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The inflammatory response is a significant factor in acetaminophen (APAP)-induced acute liver injury. And it can be mediated by macrophages of different origins. However, whether Kupffer cells and mononuclear-derived macrophages play an injury or protective role in APAP hepatotoxicity is still unclear. In this study, C57/BL6N mice were performed to establish the APAP acute liver injury model. Intervention experiments were also carried out using clodronate liposomes or TREM2 knockout. We found that APAP overdose triggered the activation of inflammatory factors and enhanced the expression of the RIPK1-MLKL pathway in mice's livers. Moreover, our study showed that inflammation-related protein expression was increased after clodronate liposome administration or TREM2 knockout. The RIPK1-MLKL-mediated necroptosis was also significantly activated after the elimination of Kupffer cells or the inhibition of mononuclear-derived macrophages. More importantly, clodronate liposomes treatment and TREM2 deficiency all worsen APAP-induced liver damage in mice. In conclusion, the results indicate that Kupffer cells and mononuclear macrophages play a protective role in APAP-induced liver injury by regulating necroptosis. Therefore, macrophages hold as a potential therapeutic target for APAP-induced liver damage., 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.)

The aim of this study was to examine the effects of ML365, a two-pore potassium channel (K2P) inhibitor, on postoperative cognitive impairment (POCD). A mouse model of POCD was constructed by subjecting aged C57BL/6 mice to exploratory laparotomy. Changes in cognitive function were assessed using the Morris water maze test. Western blotting and qPCR were used to detect hippocampal NLRP3, Caspase-1 and IL-1β expression levels on days 3 and 7 post-surgery. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) expression level was also assessed by western blotting. Pathological changes and nerve damage in the hippocampal CA1 and CA3 regions were detected by H&E staining, while the concentration of malondialdehyde (MDA) in the plasma was measured. We found that pretreatment with ML365 (administered intraperitoneally at a dose of 10 mg/kg) 30 min prior to exploratory laparotomy effectively ameliorated POCD in mice. ML365 pretreatment also reduced NLRP3, Caspase-1, ASC and IL-1β expression levels in the hippocampus, improved POCD-induced pathological changes in the hippocampal CA1 and CA3 areas of aged mice, and decreased levels of plasma MDA and oxidative stress. Together, our findings indicate that ML365 can alleviate POCD in mice by inhibiting NLRP3 inflammasome activation in the hippocampus., 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.)

Ferroelectricity in metal-free perovskites (MFPs) has emerged as an academic hotspot for their lightweight, eco-friendly processability, flexibility, and degradability, with considerable progress including large spontaneous polarization, high Curie temperature, large piezoelectric response, and tailoring coercive field. However, their equivalent polarization axes as a key indicator are far from enough, although multiaxial ferroelectrics are highly preferred for performance output and application flexibility that profit from as many equivalent polarization directions as possible with easier reorientation. Here, by implementing the synergistic overlap of regulating anionic geometries (from spherical I - to octahedral [PF 6 ] - and to tetrahedral [ClO 4 ] - or [BF 4 ] - ) and cationic asymmetric modification, we successfully designed multiaxial MFP ferroelectrics CMDABCO-NH 4 -X 3 (CMDABCO = N -chloromethyl- N '-diazabicyclo[2.2.2]octonium; X = [ClO 4 ] - or [BF 4 ] - ) with the lowest P 1 symmetry. More impressively, systemic characterizations indicate that they possess 24 equivalent polarization axes (Aizu notations of 432F1 and m 3̅ m F1, respectively)─the maximum number achievable for ferroelectrics. Benefiting from the multiaxial feature, CMDABCO-NH 4 -[ClO 4 ] 3 has been demonstrated to have excellent piezoelectric sensing performance in its polycrystalline sample and prepared composite device. Our study provides a feasible strategy for designing multiaxial MFP ferroelectrics and highlights their great promise for use in microelectromechanical, sensing, and body-compatible devices.

The one-step direct laser writing process has been an efficient strategy for constructing flexible metal structures. However, the effect of laser wavelength on the structuring process remains unclear, thus restricting the universal manufacturing process development. In this work, the feasibility of one-step writing of flexible Cu structures with different wavelength continuous diode lasers has been verified. Here, photothermal reactions dominate in the decomposition of the reducing agent to form copper structures. Differences in the wavelength primarily affect the photothermal reaction amplitude for structuring, resulting in a variation in the formation of Cu structures. Under our processing conditions, the photothermal reaction induced by 532 nm laser is higher than 808 nm laser, a higher reduced-joining degree of the Cu structure can be achieved by 532 nm laser. This results in a superior conductivity, adhesion, and bendability of Cu structures fabricated by 532 nm laser than that of 808 nm laser. Furthermore, strain sensors that can detect different bending angles and bending frequencies have been fabricated by 532 nm laser-written structures to demonstrate their practical applications., (© 2024 IOP Publishing Ltd.)

Background and Aims: Bone marrow failure (BMF) is chronic benzene-induced hematotoxicity, which is associated with differential gene expression abnormality. Benzene-induced BMF is characterized by irreversible bone marrow depression. Despite extensive studies have been conducted, there is a lack of reliable, useful and simple diagnostic method for BMF. Previous studies have shown that the aberrant gene expression changes and reactive oxygen species production in bone marrow cells related to the development of BMF. Early detection of differentially expressed genes (DEGs) as potential biomarkers is important for diagnosis and treatment. However, the validation of effective biomarker through DEGs analysis in benzene-induced BMF still deserve to be clarified. This study aimed to identify target genes as potential biomarkers with benzene-induced BMF based on DEGs analysis., Methods: First, we developed a benzene-induced BMF mouse model and obtained the DEGs in bone marrow cells of benzene-exposed CD1 mice. Next, after obtaining the DEGs via RNA-Sequencing (RNA-seq) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were also used, key genes associated with benzene-induced BMF were identified. Additionally, the key markers for benzene poisoning was evaluated using qRT-PCR technique., Results: We identified DEGs for further KEGG functional analysis. Ten statistically significantly (up or down) regulated genes, namely Mapk11, Foxo1, Lefty1, Ren1, Bank1, Fgf3, Cdc42ep2, Rasgrf1, P2rx7, and Shank3 were found mainly associated with mitogen-activated protein kinases (MAPK) oxidative stress pathway . Further analysis using qRT-PCR identified that eight statistically significant DEGs associated with signaling pathways such as MAPK. We found that the level of mRNA expression of Mapk11, Foxo1, Bank1, Lefty1, Ren1, P2rx7, and Fgf3 genes were increased and Cdc42ep2 gene was decreased in BMF mice compared to control mice. Additionally, we validated the eight candidate genes for potential biomarkers in peripheral blood mononuclear cells of benzene poisoning patients by qRT-PCR., Conclusion: Our results indicated that Mapk11 and Fgf3 were predominantly candidate genes linked to novel biomarkers for benzene hematotoxicity in human beings. Our study will provide new candidate genes as useful biomarkers involved in benzene-induced hematotoxicity., 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.)

Objectives: Ulcerative colitis (UC) is a colonic immune system disorder, manifested with long duration and easy relapse. Genistein has been reported to possess various biological activities. However, it remains unclear whether genistein can ameliorate UC by modulating the homeostasis of the intestinal bacterial community., Methods: The dextran sodium sulfate (DSS)-induced UC mice were administrated with genistein (20 mg/kg/day) or genistein (40 mg/kg/day) for ten days. The general physical condition of the mice was monitored. After sacrifice, the changes in colon length and colonic pathological morphology were observed. The expression of intestinal barrier proteins, inflammatory cytokines, and macrophage markers in the colon was detected. The composition and metabolic products of the intestinal microbiota were analyzed., Results: Genistein treatment visibly improved body weight change and disease activity index in DSS-induced mice. Genistein treatment ameliorated colonic pathological alterations and promoted the expression of mucin-2 and tight junction proteins. Genistein administration inhibited myeloperoxidase activity and colonic inflammatory cytokines. Furthermore, genistein administration improved the structure of the intestinal microbial community, promoted the production of short-chain fatty acids, and modulated macrophage polarization., Conclusions: These results revealed that genistein mediated macrophage polarization balance by improving intestinal microbiota and its metabolites, thereby alleviating DSS-induced colitis., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

2,5-hexanedione (HD) is the γ-diketone metabolite of industrial organic solvent n-hexane, primarily responsible for n-hexane neurotoxicity. Previous studies have shown that the formation of pyrrole adducts (PAs) is crucial for the toxic axonopathy induced by HD. However, the exact mechanism underlying PAs-induced axonal degeneration remains unclear. Recently, Sterile α and toll/interleukin 1 receptor motif-containing protein 1 (SARM1) has been identified as the central executor of axon degeneration. This study was designed to investigate the role of SARM1-mediated axon degeneration in rats exposed to HD. Furthermore, the causal relationship between PAs and SARM1-mediated axon degeneration was further explored using Sarm1 KO mice. Our findings suggest that HD causes axon degeneration and neuronal loss in animals. Mechanistic studies revealed that HD activates SARM1-dependent axonal degeneration machinery. In contrast, Sarm1 KO attenuates motor dysfunction and rescues neuron loss following HD exposure. Interestingly, the PAs formed by the binding of HD to proteins primarily accumulate on mitochondria, leading to mitochondrial dysfunction. This dysfunction serves as an upstream event in HD-induced nerve injuries. Our findings highlight the crucial role of PAs formation in the major pathological changes during n-hexane poisoning, providing a potential therapeutic target for n-hexane neuropathy., 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.)

