Multi-omics blood atlas reveals unique features of immune and platelet responses to SARS-CoV-2 Omicron breakthrough infection.

Although host responses to the ancestral SARS-CoV-2 strain are well described, those to the new Omicron variants are less resolved. We profiled the clinical phenomes, transcriptomes, proteomes, metabolomes, and immune repertoires of >1,000 blood cell or plasma specimens from SARS-CoV-2 Omicron patients. Using in-depth integrated multi-omics, we dissected the host response dynamics during multiple disease phases to reveal the molecular and cellular landscapes in the blood. Specifically, we detected enhanced interferon-mediated antiviral signatures of platelets in Omicron-infected patients, and platelets preferentially formed widespread aggregates with leukocytes to modulate immune cell functions. In addition, patients who were re-tested positive for viral RNA showed marked reductions in B cell receptor clones, antibody generation, and neutralizing capacity against Omicron. Finally, we developed a machine learning model that accurately predicted the probability of re-positivity in Omicron patients. Our study may inspire a paradigm shift in studying systemic diseases and emerging public health concerns.

The RNA-binding protein CSDE1 promotes hematopoietic stem and progenitor cell generation via translational control of Wnt signaling.

In vertebrates, the earliest hematopoietic stem and progenitor cells (HSPCs) are derived from a subset of specialized endothelial cells, hemogenic endothelial cells, in the aorta-gonad-mesonephros region through endothelial-to-hematopoietic transition. HSPC generation is efficiently and accurately regulated by a variety of factors and signals; however, the precise control of these signals remains incompletely understood. Post-transcriptional regulation is crucial for gene expression, as the transcripts are usually bound by RNA-binding proteins (RBPs) to regulate RNA metabolism. Here, we report that the RBP protein Csde1-mediated translational control is essential for HSPC generation during zebrafish early development. Genetic mutants and morphants demonstrated that depletion of csde1 impaired HSPC production in zebrafish embryos. Mechanistically, Csde1 regulates HSPC generation through modulating Wnt/ß-catenin signaling activity. We demonstrate that Csde1 binds to ctnnb1 mRNAs (encoding ß-catenin, an effector of Wnt signaling) and regulates translation but not stability of ctnnb1 mRNA, which further enhances ß-catenin protein level and Wnt signal transduction activities. Together, we identify Csde1 as an important post-transcriptional regulator and provide new insights into how Wnt/ß-catenin signaling is precisely regulated at the post-transcriptional level.

Inhalable Polymeric Microparticles for Phage and Photothermal Synergistic Therapy of Methicillin-Resistant Staphylococcus aureus Pneumonia.

Acute methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is a common and serious lung infection with high morbidity and mortality rates. Due to the increasing antibiotic resistance, toxicity, and pathogenicity of MRSA, there is an urgent need to explore effective antibacterial strategies. In this study, we developed a dry powder inhalable formulation which is composed of porous microspheres prepared from poly(lactic-co-glycolic acid) (PLGA), internally loaded with indocyanine green (ICG)-modified, heat-resistant phages that we screened for their high efficacy against MRSA. This formulation can deliver therapeutic doses of ICG-modified active phages to the deep lung tissue infection sites, avoiding rapid clearance by alveolar macrophages. Combined with the synergistic treatment of phage therapy and photothermal therapy, the formulation demonstrates potent bactericidal effects in acute MRSA pneumonia. With its long-term stability at room temperature and inhalable characteristics, this formulation has the potential to be a promising drug for the clinical treatment of MRSA pneumonia.

Salmonella Typhimurium alters galactitol metabolism under ciprofloxacin treatment to balance resistance and virulence.

