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Pectobacterium carotovorum and Pectobacterium aroidearum represent the primary pathogens causing variable soft rot disease. However, the fundamental defense responses of Pinellia ternata to pathogens remain unclear. Our investigation demonstrated that the disease produced by P. carotovorum is more serious than P. aroidearum. RNA-seq analysis indicated that many cell wall-related genes, receptor-like kinase genes, and resistance-related genes were induced by P. aroidearum and P. carotovorum similarly. But many different regulatory pathways exert a crucial function in plant immunity against P. aroidearum and P. carotovorum, including hormone signaling, whereas more auxin-responsive genes were responsive to P. carotovorum, while more ethylene and gibberellin-responsive genes were responsive to P. aroidearum. 12 GDSL esterase/lipase genes and 3 fasciclin-like arabinogalactan protein genes were specifically upregulated by P. carotovorum, whereas 11 receptor-like kinase genes and 8 disease resistance genes were up-regulated only by P. aroidearum. Among them, a lectin gene (part1transcript/39001) was induced by P. carotovorum and P. aroidearum simultaneously. Transient expression in N. benthamiana demonstrated that the lectin gene improves plant resistance to P. carotovorum. This study offers a comprehensive perspective on P. ternata immunity produced by different soft rot pathogens and reveals the importance of lectin in anti-soft rot of P. ternata for the first time., (© 2024. The Author(s).)

Dinoflagellates, a class of unicellular eukaryotic phytoplankton, exhibit minimal transcriptional regulation, representing a unique model for exploring gene expression. The biosynthesis, distribution, regulation, and function of mRNA N1-methyladenosine (m 1 A) remain controversial due to its limited presence in typical eukaryotic mRNA. This study provides a comprehensive map of m 1 A in dinoflagellate mRNA and shows that m 1 A, rather than N6-methyladenosine (m 6 A), is the most prevalent internal mRNA modification in various dinoflagellate species, with an asymmetric distribution along mature transcripts. In Amphidinium carterae, we identify 6549 m 1 A sites characterized by a non-tRNA T-loop-like sequence motif within the transcripts of 3196 genes, many of which are involved in regulating carbon and nitrogen metabolism. Enriched within 3'UTRs, dinoflagellate mRNA m 1 A levels negatively correlate with translation efficiency. Nitrogen depletion further decreases mRNA m 1 A levels. Our data suggest that distinctive patterns of m 1 A modification might influence the expression of metabolism-related genes through translational control., (© 2024. The Author(s).)

Antidiabetic peptides (ADPs), peptides with potential antidiabetic activity, hold significant importance in the treatment and control of diabetes. Despite their therapeutic potential, the discovery and prediction of ADPs remain challenging due to limited data, the complex nature of peptide functions, and the expensive and time-consuming nature of traditional wet lab experiments. This study aims to address these challenges by exploring methods for the discovery and prediction of ADPs using advanced deep learning techniques. Specifically, we developed two models: a single-channel CNN and a three-channel neural network (CNN + RNN + Bi-LSTM). ADPs were primarily gathered from the BioDADPep database, alongside thousands of non-ADPs sourced from anticancer, antibacterial, and antiviral peptide datasets. Subsequently, data preprocessing was performed with the evolutionary scale model (ESM-2), followed by model training and evaluation through 10-fold cross-validation. Furthermore, this work collected a series of newly published ADPs as an independent test set through literature review, and found that the CNN model achieved the highest accuracy (90.48 %) in predicting the independent test set, surpassing existing ADP prediction tools. Finally, the application of the model was considered. SeqGAN was used to generate new candidate ADPs, followed by screening with the constructed CNN model. Selected peptides were then evaluated using physicochemical property prediction and structural forecasts for pharmaceutical potential. In summary, this study not only established robust ADP prediction models but also employed these models to screen a batch of potential ADPs, addressing a critical need in the field of peptide-based antidiabetic research., Competing Interests: Declaration of competing interest The authors declared that they have no conflicts of interest to this work, the manuscript entitled, “Discovery of potential antidiabetic peptides using deep learning”., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Enhancing proton storage in the zinc-ion battery cathode material of MnO 2 holds promise in promoting its electrochemical performance by mitigating the intense Coulombic interaction between divalent zinc ions and the host structure. However, challenges persist in addressing the structural instability caused by Jahn-Teller effects and accurately modulating H + intercalation in MnO 2 . Herein, the doping of high-electronegativity Sb with fully occupied d-orbital in MnO 2 is reported. The Sb doping strategy engenders the formation of Mn-O-Sb path in the structure with a strong dipole polarization field, which facilitates the delocalization of e g orbital electron in Mn and thus mitigates the Jahn-Teller effects. Simultaneously, adjusting the level of Sb doping in MnO 2 leads to modulation of the p-band center of O, optimizing its interaction with hydrogen and thereby enhancing proton storage. Consequently, MnO 2 doped with 6% Sb exhibits commendable performance in both rate capability and cycling endurance, delivering 113 mAh g -1 at 2 A g -1 after 2000 cycles. This investigation underscores the crucial role of electronic structural engineering in elevating the electrochemical performance of cathode materials for zinc-ion batteries.

Associative memory is a cornerstone of cognitive intelligence within the human brain. The Bayesian confidence propagation neural network (BCPNN), a cortex-inspired model with high biological plausibility, has proven effective in emulating high-level cognitive functions like associative memory. However, the current approach using GPUs to simulate BCPNN-based associative memory tasks encounters challenges in latency and power efficiency as the model size scales. This work proposes a scalable multi-FPGA high performance computing (HPC) architecture designed for the associative memory system. The architecture integrates a set of hypercolumn unit (HCU) computing cores for intra-board online learning and inference, along with a spike-based synchronization scheme for inter-board communication among multiple FPGAs. Several design strategies, including population-based model mapping, packet-based spike synchronization, and cluster-based timing optimization, are presented to facilitate the multi-FPGA implementation. The architecture is implemented and validated on two Xilinx Alveo U50 FPGA cards, achieving a maximum model size of 200×10 and a peak working frequency of 220 MHz for the associative memory system. Both the memory-bounded spatial scalability and compute-bounded temporal scalability of the architecture are evaluated and optimized, achieving a maximum scale-latency ratio (SLR) of 268.82 for the two-FPGA implementation. Compared to a two-GPU counterpart, the two-FPGA approach demonstrates a maximum latency reduction of 51.72× and a power reduction exceeding 5.28× under the same network configuration. Compared with the state-of-the-art works, the two-FPGA implementation exhibits a high pattern storage capacity for the associative memory task.

Fish passage facilities are essential for restoring river connectivity and protecting ecosystems, effectively balancing economic and ecological benefits. Systematic and comprehensive monitoring, assessment, and optimized management are therefore crucial. This study quantitatively evaluated the entire upstream migration process of fish from the downstream river to the entrance and exit of the fishway and investigated the upstream movement patterns of fish under various environmental factors. A total of 19 fish species were monitored in the Heishuihe River downstream of the dam, with 15 species reaching the fishway entrance and 12 species successfully passing through it. The entrance attraction and passage rates of the vertical-slot fishway at the Songxin hydropower station were 15.7% and 40.42%, respectively. The best upstream performance was observed in May, with fish demonstrating better upstream timing and speed during nighttime compared to daytime. Specifically, the highest entrance attraction efficiency was recorded at a flow rate of 6-7 m 3 /s and a temperature of 19-20 °C, while the optimal passage efficiency was observed at a flow rate of 0-0.5 m 3 /s and a temperature of 17-20 °C. Additionally, a multifactorial Cox proportional hazards regression model was constructed to identify key factors influencing the probability of fishway entrance attraction and successful passage. The model elucidated the impact patterns of these key factors on fish upstream migration, ultimately generating an alignment diagram for prediction and control. This study provides a theoretical foundation and data support for developing optimized operational schedules for fishways. The findings offer a more comprehensive and systematic approach for monitoring and evaluating fish passage facilities, serving as a scientific basis for ecological restoration and fish conservation in this region and similar areas.

