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Objectives: To explore the impact of hepatic steatosis measured by MRI-proton density fat fraction (MRI-PDFF) on liver stiffness measurement (LSM) value and its diagnostic performance for staging liver fibrosis in patients with chronic hepatitis B (CHB)., Methods: A total of 914 patients with CHB who underwent liver biopsy and MRI-PDFF were retrospectively reviewed. The influence of MRI-PDFF on LSM value was assessed using univariate and multivariate linear analyses. To assess the influence of liver steatosis on the diagnostic performance of LSM, a series of ROC analyses were performed and compared by stratifying patients into non-steatosis (PDFF < 5%) and steatosis (PDFF ≥ 5%) groups according to MRI-PDFF values. The effects of different LSM cut-off values on the false-positive rate in the steatosis cohort were compared using McNemar's test., Results: LSM values were significantly affected by MRI-PDFF in the entire cohort (B-coefficient: 0.003, p < 0.001), F1 cohort (B-coefficient: 0.005, p < 0.001), and F2 cohort (B-coefficient: 0.003, p = 0.002). Hepatic steatosis was not observed to have a significant influence on the ROC curve of LSM for staging liver fibrosis. Compared with using the cut-off values for the CHB cohort, using relatively higher cut-off values for hepatic steatosis significantly improved the false-positive rate of LSM in the steatosis cohort., Conclusion: Steatosis significantly influenced LSM, with a higher value in the early stage of liver fibrosis but did not affect the diagnostic efficiency of LSM for staging liver fibrosis. Moreover, using relatively high cut-off values significantly improved the false-positive rate of LSM in CHB patients with steatosis., Clinical Relevance Statement: The identified correlation between MRI-PDFF and VCTE-measured LSM is not clinically relevant since the diagnostic performance of LSM in staging liver fibrosis is not affected by steatosis. A higher cut-off should be applied in CHB patients with steatosis to improve the false-positive rate., Key Points: Steatosis can affect liver stiff measurement (LSM) values in the early stage of liver fibrosis. The diagnostic performance of LSM in staging liver fibrosis is not affected by steatosis. LSM's cutoffs should be increased in patients with steatosis to improve the false-positive rate., Competing Interests: Declarations. Ethics approval and consent to participate: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The ethics committee of Guangdong Provincial Hospital of Chinese Medicine approved this retrospective study (no: YE2019-056-01), and the requirement for written informed consent was waived. Consent for publication: Not applicable. Competing interests: The author H.X.L from the Department of Radiology of Bayer Healthcare Limited Company provided statistical advice. This study does not involve any drugs or products from Bayer Healthcare. The other authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: This meta-analysis aimed to determine the incidence and overall risk of major adverse cardiovascular events (MACEs) related to immune checkpoint inhibitors (ICIs)., Methods: We systematically searched all cohort studies, including the available MACE data in cancer patients receiving ICIs, in PubMed, Embase, and the Cochrane Library, from their inception to September 5, 2023. The primary outcome was the incidence of MACEs associated with ICI exposure, and the secondary outcome was the overall risk of MACEs associated with ICI exposure versus non-ICI exposure controls. Risk ratios with 95% confidence intervals were used in the random- or fixed-effects models., Results: Overall, 26 cohort studies met the inclusion criteria, involving 109,883 cancer patients. In the median follow-up period ranging from 3.3 to 55.2 months, the incidence of MACEs associated with ICI exposure was 8.22%, ranging from 0.55% to 3.98%, among the nine MACEs, including myocarditis, tachyarrhythmia, pericarditis, pericardial effusions, cardiovascular death, myocardial infarction, heart failure, stroke, and conduction disorder. The incidence of MACE associated with non-ICI exposure was 3.84%, ranging from 0.81% to 4.72%. The risks of all-grade MACEs and pericardial effusions were significantly higher in the ICI group than in the non-ICI controls. ICI treatment, age, male sex, and prior radiation therapy were significantly associated with MACEs., Conclusion: The risk of MACEs during ICI treatment in patients with cancer is more common than is currently recognized. ICI use is closely associated with an increased risk of MACEs. Patients at risk were older, male, and had a history of radiation therapy., (© 2024 The Association for the Publication of the Journal of Internal Medicine.)

Sulfurized polyacrylonitrile (SPAN) is recognized as a promising organic cathode for long-lifespan lithium metal batteries. Nevertheless, the irreversible cleavage/formation of multiple sulfur-sulfur (S-S) bonds of SPAN within conventional ether-based electrolytes results in loss of active S species, severe capacity fading and shuttle effects. Herein, we propose a new electrolyte based on dipropyl ether (PE) solvent for Li-SPAN batteries. Benefiting from the particular chain-coordination structure and weak dipole interactions with Li + and active species, the resulting electrolyte not only achieves low desolvation energy barrier and high Li + transference number, but also displays stable electrolyte-electrode interface (EEI). Consequently, the full cells utilizing this electrolyte exhibit good cyclability, outstanding capacity retention and superior extreme-temperature (-50 °C to 50 °C) performance. Furthermore, the Ah-scale pouch cell with lean electrolyte (2.5 g Ah -1 ) achieves record cycle stability with 96.5 % capacity retention after 75 cycles, which deliver an initial specific energy density of 150 Wh kg -1 (based on the weight of the entire cell). Impressively, this strategy demonstrates universality in a series of organic electrodes employing with PE-based electrolytes. This work highlights the strategy for modulating the dipole interaction at EEI for long-lifespan Li-organic batteries at extreme conditions., (© 2024 Wiley-VCH GmbH.)

Background and Objective: Chronic kidney disease (CKD) is a major public health issue, and accurate prediction of the progression of kidney failure is critical for clinical decision-making and helps improve patient outcomes. As such, we aimed to develop and externally validate a machine-learned model to predict the progression of CKD using common laboratory variables, demographic characteristics, and an electronic health records database., Methods: We developed a predictive model using longitudinal clinical data from a single center for Chinese CKD patients. The cohort included 987 patients who were followed up for more than 24 months. Fifty-three laboratory features were considered for inclusion in the model. The primary outcome in our study was an estimated glomerular filtration rate ≤15 mL/min/1.73 m 2 or kidney failure. Machine learning algorithms were applied to the modeling dataset ( n = 296), and an external dataset ( n = 71) was used for model validation. We assessed model discrimination via area under the curve (AUC) values, accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and F1 score., Results: Over a median follow-up period of 3.75 years, 148 patients experienced kidney failure. The optimal model was based on stacking different classifier algorithms with six laboratory features, including 24-h urine protein, potassium, glucose, urea, prealbumin and total protein. The model had considerable predictive power, with AUC values of 0.896 and 0.771 in the validation and external datasets, respectively. This model also accurately predicted the progression of renal function in patients over different follow-up periods after their initial assessment., Conclusions: A prediction model that leverages routinely collected laboratory features in the Chinese population can accurately identify patients with CKD at high risk of progressing to kidney failure. An online version of the model can be easily and quickly applied in clinical management and treatment., Competing Interests: The authors declare that they have no competing interests., (© 2024 Du et al.)

Intermittent androgen-deprivation therapy (IADT) can be beneficial to delay the occurrence of treatment resistance and cancer relapse compared to the standard continuous therapy. To study the effect of IADT in controlling prostate cancer, we developed a Filippov prostate cancer model with a joint threshold function: therapy is implemented once the total population of androgen-dependent cells (AC-Ds) and androgen-independent cells (AC-Is) is greater than the threshold value ET, and it is suspended once the population is less than ET. As the parameters vary, our model undergoes a series of sliding bifurcations, including boundary node, focus, saddle, saddle-node and tangency bifurcations. We also obtained the coexistence of one, two or three real equilibria and the bistability of two equilibria. Our results demonstrate that the population of AC-Is can be contained at a predetermined level if the initial population of AC-Is is less than this level, and we choose a suitable threshold value., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The inferior oxidative stability of commercial carbonate electrolytes and overgrowth of the electrode-electrolyte interphase (EEI) have largely hindered the development of high-voltage lithium metal batteries. In this study, these challenges are addressed by designing Li + -solvent chelating solvation structures to inhibit solvent decomposition using cyano-alkyl-phosphate as a demonstration. Theoretical and experimental studies confirm that the -P═O and -C≡N groups within diethyl (2-cyanethyl) phosphonate exhibit a comparable ability to coordinate with Li + , facilitating the formation of seven-membered chelating structures. This unique solvation structure contributes to the formation of anion-derived inorganic-rich EEI with high stability and robustness, hindering the further decomposition of the electrolyte. Additionally, the cyano group has a strong complexation with the transition metal (TM) in the cathode to inhibit TM dissolution, thereby ensuring the structural stability of the cathode particle. Utilizing this special chelating structure, the designed electrolyte demonstrates favorable Li plating/stripping reversibility and promising oxidative stability in high-voltage batteries. Consequently, the LiNi 0.8 Co 0.1 Mn 0.1 O 2 (NCM811) cathode exhibits a high capacity retention (90%) after operating 300 cycles. Under harsh testing conditions, the 4.6 V Li||NCM811 pouch cell with a capacity of 1.4 Ah (∼295 Wh kg -1 based on the total mass of the cell) retains 70% capacity after 80 cycles. This work provides new insights into the correlation between the solvation structure and oxidative stability of electrolytes, contributing significantly to the advancement of high-voltage lithium metal batteries.