Ciprofloxacin-resistant Salmonella Typhimurium (S. Typhimurium) causes a significant health burden worldwide. A wealth of studies has been published on the contributions of different mechanisms to ciprofloxacin resistance in Salmonella spp. But we still lack a deep understanding of the physiological responses and genetic changes that underlie ciprofloxacin exposure. This study aims to know how phenotypic and genotypic characteristics are impacted by ciprofloxacin exposure, from ciprofloxacin-susceptible to ciprofloxacin-resistant strains in vitro. Here, we investigated the multistep evolution of resistance in replicate populations of S. Typhimurium during 24 days of continuously increasing ciprofloxacin exposure and assessed how ciprofloxacin impacts physiology and genetics. Numerous studies have demonstrated that RamA is a global transcriptional regulator that prominently perturbs the transcriptional landscape of S. Typhimurium, resulting in a ciprofloxacin-resistant phenotype appearing first; the quinolone resistance-determining region mutation site can only be detected later. Comparing the microbial physiological changes and RNA sequencing (RNA-Seq) results of ancestral and selectable mutant strains, the selectable mutant strains had some fitness costs, such as decreased virulence, an increase of biofilm-forming ability, a change of "collateral" sensitivity to other drugs, and inability to utilize galactitol. Importantly, in the ciprofloxacin induced, RamA directly binds and activates the gatR gene responsible for the utilization of galactitol, but RamA deletion strains could not activate gatR. The elevated levels of RamA, which inhibit the galactitol metabolic pathway through the activation of gatR, can lead to a reduction in the growth rate, adhesion, and colonization resistance of S. Typhimurium. This finding is supported by studies conducted in M9 medium as well as in vivo infection models. IMPORTANCE: Treatment of antibiotic resistance can significantly benefit from a deeper understanding of the interactions between drugs and genetics. The physiological responses and genetic mechanisms in antibiotic-exposed bacteria are not well understood. Traditional resistance studies, often retrospective, fail to capture the entire resistance development process and typically exhibit unpredictable dynamics. To explore how clinical isolates of S. Typhimurium respond to ciprofloxacin, we analyzed their adaptive responses. We found that S. Typhimurium RamA-mediated regulation disrupts microbial metabolism under ciprofloxacin exposure, affecting genes in the galactitol metabolic pathways. This disruption facilitates adaptive responses to drug therapy and enhances the efficiency of intracellular survival. A more comprehensive and integrated understanding of these physiological and genetic changes is crucial for improving treatment outcomes.

A CsEIL3-CsARN6.1 module promotes waterlogging-triggered adventitious root formation in cucumber by activating the expression of CsPrx5.

The formation of adventitious roots (ARs) derived from hypocotyl is the most important morphological adaptation to waterlogging stress in Cucumis sativus (cucumber). Our previous study showed that cucumbers with the gene CsARN6.1, encoding an AAA ATPase domain-containing protein, were more tolerant to waterlogging through increased AR formation. However, the apparent function of CsARN6.1 remained unknown. Here, we showed that the CsARN6.1 signal was predominantly observed throughout the cambium of hypocotyls, where de novo AR primordia are formed upon waterlogging treatment. The silencing of CsARN6.1 expression by virus-induced gene silencing and CRISPR/Cas9 technologies adversely affects the formation of ARs under conditions of waterlogging. Waterlogging treatment significantly induced ethylene production, thus upregulating CsEIL3 expression, which encodes a putative transcription factor involved in ethylene signaling. Furthermore, yeast one-hybrid, electrophoretic mobility assay and transient expression analyses showed that CsEIL3 binds directly to the CsARN6.1 promoter to initiate its expression. CsARN6.1 was found to interact with CsPrx5, a waterlogging-responsive class-III peroxidase that enhanced H2 O2 production and increased AR formation. These data provide insights into understanding the molecular mechanisms of AAA ATPase domain-containing protein and uncover a molecular mechanism that links ethylene signaling with the formation of ARs triggered by waterlogging.

In Situ Quantitative Imaging of Plasma Membrane Stiffness in Live Cells Using a Genetically Encoded FRET Sensor.

Cell membrane stiffness is critical for cellular function, with cholesterol and sphingomyelin as pivot contributors. Current methods for measuring membrane stiffness are often invasive, ex situ, and slow in process, prompting the need for innovative techniques. Here, we present a fluorescence resonance energy transfer (FRET)-based protein sensor designed to address these challenges. The sensor consists of two fluorescent units targeting sphingomyelin and cholesterol, connected by a linker that responds to the proximity of these lipids. In rigid membranes, cholesterol and sphingomyelin are in close proximity, leading to an increased FRET signal. We utilized this sensor in combination with confocal microscopy to explore changes in plasma membrane stiffness under various conditions, including differences in osmotic pressure, the presence of reactive oxygen species (ROS) and variations in substrate stiffness. Furthermore, we explored the impact of SARS-CoV-2 on membrane stiffness and the distribution of ACE2 after attachment to the cell membrane. This tool offers substantial potential for future investigations in the field of mechanobiology.