The production of ammonia (NH3) from nitrogen sources involves competitive adsorption of different intermediates and multiple electron and proton transfers, presenting grand challenges in catalyst design. In nature nitrogenases reduce dinitrogen to NH3 using two component proteins, in which electrons and protons are delivered from Fe protein to the active site in MoFe protein for transfer to the bound N2. We draw inspiration from this structural enzymology, and design a two-component metal-sulfur-carbon (M-S-C) catalyst composed of sulfur-doped carbon-supported ruthenium (Ru) single atoms (SAs) and nanoparticles (NPs) for the electrochemical reduction of nitrate (NO3-) to NH3. The catalyst demonstrates a remarkable NH3 yield rate of ~37 mg L-1 h-1 and a Faradaic efficiency of ~97% for over 200 hours, outperforming those consisting solely of SAs or NPs, and even surpassing most reported electrocatalysts. Our experimental and theoretical investigations reveal the critical role of Ru SAs with the coordination of S in promoting the formation of the HONO intermediate and the subsequent reduction reaction over the NP-surface nearby. This study proves a better understanding of how M-S-Cs act as a synthetic nitrogenase mimic during ammonia synthesis, and contributes to the future mechanism-based catalyst design., (© 2024 Wiley‐VCH GmbH.)

Cross-dehydrogenative couplings (CDC) present an efficient strategy for the assembly of biorelevant heterocycles, but are thus far largely limited to toxic transition metals and rather harsh reaction conditions. In sharp contrast, we, herein report on a mild photoelectrocatalyzed CDC-[4+2] annulation enabling the synthesis of functionalized isothiochromenes enabled by a proton-coupled electron transfer (PCET) strategy. The transformative photoelectrocatalysis obviated toxic transition-metal, high reaction temperatures, and stoichiometric chemical redox reagents. This approach was characterized by exceedingly mild conditions, ample substrate scope, and a commercially available catalyst. Gram-scale reactions and a telescoped synthesis route reflected the unique potential in the green synthesis of important S-heterocycles., (© 2024 Wiley‐VCH GmbH.)

An electrochemical and selective decarboxylation and dehydration using α-keto acids with amines is accomplished, which leads to the easy accessibility of amides and α-ketoamides, which are not only ubiquitous and valuable structure motifs found in pharmaceuticals, but also versatile building blocks in synthetic chemistry. Notably, for this efficient and green protocol, neither metal catalysts nor external oxidants are required. The process exhibits a broad scope and functional group tolerance to deliver various amides and α-ketoamides. Moreover, these two reactions have also been applied to late-stage derivatization and can be safely conducted on gram scale.

Purpose: Approximately 25-30% of patients suffer from breast deformity and/or asymmetry after conventional breast-conserving surgery (CBCS). Generally, it is thought that oncoplastic breast-conserving surgery (OBCS) results in an improved cosmetic result; however, studies comparing the prognosis and aesthetic outcomes of CBCS and OBCS in early breast cancer (EBC) are inadequate., Methods: A total of 143 patients were included in this retrospective cohort study; 53 underwent OBCS and 90 underwent CBCS. The resected weight, complications, esthetic results, patient satisfaction, and recurrence rate were compared between the groups. Patient-reported outcomes (PRO) were assessed by the BREAST-Q questionnaire., Results: The mean age of the patients in OBCS group was 43.8 years. This was younger than that in CBCS group (49.1 years, p < 0.001). Postoperative complications (11.3% vs. 8.9%, p = 0.64) and re-excision (5.7% vs. 6.7%, p > 0.99) rates were similar. The OBCS group had higher breast satisfaction and psychosocial well-being than the CBCS group (75 vs. 63, p < 0.001 and 84 vs. 77, p = 0.05); however, sexual well-being (56 vs. 66, p = 0.05) and physical well-being (65 vs. 76, p < 0.001) were worse in OBCS. After 42.3 (range: 12.6-69.2)-month median follow-up, no difference in event-free survival (EFS) was demonstrated between the groups (p = 0.13)., Conclusion: Although OBCS has the better aesthetic outcomes and identical oncological safety in comparison with CBCS, the sexual and physical well-being in OBCS are not improved for Asian patients. Hence, choosing an appropriate procedure may be more important for the typically small to moderate-sized breasts characteristic of Asian females unlike Westerners., Level of Evidence Iv: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Estrogen and related receptors have been shown to have a significant impact on human development, reproduction, metabolism and immune regulation and to play a critical role in tumor development and treatment. Traditionally, the nuclear estrogen receptors (nERs) ERα and ERβ have been thought to be involved in mediating the estrogenic effects. However, our group and others have previously demonstrated that the G protein-coupled estrogen receptor (GPER) is the third independent ER, and estrogen signaling mediated by GPER is known to play an important role in normal physiology and a variety of abnormal diseases. Interestingly, recent studies have progressively revealed GPER involvement in the maintenance of the normal immune system, abnormal immune diseases, and inflammatory lesions, which may be of significant clinical value primarily in the immunotherapy of tumors. In this article, we review current advances in GPER-related immunomodulators and provide a theoretical basis and potential clinical targets to ameliorate immune-related diseases and immunotherapy for tumors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In the development and progression of cervical cancer, oxidative stress plays an important role within the cells. Among them, Solute Carrier Family 7 Member 11 (SLC7A11/xCT) is crucial for maintaining the synthesis of glutathione and the antioxidant system in cervical cancer cells. In various tumor cells, studies have shown that SLC7A11 inhibits ferroptosis, a form of cell death, by mediating cystine uptake and maintaining glutathione synthesis. Additionally, SLC7A11 is also involved in promoting tumor metastasis and immune evasion. Therefore, inhibiting the SLC7A11/xCT axis has become a potential therapeutic strategy for cervical cancer. In this study, through structure-based high-throughput virtual screening, a compound targeting the SLC7A11/xCT axis named compound 1 (PubChem CID: 3492258) was discovered. In vitro experiments using HeLa cervical cancer cells as the experimental cell model showed that compound 1 could reduce intracellular glutathione levels, increase glutamate and reactive oxygen species (ROS) levels, disrupt the oxidative balance within HeLa cells, and induce cell death. Furthermore, molecular dynamics simulation results showed that compound 1 has a stronger binding affinity with SLC7A11 compared to the positive control erastin. Overall, all the results mentioned above indicate the potential of compound 1 in targeting the SLC7A11/xCT axis and treating cervical cancer both in vitro and in silico.

Our recent study demonstrated that knockout of microRNA-301a attenuates migration and phagocytosis in macrophages. Considering that macrophages and Schwann cells synergistically clear the debris of degraded axons and myelin during Wallerian degeneration, which is a prerequisite for nerve regeneration, we hypothesized that microRNA-301a regulates Wallerian degeneration and nerve regeneration via impacts on Schwann cell migration and phagocytosis. Herein, we found low expression of microRNA-301a in intact sciatic nerves, with no impact of the microRNA-301a knockout on nerve structure and function. By contrast, we found significant upregulation of microRNA- 301a in injured sciatic nerves. We established a sciatic nerve crush model in microRNA-301a knockout mice, which exhibited attenuated morphological and functional regeneration following sciatic nerve crush injury. The microRNA-301a knockout also led to significantly inhibited Wallerian degeneration in an in vivo sciatic nerve-transection model and in an in vitro nerve explant block model. Schwann cells with the microRNA-301a knockout showed inhibition of phagocytosis and migration, which was reversible under transfection with microRNA-301a mimics. Rescue experiments involving transfection of microRNA-301a-knockout Schwann cells with microRNA-301a mimics or treatment with the C-X-C motif receptor 4 inhibitor WZ811 indicated the mechanistic involvement of the Yin Yang 1/C-X-C motif receptor 4 pathway in the role of microRNA-301a. Combined with our previous findings in macrophages, we conclude that microRNA-301a plays a key role in peripheral nerve injury and repair by regulating the migratory and phagocytic capabilities of Schwann cells and macrophages via the Yin Yang 1/C-X-C motif receptor 4 pathway., (Copyright © 2025 Copyright: © 2025 Neural Regeneration Research.)