Since the concept of "multiferroic" was first proposed in 1968, the coupling effect between different ferroic orders has attracted great interest in energy, information, and biomedical fields. However, the fully ferroelectric-fully ferroelastic effect has never been experimentally observed in hybrid perovskites, even though this effect was predicted to exist half a century ago. Realizing such cross-linking effects of polarization vectors and strain tensors has always been a huge challenge because of the complex difference in these two ferroic origins. Here, we report a multiferroic with full ferroelectricity and full ferroelasticity in two-dimensional (2D) hybrid perovskites based on ferroelectrochemistry. The dynamic molecular reorientations endow (cyclohexanemethylaminium) 2 PbCl 4 with a desired symmetry change of 4̅2 m F mm 2 at a Curie temperature of 411.8 K. More strikingly, the switchable evolution of ferroelastic domains was directly observed under the control of either electric or mechanical fields, which is the first experimental observation of a fully ferroelectric-fully ferroelastic effect in hybrid perovskites. This work would provide new insights into understanding the intrinsic cross-linking mechanism between ferroelectricity and ferroelasticity toward the development of multichannel interactive microelectronic devices.

Background: Influenza A (H1N1) virus is a highly contagious respiratory disease that causes severe illness and death. Vaccines and antiviral drugs are limited by viral variation and drug resistance, so developing efficient integrated theranostic options appears significant in anti-influenza virus infection., Methods: In this study, we designed and fabricated covalent organic framework (COF) based theranostic platforms (T705@DATA-COF-Pro), which was composed of an RNA polymerase inhibitor (favipiravir, T705), the carboxyl-enriched COF (DATA-COF) nano-carrier and Cy3-labeled single DNA (ssDNA) probe., Results: The multi-porosity COF core provided an excellent micro-environment and smooth delivery for T705. The ssDNA probe coating bound to the nucleic acids of H1N1 selectively, thus controlling drug release and allowing fluorescence imaging. The combination of COF and probe triggered the synergism, promoting drug further therapeutic outcomes. With the aid of T705@DATA-COF-Pro platforms, the H1N1-infected mouse models lightly achieved diagnosis and significantly prolonged survival., Conclusion: This research underscores the distinctive benefits and immense potential of COF materials in nano-preparations for virus infection, offering novel avenues for the detection and treatment of H1N1 virus infection., Competing Interests: The authors declare no conflicts of interest in this work., (© 2024 Ding et al.)

Objective: Sensory intelligence in the brain helps listeners automatically extract abstract auditory rules formed by invariant acoustic features from complex speech sound streams, presumably serving as the neural basis for speech comprehension. However, whether this intelligence is deficient in children with cochlear implants (CIs) remains unclear., Methods: Mandarin Chinese monosyllables shared a flat lexical tone contour to form an abstract auditory rule but differed in other acoustic features to construct a complex speech sound stream. The abstract rule was occasionally violated by monosyllables with a rising or falling lexical tone., Results: In normal hearing (NH) children, the abstract auditory rule could be extracted, as revealed by a mismatch negativity (MMN) and a late discriminative negativity (LDN). However, the MMN and LDN were only evoked in CI children with good hearing and speech performance. NH children with a higher speech perception or spatial hearing score had a greater MMN. The LDN was attenuated with increasing age in NH children., Conclusions: The sensory intelligence for extraction of auditory abstract rules, associated with speech perception, is deficient in CI children. This intelligence may gradually develop during childhood and adolescence., Significance: Deficient sensory intelligence in CI children may aid in understanding poor speech comprehension in complex environments., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Anaplastic thyroid carcinoma (ATC) is a rare but highly aggressive thyroid cancer with poor prognosis. Killing cancer cells by inducing DNA damage or blockage of DNA repair is a promising strategy for chemotherapy. It is reported that aldehyde-reactive alkoxyamines can capture the AP sites, one of the most common DNA lesions, and inhibit apurinic/apyrimidinic endonuclease 1(APE1)-mediated base excision repair (BER), leading to cell death. Whether this strategy can be employed for ATC treatment is rarely investigated. The aim of this study is to exploit GSH-responsive AP site capture reagent (AP probe-net), which responses to the elevated glutathione (GSH) levels in the tumor micro-environment (TME), releasing reactive alkoxyamine to trap AP sites and block the APE1-mediated BER for targeted anti-tumor activity against ATC. In vitro experiments, including MTT andγ-H2AX assays, demonstrate their selective cytotoxicity towards ATC cells over normal thyroid cells. Flow cytometry analysis suggests that AP probe-net arrests the cell cycle in the G2/M phase and induces apoptosis. Western blotting (WB) results show that the expression of apoptotic protein increased with the increased concentration of AP probe-net. Further in vivo experiments reveal that the AP probe-net has a good therapeutic effect on subcutaneous tumors of the ATC cells. In conclusion, taking advantage of the elevated GSH in TME, our study affords a new strategy for targeted chemotherapy of ATC with high selectivity and reduced adverse effects., (© 2024. The Author(s).)

Background: The effect of combined radiation and chemotherapy (combination therapy) versus monotherapy on anaplastic thyroid carcinoma (ATC) has not yet been clear., Methods: We identified 516 ATC patients during 2010-2015 from the Surveillance, Epidemiology and End Results (SEER) database and evaluated their survival outcome using the Kaplan-Meier method, Cox regression analysis and propensity score matching (PSM) technique., Results: The median overall survival (OS) among the entire cohort was 3 months (95 % confidence interval [CI], 2.58-3.42 months), and the 6- and 12-month OS rates were 29 % (95 % CI, 25.01%-32.88 %) and 13 % (95 % CI, 10.60%-16.58 %), respectively. Multivariable analysis demonstrated that ATC patients not receiving radiotherapy or chemotherapy were unquestionably associated with worse OS (hazard ratio [HR] 3.000, 95 % CI, 2.390-3.764) and cancer-specific survival (CSS) (HR = 3.107, 95 % CI, 2.388-4.043), compared with those receiving combination therapy. However, combination therapy did not predict better prognosis compared with monotherapy (all P  > 0.05). After PSM, the median OS and CSS were also not significantly improved in patients undergoing chemoradiotherapy versus chemotherapy alone (OS, P  = 0.382; CSS, P  = 0.420) or radiotherapy alone (OS, P  = 0.065; CSS, P  = 0.251)., Conclusion: Combination therapy, compared to monotherapy, does not have the expected improvement in survival beyond the benefits achievable with each single-modality treatment, necessitating further prospective research to tailor its treatment management., 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. Published by Elsevier Ltd.)

