The diagnostic value of bronchoalveolar lavage fluid metagenomic next-generation sequencing in critically ill patients with respiratory tract infections.

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.

Lentivirus-modified hematopoietic stem cell gene therapy for advanced symptomatic juvenile metachromatic leukodystrophy: A long-term follow-up pilot study.

Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre- and early-symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early-onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with post-symptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over nine years. The most common adverse events (AEs) within two months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with post-symptomatic juvenile MLD.

Vaccination induces broadly neutralizing antibody precursors to HIV gp41.

A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.

Hydrochemical fingerprints of karst underground river systems impacted by urbanization in Guiyang, Southwest China.

Karst groundwater plays an irreplaceable role in the formation and development of urban areas, and land-use and land-cover change (LUCC) and the input of pollutants during the urbanization process would pose potential environmental risks to underground rivers. We analysed the relationship between urbanization processes and underground river hydrochemistry over nearly 35 years in Guiyang city, southwest of China, it was found that concentrations of various cations and anions, as well as total dissolved solids (TDS), gradually increased with the urbanization process, with significant fluctuations during the rapid urbanization periods. The Hydrochemical Facies Evolution Diagram (HFED) clearly showed the influence of urbanization on the hydrochemistry of the underground rivers. The ion ratios of γMg2+/γCa2+-γHCO3-, γNa+/γCl-, Ca2+/Mg2+-Ca2+ or Mg2+/Σ cations, HCO3-/SO42--HCO3- or SO42-/Σ anions revealed two distinct phases in the hydrochemical evolution of the underground river system, highly consistent with the urbanization process. Before the rapid urbanization, acid deposition and agricultural activities affected the hydrochemistry, with HCO3-Ca·Mg and HCO3·SO4-Ca·Mg as the dominant types controlled by limestone and dolomite dissolution in water-rock interactions. As acid deposition diminished, the input of SO42- from urban sewage compensated for the reduced impact, but the increased impermeable surfaces reduced the infiltration of atmospheric precipitation, leading to a reduced dissolution of dolomite minerals in water-rock interactions, resulting in a decrease in Mg2+ and a change in the hydrochemical type. The hydrochemical type evolved from a single HCO3·SO4-Ca·Mg type and HCO3-Ca·Mg type to multiple types, such as HCO3·Cl-Ca, HCO3·SO4-Ca, HCO3-Ca, and HCO3·SO4-Ca·Mg, and was highly unstable. With changes in land use, the proportions of various cations and anions in the hydrochemistry changed, especially NH4+, NO3-, SO42-, Na+, and Cl-, which were more sensitive to human activities. This study indicated the impact of urbanization on the hydrochemistry of the underground river system, with the input of SO42- from human activities and the increase in paved surfaces due to urbanization collectively altering the hydrochemical types of the underground river system. The rapid response of karst underground river system hydrochemistry indicates a potential impact on groundwater system by urbanization that should not be ignored.

Symmetry-Reduction Enhanced Polarization-Sensitive Photoresponse Based on One-Dimensional van der Waals Materials.

Designing high-performance polarization-sensitive photodetectors is essential for photonic device applications. Anisotropic one-dimensional (1D) van der Waals (vdW) materials have provided a promising platform to that end. Despite significant advances in 1D vdW photonic devices, their performance is still far from delivering practical potential. Herein, we propose the design of high-performance polarization-sensitive photodetectors using unique 1D vdW materials. By leveraging the chemical vapor transport technique, we successfully fabricate high-quality 1D vdW Nb2Pd1-xSe5 (x = 0.29) nanowires. The 1D vdW Nb2Pd1-xSe5 photodetector exhibits a high mobility of ∼56 cm2/(V s) and superior photoresponse performance, including a high responsivity of 1A/W and an ultrafast response time of ∼8 µs under 638 nm illumination. Moreover, the 1D vdW Nb2Pd1-xSe5 photodetector demonstrates excellent polarization-sensitive photoresponse with a degree of linear polarization (DOLP) up to 0.85 and can be modulated by adjusting the gate voltage, laser power density, and wavelength. Those exceptional performance are believed to be relevant to the symmetry-reduction induced by the partial occupation of Pd sites. This study offers feasible approaches to enhance the anisotropy of 1D vdW materials and the modulation of their polarization-sensitive photoresponse, which may provide deep insights into the physical origin of anisotropic properties of 1D vdW materials.