In this work, a two-parameter inversion problem is analyzed, related to surface crack widths for measuring depths of normal surface notches, based on a laser-based ultrasonic measurement method in the time domain. In determining the depth measurement formulas, the main technique is the time delay between reflected and scattered waves. Scattered waves are generated by two reflections along the bottom and three mode transformations at the surface of the crack tips. Moreover, the scattering angle of the mode-conversion waves is 30°. These two key factors lead to corrected item "2wβ" in the depth measurement formula. A laser-based ultrasonic experimental platform is built to generate and receive surface waves in a non-contact manner on aluminum and steel specimens with surface cracks. The depth measurement method proposed in this paper has been validated through theoretical, simulation, and experimental methods. Finally, in this paper, an effective approach for quantitatively measuring crack depths, based on laser ultrasound, using the time-domain properties of surface wave propagation is provided.

The dramatic rise in the number of obese/overweight people is a global public health challenge that urgently requires novel and effective therapies. In this study, we designed a fast dissolving polymer microneedle array patch (SGN-PVP/PVA-MN) with sitagliptin as a model drug for treating obesity, focusing on the preparation process of the patch. We then characterized the morphology and dimensions of SGN-PVP/PVA-MN. Furthermore, we delved into the mechanical properties, solubility, skin-puncturing capability, and transdermal drug diffusion and release kinetics of SGN-PVP/PVA-MN. The results demonstrated that SGN-PVP/PVA-MN exhibited favorable morphology and mechanical properties, effectively penetrating the stratum corneum and creating microchannels for rapid transdermal drug diffusion. The in vitro transdermal diffusion assays revealed the release of 64.5% of the drug within 2 min and 95.7% within 10 min. With rapid dissolution and high drug diffusion efficiency, SGN-PVP/PVA-MN is poised to serve as an effective and safe treatment option for the individuals with obesity.

Introduction: Despite the available secondary preventive treatments, the management of stable coronary artery disease (SCAD) remains challenging. Intermediate coronary lesion (ICL), defined as luminal stenosis between 50% and 70%, is a key stage of SCAD. However, existing therapeutic strategies are limitated in delaying plaque progression and associated with various adverse effects and economic burdens. Qing-Xin-Jie-Yu Granules (QXJYG) with proven anti-platelet, anti-inflammatory, and lipid-lowering effects may compensate for the drawbacks of current treatments and can be tested as a complementary therapy. Therefore, this study aims to investigate the efficacy and safety of QXJYG in treating ICL, with a particular focus on its impact on myocardial ischemia and plaque progression., Materials and Methods: This is a multicenter, randomized, double-blind, placebo-controlled trial. A total of 120 participants with ICL will be randomly assigned to two groups in a 1:1 ratio. In addition to basic medications, the intervention group will receive QXJYG, while the control group will receive a placebo for over 6 months, followed by a 12-month follow-up. The primary efficacy outcome is computed tomography-derived fractional flow reserve. The secondary outcomes include the degree of coronary stenosis, coronary artery calcification score, Gensini score, Seattle Angina Questionnaire score, high-sensitivity C-reactive protein, matrix metalloproteinase-9, blood lipids, and carotid artery ultrasound parameters. Major adverse cardiovascular events are recorded as endpoints. The safety outcomes include composite events of bleeding, laboratory test results, and adverse events. Clinical visits are scheduled at baseline, every 2 months during the treatment, and after a 12-month follow-up., Discussion: This trial is anticipated to yield reliable results to verify the efficacy and safety of QXJYG in the treatment of ICL, which will provide novel insights to help address the prevailing therapeutic dilemma of ICL, thereby facilitating for the management of SCAD., Trial Registration: Chinese Clinical Trial Registry, ChiCTR2200059262. Registered on April 27, 2022., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Airway epithelial cell (AEC) necroptosis contributes to airway allergic inflammation and asthma exacerbation. Targeting the tumor necrosis factor-like ligand 1 A (TL1A)/death receptor 3 (DR3) axis has a therapeutic effect on asthmatic airway inflammation. The role of TL1A in mediating necroptosis of AECs challenged with ovalbumin (OVA) and its contribution to airway inflammation remains unclear., Methods: We evaluated the expression of the receptor-interacting serine/threonine-protein kinase 3(RIPK3) and the mixed lineage kinase domain-like protein (MLKL) in human serum and lung, and histologically verified the level of MLKL phosphorylation in lung tissue from asthmatics and OVA-induced mice. Next, using MLKL knockout mice and the RIPK3 inhibitor GSK872, we investigated the effects of TL1A on airway inflammation and airway barrier function through the activation of necroptosis in experimental asthma., Results: High expression of necroptosis marker proteins was observed in the serum of asthmatics, and necroptosis was activated in the airway epithelium of both asthmatics and OVA-induced mice. Blocking necroptosis through MLKL knockout or RIPK3 inhibition effectively attenuated parabronchial inflammation, mucus hypersecretion, and airway collagen fiber accumulation, while also suppressing type 2 inflammatory factors secretion. In addition, TL1A/ DR3 was shown to act as a death trigger for necroptosis in the absence of caspases by silencing or overexpressing TL1A in HBE cells. Furthermore, the recombinant TL1A protein was found to induce necroptosis in vivo, and knockout of MLKL partially reversed the pathological changes induced by TL1A. The necroptosis induced by TL1A disrupted the airway barrier function by decreasing the expression of tight junction proteins zonula occludens-1 (ZO-1) and occludin, possibly through the activation of the NF-κB signaling pathway., Conclusions: TL1A-induced airway epithelial necroptosis plays a significant role in promoting airway inflammation and barrier dysfunction in asthma. Inhibition of the TL1A-induced necroptosis pathway could be a promising therapeutic strategy., (© 2024. The Author(s).)

Purpose: Asthma, an airway inflammatory disease, involves multiple tumor necrosis factors (TNF). TNF ligand superfamily member 11 (TNFSF11) and its known receptor, TNF receptor superfamily 11A (TNFRSF11A), has been implicated in asthma; however, the related mechanisms remain unknown., Methods: The serum and bronchial airway of patients with asthma and healthy subjects were examined. The air-liquid interface of primary human bronchial epithelial (HBE) cells, and Tnfsf11 +/- mouse, Tnfrsf11a +/- mouse, and a humanized HSC-NOG-EXL mouse model were established. This study constructed short hairpin RNA (shRNA) of TNFSF11 , TNFRSF11A , transforming growth factor β1 ( TGFβ1 ), and transforming growth factor β receptor type 1 ( TGFβR1 ) using lentivirus to further examine the ability of TNFSF11 protein., Results: This study was the first to uncover TNFSF11 overexpression in the airway and serum of asthmatic human subjects, and the TNFSF11 in serum was closely correlated with lung function. The TNFSF11/TNFRSF11A axis deficiency in Tnfsf11 +/- or Tnfrsf11a +/- mice remarkably attenuated the house dust mite (HDM)-induced signal transducer and activator of transcription 3 (STAT3) action and remodeling protein expression. Similarly, the HDM-induced STAT3 action and remodeling protein expression in HBE cells decreased after pretreatment with TNFSF11 or TNFRSF11A shRNA. Meanwhile, the expression of the remodeling proteins induced by TNFSF11 significantly decreased after pretreatment with-stattic (inhibitor of STAT3 phosphorylation) in HBE cells. The STAT3 phosphorylation and remodeling protein expression induced by TNFSF11 obviously decreased after pretreatment with TGFβ1 or TGFβR1 shRNA in HBE cells. The above results also verified that blocking TNFSF11 with denosumab alleviated airway remodeling via the TGFβ1/STAT3 signaling in the humanized HSC-NOG-EXL mice with HDM-induced asthma., Conclusions: TGFβ1/STAT3 action was closely correlated with TNFSF11/TNFRSF11A axis-mediated airway remodeling. This study presented a novel strategy that blocks the TNFSF11/TNFRSF11A axis to exert a protective effect against asthma., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2024 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease.)

