Engineering of Substrate-Binding Domain to Improve Catalytic Activity of Chondroitin B Lyase with Semi-Rational Design.

Dermatan sulfate and chondroitin sulfate are dietary supplements that can be utilized as prophylactics against thrombus formation. Low-molecular-weight dermatan sulfate (LMWDS) is particularly advantageous due to its high absorbability. The enzymatic synthesis of low-molecular-weight dermatan sulfates (LMWDSs) using chondroitin B lyase is a sustainable and environmentally friendly approach to manufacturing. However, the industrial application of chondroitin B lyases is severely hampered by their low catalytic activity. To improve the activity, a semi-rational design strategy of engineering the substrate-binding domain of chondroitin B lyase was performed based on the structure. The binding domain was subjected to screening of critical residues for modification using multiple sequence alignments and molecular docking. A total of thirteen single-point mutants were constructed and analyzed to assess their catalytic characteristics. Out of these, S90T, N103C, H134Y, and R159K exhibited noteworthy enhancements in activity. This study also examined combinatorial mutagenesis and found that the mutant H134Y/R159K exhibited a substantially enhanced catalytic activity of 1266.74 U/mg, which was 3.21-fold that of the wild-type one. Molecular docking revealed that the enhanced activity of the mutant could be attributed to the formation of new hydrogen bonds and hydrophobic interactions with the substrate as well as neighbor residues. The highly active mutant would benefit the utilization of chondroitin B lyase in pharmaceuticals and functional foods.

Identification of sanguinarine as c-MYC transcription inhibitor through enhancing the G-quadruplex-NM23-H2 interactions.

c-MYC is a proto-oncogene ubiquitously overexpressed in various cancers. The formation of G-quadruplex (G4) structures within the c-MYC promoter region can regulate its transcription by interfering with protein binding. Consequently, small molecules targeting c-MYC G4 have emerged as promising anticancer agents. Herein, we report that sanguinarine (SG) and its analogs exhibit a high affinity for c-MYC G4 and potently modulate G4-protein interactions within a natural product library. Notably, SG uniquely enhances NM23-H2 binding to c-MYC G4, both in vitro and in cellular contexts, leading to c-MYC transcriptional repression and subsequent inhibition of cancer cell growth in an NM23-H2-dependent manner. Mechanistic studies and molecular modeling suggest that SG binds to the c-MYC G4/NM23-H2 interface, acting as an orthosteric stabilizer of the DNA-protein complex and preventing c-MYC transcription. Our findings identify SG as a potent c-MYC transcription inhibitor and provide a novel strategy for developing G4-targeting anticancer therapeutics through modulation of G4-protein interactions.

α-Ketoglutarate promotes cardiomyocyte proliferation and heart regeneration after myocardial infarction.

The neonatal mammalian heart can regenerate following injury through cardiomyocyte proliferation but loses this potential by postnatal day 7. Stimulating adult cardiomyocytes to reenter the cell cycle remains unclear. Here we show that cardiomyocyte proliferation depends on its metabolic state. Given the connection between the tricarboxylic acid cycle and cell proliferation, we analyzed these metabolites in mouse hearts from postnatal day 0.5 to day 7 and found that α-ketoglutarate ranked highest among the decreased metabolites. Injection of α-ketoglutarate extended the window of cardiomyocyte proliferation during heart development and promoted heart regeneration after myocardial infarction by inducing adult cardiomyocyte proliferation. This was confirmed in Ogdh-siRNA-treated mice with increased α-ketoglutarate levels. Mechanistically, α-ketoglutarate decreases H3K27me3 deposition at the promoters of cell cycle genes in cardiomyocytes. Thus, α-ketoglutarate promotes cardiomyocyte proliferation through JMJD3-dependent demethylation, offering a potential approach for treating myocardial infarction.

An updated resource for the detection of protein-coding circRNA with CircProPlus.