Designing spinel nanocrystals (NCs) with tailored structural composition and cation distribution is crucial for superior catalytic performance but remarkably challenging due to their intricate nature. Here, an aggregation growth restricted hot-injection method is presented by meticulously investigating the fundamental nucleation and aggregation-driven growth kinetics governing spinel NC formation to address this challenge. Through controlled collision probability of nuclei during growth, this approach enables the synthesis of spinel NCs with unprecedented, single nanometer (1.2 nm). Single-nanometer CoMn 2 O 4 spinel via this method exhibits a highly tailored structure with a maximized population of highly active octahedral Mn atoms, thereby optimizing oxygen intermediate adsorption during oxygen reduction reaction (ORR). Consequently, it exhibits a remarkable half-wave potential of 0.88 V in ORR and leads to a superior power density (170.9 mW cm -2 ) in zinc-air battery, outperforming commercial Pt/C and most reported spinel oxides, revealing a clear structure-property relationship. This structure design strategy is readily adaptable for the precise synthesis and engineering of various spinel structures, opening new avenues for developing advanced electrocatalysts and energy storage materials., (© 2024 Wiley‐VCH GmbH.)

Sodium-ion batteries (SIBs) as a promising technology for large-scale energy storage have received unprecedented attention. However, the cathodes in SIBs generally suffer from detrimental cathode-electrolyte interfacial side reactions and structural degradation during cycling, which leads to severe capacity fade and voltage decay. Here, we have developed an ultra-stable Na 0.72 Ni 0.20 Co 0.21 Mn 0.55 Mg 0.036 O 2 (NCM-CS-GMg) cathode material in which a Mg-free core is encapsulated by a shell with gradient distribution of Mg using coprecipitation method with Mg-hysteretic cascade feedstock followed by calcination. From the interior to outer surface of the shell, as the content of electrochemically inactive Mg gradually increases, the Na + deintercalation amount gradually decreases after charged. Benefiting from this surface gradient desodiation, the surface transition metal (TM) ion migration from TM layers to Na layers is effectively inhibited, thus suppressing the layered-to-rock-salt phase transition and the resultant microcracks. Besides, the less formation of high-valence TM ions on the surface contributes to a stable cathode-electrolyte interface. The as-prepared NCM-CS-GMg exhibits remarkable cycling life over 3000 cycles with a negligible voltage drop (0.127 mV per cycle). Our findings highlight an effective way to developing sustainable cathode materials without compromising on the initial specific capacity for SIBs., (© 2024 Wiley-VCH GmbH.)

Formononetin (FMN), an isoflavone mainly derived from leguminous plants, is a natural secondary metabolite with valuable pharmacological effects in the regulation of numerous chronic diseases. This study aimed to investigate the influence of FMN on liver fibrosis and clarify the underlying mechanisms. In vivo FMN administration protected mice from BDL or CCl 4 -induced liver fibrosis. In vitro experimental findings revealed the FMN-mediated inhibitory effects on hepatic stellate cell (HSC) activation. Transcriptome analyses showed that YAP silencing and the subsequent HSC senescence might be responsible for the FMN-mediated antifibrotic outcomes. Furthermore, FMN suppressed EZH2 and its substrate H3K27me3, which are essential for YAP activation and HSC senescence. Remarkably, EZH2 overexpression reversed the FMN potential therapeutic effects on YAP that impact HSC senescence. Our study demonstrated that FMN potentially mitigated hepatic fibrosis by inhibiting EZH2/YAP axis and promoting HSC senescence. Together, these findings provide insights into the prospective therapeutic targets of FMN in liver fibrosis management.

Sinomenium acutum (Thunb.) Rehd. et Wils is widely used in the treatment of rheumatoid arthritis, with its alkaloid compound sinomenine (SIN) being renowned for its significant anti-inflammatory properties. However, despite its widespread application, the in vivo anti-inflammatory mechanisms and metabolic pathways of SIN remain incompletely understood. This study established a rapid and reliable method based on an ultra-high-performance liquid chromatography method coupled with Quadrupole-Exactive Orbitrap mass spectrometry and molecular docking to identify and characterize SIN and 69 metabolites in rat plasma, urine, and feces, revealing primary metabolic pathways of hydroxylation, demethylation, sulfation, and glucuronidation. Molecular docking results revealed that phase I reactions, including dedimethylation, demethylation, dehydrogenation, and dihydroxylation, along with their composite reactions, were pivotal in influencing SIN's in vivo anti-inflammatory activity. M28, M36, and M59 are potentially the most anti-inflammatory active metabolites of SIN in vivo. This comprehensive analysis unveils SIN's metabolic pathways, offering insights into its biological processes and suggesting a novel approach for exploring active drug constituents. These findings pave the way for further understanding SIN's anti-inflammatory mechanisms, contributing significantly to the development of new therapeutic strategies., (© 2024 Wiley‐VCH GmbH.)

The continuous electrolyte decomposition and uncontrolled dendrite growth caused by the unstable solid electrolyte interphase (SEI) have largely hindered the development of Li metal batteries. Here, we demonstrate that tuning the facet of current collector can regulate the composition of SEI and the subsequent Li deposition behavior using single-crystal Cu foils as an ideal platform. The theoretical and experimental studies reveal that the (100) facet of Cu possesses strong adsorption to anions, guiding more anions to participate preferentially in the inner Helmholtz plane and further promoting the formation of the stable inorganic-rich SEI. Consequently, the single-crystal Cu foils with a single [100] orientation (s-Cu(100)) achieve the dendrite-free Li deposition with enhanced Li plating/stripping reversibility. Moreover, the Li anode deposited on s-Cu(100) can stabilize the operation of an Ah-level pouch cell (350 Wh kg -1 ) with a low negative/positive capacity ratio (~2) and lean electrolyte (2.4 g Ah -1 ) for 150 cycles. Impressively, this strategy demonstrates universality in a series of electrolytes employed different anions. This work provides new insights into the correlation between the SEI and current collector, opening a universal avenue towards high-performance Li metal batteries., (© 2024 Wiley-VCH GmbH.)

Small molecule drug conjugates are an emerging targeted therapy for cancer treatment. Building upon the overexpressed prostate-specific membrane antigen (PSMA) in prostate cancer, we herein report the design and synthesis of a novel PSMA-PI3K small molecule drug conjugate 1. Conjugate 1 demonstrates potent inhibition against PI3K with an IC 50 value of 0.40 nM and simultaneously targets PSMA, giving rise to selective growth inhibition activity for PSMA-positive cancer cells. Conjugate 1 also potently inhibits the phosphorylation of PI3K main downstream effectors and arrests the cell cycle in the G0/G1 phase in PSMA-positive 22Rv1 prostate cancer cells. Further in vivo evaluation shows that conjugate 1 has favorable efficacy and tolerability in a 22Rv1 xenograft model, demonstrating its potential application in targeted cancer therapy., Competing Interests: There is no conflict of interest to declare., (This journal is © The Royal Society of Chemistry.)

Limited exploration in fungal mitochondrial genetics has uncovered diverse inheritance modes. The mitochondrial genomes are inherited uniparentally in the majority of sexual eukaryotes, our discovery of persistent mitochondrial heterogeneity within the natural population of the basidiomycete fungus Thelephora ganbajun represents a significant advance in understanding mitochondrial inheritance and evolution in eukaryotes. Here, we present a comprehensive analysis by sequencing and assembling the complete mitogenomes of 40 samples exhibiting diverse cox1 heterogeneity patterns from various geographical origins. Additionally, we identified heterogeneous variants in the nad5 gene, which, similar to cox1 , displayed variability across multiple copies. Notably, our study reveals a distinct prevalence of introns and homing endonucleases in these heterogeneous genes. Furthermore, we detected potential instances of horizontal gene transfer involving homing endonucleases. Population genomic analyses underscore regional variations in mitochondrial genome composition among natural samples exhibiting heterogeneity. Thus, polymorphisms in heterogeneous genes, introns, and homing endonucleases significantly influence mitochondrial structure, structural variation, and evolutionary dynamics in this species. This study contributes valuable insights into mitochondrial genome architecture, population dynamics, and the evolutionary implications of mitochondrial heterogeneity in sexual eukaryotes.