Selenoprotein I (Selenoi) is highly expressed in liver and plays a key role in lipid metabolism as a phosphatidylethanolamine (PE) synthase. However, the precise function of Selenoi in the liver remains elusive. In the study, we generated hepatocyte-specific Selenoi conditional knockout (cKO) mice on a high-fat diet to identify the physiological function of Selenoi. The cKO group exhibited a significant increase in body weight, with a 15.6% and 13.7% increase in fat accumulation in white adipose tissue (WAT) and the liver, respectively. Downregulation of the lipolysis-related protein (p-Hsl) and upregulation of the adipogenesis-related protein (Fasn) were observed in the liver of cKO mice. The cKO group also showed decreased oxygen consumption (VO 2 ), carbon dioxide production (VCO 2 ), and energy expenditure (p < .05). Moreover, various metabolites of the steroid hormone synthesis pathway were affected in the liver of cKO mice. A potential cascade of Selenoi-phosphatidylethanolamine-steroid hormone synthesis might serve as a core mechanism that links hepatocyte-specific Selenoi cKO to biochemical and molecular reactions. In conclusion, we revealed that Selenoi inhibits body fat accumulation and hepatic steatosis and elevates energy consumption; this protein could also be considered a therapeutic target for such related diseases., (© 2024 Federation of American Societies for Experimental Biology.)

Targeting the homeostasis of anions and iron has emerged as a promising therapeutic approach for the treatment of cancers. However, single-targeted agents often fall short of achieving optimal treatment efficacy. Herein we designed and synthesized a series of novel dual-functional squaramide-hydroxamic acid conjugates that are capable of synergistically modulating the homeostasis of anions and iron. Among them, compound 16 exhibited the most potent antiproliferative activity against a panel of selected cancer cell lines, and strong in vivo anti-tumor efficacy. This compound effectively elevated lysosomal pH through anion transport, and reduced the levels of intracellular iron. Compound 16 could disturb autophagy in A549 cells and trigger robust apoptosis. This compound caused cell cycle arrest at the G1/S phase, altered the mitochondrial function and elevated ROS levels. The present findings clearly demonstrated that synergistic modulation of anion and iron homeostasis has high potentials in the development of promising chemotherapeutic agents with dual action against cancers., 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 Inc. All rights reserved.)

Objective: This study utilized the stimulated thyroglobulin (sTg) to thyroid stimulating hormone (TSH) ratio to predict the long-term efficacy of 131 I therapy in patients with moderate-to-high-risk differentiated thyroid cancer (DTC)., Methods: This study retrospectively analyzed 960 DTC patients with a median follow-up time of 30 months (6-92 months). The median age was 44 years. All patients underwent total thyroidectomy, lymph node dissection, and at least one 131 I therapy. Patients were subjected to a final efficacy evaluation according to American Thyroid Association's 2015 guidelines. Patients were grouped according to their TSH levels before the initial 131 I therapy and the final efficacy evaluation, and factors influencing TSH levels and final efficacy were analyzed. Construction of nomograms using independent risk factors affecting long-term outcomes. The cut-offs of sTg and sTg/TSH ratios were calculated for different long-term outcomes. Progression-free survival (PFS) of patients was analyzed by making Kaplan-Meier survival according to the cut-offs of sTg and sTg/TSH ratio., Results: TSH (mU/L) levels were more concentrated at 60-90 in females (71.5%) and 30-60 in males (39.0%), while patients with younger age, more lymph node metastases, shorter time interval between surgery and the first 131 I therapy, and lower dose of levothyroxine sodium taken prior to the first 131 I therapy would have higher TSH levels (All P < 0.05).Patients who are male, have primary tumor involvement of the strap muscles, lymph node metastasis, distant metastasis, and higher sTg and sTg/TSH are more likely to have poor long-term outcomes (All P < 0.05).The cut-offs of sTg and sTg/TSH for long-term efficacy were 7.515 and 0.095. STg, sTg/TSH, tumor size, lymph node metastasis, and distant metastasis were shown to be independent risk factors for long-term efficacy. The mean PFSs were longer for patients who had sTg/TSH ≤ 0.095 and/or sTg≤7.515 ug/L., Conclusions: For patients with moderate-to-high-risk DTC, when sTg>7.515 ug/L and/or sTg/TSH > 0.095 before the first 131 I therapy, patients are more likely to have a poor long-term efficacy after full 131 I therapy. This means that this group of patients may require further surgical treatment or targeted drug therapy after 131 I therapy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disease. Metal ion dyshomeostasis and Aβ aggregation have been proposed to contribute to AD progression. Metal ions can bind to Aβ and promote Aβ aggregation, and ultimately lead to neuronal death. Bifunctional (metal chelation and Aβ interaction) compounds are showing promise against AD. In this work, eleven new 3,3'-diamino-2,2'-bipyridine derivatives 4a-4k were synthesized, and evaluated as bifunctional agents for AD treatment. In vitro Aβ aggregation inhibition assay confirmed that most of the synthesized compounds exhibited significant self-induced Aβ 1-42 aggregation inhibition. Among them, compound 4d displayed the best inhibitory potency of self-induced Aβ 1-42 aggregation with IC 50 value of 9.4 µM, and it could selectively chelate with Cu 2+ and exhibited 66.2% inhibition of Cu 2+ -induced Aβ 1-42 aggregation. Meanwhile, compound 4d showed strong neuroprotective activity against Aβ 1-42 and Cu 2+ -treated Aβ 1-42 induced cell damage. Moreover, compound 4d in high dose significantly reversed Aβ-induced memory impairment in mice., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Rheumatoid arthritis (RA) is a progressive autoimmune disease and drug therapy has been restricted due to poor therapeutic efficacy and adverse effects. In RA synovium, dendritic cells present self-antigens to activate cascade immune pathway. Furthermore, downstream macrophages secrete high levels of pro-inflammatory cytokines; Hyperplasia of activated synovial fibroblasts (FLS) is responsible for hypoxic synovium microenvironment, secretion of cytokines/chemokines and erosion of bone/cartilage tissues. Positive feedback loop of inflammation between macrophages and FLS independent of antigen-presentation is constructed. Herein, an injectable pH-sensitive peptide hydrogel encapsulating siRNA/Methotrexate-polyethyleneimine (siMP, including sip65MP, sip38MP, siCD86MP) and Bismuthene nanosheet/Methotrexate-polyethyleneimine (BiMP) is successfully developed. Among them, siCD86MP reduces protein level of co-stimulatory molecule CD86 while sip65MP and sip38MP separately inhibit NF-κB and MAPK-p38 pathways of macrophages and FLS to suppress secretion of cytokines and MMPs. Meanwhile, reduction in anti-apoptotic property of FLS induced by inhibition of NF-κB pathway has a synergistic effect with photodynamic therapy (PDT) and photothermal therapy (PTT) mediated by BiMP for FLS elimination, effectively ameliorating hypoxic synovium microenvironment. After being injected into synovium, hydrogel responds to acidic microenvironment and serves as a reservoir for sustained drug release and inherent retention capacity of which enables cationic nanoparticles to bypass tissue barrier for precise synovium targeting. This brand-new drug delivery system combines modulating cascade immune pathway from beginning to end by RNAi and eliminating FLS for improving synovium microenvironment by phototherapy together, providing a robust strategy for clinical RA treatment., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Polystyrene nanoplastics (PS-NPs), a group of ubiquitous pollutants, may injure the central nervous system through the blood‒brain barrier (BBB). However, whether exposure to PS-NPs contributes to BBB disruption and the underlying mechanisms are still unclear. In vivo, we found that PS-NPs (25 mg/kg BW) could significantly increase BBB permeability in mice and downregulate the distribution of the tight junction-associated protein zona occludens 1 (ZO-1) in brain microvascular endothelial cells (BMECs). Using an in vitro BBB model, exposure to PS-NPs significantly reduced the transendothelial electrical resistance and altered ZO-1 expression and distribution in a dose-dependent manner. RNA-seq analysis and functional investigations were used to investigate the molecular pathways involved in the response to PS-NPs. The results revealed that the ferroptosis and glutathione metabolism signaling pathways were related to the disruption of the BBB model caused by the PS-NPs. PS-NPs treatment promoted ferroptosis in bEnd.3 cells by inducing disordered glutathione metabolism in addition to Fe 2+ and lipid peroxide accumulation, while suppressing ferroptosis with ferrostatin-1 (Fer-1) suppressed ferroptosis-related changes in bEnd.3 cells subjected to PS-NPs. Importantly, Fer-1 alleviated the decrease in ZO-1 expression in bEnd.3 cells and the exacerbation of BBB damage induced by PS-NPs. Collectively, our findings suggest that inhibiting ferroptosis in BMECs may serve as a potential therapeutic target against BBB disruption induced by PS-NPs exposure., 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 Inc. All rights reserved.)