Protein-encoding circular RNAs (circRNAs) are newly identified RNA molecules characterized by intense interaction with translating ribosome. Emerging evidence has implicated physiological and pathological significance of these non-canonical RNAs, yet a large body of them remains unidentified. Due to limited tools at hand, we developed CircProPlus, an automated computational pipeline for de novo detection of translated circRNAs. In comparison to previously established CircPro, CircProPlus adjusts the overall workflow and integrates more robust implements for achieving easier accessibility, higher flexibility and productivity. In present study, we tested the performance of CircProPlus when using different circRNA-detecting implements (i.e., CIRI2, CirComPara2) in the evaluation of coding ability of circRNAs. Results showed that CirComPara2, a state-of-the-art algorithm, consistently outperformed CIRI2 when coupled with CircProPlus in testing real data collected from different RNA libraries and species, which highlighted its potency in data mining of circRNAs with protein-coding potential.

Interfacial Coupling toward Bismuth Sulfide/MXene Heterostructures Empowering Reversible Magnesium Storage.

Bismuth-based compounds based on conversion-alloying reactions of multielectron transfer have attracted extensive attention as alternative anode candidates for rechargeable magnesium batteries (rMBs). However, the inadequate magnesium storage capability induced by the sluggish kinetics, poor reversibility, and terrible structural stability impedes their practical utilization. Herein, monodispersed Bi2S3 anchored on MXene has been prepared via a simple self-assembly strategy to induce the interfacial bonding of Ti-S and Ti-O-Bi. Unique superiority, including good electrical conductivity, high mechanical strength, and rapid charge transfer, is cleverly integrated together in the Bi2S3/MXene heterostructures, which endowed heterostructures with enhanced magnesium storage performance. Density functional theory calculations combined with kinetic behavior analyses confirm the favorable charge transfer and low ion diffusion barrier in hybrids. Furthermore, a stepwise insertion-conversion-alloying reaction mechanism is revealed in depth by ex situ investigations, which may also account for promoting performance. This work provides significant inspirations for constructing ingenious multicompositional hybrids by strong interfacial coupling engineering toward high-performance energy storage devices.

Development and validation of a predictive model for preoperative deep vein thrombosis following traumatic thoracolumbar fractures.

Although a sequential work-up for deep vein thrombosis has reached agreement worldwide, the mysterious nature of DVT following fractures brings challenges to early diagnosis and intervention. The objective of the present study was to develop and validate a nomogram for predicting preoperative DVT risk in patients with thoracolumbar fractures using readily available clinical data. Of the 1350 patients, 930 were randomly assigned to the training cohort. A prediction model was established and visualized as a nomogram based on eight predictors related to preoperative DVT. The performance of the model was tested by the receiver operating characteristic curve, Hosmer-Lemeshow test, calibration curve, and decision curve analysis. We further verified the model in the validation cohort. The AUCs of the prediction model were 0.876 and 0.853 in training and validation cohorts, respectively. The Hosmer-Lemeshow test demonstrated good fitness in the training set (X2 = 5.913, P = 0.749) and the validation set (X2 = 9.460, P = 0.396). Calibration and decision curve analyses performed well in training and validation sets. In short, we developed a prediction model for preoperative DVT risk in patients with thoracolumbar fractures and verified its accuracy and clinical utility.

Core-shell structured MgCo2O4@Ni(OH)2 nanorods as electrode materials for high-performance asymmetric supercapacitors.

In the field of energy storage, supercapacitors have received extensive attention in recent years. However, achieving the expected electrochemical performance and energy density of supercapacitors is still a huge challenge. The design and synthesis of binder-free composite electrode with core-shell structure is an effective strategy to improve the electrochemical performance of supercapacitors. In this paper, a heterogeneous core-shell structured and binder-free electrode material MgCo2O4@Ni(OH)2 (MCO@NH) grown on nickel foam (NF) is prepared by a simple hydrothermal and oil bath method. The unique core-shell structure makes the MCO@NH have a large specific surface area, which provides abundant active sites for ion transport and storage, thereby improving the electrochemical performance. The MCO@NH/NF nanocomposite demonstrates a high specific capacitance (Cs) of 1583 F g-1 at 1 A/g. A solid-state asymmetric supercapacitor (ASC) assembled with MCO@NH/NF and active carbon (AC) exhibits excellent energy density (45 Wh kg-1 at 457.5 W kg-1) and outstanding capacitance (89.51 %) and coulombic efficiency (97.8 %) after 12,000 cycles, evidencing its good operation stability and potential practical applications. Therefore, the prepared core-shell MCO@NH/NF electrode can be a promising candidate for energy storage devices.