Sepsis-induced acute lung injury (SALI) is the common complication of sepsis, resulting in high incidence and mortality rates. The primary pathogenesis of SALI is the interplay between acute inflammation and endothelial barrier damage. Studies have shown that kaempferol (KPF) has anti-sepsis properties. Sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P) signaling pathway's significance in acute lung damage and S1P receptor 1 (S1PR1) agonists potential in myosin light chain 2 (MLC2) phosphorylation are documented. Whether KPF can regulate the SphK1/S1P/S1PR1/MLC2 signaling pathway to protect the lung endothelial barrier remains unclear. This study investigates the KPF's therapeutic effects and molecular mechanisms in repairing endothelial cell barrier damage in both LPS-induced sepsis mice and human umbilical vein endothelial cells (HUVECs). KPF significantly reduced lung tissue damage and showed anti-inflammatory effects by decreasing IL-6 and TNF-α synthesis in the sepsis mice model. Further, KPF administration can reduce the high permeability of the LPS-induced endothelial cell barrier and alleviate lung endothelial cell barrier injury. Mechanistic studies showed that KPF pretreatment can suppress MLC2 hyperphosphorylation and decrease SphK1, S1P, and S1PR1 levels. The SphK1/S1P/S1PR1/MLC2 signaling pathway controls the downstream proteins linked to endothelial barrier damage, and the Western blot (WB) showed that KPF raised the protein levels. These proteins include zonula occludens (ZO)-1, vascular endothelial (VE)-cadherin and Occludin. The present work revealed that in mice exhibiting sepsis triggered by LPS, KPF strengthened the endothelial barrier and reduced the inflammatory response. The SphK1/S1P/S1PR1/MLC2 pathway's modulation is the mechanism underlying this impact., 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.)

Morphological anisotropic engineering is powerful to synthesize metal-organic frameworks (MOFs) with versatile physicochemical properties for diverse applications ranging from gas storage/separation to electrocatalysis and batteries, etc. Herein, we developed a carbon substrate guided strategy to manipulate the facet-dependent coordination for morphology engineering of Fe-THBQ (tetrahydroxy-1,4-benzoquinone) frameworks, which is built with cubic Fe octamer bridged by two parallel THBQ ligands along three orthogonal axes, extending to a three-dimensional (3D) framework with pcu-e network topology. The electronegative O-containing functional groups on carbon surfaces compete with THBQ linkers to selectively interact with the unsaturated coordinated Fe cations on the {111} facets and inhibit crystal growth along the <111> direction. The morphology of Fe-THBQ evolves from thermodynamically favored truncated cube to cuboctahedron depending on the content of O-containing functional groups on the carbon substrate. The Fe-THBQ with varied morphologies exhibits facet-dependent performances for electrochemical lithium storage. This work will shed light on the morphology modulation of MOFs for promising applications., (© 2024 Wiley-VCH GmbH.)

Intracerebral hemorrhage (ICH), known as non-traumatic cerebrovascular rupture and hemorrhage, often occurs in the deep basal brain segment. It is known for its high morbidity and mortality rates. Subarachnoid hemorrhage (SAH) is a clinical syndrome caused by the rupture of blood vessels at the base or surface of the brain that allows blood to flow directly into the subarachnoid space. It progresses quickly and typically manifests at younger ages compared with ICH. ICH and SAH are both devastating events in the category of hemorrhagic strokes and are attracting increasing attention from researchers. Flavonoids, being important natural molecules, have remarkable anti-inflammatory and antioxidant effects. Flavonoids have extensive biological activities in inflammation and oxidative stress (OS), and have protective effects in vascular function associated with cerebrovascular diseases. They have an impact on the onset of ICH and SAH by targeting various pathways, including the suppression of inflammation and OS. Recently, the role of flavonoid compounds in ICH and SAH has also received increasing interest. Thus, to serve as a resource for the prevention and treatment of ICH and SAH, the present review provided an overview of the research on flavonoid compounds in the prevention of brain damage after these two conditions have occurred., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Dong et al.)

Background: Euphorbia helioscopia L (EHL), a widely used medicinal plant in traditional Chinese medicine, has shown promising effects on certain cancers. However, previous studies on EHL did not elucidate the underlying molecular mechanisms. Herein, for the first time, we present the strong therapeutic potential of EHL extracts on malignant hemangioendothelioma, a rare type of vascular tumor., Purpose: To investigate the potential anti-tumor mechanism of extracts of EHL on hemangioendothelioma and melanoma., Methods: The dried stems and leaves of EHL were extracted with Ethyl Acetate and n-Butyl alcohol, yielding two crude extracts Ethyl Acetate fraction (EA) and n-Butyl alcohol fraction (Bu). EA and Bu were prepared to assess the potential mechanism by assays for cell proliferation, cell cycle, apoptosis, colony formation, tube formation, cellular metabolic activity, reactive oxygen species (ROS), N-Acetylcysteine (NAC) antagonism, RNA expression and western blot. To further confirm the anti-tumor effect of EHL in vivo, we established hemangioendothelioma and melanoma tumor-bearing mouse model using node mice and administered with EA and Bu, tracked alterations in tumor volume and survival rate. Furthermore, tissue samples were obtained for histological, protein, and genetic investigations., Results: We demonstrate that the injection of EA and Bu, significantly inhibits tumor growth and prolongs the lifespan of tumor-bearing mice. Bu treatment exhibited a remarkable 33 % healing effect on the primary hemangioendothelioma tumor, bringing the survival rate to a level comparable to that of healthy mice. Mechanically, both EA and Bu impair respiratory chain complexes, leading to mitochondrial dysfunction and accumulation of reactive oxygen species (ROS), resulting in DNA damage, cell apoptosis, and finally blocked angiogenesis. While EA demonstrates robust inhibitory effects on cancer cell growth and a broader impact on metabolism in vitro, the in vivo effect of Bu surpasses that of EA in terms of strength. EA and Bu also exhibit potent anti-tumor effects on a primary melanoma model by inhibiting angiogenesis. Importantly, when compared to other compounds used in the treatment of hemangioendothelioma, EA and Bu demonstrate more profound anti-tumor effects., Conclusion: For the first time, our findings reveal that EHL extracts, especially the high polarity compounds, exhibit potent anti-tumor effects by targeting cellular metabolism, specifically through the inhibition of mitochondria-related metabolic activities. This leads to the accumulation of ROS and effectively suppresses abnormal angiogenesis., 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 GmbH.)

Backgroud: Routine metabolic assessments for methylmalonic acidemia (MMA), propionic acidemia (PA), and homocysteinemia involve detecting metabolites in dried blood spots (DBS) and analyzing specific biomarkers in serum and urine. This study aimed to establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous detection of three specific biomarkers (methylmalonic acid, methylcitric acid, and homocysteine) in DBS, as well as to appraise the applicability of these three DBS metabolites in monitoring patients with MMA, PA, and homocysteinemia during follow-up., Methods: A total of 140 healthy controls and 228 participants were enrolled, including 205 patients with MMA, 17 patients with PA, and 6 patients with homocysteinemia. Clinical data and DBS samples were collected during follow-up visits., Results: The reference ranges (25th-95th percentile) for DBS methylmalonic acid, methylcitric acid, and homocysteine were estimated as 0.04-1.02 μmol/L, 0.02-0.27 μmol/L and 1.05-8.22 μmol/L, respectively. Following treatment, some patients achieved normal metabolite concentrations, but the majority still exhibited characteristic biochemical patterns. The concentrations of methylmalonic acid, methylcitric acid, and homocysteine in DBS showed positive correlations with urine methylmalonic acid ( r  = 0.849, p  < 0.001), urine methylcitric acid ( r  = 0.693, p  < 0.001), and serum homocysteine ( r  = 0.721, p  < 0.001) concentrations, respectively. Additionally, higher levels of DBS methylmalonic acid and methylcitric acid may be associated with increased cumulative complication scores., Conclusion: The LC-MS/MS method established in this study reliably detects methylmalonic acid, methylcitric acid, and homocysteine in DBS. These three DBS metabolites can be valuable for monitoring patients with MMA, PA, and homocysteinemia during follow-up. Further investigation is required to determine the significance of these DBS biomarkers in assessing disease burden over time., 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 Liu, Ma, Kang, Jin, Li, Song, Li, Cao and Yang.)

Vehicle detection is a research direction in the field of target detection and is widely used in intelligent transportation, automatic driving, urban planning, and other fields. To balance the high-speed advantage of lightweight networks and the high-precision advantage of multiscale networks, a vehicle detection algorithm based on a lightweight backbone network and a multiscale neck network is proposed. The mobile NetV3 lightweight network based on deep separable convolution is used as the backbone network to improve the speed of vehicle detection. The icbam attention mechanism module is used to strengthen the processing of the vehicle feature information detected by the backbone network to enrich the input information of the neck network. The bifpn and icbam attention mechanism modules are integrated into the neck network to improve the detection accuracy of vehicles of different sizes and categories. A vehicle detection experiment on the Ua-Detrac dataset verifies that the proposed algorithm can effectively balance vehicle detection accuracy and speed. The detection accuracy is 71.19%, the number of parameters is 3.8 MB, and the detection speed is 120.02 fps, which meets the actual requirements of the parameter quantity, detection speed, and accuracy of the vehicle detection algorithm embedded in the mobile device., Competing Interests: The authors declare no conflicts of interest.

