized by elemental analysis (EA), Fourier transform infrared spectroscopy (FTIR) and thermo- gravimetric analysis (TGA). The influence of lanthanum sulfadiazine with calcium stearate (CaSt2) and epoxidized soybean oil (ESBO) on stabilizing PVC was studied by using the Congo red test, oven discoloration test, UV-vis spectroscopy and thermal decomposition kinetics. The results showed that the addition of LaSD as a thermal stabilizer can significantly improve the initial whiteness and long-term stability of PVC. In addition, the synergies between LaSD, ESBO, and CaSt2 can provide outstanding improvement in the long-term thermal stability of PVC. When the ratio of LaSD/ESBO/CaSt2 is 1.8/0.6/0.6, its thermal stability time is 2193 s which is the best state for stabilizing PVC. Furthermore, comparing the reaction energy (Ea) and the variations in the conjugate double bond concentration in PVC samples, the order of thermal stability of PVC was PVC/LaSD/ESBO/CaSt2 > PVC/LaSD/ESBO > PVC/LaSD. The thermal stability mechanism of LaSD on PVC was studied by the AgCl precipitation method and FTIR spectrum. The results showed that the action of LaSD on PVC was achieved through replacing unstable chlorine atoms and absorbing hydrogen chloride.

It is well known that when excited by a stochastic base acceleration, the power absorbed by a nonlinear Duffing-type piezoelectric (PE) or electromagnetic (EM) energy harvester might not be increased effectively compared to a linear one. When intentionally introducing nonlinear magnetic forces into a doubly-clamped hybrid PE and EM energy harvester subjected to narrow-band (colored) excitation however, the power output could be improved to a much higher value. Also, in comparison with the typical nonlinear PE or EM generator, the influence of load and excitation parameters on the performance of a nonlinear hybrid energy harvester under colored excitation has been proven rather different as well. These results are derived analytically by solving the Fokker-Planck (FP) equation, and numerically by Monte Carlo (MC) simulations for validation. Besides, for a nonlinear hybrid configuration excited by colored noise approaching white Gaussian excitation, theoretical output characteristics are discussed and compared with results from a reported theory for white Gaussian excited case, which again verifies the feasibility of the theoretical analysis.

High night temperature stress is one of the main environmental factors affecting rice yield and quality. More and more evidence shows that microRNA (miRNA) plays an important role in various abiotic stresses. However, the molecular network of miRNA regulation on rice tolerance to high night temperatures remains unclear. Here, small RNA, transcriptome and degradome sequencing were integrated to identify differentially expressed miRNAs, genes, and key miRNA-target gene pairs in rice heat-sensitive and heat-tolerant lines at the filling stage suffering from high night temperature stress. It was discovered that there were notable differences in the relative expression of 102 miRNAs between the two rice lines under stress. Meanwhile, 5263 and 5405 mRNAs were differentially expressed in the heat-sensitive line and heat-tolerant line, and functional enrichment analysis revealed that these genes were involved in heatrelated processes and pathways. The miRNAs-mRNAs target relationship was further verified by degradome sequencing. Eventually, 49 miRNAs-222 mRNAs target pairs with reverse expression patterns showed significant relative expression changes between the heat-tolerant and the heat-sensitive line, being suggested to be responsible for the heat tolerance difference of these two rice lines. Functional analysis of these 222 mRNA transcripts showed that high night temperature-responsive miRNAs targeted these mRNAs involved in many heat-related biological processes, such as transcription regulation, chloroplast regulation, mitochondrion regulation, protein folding, hormone regulation and redox process. This study identified possible miRNA-mRNA regulation relationships in response to high night temperature stress in rice and potentially contributed to heat resistance breeding of rice in the future. [ABSTRACT FROM AUTHOR]

