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Invasive Microelectrode Arrays (MEAs) have been a significant and useful tool for us to gain a fundamental understanding of how the brain works through high spatiotemporal resolution neuron-level recordings and/or stimulations. Through decades of research, various types of microwire, silicon, and flexible substrate-based MEAs have been developed using the evolving new materials, novel design concepts, and cutting-edge advanced manufacturing capabilities. Surgical implantation of the latest minimal damaging flexible MEAs through the hard-to-penetrate brain membranes introduces new challenges and thus the development of implantation strategies and instruments for the latest MEAs. In this paper, studies on the design considerations and enabling manufacturing processes of various invasive MEAs as in vivo brain-machine interfaces have been reviewed to facilitate the development as well as the state-of-art of such brain-machine interfaces from an engineering perspective. The challenges and solution strategies developed for surgically implanting such interfaces into the brain have also been evaluated and summarized. Finally, the research gaps have been identified in the design, manufacturing, and implantation perspectives, and future research prospects in invasive MEA development have been proposed., Competing Interests: Declaration of 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.

Background: Anemia frequently occurs in patients with hip fractures and represents a risk factor that can potentially be altered. To evaluate the association between admission anemia and complications in older hip fracture patients while exploring the potential impact of anemia on complications from the perspective of overall, operation and non-operation., Methods: This retrospective study enrolled in-patients over 60 years old with hip fractures from January 2020 to November 2023. At admission, anemic patients were identified as having a hemoglobin level below 12 g/dL in females and 13 g/dL in males. Anemia was further classified as mild, moderate, or severe. Data encompassing demographics, comorbidities, medications, information on fracture and surgery, and complications were collected., Results: A total of 462/679 patients had anemia, including 348, 105, and 9 with mild, moderate, and severe anemia, respectively. A total of 281 individuals experienced complications, including 212 and 69 with and without operation, respectively. Multivariate regression analysis identified anemia as a greater risk for acute heart failure (OR = 2.056, p = 0.037, 95% CI 1.043-4.052) than non-anemia. Moderate to severe anemia was a significant risk factor for any complication (OR = 1.584, p = 0.028, 95% CI 1.050-2.390), ≥ 2 (OR = 2.364, p = 0.001, 95% CI 1.443-3.872) or 3 (OR = 2.311, p = 0.022, 95% CI 1.131-4.720) complications, delirium (OR = 2.301, p = 0.018, 95% CI 1.156-4.579), venous thromboembolism (OR = 2.031, p = 0.042, 95% CI 1.025-4.025), and acute heart failure (OR = 2.095, p = 0.016, 95% CI 1.145-3.834), compared with mild to non-anemia. Similar results were observed in operated patients, while anemia and its severity were not associated with complications in non-operated patients., Conclusion: Moderate to severe anemia caused complications in elderly hip fracture patients, but it was not observed in non-operated individuals. These findings would support orthopedic physicians' hierarchical management of anemic patients., (© 2024. The Author(s).)

An enantioselective Mannich reaction with cyclic N -sulfonyl ketimines as the nucleophiles was developed. In the presence of 5 mol % chiral thiourea catalyst C11 , the asymmetric Mannich reaction between cyclic N -sulfonyl ketimines and isatin-derived ketimines was achieved in high yields and good-to-excellent enantioselectivities (84-99% yields with 75-99.8% ee). This methodology provided an effective route to construct chiral 3-amino-2-oxindoles containing a cyclic N -sulfonyl ketimine scaffold. The initial biological evaluation of the products in cell-based assays demonstrated that some compounds have excellent antiproliferative activity against human osteosarcoma cells.

DNA circuits are important fundamental tools for performing temporal logic operations with complex structures, but they lack sequence orthogonality. Here, we developed a simple and orthogonal hairpin exonuclease assistance signal (H-EAST) architecture to construct DNA domino circuits with time-delay characteristics and temporal logic operations, which has potential applications in biomolecular computing.

Porcine respiratory and reproductive syndrome (PRRS) is one of the most devastating infectious diseases of pigs, causing reproductive failures in sows and severe respiratory symptoms in piglets and growing pigs. MicroRNAs (miRNAs) are reported to play an essential role in virus-host interactions. In this study, we demonstrated that miR-451 enhanced type I interferon (IFN-I) production through targeting proteasome subunit β8 (PSMB8), therefore restricting PRRS virus (PRRSV) replication. We showed that the expression of PSMB8 was upregulated by PRRSV infection, and knockdown of PSMB8 inhibited PRRSV replication by promoting IFN-I production. Moreover, we demonstrated that PSMB8 interacted with the regulatory domain of IRF3 to mediate K48-linked polyubiquitination and degradation of IRF3. Also, importantly, we showed that PSMB8, as a target gene of miR-451, negatively regulated IFN-I production by promoting IRF3 degradation, which is a previously unknown mechanism for PSMB8 to modulate innate immune responses., Importance: Porcine respiratory and reproductive syndrome virus (PRRSV), as a huge threat to the swine industry, is a causative agent that urgently needs to be solved. The dissecting of PRRSV pathogenesis and understanding of the host-pathogen interaction will provide insights into developing effective anti-PRRSV strategies. In this study, we showed that miR-451 dramatically inhibited PRRSV replication by targeting proteasome subunit β8 (PSMB8), a subunit of the immunoproteasome. Mutation of PSMB8 is often related to autoinflammatory diseases due to the elevated IFN production. We revealed that PSMB8 downregulated IFN production by promoting IRF3 degradation. In addition, we showed that PRRSV infection upregulated PSMB8 expression. Taken together, our findings reveal that miR-451 is a negative regulator of PRRSV replication, and PSMB8, a target gene of miR-451, negatively regulates IFN-I production by promoting IRF3 degradation, which is a previously unknown mechanism for PSMB8 to regulate innate immune responses., Competing Interests: The authors declare no conflict of interest.

The HIV/AIDS epidemic in China is severe and complex. Comprehensive spatiotemporal analysis provides valuable insights for intervention policy formulation. Previous studies often overlooked local changes in time trends and regional disease development patterns. In this study, we propose a new spatiotemporal analysis method based on the Joinpoint Regression (JPR) model and K-means clustering to refine the division of stages in China's AIDS epidemic and differentiate geographical areas based on development patterns. We then use hotspot analysis to describe the current status of AIDS, presenting a comprehensive view of the epidemic in China from 2004 to 2018. JPR results show China's AIDS incidence generally increased during 2004-2018 (AAPC = 23.2), with a significant turning point in 2012. Time series feature clustering classifies the country into three regions: Southwest, Central and Eastern, and the other region. Each region corresponds to different epidemic causes and transmission pathways, informing targeted interventions. Hotspot analysis reveals the Southwest region as the most severely affected area, requiring intensified prevention and control efforts. This study offers a novel from both time and space dimensions for understanding and combating the AIDS epidemic, furnishing valuable references for policymakers in the further development of strategies., 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.)

Conductive hydrogels have been increasingly employed to construct wearable mechanosensors due to their excellent mechanical flexibility close to that of soft tissues. In this work, piezoelectric hydrogels are prepared through free radical copolymerization of acrylamide (AM) and acrylonitrile (AN) and further utilized in assembling flexible wearable mechanosensors. Introduction of the polyacrylonitrile (PAN) component in the copolymers endows the hydrogels with excellent piezoelectric properties. Meanwhile, significant enhancement of mechanical properties has been accessed by forming dipole-dipole interactions, which results in a tensile strength of 0.51 MPa. Flexible wearable mechanosensors are fabricated by utilizing piezoelectric hydrogels as key signal converting materials. Self-powered piezoelectric pressure sensors are assembled with a sensitivity ( S ) of 0.2 V kPa -1 . Additionally, resistive strain sensors (gauge factor (GF): 0.84, strain range: 0-250%) and capacitive pressure sensors ( S : 0.23 kPa -1 , pressure range: 0-8 kPa) are fabricated by utilizing such hydrogels. These flexible wearable mechanosensors can monitor diverse body movements such as joint bending, walking, running, and stair climbing. This work is anticipated to offer promising soft materials for efficient mechanical-to-electrical signal conversion and provides new insights into the development of various wearable mechanosensors.