Rechargeable sodium-oxygen (Na-O 2 ) battery is deemed as a promising high-energy storage device due to the abundant sodium resources and high theoretical energy density (1,108 Wh kg -1 ). A series of quasisolid electrolytes are constantly being designed to restrain the dendrites growth, the volatile and leaking risks of liquid electrolytes due to the open system of Na-O 2 batteries. However, the ticklish problem about low operating current density for quasisolid electrolytes still hasn't been conquered. Herein, we report a rechargeable Na-O 2 battery with polyvinylidene fluoride-hexafluoropropylene recombination Nafion (PVDF-HFP@Nafion) based quasisolid polymer electrolyte (QPE) and MXene-based Na anode with gradient sodiophilic structure (M-GSS/Na). QPE displays good flame resistance, locking liquid and hydrophobic properties. The introduction of Nafion can lead to a high Na + migration number ( t Na + = 0.68) by blocking the motion of anion and promote the formation of NaF-rich solid electrolyte interphase, resulting in excellent cycling stability at relatively high current density under quasisolid environment. In the meantime, the M-GSS/Na anode exhibits excellent dendrite inhibition ability and cycling stability. Therefore, with the synergistic effect of QPE and M-GSS/Na, constructed Na-O 2 batteries run more stably and exhibit a low potential gap (0.166 V) after an initial 80 cycles at 1,000 mA g -1 and 1,000 mAh g -1 . This work provides the reference basis for building quasisolid state Na-O 2 batteries with long-term cycling stability., Competing Interests: Competing interests statement:The authors declare no competing interest.

Studies have shown that a lot of traditional Chinese medicines could improve the immunity of the body. Dangdi oral liquid (DDO) was mainly composed of Angelica sinensis (Oliv.) Diels (Danggui), Rehmannia glutinosa Libosch. (Dihuang), Achyranthes bidentata Bl. (Niuxi), Glycyrrhiza uralensis Fisch. (Gancao). In this study, the rapid ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) method was used to identify the potentially effective compounds of DDO. Then the immune activity of DDO was measured by lymphocyte proliferation, macrophage phagocytic function, NK cell activity, delayed type hypersensitivity reaction, hemolytic plaque number, sIgA content and immune organ index. The results showed that a total of 51 compounds were identified. In addition, DDO could significantly promote the lymphocyte proliferation, improve macrophage phagocytic ability, NK cell activity, hemolytic plaque number, sIgA content and immune organ index compared with control group, and the medium dose possessed the best efficacy (P＜0.05). These results indicated that DDO could enhance the immunity of mice., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interestsZhihong Zhou reports financial support was provided by 10.13039/501100004735Hunan Provincial Natural Science Foundation of China. Zhihong Zhou reports financial support was provided by Scientific Research Project of Hunan Provincial Health Commission. If there are other authors, they 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. Published by Elsevier Ltd.)

Background: Inflammation and oxidative stress play an important role in the pathophysiology of inflammatory bowel disease (IBD). This study aimed to explore the effects of copper chaperone Antioxidant-1 (Atox1) on macrophages in a mouse model of intestinal inflammation., Methods: A mouse model of TNBS-induced colitis was established and verified using the disease activity index. Atox1 conditional knockout mice were applied. The proportion of macrophages in colonic lamina propria mononuclear cells and ROS production were analyzed using flow cytometry. Inflammatory cytokines were measured using ELISA. Expression of macrophage M1/M2 polarization markers, p47phox, NLRP3, and Caspase-1 p20 was measured using quantitative RT-PCR and Western blotting., Results: Atox1 expression was up-regulated in colon tissues of TNBS-induced colitis mice. Macrophages isolated from TNBS-induced colitis mice showed M1 polarization and nuclear translocation of Atox1. Inhibiting copper chaperone activity decreased p47phox, ROS production, and M1 polarization induced by CuCl 2 in macrophages. TNBS induced up-regulation of inflammatory cytokines, M1 polarization markers, and p47phox expression in mice, an effect which was preempted by Atox1 knockout. Inflammatory cytokines and expression of M1 polarization markers, p47phox, NLRP3, Caspase-1 p20 were also increased in macrophages isolated from TNBS-induced colitis mice. These changes were alleviated in mice with Atox1 knockout. The effects of Atox1 on macrophage polarization were mediated via the ROS-NLRP3 inflammasome pathway., Conclusion: Atox1 plays a pro-inflammatory role, promotes M1 polarization of macrophages, and increases the concentrations of pro-inflammatory cytokines in intestinal tissue by regulating the ROS-NLRP3 inflammasome pathway. Atox1 is a potential therapeutic target in IBD., (© 2024. The Author(s).)

Objective: To develop a deep learning model based on contrast-enhanced magnetic resonance imaging (MRI) data to predict post-surgical overall survival (OS) in patients with hepatocellular carcinoma (HCC)., Methods: This bi-center retrospective study included 564 surgically resected patients with HCC and divided them into training (326), testing (143), and external validation (95) cohorts. This study used a three-dimensional convolutional neural network (3D-CNN) ResNet to learn features from the pretreatment MR images (T1WIpre, late arterial phase, and portal venous phase) and got the deep learning score (DL score). Three cox regression models were established separately using the DL score (3D-CNN model), clinical features (clinical model), and a combination of above (combined model). The concordance index (C-index) was used to evaluate model performance., Results: We trained a 3D-CNN model to get DL score from samples. The C-index of the 3D-CNN model in predicting 5-year OS for the training, testing, and external validation cohorts were 0.746, 0.714, and 0.698, respectively, and were higher than those of the clinical model, which were 0.675, 0.674, and 0.631, respectively (P = 0.009, P = 0.204, and P = 0.092, respectively). The C-index of the combined model for testing and external validation cohorts was 0.750 and 0.723, respectively, significantly higher than the clinical model (P = 0.017, P = 0.016) and the 3D-CNN model (P = 0.029, P = 0.036)., Conclusions: The combined model integrating the DL score and clinical factors showed a higher predictive value than the clinical and 3D-CNN models and may be more useful in guiding clinical treatment decisions to improve the prognosis of patients with HCC., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Haixia Li reports a relationship with Bayer Corporation that includes: employment. Kan Deng reports a relationship with Philips Healthcare that includes: employment. If there are other authors, they 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.)

Glucocorticoids (GCs) have been used in the treatment of sepsis because of their potent anti-inflammatory effects. However, their clinical efficacy against sepsis remains controversial because of glucocorticoid receptor (GR) downregulation and side effects. Herein, we designed and synthesized 30 ocotillol derivatives and evaluated their anti-inflammatory activities. Ocotillol 24(R/S) differential isomers were stereoselective in their pharmacological action. Specifically, 24(S) derivatives had better anti-inflammatory activity than their corresponding 24(R) derivatives. Compound 20 most effectively inhibited NO release (85.97% reduction), and it exerted dose-dependent inhibitory effects on interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels. Mechanistic studies revealed that compound 20 reduces the degradation of GR mRNA and GR protein. Meanwhile, compound 20 inhibited the activation of nuclear factor-κB (NF-κB) signaling, thereby inhibiting the nuclear translocation of p65 and attenuating the inflammatory response. In vivo studies revealed that compound 20 attenuated hepatic, pulmonary, and renal pathology damage in mice with sepsis and suppressed the production of inflammatory mediators. These results indicated that compound 20 is a promising lead compound for designing and developing anti-sepsis drugs., 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 Masson SAS.)

Serial casting as one of the applications to treat early-onset scoliosis has been reported efficiently to improve deformity, but no report has focused on the efficacy of braces in the treatment of congenital early-onset scoliosis and comparison with progressive idiopathic early-onset scoliosis. Patients with progressive EOS treated with braces in our institution with a minimum of 4 years follow-up were reviewed. Two groups according to the etiological diagnosis were analyzed and compared: the congenital scoliosis (CS) group and idiopathic scoliosis (IS) group. The success cases and the failure cases were also compared. 27 patients with an average main Cobb angle of 38.19° (20-55) underwent initial bracing at an average age of 55.7 months (24-108), the average follow-up time was 76.19 months (49-117). In IS group the main Cobb angle was corrected to 18.69 ± 12.06° (48.61%) following the first bracing; the final Cobb angle was 23.08 ± 22.15°(38.76%) after brace removal. In CS group the main Cobb angle was corrected to 33.93 ± 10.31°(17.1%) following the first bracing and 37.93 ± 14.74°(3.53%) after brace removal. Both coronal chest width and T1-T12 height increased dramatically from pre-bracing to the last follow-up. Patients diagnosed as IS tended to have a better result in main Cobb angle correction than that of CS (P = 0.049). By the time of last follow-up, 8 patients had undergone surgery, and the operation time was postponed by 68.88 ± 26.43 months. For patients with progressive early-onset scoliosis, bracing is an efficient nonsurgical alternative to casting, and some of them can be cured; if not, eventual surgical intervention can be delayed for a period of time without restrictions on the thoracic cavity., (© 2024. The Author(s).)

