Integrative metabolomics dictate distinctive signature profiles in patients with Tetralogy of Fallot.

BACKGROUND: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease (CCHD) with multifactorial etiology. We aimed to investigate the metabolic profiles of CCHD and their independent contributions to TOF. METHODS: A cohort comprising 42 individuals with TOF and atrial septal defect (ASD) was enrolled. Targeted ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) was employed to systematically analyze metabolite levels and identify TOF-associated metabolic profiles. RESULTS: Of 370 identified metabolites in tissue and 284 in plasma, over one-third of metabolites showed an association with microbiome. Differential metabolic pathways including amino acids biosynthesis, ABC (ATP-binding cassette) transporters, carbon metabolism, and fatty acid biosynthesis, shed light on TOF biological phenotypes. Additionally, ROC curves identified potential biomarkers, such as erythronic acid with an AUC of 0.868 in plasma, and 3-ß-hydroxy-bisnor-5-cholenic acid, isocitric acid, glutaric acid, ortho-Hydroxyphenylacetic acid, picolinic acid with AUC close to 1 in tissue, whereas the discriminative performance of those substances significantly improved when combined with clinical phenotypes. CONCLUSIONS: Distinct metabolic profiles exhibited robust discriminatory capabilities, effectively distinguishing TOF from ASD patients. These metabolites may serve as biomarkers or key molecular players in the intricate metabolic pathways involved in CCHD development. IMPACT: Distinct metabolic profiles exhibited robust discriminatory capabilities, effectively distinguishing Tetralogy of Fallot from atrial septal defect patients. Similar profiling but inconsistent differential pathways between plasma and tissue. More than one-third metabolites in plasma and tissue are associated with the microbiome. The discovery of biomarkers is instrumental in facilitating early detection and diagnosis of Tetralogy of Fallot. Disturbed metabolism offers insights into interpretation of pathogenesis of Tetralogy of Fallot.

Potential and application of abortive transcripts as a novel molecular marker of cancers.

Abortive transcript (AT) is a 2-19 nt long non-coding RNA that is produced in the abortive initiation stage. Abortive initiation was found to be closely related to RNA polymerase through in vitro experiments. Therefore, the distribution of AT length and the scale of abortive initiation are correlated to the promoter, discriminator, and transcription initiation sequence, and can be affected by transcription elongation factors. AT plays an important role in the occurrence and development of various diseases. Here we summarize the discovery of AT, the factors responsible for AT formation, the detection methods and biological functions of AT, to provide new clues for finding potential targets in the early diagnosis and treatment of cancers.

Genome-wide characterization and functional analysis of the melon TGA gene family in disease resistance through ectopic overexpression in Arabidopsis thaliana.

TGA-binding (TGA) transcription factors, characterized by the basic region/leucine zipper motif (bZIP), have been recognized as pivotal regulators in plant growth, development, and stress responses through their binding to the as-1 element. In this study, the TGA gene families in melon, watermelon, cucumber, pumpkin, and zucchini were comprehensively characterized, encompassing analyses of gene/protein structures, phylogenetic relationships, gene duplication events, and cis-acting elements in gene promoters. Upon transient expression in Nicotiana benthamiana, the melon CmTGAs, with typical bZIP and DOG1 domains, were observed to localize within the nucleus. Biochemical investigation revealed specific interactions between CmTGA2/3/5/8/9 and CmNPR3 or CmNPR4. The CmTGA genes exhibited differential expression patterns in melon plants in response to different hormones like salicylic acid, methyl jasmonate, and ethylene, as well as a fungal pathogen, Stagonosporopsis cucurbitacearum that causes gummy stem blight in melon. The overexpression of CmTGA3, CmTGA8, and CmTGA9 in Arabidopsis plants resulted in the upregulation of AtPR1 and AtPR5 expression, thereby imparting enhanced resistance to Pseudomonas syringae pv. Tomato DC3000. In contrast, the overexpression of CmTGA7 or CmTGA9 resulted in a compromised resistance to Botrytis cinerea, coinciding with a concomitant reduction in the expression levels of AtPDF1.2 and AtMYC2 following infection with B. cinerea. These findings shed light on the important roles of specific CmTGA genes in plant immunity, suggesting that genetic manipulation of these genes could be a promising avenue for enhancing plant immune responses.