Heart failure (HF) is still the main cause of mortality worldwide. This study investigated the characteristics of human pericardial fluid-derived cells (hPFCs) and their effects in treating doxorubicin (DOX)-induced HF rats through intrapericardial injection. hPFCs were isolated from patients who underwent heart transplantation ( N = 5). These cells that primarily expressed SCA-1, NANOG, and mesenchymal markers, CD90, CD105, and CD73, were able to form adipocytes, osteoblasts, and cardiomyocytes in vitro. Passage 3 hPFCs (2.5 × 10 5 cells/heart) were injected into the pericardial cavity of the DOX-injured rat hearts, significantly improving cardiac functions after 4 weeks. The tracked and engrafted red fluorescent protein-tagged hPFCs coexpressed cardiac troponin T and connexin 43 after 4 weeks in the host myocardium. This observation was also coupled with a significant reduction in cardiac fibrosis following hPFC treatment (P < 0.0001 vs. untreated). The elevated inflammatory cytokines interleukin (IL)-6, IL-10, and tumor necrosis factor-α in the DOX-treated hearts were found to be significantly reduced ( P < 0.001 vs. untreated), while the regional proangiogenic vascular endothelial growth factor A (VEGFA) level was increased in the hPFC-treated group after 4 weeks ( P < 0.05 vs. untreated). hPFCs possess stem cell characteristics and can improve the cardiac functions of DOX-induced HF rats after 4 weeks through pericardial administration. The improvements were attributed to a significant reduction in cardiac fibrosis, inflammation, and elevated regional proangiogenesis factor VEGFA, with evidence of cellular engraftment and differentiation in the host myocardium.

Previous studies have suggested that cancer-associated fibroblasts (CAFs) within the tumor microenvironment are a critical factor in tumorigenesis and tumor development. However, the regulatory mechanisms of CAFs on oral squamous cell carcinoma (OSCC) are poorly defined. A CAF-conditioned medium (CAF-CM) was collected and applied to culture OSCC cells. Then, cell viability, proliferation, migration, and invasion were evaluated using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), Transwell, and scratch healing assays. T-Lymphoma Invasion and Metastasis 1 (TIAM1), zinc finger E-box-binding homeobox 2 (ZEB2), E-cadherin, and increased N-cadherin protein levels were determined using western blot. TIAM1 and ZEB2 mRNA levels were measured using real-time quantitative polymerase chain reaction (RT-qPCR). Their interaction was analyzed using Co-immunoprecipitation (Co-IP) assay. SCC25 cells with or without (TIAM1-silencing) CAFs were subcutaneously inoculated in nude mice to assess the effect of TIAM1 in CAFs on OSCC tumor growth in vivo. CAFs expedited OSCC cell proliferation, migration, invasion, and EMT. TIAM1 and ZEB2 expression were upregulated in OSCC patients and OSCC cells, and the TIAM1 level was much higher in CAFs than in OSCC cells. Furthermore, TIAM1 knockdown in CAFs might partly abolish the promotion of CAFs on OSCC cell development, implying that TIAM1 might be secreted by CAFs into the culture medium to exert its effects inside OSCCs. TIAM1 might increase ZEB2 expression, and ZEB2 upregulation might partly reverse the repression of TIAM1 silencing in CAFs on OSCC cell malignant behaviors. In vivo studies confirmed that CAFs accelerated OSCC tumor growth, these effects were partially counteracted by TIAM1 downregulation. Overall, TIAM1 secreted by CAFs could expedite OSCC cell growth and metastasis by regulating ZEB2, providing a promising therapeutic target for OSCC treatment., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: There are few studies about the differences in the composition of moisture, ash, crude protein, crude fat, crude polysaccharide and ergothioneine in Ganoderma lucidum spore powder (GLSP) from different origins. As for GLSP after oil extraction (OE-GLSP), there are still lots of bioactive substance in it. It can be seen that OE-GLSP has certain biological activity. The effect of OE-GLSP on the improvement of intestinal barrier function has been less studied., Results: The results showed that there were significant differences for GLSP from five different origins (Anhui, Jilin, Jiangxi, Shandong and Zhejiang) in moisture (0.065-0.113%), ash (0.603-0.955%), crude fat (42.444-44.773%), crude polysaccharide (2.977-4.127%), crude protein (14.761-17.639%) and ergothioneine (0.552-1.816 mg g -1 ) (P < 0.05). The monosaccharides of GLSP polysaccharide mainly consist of glucose, galactose, mannose, rhamnose, etc. Moreover, the effects of OE-GLSP supplementation on the regulation of organ index, colonic tissue and intestinal microbiota in C57BL/6J mice were investigated. The supplement of OE-GLSP could restore the organ index and weight loss of antibiotic-treated mice. Moreover, OE-GLSP led to the improvement of intestinal dysbiosis by enriching Bacteroidetes, Firmicutes, Lactobacillus and Roseburia, and increasing the Firmicutes/Bacteroidetes ratio. In addition, OE-GLSP intervention repaired intestinal barrier dysfunction by increasing the expression of tight junction proteins (Occludin, Claudin-1 and E-cadherin)., Conclusion: Different GLSP from five origins exhibited significant differences in microstructure and contents of crude polysaccharide, crude protein, crude fat, water, ash and ergothioneine. Moreover, it was found that OE-GLSP could improve the intestinal barrier function and induce potentially beneficial changes in intestinal flora. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

The examination of the characteristic law of traditional village transformation over time represents a vital nexus in cultural heritage preservation and the transmission of vernacular culture. Historical event points were used to augment village development information, facilitating the restoration of the village's historical pattern. Geographical analysis methods, including Standard Deviation Ellipse Analysis (SDSEA), Nearest Neighbor Analysis (NNA), and Source-Destination Analysis (SDA), were employed to explore the characteristics of the village's geographical center of gravity, changes in concentration and dispersion, and functional transfer. The stepwise progression of the village's evolution was investigated, as well as the mechanism of residents' behavior during the evolution process. The results reveal: 1) The spatial evolution of the settlement shows a trend of agglomeration. As time passes, the center of gravity of each functional space gradually converges, and the average distance between elements decreases, resulting in a shift from a dispersed to a clustered distribution. 2) The village space changes from simple to complex due to the conduct of the villagers. Residential behaviors promote the establishment of residential space and the development of public and commercial space. The usage, abandonment, and functional transitions that occur inside the space cause functional zones to nest with each other, resulting in a more intricate spatial structure. 3) Both the degree of change and the preservation of the village's functional space show an increasing trend, indicating that the protection of the built space and the expansion of the unbuilt space occur simultaneously. This represents a developmental trend that is consistent with the social surroundings and the villagers' ambitions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Deng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Postmenopausal osteoporosis (PMO) is a common disease associated with aging, and estrogen deficiency is considered to be the main cause of PMO. Recently, however, osteoimmunology has been revealed to be closely related to PMO. On the one hand, estrogen deficiency directly affects the activity of bone cells (osteoblasts, osteoclasts, osteocytes). On the other hand, estrogen deficiency-mediated osteoimmunity also plays a crucial role in bone loss in PMO. In this review, we systematically describe the progress of the mechanisms of bone loss in PMO, estrogen deficiency-mediated osteoimmunity, the differences between PMO patients and postmenopausal populations without osteoporosis, and estrogen deficiency-mediated immune cells (T cells, B cells, macrophages, neutrophils, dendritic cells, and mast cells) activity. The comprehensive summary of this paper provides a clear knowledge context for future research on the mechanism of PMO bone loss., (© 2024 Wiley Periodicals LLC.)