DNA methylation indicates the individual's aging, so-called Epigenetic clocks, which will improve the research and diagnosis of aging diseases by investigating the correlation between methylation loci and human aging. Although this discovery has inspired many researchers to develop traditional computational methods to quantify the correlation and predict the chronological age, the performance bottleneck delayed access to the practical application. Since artificial intelligence technology brought great opportunities in research, we proposed a perceptron model integrating a channel attention mechanism named PerSEClock. The model was trained on 24,516 CpG loci that can utilize the samples from all types of methylation identification platforms and tested on 15 independent datasets against seven methylation-based age prediction methods. PerSEClock demonstrated the ability to assign varying weights to different CpG loci. This feature allows the model to enhance the weight of age-related loci while reducing the weight of irrelevant loci. The method is free to use for academics at www.dnamclock.com/#/original., 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 Zhao, Li, Qu, Zong, Liu, Kuang and Wang.)

Background: The interaction between the host and Candida albicans is dynamic and intricate. We performed proteomic analysis to explore monocyte -C. albicans hyphae interaction. Materials & methods: Primary human monocytes were stimulated by heat-killed C. albicans hyphae and their proteins were profiled by tandem liquid chromatography with mass spectrometry (LC-MS/MS). Results: Based on the protein database of different species for analysis, we found that stimulation of monocytes by hyphae was accompanied by upregulation of histones and activation of extracellular traps (ETs) formation pathway. Meanwhile, monocyte ETs (MoETs) were evoked by synthesis or alteration of C. albicans cell wall proteins expression during the morphological switch to hyphal. Conclusion: MoETs formation is linked to cell wall proteins of C. albicans hyphae.

Objectives: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Its diagnosis poses significant challenges especially at early stages and in atypical cases. The aim of this study was to develop a machine learning model based on common laboratory tests that can aid SLE diagnosis., Methods: A standard protocol was developed to collect data of SLE and control immune diseases. A 10-fold cross-validation was performed in the modeling dataset (n=862), and an external dataset (n=198) was used for model validation. Machine learning algorithms were applied to construct a diagnostic model. Performance was evaluated based on area under the curve (AUC) values, F1-score, negative predictive value, positive predictive value, accuracy, sensitivity, and specificity., Results: The optimal model was based on a random forest algorithm with 10 clinical features. Thrombin time, prothrombin activity, and uric acid contributed most to the diagnostic model. The SLE diagnostic model showed sufficient predictive accuracy, with AUC values of 0.8286 in the validation dataset., Conclusions: Our diagnostic model based on 10 common laboratory tests identified the patients with SLE with high accuracy. An online version of the model can potentially be applied in clinical settings for the differential diagnosis of SLE.

Background: Treatment of chronic osteomyelitis (bone infection) remains a clinical challenge; in particular, it requires enhanced delivery of antibiotic drugs for the treatment of intracellular Staphylococcus aureus ( S. aureus ), which prevents infection recurrence and resistance. Previous studies have found that noninvasive shock waves used to treat musculoskeletal diseases can alter cell permeability, however, it is unclear whether shock waves alter cell membrane permeability in chronic osteomyelitis. Furthermore, it remains unknown whether such changes in permeability promote the entry of antibiotics into osteoblasts to exert antibacterial effects., Methods: In our study, trypan blue staining was used to determine the shock wave parameters that had no obvious damage to the osteoblast model; the effect of shocks waves on the cell membrane permeability of osteoblast model was detected by BODIPY®FL vancomycin; high performance liquid chromatography-mass spectrometry (HLPC-MS) was used to detect the effect of shock wave on the entry of antibiotics into the osteoblast model; plate colony counting method was used to detect the clearance effect of shock wave assisted antibiotics on S. aureus in the osteoblast model. To explore the mechanism, the effect of different pulses of shock waves on S. aureus was examined by plate colony counting method, besides, P2X7 receptor in osteoblast was detected by immunofluorescence and the extracellular ATP levels was detected. Furthermore, the effect of P2X7 receptor antagonists KN-62 or A740003 on the intracellular antibacterial activity of shock-assisted antibiotics was observed. Then, we used S. aureus to establish a rat model of chronic tibial osteomyelitis and investigated the efficacy and safety of shock-wave assisted antibiotics in the treatment of chronic osteomyelitis in rats., Results: The viability of the osteoblast models of intracellular S. aureus infection was not significantly affected by the application of up to 400 shock wave pulses at 0.21 mJ/mm 2 . Surprisingly, the delivery of BODIPY®FL vancomycin to osteoblast model cells was markedly enhanced by this shock wave treatment. Furthermore, the shock wave therapy increased the delivery of hydrophilic antibiotics (vancomycin and cefuroxime sodium), but not lipophilic antibiotics (rifampicin and levofloxacin), which improved the intracellular antibacterial effect. Afterwards, we discovered that shock wave treatment increased the extracellular concentration of ATP (the P2X7 receptor activator)， while KN-62 or A740003, a P2X7 receptor inhibitor, decreased intracellular antibacterial activity. We then found that 0.1 mL of 1 × 10 11  CFU/mL ATCC25923 S. aureus was suitable for modeling chronic osteomyelitis in rats. Besides, the shock wave-assisted vancomycin treatment with the strongest antibacterial and osteogenic effects among the tested treatments was confirmed in vivo by imaging examination, microbiological cultures, and histopathology, with favorable safety., Conclusions: Our results suggest that shock waves can promote the entry of antibiotics into osteoblasts for antibacteria by changing the cell membrane permeability in a P2X7 receptor-dependent manner. Besides, considering antibacterial and osteogenic efficiency and a high degree of safety in rat osteomyelitis model, shock wave-assisted vancomycin treatment may thus represent a possible adjuvant therapy for chronic osteomyelitis., Competing Interests: The authors declare no conflict of interests., (© 2023 The Authors.)

Bladder cancer is a common kind of urinary system cancer, in which bladder urothelial carcinoma (BLCA) comprises approximately 90% of all bladder cancer types. In our previous study, we discovered KLHDC7B in urine exosomal messenger RNA (mRNA) as a prospective molecular marker for bladder cancer detection. To systematically study the role and mechanism of KLHDC7B in BLCA, we focused on the most common type of BLCA in this study. First, we used RNA sequencing to discover that KLHDC7B was considerably increased in BLCA patients' urine exosomes compared to healthy controls. Then, we validated this result in an independent cohort and identified it as an effective tool for diagnosing and distinguishing high-grade and low-grade BLCA. Finally, we studied the role and mechanism of KLHDC7B in BLCA at the cellular level, providing a functional basis for its expression as a novel laboratory diagnostic biomarker for BLCA exosomal mRNA, which has important theoretical and clinical significance., (© 2023 Wiley Periodicals LLC.)