Understanding the transformation process of dissolved organic matter (DOM) in the sewer is imperative for comprehending material circulation and energy flow within the sewer. The machine learning (ML) model provides a feasible way to comprehend and simulate the DOM transformation process in the sewer. In contrast, the model accuracy is limited by data restriction. In this study, a novel framework by integrating generative adversarial network algorithm-machine learning models (GAN-ML) was established to overcome the drawbacks caused by the data restriction in the simulation of the DOM transformation process, and humification index (HIX) was selected as the output variable to evaluate the model performance. Results indicate that the GAN algorithm's virtual dataset could generally enhance the simulation performance of regression models, deep learning models, and ensemble models for the DOM transformation process. The highest prediction accuracy on HIX (R 2 of 0.5389 and RMSE of 0.0273) was achieved by the adaptive boosting model which belongs to ensemble models trained by the virtual dataset of 1000 samples. Interpretability analysis revealed that dissolved oxygen (DO) and pH emerge as critical factors warranting attention for the future development of management strategies to regulate the DOM transformation process in sewers. The integrated framework proposed a potential approach for the comprehensive understanding and high-precision simulation of the DOM transformation process, paving the way for advancing sewer management strategy under data restriction., 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.)

This study investigated the disinfection efficiency of a photoreactor equipped with a helical water flow channel and ultraviolet-C (UV-C) light emitting diodes (LEDs). Theoretical simulations and biodosimetry tests were conducted to investigate the effects of coil diameter and flow rate on the reactor's performance in inactivating Escherichia coli . The interplay between hydrodynamics and UV radiation was analyzed to determine the UV fluence absorbed by the microbes. The simulations revealed that, primarily due to the specific radiation pattern of the UV LEDs, the coil diameter strongly influenced the distribution of irradiance in the water and the UV fluence received by microbes. The experimental results indicated that the photoreactor achieved the highest inactivation value of 2.8 log when the coil diameter was 48 mm for a flow rate of 40 mL/min; this log value was superior to those for coil diameters of 16, 32, 64, and 80 mm by approximately 1.9, 0.4, 0.5, and 0.7 log units, respectively. This optimal coil diameter leading to the maximal UV irradiance and the highest degree of irradiance uniformity along the flow channel. This study offers design guidelines for constructing a high-efficiency water disinfection reactor with a helical flow channel configuration.

Background: Simvastatin (Sim), a hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been widely used in prevention and treatment of cardiovascular diseases. Studies have suggested that Sim exerts anti-fibrotic effects by interfering fibroblast proliferation and collagen synthesis. This study was to determine whether Sim could alleviate silica-induced pulmonary fibrosis and explore the underlying mechanisms., Methods: The rat model of silicosis was established by the tracheal perfusion method and treated with Sim (5 or 10 mg/kg), AICAR (an AMPK agonist), and apocynin (a NOX inhibitor) for 28 days. Lung tissues were collected for further analyses including pathological histology, inflammatory response, oxidative stress, epithelial mesenchymal transformation (EMT), and the AMPK-NOX pathway., Results: Sim significantly reduced silica-induced pulmonary inflammation and fibrosis at 28 days after administration. Sim could reduce the levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α and transforming growth factor-β1 in lung tissues. The expressions of hydroxyproline, α-SMA and vimentin were down-regulated, while E-cad was increased in Sim-treated rats. In addition, NOX4, p22pox, p40phox, p-p47phox/p47phox expressions and ROS levels were all increased, whereas p-AMPK/AMPK was decreased in silica-induced rats. Sim or AICAR treatment could notably reverse the decrease of AMPK activity and increase of NOX activity induced by silica. Apocynin treatment exhibited similar protective effects to Sim, including down-regulating of oxidative stress and inhibition of the EMT process and inflammatory reactions., Conclusions: Sim attenuates silica-induced pulmonary inflammation and fibrosis by downregulating EMT and oxidative stress through the AMPK-NOX pathway., (© 2024. The Author(s).)

Range-limited endemic species, often labeled as endangered due to their low adaptability to climate change, exhibit unclear evolutionary mechanisms influencing their distribution. This study explores the relationship between leaf length, maximum height, and seed diameter and their linkage to phylogeny and climate in the macroecology of 1,370 woody endemics. Using Bayesian analytical method that allows partitioning phylogenetic and environmental variances and covariance, we revealed moderate to high phylogenetic signals in these traits, indicating evolutionary constraints potentially impacting climate change adaptability. The study uncovered a phylogenetically conserved coordination between height and leaf length which showed to be independent of macroecological patterns of temperature and precipitation. These findings emphasize the role of phylogenetic ancestry in shaping the distribution of woody endemics, highlighting the need for prioritized in-situ conservation and providing insights for ex situ conservation strategies., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. Published by Elsevier Inc.)

Background: BRAF V600E is the most common genetic mutation in differentiated thyroid cancer (DTC) occurring in 60% of patients and drives malignant tumour cell phenotypes including proliferation, metastasis and immune-escape. BRAF V600E -mutated papillary thyroid cancer (PTC) also displays greatly reduced expression of thyroid differentiation markers, thus tendency to radioactive iodine (RAI) refractory and poor prognosis. Therefore, understanding the molecular mechanisms and main oncogenic events underlying BRAF V600E will guide future therapy development., Methods: Bioinformatics and clinical specimen analyses, genetic manipulation of BRAF V600E -induced PTC model, functional and mechanism exploration guided with transcriptomic screening, as well as systematic rescue experiments were applied to investigate miR-31 function within BRAF V600E -induced thyroid cancer development. Besides, nanoparticles carrying miR-31 antagomirs were testified to alleviate 131 I iodide therapy on PTC models., Results: We identify miR-31 as a significantly increased onco-miR in BRAF V600E -associated PTC that promotes tumour progression, metastasis and RAI refractoriness via sustained Wnt/β-catenin signalling. Mechanistically, highly activated BRAF/MAPK pathway induces miR-31 expression via c-Jun-mediated transcriptional regulation across in vitro and transgenic mouse models. MiR-31 in turn facilitates β-catenin stabilisation via directly repressing tumour suppressors CEBPA and DACH1, which direct the expression of multiple essential Wnt/β-catenin pathway inhibitors. Genetic functional assays showed that thyroid-specific knockout of miR-31 inhibited BRAF V600E -induced PTC progression, and strikingly, enhanced expression of sodium-iodide symporter and other thyroid differentiation markers, thus promoted 131 I uptake. Nanoparticle-mediated application of anti-miR-31 antagomirs markedly elevated radio-sensitivity of BRAF V600E -induced PTC tumours to 131 I therapy, and efficiently suppressed tumour progression in the pre-clinical mouse model., Conclusions: Our findings elucidate a novel BRAF/MAPK-miR-31-Wnt/β-catenin regulatory mechanism underlying clinically BRAF V600E -associated DTC tumourigenesis and dedifferentiation, also highlight a potential adjuvant therapeutic strategy for advanced DTC., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Purpose: To investigate the relationship between bone turnover markers (BTMs) and thyroid indicators in Graves' disease (GD) and to further assess predictive value of changes in early stage retrospectively., Methods: We studied 435 patients with GD and 113 healthy physical examiners retrospectively and followed up these two groups of patients after 6 months. We investigated the correlations between BTMs and other 15 observed factors, and analyzed the predictive value of FT 3 and FT 4 before and after treatment (FT 3 -P/FT 3 -A, FT 4 -P/FT 4 -A) on whether BTMs recovered., Results: The levels of thyroid hormones and BTMs in GD group were significantly higher than those in control group (P < 0.05) and decreased after 6 months of treatment. FT3, W, Ca and ALP were independent factors in predicting the elevation of OST. Duration of disease, FT3, TSH and ALP were independent factors in predicting the elevation of P1NP. Age, duration of disease, TRAb and ALP were independent factors in predicting the elevation of CTX-1. The AUC of FT 3 -P/FT 3 -A and FT 4 -P/FT 4 -A for predicting OST recovery were 0.748 and 0.705 (P < 0.05), respectively, and the cut-off values were 0.51 and 0.595. There was no predictive value for P1NP and CTX-1 recovery (P > 0.05)., Conclusion: BTMs were abnormally elevated in GD and were significantly correlated with serum levels of FT3, FT4, TRAb, Ca, and ALP. FT 3 decreased more than 51% and FT 4 dropped more than 59.5% after 6 months of treatment were independent predictors for the recovery of BTMs in GD., 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 Su, Chai, Zheng, Jia, Tan, He, Zhang, Men, Liu, Shi, Ren, Dong, Liu and Meng.)