Systematic identification and characterization of microRNAs with target genes involved in high night temperature stress at the filling stage of rice.

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 heat-related 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.

Noninvasive neuromodulation protects against doxorubicin-induced cardiotoxicity and inhibits tumor growth.

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.

AdipoRon ameliorates the progression of heart failure with preserved ejection fraction via mitigating lipid accumulation and fibrosis.

INTRODUCTION: Obesity and imbalance in lipid homeostasis contribute greatly to heart failure with preserved ejection fraction (HFpEF), the dominant form of heart failure. Few effective therapies exist to control metabolic alterations and lipid homeostasis. OBJECTIVES: We aimed to investigate the cardioprotective roles of AdipoRon, the adiponectin receptor agonist, in regulating lipid accumulation in the two-hit HFpEF model. METHODS: HFpEF mouse model was induced using 60 % high-fat diet plus L-NAME drinking water. Then, AdipoRon (50 mg/kg) or vehicle were administered by gavage to the two-hit HFpEF mouse model once daily for 4 weeks. Cardiac function was evaluated using echocardiography, and Postmortem analysis included RNA-sequencing, untargeted metabolomics, transmission electron microscopy and molecular biology methods. RESULTS: Our study presents the pioneering evidence that AdipoR was downregulated and impaired fatty acid oxidation in the myocardia of HFpEF mice, which was associated with lipid metabolism as indicated by untargeted metabolomics. AdipoRon, orally active synthetic adiponectin receptor agonist, could upregulate AdipoR1/2 (independently of adiponectin) and reduce lipid droplet accumulation, and alleviate fibrosis to restore HFpEF phenotypes. Finally, AdipoRon primarily exerted its effects through restoring the balance of myocardial fatty acid intake, transport, and oxidation via the downstream AMPKα or PPARα signaling pathways. The protective effects of AdipoRon in HFpEF mice were reversed by compound C and GW6471, inhibitors of AMPKα and PPARα, respectively. CONCLUSIONS: AdipoRon ameliorated the HFpEF phenotype by promoting myocardial fatty acid oxidation, decreasing fatty acid transport, and inhibiting fibrosis via the upregulation of AdipoR and the activation of AdipoR1/AMPKα and AdipoR2/PPARα-related downstream pathways. These findings underscore the therapeutic potential of AdipoRon in HFpEF. Importantly, all these parameters get restored in the context of continued mechanical and metabolic stressors associated with HFpEF.

Efficacy of a WeChat-Based Multimodal Digital Transformation Management Model in New-Onset Mild to Moderate Hypertension: Randomized Clinical Trial.