Copper is one of the common among the heavy metal pollution in Chinese herbal medicine (CHM). So, it is essential to develop rapid and accurate testing method to quantify the Cu 2+ content in CHM. Herein, we prepared a coordination-based near-infrared fluorescent probe (NRh6G-FA) by introducing a hemicyanine dye in rhodamine 6G scaffold. NRh6G-FA had a high sensitivity, anti-interference performance, fast response (within 60 s), visualization (from light yellow to green) for Cu 2+ and excellent sensing performance for the detection of Cu 2+ at low concentrations (LOD = 0.225 μM). The most likely mechanism was verified on the basis of Job's plot, ESI-HRMS and DFT calculations. NRh6G-FA could be successfully applied for the detection and "naked eye" recognition of Cu 2+ in CHM samples. Moreover, NRh6G-FA was used to visualize Cu 2+ in living MCF-7 cells by confocal fluorescence imaging., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Ginseng, from the roots of Panax ginseng C. A. Meyer, is a widely used herbal medicine in Asian countries, known for its excellent therapeutic properties. The growth of P. ginseng is depend on specific and strict environments, with a preference for wetness but intolerance for flooding. Under excessive soil moisture, some irregular rust-like substances are deposited on the root epidermis, causing ginseng rusty symptoms (GRS). This condition leads to a significant reduce in yield and quality, resulting in substantial economic loses. However, there is less knowledge on the cause of GRS and there are no effective treatments available for its treatment once it occurs. Unsuitable environments lead to the generation of large amounts of reactive oxygen species (ROS). We investigated the key indicators associated with the stress response during different physiological stages of GRS development. We observed a significant change in ROS level, MDA contents, antioxidant enzymes activities, and non-enzymatic antioxidants contents prior to the GRS. Through the analysis of soil features with an abundance of moisture, we further determined the source of ROS. The levels of nitrate reductase (NR) and nitric oxide synthase (NOS) activities in the inter-root soil of ginseng with GRS were significantly elevated compared to those of healthy ginseng. These enzymes boost nitric oxide (NO) levels, which in turn showed a favorable correlation with the GRS. The activities of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase first rose and then decreased as GRS developed. Excess soil moisture causes a decrease in oxygen levels. This activated NR and NOS in the soil, resulting in a production of excess NO. The NO then diffused into the ginseng root and triggered a burst of ROS through NADPH located on the cell membrane. Additionally, Fe 2+ in soil was oxidized to red Fe 3+ , and finally led to GRS. This conclusion was also verified by the Sodium Nitroprusside (SNP), a precursor compound producing NO. The presence of NO from NR and NOS in water-saturated soil is responsible for the generation of ROS. Among these, NO is the main component that contribute to the occurrence of GRS., (© 2024. The Author(s).)

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. Sorafenib (Sf) is currently the first-line treatment for HCC. However, due to the side effects and unsatisfied efficiency of Sf, it is urgent to combine different therapeutic agents to inhibit HCC progression and increase the therapeutic efficacy. Here, our study constructed a Sf and KIAA1199-siRNA co-loaded liposome Sf-Lp-KIAA, which was prepared by electrostatic interaction of KIAA1199-siRNA and Sf loaded liposome (Sf-Lp). The particle size, zeta potential, the in vitro cumulative release was investigated. The physical and chemical properties were characterized, and the inhibition of HepG2 growth and metastasis in vitro was investigated. The cellular uptake of the co-loaded liposome was significantly higher than that of free siRNA, and the drug/siRNA could be co-delivered to the target cells. Sf-Lp-KIAA could significantly inhibit the growth, migration, invasion and down-regulate KIAA1199 expression of HepG2 cells in vitro than that of single Sf treated group. In addition, the co-delivery liposome accumulated in the HepG2 subcutaneous tumor model and suppress tumor growth after systemic administration without induce obvious toxicity. The present study implied that the co-delivery of Sf and KIAA1199-siRNA through the co-loaded liposomes exerted synergistic antitumor effects on HCC, which would lay a foundation for HCC therapy in the future., 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.)

Background: Acute myocardial infarction (AMI) is a leading cause of mortality worldwide, with reduced elastin/collagen ratios exacerbating cardiac dysfunction due to collagen-rich scar tissue replacing necrotic myocardial cells. This study aims to evaluate pirfenidone's therapeutic effect on early cardiac function post-AMI and elucidate its impact on the elastin/collagen ratio., Methods: Sprague-Dawley rats were divided into four groups: Sham, AMI, AMI treated with PBS (AMI-PBS), and AMI treated with pirfenidone (AMI-PFD) (n=12 each). AMI was induced via coronary artery ligation. The AMI-PFD and AMI-PBS groups received pirfenidone and PBS for 14 days, respectively. Cardiac function, fibrosis, serum cytokines, collagen and elastin content, and their ratios were assessed. Cardiac fibroblasts (CFs) from neonatal rats were categorized into control, hypoxia-induced (LO), LO+PBS, and LO+PFD groups. ELISA measured inflammatory factors, and RT-PCR analyzed collagen and elastin gene expression., Results: The AMI-PFD group showed improved cardiac function and reduced serum interleukin-1β (IL-1β), IL-6, and transforming growth factor-β (TGF-β). Type I and III collagen decreased by 22.6 % (P=0.0441) and 34.4 % (P=0.0427), respectively, while elastin content increased by 79.4 % (P=0.0126). E/COLI and E/COLIII ratios rose by 81.1 % (P=0.0026) and 88.1 % (P=0.0006). CFs in the LO+PFD group exhibited decreased IL-1β, IL-6, TGF-β, type I and III collagen, with increased elastin mRNA, enhancing the elastin/collagen ratio., Conclusion: Pirfenidone enhances cardiac function by augmenting the early elastin/collagen ratio post-AMI., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier Masson SAS.)

Although most laminin isoforms are neuroprotective in stroke, mural cell-derived laminin-α5 plays a detrimental role in an ischemia-reperfusion model. To determine whether this deleterious effect is an intrinsic feature of mural cell-derived laminin-α5 or unique to ischemic stroke, we performed loss-of-function studies using middle-aged mice with laminin-α5 deficiency in mural cells (α5-PKO) in an intracerebral hemorrhage (ICH) model. Control and α5-PKO mice exhibited comparable changes in all parameters examined, including hematoma size, neuronal death, neurological function, blood-brain barrier integrity, and reactive gliosis. These findings highlight a minimal role of mural cell-derived laminin-α5 in ICH. Together with the detrimental role of mural cell-derived laminin-α5 in ischemic stroke, these negative results in ICH model suggest that mural cell-derived laminin-α5 may exert distinct functions in different diseases., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: The role of dual-specificity phosphatase-5 (DUSP5) in BRAF-mutant thyroid cancers remains unclear. The aims of this study are to investigate the role of DUSP5 in BRAF-mutant thyroid cancer cells, explore its value in the diagnosis and evaluate therapeutic potential of targeting DUSP5 combined with sorafenib for BRAF-mutant thyroid cancer patients., Methods: The role of DUSP5 in thyroid cancer cells was determined by a series of in vitro and in vivo experiments. Underlying mechanisms were explored by western blotting analysis. The diagnostic value of combination detection of DUSP5 expression and BRAF V600E mutation was evaluated using ROC curve., Results: Knocking down DUSP5 in BRAF-mutant thyroid cancer cells significantly inhibited colony formation, cell migration and invasion, meanwhile, induced cell cycle arrest and cell apoptosis. Moreover, inhibition of DUSP5 improved the anti-tumor efficacy of sorafenib both in vitro and in vivo. Besides, combination detection of DUSP5 expression and BRAF V600E mutation showed much more accuracy in preoperative diagnosis of thyroid cancer., Conclusions: Our data demonstrate an oncogenic role of DUSP5 in BRAF-mutant thyroid cancer cells, and combined analysis of its expression and BRAF V600E mutation can accurately diagnose thyroid cancer. In addition, inhibition of DUSP5 improves the response of BRAF-mutant thyroid cancer cells to sorafenib., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Transdermal drug delivery systems for rheumatoid arthritis (RA) have garnered substantial attention due to their great potential to overcome limitations observed in conventional oral or injection strategies, including limited selectivity and adverse effects on extra-articular tissues. Microneedles (MNs) appear to be highly desirable carriers for transdermal drug delivery of RA. However, microneedles typically are unable to keep up with the flexibility of joints, which decreases the effectiveness of administration. In this study, we developed a flexible microneedles (FMNs) delivery system. And gelatin was employed for the fabrication of flexible backings for microneedles owing to its excellent ductility and biocompatibility. We achieved synergisticphotothermal-chemotherapy of RA by incorporating the chemical drug Tacrolimus (TAC) and the photothermal agent gold nanorods (AuNRs) into dissolving microneedles. Results showed a high mechanical strength of the proposed FMNs. In the animal model of adjuvant-induced arthritis (AA), it is indicated that the prepared FMNs inhibited the expression of related inflammatory cytokines such as IL-1ß and TNF-α while enhancing bone repair and other related factors. Thus, the combination therapy of FMNs-mediated hyperthermia and chemotherapy can serve as a novel and synergistic treatment option for RA., 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.)