PHPB ameliorates memory deficits and reduces oxidative injury in Alzheimer's disease mouse model by activating Nrf2 signaling pathway.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in elderly people and substantially affects patient quality of life. Oxidative stress is considered a key factor in the development of AD. Nrf2 plays a vital role in maintaining redox homeostasis and regulating neuroinflammatory responses in AD. Previous studies show that potassium 2-(1-hydroxypentyl)-benzoate (PHPB) exerts neuroprotective effects against cognitive impairment in a variety of dementia animal models such as APP/PS1 transgenic mice. In this study we investigated whether PHPB ameriorated the progression of AD by reducing oxidative stress (OS) damage. Both 5- and 13-month-old APP/PS1 mice were administered PHPB (100 mg·kg-1·d-1, i.g.) for 10 weeks. After the cognition assessment, the mice were euthanized, and the left hemisphere of the brain was harvested for analyses. We showed that 5-month-old APP/PS1 mice already exhibited impaired performance in the step-down test, and knockdown of Nrf2 gene only slightly increased the impairment, while knockdown of Nrf2 gene in 13-month-old APP/PS1 mice resulted in greatly worse performance. PHPB administration significantly ameliorated the cognition impairments and enhanced antioxidative capacity in APP/PS1 mice. In addition, PHPB administration significantly increased the p-AKT/AKT and p-GSK3ß/GSK3ß ratios and the expression levels of Nrf2, HO-1 and NQO-1 in APP/PS1 mice, but these changes were abolished by knockdown of Nrf2 gene. In SK-N-SH APPwt cells and primary mouse neurons, PHPB (10 µM) significantly increased the p-AKT/AKT and p-GSK3ß/GSK3ß ratios and the level of Nrf2, which were blocked by knockdown of Nrf2 gene. In summary, this study demonstrates that PHPB exerts a protective effect via the Akt/GSK3ß/Nrf2 pathway and it might be a promising neuroprotective agent for the treatment of AD.

Overexpression of PRDM16 improves muscle function after rotator cuff tears.

BACKGROUND: Muscle atrophy, fibrosis, and fatty infiltration are commonly seen in rotator cuff tears (RCTs), which are critical factors that directly determine the clinical outcomes for patients with this injury. Therefore, improving muscle quality after RCT is crucial in improving the clinical outcome of tendon repair. In recent years, it has been discovered that adults have functional beige/brown adipose tissue (BAT) that can secrete batokines to promote muscle growth. PRDM16, a PR-domain-containing protein, was discovered with the ability to determine the brown fat cell fate and stimulate its development. Thus, the goal of this study was to discover the role of PRDM16 in improving muscle function after massive tendon tears using a transgenic mouse model with an elevated level of PRDM16 expression. METHODS: Transgenic aP2-driven PRDM16-overexpressing mice and C57BL/6J mice underwent unilateral supraspinatus (SS) tendon transection and suprascapular nerve transection (TTDN) as described previously (n = 8 in each group). DigiGait was performed to evaluate forelimb function at 6 weeks post the TTDN injury. Bilateral SS muscles, interscapular brown fat, epididymal white fat, and inguinal beige fat were harvested for analysis. The expression of PRDM16 in adipose tissue was detected by Western blot. Masson Trichrome staining was conducted to evaluate the muscle fibrosis, and Oil Red O staining was used to determine the fat infiltration. Muscle fiber type was determined by major histocompatibility complex (MHC) expression via immunostaining. All data were presented in the form of mean ± standard deviation. t test and 2-way analysis of variance was performed to determine a statistically significant difference between groups. Significance was considered when P < .05. RESULTS: Western blot data showed an increased expression of PRDM16 protein in both white and brown fat in PRDM16-overexpressing mice compared with wild-type (WT) mice. Even though PRDM16 overexpression had no effect on increasing muscle weight, it significantly improved the forelimbs function with longer brake, stance, and stride time and larger stride length and paw area in mice after RCT. Additionally, PRDM16-overexpressing mice showed no difference in the amount of fibrosis when compared to WT mice; however, they had a significantly reduced area of fatty infiltration. These mice also exhibited abundant MHC-IIx fiber percentage in the supraspinatus muscle after TTDN. CONCLUSION: Overexpression of PRDM16 significantly improved muscle function and reduced fatty infiltration after rotator cuff tears. Promoting BAT activity is beneficial in improving rotator cuff muscle quality and shoulder function after RCT.