BACKGROUND: The advantages of multimodal digitally transformed mobile health management for patients diagnosed with mild to moderate hypertension are not yet established. OBJECTIVE: We aim to evaluate the therapeutic benefits of a novel WeChat-based multimodal digital transforming management model in mobile health blood pressure (BP) management. METHODS: This 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. RESULTS: The 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<.001) and -4.85 mm Hg (95% CI -8.41 to -1.30 mm Hg; P=.008), respectively. The mean office BP decreased from 153.64 (SD 8.39)/93.56 (SD 8.45) to 127.81 (SD 8.04)/ 82.16 (SD 8.06) mm Hg in the multimodal intervention group and from 151.48 (SD 7.14)/(91.31 (SD 9.61) to 134.92 (SD 10.11)/85.09 (SD 8.26) mm Hg in the usual care group, with a mean difference in systolic blood pressure and diastolic blood pressure of -9.27 mm Hg (95% CI -12.62 to -5.91 mm Hg; P<.001) and -5.18 mm Hg (95% CI -8.47 to -1.89 mm Hg; P=.002), respectively. From baseline to 6 months, home BP control <140/90 mm Hg was achieved in 64 (72.7%) patients in the multimodal intervention group and 46 (52.9%) patients in the usual care group (P=.007). Meanwhile, home BP control <130/80 mm Hg was achieved in 32 (36.4%) patients in the multimodal intervention group and 16 (18.4%) patients in the usual care group (P=.008). After 6 months, there were significant differences in the quality-of-life total and graded scores, including self-rating anxiety scale scores (P=.04), self-rating depression scale scores (P=.03), and Pittsburgh Sleep Quality Index scores (P<.001), in the multimodal intervention group compared with the usual care group. CONCLUSIONS: The WeChat-based multimodal intervention model improved the BP control rates and lowered the BP levels more than the usual care approach. The multimodal digital transforming management model for hypertension represents an emerging medical practice that utilizes the individual's various risk factor profiles for primary care and personalized therapy decision-making in patients with hypertension. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200063550; https://www.chictr.org.cn/showproj.html?proj=175816.

Binary Transition-Metal Sulfides/MXene Synergistically Promote Polysulfide Adsorption and Conversion in Lithium-Sulfur Batteries.

Currently, severe shuttle effects and sluggish conversion kinetics are the main obstacles to the advancement of lithium-sulfur (Li-S) batteries. Modification of the battery separator by a catalyst is a promising approach to tackle these problems, but simultaneously obtaining rich catalytic active sites, high conductivity, and remarkable stability remains a great challenge. Herein, a flower-like MXene/MoS2/SnS@C heterostructure as the functional intercalation of Li-S batteries was prepared for accelerating the synergistic adsorption-electrocatalysis of sulfur conversion. The MXene skeleton constructs a three-dimensional conductive network that anchors polysulfides and enhances charge transfer. Meanwhile, the MoS2/SnS has rich active sites for accelerating polysulfide conversion, leading to excellent electrochemical performances. A battery with MXene/MoS2/SnS@C displays an extraordinary capacity of 836.1 mAh g-1 over 200 cycles at 0.5C and demonstrates a remarkable cycling stability with a capacity attenuation of approximately 0.051% per cycle during 1000 cycles at 2C. When the sulfur loading reaches 5.1 mg cm-2, the capacity still maintains 722.4 mAh g-1 over 50 cycles. This research proposes a novel strategy to design stable catalysts for Li-S batteries with an extended lifespan.

Dual-Defect Engineering of Bidirectional Catalyst for High-Performing Lithium-Sulfur Batteries.

Practical applications of lithium-sulfur (Li-S) batteries have been hindered by sluggish reaction kinetics and severe capacity decay during charge-discharge cycling due to the notorious shuttle effect of polysulfide and the unfavored deposition and dissolution of Li2 S. Herein, to address these issues, a double-defect engineering strategy is developed for preparing Co-doped FeP catalyst containing P vacancies on MXene, which effectively improves the bidirectional redox of Li2 S. Mechanism analysis indicates that P vacancy accelerates Li2 S nucleation via increased unsaturated sites, and Co doping generates local electric field to reduce the reaction energy barrier and accelerate Li2 S dissolution. MXene provides highly conductive channels for electron transport, and effectively captures polysulfide. The double-defect catalyst enables an impressive reversible specific capacity of 1297.9 mAh g-1 at 0.2 C, and excellent rate capability of 726.5 mAh g-1 at 4 C. Remarkably, it demonstrates excellent cycling stability with capacity retention of 533.3 mAh g-1 after 500 cycles at 2 C. The results can unlock the double-defect engineering of vacancy induction and heteroatomic doping towards practical Li-S batteries.

Gut AstA mediates sleep deprivation-induced energy wasting in Drosophila.

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.