HDAC inhibitors as a potential therapy for chemotherapy-induced neuropathic pain.

Cancer, a chronic disease characterized by uncontrolled cell development, kills millions of people globally. The WHO reported over 10 million cancer deaths in 2020. Anticancer medications destroy healthy and malignant cells. Cancer treatment induces neuropathy. Anticancer drugs cause harm to spinal cord, brain, and peripheral nerve somatosensory neurons, causing chemotherapy-induced neuropathic pain. The chemotherapy-induced mechanisms underlying neuropathic pain are not fully understood. However, neuroinflammation has been identified as one of the various pathways associated with the onset of chemotherapy-induced neuropathic pain. The neuroinflammatory processes may exhibit varying characteristics based on the specific type of anticancer treatment delivered. Neuroinflammatory characteristics have been observed in the spinal cord, where microglia and astrocytes have a significant impact on the development of chemotherapy-induced peripheral neuropathy. The patient's quality of life might be affected by sensory deprivation, loss of consciousness, paralysis, and severe disability. High cancer rates and ineffective treatments are associated with this disease. Recently, histone deacetylases have become a novel treatment target for chemotherapy-induced neuropathic pain. Chemotherapy-induced neuropathic pain may be treated with histone deacetylase inhibitors. Histone deacetylase inhibitors may be a promising therapeutic treatment for chemotherapy-induced neuropathic pain. Common chemotherapeutic drugs, mechanisms, therapeutic treatments for neuropathic pain, and histone deacetylase and its inhibitors in chemotherapy-induced neuropathic pain are covered in this paper. We propose that histone deacetylase inhibitors may treat several aspects of chemotherapy-induced neuropathic pain, and identifying these inhibitors as potentially unique treatments is crucial to the development of various chemotherapeutic combination treatments.

Mechanical strength recognition and classification of thermal protective fabric images after thermal aging based on deep learning.

Objectives. Currently, numerous studies have focused on testing or modeling to evaluate the safe service life of thermal protective clothing after thermal aging, reducing the risk to occupational personnel. However, testing will render the garment unsuitable for subsequent use and a series of input parameters for modeling are not readily available. In this study, a novel image recognition strategy was proposed to discriminate the mechanical strength of thermal protective fabric after thermal aging based on transfer learning. Methods. Data augmentation was used to overcome the shortcoming of insufficient training samples. Four pre-trained models were used to explore their performance in three sample classification modes. Results. The experimental results show that the VGG-19 model achieves the best performance in the three-classification mode (accuracy = 91%). The model was more accurate in identifying fabric samples in the early and late stages of strength decline. For fabric samples in the middle stage of strength decline, the three-classification mode was better than the four-classification and six-classification modes. Conclusions. The findings provide novel insights into the image-based mechanical strength evaluation of thermal protective fabrics after aging.

Delayed luminescence to monitor growth stages and assess the entropy of Saccharomyces cerevisiae.

Delayed luminescence (DL) refers to the photon-induced ultra-weak luminescence emitted by samples after the light source is switched off. As a noninvasive method for health monitoring and disease diagnosis, DL has attracted increasing attention. The further development of this technology is valuable for the study of complex biological processes, such as different growth stages. If such studies were to be conducted in humans, large numbers of subjects of all ages would need to be recruited, and individual differences would be inevitable. The budding yeast Saccharomyces cerevisiae (S. cerevisiae) has a short population lifespan, and the growth phases can be monitored within dozens of hours. Therefore, S. cerevisiae is an ideal model organism for research. In this study, we investigated the physiological characteristics and DL emission of S. cerevisiae during growth in glucose-based media and entry into stationary phase, and the results showed that DL kinetic curves of yeast cells in the growing phase were obviously separated from those of stationary phase cells. Moreover, the metabolic and physiological characteristics of the yeast cell population were discussed using the DL emission parameters I0, τ and γ. We also discussed the possibility of assessing entropy using DL emission parameters. Our research demonstrates the potential of this technology to be used in wider applications.