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of β-amyloid (Aβ) plaques and neurofibrillary tangles composed of tau protein in the brain. These neuropathological hallmarks contribute to cognitive impairment by inducing neuronal loss in the cerebral cortex and hippocampus. Unfortunately, current therapeutic approaches only target symptomatic relief and do not impede disease progression. Nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD + ), has emerged as a promising candidate for the treatment of age-related neurodegenerative disorders. NMN supplementation could restore NAD + levels, thereby alleviating neuronal damage and slowing the progression of AD and other aging-associated diseases. AD is closely associated with autophagic impairment and oxidative stress. Our in vivo experiments demonstrated that NMN could ameliorate pathological and behavioral impairments in AD mice. Specifically, NMN enhanced autophagy and promoted p-tau clearance. Meanwhile, NMN could activate the Nrf2/Keap1/NQO1 pathway, thereby reducing the oxidative stress. Immunofluorescence results demonstrated that NMN could alleviate neuronal damage in AD mice. Furthermore, in vitro results showed that the p-tau clearance and antioxidant stress effects of NMN were suppressed by autophagy inhibitor, chloroquine (CQ) or bafilomycin A1 (BafA1), in Aβ-induced PC12 cells. Lastly, when Nrf2 was knocked down, the antioxidant stress, autophagy enhancement, and p-tau clearance effects of NMN were all inhibited. In conclusion, our research indicates that NMN exerts therapeutic effect against AD by activating autophagy and the Nrf2/Keap1/NQO1 pathway through a mutual regulating mechanism of autophagy and antioxidative stress. These findings highlight the promising potential of NMN for the treatment of AD., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people organizations that can inappropriately influence our work, there is no professional other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: A major challenge faced by patients with rare diseases (RDs) often stems from delays in diagnosis, typically due to nonspecific clinical symptoms or doctors' limited experience in connecting symptoms to the underlying RD. Using patient-oriented questionnaires (POQs) as a data source for machine learning (ML) techniques can serve as a potential solution. These questionnaires enable patients to portray their day-to-day experiences living with their condition, irrespective of clinical symptoms. This systematic review-registered at PROSPERO with the Registration-ID: CRD42023490838-aims to present the current state of research in this domain by conducting a systematic literature search and identifying the potentials and limitations of this methodology. Methods: The review adheres to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was primarily funded by the German Federal Ministry of Education and Research under grant no. 16DHBKI056 (ki4all). The methodology involved a systematic search across the databases PubMed, Semantic Scholar and Google Scholar, covering articles published until June 2023. The inclusion criteria encompass examining the use of POQs in diagnosing rare and common diseases. Additionally, studies that focused on applying ML techniques to the resulting datasets were considered for inclusion. The primary objective was to include English as well as German research that involved the generation of predictions regarding the underlying disease based on the information gathered from POQs. Furthermore, studies exploring identifying predictive indicators associated with the underlying disease were also included in the literature review. The following data were extracted from the selected studies: year of publication, number of questions in the POQs, answer scale in the questionnaires, the ML algorithms used, the input data for the ML algorithms, the performance of these algorithms and how the performance was measured. In addition, information on the development of the questionnaires was recorded. Results: This search retrieved 421 results in total. After one superficial and two comprehensive screening runs performed by two authors independently, we ended up with 26 studies for further consideration. Sixteen of these studies deal with diseases and ML algorithms to analyse data; the other ten studies provide contributing research in this field. We discuss several potentials and limitations of the evaluated approach. Conclusions: Overall, the results show that the full potential has not yet been exploited and that further research in this direction is worthwhile, because the study results show that ML algorithms can achieve promising results on POQ data; however, their use in everyday medical practice has not yet been investigated.

Crack-based flexible strain sensors with ultra-high sensitivity under tiny strain are highly desired for environmental perception and motion detection of novel flexible and miniature robots. However, previously reported methods for fabricating crack patterns have often sacrificed the cyclic stability of the sensor, leading to a trade-off relationship between the sensitivity and the cyclic stability. Here, a universal and simple strategy based on fatigue loading with an ultra-large cumulative strain of up to ∼1.2 × 10 7 %, rather than the traditionally quasi-static pre-overloading methods, is proposed to introduce channel cracks in the sensing layer without sacrificing the cyclic stability. The developed flexible strain sensors exhibit high strain-sensitivity (gauge factor = 5798) under tiny strain (< 3%), high cyclic stability (15 000 cycles) and a low strain detecting limit (0.02%). Furthermore, a leaf-like mechanosensor is developed using the fatigue crack-based strain sensor for the realization of multifunctional applications in environment perception and micro-motion detection. Brilliant airflow sensing performance with a wide sensing range (0.93-11.93 m s -1 ) and a fast response time (0.28 s) for amphibious applications is demonstrated. This work provides a new strategy for overcoming limits of crack-based flexible strain sensors and the developed leaf-like mechanosensor shows great application potential in miniature and flexible reconnaissance robots.

Solar-driven water-electricity cogeneration is a promising strategy for tackling water scarcity and power shortages. However, comprehensive reviews on performance, scalability, commercialization, and power density are lacking. This Perspective presents an overview of recent developments and insights into the challenges and future outlooks for practical applications in this area. We summarize recent advances in high-efficiency water production, focusing on rapid evaporation and condensation. Then we categorize power-water cogeneration systems by power generation mechanisms like steam, evaporation, salinity gradient, photovoltaics, and temperature gradient, providing a comprehensive summary of the performance and applicability of these systems in different scenarios. Finally, we highlight challenges in current systems, considering nanoscale mechanisms and large-scale manufacturing, while also exploring potential trends for future practical applications.

A predictive model utilizing near-infrared spectroscopy was developed to estimate the loss on drying, total contents of crocin I and crocin II, and picrocrocin content of saffron. Initially, the LD values were determined using a moisture-ash analyzer, while HPLC was employed for measuring the total contents of crocin I, crocin II, and picrocrocin. The near-infrared spectra of 928 saffron samples were collected and preprocessed using first derivative, standard normal variable transformation, detrended correction, multivariate scattering correction, Savitzky-Golay smoothing, and mean centering methods. Leveraging the partial least squares method, regression models were constructed, with parameters optimized through a selective combination of the above six preprocessing methods. Subsequently, prediction models for loss on drying, total contents of crocin I and crocin II, and picrocrocin content were established, and the prediction accuracy of the models was verified. The correlation coefficients and root mean square error of loss on drying, total contents of crocin I and crocin II, and picrocrocin content demonstrated high accuracy, with R 2 values of 0.8627, 0.8851, and 0.8592 and root mean square error values of 0.0260, 0.0682, and 0.0465. This near-infrared prediction model established in the present study offers a precise and efficient means of assessing loss on drying, total contents of crocin I and crocin II, and picrocrocin content in saffron and is useful for the development of a rapid quality evaluation system.