The factors affecting the antibody responses to the ZF2001 vaccine remain unknown. To address this, we conducted a cross-sectional serological study in the real world. Adults with no prior SARS-CoV-2 infection history and received three doses of ZF2001 vaccine were invited to our study in the early stages of the COVID-19 epidemic in Chongqing between 7 April 2021 and 17 November 2021. A questionnaire survey was conducted to obtain demographic characteristics, health information, and the frequency of lifestyles at the time of enrollment. A total of 266 eligible subjects aged 18 to 86 years, with a median age of 56.00 (IQR: 34-66) participated. 68.80% of them were female. Hypertension (13.16%) and diabetes (6.02%) were common comorbidities. Serum samples were collected at one month after the third dose of ZF2001 vaccination, and serological testing was conducted using the Pseudovirus-Based Neutralization Assay. The chi-square test was employed to compare seropositivity rates, and the Mann-Whitney U test or the Kruskal-Wallis test was used to analyze the neutralizing antibodies level in stratified groups. Subsequently, univariate and multivariate linear regression analyses were conducted to identify the influencing factors. We observed that seropositivity rates was 76.32%, with 95% confidence interval (95%CI) 70.85%-81.03%, and geometric mean titer (GMT) was 120.26, with 95%CI 100.38-144.08. Age, diabetes, and frequently of alcohol were negative associations with antibody response ( β = -0.2021, 95% CI: -0.2507 to -0.1535, β = -0.2873, 95% CI: -0.5590 to -0.0155, β = -0.2082, 95% CI: -0.3419 to-0.0746, P < 0.0001, P  = 0.0384, P  = 0.0024). Conversely, the -interval between 1 and 2 dose and frequently of tea were positive associations with antibody response ( β  = 0.1369, 95% CI: 0.0463 to 0.2275, β  = 0.0830, 95% CI: 0.0106 to 0.1554, P  = 0.0032, P  = 0.0247). Overall, the ZF2001 vaccine-induced antibody response was influenced by a multifactor that may provide a reference for the development of personalized antigen vaccines and vaccination strategies in the future.

Previous studies showed that transglutaminase (TGase) and microwaves acted synergistically to improve the functional properties of proteins. The mechanism behind this has yet to be elucidated. In this study, the phenomenon of microwaves enhancing TGase activity was experimentally validated. Molecular docking and molecular dynamics simulations revealed that moderate microwaves (10 5 and 10 8 V/m) increased the structural flexibility of TGase and promoted the orientation of the side chain carboxylate anion group on Asp255, driving the reaction forward. Also, TGase underwent partial transformation from α-helix to turns or coils at 10 5 and 10 8 V/m, exposing more residues in the active site and facilitating the binding of the substrate (CBZ-Gln-Gly) to TGase. However, 10 9 V/m microwaves completely destroyed the TGase structure, inactivating the enzyme. This study provides insights into the molecular mechanisms underlying the interactions between TGase and substrate subjected to microwaves, promoting the future applications of TGase and microwaves in food processing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Tumor microenvironment (TME)-responsive size-changeable and biodegradable nanoplatforms for multimodal therapy possess huge advantages in anti-tumor therapy. Hence, we developed a hyaluronic acid (HA) modified CuS/MnO 2 nanosheets (HCMNs) as a multifunctional nanoplatform for synergistic chemodynamic therapy (CDT)/photothermal therapy (PTT)/photodynamic therapy (PDT). The prepared HCMNs exhibited significant NIR light absorption and photothermal conversion efficiency because of the densely deposited ultra-small sized CuS nanoparticles on the surface of MnO 2 nanosheet. They could precisely target the tumor cells and rapidly decomposed into small sized nanostructures in the TME, and then efficiently promote intracellular ROS generation through a series of cascade reactions. Moreover, the local temperature elevation induced by photothermal effect also promote the PDT based on CuS nanoparticles and the Fenton-like reaction of Mn 2+ , thereby enhancing the therapeutic efficiency. Furthermore, the T 1 -weighted magnetic resonance (MR) imaging was significantly enhanced by the abundant Mn 2+ ions from the decomposition process of HCMNs. In addition, the CDT/PTT/PDT synergistic therapy using a single NIR light source exhibited considerable anti-tumor effect via in vitro cell test. Therefore, the developed HCMNs will provide great potential for MR imaging and multimodal synergistic cancer therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Airway epithelium is an important component of airway structure and the initiator of airway remodeling in asthma. The changes of extracellular matrix (ECM), such as collagen deposition and structural disturbance, are typical pathological features of airway remodeling. Thus, identifying key mediators that derived from airway epithelium and capable of modulating ECM may provide valuable insights for targeted therapy of asthma., Methods: The datasets from Gene Expression Omnibus database were analyzed to screen differentially expressed genes in airway epithelium of asthma. We collected bronchoscopic biopsies and serum samples from asthmatic and healthy subjects to assess lysyl oxidase like 2 (LOXL2) expression. RNA sequencing and various experiments were performed to determine the influences of LOXL2 knockdown in ovalbumin (OVA)-induced mouse models. The roles and mechanisms of LOXL2 in bronchial epithelial cells were explored using LOXL2 small interfering RNA, overexpression plasmid and AKT inhibitor., Results: Both bioinformatics analysis and further experiments revealed that LOXL2 is highly expressed in airway epithelium of asthmatics. In vivo, LOXL2 knockdown significantly inhibited OVA-induced ECM deposition and epithelial-mesenchymal transition (EMT) in mice. In vitro, the transfection experiments on 16HBE cells demonstrated that LOXL2 overexpression increases the expression of N-cadherin and fibronectin and reduces the expression of E-cadherin. Conversely, after silencing LOXL2, the expression of E-cadherin is up-regulated. In addition, the remodeling and EMT process that induced by transforming growth factor-β1 could be enhanced and weakened after LOXL2 overexpression and silencing in 16HBE cells. Combining the RNA sequencing of mouse lung tissues and experiments in vitro, LOXL2 was involved in the regulation of AKT signaling pathway. Moreover, the treatment with AKT inhibitor in vitro partially alleviated the consequences associated with LOXL2 overexpression., Conclusions: Taken together, the results demonstrated that epithelial LOXL2 plays a role in asthmatic airway remodeling partly via the AKT signaling pathway and highlighted the potential of LOXL2 as a therapeutic target for airway remodeling in asthma., (© 2024. The Author(s).)

An ideal bone metastasis animal model is critical and fundamental for mechanistic research and following development of new drug and treatment. Caudal artery (CA) injection allows bone metastasis in the hindlimb, while in-depth targeted and quantitative studies of bone metastasis require a new model to overcome its limitations. Here, we developed a targeted, quantitative, and highly consistent method for the modeling of bone metastasis with cell-based magnetic micro-living-motor (MLM) system created by effectively combining Fe 3 O 4 -PDA-Au with biosafety. The MLM system can achieve efficient migration, target site colonization and control tumorigenesis in bone precisely with the application of a magnetic field. In vivo, day 3 post cell injection, tumor bone metastasis signals were observed locally in the injected femur among 82.76% mice of the MLM group as compared to the 56.82% in the CA group, and the signal intensity was 45.1 and 95.9 times stronger than that in the left and right lower limbs of the CA group, respectively. Post-injection day 28, metastasis in vital organs was reduced by approximately 90% in the MLM group compared to the CA group. Our innovative use of the MLM system in the field of tumor modeling opens a new avenue for exploring the mechanisms of tumor bone metastasis, recurrence and drug resistance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: To assess the immunogenicity of the current primary polio vaccination schedule in China and compare it with alternative schedules using Sabin or Salk-strain IPV (sIPV, wIPV)., Methods: A cross-sectional investigation was conducted at four sites in Chongqing, China, healthy infants aged 60-89 days were conveniently recruited and divided into four groups according to their received primary polio vaccination schedules (2sIPV + bOPV, 2wIPV + bOPV, 3sIPV, and 3wIPV). The sero-protection and neutralizing antibody titers against poliovirus serotypes (type 1, 2, and 3) were compared after the last dose., Results: There were 408 infants completed the protocol. The observed seropositivity was more than 96% against poliovirus types 1, 2, and 3 in all groups. IPV-only groups induced higher antibody titers(GMT) against poliovirus type 2 (Median:192, QR: 96-384, P<0.05) than the "2IPV + bOPV" group. While the "2IPV + bOPV" group induced significantly higher antibody titers against poliovirus type 1 (Median:2048, QR: 768-2048, P<0.05)and type 3 (Median:2048, QR: 512-2048, P<0.05) than the IPV-only group., Conclusions: Our findings have proved that the two doses of IPV with one dose of bOPV is currently the best polio routine immunization schedule in China., (© 2024. The Author(s).)