Investigating the Impact Behavior of Carbon Fiber/Polymethacrylimide (PMI) Foam Sandwich Composites for Personal Protective Equipment.

To improve the shock resistance of personal protective equipment and reduce casualties due to shock wave accidents, this study prepared four types of carbon fiber/polymethacrylimide (PMI) foam sandwich panels with different face/back layer thicknesses and core layer densities and subjected them to quasi-static compression, low-speed impact, high-speed impact, and non-destructive tests. The mechanical properties and energy absorption capacities of the impact-resistant panels, featuring ceramic/ultra-high molecular-weight polyethylene (UHMWPE) and carbon fiber/PMI foam structures, were evaluated and compared, and the feasibility of using the latter as a raw material for personal impact-resistant equipment was also evaluated. For the PMI sandwich panel with a constant total thickness, increasing the core layer density and face/back layer thickness enhanced the energy absorption capacity, and increased the peak stress of the face layer. Under a constant strain, the energy absorption value of all specimens increased with increasing impact speed. When a 10 kg hammer impacted the specimen surface at a speed of 1.5 m/s, the foam sandwich panels retained better integrity than the ceramic/UHMWPE panel. The results showed that the carbon fiber/PMI foam sandwich panels were suitable for applications that require the flexible movement of the wearer under shock waves, and provide an experimental basis for designing impact-resistant equipment with low weight, high strength, and high energy absorption capacities.

Heterostructures Assembled from Bi2O2CO3 and MXene for Boosted Potassium-Ion Storage by Arousing the Built-in Electric Field.

Bismuth-based materials have been recognized as the appealing anodes for potassium-ion batteries (PIBs) due to their high theoretical capacity. However, the kinetics sluggishness and capacity decline induced by the structure distortion predominately retard their further development. Here, a heterostructure of polyaniline intercalated Bi2O2CO3/MXene (BOC-PA/MXene) hybrids is reported via simple self-assembly strategy. The ingenious design of heterointerface-rich architecture motivates significantly the interior self-built-in electric field (IEF) and high-density electron flow, thus accelerating the charge transfer and boosting ion diffusion. As a result, the hybrids realize a high reversible specific capacity, satisfying rate capability as well as long-term cycling stability. The in/ex situ characterizations further elucidate the stepwise intercalation-conversion-alloying reaction mechanism of BOC-PA/MXene. More encouragingly, the full cell investigation further highlights its competitive merits for practical application in further PIBs. The present work not only opens the way to the design of other electrodes with an appropriate working mechanism but also offers inspiration for built-in electric-field engineering toward high-performance energy storage devices.

Design, synthesis, and evaluation of novel quindoline derivatives with fork-shaped side chains as RNA G-quadruplex stabilizers for repressing oncogene NRAS translation.

NRAS mutation is the second most common oncogenic factor in cutaneous melanoma. Inhibiting NRAS translation by stabilizing the G-quadruplex (G4) structure with small molecules seems to be a potential strategy for cancer therapy due to the NRAS protein's lack of a druggable pocket. To enhance the effects of previously reported G4 stabilizers quindoline derivatives, we designed and synthesized a novel series of quindoline derivatives with fork-shaped side chains by introducing (alkylamino)alkoxy side chains. Panels of experimental results showed that introducing a fork-shaped (alkylamino)alkoxy side chain could enhance the stabilizing abilities of the ligands against NRAS RNA G-quadruplexes and their anti-melanoma activities. One of them, 10b, exhibited good antitumor activity in the NRAS-mutant melanoma xenograft mouse model, showing the therapeutic potential of this kind of compounds.

Investigating the influencing factors and prediction models of skin burns for firefighters' occupational safety.

Relevant studies in the fields of fire safety, occupational health and firefighter clothing were analyzed in this study to address the high injury rate among firefighters during fire rescue and the complexity of factors affecting skin burns. The findings indicate that the degree of skin burns in firefighters is primarily influenced by the heat source (heat flux, type), firefighter clothing (fabric, pattern) and the under-clothing air gap (thickness, characteristics). Since skin burns cannot be directly measured, internal skin heat transfer and burn prediction models are commonly employed to assess the impact of external factors on skin burns. These models can predict the safe working distance or time for firefighters. Investigating the influencing factors and prediction models of skin burns among firefighters holds significant value in enhancing operating procedures, optimizing firefighter clothing design and effectively preventing skin burns.