Improving Triethylamine-Sensing Performance of WO3 Nanoplates through In Situ Heterojunction Construction.

Surface engineering techniques can be used to develop high-performance gas sensing materials and advance the development of sensors. In this study, we improved the gas sensing performance of two-dimensional (2D) WO3 nanoplates by combining surface Zn modification and the in situ formation of ZnWO4/WO3 heterojunctions. Introducing Zn atoms by surface modification can reconstruct the atomic surface of 2D WO3 nanoplates, creating additional active sites. This allowed for the preparation of various types of ZnWO4/WO3 heterojunctions on the surface of the WO3 nanoplates, which improved the selectivity and sensitivity to the target gas triethylamine. The sensor exhibited good gas sensing performance for triethylamine even at low operating temperatures and strongly resisted humidity changes. The ZnWO4/WO3 material we prepared demonstrated a nearly threefold improvement in the triethylamine (TEA) response, with a gas sensing responsivity of 40.75 for 10 ppm of TEA at 250 °C. The sensor based on ZnWO4/WO3 has a limit of detection (LOD) for TEA of 200 ppb in practical measurements (its theoretical LOD is even as low as 31 ppb). The method of growing ZnWO4 on the surface of WO3 nanoplates using surface modification techniques to form surface heterojunctions differs from ordinary composites. The results suggest that the in situ construction of surface heterojunctions using surface engineering strategies, such as in situ modifying, is a practical approach to enhance the gas sensing properties and resistance to the humidity changes of metal oxide materials.

His-Purkinje system pacing versus biventricular pacing in clinical efficacy: a systematic review and meta-analysis.

BACKGROUND: His-Purkinje system pacing (HPSP), including his-bundle pacing (HBP) and left bundle branch area pacing (LBBaP), imitates the natural conduction of the heart as an alternative to biventricular pacing (BVP) in cardiac resynchronization therapy (CRT). However, the feasibility and efficacy of HPSP were currently only evidenced by studies with a limited sample size, so this study aimed to provide a comprehensive assessment through a systematic review and meta-analysis. METHODS: In order to compare the clinical outcomes associated with HPSP and BVP in patients for CRT, PubMed, EMBASE, Cochrane Library and Web of Science database were searched from inception to April 10, 2023. Clinical outcomes of interest including QRS duration (QRSd), left ventricular (LV) function and New York Heart Association (NYHA) functional classification, pacing threshold, echocardiographic and clinical response, hospitalization rate of HF and all-cause mortality were also extracted and summarized for meta-analysis. RESULTS: A total of 13 studies (ten observational studies and three randomized studies) involving 1,121 patients were finally included. The patients were followed up for 6-27 months. Compared with BVP, CRT patients treated by HPSP presented shorter QRSd [mean difference (MD): -26.23 ms, 95% confidence interval (CI): -34.54 to -17.92, P < 0.001, I2 = 91%], greater LV functional improvement with increased left ventricular ejection fraction (LVEF) (MD: 6.01, 95% CI: 4.81 to 7.22, P < 0.001, I2 = 0%), decreased left ventricular end-diastolic dimension (LVEDD) (MD: -2.91, 95% CI: -4.86 to -0.95, P = 0.004, I2 = 35%), and more improved NYHA functional classification (MD: -0.45, 95% CI: -0.67 to -0.23, P < 0.001, I2 = 70%). In addition, HPSP was more likely to have higher echocardiographic [odds ratio (OR): 2.76, 95% CI: 1.74 to 4.39, P < 0.001, I2 = 0%], clinical (OR: 2.10, 95% CI: 1.16 to 3.80, P = 0.01, I2 = 0%) and super clinical (OR: 3.17, 95% CI: 2.09 to 4.79, P < 0.001, I2 = 0%) responses than BVP, and a lower hospitalization rate of HF (OR: 0.34, 95% CI: 0.22 to 0.51, P < 0.001, I2 = 0%), while presented no difference (OR: 0.68, 95% CI: 0.44 to 1.06, P = 0.09, I2 = 0%) in all-cause mortality compared with BVP. With threshold change taking into account, BVP was less stable than LBBaP (MD: -0.12 V, 95% CI: -0.22 to -0.03, P = 0.01, I2 = 57%), but had no difference with HBP (MD: 0.11 V, 95% CI: -0.09 to 0.31, P = 0.28, I2 = 0%). CONCLUSION: The present findings suggested that HPSP was associated with greater improvement of cardiac function in patients with indication for CRT and was a potential alternative to BVP to achieve physiological pacing through native his-purkinje system.