Sepsis induces profound disruptions in cellular homeostasis, particularly impacting mitochondrial function in cardiovascular and cerebrovascular systems. This study elucidates the regulatory role of the Pyruvate Kinase M2 (PKM2)- Prohibitin 2 (PHB2) axis in mitochondrial quality control during septic challenges and its protective effects against myocardial and cerebral injuries. Employing LPS-induced mouse models, we demonstrate a significant downregulation of PKM2 and PHB2 in both heart and brain tissues post-sepsis, with corresponding impairments in mitochondrial dynamics, including fission, fusion, and mitophagy. Overexpression of PKM2 and PHB2 not only restores mitochondrial function, as evidenced by normalized ATP production and membrane potential but also confers resistance to oxidative stress by mitigating reactive oxygen species generation. These cellular mechanisms translate into substantial in vivo benefits, with transgenic mice overexpressing PKM2 or PHB2 displaying remarkable resistance to sepsis-induced cardiomyocyte and neuronal apoptosis, and organ dysfunction. Our findings highlight the PKM2-PHB2 interaction as a novel therapeutic target for sepsis, providing a foundation for future research into mitochondrial-based interventions to treat this condition. The study's insights into the molecular underpinnings of sepsis-induced organ failure pave the way for potential clinical applications in the management of sepsis and related pathologies., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Acute lung injury (ALI) presents a significant clinical challenge due to its high mortality rates and the lack of effective treatment strategies. The most effective approaches to treating ALI include disrupting inflammatory cascades and associated inflammatory damage within the lung. Hederagenin was utilized as a core skeleton to design and synthesize 33 hederagonic acid derivatives. Among these derivatives, compound 29 demonstrated potent anti-inflammatory activity without inducing cytotoxicity, inhibiting nitric oxide (NO) release by 78-86 %. Detailed structure-activity relationship studies and the reverse virtual screening of ALI-related targets revealed that compound 29 exhibits a high affinity for the STING protein. Mechanistic studies revealed that compound 29 suppresses macrophage activation, inhibits the nuclear translocation of IRF3 and p65, and disrupts the STING/IRF3/NF-κB signaling pathway, thereby attenuating the inflammatory response. The in vivo administration of compound 29 was sufficient to protect against lipopolysaccharide (LPS)-induced ALI by suppressing the production of inflammatory mediators, including IL-6, TNF-α, and IFN-β, thereby preserving lung tissue integrity. These results substantiate the anti-inflammatory efficacy of compound 29, both in vitro and in vivo, indicating its potential as a promising lead compound in ALI treatment strategies., Competing Interests: Declaration of competing interest No conflict of interest exits in the submission of this manuscript, and the manuscript is approved by all authors for publication. I would like to declare on behalf of all authors that the work described was original research that has not been published previously, and is not under consideration for publication elsewhere, in whole or in part. All the authors listed have approved the manuscript that is enclosed. We deeply appreciate your consideration of our manuscript and we look forward to receiving comments from the reviewers. If you have any queries, please don't hesitate to contact me at the address below., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Alzheimer's disease (AD) is a significant global medical concern due to the aging population. AD is featured by gradual cognitive impairment, impacting daily functioning and causing behavioral and personality changes, causing disruptive psychiatric symptoms. While pharmacological interventions are the primary clinical approach, their efficacy is variable and limited. Acupuncture, with its distinctive theoretical framework and treatment approach, has garnered attention as a non-pharmacological intervention for AD through extensive preclinical and clinical research. Neurobiological investigations into the machinery of acupuncture in AD have provided compelling evidence of its therapeutic efficacy and unique advantages. This review commences with an in-depth exploration of acupuncture's clinical applications, emphasizing its various parameters and its potential combination with first-line drugs and other therapies in the context of AD. Subsequently, we delve into the underlying therapeutic mechanisms of acupuncture in AD. Finally, we summarize these aspects, highlight current study limitations, and offer recommendations for future research. Taken together, in a rapidly aging society, both clinical application and mechanistic exploration of acupuncture in AD treatment have gained momentum. This trajectory suggests that acupuncture will continue to make significant strides in AD therapeutics as research progresses.

Background: Robot-assisted gait training (RAGT) has been reported to treat motor dysfunction in patients with Parkinson's disease (PD) in the last few years. However, the benefits of RAGT for treating motor dysfunction in PD are still unclear., Objectives: To investigate the efficacy of RAGT for motor dysfunction in PD patients., Methods: We searched PubMed, Web of Science, Cochrane Library, Embase, CNKI, Wanfang, Chinese Biomedical Literature Database (CBM), and Chinese VIP Database for randomized controlled trials investigating RAGT to improve motor dysfunction in PD from the databases' inception dates until September 1, 2022. The following outcome indexes were employed to evaluate motor dysfunction: the Berg Balance Scale (BBS), Activities-specific Balance Confidence Scale (ABC), 10-Meter Walk Test gait speed (10-MWT), gait speed, stride length, cadence Unified Parkinson Disease Rating Scale Part III (UPDRS III), 6-Minute Walk Test (6MWT), and the Timed Up and Go test (TUG). The meta-analysis was performed using the proper randomeffect model or fixed-effect model to evaluate the difference in efficacy between the RAGT and the control groups. The Cochrane Risk of Bias Tool was used for the included studies and Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) was used to interpret the certainty of the results., Results: The results consisted of 17 studies comprising a total of 670 participants. Six hundred and seven PD patients with motor dysfunction were included: 335 in the RAGT group and 335 in the control group. This meta-analysis results established that when compared with the control group, robot-assisted gait training improved the BBS results of PD patients (MD: 2.80, 95%CI: 2.11-3.49, P< 0.00001), ABC score (MD: 7.30, 95%CI: 5.08-9.52, P< 0.00001), 10-MWT (MD: 0.06, 95%CI: 0.03-0.10, P= 0.0009), gait speed (MD: 3.67, 95%CI: 2.58-4.76, P< 0.00001), stride length (MD: 5.53, 95%CI: 3.64-7.42, P< 0.00001), cadence (MD: 4.52, 95%CI: 0.94-8.10, P= 0.01), UPDRS III (MD: -2.16, 95%CI: -2.48--1.83, P< 0.00001), 6MWT (MD: 13.87, 95%CI: 11.92-15.82, P< 0.00001). However, RAGT did not significantly improve the TUG test result of patients with PD (MD =-0.56, 95% CI: -1.12-0.00, P= 0.05). No safety concerns or adverse reactions among robot-assisted gait training patients were observed., Conclusion: Even though RAGT can improve balance function, walking function, and gait performance and has demonstrated positive results in several studies, there is currently insufficient compelling evidence to suggest that it can improve all aspects of lower motor function.

Human infection with Curvularia lunata ( C. lunata ) is exceptionally rare. A 23-year-old female patient contracted both bacterial and Curvularia lunata infections during influenza A virus infection. Multiple etiological tests were performed repeatedly during hospitalization due to fluctuations in condition. On the 17th day after hospital admission, mold hyphae were discovered in the pathogen culture of the patient's bronchoalveolar lavage fluid during one of these examinations. The patient was suspected to have a filamentous fungal infection. Consequently, we further obtained sputum samples for fungal culture, which confirmed the diagnosis of Curvularia infection. The patient, in this case, was in a critical condition, experiencing complications of lung abscess, pneumothorax, sepsis, and multiorgan failure. Despite prompt initiation of antifungal therapy including amphotericin B cholesteryl sulfate complex and isavuconazole upon detection of the fungal infection and concurrent administration of active organ function support treatment, the patient's condition rapidly deteriorated due to compromised immune function. Ultimately, on the 27th day of treatment, the patient succumbed to septic shock and multiple organ dysfunction syndrome. This is the first case of Curvularia lunata infection in our hospital. In this paper, we aim to raise awareness of Curvularia lunata infection and to emphasize that the possibility of this fungal infection should be considered in patients with severe pneumonia caused by influenza A virus and that empirical antifungal therapy should be given promptly when the patient has invasive lung damage., 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 © 2023 Zhang, Li, Chen, Feng, Liu and Guo.)

A novel time-resolved fluorescence nanoprobe (PBMO, PLNR-BSA-Mn 2+ -OPD) is fabricated for the label-free determination of acetylcholinesterase (AChE). The ZnGeO:Mn persistent luminescence nanorod (PLNR) and Mn(II) are, respectively, exploited as the signal molecule and quencher to construct the PBMO nanopobe using bovine serum albumin (BSA) as the surface-modified shell and o-phenylenediamine (OPD) as the reducing agent. In the presence of H 2 O 2 , the persistent luminescence of PBMO at 530 nm is enhanced remarkably within 30 s due to the oxidation of Mn(II). H 2 O 2 can react with thiocholine (TCh), which is produced through the enzymatic degradation of acetylcholine (ATCh) by AChE. The PBMO nanoprobe is successfully applied to the determination of AChE in the linear range of 0.08-10 U L -1 , with a detection limit of 0.03 U L -1 (3σ/s). The practicability of this PBMO nanoprobe is confirmed by accurately monitoring AChE contents in human serum samples, giving rise to satisfactory spiking recoveries of 96.2-103.6%., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Through bioinformatics predictions, we identified that GTF2I and FAT1 were downregulated in thyroid carcinoma (TC). Further, Pearson's correlation coefficient revealed a positive correlation between GTF2I expression and FAT1 expression. Therefore, we selected them for this present study, where the effects of bone marrow mesenchymal stem cell-derived EVs (BMSDs-EVs) enriched with GTF2I were evaluated on the epithelial-to-mesenchymal transition (EMT) and stemness maintenance in TC. The under-expression of GTF2I and FAT1 was validated in TC cell lines. Ectopically expressed GTF2I and FAT1 were found to augment malignant phenotypes of TC cells, EMT, and stemness maintenance. Mechanistic studies revealed that GTF2I bound to the promoter region of FAT1 and consequently upregulated its expression. MSC-EVs could shuttle GTF2I into TPC-1 cells, where GTF2I inhibited TC malignant phenotypes, EMT, and stemness maintenance by increasing the expression of FAT1 and facilitating the FAT1-mediated CDK4/FOXM1 downregulation. In vivo experiments confirmed that silencing of GTF2I accelerated tumor growth in nude mice. Taken together, our work suggests that GTF2I transferred by MSC-EVs confer antioncogenic effects through the FAT1/CDK4/FOXM1 axis and may be used as a promising biomarker for TC treatment., (© 2023. Higher Education Press.)