Pristine cobalt humic acid xerogels embedded with ultrafine cobalt sulfide for enhanced and stable lithium-ion storage.

The electrochemical performance of pristine metal-organic xerogels as anodes in lithium-ion batteries is reported for the first time. We propose a novel synthesis approach for the in situ generation of highly dispersed, ultrafine cobalt sulfide nanoparticles on humic acid gels (CoSHA). The CoS nanoparticles in CoSHA have an average diameter of approximately 3 nm. CoSHA electrodes demonstrate enhanced lithium storage capacity, delivering a capacity of 662 mAh g-1 at 0.1 A g-1. They also show stable long-term cycling performance, with no capacity decay after 900 cycles at 1.0 A g-1. Furthermore, our experiments indicate that the improved lithium-ion adsorption results from the oxygen-containing functional groups in humic acid and the ultrafine CoS active sites. This study offers a practical methodology for synthesizing ultrafine metal sulfides and new insights into using pristine gel-based electrodes for energy storage and conversion.

Light-Driven Photocatalyst-Free Synthesis of ß, δ-Functionalized Ketones from Aldehydes.

The synthesis of ketones has been a long focus of chemistry research, on account of its unique reactivity. Herein, we report a simple light-driven photocatalyst-free synthesis of ß, δ-functionalized ketones from aldehydes, using inexpensive and commercially abundant feedstock chemicals. This reaction is enabled by the direct acyl radical generation via hydrogen atom transfer and the subsequent radical addition process, avoiding the need for prefunctionalized substrates and organometallic reagent.

SARS-CoV-2 Membrane protein regulates the function of Spike by inhibiting its plasma membrane localization and enzymatic activity of Furin.

The presence of a multibasic cleavage site in the Spike protein of SARS-CoV-2 makes it prone to be cleaved by Furin at the S1/S2 junction (aa. 685-686), which enhances the usage of TMPRSS2 to promote cell-cell fusion to form syncytia. Syncytia may contribute to pathology by facilitating viral dissemination, cytopathicity, immune evasion, and inflammation. However, the role of other SARS-CoV-2 encoding viral proteins in syncytia formation remains largely unknown. Here, we report that SARS-CoV-2 M protein effectively inhibits syncytia formation triggered by Spike or its variants (Alpha, Delta, Omicron, etc.) and prevents Spike cleavage into S1 and S2 based on a screen assay of 20 viral proteins. Mechanistically, M protein interacts with Furin and inhibits its enzymatic activity, preventing the cleavage of Spike. In addition, M interacts with Spike independent of its cytoplasmic tail, retaining it within the cytoplasm and reducing cell membrane localization. Our findings offer new insights into M protein's role in regulating Spike's function and underscore the importance of functional interplay among viral proteins, highlighting potential avenues for SARS-CoV-2 therapy development.

Cloning, heterologous expression, and molecular characterization of a highly active and stable non-specific endonuclease from Pseudomonas fluorescens.

Non-specific endonucleases can be used for the digestion of nucleic acids because they hydrolyze DNA/RNA into 3-5 base pairs (bp) length oligonucleotide fragments without strict selectivity. In this work, a novel non-specific endonuclease from Pseudomonas fluorescens (PfNuc) with high activities for both DNA and RNA was successfully cloned and expressed in Escherichia coli. The production of PfNuc in flask scale could be achieved to 1.73 × 106 U/L and 4.82 × 106 U/L for DNA and RNA by investigation of the culture and induction conditions. The characterization of PfNuc indicated that it was Mg2+-dependent and the catalytic activity was enhanced by 3.74 folds for DNA and 1.06 folds for RNA in the presence of 5 mM Mg2+. The specific activity of PfNuc for DNA was 1.44 × 105 U/mg at pH 8.0 and 40 °C, and 3.93 × 105 U/mg for RNA at pH 8.5 and 45 °C. The Km of the enzyme for both DNA and RNA was close to 43 µM. The Vmax was 6.40 × 105 U/mg and 1.11 × 106 U/mg for DNA and RNA, respectively. There was no observed activity loss when PfNuc was stored at 4 °C and - 20 °C after 28 days or 10 repeated freeze-thaw cycles at - 80 °C. Molecular docking revealed that PfNuc formed 17 and 19 hydrogen bonds with single-stranded RNA and double-stranded DNA, respectively. These results could explain the high activity and stability of PfNuc, suggesting its great potential applications in the industry and clinic.