Objectives: STAT3 is a transcriptional activator of breast cancer oncogenes, suggesting that it could be a potential therapeutic target for breast cancer. Therefore, this study investigated the potential application of C188-9, a STAT3 signal pathway inhibitor, in the treatment of breast cancer through a novel pre-clinical platform with patient-specific primary cells (PSPCs)., Methods: PSPCs were isolated from breast cancer samples obtained via biopsy or surgery from fifteen patient donors with their full acknowledgements. PSPCs were treated with C188-9 or other chemotherapeutic agents, and then analyzed with cell viability assay. Western blot assay and real-time quantitative PCR were also used to determine the expression and activity of STAT3 signaling pathway of corresponding PSPCs., Results: C188-9 treatment at normal (experimental) concentration had valid inhibition on PSPCs proliferation. Meanwhile, treatment at a low (clinic-relevant) concentration of C188-9 for an extended period reduced cell viability of PSPCs still more than some of other traditional chemotherapy drugs. In addition, C188-9 decreased expression level of pSTAT3 in PSPCs from some, but not all patient samples. The treatment of C188-9 reduced cell viability of the breast cancer samples through inhibiting the STAT3 to C-myc signaling pathway., Conclusions: In this study, we tested a novel drug C188-9 at a low, clinic-relevant concentration, together with several traditional chemotherapy agents. PSPCs from ten out of fifteen patient donors were sensitive to C188-9, while some of traditional chemotherapy agents failed. This finding suggested that C188-9 could have treatment effects only on those ten PSPC patient donors, indicating the future personalized utilization of PSPCs., (© 2024. The Author(s).)

Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents.

Flavors and fragrances (F&F) are interesting organic compounds in chemistry. These compounds are widely used in the food, cosmetic, and medical industries. Enzymatic synthesis exhibits several advantages over natural extraction and chemical preparation, including a high yield, stable quality, mildness, and environmental friendliness. To date, many oxidoreductases and hydrolases have been used to biosynthesize F&F. Ene-reductases (ERs) are a class of biocatalysts that can catalyze the asymmetric reduction of α,β -unsaturated compounds and offer superior specificity and selectivity; therefore, ERs have been increasingly considered an ideal alternative to their chemical counterparts. This review summarizes the research progress on the use of ERs in F&F synthesis over the past 20 years, including the achievements of various scholars, the differences and similarities among the findings, and the discussions of future research trends related to ERs. We hope this review can inspire researchers to promote the development of biotechnology in the F&F industry.

Untargeted metabolomic analysis using mass spectrometry provides comprehensive metabolic profiling, but its medical application faces challenges of complex data processing, high inter-batch variability, and unidentified metabolites. Here, we present DeepMSProfiler, an explainable deep-learning-based method, enabling end-to-end analysis on raw metabolic signals with output of high accuracy and reliability. Using cross-hospital 859 human serum samples from lung adenocarcinoma, benign lung nodules, and healthy individuals, DeepMSProfiler successfully differentiates the metabolomic profiles of different groups (AUC 0.99) and detects early-stage lung adenocarcinoma (accuracy 0.961). Model flow and ablation experiments demonstrate that DeepMSProfiler overcomes inter-hospital variability and effects of unknown metabolites signals. Our ensemble strategy removes background-category phenomena in multi-classification deep-learning models, and the novel interpretability enables direct access to disease-related metabolite-protein networks. Further applying to lipid metabolomic data unveils correlations of important metabolites and proteins. Overall, DeepMSProfiler offers a straightforward and reliable method for disease diagnosis and mechanism discovery, enhancing its broad applicability., (© 2024. The Author(s).)

Aim: To investigate the effects of fibrillin-1 (FBN1) deletion on the integrity of retina-blood barrier function and the apoptosis of vascular endothelial cells under diabetic conditions., Methods: Streptozotocin (STZ)-induced diabetic mice were used to simulate the diabetic conditions of diabetic retinopathy (DR) patients, and FBN1 expression was detected in retinas from STZ-diabetic mice and controls. In the Gene Expression Omnibus (GEO) database, the GSE60436 dataset was selected to analyze FBN1 expressions in fibrovascular membranes from DR patients. Using lentivirus to knock down FBN1 levels, vascular leakage and endothelial barrier integrity were detected by Evans blue vascular permeability assay, fluorescein fundus angiography (FFA) and immunofluorescence labeled with tight junction marker in vivo . High glucose-induced monkey retinal vascular endothelial cells (RF/6A) were used to investigate effects of FBN1 on the cells in vitro . The vascular endothelial barrier integrity and apoptosis were detected by trans-endothelial electrical resistance (TEER) assay and flow cytometry, respectively., Results: FBN1 mRNA expression was increased in retinas of STZ-induced diabetic mice and fibrovascular membranes of DR patients (GSE60436 datasets) using RNA-seq approach. Besides, knocking down of FBN1 by lentivirus intravitreal injection significantly inhibited the vascular leakage compared to STZ-DR group by Evans blue vascular permeability assay and FFA detection. Expressions of tight junction markers in STZ-DR mouse retinas were lower than those in the control group, and knocking down of FBN1 increased the tight junction levels. In vitro , 30 mmol/L glucose could significantly inhibit viability of RF/6A cells, and FBN1 mRNA expression was increased under 30 mmol/L glucose stimulation. Down-regulation of FBN1 reduced high glucose (HG)-stimulated retinal microvascular endothelial cell permeability, increased TEER, and inhibited RF/6A cell apoptosis in vitro ., Conclusion: The expression level of FBN1 increases in retinas and vascular endothelial cells under diabetic conditions. Down-regulation of FBN1 protects the retina of early diabetic rats from retina-blood barrier damage, reduce vascular leakage, cell apoptosis, and maintain vascular endothelial cell barrier function., Competing Interests: Conflicts of Interest: Zhang Y, None; Liu XJ, None; Zhai XR, None; Yao Y, None; Shao B, None; Zhen YH, None; Zhang X, None; Xiao Z, None; Wang LF, None; Zhang ML, None; Chen ZM, None., (International Journal of Ophthalmology Press.)

Background: The failure of proper recognition of the intricate nature of pathophysiology in colorectal cancer (CRC) has a substantial effect on the progress of developing novel medications and targeted therapy approaches. Imbalances in the processes of lipid oxidation and biosynthesis of fatty acids are significant risk factors for the development of CRC. Therapeutic intervention that specifically targets the peroxisome proliferator-activated receptor gamma (PPARγ) and its downstream response element, in response to lipid metabolism, has been found to promote the growth of tumors and has shown significant clinical advantages in cancer patients., Methods: Clinical CRC samples and extensive in vitro and in vivo experiments were carried out to determine the role of ZDHHC6 and its downstream targets via a series of biochemical assays, molecular analysis approaches and lipid metabolomics assay, etc. RESULTS: To study the effect of ZDHHC6 on the progression of CRC and identify whether ZDHHC6 is a palmitoyltransferase that regulates fatty acid synthesis, which directly palmitoylates and stabilizes PPARγ, and this stabilization in turn activates the ACLY transcription-related metabolic pathway. In this study, we demonstrate that PPARγ undergoes palmitoylation in its DNA binding domain (DBD) section. This lipid-related modification enhances the stability of PPARγ protein by preventing its destabilization. As a result, palmitoylated PPARγ inhibits its degradation induced by the lysosome and facilitates its translocation into the nucleus. In addition, we have identified zinc finger-aspartate-histidine-cysteine 6 (ZDHHC6) as a crucial controller of fatty acid biosynthesis. ZDHHC6 directly interacts with and adds palmitoyl groups to stabilize PPARγ at the Cys-313 site within the DBD domain of PPARγ. Consequently, this palmitoylation leads to an increase in the expression of ATP citrate lyase (ACLY). Furthermore, our findings reveals that ZDHHC6 actively stimulates the production of fatty acids and plays a role in the development of colorectal cancer. However, we have observed a significant reduction in the cancer-causing effects when the expression of ZDHHC6 is inhibited in in vivo trials. Significantly, in CRC, there is a strong positive correlation between the high expression of ZDHHC6 and the expression of PPARγ. Moreover, this high expression of ZDHHC6 is connected with the severity of CRC and is indicative of a poor prognosis., Conclusions: We have discovered a mechanism in which lipid biosynthesis is controlled by ZDHHC6 and includes the signaling of PPARγ-ACLY in the advancement of CRC. This finding provides a justification for targeting lipid synthesis by blocking ZDHHC6 as a potential therapeutic approach., (© 2024. The Author(s).)