The Python-based program, XMECP, is developed for realizing robust, efficient, and state-of-the-art minimum energy crossing point (MECP) optimization in multiscale complex systems. This article introduces the basic capabilities of the XMECP program by theoretically investigating the MECP mechanism of several example systems including (1) the photosensitization mechanism of benzophenone, (2) photoinduced proton-coupled electron transfer in the cytosine-guanine base pair in DNA, (3) the spin-flip process in oxygen activation catalyzed by an iron-containing 2-oxoglutarate-dependent oxygenase (Fe/2OGX), and (4) the photochemical pathway of flavoprotein adjusted by the intensity of an external electric field. MECPs related to multistate reaction and multistate reactivity in large-scale complex biochemical systems can be well-treated by workflows suggested by the XMECP program. The branching plane updating the MECP optimization algorithm is strongly recommended as it provides derivative coupling vector (DCV) with explicit calculation and can equivalently evaluate contributions from non-QM residues to DCV, which can be nonadiabatic coupling or spin-orbit coupling in different cases. In the discussed QM/MM examples, we also found that the influence on the QM region by DCV can occur through noncovalent interactions and decay with distance. In the example of DNA base pairs, the nonadiabatic coupling occurs across the π-π stacking structure formed in the double-helix system. In contrast to general intuition, in the example of Fe/2OGX, the central ferrous and oxygen part contribute little to the spin-orbit coupling; however, a nearby arginine residue, which is treated by molecular mechanics in the QM/MM method, contributes significantly via two hydrogen bonds formed with α-ketoglutarate (α-KG). This indicates that the arginine residue plays a significant role in oxygen activation, driving the initial triplet state toward the productive quintet state, which is more than the previous knowledge that the arginine residue can bind α-KG at the reaction site by hydrogen bonds.

Rhodium(III)-catalyzed enantioselective C-H activation has emerged as a powerful tool for assembling enabling chiral molecules. However, this approach is significantly hampered by the cumbersome synthetic routes for preparing chiral rhodium catalysts. In sharp contrast, we herein report on an electrochemical domino catalysis system that exploits an achiral Cp*-rhodium catalyst along with an easily accessible chiral Brønsted base for an enantioselective C-H activation/annulation reaction of alkenes by benzoic acids. Our strategy offers an environmentally benign and most user-friendly approach for assembling synthetically useful chiral phthalides in good enantioselectivity, employing electricity as the sustainable oxidant., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Hepatocellular carcinoma (HCC) is the most common pathologic type of primary liver cancer. Liver transplantation (LT) is a radical strategy for treating patients with early-stage HCC, which may lead to a better prognosis compared to hepatectomy and ablation. However, survival of patients who develop HCC recurrence after LT is short, and early recurrence is the most common cause of death. Thus, efficient biomarkers are also needed in LT to guide precision therapy to improve patient prognosis and 5-year survival. Protein induced by vitamin K absence or antagonist II (PIVKA-II) is an abnormal prothrombin that cannot activate coagulation, and it is significantly increased in patients with HCC, obstructive jaundice, and those taking vitamin K antagonists. Over the past decades, substantial progress has been made in the study of PIVKA-II in diagnosing, surveilling, and treating HCC, but its role in LT still needs to be elaborated. In this review, we focused on the role of PIVKA-II as a biomarker in LT for HCC, especially its relationship with clinicopathologic features, early recurrence, long-term survival, and donor-recipient selection., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

The transpedicular procedure has been widely used in spinal surgery. The determination of the best entry point is the key to perform a successful transpedicular procedure. Various techniques have been used to determine this point, but the results are variable. This study was carried out to determine the posterior endpoint of the lumbar pedicle central axis on the standard anterior-posterior (AP) fluoroscopic images. Computer-aided design technology was used to determine the pedicle central axis and the posterior endpoint of the pedicle central axis on the posterior aspect of the vertebra. The standard AP fluoroscopic image of the lumbar vertebral models by three-dimensional printing was achieved. The endpoint projection on the AP fluoroscopic image was determined in reference to the pedicle cortex projection by the measurements of the angle and distance on the established X-Y coordinate system of the radiologic image. The projection of posterior endpoint of the lumbar pedicle central axis were found to be superior to the X-axis of the established X-Y coordinate system and was located on the pedicle cortex projection on the standard AP fluoroscopic image of the vertebra. The projection point was distributed in different sectors in the coordinate system. It was located superior to the X-axis by 18° to 26° at L1, while they were located superior to the X-axis by 12° to 14° at L2 to L5. The projections of posterior endpoints of the lumbar pedicle central axis were located in different positions on the standard AP fluoroscopic image of the vertebra. The determination method of the projection point was helpful for selecting an entry point for a transpedicular procedure with a fluoroscopic technique., (© 2024. The Author(s).)

The visible light-induced C-H arylation of azoles has been accomplished by dual-catalytic system with the aid of an inexpensive ligand-free copper(i)-catalyst in combination with a suitable photoredox catalyst. An organic photoredox catalyst, 10-phenylphenothiazine (PTH), was identified as effective, cost-efficient and environmentally-benign alternative to commonly-used, expensive Ir(iii)-based complexes. The method proved applicable for the C-H arylation of various azole derivatives, including oxazoles, benzoxazoles, thiazoles, benzothiazoles as well as more challenging imidazoles and benzimidazoles. Moreover, the derivatization of complex molecules and the gram scale synthesis of the natural product balsoxin reflected the synthetic utility of the developed strategy. Mechanistic studies were indicative of a single electron transfer-based (SET) mechanism with an aryl radical as key intermediate., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Zygotic genome activation (ZGA) is a critical event in early embryonic development, and thousands of genes are involved in this delicate and sophisticated biological process. To date, however, only a handful of these genes have revealed their core functions in this special process, and therefore the roles of other genes still remain unclear. In the present study, we used previously published transcriptome profiling to identify potential key genes (candidate genes) in minor ZGA and major ZGA in both human and mouse specimens, and further identified the conserved genes across species. Our results showed that 887 and 760 genes, respectively, were thought to be specific to human and mouse in major ZGA, and the other 135 genes were considered to be orthologous genes. Moreover, the conserved genes were most enriched in rRNA processing in the nucleus and cytosol, ribonucleoprotein complex biogenesis, ribonucleoprotein complex assembly and ribosome large subunit biogenesis. The findings of this first comprehensive identification and characterization of candidate genes in minor and major ZGA provide relevant insights for future studies on ZGA.