In previous research, a synthetic α-carboxyl terminus 1 (αCT1) peptide derived from connexin 43 (Cx43) and its variant (αCT11) showed beneficial effects in an ex vivo ischemia-reperfusion (I/R) heart injury model in mouse. In an in vivo mouse model of cryo-induced ventricular injury, αCT1 released from adhesive cardiac patches reduced Cx43 remodeling and arrhythmias, as well as maintained cardiac conduction. Whether intravenous injection of αCT1 or αCT11 produces similar outcomes has not been investigated. Given the possibility of peptide degradation in plasma, this study utilized in vivo I/R cardiac injury and ex vivo blood plasma models to examine factors that may limit the therapeutic potential of peptide therapeutics in vivo . Following tail vein administration of αCT11 (100 μM) in blood, no effect on I/R infarct size was observed in adult rat hearts on day 1 (D1) and day 28 (D28) after injury ( p > 0.05). There was also no difference in the echocardiographic ejection fraction (EF%) between the control and the αCT11 groups ( p > 0.05). Surprisingly, αCT11 in blood plasma collected from these rats was undetectable within ∼10 min after tail vein injection. To investigate factors that may modulate αCT11 degradation in blood, αCT11 was directly added to blood plasma isolated from normal rats without I/R and peptide levels were measured under different experimental conditions. Consistent with in vivo observations, significant αCT11 degradation occurred in plasma within 10 min at 22 and 37 °C and was nearly undetectable by 30 min. These responses were reduced by the addition of protease/phosphatase (PTase/PPTase) inhibitors to the isolated plasma. Interestingly, no significant differences in αCT11 degradation in plasma were noted between male and female rats. We conclude that fast degradation of αCT11 is likely the reason that no beneficial effects were observed in the in vivo I/R model and inhibition or shielding from PTase/PPTase activity may be a strategy that will assist with the viability of peptide therapeutics., Competing Interests: The authors declare the following competing financial interest(s): Robert Gourdie holds stock in and is a company officer of the Tiny Cargo Company Inc., which has licensed exosomal technology developed by him at Virginia Tech. RGG is also a stockholder of FirstString Research Inc (<1 % ownership), which licensed aCT1 peptide from the Medical University of South Carolina., (© 2024 The Authors. Published by American Chemical Society.)

Rheumatoid arthritis (RA) is a progressive autoimmune disease accompanied by joint swelling, cartilage erosion and bone damage. Drug therapy for RA has been restricted due to poor therapeutic effect, recurrence and adverse effects. Macrophages and synovial fibroblasts both play important roles in the pathology of RA. Macrophages secrete large amount of pro-inflammatory cytokines, while synovial fibroblasts are tightly correlated with hypoxia synovium microenvironment, cytokine release, recruitment of pro-inflammatory cells, bone and cartilage erosion. Therefore, in this timely research, an injectable and pH-sensitive peptide hydrogel loading methotrexate (MTX) and bismuthene nanosheet/polyethyleneimine (BiNS/PEI) has been developed to reduce the activity of macrophages and eliminate over-proliferated synovial fibroblasts simultaneously. MTX can reduce the cytokine secretion of macrophages/anti-apoptosis property of synovial fibroblasts and BiNS/PEI can eliminate synovial fibroblasts via photodynamic therapy (PDT) and photothermal therapy (PTT) routes. The hydrogel was injected into the acidic inflammatory synovium for precise targeting and served as a drug reservoir for pH responsive and sustained drug release, while improving the bioavailability and reducing the toxicity of MTX. Excellent therapeutic efficacy has been achieved in both in vivo and in vitro studies, and this unique drug delivery system provides a new and robust strategy to eliminate synovial fibroblasts and modulate immune system for RA treatment in clinical., (© 2024. The Author(s).)

Luminescent ferroelectrics are holding exciting prospect for integrated photoelectronic devices due to potential light-polarization interactions at electron scale. Integrating ferroelectricity and long-lived afterglow emission in a single material would offer new possibilities for fundamental research and applications, however, related reports have been a blank to date. For the first time, we here achieved the combination of notable ferroelectricity and afterglow emission in an organic-inorganic hybrid material. Remarkably, the presented (4-methylpiperidium)CdCl 3 also shows noticeable antiferroelectric behavior. The implementation of cationic customization and halogen engineering not only enables a dramatic enhancement of Curie temperature of 114.4 K but also brings a record longest emission lifetime up to 117.11 ms under ambient conditions, realizing a leapfrog improvement of at least two orders of magnitude compared to reported hybrid ferroelectrics so far. This finding would herald the emergence of novel application potential, such as multi-level density data storage or multifunctional sensors, towards the future integrated optoelectronic devices with multitasking capabilities., (© 2024 Wiley‐VCH GmbH.)

Purpose: To investigate the effect of the interval between bilateral cochlear implantation on the development of bilateral peripheral auditory pathways as revealed by the electrically evoked auditory brainstem response (EABR)., Methods: Fifty-eight children with profound bilateral sensorineural hearing loss were recruited. Among them, 33 children received sequential bilateral cochlear implants (CIs), and 25 children received simultaneous bilateral CIs. The bilateral EABRs evoked by electrical stimulation from the CI electrode were recorded on the day of second-side CI activation., Results: The latencies of wave III (eIII) and wave V (eV) were significantly shorter on the first CI side than on the second CI side in children with sequential bilateral CIs but were similar between the two sides in children with simultaneous bilateral CIs. Furthermore, the latencies were prolonged from apical to basal channels along the cochlea in the two groups. In children with sequential CIs, the inter-implant interval was negatively correlated with the eV latency on the first CI side and was positively correlated with bilateral differences in the eIII and eV latencies., Conclusions: Unilateral CI use promotes the maturation of ipsilateral auditory conduction function. However, a longer inter-implant interval results in more unbalanced development of bilateral auditory brainstem pathways. Bilateral cochlear implantation with no or a short interval is recommended., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hybrid organic-inorganic perovskite (HOIP) ferroelectric materials have great potential for developing self-powered electronic transducers owing to their impressive piezoelectric performance, structural tunability and low processing temperatures. Nevertheless, their inherent brittle and low elastic moduli limit their application in electromechanical conversion. Integration of HOIP ferroelectrics and soft polymers is a promising solution. In this work, a hybrid organic-inorganic rare-earth double perovskite ferroelectric, [RM3HQ] 2 RbPr(NO 3 ) 6 (RM 3 HQ = (R)-N-methyl-3-hydroxylquinuclidinium) is presented, which possesses multiaxial nature, ferroelasticity and satisfactory piezoelectric properties, including piezoelectric charge coefficient (d 33 ) of 102.3 pC N -1 and piezoelectric voltage coefficient (g 33 ) of 680 × 10 -3  V m N -1 . The piezoelectric generators (PEG) based on composite films of [RM3HQ] 2 RbPr(NO 3 ) 6 @polyurethane (PU) can generate an open-circuit voltage (V oc ) of 30 V and short-circuit current (I sc ) of 18 µA, representing one of the state-of-the-art PEGs to date. This work has promoted the exploration of new HOIP ferroelectrics and their development of applications in electromechanical conversion devices., (© 2023 Wiley‐VCH GmbH.)

Anxiety is a remarkably common condition among patients with pharyngitis, but the relationship between these disorders has received little research attention, and the underlying neural mechanisms remain unknown. Here, we show that the densely innervated pharynx transmits signals induced by pharyngeal inflammation to glossopharyngeal and vagal sensory neurons of the nodose/jugular/petrosal (NJP) superganglia in mice. Specifically, the NJP superganglia project to norepinephrinergic neurons in the nucleus of the solitary tract (NTS NE ). These NTS NE neurons project to the ventral bed nucleus of the stria terminalis (vBNST) that induces anxiety-like behaviors in a murine model of pharyngeal inflammation. Inhibiting this pharynx→NJP→NTS NE →vBNST circuit can alleviate anxiety-like behaviors associated with pharyngeal inflammation. This study thus defines a pharynx-to-brain axis that mechanistically links pharyngeal inflammation and emotional response., Competing Interests: Competing interests statement:The authors declare no competing interest.