Anaerobic ammonium oxidation (anammox), an energy-efficient deamination biotechnology, faces operational challenges in low-temperature environments. Enhancing the metabolic activity of anammox bacteria (AnAOB) is pivotal for advancing its application in mainstream municipal wastewater treatment. Inspired by the metabolic adaptability of AnAOB and based on our previous findings, this work investigated the enhancement of intracellular ATP and NADH synthesis through the exogenous supply of reduced humic acid (HA red ) and H 2 O 2 redox couple, aiming to augment AnAOB activity under low-temperature conditions. Our experimental setup involved continuous dosing of 0.0067 μmol g -1 volatile suspended solid of H 2 O 2 and 10 mg g -1 volatile suspended solid of HA red into a mainstream anammox reactor operated at 15 °C with an influent TN content of 60 mg/L. The results showed that HA red / H 2 O 2 couple succeeded in maintaining the effluent TN at 10.72 ± 0.91 mg l -1 . The specific anammox activity, ATP and NADH synthesis levels of sludge increased by 1.34, 2.33 and 6.50 folds, respectively, over the control setup devoid of the redox couple. High-throughput sequencing analysis revealed that the relative abundance of Candidatus Kuenenia after adding HA red / H 2 O 2 couple reached 3.65 % at the end of operation, which was 5.14 folds higher than that of the control group. Further metabolomics analysis underscored an activation in the metabolism of amino acids, nucleotides, and phospholipids, which collectively enhanced the availability of ATP and NADH for the respiratory processes. These findings may provide guidance on strategy development for improving the electron transfer efficiency of AnAOB and underscore the potential of using redox couples to promote the mainstream application of anammox technology., 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.)

Porcine epidemic diarrhea virus (PEDV) is an enteropathogenic coronavirus that causes substantial economic loss to the global pig industry. The emergence of PEDV variants has increased the need for new vaccines, as commercial vaccines confer inferior protection against currently circulating strains. It is well established that the induction of mucosal immunity is crucial for PEDV vaccines to provide better protection against PEDV infection. In this study, we constructed a recombinant adenovirus expressing the core neutralization epitope (COE) of G2b PEDV based on human adenovirus serotype 5 (Ad5). We evaluated the effects of different administration routes and doses of vaccine immunogenicity in Balb/c mice. Both intramuscular (IM) and intranasal (IN) administration elicited significant humoral responses, including COE-specific IgG in serum and mucosal secretions, along with serum-neutralizing antibodies. Moreover, IN delivery was more potent than IM in stimulating IgA in serum and mucosal samples and in dampening the immune response to the Ad5 vector. The immune response was stronger after high versus low dose IM injection, whereas no significant difference was observed between high and low IN doses. In summary, our findings provide important insights for developing novel PEDV vaccines.IMPORTANCEPorcine epidemic diarrhea (PED) is a highly contagious disease that has severe economic implications for the pork industry. Developing an effective vaccine against PEDV remains a necessity. Here, we generated a recombinant adenovirus vaccine based on Ad5 to express the COE protein of PEDV (rAd5-PEDV-COE) and systematically evaluated the immunogenicity of the adenovirus-vectored vaccine using different administration routes (intramuscular and intranasal) and doses in a mouse model. Our results show that rAd5-PEDV-COE induced potent systemic humoral response regardless of the dose or immunization route. Notably, intranasal delivery was superior to induce peripheral and mucosal IgA antibodies compared with intramuscular injection. Our data provide valuable insights into designing novel PEDV vaccines.

Various isomers have been developed to regulate the morphology and reduce defects in state-of-the-art perovskite solar cells. To insight the structure-function-effect correlations for the isomerization of thiourea derivatives on the performance of the perovskite solar cells (PSCs), we developed two thiourea derivatives [(3,5-dichlorophenyl)amino]thiourea (AT) and N-(3,5-dichlorophenyl)hydrazinecarbothioamide (HB). Supported by experimental and calculated results, it was found that AT can bind with undercoordinated Pb2+ defect through synergistic interaction between N1 and C=S group with a defect formation energy of 1.818 eV, which is much higher than that from the synergistic interaction between two -NH- groups in HB and perovskite (1.015 eV). Moreover, the stronger interaction between AT and Pb2+ regulates the crystallization process of perovskite film to obtain a high-quality perovskite film with high crystallinity, large grain size, and low defect density. Consequently, the AT-treated FACsPbI3 device engenders an efficiency of 25.71% (certified as 24.66%), which is greatly higher than control (23.74%) and HB-treated FACsPbI3 devices (25.05%). The resultant device exhibits a remarkable stability for maintaining 91.0% and 95.2% of its initial efficiency after aging 2000 h in air condition or tracking at maximum power point for 1000 h, respectively., (© 2024 Wiley‐VCH GmbH.)

Abstract: Because multiple myeloma (MM) poses a formidable therapeutic challenge despite recent progress, exploring novel targets is crucial. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) emerges as a promising paracaspase with druggable potential, especially unexplored in MM. Our study provided compelling evidence demonstrating a statistically significant elevation of MALT1 expression in human primary MM cells. Moreover, elevated MALT1 expression was associated with a poorer prognosis in MM. Genetic deletion of MALT1 reduced cell growth, colony formation, and tumor growth in vivo. Pharmacological inhibition with 1 μM of a small-molecular MALT1 inhibitor, Mi-2, effectively inhibited cell growth, inducing mitochondria-dependent apoptotic cell death. Mechanistically, MALT1 inhibition disrupted diverse signal transduction pathways, notably impeding nuclear factor κB (NF-κB). Significantly, the inhibition of MALT1 demonstrated a substantial suppression of NF-κB activation by elevating inhibitor of NF-κB, disrupting the nuclear localization of p65 and c-REL. This effect was observed in both the basal state and when stimulated by B-cell maturation antigen, highlighting the pivotal role of MALT1 inhibition in influencing MM cell survival. It was noteworthy that Mi-2 induces properties associated with immunogenic cell death (ICD), as evidenced by increased calreticulin, adenosine triphosphate release, and high-mobility group protein B1 upregulation, consequently triggering ICD-associated immune activation and enhancing CD8+ T-cell cytotoxicity in vitro. In conclusion, our research highlights MALT1 as a promising druggable target for therapeutic interventions in MM, providing insights into its molecular mechanisms in MM progression., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Abstact: To our knowledge, venetoclax is the first example of personalized medicine for multiple myeloma (MM), with meaningful clinical activity as a monotherapy and in combination in patients with myeloma harboring the t(11:14) translocation. However, despite the high response rates and prolonged progression-free survival, a significant proportion of patients eventually relapse. Here, we aim to study adaptive molecular responses after the acquisition of venetoclax resistance in sensitive t(11:14) MM cell models. We therefore generated single-cell venetoclax-resistant t(11:14) MM cell lines and investigated the mechanisms contributing to resistance as well as the cells' sensitivity to other treatments. Our data suggest that acquired resistance to venetoclax is characterized by reduced mitochondrial priming and changes in B-cell lymphoma-2 (BCL-2) family proteins' expression in MM cells, conferring broad resistance to standard-of-care antimyeloma drugs. However, our results show that the resistant cells are still sensitive to immunotherapeutic treatments, highlighting the need to consider appropriate sequencing of these treatments after venetoclax-based regimens., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Organic self-assembled molecules (OSAMs) based hole-transporting materials play a pivotal role in achieving highly efficient and stable inverted perovskite solar cells (IPSCs). However, the reported carbazol-based OSAMs have serious drawbacks, such as poor wettability for perovskite solution spreading due to the nonpolar surface, worse matched energy arrangement with perovskite, and limited molecular species, which greatly limit the device performance. To address above problems, a novel OSAM [4-(3,6-glycol monomethyl ether-9H-carbazol-9-yl) butyl]phosphonic acid (GM-4PACz) was synthesized as hole-transporting material by introducing glycol monomethyl ether (GM) side chains at carbazolyl unit. GM groups enhance the surface energy of Indium Tin Oxide (ITO)/SAM substrate to facilitate the nucleation and growth of up perovskite film, suppress cation defects, release the residual stress at SAM/perovskite interface, and evaluate energy level for matching with perovskite. Consequently, the GM-4PACz based IPSC achieves a champion PCE of 25.52 %, a respectable open-circuit voltage (V OC ) of 1.21 V, a high stability, possessing 93.29 % and 91.75 % of their initial efficiency after aging in air for 2000 h or tracking at maximum power point for 1000 h, respectively., (© 2024 Wiley-VCH GmbH.)