Transcription Factor ZmNAC20 Improves Drought Resistance by Promoting Stomatal Closure and Activating Expression of Stress-Responsive Genes in Maize.

Drought is a major environmental threat that limits crop growth, development, and productivity worldwide. Improving drought resistance with genetic engineering methods is necessary to tackle global climate change. It is well known that NAC (NAM, ATAF and CUC) transcription factors play a critical role in coping with drought stress in plants. In this study, we identified an NAC transcription factor ZmNAC20, which regulates drought stress response in maize. ZmNAC20 expression was rapidly upregulated by drought and abscisic acid (ABA). Under drought conditions, the ZmNAC20-overexpressing plants had higher relative water content and survival rate than the wild-type maize inbred B104, suggesting that overexpression of ZmNAC20 improved drought resistance in maize. The detached leaves of ZmNAC20-overexpressing plants lost less water than those of wild-type B104 after dehydration. Overexpression of ZmNAC20 promoted stomatal closure in response to ABA. ZmNAC20 was localized in the nucleus and regulated the expression of many genes involved in drought stress response using RNA-Seq analysis. The study indicated that ZmNAC20 improved drought resistance by promoting stomatal closure and activating the expression of stress-responsible genes in maize. Our findings provide a valuable gene and new clues on improving crop drought resistance.

The Role of Matrix Metalloproteinase-13 (MMP13) in TGFß/BMP Pathway Regulation of Fibro-Adipogenic Progenitor (FAP) Differentiation.

BACKGROUND/AIMS: Muscle fibrosis and fatty infiltration (FI) are common complications seen in various muscle disease states. Recent studies indicate that muscle residential fibro/adipogenic progenitors (FAPs) are the major cellular source for muscle fibrosis and FI. We previously showed that MMP13 knockout (KO) mice have significantly increased FI, suggesting an important role of MMP13 in muscle FI. However, how MMP13 affects the differentiation of FAPs remains unknown. METHODS: In order to assess the role of MMP-13 on FAP differentiation, we isolated FAPs from wildtype C57BL/6 and MMP13 knock out mice with FACS using CD31-, CD45-, Integrin α7- and Sca-1+ markers. FAPs were cultured in 24 well plate after FACS.in standard media till 80% confluent and then switched to adipogenic medium. In order to study the role of TGFß and BMP in their differentiation, FAPs from both wildtype and MMP13 KO mice were treated with TGFß1 (5 ng/ml). For MMP13 inhibitor treatment, FAPs from wildtype mice were incubated in adipogenic medium containing 10 µM MMP13 inhibitor (or vehicle) for 2 weeks. Immunofluorescence and gene expression analysis were used to assess FAP adipogenic and fibrogenic differentiation. FAPs were stained with Perilipin A (FITC, adipogenesis marker) and αSMA (Red, fibroblast marker), and DAPI. Real time PCR was performed for gene expression evaluation. A two-tailed Anova was used for statistical comparisons between groups, withp ≤ 0.05. Data are presented as mean ± standard deviation. RESULTS: In this study, we isolated FAPs from wildtype C57BL/6 and MMP13 KO mice and evaluated their adipogenic and fibrogenic differentiation in vitro. MMP13 KO FAPs demonstrated enhanced adipogenesis but reduced fibrogenesis compared to wildtype FAPs. Treating wildtype FAPs with an MMP13 inhibitor simulated phenotypes seen in MMP13 KO FAPs. In order to assess the role of MMP13 on TGFß/BMP signaling in regulating FAP differentiation, we treated wildtype and MMP13 KO FAPs with TGFß1, BMP7, TGFß inhibitor, and BMP inhibitor. TGFß1 treatment significantly enhanced fibrogenesis, but inhibited adipogenesis of wildtype FAPs. However, treatment with BMP7 showed the opposite effect. Interestingly, the effect of TGFß1/BMP7 was voided in MMP13 KO FAPs. Treating wildtype FAPs with MMP13 inhibitor also abolished the effect of TGFß1/BMP7 in FAP differentiation. CONCLUSION: Results from this study showed that TGFß1 inhibits FAP adipogenesis but stimulates FAP fibrogenesis. BMP7 was shown to promote FAP adipogenesis but reduce its fibrogenesis. The role of the TGFß/BMP signaling pathway regulating FAP differentiation was found to be MMP13 dependent. This study suggests that MMP13 is a critical downstream effector in TGFß/BMP pathway which may serve as a new therapeutic target for muscle fibrosis and FI.