Objective: This study aimed to investigate the underlying reasons for unexplained elevated thyroglobulin (Tg) in postoperative papillary thyroid cancer (PTC) patients according to follow-up results post RAT and to explore the long-term clinical outcomes and prognostic factors associated with these patients., Methods: From April 2016 to June 2019, a retrospective study was conducted on postoperative PTC patients who underwent RAT at our institution. Patients with preablative stimulated thyroglobulin (psTg) > 10 ng/mL but no structurally evident disease were enrolled. The causal categorization for elevated Tg was analyzed 6 months post RAT and the long-term therapeutic responses were assessed at the end of follow-up. To identify risk factors influencing recurrence-free survival (RFS), both univariate and multivariate Cox regression analysis were employed. Kaplan-Meier method was utilized for plotting survival curves., Results: A cohort of 165 subjects was enrolled for the analyses. Based on the results of a six-month follow-up, the postoperative unexplained elevated Tg among 165 patients could be ultimately attributed to thyroid remnant in 13.94% (23/165), biochemical disease in 60.00% (99/165), and structural disease in 26.06% (43/165). With a median follow-up of 58 months, 51 (30.91%), 34 (20.60%), 21 (12.73%), and 59 (35.76%) of the 165 patients achieved ER, IDR, BIR and SIR, respectively. Univariate analysis showed that N stage, TNM stage and suppressed Tg 6 months post RAT may be prognostic factors affecting RFS. Multivariate analysis showed that N1b stage [HR:2.749, P = 0.003] and II/III stage [HR:2.910, P = 0.001] were independent risk factors for RFS., Conclusion: The proportion of 165 postoperative PTC patients with unexplained elevated Tg developing structural disease within nearly 5 years was over 30%. Patients with N1b stage and higher TNM stage were more likely to develop structural disease., 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 purpose of this retrospective study is to compare the efficacy and safety of the centrifugal separation therapeutic plasma exchange (TPE) using citrate anticoagulant (cTPEc) with membrane separation TPE using heparin anticoagulant (mTPEh) in liver failure patients. The patients treated by cTPEc were defined as cTPEc group and those treated by mTPEh were defined as mTPEh group, respectively. Clinical characteristics were compared between the two groups. Survival analyses of two groups and subgroups classified by the model for end-stage liver disease (MELD) score were performed by Kaplan-Meier method and were compared by the log-rank test. In this study, there were 51 patients in cTPEc group and 18 patients in mTPEh group, respectively. The overall 28-day survival rate was 76% (39/51) in cTPEc group and 61% (11/18) in mTPEh group (P > .05). The 90-day survival rate was 69% (35/51) in cTPEc group and 50% (9/18) in mTPEh group (P > .05). MELD score = 30 was the best cut-off value to predict the prognosis of patients with liver failure treated with TPE, in mTPEh group as well as cTPEc group. The median of total calcium/ionized calcium ratio (2.84, range from 2.20 to 3.71) after cTPEc was significantly higher than the ratio (1.97, range from 1.73 to 3.19) before cTPEc (P < .001). However, there was no significant difference between the mean concentrations of total calcium before cTPEc and at 48 h after cTPEc. Our study concludes that there was no statistically significant difference in survival rate and complications between cTPEc and mTPEh groups. The liver failure patients tolerated cTPEc treatment via peripheral vascular access with the prognosis similar to mTPEh. The prognosis in patients with MELD score < 30 was better than in patients with MELD score ≥ 30 in both groups. In this study, the patients with acute liver failure (ALF) and acute on chronic liver failure (ACLF) treated with cTPEc tolerated the TPE frequency of every other day without significant clinical adverse event of hypocalcemia with similar outcomes to the mTPEh treatment. For liver failure patients treated with cTPEc, close clinical observation and monitoring ionized calcium are necessary to ensure the patients' safety., (© 2023 The Authors. Journal of Clinical Apheresis published by Wiley Periodicals LLC.)

Bifidobacteria as a strictly anaerobic gram-positive bacteria, is widely distributed in the intestine, vagina and oral cavity, and is one of the first gut flora to colonize the early stages of life. Intestinal flora is closely related to health, and dysbiosis of intestinal flora, especially Bifidobacteria, has been found in a variety of diseases. Numerous studies have shown that in addition to maintaining intestinal homeostasis, Bifidobacteria may be involved in diseases covering all parts of the body, including the nervous system, respiratory system, genitourinary system and so on. This review collects evidence for the variation of Bifidobacteria in typical diseases among various systems, provides mild and effective therapeutic options for those diseases that are difficult to cure, and moves Bifidobacteria from basic research to further clinical applications., (© 2023. Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i.)

Androgen deprivation therapy is administered to suppress the growth of prostate cancer (PCa). However, some cells continue to proliferate independent of hormones, leading to the development of castration-resistant prostate cancer (CRPC). Overexpression of the epidermal growth factor receptor (EGFR) has been observed in CRPC and is associated with an unfavorable prognosis. Gefitinib (GEF) is an EGFR inhibitor used to treat patients with CRPC. Nevertheless, some clinical studies have reported that gefitinib does not result in prostate-specific antigen (PSA) or objectively measurable CRPC reactions. This lack of response may be attributed to the limited solubility in water, high side effects, low tumor aggregation, and insufficient tumor-specific reactions of GEF. In order to tackle these obstacles, we present a practical and efficient approach to administer GEF, encompassing the utilization of biocompatible nanostructures as a vehicle for drug delivery to augment its bioaccessibility and curative potency. Despite their small particle size, poly(D,L-lactide- co -glycolide) acid nanoparticles (PLGA NPs) exhibit a high drug-loading capacity, low toxicity, biocompatibility, biodegradability, and minimal immunogenicity. The drug delivery efficiency can be improved by employing GEF@PLGA NPs, which could also enhance drug cytotoxicity and impede the advancement of prostate cancer. Moreover, through experiments in vivo , it has been verified that GEF@PLGA NPs exhibit selective accumulation in the tumor and effectively restrain tumor growth. Therefore, the GEF@PLGA NPs hold great promise for the treatment of PCa.

Background: Risk stratification and personalized care are crucial in managing osteosarcoma due to its complexity and heterogeneity. However, current prognostic prediction using clinical variables has limited accuracy. Thus, this study aimed to explore potential molecular biomarkers to improve prognostic assessment., Methods: High-throughput inhibitor screening of 150 compounds with broad targeting properties was performed and indicated a direction towards super-enhancers (SEs). Bulk RNA-seq, scRNA-seq, and immunohistochemistry (IHC) were used to investigate SE-associated gene expression profiles in osteosarcoma cells and patient tissue specimens. Data of 212 osteosarcoma patients who received standard treatment were collected and randomized into training and validation groups for retrospective analysis. Prognostic signatures and nomograms for overall survival (OS) and lung metastasis-free survival (LMFS) were developed using Cox regression analyses. The discriminatory power, calibration, and clinical value of nomograms were evaluated., Results: High-throughput inhibitor screening showed that SEs significantly contribute to the oncogenic transcriptional output in osteosarcoma. Based on this finding, focus was given to 10 SE-associated genes with distinct characteristics and potential oncogenic function. With multi-omics approaches, the hyperexpression of these genes was observed in tumor cell subclusters of patient specimens, which were consistently correlated with poor outcomes and rapid metastasis, and the majority of these identified SE-associated genes were confirmed as independent risk factors for poor outcomes. Two molecular signatures were then developed to predict survival and occurrence of lung metastasis: the SE-derived OS-signature (comprising LACTB, CEP55, SRSF3, TCF7L2, and FOXP1) and the SE-derived LMFS-signature (comprising SRSF3, TCF7L2, FOXP1, and APOLD1). Both signatures significantly improved prognostic accuracy beyond conventional clinical factors., Conclusions: Oncogenic transcription driven by SEs exhibit strong associations with osteosarcoma outcomes. The SE-derived signatures developed in this study hold promise as prognostic biomarkers for predicting OS and LMFS in patients undergoing standard treatments. Integrative prognostic models that combine conventional clinical factors with these SE-derived signatures demonstrate substantially improved accuracy, and have the potential to facilitate patient counseling and individualized management., (© 2024. The Author(s).)