A new approach to control the n-doping reaction of organic semiconductors is reported using surface-functionalized gold nanoparticles (f-AuNPs) with alkylthiols acting as the catalyst only upon mild thermal activation. To demonstrate the versatility of this methodology, the reaction of the n-type dopant precursor N-DMBI-H with several molecular and polymeric semiconductors at different temperatures with/without f-AuNPs, vis-à-vis the unfunctionalized catalyst AuNPs, was investigated by spectroscopic, morphological, charge transport, and kinetic measurements as well as, computationally, the thermodynamic of catalyst activation. The combined experimental and theoretical data demonstrate that while f-AuNPs is inactive at room temperature both in solution and in the solid state, catalyst activation occurs rapidly at mild temperatures (~70 °C) and the doping reaction completes in few seconds affording large electrical conductivities (~10-140 S cm -1 ). The implementation of this methodology enables the use of semiconductor+dopant+catalyst solutions and will broaden the use of the corresponding n-doped films in opto-electronic devices such as thin-film transistors, electrochemical transistors, solar cells, and thermoelectrics well as guide the design of new catalysts., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Competing Interests: Declaration of interests SA declares grants from the Indian Council for Medical Research (2022–25), the Government of Karnataka (2022–23), Rotary Bangalore Midtown (2022–23), Lowes Services India (2022–25), and Wellcome Trust (2023–26); payment for expert testimony received by Indian Council of Medical Research and Ashoka University; and a travel grant paid by University College London for being part of the Lancet Commission. SB declares grants from National Institute for Health and Care Research (NIHR), Economic and Social Research Council, Engineering and Physical Science Research Council, Canadian Institute for Health Research, the Alzheimer's Association, the Alzheimer's Society, Health Education England, Alzheimer's Association, Alzheimer's Society, and Health Education England. He has held the following positions: Non-Executive Director Somerset NHS Foundation Trust, Trustee of the Alzheimer's Society, Executive Dean of the University of Plymouth, and Pro-Vice Chancellor of the University of Nottingham. AB acts as a consultant for Lilly, TauRx Pharmaceuticals, and Eisai and carries out medico–legal work for solicitors. NCF declares consulting fees from F Hoffmann-La Roche, Eli Lilly, Ionis, Biogen, and Siemens; participation in data safety monitoring or advisory board for Biogen; and being a member of the Research Strategy Council for the Alzheimer's Society. LNG declares owning tailored activity programme licences. MK declares grants from Wellcome Trust (221854/Z/20/Z), the Medical Research Council (R024227), the National Institute on Aging (R01AG062553, R01AG056477), and the Academy of Finland (350426). KYL declared fellowship from Medical Research Council. EBL receives grants from the National Institutes of Health (NIH) and royalties from UpToDate. GL declares support for the manuscript from the Alzheimer's Society, the Alzheimer's Society UK, and UK Research and Innovation, who gave grants to pay for travel and accommodation. She is supported by the University College London Hospitals' NIHR Biomedical Research Centre, by North Thames NIHR Applied Research Collaboration, and as an NIHR Senior Investigator and has grants from NIHR Health Technology Assessment, NIHR Programme Grants for Applied Research, the Alzheimer's Association, the Norwegian Research Council, and Wellcome, outside of the submitted work. She works with the Alzheimer's Society as a member of the Research Strategy Council and is a trustee of Nightingale Hammerson care homes. KR declares grants from Canadian Institutes of Health Research, the Canadian Frailty Network, and Research Nova Scotia; royalties from Biotest, Qu Biologics, AstraZeneca UK, BioAge Labs, Congenica, Icosavax, KCR, Faraday Pharmaceuticals, Synairgen Research, Enanta Pharmaceuticals, Pfizer, Boehringer Ingelheim International, Fresenius Kabi Deutschland, Baycrest Geriatric Care, and Shanghai Ark Biopharmaceutical; payment or honoraria from University of British Columbia, Fraser Health Authority, McMaster University, Chinese Medical Association, Wake Forest University Medical School Centre, University of Omaha, and Atria Institute; participation on data safety or advisory board for EpiPharma; and leadership of the Canadian Consortium on Neurodegeneration in Dementia, Cap Breton University, and Nova Scotia Health. KS declares support from the Japan Society for the Promotion of Science fund (22H03352, 21KK0168, 16KK0059). LSS declares support from Della Martin Foundation, the NIH (P30 AG066530, R01 AG051346, R01 AG062687, R01 AG051346, R01 AG055444, P01 AG052350, R01 AG053267, R01 AG074983, R01 AG063826), Abbott, Biohaven, Biogen, Eisai, and Eli Lilly and consulting fees from AC Immune, Cortexyme, Alpha-cognition, BioVie, Athira, Eli Lilly/Avid, Corium, Lundbeck, Merck, Muna Therapeutics, Novo-Nordisk, Neurim, NeuroDiagnostics, Ono, Otsuka, Roche/Genentech, Cognition, Lighthouse, GW Research, ImmunoBrain, and Bristol Myers Squibb. AS declares grants from Wellcome Trust, the Alzheimer's Association, Brain Canada, and the NIHR. YY declares support from the National Natural Science Foundation of China (72374013) and the National Key R&D Program of China (2023YFB4603200, 2023YFC3606400). SW declares an NIHR doctoral training fellowship. GS has participated on advisory boards for the following pharmaceutical companies manufacturing drugs against Alzheimer's disease: Biogen, Roche, and Eisai. LG is an inventor of a training program for health and human service professionals in an evidence-based tailored activity intervention, the Tailored Activity Program; she and her respective universities are entitled to fees. All other authors declare no competing interests.

The concept of creating room-temperature ferromagnets from organic radicals proposed nearly sixty years ago, has recently experienced a resurgence due to advances in organic radical chemistry and materials. However, the lack of definitive design paradigms for achieving stable long-range ferromagnetic coupling between organic radicals presents an uncertain future for this research. Here, an innovative strategy is presented to achieve room-temperature ferromagnets by assembling π-conjugated radicals into π-π stacking aggregates. These aggregates, with ultra-close π-π distances and optimal π-π overlap, provide a platform for strong ferromagnetic (FM) interaction. The planar aromatic naphthalene diimide (NDI) anion radicals form nanorod aggregates with a π-π distance of just 3.26 Å, shorter than typical van der Waals distances. The suppressed electron paramagnetic resonance (EPR) signal and emergent near-infrared (NIR) absorption of the aggregates confirm strong interactions between the radicals. Magnetic measurements of NDI anion radical aggregates demonstrate room-temperature ferromagnetism with a saturated magnetization of 1.1 emu g -1 , the highest among pure organic ferromagnets. Theoretical calculations reveal that π-stacks of NDI anion radicals with specific interlayer translational slippage favor ferromagnetic coupling over antiferromagnetic coupling., (© 2024 Wiley‐VCH GmbH.)