A putative effector of the rubber-tree powdery mildew fungus has elicitor activity that can trigger plant immunity.

MAIN CONCLUSION: A putative powdery mildew effector can elicit defense responses including reactive oxygen species and callose accumulations in model plants Nicotiana benthamiana and Arabidopsis thaliana and host plant Hevea brasiliensis. Powdery mildew fungi cause severe diseases in many agricultural plants, such as the mildew fungus Erysiphe quercicola infecting the rubber tree (Hevea brasiliensis), causing latex yield losses. However, effectors of E. quercicola were rarely functionally characterized. In this study, we identified a highly specific candidate-secreted effector protein, EqCSEP04187, from E. quercicola. This putative effector is expressed at the late stage but not the early stage during infection. The constitutive expression of EqCSEP04187 in model plants Nicotiana benthamiana and Arabidopsis thaliana elicited defense responses, as did transient expression of EqCSEP04187 in protoplasts of H. brasiliensis. Introducing EqCSEP04187 into another H. brasiliensis-associated fungal pathogen, Colletotrichum gloeosporioides, inhibited H. brasiliensis infection, and infection by E. quercicola was decreased in the A. thaliana eds1 mutant expressing EqCSEP04187. Further analysis suggests that these reductions in infection were the consequences of EqCSEP04187 eliciting defense responses. Our study suggests that this putative effector has elicitor activity that can improve plant resistance.

Atmospheric-Temperature Chain Reaction towards Ultrathin Non-Crystal-Phase Construction for Highly Efficient Water Splitting.

Combining the self-sacrifice of a highly crystalline substance to design a multistep chain reaction towards ultrathin active-layer construction for high-performance water splitting with atmospheric-temperature conditions and an environmentally benign aqueous environment is extremely intriguing and full of challenges. Here, taking cobalt carbonate hydroxides (CCHs) as the initial crystalline material, we choose the Lewis acid metal salt of Fe(NO3 )3 to induce an aqueous-phase chain reaction generating free CO3 2- ions with subsequent instant FeCO3 hydrolysis. The resultant ultrathin (∼5 nm) amorphous Fe-based hydroxide layer on CCH results in considerable activity in catalyzing the oxygen evolution reaction (OER) and hydrogen evolution reaction (HER), yielding 10/50 mA ⋅ cm-2 at overpotentials of 230/266.5 mV for OER and 72.5/197.5 mV for HER. The catalysts can operate constantly in 1.0 M KOH over 48 and 45 h for the OER and HER, respectively. For bifunctional catalysis for alkaline electrolyzer assembly, a cell voltage as low as 1.53 V was necessary to yield 10 mA cm-2 (1.7 V at 50 mA cm-2 ). This work rationally builds high-efficiency electrochemical bifunctional water-splitting catalysts and offers a trial in establishing a controllable nanolevel ultrathin lattice disorder layer through an atmospheric-temperature chemical route.

Reduced graphene oxide-supported CuO nanoparticles with synergistically enhanced electrocatalytic activity for nitric oxide sensing.

As an important signal molecule, nitric oxide (NO) is involved in a variety of physiological and pathophysiological processes, which makes real-time NO detection imperative in the physiological environment. However, probing NO in physiological systems remains a great challenge due to its short half-life, low concentration, rapid diffusion, and easy interference by other chemicals. To be noted, traditional detection methods often require time-consuming sample pretreatment and cannot be used for continuous monitoring in vivo. Herein, we report copper oxide-decorated reduced graphene oxide (rGO/CuO) synthesized via a facile and eco-friendly solvothermal method. By taking advantage of the synergetic effect of CuO and rGO, the rGO/CuO sensor demonstrates impressive electrochemical performance for NO detection with a low detection limit (9.57 nM), wide linear range (90 nM to 138 µM), and high sensitivity (5.48 µA µM-1 cm-2). More importantly, the prepared sensor also shows excellent selectivity, repeatability, reproducibility, long-term operational stability, and fast response for NO detection, which meets the requirements of monitoring of NO released from living cells. Therefore, we believe that the reported rGO/CuO sensor has great potential for in vivo detection and even clinical diagnosis.