Dry Nutrition Delivery System Based on Defatted Soybean Particles and Its Application with ß-Carotene.

Many nutrition delivery systems (NDSs) have been developed for the encapsulation, protection, and delivery of bioactive compounds, such as ß-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 ß-carotene-DSP mixture. The loading efficiency of the NDS reached 89.0%, and the cumulative release rate decreased from 15.1% (free ß-carotene) to 6.0% within 8 h. The stability of ß-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 ß-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 ß-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 ß-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.

Construction of Co3 O4 /ZnO Heterojunctions in Hollow N-Doped Carbon Nanocages as Microreactors for Lithium-Sulfur Full Batteries.

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 Co3 O4 /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.

Increased sympathetic outflow induced by emotional stress aggravates myocardial ischemia-reperfusion injury via activation of TLR7/MyD88/IRF5 signaling pathway.

BACKGROUND AND OBJECTIVE: Emotional stress substantially increases the risk of ischemic cardiovascular diseases. Previous study indicates that sympathetic outflow is increased under emotional stress. We aim to investigate the role of increased sympathetic outflow induced by emotional stress in myocardial ischemia-reperfusion (I/R) injury, and explore the underlying mechanisms. METHODS AND RESULTS: We used Designer Receptors Exclusively Activated by Designer Drugs technique to activate the ventromedial hypothalamus (VMH), a critical emotion-related nucleus. The results revealed that emotional stress stimulated by VMH activation increased sympathetic outflow, enhanced blood pressure, aggravated myocardial I/R injury, and exacerbated infarct size. The RNA-seq and molecular detection demonstrated that toll-like receptor 7 (TLR7), myeloid differentiation factor 88 (MyD88), interferon regulatory factor 5 (IRF5), and downstream inflammatory markers in cardiomyocytes were significantly upregulated. Emotional stress-induced sympathetic outflow further exacerbated the disorder of the TLR7/MyD88/IRF5 inflammatory signaling pathway. While inhibition of the signaling pathway partially alleviated myocardial I/R injury aggravated by emotional stress-induced sympathetic outflow. CONCLUSION: Increased sympathetic outflow induced by emotional stress activates TLR7/MyD88/IRF5 signaling pathway, ultimately aggravating I/R injury.

Allergenicity of peanut allergens and its dependence on the structure.

Food allergies are a global food safety problem. Peanut allergies are common due, in part, to their popular utilization in the food industry. Peanut allergy is typically an immunoglobulin E-mediated reaction, and peanuts contain 17 allergens belonging to different families in peanut. In this review, we first introduce the mechanisms and management of peanut allergy, followed by the basic structures of associated allergens. Subsequently, we summarize methods of epitope localization for peanut allergens. These methods can be instrumental in speeding up the discovery of allergenicity-dependent structures. Many attempts have been made to decrease the allergenicity of peanuts. The structures of hypoallergens, which are manufactured during processing, were analyzed to strengthen the desensitization process and allergen immunotherapy. The identification of conformational epitopes is the bottleneck in both peanut and food allergies. Further, the identification and modification of such epitopes will lead to improved strategies for managing and preventing peanut allergy. Combining traditional wet chemistry research with structure simulation studies will help in the epitopes' localization.

Wireless Self-Powered Optogenetic System for Long-Term Cardiac Neuromodulation to Improve Post-MI Cardiac Remodeling and Malignant Arrhythmia.

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.

Subthreshold splenic nerve stimulation prevents myocardial Ischemia-Reperfusion injury via neuroimmunomodulation of proinflammatory factor levels.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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-1ß, 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. CONCLUSIONS: 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.

Effect of Structural Targeted Modifications on the Potential Allergenicity of Peanut Allergen Ara h 2.

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 R62DPYSPSQDPYSPS75. In conclusion, the disulfide bond and the SASA of aromatic residues are important for the allergenicity of Ara h 2. The localized structure R62DPYSPSQDPYSPS75 is also crucial for the allergenicity of Ara h 2.