Introduction: Chronic heart failure (CHF), as the final stage of the progression of many cardiovascular disorders, is one of the main causes of hospitalization and death in the elderly and has a substantial impact on patients' quality of life (QOL). Exercise-based cardiac rehabilitation (CR) has been shown to considerably enhance QOL and prognosis. Given the barriers to center-based CR faced by most developing countries in the form of expensive instruments, the development of home-based CR is necessary. Tai Chi, as an instrument-free exercise, has been shown to be successful in treating elderly CHF individuals. Fu Yang, as one of the academic concept of Traditional Chinese Medicine (TCM), believes that the fundamental pathogenesis of CHF is the gradual decline of Yang, and emphasizes the restoration of Yang physiological function in the treatment process. Therefore, we develope a home-based Tai Chi exercise rehabilitation program called Fu Yang Tai Chi (FYTC) for elderly CHF patients by combining the Fu Yang Theory of TCM with the CR theory. The objective of this study is to evaluate the effectiveness, acceptability, and safety of the program., Methods and Analysis: We suggest conducting a parallel randomized controlled clinical trial with open label. Eighty CHF elderly participants will be randomly assigned in a 1:1 ratio to the FYTC rehabilitation program group or the moderate-intensity aerobic walking control group. Eligible participants will engage in either three sessions weekly of FYTC or walking exercise for 12 weeks. The primary outcome is the relative change in 6 min walk distance (6MWD). The secondary outcomes are the plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), QOL, left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDd), self-rating anxiety scale (SAS) and depression scale (SDS), exercise skills, and noninvasive hemodynamic monitoring. Throughout the trial, adverse events will be recorded for safety evaluation. Researchers who are blinded to the treatment allocation will analyze the data., Ethics and Dissemination: This research was authorized by the Guang'anmen Hospital Ethics Committee of the Chinese Academy of Medical Sciences (2022-141-KY). Our findings will be shared online and in academic conferences as well as in peer-reviewed journals., Trial Registration Number: ChiCTR2200063511., 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., (© 2023 Jiao, Meng, He, Li, Xu, Cui, Lou, Li, Ma, Sun, Wu and Li.)

Hederagenin is a pentacyclic triterpenoid that is widely distributed as the main pharmaceutical ingredient in various medicinal plants. Similarly as other pentacyclic triterpenoids, hederagenin has various pharmacological effects such as anti-tumor, anti-inflammatory, anti-depressant, and anti-viral activities. In particular, the anti-tumor activity of hederagenin indicates its potential for development into highly effective chemotherapeutic agents. Studies revealed that hederagenin effectively suppresses the growth of various tumor cell lines in vitro and interacts with several molecular targets that play essential roles in various cellular signaling pathways. The compound suppresses transformation, inhibits proliferation, and induces apoptosis in tumor cells. In this review, we highlight research progress on the source, pharmacokinetics, pharmacological activity, and mechanism of action of hederagenin and the anti-tumor activity of its analogs by integrating and analyzing relevant domestic and international studies and providing a basis for their further development and application., Competing Interests: Declaration of competing interest No conflict of interest exits in the submission of this manuscript, and the manuscript is approved by all authors for publication. I would like to declare on behalf of all authors that the work described was original research that has not been published previously, and is not under consideration for publication elsewhere, in whole or in part. All the authors listed have approved the manuscript that is enclosed., (Copyright © 2023. Published by Elsevier B.V.)

All inorganic CsPbX 3 perovskite has aroused broad interests in building efficient light-emitting devices with wide color gamut and flexible fabrication process. So far, the realization of high-performance blue perovskite light-emitting devices (PeLEDs) is still a critical challenge. Herein, we propose an interfacial induction strategy to generate low-dimensional CsPbBr 3 with sky blue emission by employing γ-aminobutyric acid (GABA) modified poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS). The interaction between GABA and Pb 2+ inhibited the formation of bulk CsPbBr 3 phase. Further assisted by the polymer networks, the sky-blue CsPbBr 3 film exhibited much improved stability under both photoluminescence and electrical excitation. This can be ascribed to the scaffold effect and the passivation function of the polymer. Consequently, the obtained sky-blue PeLEDs exhibited an average external quantum efficiency (EQE) of 5.67% (maximum of 7.21%) with a maximum brightness of 3308 cd/m 2 and a working lifespan reaching 0.41 h. The strategy in this work provides a new opportunity for exploitation the full potential of blue PeLEDs towards application in lighting and display devices., 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 © 2023. Published by Elsevier Inc.)

Objective: To describe negative conversion and rebound of patients with severe and critical acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection after treatment with Nirmatrelvir/Ritonavir, and to analyze related factors associating with failure of SARS-CoV-2 negative conversion and relapse and prognosis., Methods: A single center retrospective cohort study was conducted. Patients aged ≥ 16 years old who were diagnosed with severe or critical SARS-CoV-2 infection and took Nirmatrelvir/Ritonavir for 5 days in Peking University First Hospital from December 7, 2022 to January 27, 2023, were included. General characteristics and clinical data were collected from electronic medical record system. The Kaplan-Meier curve of SARS-CoV-2 negative conversion was drawn. Factors with P < 0.10 were incorporated into multivariate Logistic regression model to analyze the relationship between the factors and persistent nucleic acid positive and rebound., Results: A total of 31 severe and 37 critical SARS-CoV-2 infection patients were included. The median duration from initiation of Nirmatrelvir/Ritonavir to negative conversion of SARS-CoV-2 for both was 6.0 days, and the negative conversion rate on day 15 was 93.5% and 86.5%, respectively. SARS-CoV-2 rebound was observed in 7 patients (11.3%), among whom were 1 severe patient and 6 critical patients. The above 7 patients with SARS-CoV-2 rebound and 6 patients with failure of SARS-CoV-2 negative conversion were compared with 55 patients with persistent negative conversion. Factors with P < 0.10, including the lowest lymphocyte count (LYM), the highest D-dimer, the highest procalcitonin (PCT), the lowest Ct value, cardiovascular diseases other than hypertension and coronary heart disease, were incorporated into multivariate Logistic regression analysis. The decreased LYM [odds ratio (OR) = 0.146, 95% confidence interval (95%CI) was 0.031-0.689, P = 0.015] and the increased PCT (OR = 2.008, 95%CI was 1.042-3.868, P = 0.037) were revealed to be independent risk factors of the failure of SARS-CoV-2 negative conversion or rebound. The proportion of mechanical ventilation and invasive ventilation were significantly higher in patients with persistent SARS-CoV-2 infection or rebound than those in patients with SARS-CoV-2 negative conversion (84.6% vs. 38.2%, 69.2% vs. 25.5%, both P < 0.01), but no significant difference in mechanical ventilation and invasive ventilation duration was observed. Compared with the patients with SARS-CoV-2 negative conversion, more patients with persistent SARS-CoV-2 infection or rebound were admitted to intensive care unit (ICU, 76.9% vs. 50.9%), and length of ICU stay in patients with persistent SARS-CoV-2 infection or rebound tended to be longer [days: 13.0 (10.3, 24.3) vs. 11.0 (5.3, 23.0), P > 0.05]., Conclusions: The decreased LYM and increased PCT are independent risk factors for the failure of SARS-CoV-2 negative conversion or rebound in patients with severe and critical SARS-CoV-2 infection. Attention should be paid to these patients for their poor prognosis.

Purpose: Hospital-acquired pneumonia (HAP) caused by carbapenem-resistant K. pneumoniae (CRKP), especially in elderly patients, results in high morbidity and mortality. Studies on risk factors, mortality, and antimicrobial susceptibility of CRKP pulmonary infection among elderly patients are lacking., Patients and Methods: A retrospective case-control study was conducted from January 2019 to December 2021. The elderly inpatients (≥65 years) who were diagnosed with HAP caused by K. pneumoniae were enrolled. Clinical data were collected. Univariate and multivariate logistic regression analyses were used to identify risk factors. Propensity score matching was used to minimize the effect of potential confounding variables. Kaplan-Meier analysis was used to compare survival., Results: A total of 115 patients with CRKP infection and 78 patients with carbapenem-susceptible K. pneumoniae (CSKP) infection were recruited. There were four independent risk factors for CRKP infection: history of intensive care unit (ICU) stays from hospital admission to positive respiratory specimen culture for K. pneumoniae (odds ratio (OR)=2.530), Charlson comorbidity index score ≥3 (OR = 2.420), prior exposure to carbapenems (OR = 5.280), and prior K. pneumoniae infection or colonization in the preceding 3 years (OR = 18.529). The all-cause 30-day mortality was 22.3%, the mortality of CRKP and CSKP infection was 28.7% and 12.8%, respectively. Independent risk factors for mortality included: older age (OR = 1.107), immunocompromised patients (OR = 8.632), severe pneumonia (OR = 51.244), quick Sepsis-related Organ Failure Assessment (qSOFA) score ≥2 (OR = 6.187), exposure to tigecycline before infection (OR = 24.702), and prolonged ICU stay (OR = 0.987). Thirty-day mortality was significantly lower in patients receiving ceftazidime-avibactam (CAZ-AVI) containing regimens than patients receiving polymyxin B sulfate (PB) containing regimens (P = 0.048). qSOFA score had a good prognostic effect [area under receiver operating characteristic curve (AUROC) of 0.838]., Conclusion: Active screening of CRKP for the high-risk populations, especially elderly patients, is significant for early detection and successful management of CRKP infection., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Zhou et al.)