Failure of the three-way catalyst (TWC) introduces "super emitters".

Vehicle exhaust is one of the major organic sources in urban areas. Old taxis equipped with failed three-way catalysts (TWCs) have been regarded as "super emitters". Compressed natural gas (CNG) is a regular substitution fuel for gasoline in taxis. The relative effect of fuel substitution and TWC failure has not been thoroughly investigated. In this work, vehicle exhausts from gasoline and CNG taxis with optimally functioning and malfunctioning TWCs are sampled by Tenax TA tubes and then analyzed by a comprehensive two-dimensional gas chromatography-mass spectrometer (GC×GC-MS). A total of 216 organics are quantified, including 80 volatile organic compounds (VOCs) and 132 intermediate volatility organic compounds (IVOCs). Failure of TWC introduces super emitters with 30 - 70 times emission factors (EFs), 60 - 112 times ozone formation potentials (OFPs), and 34 - 92 times secondary organic aerosols (SOAs) more than normal vehicles. Specifically, for the taxi with failed TWC, the total organic EF of CNG is 16 times that of gasoline, indicating that the failure of TWC exceeds the emission reduction achieved by CNG-gasoline substitution. A significant but unbalanced reduction of ozone and SOA is observed after TWC, whereas a notable "enrichment" in IVOCs was observed. Naphthalene is a typical IVOC component strongly associated with CNG-gasoline substitution and TWC failure, which is lacking in current VOC measurement. We especially emphasize that there is an urgent need to scrap vehicles with failed TWCs in order to significantly reduce air pollution.

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.

Hybridization of short-range and long-range charge transfer boosts room-temperature phosphorescence performance.

At present, mainstream room-temperature phosphorescence (RTP) emission relies on organic materials with long-range charge-transfer effects; therefore, exploring new forms of charge transfer to generate RTP is worth studying. In this work, indole-carbazole was used as the core to ensure the narrowband fluorescence emission of the material based on its characteristic short-range charge-transfer effect. In addition, halogenated carbazoles were introduced into the periphery to construct long-range charge transfer, resulting in VTCzNL-Cl and VTCzNL-Br. By encapsulating these phosphors into a robust host (TPP), two host-guest crystalline systems were further developed, achieving efficient RTP performance with phosphorescence quantum yields of 26% and phosphorescence lifetimes of 3.2 and 39.2 ms, respectively.

Ventricular Morphology and Outcomes in Fontan Circulation without Hypoplastic Left Heart Syndrome: A Single-Center's Experience.

Background: The impact of dominant ventricular morphology on Fontan patient outcomes remain controversial. This study evaluates long-term results of right ventricle (RV) dominance versus left ventricle (LV) dominance in Fontan circulation without hypoplastic left heart syndrome (HLHS). Methods: We retrospectively examined 323 Fontan operations from our center. To minimize pre- and intra-Fontan heterogeneity, 42 dominant RV patients were matched with 42 dominant LV patients using propensity score matching, allowing for a comparative analysis of outcomes between groups. Results: The mean follow-up was 8.0 ± 4.6 years for matched RV dominant and 6.5 ± 4.7 years for matched LV dominant group (p > 0.05), showing no significant difference. The cumulative incidence of moderate or greater atrioventricular valve regurgitation was also comparable between the two groups (p > 0.05). Similarly, 10-year freedom from death or transplantation following the Fontan operation was 84% ± 7% in the matched dominant RV group, similar to 81% ± 7% in the matched dominant LV group (p > 0.05). The 10-year freedom from Fontan failure was 78% ± 8% in the matched dominant RV group, also similar to 75% ± 8% in the matched dominant LV group (p > 0.05). Multivariate analysis did not identify RV dominance as a risk factor for Fontan failure (p > 0.05). Conclusions: In the pre- and intra-Fontan context, RV dominance demonstrated similar and comparable long-term outcomes compared to LV dominance in non-HLHS Fontan circulation.

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.

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.

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.

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.

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.

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.

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.

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.

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.