Considerable Unaccounted Local Sources of NOx Emissions in China Revealed from Satellite.

High-resolution (e.g., 5 km) emission data of nitrogen oxides (NOx = NO + NO2) provide localized knowledge of pollution sources for targeted regulations, yet such data are lacking or inaccurate over most regions at present. Here we improve our PHLET-based inversion method to derive NOx emissions in China at a 5-km resolution in summer 2019, based on the TROPOMI-POMINO satellite product of nitrogen dioxide (NO2) columns. With low computational costs, our inversion explicitly accounts for the effects of horizontal transport and nonlinear chemistry. We find numerous small-to-medium sources related to minor roads and small human settlements at relatively low affluence levels, in addition to clear emission signals along major transportation lines, consistent with road line density and Tencent location data. Many small-to-medium sources and transportation emissions are unclear or missing in the spatial distributions of four widely used emission inventories. Our emissions offer a unique reference for targeted emission control.

Monosaccharide-mediated rational synthesis of a universal plasmonic platform with broad spectral fluorescence enhancement for high-sensitivity cancer biomarker analysis.

BACKGROUND: Effective and accurate screening of oncological biomarkers in peripheral blood circulation plays an increasingly vital role in diagnosis and prognosis. High-sensitivity assays can effectively aid clinical decision-making and intervene in cancer in a localized status before they metastasize and become unmanageable. Meanwhile, it is equally pivotal to prevent overdiagnosis of non-life-threatening cancer by eliminating unnecessary treatment and repeated blood draws. Unfortunately, current clinical screening methodologies can hardly simultaneously attain sufficient sensitivity and specificity, especially under resource-restrained circumstances. To circumvent such limitations, particularly for cancer biomarkers from early-onset and recurrence, we aim to develop a universal plasmonic platform for clinical applications, which macroscopically amplifies multiplexed fluorescence signals in a broad spectral window and readily adapts to current assay setups without sophisticated accessories or expertise at low cost. METHODS: The plasmonic substrate was chemically synthesized in situ at the solid-liquid interface by rationally screening a panel of reducing monosaccharides and tuning the redox reactions at various catalyst densities and precursor concentrations. The redox properties were studied by Benedict's assay and electrochemistry. We systemically characterized the morphologies and optical properties of the engineered plasmonic Ag structures by scanning electron microscopy (SEM) and spectroscopy. The structure-fluorescence enhancement correlation was explicitly explained by the finite-difference time-domain (FDTD) simulation and a computational model for gap distribution. Next, we established an enhanced fluoroimmunoassay (eFIA) using a model biomarker for prostate cancer (PCa) and validated it in healthy and PCa cohorts. Prognosis was explored in patients subject to surgical and hormonal interventions following recommended PCa guidelines. RESULTS: The monosaccharide-mediated redox reaction yielded a broad category of Ag structures, including sparsely dispersed nanoparticles (NPs) of various sizes, semi-continuous nanoislands, and crackless continuous films. Optimal broad-spectral fluorescence enhancement from green to far-red was observed for the inhomogeneous, irregularly-shaped semi-continuous Ag nanoisland substrate (AgNIS), synthesized from a well-balanced redox reaction at a stable rate mediated by mannose. In addition, different local electric field intensity distributions in response to various incident excitations were observed at the nanoscale, elucidating the need for irregular and inhomogeneous structures. AgNIS enabled a maximized 54.7-fold macroscopically amplified fluorescence and long-lasting photostability. Point-of-care availability was fulfilled using a customized smartphone prototype with well-paired optics. The eFIA effectively detected the PCa marker in cell lines, xenograft tumors, and patient sera. The plasmonic platform rendered a diagnostic sensitivity of 86.0% and a specificity of 94.7% and capably staged high-grade PCa that the clinical gold standard test failed to stratify. Patient prognosis of robotic-assisted surgeries and hormone therapies was non-invasively monitored following efficient medical interventions. The assay time was significantly curtailed on the plasmonic platform upon microwave irradiation. CONCLUSIONS: By investigating the effects of reducing monosaccharides on the seed-mediated chemical synthesis of plasmonic Ag structures, we deduced that potent multiplexed fluorescence enhancement originated from both an adequate reducing power and a steady reduction rate. Furthermore, the inhomogeneous structure with adequate medium gap distances afforded optimal multiwavelength fluorescence enhancement, thus empowering an effective eFIA for PCa. The clinically validated diagnostic and prognostic features, along with the low sample volume, point-of-care feasibility with a smartphone, and microwave-shortened assay time, warrant its potential clinical translation for widespread cancer biomarker analysis.