Background: The administration of inhaled prostanoids to patients with pulmonary hypertension (PH) related to idiopathic pulmonary fibrosis (IPF) and other fibrotic lung diseases improves functional outcomes. Selection of patients with IPF at risk for concomitant PH to undergo right heart catheterization (RHC) remains challenging. We sought to develop a clinical prediction tool based on common noninvasive parameters to identify PH in patients with IPF., Methods: A prediction model based on noninvasive parameters was derived from patients enrolled in the ARTEMIS-IPF randomized, placebo-controlled clinical trial. Predictor variables were tested for association with the presence of PH diagnosed based on RHC. The derived multivariable logistic regression model and associated point-score index were then externally validated in a real-world cohort of patients with IPF., Results: Of the 481 patients included in the ARTEMIS-IPF study, 9.8% (N = 47) were diagnosed with PH related to IPF. Four variables were associated with PH and were included in the final model: forced vital capacity/diffusing capacity for carbon monoxide ratio (F), oxygen saturation nadir during 6-minute walk test (6MWT) (O), race (R), and distance ambulated during 6MWT (D). A model containing continuous predictors (FORD calculator) and a simple point-score system (FORD index) performed similarly well in the derivation cohort (area under the curve [AUC]: 0.75 and 0.75, respectively) and validation cohort (AUC: 0.69 and 0.69, respectively)., Conclusions: The FORD models are simple, validated tools incorporating noninvasive parameters that can be applied to identify patients at risk of PH related to IPF who may benefit from invasive testing., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Nowadays, diabetic wound healing remains a crucial challenge due to their protracted and uncertain healing process. Traditional Chinese medicine (TCM) has demonstrated the therapeutic value of Sanguis draconis (SD)-Salvia miltiorrhiza (SMR) Herb Pair in diabetic wound healing. However, new administration modes are urgently needed for their convenient and wide-ranging applications., Objective: We propose a soluble polyvinylpyrrolidone-based microneedle patch containing the herbal extracts of SD and SMR (MN-SD@SMR) for diabetic wound healing., Methods: The herbal extracts of SD and SMR are purification and concentration via traditional lyophilization. SD endowed MN-SD@SMR with functions to improve high glycemic blood environment and migration of keratinocyte and fibroblast cells., Results: SMR in MN-SD@SMR could improve blood flow velocity and microcirculation in the wound area. The effectiveness of transdermal release and mechanical strengths of MN-SD@SMR were verified., Conclusion: Integrating the advantages of these purified herbal compositions, we demonstrated that MN-SD@SMR had a positive healing effect on the wounds in vitro and vivo. These results indicate that soluble polyvinylpyrrolidone-based microneedle patch containing the herbal extracts of SD and SMR has a promising application value due to their superior capability to promote diabetic wound healing., (© 2024 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

Exploiting emissive hydrophobic nanoclusters for hydrophilic applications remains a challenge because of photoluminescence (PL) quenching during phase transfer. In addition, the mechanism underlying PL quenching remains unclear. In this study, the PL-quenching mechanism was examined by analyzing the atomically precise structures and optical properties of a surface-engineered Ag 29 nanocluster with an all-around-carboxyl-functionalized surface. Specifically, phase-transfer-triggered PL quenching was justified as molecular decoupling, which directed an unfixed cluster surface and weakened the radiative transition. Furthermore, emission recovery of the quenched nanoclusters was accomplished by using a supramolecular recoupling approach through the glutathione-addition-induced aggregation of cluster molecules, wherein the restriction of intracluster motion and intercluster rotation strengthened the radiative transition of the clusters. The results of this work offer a new perspective on structure-emission correlations for atomically precise nanoclusters and hopefully provide insight into the fabrication of highly emissive cluster-based nanomaterials for downstream hydrophilic applications., (© 2024 Wiley-VCH GmbH.)

The Influenza A virus (IAV) is a zoonotic pathogen that infects humans and various animal species. Infection with IAV can cause fever, anorexia, and dyspnea and is often accompanied by pneumonia characterized by an excessive release of cytokines (i.e., cytokine storm). Nanodrug delivery systems and nanoparticles are a novel approach to address IAV infections. Herein, UiO-66 nanoparticles (NPs) are synthesized using a high-temperature melting reaction. The in vitro and in vivo optimal concentrations of UiO-66 NPs for antiviral activity are 200 μg mL -1 and 60 mg kg -1 , respectively. Transcriptome analysis revealed that UiO-66 NPs can activate the RIG-I-like receptor signaling pathway, thereby enhancing the downstream type I interferon antiviral effect. These NPs suppress inflammation-related pathways, including the FOXO, HIF, and AMPK signaling pathways. The inhibitory effect of UiO-66 NPs on the adsorption and entry of IAV into A549 cells is significant. This study presents novel findings that demonstrate the effective inhibition of IAV adsorption and entry into cells via UiO-66 NPs and highlights their ability to activate the cellular RIG-I-like receptor signaling pathway, thereby exerting an anti-IAV effect in vitro or in mice. These results provide valuable insights into the mechanism of action of UiO-66 NPs against IAV and substantial data for advancing innovative antiviral nanomedicine., (© 2024. The Author(s).)

Non-invasive, closed-loop brain modulation offers an accessible and cost-effective means of evaluating and modulating one's mental and physical well-being, such as Parkinson's disease, epilepsy, and sleep disorders. However, wearable EEG systems pose significant challenges for the analog front-end (AFE) circuits in view of μV-level EEG signals of interest, multiple sources of interference, and ill-defined skin contact. This paper presents a direct-digitization AFE tailored for dry-electrode scalp EEG recording, characterized by wide input dynamic range (DR) and high input impedance. The AFE utilizes a second-order 5-bit delta-delta sigma (Δ-ΔΣ) ADC to shape DC electrode offset (DEO) and low-frequency disturbances while retaining high accuracy. A non-inverting pseudo-differential instrumentation amplifier (IA) embedded in the ADC ensures high input impedance (Zin) and common-mode rejection ratio (CMRR). Fabricated in a standard 0.18-μm CMOS process, the AFE delivers 700-mVpp input signal range, 95.3-dB DR, 87-dB SNDR, and 800-MΩ input impedance at 50 Hz while consuming 88.4μW from a 1.2 V supply. The benefits of high DR and high input impedance have been validated by dry-electrode EEG measurement.

Skeletal muscle growth and development in livestock and poultry play a pivotal role in determining the quality and yield of meat production. However, the mechanisms of myogenesis are remained unclear due to it finely regulated by a complex network of biological macromolecules. In this study, leveraging previous sequencing data, we investigated a differentially expressed circular RNA (circSGCB) present in fetal and adult muscle tissues among various ruminant species, including cattle, goat, and sheep. Our analysis revealed that circSGCB is a single exon circRNA, potentially regulated by an adjacent bovine enhancer. Functional analysis through loss-of-function tests demonstrated that circSGCB exerts inhibitory effects on bovine myoblast proliferation while promoting myocytes generation. Furthermore, we discovered that circSGCB primarily localizes to the cytoplasm, where it functions as a molecular sponge by binding to bta-miR-27a-3p. This interaction releases the mRNAs of KLF3 gene and further activates downstream functional pathways. In vivo, studies provided evidence that up-regulation of KLF3 contributes to muscle regeneration. These findings collectively suggest that circSGCB operates via a competing endogenous RNA (ceRNA) mechanism to regulate KLF3, thereby influencing myogenesis in ruminants and highlights it may as potential molecular targets for enhancing meat production in livestock and poultry industries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Autism spectrum disorder (ASD) is a highly variable neurodevelopmental disorder that typically manifests childhood, characterized by a triad of symptoms: impaired social interaction, communication difficulties, and restricted interests with repetitive behaviors. De novo variants in related genes can cause ASD. We present the case of a 6-year-old Chinese boy with autistic behavior, including language communication impairments, intellectual disabilities, stunted development, and irritability in social interactions. Using Sanger sequencing, we confirmed a pathogenic in the RERE gene (NM&#95;012102.4) (c.3732delC, p.Tyr1245Thrfs*12; EX21; Het). Subsequently, we generated an RERE point mutation cell line (ReMut) using CRISPR/Cas9 Targeted Genome Editing. Immunofluorescence was conducted to determine the location of the mutant RERE. RNA-sequencing and mass spectrometry analyses were performed to elucidate the ASD-related genes and signaling pathways disrupted by this variant in RERE. We identified 3790 differentially expressed genes and 684 differentially expressed proteins. The SHH signaling pathway was found to be downregulated, and the Hippo pathway was upregulated in ReMut. Genes implicated in autism, such as CNTNAP2, STX1A, FARP2, and GPC1, were significantly downregulated. Simultaneously, we noted alterations in HDAC1 and HDAC2, which are members of the WHHERE complex, suggesting their role in the pathogenesis of this patient. In conclusion, we report a de novo variant in RERE associated with autistic behavior. The finding that ASD is associated with RERE variants underscore the role of genetic factors in ASD and provides insights regarding the mechanisms underlying RERE variants in disease onset., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In humans and animals, the pyruvate dehydrogenase kinase (PDK) family proteins (PDKs 1-4) are excessively activated in metabolic disorders such as obesity, diabetes, and cancer, inhibiting the activity of pyruvate dehydrogenase (PDH) which plays a crucial role in energy and fatty acid metabolism and impairing its function. Intervention and regulation of PDH activity have become important research approaches for the treatment of various metabolic disorders. In this study, a small molecule (g25) targeting PDKs and activating PDH, was identified through multi-level computational screening methods. In vivo and in vitro experiments have shown that g25 activated the activity of PDH and reduced plasma lactate and triglyceride level. Besides, g25 significantly decreased hepatic fat deposition in a diet-induced obesity mouse model. Furthermore, g25 enhanced the tumor-inhibiting activity of cisplatin when used in combination. Molecular dynamics simulations and in vitro kinase assay also revealed the specificity of g25 towards PDK2. Overall, these findings emphasize the importance of targeting the PDK/PDH axis to regulate PDH enzyme activity in the treatment of metabolic disorders, providing directions for future related research. This study provides a possible lead compound for the PDK/PDH axis related diseases and offers insights into the regulatory mechanisms of this pathway in diseases., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024. Published by Elsevier B.V.)