NIR-II Conjugated Electrolytes as Biomimetics of Lipid Bilayers for In Vivo Liposome Tracking.

Liposomes serve as promising and versatile vehicles for drug delivery. Tracking these nanosized vesicles, particularly in vivo, is crucial for understanding their pharmacokinetics. This study introduces the design and synthesis of three new conjugated electrolyte (CE) molecules, which emit in the second near-infrared window (NIR-II), facilitating deeper tissue penetration. Additionally, these CEs, acting as biomimetics of lipid bilayers, demonstrate superior compatibility with lipid membranes compared to commonly used carbocyanine dyes like DiR. To counteract the aggregation-caused quenching effect, CEs employ a twisted backbone, as such their fluorescence intensities can effectively enhance after a fluorophore multimerization strategy. Notably, a "passive" method was employed to integrate CEs into liposomes during the liposome formation, and membrane incorporation efficiency was significantly promoted to nearly 100%. To validate the in vivo tracking capability, the CE-containing liposomes were functionalized with cyclic arginine-glycine-aspartic acid (cRGD) peptides, serving as tumor-targeting ligands. Clear fluorescent images visualizing tumor site in living mice were captured by collecting the NIR-II emission. Uniquely, these CEs exhibit additional emission peak in visible region, enabling in vitro subcellular analysis using routine confocal microscopy. These results underscore the potential of CEs as a new-generation of membrane-targeting probes to facilitate the liposome-based medicine research.

Re-analysis of single-cell transcriptomics reveals a critical role of macrophage-like smooth muscle cells in advanced atherosclerotic plaque.

Aims: Smooth muscle cell (SMC) remodeling poses a critical feature in the development and progression of atherosclerosis. Although fate mapping and in silicon approaches have expanded SMC phenotypes in atherosclerosis, it still remains elusive about the contributions of individual SMC phenotypes and molecular dynamics to advanced atherosclerotic plaque. Methods: Using single-cell transcriptome, we investigated cellular compositions of human carotid plaque laden with atherosclerotic core, followed by in vivo experiments utilizing SMC-lineage tracing technology, bulk RNA sequencing (RNA-seq) and both in vivo and in vitro validation of the underlying molecular mechanism. Results: 5 functionally distinct SMC subtypes were uncovered based on transcriptional features (described as contractile, fibroblast-like, osteogenic, synthetic and macrophage-like) within the niche. A proinflammatory, macrophage-like SMC subtype displaying an intermediary phenotype between SMC and macrophage, exhibits prominent potential in destabilizing plaque. At the molecular level, we explored cluster-specific master regulons by algorithm, and identified interferon regulatory factor-8 (IRF8) as a potential stimulator of SMC-to-macrophage transdifferentiation via activating nuclear factor-κB (NF-κB) signaling. Conclusions: Our study illustrates a comprehensive cell atlas and molecular landscape of advanced atherosclerotic lesion, which might renovate current understanding of SMC biology in atherosclerosis.

Characterizing NOx emissions from diesel trucks with tampered aftertreatment systems and its implications for identifying high emitters.

Reducing the differences between real-world and certificated NOx emission levels is an important element of in-use emission surveillance programs. Therefore, investigating the characteristics of the vehicles which have much higher NOx emissions (i.e., high-emitters) and determining a reasonable cut-off point to identify high-emitters with a low false detection rate is important. In this study, six diesel trucks were tested under different aftertreatment conditions. The results showed that the discrepancies of fuel-specific NOx emissions between vehicles with functioning and tampered selective catalytic reduction (SCR) systems occur mainly from medium- to high-speed modes. This is because the SCR systems were at low conversion efficiencies when the exhaust temperature was low, including cold-start and urban creep conditions. By using binary classification, we selected fuel-specific NOx cut-off points for high-emitters from China V and China VI diesel trucks. The false detection rate of high-emitters can decrease by 33 % and 95 %, if only NOx emissions from medium- to high-speed modes were used for the chosen cut-off points, respectively. This work highlights the importance of in-use emission compliance programs. It also suggests that high-emitters can be more accurately identified at medium- to high-speed modes if using instantaneous emission data.