Microbial cement, known for its superior fluidity, stable crystal formation, and strong bond with concrete, is an effective solution in fixing defects such as voids that appear due to insufficient grouting in the joints of precast concrete components. To evaluate the mechanical properties of rebar anchored with microbial cement grout, three pull-out tests were designed, taking into account parameters such as calcium source concentration, the filler in borehole voids, and the shape of the rebar. The results indicate that specimens with a higher concentration of calcium source require fewer grouting cycles, but the pull-out bearing capacity of the anchored rebar is lower. However, the introduction of quartz sand as a filler in the borehole voids results in a significant increase in the pull-out bearing capacity of the rebar compared to specimens without filler. Among these, the specimens with a medium particle size of 0.5 ~ 1 mm (1/4δ ~ 1/2δ, the gap of δ = 2 mm between the steel bars and hole wall) have the highest pull-out bearing capacity. In comparing rebar shapes, ribbed rebar slightly outperforms smooth round rebar in terms of pull-out bearing capacity. Based on the experimental results analysis, the anchoring mechanism of microbial cement grouting on reinforcement has been elucidated., (© 2024. The Author(s).)

The ability to generate and manipulate photoluminescence (PL) behavior has been of primary importance for applications in information security. Excavating novel optical effects to create more possibilities for information encoding has become a continuous challenge. Herein, we present an unprecedented PL temporary quenching that highly couples with thermodynamic phase transition in a hybrid crystal (DMML) 2 MnBr 4 (DMML=N,N-dimethylmorpholinium). Such unusual PL behavior originates from the anomalous variation of [MnBr 4 ] 2- tetrahedrons that leads to non-radiation recombination near the phase transition temperature of 340 K. Remarkably, the suitable detectable temperature, narrow response window, high sensitivity, and good cyclability of this PL temporary quenching will endow encryption applications with high concealment, operational flexibility, durability, and commercial popularization. Profited from these attributes, a fire-new optical encryption model is devised to demonstrate high confidential information security. This unprecedented optical effect would provide new insights and paradigms for the development of luminescent materials to enlighten future information encryption., (© 2023 Wiley-VCH GmbH.)

Patients with type 2 diabetes mellitus (T2DM) are at higher risk for urinary tract infections (UTIs), which greatly impacts their quality of life. Developing a risk prediction model to identify high-risk patients for UTIs in those with T2DM and assisting clinical decision-making can help reduce the incidence of UTIs in T2DM patients. To construct the predictive model, potential relevant variables were first selected from the reference literature, and then data was extracted from the Hospital Information System (HIS) of the Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital for analysis. The data set was split into a training set and a test set in an 8:2 ratio. To handle the data and establish risk warning models, four imputation methods, four balancing methods, three feature screening methods, and eighteen machine learning algorithms were employed. A 10-fold cross-validation technique was applied to internally validate the training set, while the bootstrap method was used for external validation in the test set. The area under the receiver operating characteristic curve (AUC) and decision curve analysis (DCA) were used to evaluate the performance of the models. The contributions of features were interpreted using the SHapley Additive ExPlanation (SHAP) approach. And a web-based prediction platform for UTIs in T2DM was constructed by Flask framework. Finally, 106 variables were identified for analysis from a total of 119 literature sources, and 1340 patients were included in the study. After comprehensive data preprocessing, a total of 48 datasets were generated, and 864 risk warning models were constructed based on various balancing methods, feature selection techniques, and a range of machine learning algorithms. The receiver operating characteristic (ROC) curves were used to assess the performances of these models, and the best model achieved an impressive AUC of 0.9789 upon external validation. Notably, the most critical factors contributing to UTIs in T2DM patients were found to be UTIs-related inflammatory markers, medication use, mainly SGLT2 inhibitors, severity of comorbidities, blood routine indicators, as well as other factors such as length of hospital stay and estimated glomerular filtration rate (eGFR). Furthermore, the SHAP method was utilized to interpret the contribution of each feature to the model. And based on the optimal predictive model a user-friendly prediction platform for UTIs in T2DM was built to assist clinicians in making clinical decisions. The machine learning model-based prediction system developed in this study exhibited favorable predictive ability and promising clinical utility. The web-based prediction platform, combined with the professional judgment of clinicians, can assist to make better clinical decisions., 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 Xiong, Liu, Hu, Zhu, Wei, Yang, Wu and Long.)

Hearing loss has become increasingly prevalent and causes considerable disability, thus gravely burdening the global economy. Irreversible loss of hair cells is a main cause of sensorineural hearing loss, and currently, the only relatively effective clinical treatments are limited to digital hearing equipment like cochlear implants and hearing aids, but these are of limited benefit in patients. It is therefore urgent to understand the mechanisms of damage repair in order to develop new neuroprotective strategies. At present, how to promote the regeneration of functional hair cells is a key scientific question in the field of hearing research. Multiple signaling pathways and transcriptional factors trigger the activation of hair cell progenitors and ensure the maturation of newborn hair cells, and in this article, we first review the principal mechanisms underlying hair cell reproduction. We then further discuss therapeutic strategies involving the co-regulation of multiple signaling pathways in order to induce effective functional hair cell regeneration after degeneration, and we summarize current achievements in hair cell regeneration. Lastly, we discuss potential future approaches, such as small molecule drugs and gene therapy, which might be applied for regenerating functional hair cells in the clinic., (© 2023. The Author(s).)

The regulation of spermatogonial proliferation and apoptosis is of great significance for maintaining spermatogenesis. The single-cell RNA sequencing (scRNA-seq) analysis of the testis was performed to identify genes upregulated in spermatogonia. Using scRNA-seq analysis, we identified the spermatogonia upregulated gene origin recognition complex subunit 6 ( Orc6 ), which is involved in DNA replication and cell cycle regulation; its protein expression in the human and mouse testis was detected by western blot and immunofluorescence. To explore the potential function of Orc6 in spermatogonia, the C18-4 cell line was transfected with control or Orc6 siRNA. Subsequently, 5-ethynyl-2-deoxyuridine (EdU) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, flow cytometry, and western blot were used to evaluate its effects on proliferation and apoptosis. It was revealed that ORC6 could promote proliferation and inhibit apoptosis of C18-4 cells. Bulk RNA sequencing and bioinformatics analysis indicated that Orc6 was involved in the activation of wingless/integrated (Wnt)/β-catenin signaling. Western blot revealed that the expression of β-catenin protein and its phosphorylation (Ser675) were significantly decreased when silencing the expression of ORC6. Our findings indicated that Orc6 was upregulated in spermatogonia, whereby it regulated proliferation and apoptosis by activating Wnt/β-catenin signaling., (Copyright © 2023 Copyright: © The Author(s)(2023).)

Indole-3-carbinol, bisindolylmethanes (BIMs) and indole-3-methanamines exhibit diverse therapeutic activities. Fluorinated molecules are widely used in pharmaceuticals. Herein we report a facile and straightforward method for the successful synthesis of difluoromethylated indole-3-carbinols, bisindolylmethanes and indole-3-methanamines by a Friedel-Crafts reaction. The reaction involves the in situ generation of difluoroacetaldehyde from difluoroacetaldehyde ethyl hemiacetal in the presence of a base or an acid. This protocol is distinguished by its good to excellent yields, broad substrate compatibility, good functional group tolerance and scalability.

Organic-inorganic hybrid lead halide perovskites (OLHPs), represented by (CH 3 NH 3 )PbI 3 , are one of the research focus due to their exceptional performance in optoelectronic applications, and ferroelastic domain walls are benign to their charge carrier transport that is confirmed recently. Among them, the 1D OLHPs feature better stability against desorption and moisture, but related 1D ones possessing ferroelasticity are rarely investigated and reported so far. In this work, the 1D ferroelastic semiconductor (N-iodomethyl-N-methyl-morpholinium)PbI 3 ((IDMML)PbI 3 ) is prepared successfully by introducing successively halogenate atoms from Cl, Br to I into the organic cation of the prototype (N,N-dimethylmorpholinium)PbI 3 ((DMML)PbI 3 ). Notably, (IDMML)PbI 3 shows the narrow bandgap energy (≈2.34 eV) according to the ultraviolet-visible absorption spectrum and the theoretical calculation, and possesses the evident photoconductive characteristic with the on/off ratio of current of ≈50 under the 405 nm light irradiation. This work provides a new case for the ferroelastic OLHPs and will inspire intriguing research in the field of optoelectronic., (© 2023 Wiley-VCH GmbH.)