After entering the human body, drugs for treating diseases, which are prone to delivery and release in an uncontrolled manner, are affected by various factors. Based on this, many researchers utilize various microenvironmental changes encountered during drug delivery to trigger drug release and have proposed stimuli-responsive drug delivery systems. In recent years, metal-organic frameworks (MOFs) have become promising stimuli-responsive agents to release the loaded therapeutic agents at the target site to achieve more precise drug delivery due to their high drug loading, excellent biocompatibility, and high stimuli-responsiveness. The MOF-based stimuli-responsive systems can respond to various stimuli under pathological conditions at the site of the lesion, releasing the loaded therapeutic agent in a controlled manner, and improving the accuracy and safety of drug delivery. Due to the changes in different physical and chemical factors in the pathological process of diseases, the construction of stimuli-responsive systems based on MOFs has become a new direction in drug delivery and controlled release. Based on the background of the rapidly increasing attention to MOFs applied in drug delivery, we aim to review various MOF-based stimuli-responsive drug delivery systems and their response mechanisms to various stimuli. In addition, the current challenges and future perspectives of MOF-based stimuli-responsive drug delivery systems are also discussed in this review.

Rationale: Phenylethylamines are one of the most common types of new psychoactive substances, following synthetic cannabinoids and synthetic cathinones. They are regulated in many countries because of their strong hallucinogenic effects, which can cause serious nerve damage. There is a wide variety of phenylethylamines, exhibiting rapid renewal and extremely similar structures, therefore accurate qualitative analysis of isomers is a difficult problem in current drug analysis., Methods: The dissociation pathways of the position isomers 2-(2-methylaminoprolyl)benzofuran (2-MAPB) and 5-(2-methylaminopropyl)benzofuran (5-MAPB) were investigated by gas chromatography-mass spectrometry and liquid chromatography coupled to high-resolution quadrupole Orbitrap MS. The dissociation patterns of the phenethylamine-based designer drugs 2-MAPB and 5-MAPB were explored and extended in this work based on MS combined with density functional theory studies., Results: For electron ionization mass spectrometry (EI-MS) analysis, the dissociation patterns of 2-MAPB were similar to those of 5-MAPB. For electrospray ionization mass spectrometry (ESI-MS n ) analysis, the hydrogen atom on amino group was facile to form a intramolecular hydrogen bond with the oxygen atom on the parent nucleus of benzofuran in the structure of 2-MAPB, leading to higher abundance of the product ion at m/z 58. However, there was a conjugated system between the positive charge formed by the cleavage of the 5-MAPB side chain and the benzofuran ring, enabling the 5-MAPB to generate a product ion at m/z 131. Computational study showed that energy barrier and spin density difference distribution jointly control the selective dissociation in EI-MS, while different types of orbital interaction induced by intramolecular hydrogen bond led to different dissociation results in ESI-MS n ., Conclusions: These different dissociation patterns could be used to distinguish 2-MAPB from 5-MAPB. This could assist forensic laboratories in the differentiation and characterization of potential isomers in these kinds of compounds, especially in mixtures., (© 2023 John Wiley & Sons Ltd.)

Drug-eluting stents (DES) play a crucial role in treating coronary artery disease (CAD) by preventing restenosis. These stents are coated with drug carriers that release antiproliferative drugs within the vessel. Over the past two decades, DES have been employed in clinical practice using various materials, polymers, and drug types. Despite optimizations in their design and materials to enhance biocompatibility and antithrombotic properties, evaluating their long-term efficacy and safety necessitates improved clinical follow-up and monitoring. To delineate future research directions, this study employs a bibliometric analysis approach. We comprehensively surveyed two decades' worth of literature on DES for CAD using the Web of Science Core Collection (WOSCC). Out of 5,778 articles, we meticulously screened them based on predefined inclusion and exclusion criteria. Subsequently, we conducted an in-depth analysis encompassing annual publication trends, authorship affiliations, journal affiliations, keywords, and more. Employing tools such as Excel 2021, CiteSpace 6.2R3, VOSviewer 1.6.19, and Pajek 5.17, we harnessed bibliometric methods to derive insights from this corpus. Analysis of annual publication data indicates a recent stabilisation or even a downward trend in research output in this area. The United States emerged as the leading contributor, with Columbia University and CRF at the forefront in both publication output and citation impact. The most cited document pertained to standardized definitions for clinical endpoints in coronary stent trials. Our author analysis identifies Patrick W. Serruys as the most prolific contributor, underscoring a dynamic exchange of knowledge within the field.Moreover, the dual chart overlay illustrates a close interrelation between journals in the "Medicine," "Medical," and "Clinical" domains and those in "Health," "Nursing," and "Medicine." Frequently recurring keywords in this research landscape include DES coronary artery disease, percutaneous coronary intervention, implantation, and restenosis. This study presents a comprehensive panorama encompassing countries, research institutions, journals, keyword distributions, and contributions within the realm of DES therapy for CAD. By highlighting keywords exhibiting recent surges in frequency, we elucidate current research hotspots and frontiers, thereby furnishing novel insights to guide future researchers in this evolving field., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Zeng, Xu, Deng, Li, Chen and Tang.)

Background: Previous research has indicated that there may be a link between Crohn's disease (CD) and breast cancer (BC), but the causality remains unclear. This study aimed to investigate the causal association between CD and BC using Mendelian randomization (MR) analysis., Methods: The summary data for CD (5,956 cases/14,927 controls) was obtained from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). And the summary data for BC (122,977 cases/105,974 controls) was extracted from the Breast Cancer Association Consortium (BCAC). Based on the estrogen receptor status, the cases were classified into two subtypes: estrogen receptor-positive (ER + ) BC and estrogen receptor-negative (ER - ) BC. We used the inverse variance weighted method as the primary approach for two-sample MR. MR-PRESSO method was used to rule out outliers. Heterogeneity and pleiotropy tests were carried out to improve the accuracy of results. Additionally, multivariable MR was conducted by adjusting for possible confounders to ensure the stability of the results., Results: The two-sample MR indicated that CD increased the risks of overall (OR: 1.020; 95% CI: 1.010-1.031; p =0.000106), ER + (OR: 1.019; 95%CI: 1.006-1.034; p =0.006) and ER - BC (OR: 1.019; 95%CI: 1.000-1.037; p =0.046) after removal of outliers by MR-PRESSO. This result was reliable in the sensitivity analysis, including Cochran's Q and MR-Egger regression. In multivariate MR analyses, after adjusting for smoking and drinking separately or concurrently, the positive association between CD and the risks of overall and ER + BC remained, but it disappeared in ER - BC. Furthermore, reverse MR analysis suggested that BC did not have a significant impact on CD risk., Conclusion: Our findings provide evidence for a possible positive association between CD and the risk of BC. However, further studies are needed to fully understand the underlying mechanisms and establish a stronger causal relationship., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yu, Xu, Xu, Huang, Tang, Zeng, Yu, Chen and Sun.)