Study on coupling coordination degree of urbanization and ecological environment in Chengdu-Chongqing economic circle from 2002 to 2018.

Under the western development strategy of China, the urbanization process of Chengdu-Chongqing economic circle (CCEC) develops rapidly, but also brings a series of ecological and environmental problems. Understanding the coordination mechanism that links urbanization and the ecological environment (UE) is crucial for promoting environmental conservation and sustainable development. Using the comprehensive nighttime light index (CNLI) and the remote sensing ecological index (RSEI), this study objectively evaluated the urbanization level and ecological environment quality and used the modified coupling coordination degree model to quantify the coupling coordination of UE for the two indexes. The results show that (1) the urbanization level of each city in the CCEC presents an increasing trend year by year, showing a circle distribution pattern with the twin cities as the core. (2) The overall eco-environmental quality presents a fluctuating upward trend, and in recent years, it has been significantly improved, showing a spatial pattern of higher in the surrounding areas and lower in the middle. (3) The overall coupling coordination of the study area is developing, and the upward trend is larger in recent years. The spatial distribution is centered on the "double nucleus," and the distribution of circles is characterized by a gradual decrease from the inside to the outside; the coupling coordination of cities in the northwest and east of the CCEC is decreasing, and that of cities in the northeast and southwest is increasing. During the study period, a total of 5 cities have reached the level of coordinated development, while most other cities are in the stage of uncoordinated development, mainly due to the lagging development of urbanization. CCEC still needs to strengthen the construction of urbanization, in order to improve the degree of coordination between economic development and ecological environment.

Effective degradation of phenol by activating PMS with bimetallic Mo and Ni Co-doped g C3N4 composite catalyst: A Fenton-like degradation process promoted by non-free radical 1O2.

The application of bimetal supported graphite phase carbon nitride in activated peroxymonosulfate (PMS) process has become a research hotspot in recent years. In this study, 8-g C3N4/Mo/Ni composite catalyst material was successfully prepared by doping Mo and Ni in graphite phase carbon nitride. The bimetallic active sites were formed in the catalyst, and PMS was activated by the metal valence Mo6+/Mo4+ and Ni2+/Ni(0) through redox double cycle to effectively degrade phenol. When pH was neutral, the degradation rate of 20 mg/L phenol solution with 8-g C3N4/Mo/Ni (0.35 g/L) and PMS (0.6 mM) could reach 95% within 20 min. The degradation rate of 8-g C3N4/Mo/Ni/PMS catalytic system could reach more than 90% within 20min under the condition of pH range of 3-11 and different anions. Meanwhile, the degradation effects of RhB, MB and OFX on different pollutants within 30min were 99%, 100% and 82%, respectively. Electron spin resonance and quenching experiments showed that in 8-g C3N4/Mo/Ni/PMS system, the degradation mechanism was mainly non-free radicals, and the main active species in the degradation process was 1O2. This study provides a new idea for the study of bimetal supported graphite phase carbon nitride activation of PMS and the theoretical study of degradation mechanism.

Comprehensive scRNA-seq Model Reveals Artery Endothelial Cell Heterogeneity and Metabolic Preference in Human Vascular Disease.

Vascular disease is one of the major causes of death worldwide. Endothelial cells are important components of the vascular structure. A better understanding of the endothelial cell changes in the development of vascular disease may provide new targets for clinical treatment strategies. Single-cell RNA sequencing can serve as a powerful tool to explore transcription patterns, as well as cell type identity. Our current study is based on comprehensive scRNA-seq data of several types of human vascular disease datasets with deep-learning-based algorithm. A gene set scoring system, created based on cell clustering, may help to identify the relative stage of the development of vascular disease. Metabolic preference patterns were estimated using a graphic neural network model. Overall, our study may provide potential treatment targets for retaining normal endothelial function under pathological situations.