In-situ high-pressure and high-temperature X-ray powder diffraction has been employed to investigate the compressibility and volume thermal expansion of a naturally occurring hypersthene specimen (En0.540Fs0.424Ts0.028), using an externally heated diamond anvil cell (DAC) combined with synchrotron radiation up to 9.3 GPa and 673 K. The isothermal bulk modulus K0 = 120(5) GPa and its pressure derivative K0′ = 7.7(1.7) are obtained by analyzing room-temperature P-V data with the third-order Birch-Murnaghan equation of state (B-M EoS). The present study appears to be in agreement with previous data that the enrichment of Al stiffens the structure. The volume thermal expansion coefficient of hypersthene at ∼6.6(2) GPa is determined to be α0 = 3.23(7) ×10-5/K, which is comparable to that of Fe-poor compositions, suggesting that the substitution of Fe for Mg has a weak influence on the thermal expansivity of orthopyroxene. [ABSTRACT FROM AUTHOR]

Subduction zones can generally be classified into Mariana type and Chilean type depending on plate ages, plate thicknesses, subduction angles, back-arc deformation patterns, etc. The double seismic zones (DSZs) in subduction zones are mainly divided into type I and type II which, respectively, correspond to the Mariana type and Chilean type in most cases. Seismic anisotropy is an important parameter characterizing the geophysical features of the lithosphere, including the subduction zones, and can be described by the two parameters of delay time δt and fast wave polarization direction ϕ. We totally collected 524 seismic anisotropy data records from 24 DSZs and analyzed the statistical correlations between seismic anisotropy and the related physical parameters of DSZs. Our statistical analysis demonstrated that the fast wave polarization directions are parallel to the trench strike with no more than 30° for most type I DSZs, while being nearly perpendicular to the trench strike for type II DSZs. We also calculated roughly linear correlations that the delay time δt increases with dip angles but decreases with subduction rates. A linear equation was summarized to describe the strong correlation between DSZ's subduction angle aDSZ and seismic anisotropy in subduction zones. These results suggest that the anisotropic structure of the subducting lithosphere can be described as a possible equivalent crystal similar to the olivine crystal with three mutually orthogonal polarization axes, of which the longest and the second axes are nearly along the trench-perpendicular and trench-parallel directions, respectively. [ABSTRACT FROM AUTHOR]

High mobility group box 1 (HMGB1) protein serves an important role in myocardial ischemia/reperfusion (I/R) injury. MicroRNAs (miRNAs) are a group of small non-coding RNAs that regulate numerous signaling pathways involved in myocardial I/R injury. The present study aimed to investigate whether miR-451 protects against cardiomyocyte anoxia/reoxygenation (A/R) injury by attenuating HMGB1 expression. Neonatal rat ventricular cardiomyocytes were prepared and then subjected to A/R injury. The effect of upregulation or downregulation of miR-451 on cell viability, apoptosis, superoxide dismutase (SOD) activity, and the expression of cleaved-caspase-3 and HMGB1 were measured accordingly. A luciferase assay was performed to further confirm whether miR-451 can directly recognize the 3'-untranslated region of HMGB1 in HEK293 cells. The expression of miR-451 was significantly decreased in the cardiomyocytes during A/R, and upregulation of miR-451 led to increased miR-451 expression (P<0.05). Upregulation of miR-451 significantly attenuated the loss of cardiomyocyte viability (P<0.05) and increased the intracellular levels of SOD during A/R (P<0.05). Furthermore, upregulation of miR-451 significantly decreased the apoptosis of cardiomyocytes during A/R (P<0.05). The HMGB1 mRNA and protein expression levels were significantly downregulated in the Ad-miR-451 group compared with those in the A/R group (P<0.05). In addition, upregulation of miR-451 reduced its translocation from the nucleus to the cytoplasm. The luciferase assay confirmed that HMGB1 mRNA is a direct target of miR-451 in cardiomyocytes. In conclusion, the present study suggested that upregulation of miR-451 could protect against A/R-induced cardiomyocyte injury by inhibiting HMGB1 expression. [ABSTRACT FROM AUTHOR]