Preclinical and clinical studies have demonstrated the synergistic effect of microtubule-targeting agents in combination with Janus kinase 2 (JAK2) inhibitors, prompting the development of single agents with enhanced therapeutic efficacy by dually inhibiting tubulin polymerization and JAK2. Herein, we designed and synthesized a series of substituted 2-amino[1,2,4]triazolopyrimidines and related heterocycles as dual inhibitors for tubulin polymerization and JAK2. Most of these compounds exhibited potent antiproliferative activity against the selected cancer cells, with compound 7g being the most active. This compound effectively inhibits both tubulin assembly and JAK2 activity. Furthermore, phosphorylated compound 7g (i.e., compound 7g - P ) could efficiently convert to compound 7g in vivo . Compound 7g , whether it was administered directly or in the form of a phosphorylated prodrug (i.e., compound 7g - P ), significantly inhibited the growth of A549 xenografts in nude mice. The present findings strongly suggest that compound 7g represents a promising chemotherapeutic agent with high antitumor efficacy.

Background: The effects of obesity and diabetes on the clinical outcomes of differentiated thyroid cancer (DTC) remain unclear., Objectives: To explore the association between obesity and diabetes with pathological features and therapeutic response of DTC., Methods: Patients were categorized based on body mass index (BMI) and glycemic status. Compare the correlation between BMI and glycemic status with pathological features and therapeutic response of DTC. To analyze the independent risk factors for the aggressiveness of DTC., Results: The proportion of patients with bilateral tumors was higher in the overweight, obese and diabetes group (P = 0.001, 0.045). The overweight group demonstrated a higher TNM stage (P = 0.004), while the T and TNM stages were higher in the diabetes group (P = 0.032, 0.000). The probability of distant metastasis increases by 37.4% for each unit of BMI increase (odds ratio (OR) = 1.374, CI 95% 1.061-1.778, P < 0.05). The BMI of Biochemical Incomplete Response (BIR) is significantly higher than that of Excellent Response (ER) (P = 0.015), the fasting plasma glucose (FPG) of Structural Incomplete (SIR) was significantly higher than that of ER and BIR (P = 0.030, 0.014)., Conclusion: Obesity and diabetes have effect on DTC aggressiveness. BMI and FPG have correlation with the therapeutic response of DTC patients., (© 2023. The Author(s).)

Exposure to toluene diisocyanate (TDI) can cause pulmonary diseases such as asthma. Inhibition of high mobility group box 1 protein (HMGB1) has been found to be protective against the toxic effects of TDI on human bronchial epithelial (HBE) cells. Here, we evaluated the in vivo positive roles of HMGB1 in the TDI-caused asthma mice and explored its underlying mechanisms in HBE cells. We found that suppression of HMGB1 obviously alleviated airway inflammation, airway hyperresponsiveness, and airway remodeling in the lung tissue of the asthma mice. The in vitro results showed that inhibition of HMGB1 ameliorated TDI-induced reactive oxygen species (ROS) release, inflammatory response, and activation of autophagy in HBE cells. At the molecular level, inhibition of HMGB1 decreased the expressions of HMGB1, Toll-like receptor 4, Vimentin and matrix metalloproteinase-9 proteins, activated NF-κB and NOD-like receptor protein 3 (NLRP3) inflammasome, and increased E-cadherin expression. Importantly, activation of autophagy could lead to the overactivation of NLRP3 inflammasome in TDI-induced asthma. These results suggest that inhibition of HMGB1 can alleviate TDI-induced asthma through ROS/AMPK/autophagy pathways, which may provide valuable evidence for the pathogenesis and therapeutic targets of TDI-induced asthma., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Advanced Ag nanoparticles (Ag NPs) were prepared by wet chemical oxidation-reduction method, using mainly the tannic acid as reducing agent and carboxymethylcellulose sodium as stabilizer. The prepared Ag NPs uniformly disperse and are stable for more than one month without agglomeration. The studies of transmission electron microscopy (TEM) and ultraviolet-visible (UV-vis) absorption spectroscopy indicate that the Ag NPs are in homogeneous sphere with only 4.4 nm average size and narrow particle size distribution. Electrochemical measurements reveal that the Ag NPs behave excellent catalytic activity for electroless copper plating using glyoxylic acid as reducing agent. In situ fourier transform infrared (in situ FTIR) spectroscopic analysis combined with density functional theory (DFT) calculation illustrate that the molecular oxidation of glyoxylic acid catalyzed by Ag NPs is as the following routes: glyoxylic acid molecule first is adsorbed on Ag atoms with carboxyl oxygen terminal, then hydrolyzed to diol anionic intermediate, and last oxidized to oxalic acid. Time-resolved in situ FTIR spectroscopy further reveals the real-time reactions of electroless copper plating as follows: glyoxylic acid is continuously oxidized to oxalic acid and releases electrons at the active catalyzing spots of Ag NPs, and Cu(II) coordination ions are in situ reduced by the electrons. Based on the excellent catalytic activity, the advanced Ag NPs can replace the expensive Pd colloids catalyst and successfully apply in through-holes metallization of printed circuit board (PCB) by electroless copper plating., 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 Elsevier Inc. All rights reserved.)

Background: Silicosis is an important occupational disease caused by inhalation of free silica and is characterized by persistent pulmonary inflammation, subsequent fibrosis and lung dysfunction. Until now, there has been no effective treatment for the disease due to the complexity of pathogenesis. Fermented cordyceps powder (FCP) has a similar effect to natural cordyceps in tonifying the lung and kidney. It has started to be used in the adjuvant treatment of silicosis. This work aimed to verify the protective effects of FCP against silicosis, and to explore the related mechanism., Methods: Wistar rats were randomly divided into four groups including the saline-instilled group, the silica-exposed group, the silica + FCP (300 mg/kg) group and the silica + FCP (600 mg/kg) group. Silicosis rat models were constructed by intratracheal instillation of silica (50 mg). Rats in the FCP intervention groups received the corresponding dose of FCP daily by intragastric gavage. Rats were sacrificed on days 7, 28 and 56 after treatment, then samples were collected for further analysis., Results: FCP intervention reduced the infiltration of inflammatory cells and the concentration of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) at days 7, 28, 56, and decreased the expression of collagen, α-smooth muscle actin (α-SMA) and fibronectin (FN) at days 28 and 56 in the lung of silicosis rats. FCP also decreased the immune response of Th1 and Th17 at days 7, 28, 56 and inhibited the enhancement of the Th2 response at day 56., Conclusions: FCP intervention could alleviate silica-induced pulmonary inflammation and fibrosis, the protective effect may be achieved by reducing Th1 and Th17 immune responses and inhibiting the enhancement of the Th2 response., (© 2023. International Society for Chinese Medicine and BioMed Central Ltd.)

Background: Whether the mechanism of thyroid papillary carcinoma (PTC) is the same in patients with a Hashimoto's thyroiditis (HT) background as compared with patients with a normal background remains a highly debated and controversial issue. In this study, we aimed to analyze the differences and similarities of the metabolic mechanism of PTC in normal and HT background, and to explore the relationship between HT and PTC., Methods: The ultra performance liquid chromatography-quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF/MS) technology was used to analyze 61 PTC patient tissues (31 HT background and 30 normal tissue (NC) background). Potential biomarkers were screened from principal component analysis (PCA) to orthogonal partial least square (OPLS) discriminant analysis. HMDB was searched to identify potential differential metabolites and final metabolic pathway analysis was performed by MetaboAnalyst 5.0. We analyzed the differential metabolites diagnostic accuracy through receiver operating characteristic (ROC) curves analysis., Results: Seven different metabolites were screened from HT group and NC group, including arginine, glutamic acid, cysteine, citric acid, malic acid, uracil and taurine. Logistic regression model combined with ROC analysis of these 7 biomarkers had good discriminability for PTC (area under operating characteristic curve of HT group and NC group were 0.867 and 0.973, respectively). The HT group had specific metabolic pathways, including aminoacyl-tRNA biosynthesis, glycine, serine and threonine metabolism., Conclusions: The metabolic profiles of the NC and HT groups had important similarities and differences in PTC. The correlation of PTC with HT may be related to aminoacyl-tRNA biosynthesis, serine and threonine metabolism., 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., (© 2023 The Authors.)