Background: Previous studies have reported associations of Crohn's disease (CD) and ulcerative colitis (UC) with the risks of extraintestinal cancers, but the causality remains unclear., Methods: Using genetic variations robustly associated with CD and UC extracted from genome-wide association studies (GWAS) as instrumental variables. Nine types of extraintestinal cancers of European and Asian populations were selected as outcomes. We used the inverse variance weighted method as the primary approach for two-sample Mendelian randomization analysis. Sensitivity analyses were carried out to evaluate the reliability of our findings., Results: In the European population, we found that CD showed a potential causal relationship with pancreatic cancer (OR: 1.1042; 95% CI: 1.0087-1.2088; P=0.0318). Meanwhile, both CD (outliers excluded: OR: 1.0208; 95% CI: 1.0079-1.0339; P=0.0015) and UC (outliers excluded: OR: 1.0220; 95% CI: 1.0051-1.0393; P=0.0108) were associated with a slight increase in breast cancer risk. Additionally, UC exhibited a potential causal effect on cervical cancer (outliers excluded: OR: 1.1091; 95% CI: 1.0286-1.1960; P=0.0071). In the East Asian population, CD had significant causal effects on pancreatic cancer (OR: 1.1876; 95% CI: 1.0741-1.3132; P=0.0008) and breast cancer (outliers excluded: OR: 0.9452; 95% CI: 0.9096-0.9822; P=0.0040). For UC, it exhibited significant causal associations with gastric cancer (OR: 1.1240; 95% CI: 1.0624-1.1891; P=4.7359×10 -5 ), bile duct cancer (OR: 1.3107; 95% CI: 1.0983-1.5641; P=0.0027), hepatocellular carcinoma (OR: 1.2365; 95% CI: 1.1235-1.3608; P=1.4007×10 -5 ) and cervical cancer (OR: 1.3941; 95% CI: 1.1708-1.6599; P=0.0002), as well as a potential causal effect on lung cancer (outliers excluded: OR: 1.1313; 95% CI: 1.0280-1.2449; P=0.0116)., Conclusions: Our study provided evidence that genetically predicted CD may be a risk factor for pancreatic and breast cancers in the European population, and for pancreatic cancer in the East Asian population. Regarding UC, it may be a risk factor for cervical and breast cancers in Europeans, and for gastric, bile duct, hepatocellular, lung, and cervical cancers in East Asians. Therefore, patients with CD and UC need to emphasize screening and prevention of site-specific extraintestinal cancers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yu, Xu, Xu, Tang, Han, Zeng, Huang, Yu and Sun.)

This article describes a power-efficient, high dynamic range (DR) incremental ADC (IADC) for wearable biopotential signals recording, where DC and low-frequency disturbances such as electrode offset, 50/60 Hz interference and motion artifact must be tolerated. To achieve a wide DR, the IADC performs a three-step conversion by combining zoom-SAR and extended counting (EC) on top of a second-order incremental delta-sigma modulator (ΔΣM). The hybrid architecture notably reduces the oversampling ratio (OSR) with respect to conventional incremental ΔΣMs, while using the EC further improves the Signal-to-Noise-and-Distortion Ratio (SNDR) by 7.4 to 25.6 dB. Fabricated in a 0.18-μm CMOS technology, the IADC achieves 107.6-dB DR, 104.9-dB peak SNR, and 99.3-dB peak SNDR at 2 kS/s while dissipating 130 μW from 1.8-V (analog) / 1.2-V (digital) supply. This translates to a highly competitive FoM DR of 176.5 dB. The high-DR IADC reduces the gain of the preceding instrumentation amplifier (IA) such that significant DC and low-frequency disturbances can be tolerated. The advantages of high DR have been demonstrated by wearable Electrocardiography (ECG) and Electroencephalography (EEG) recordings under motion artifact.

Ethnopharmacological Relevance: Guben Xiezhuo Decoction (GBXZD) is an herbal compound used to treat chronic kidney disease (CKD) under the guidance of traditional Chinese medicine (TCM). Its main components are Astragalus membranaceus (Fisch.) Bunge, Codonopsis pilosula (Franch.) Nannf., Centella asiatica (L.) Urb., Salvia miltiorrhiza Bunge, Cuscuta chinensis Lam., and Rheum palmatum L.. Clinical studies have shown that it can relieve fatigue, nausea and other symptoms and improve kidney function in patients; however, its specific mechanism of action requires further study., Aim of the Study: Renal interstitial fibrosis (RIF) is the ultimate characteristic manifestation of various CKD, that cannot be cured, and appropriate treatments to delay its progression require further exploration. GBXZD, widely used in clinical practice for RIF treatment, can effectively relieve the syndrome in patients with CKD. However, the specific mechanism of action of GBXZD in RIF is unknown and requires further study. This study aimed to explore the specific effects of GBXZD on RIF through the regulation of M1 macrophages., Materials and Methods: An in vivo RIF model was obtained through unilateral ureteral obstruction (UUO), and the Sprague-Dawley (SD) rats were randomly divided into sham operation, UUO, UUO + GBXZD-low dose (GBXZD-L) and UUO + GBXZD-high dose (GBXZD-H) groups. Pathological changes in rat kidney specimens were observed using hematoxylin and eosin (HE) and Masson staining. The expression of collagen I (COL I), fibronectin (FN), α-smooth muscle actin (α-SMA), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α) was detected using immunohistochemistry, and immunofluorescence was used to detect the expression of CD86 and inducible nitric-oxide synthase (iNOS) in kidney tissue. An in vitro experiment was performed using M1 polarization model in RAW264.7 macrophages induced by lipopolysaccharide (LPS). Cells were divided into control, LPS, LPS + GBXZD-low dose (GBXZD-L) and LPS + GBXZD-high dose (GBXZD-H) groups. The changes in expression of CD86, iNOS, IL-1β, IL-6, and TNF-α were measured using western blotting, flow cytometry, immunofluorescence and enzyme-linked immunosorbent assay (ELISA). We analyzed the action pathway of GBXZD in regulating M1 polarization of macrophages using antibody microarray and verified the results using western blotting., Results: Histopathological results showed that the UUO group exhibited significant fibrotic injury compared to the sham group. After GBXZD treatment, the degree of kidney injury, RIF, and inflammatory factor expression were lower than those in the UUO group. Compared with LPS-treated cells, the expression of the M1 markers CD86, iNOS, and pathway proteins Raf1 and p-Elk1 was down-regulated in RAW 264.7 cells treated with LPS and GBXZD. The secretion of the inflammatory factors IL-1β, IL-6, and TNF-α in the LPS group was more than that in the control group. However, the levels of these factors were significantly reduced in the GBXZD-H group compared to those in the LPS group., Conclusions: This study indicates that GBXZD ameliorates RIF and inhibits the inflammatory response and macrophage M1 polarization by a potential mechanism related to the downregulation of Raf1 and p-Elk1. GBXZD therefore has therapeutic potential value for patients with CKD., Competing Interests: Declaration of competing interest No potential conflicts of interest were declared by the authors., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Cuticular wax, a critical defense layer for plants, remains a relatively unexplored factor in rumen fermentation. We investigated the impact of cuticular wax on rumen fermentation using triticale as a model. In total, six wax classes were identified, including fatty acids, aldehydes, alkane, primary alcohol, alkyresorcinol, and β-diketone, with low-bloom lines predominated by 46.05% of primary alcohols and high-bloom lines by 35.64% of β-diketone. Low-wax addition (2.5 g/kg DM) increased the gas production by 19.25% ( P < 0.05) and total volatile fatty acids by 6.34% ( P > 0.05), and enriched key carbohydrate-fermenting rumen microbes like Saccharofermentans , Ruminococcus , and Prevotellaceae , when compared to non-wax groups. Metabolites linked to nucleotide metabolism, purine metabolism, and protein/fat digestion in the rumen showed a positive correlation with low-wax, benefiting rumen microbes. This study highlights the intricate interplay among cuticular wax, rumen microbiota, fermentation, and metabolomics in forage digestion, providing insights into livestock nutrition and forage utilization.