Apigenin is the active ingredient in Ludangshen. Although previous studies reported the cardioprotective actions of apigenin against doxorubicin (Dox)-induced cardiomyopathy, the underlying mechanisms remain incompletely understood. Since apigenin beneficially regulates various aspects of mitochondrial function and dynamics, we asked whether apigenin improves heart function in mice with Dox-induced cardiomyopathy by regulating the mitochondrial unfolded protein response (UPR mt ). Co-administration of apigenin significantly restored heart function, reduced myocardial swelling, inhibited cardiac inflammation, increased cardiac transcription of UPR mt -related genes, and promoted cardiomyocyte survival in Dox-treated mice. In turn, blockade of UPR mt abolished the mito- and cytoprotective effects of apigenin, evidenced by decreased ATP production, suppressed mitochondrial antioxidant capacity, and increased apoptosis, in Dox-treated, cultured HL-1 cardiomyocytes. Furthermore, apigenin treatment prevented Dox-induced downregulation of Sirt1 and Atf5 expression, and the beneficial effects of apigenin were completely nullified in Sirt1 knockout (KO) mice or after siRNA-mediated Sirt1 knockdown in vitro . We thus provide novel evidence for a promotive effect of apigenin on UPR mt via regulation of the Sirt1/Atf5 pathway. Our findings uncover that apigenin seems to be an effective therapeutic agent to alleviate Dox-mediated cardiotoxicity., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Chemical modifications in messenger RNA (mRNA) regulate gene expression and play critical roles in stress responses and diseases. Recently we have shown that N 6 -methyladenosine (m 6 A), the most abundant mRNA modification, promotes the repair of UVB-induced DNA damage by regulating global genome nucleotide excision repair (GG-NER). However, the roles of other mRNA modifications in the UVB-induced damage response remain understudied. N4-acetylcytidine (ac4C) is deposited in mRNA by the RNA-binding acetyltransferase NAT10. This NAT10-mediated ac4C in mRNA has been reported to increase both mRNA stability and translation. However, the role of ac4C and NAT10 in the UVB-induced DNA damage response remains poorly understood. Here we show that NAT10 plays a critical role in the repair of UVB-induced DNA damage lesions through regulating the expression of the key GG-NER gene DDB2. We found that knockdown of NAT10 enhanced the repair of UVB-induced DNA damage lesions by promoting the mRNA stability of DDB2. Our findings are in contrast to the previously reported role of NAT10-mediated ac4C deposition in promoting mRNA stability and may represent a novel mechanism for ac4C in the UVB damage response. Furthermore, NAT10 knockdown in skin cancer cells decreased skin cancer cell proliferation in vitro and tumorigenicity in vivo. Chronic UVB irradiation increases NAT10 protein levels in mouse skin. Taken together, our findings demonstrate a novel role for NAT10 in the repair of UVB-induced DNA damage products by decreasing the mRNA stability of DDB2 and suggest that NAT10 is a potential novel target for preventing and treating skin cancer., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Most people are infected with COVID-19 during pandemics at the end of 2022. Older patients were more vulnerable. However, the incidence of secondary bacterial, fungal or viral pulmonary infection and co-infection is not well described in elderly hospitalized COVID-19 patients., Methods: We retrospectively reviewed the medical records of all elderly (≥65 years) hospitalized patients with laboratory-confirmed COVID-19 from December 1, 2022 to January 31, 2023. Demographics, underlying diseases, treatments, and laboratory data were collected. Univariate and multivariate logistic regression models were used to explore the risk factors associated with secondary bacterial, fungal or viral pulmonary infection and co-infection., Results: A total of 322 older patients with COVID-19 were enrolled. The incidence of secondary bacterial, fungal or viral pulmonary infection and co-infection was 27.3% (88/322) and 7.5% (24/322), respectively. The overall in-hospital mortality of all patients was 32.9% (106/322), and the in-hospital mortality among patients who acquired with secondary pulmonary infection and co-infection was 57.0% (57/100). A total of 23.9% (77/322) of patients were admitted to ICU within 48 h of hospitalization. The incidence of secondary pulmonary infection and co-infection among patients admitted to the ICU was 50.6% (39/77) and 13.0% (10/77), respectively. The overall in-hospital mortality of ICU patients was 48.1% (37/77), and the in-hospital mortality of ICU patients acquired with secondary pulmonary infection and co-infection was 61.4% (27/44). A total of 83.5% (269/322) of the included patients received empirical antibiotic therapy before positive Clinical Microbiology results. Influenza A virus (the vast majority were the H3N2 subtype) was the most common community acquired pathogen for co-infection. While A. baumannii , K. pneumoniae , and P. aeruginosa were the common hospital acquired pathogens for co-infection and secondary pulmonary infection. The incidence of Carbapenem-resistant Gram-negative bacilli (CR-GNB) infections was high, and the mortality reached 76.9%. Predictors of secondary pulmonary infection and co-infection were ICU admission within 48 h of hospitalization, cerebrovascular diseases, critical COVID-19, and PCT > 0.5 ng/mL., Conclusion: The prognosis for elderly hospitalized COVID-19 patients with secondary pulmonary infection or co-infection is poor. The inflammatory biomarker PCT > 0.5 ng/mL played an important role in the early prediction of secondary pulmonary infection and co-infection in COVID-19 patients., 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 © 2023 Zhou, Jiang, Sun, Li, Liu and Huang.)

Discrimination and quantification of amino acid (AA) enantiomers are particularly important for diagnosing and treating diseases. Recently, dual-mode probes have gained a lot of research interest because they can catch more detecting information compared with the single-mode probes. Thus, it is of great significance to develop a dual-mode sensor realizing AA enantiomer discrimination conveniently and efficiently. In this work, carbon dot L-TCDs were prepared by N -methyl-1,2-benzenediamine dihydrochloride (OTD) and l-tryptophan. With the assistance of H 2 O 2 , L-TCDs show an excellent discrimination performance for enantiomers of glutamine (Gln) and valine (Val) in both fluorescent and colorimetric modes. The fluorescence enantioselectivity of Gln ( F D / F L ) and Val ( F L / F D ) is 5.29 and 4.13, respectively, and the colorimetric enantioselectivity of Gln ( I D / I L ) and Val ( I L / I D ) is 13.26 and 3.42, individually. The chiral recognition mechanism of L-TCDs was systematically studied. L-TCDs can be etched by H 2 O 2 , and the participation of AA enantiomers results in different amounts of the released OTD, which provides fluorescent and colorimetric signals for identifying and quantifying the enantiomers of Gln and Val. This work provides a more convenient and flexible dual-mode sensing strategy for discriminating AA enantiomers, which is expected to be of great value in facile and high-throughput chiral recognition.

Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with high morbidity and mortality. The role of dysregulated circular RNAs (circRNAs) in human diseases are receiving more and more attention. In this study, we focused on the role and mechanism of circPKM2 in the progression of NSCLC., Methods: The expression levels of circPKM2, microRNA-1298-5p (miR-1298-5p) and metadherin (MTDH) in NSCLC were measured by real-time quantitative PCR (qRT-PCR) or Western blot. Cell counting kit-8 (CCK-8), colony formation, 5-ethynyl-2'-deoxyuridine (EdU) staining, flow cytometry, transwell and tube formation assays were conducted to evaluate the effects of circPKM2 on malignant phenotypes of NSCLC. Western blot was used to measure related marker protein levels., Results: CircPKM2 and MTDH were highly expressed in NSCLC tissues and cells, while miR-1298-5p was downregulated. CircPKM2 knockdown effectively suppressed cell proliferation, migration, invasion and tube formation whereas induced apoptosis in vitro. CircPKM2 had a potential targeting site with miR-1298-5p and negatively regulated the expression of miR-1298-5p. MiR-1298-5p inhibitor reversed the effect of circPKM2 knockdown on the progression of NSCLC. CircPKM2 induced MTDH expression via sponging miR-1298-5p to promote the progression of NSCLC. MiR-1298-5p directly targeted MTDH, and the addition of MTDH partially attenuated the inhibition of miR-1298-5p on the progression of NSCLC. In addition, the downregulation of circPKM2 significantly slowed down the growth of xenograft tumors in vivo., Conclusion: Our findings demonstrated that circPKM2 mediated NSCLC progression via regulating miR-1298-5p/MTDH axis, providing a novel therapeutic target for NSCLC., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)