Acanthopanax senticosus Polysaccharide Enhances the Pathogen Resistance of Radiation-Damaged Caenorhabditis elegans through Intestinal p38 MAPK-SKN-1/ATF-7 Pathway and Stress Response.

With the advancement of science and technology, humans are chronically exposed to ionizing radiation. It is crucial to look for efficient and low-toxic anti-radiation agents. Through preliminary screening, we found that Acanthopanax senticosus polysaccharide (ASPS) played a major role in regulating immune damage caused by radiation. The objective of this study was to apply the Caenorhabditis elegans-P. aeruginosa (PA14) infection model to illuminate the mechanism of ASPS increasing the pathogen resistance of radiation-damaged nematodes. Results indicated that ASPS (1 mg/mL) significantly enhanced the pathogen resistance of radiation-damaged nematodes by directly elevating the immune response of nematodes rather than by affecting the bacterial activity. Through further research on the p38 MAPK signaling pathway and related mutants, we found that ASPS functioned by the p38 MAPK pathway in the intestine, and SKN-1, ATF-7 as the downstream targets of PMK-1 participated the regulation of ASPS. In addition, ASPS markedly alleviated the stress status of damaged nematodes by regulating oxidative stress. Collectively, our findings suggest that ASPS enhances the pathogen resistance of radiation-damaged nematodes through the intestinal p38MAPK-SKN-1/ATF-7 pathway and stress response.

Metabolomics Approach on Non-Targeted Screening of 50 PPCPs in Lettuce and Maize.

The metabolomics approach has proved to be promising in achieving non-targeted screening for those unknown and unexpected (U&U) contaminants in foods, but data analysis is often the bottleneck of the approach. In this study, a novel metabolomics analytical method via seeking marker compounds in 50 pharmaceutical and personal care products (PPCPs) as U&U contaminants spiked into lettuce and maize matrices was developed, based on ultrahigh-performance liquid chromatography-tandem mass spectrometer (UHPLC-MS/MS) output results. Three concentration groups (20, 50 and 100 ng mL-1) to simulate the control and experimental groups applied in the traditional metabolomics analysis were designed to discover marker compounds, for which multivariate and univariate analysis were adopted. In multivariate analysis, each concentration group showed obvious separation from other two groups in principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) plots, providing the possibility to discern marker compounds among groups. Parameters including S-plot, permutation test and variable importance in projection (VIP) in OPLS-DA were used for screening and identification of marker compounds, which further underwent pairwise t-test and fold change judgement for univariate analysis. The results indicate that marker compounds on behalf of 50 PPCPs were all discovered in two plant matrices, proving the excellent practicability of the metabolomics approach on non-targeted screening of various U&U PPCPs in plant-derived foods. The limits of detection (LODs) for 50 PPCPs were calculated to be 0.4~2.0 µg kg-1 and 0.3~2.1 µg kg-1 in lettuce and maize matrices, respectively.

The Therapeutic Effect of Acanthopanax senticosus Components on Radiation-Induced Brain Injury Based on the Pharmacokinetics and Neurotransmitters.

Acanthopanax senticosus (AS) is a medicinal and food homologous plant with many biological activities. In this research, we generated a brain injury model by 60Co -γ ray radiation at 4 Gy, and gavaged adult mice with the extract with AS, Acanthopanax senticocus polysaccharides (ASPS), flavones, syringin and eleutheroside E (EE) to explore the therapeutic effect and metabolic characteristics of AS on the brain injury. Behavioral tests and pathological experiments showed that the AS prevented the irradiated mice from learning and memory ability impairment and protected the neurons of irradiated mice. Meanwhile, the functional components of AS increased the antioxidant activity of irradiated mice. Furthermore, we found the changes of neurotransmitters, especially in the EE and syringin groups. Finally, distribution and pharmacokinetic analysis of AS showed that the functional components, especially EE, could exert their therapeutic effects in brain of irradiated mice. This lays a theoretical foundation for the further research on the treatment of radiation-induced brain injury by AS.