Bisphenols, parabens, and triclosan (TCS) are common endocrine disrupters used in various consumer products. These chemicals have been shown to cross the placental barrier and affect intrauterine development of fetuses. In this study, we quantified serum levels of six bisphenols, five parabens, and TCS in 483 pregnant women from southern China. Quantile-based g-computation showed that combined exposure to bisphenols, parabens, and TCS was significantly ( p < 0.05) and negatively associated with birth weight (β = -39.9, 95% CI: -73.8, -6.1), birth length (β = -0.19, 95% CI: -0.34, -0.04), head circumference (β = -0.13, 95% CI: -0.24, -0.02), and thoracic circumference (β = -0.16, 95% CI: -0.29, -0.04). An inverse correlation was also identified between mixture exposure and gestational age (β = -0.12, 95% CI: -0.24, -0.01). Bisphenol A (BPA), bisphenol Z (BPZ), bisphenol AP (BPAP), propylparaben (PrP), and TCS served as the dominant contributors to the overall effect. In subgroup analyses, male newborns were more susceptible to mixture exposure than females, whereas the exposure-outcome link was prominent among pregnant women in the first and second trimesters. More evidence is warranted to elucidate the impacts of exposure to mixtures on birth outcomes, as well as the underlying mechanisms.

The tumor microenvironment demonstrates great immunophenotypic heterogeneity, which has been leveraged in traditional immune-hot/cold tumor categorization based on the abundance of intra-tumoral immune cells. By incorporating the spatial immune contexture, the tumor immunophenotype was further elaborated into immune-inflamed, immune-excluded, and immune-desert. However, the mechanisms underlying these different immune phenotypes are yet to be comprehensively elucidated. In this review, we discuss how tumor cells and the tumor microenvironment interact collectively to shape the immune landscape from the perspectives of tumor cells, immune cells, the extracellular matrix, and cancer metabolism, and we summarize potential therapeutic options according to distinct immunophenotypes for personalized precision medicine., (© 2024. The Author(s).)

As one of the common malignancies that threaten human life, bladder cancer occurs frequently with a high mortality rate in the world, due to its invasion, recurrence and drug resistance. Natural products from marine microorganisms are becoming the hotspots in discovery of new candidate drug entities, especially in the area of cancer. Brefeldin A (BFA) is a natural Arf-GEFs inhibitor, but due to the low aqueous solubility, strong toxicity, and poor bioavailability, it is urgent to conduct structural optimization research. Herein, a new BFA pyridine acrylate derivative CHNQD-01281 with improved solubility was prepared and found to exert moderate to strong antiproliferative activity on a variety of human cancer cell lines. It was noteworthy that CHNQD-01281 was most sensitive to two bladder cancer cell lines T24 and J82 (IC 50  = 0.079 and 0.081 μmol/L) with high selectivity index (SI = 14.68 and 14.32), suggesting a superior safety to BFA. In vivo studies revealed that CHNQD-01281 remarkably suppressed tumor growth in a T24 nude mice xenograft model (TGI = 52.63%) and prolonged the survival time (ILS = 68.16%) in an MB49 allogeneic mouse model via inducing infiltration of cytotoxic T cells. Further mechanism exploration indicated that CHNQD-01281 regulated both EGFR/PI3K/AKT and EGFR/ERK pathways and mediated the chemotactic effect of chemokines on immune effector cells. Overall, CHNQD-01281 may serve as a potential therapeutic agent for bladder cancer through multiple mechanisms., Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-024-00246-w., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest. Author Chang-Lun Shao is one of the Editorial Board Members, but he was not involved in the journal’s review of, or decision related to, this manuscript., (© The Author(s) 2024.)

Purpose: To investigate the associations of choline, betaine, dimethylglycine (DMG), L-carnitine, and Trimethylamine-N-oxide (TMAO) with the risk of Gestational diabetes mellitus (GDM) as well as the markers of glucose homeostasis., Methods: We performed a case-control study including 200 diagnosed GDM cases and 200 controls matched by maternal age (±2 years) and gestational age (±2 weeks). Concentrations of serum metabolites were measured by the high-performance liquid chromatography - tandem mass spectrometry (HPLC-MS/MS)., Results: Compared to the control group, GDM group had significantly lower serum betaine concentration and betaine/choline ratio, and higher DMG concentration. Furthermore, decreased betaine concentration and betaine/choline ratio, increased DMG concentration showed significant association with the risk of GDM. In addition, serum betaine concentrations were negatively associated with blood glucose levels at 1-h post-glucose load (OGTT-1h), and both betaine and L-carnitine concentrations were positively associated with 1,5-anhydroglucitol levels. Betaine/choline ratio was negatively associated with OGTT-1h and blood glucose levels at 2-h post-glucose load (OGTT-2h) and serum choline concentrations were negatively associated with fasting blood glucose and positively associated with OGTT-2h., Conclusion: Decreased serum betaine concentrations and betaine/choline ratio, and elevated DMG concentrations could be significant risk factors for GDM. Furthermore, betaine may be associated with blood glucose regulation and short-term glycemic fluctuations., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: To perform a correlation analysis on the structural and functional changes of the carotid artery in patients with H-type hypertension., Methods: Outpatients and inpatients with hypertension in our hospital between 2017 and 2018 were selected and divided into the H-type hypertension group (primary hypertension + plasma homocysteine ≥ 10 umol/l) ( n = 30) and the simple hypertension group (primary hypertension + plasma Hcy < 10 umol/l) ( n = 30) based on the plasma homocysteine (Hcy), and 30 healthy people were included in the control group. Thickness and stiffness parameters of the intima of the carotid artery (compliance coefficient [CC], stiffness index [β], and pulse wave velocity [PWV]) were measured for all study participants using ultrasound radiofrequency signal-based quality intima-media thickness (QIMT) and quantitative arterial stiffness (QAS) for contrast analysis., Results: Indexes such as QIMT, β, and PWV of the carotid artery were significantly higher, and the CC was significantly lower in the H-type hypertension group and simple hypertension group than the control group ( p < .05), and the difference was statistically significant; these indexes were significantly higher in the H-type hypertension group than in the simple hypertension group, and the CC was significantly lower than in the control group ( p < .05), and the difference was statistically significant., Conclusions: Hypertension can accelerate structural and functional changes of the carotid artery intima, with these changes being more significant in H-type hypertension. The ultrasound radiofrequency technique can be used to quantitatively evaluate the structure and function of the carotid artery in patients with H-type hypertension., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Evidence linking nitrogen dioxide (NO 2 ) air pollution to life span of high-vulnerability older adults is extensively scarce in low- and middle-income countries. This study seeks to quantify mortality risk, excess deaths, and loss of life expectancy (LLE) associated with long-term exposure to NO 2 among elderly individuals in China., Methods: A nationwide dynamic cohort of 20352 respondents ≥65 years old were enrolled from the China Longitudinal Health and Longevity Survey during 2005-2018. Residential exposures to NO 2 and co-pollutants were assessed by well-validated spatiotemporal prediction models. A Cox regression model with time-dependent covariates was utilized to quantify the association of all-cause mortality with NO 2 exposure, controlling for confounders such as demographics, lifestyle, health status, and ambient temperature. NO 2 -attributable deaths and LLE were evaluated for the years 2010 and 2020 based on the pooled NO 2 -mortality relation derived from multi-national cohort investigations. Decomposition analyses were conducted to dissociate net shift in NO 2 -related deaths between 2010 and 2020 into four primary contributing factors., Results: A total of 14313 deaths were recorded during follow-up of approximately 100 hundred person-years (median 3.6 years). We observed an approximately linear relationship (nonlinear P = 0.882) of NO 2 exposure with all-cause death across a broad range from 6.6 to 95.7 μg/m 3 . Every 10-μg/m 3 rise in yearly average NO 2 concentration was linked to a hazard ratio (HR) of 1.045 (95% confidence interval [CI]: 1.031-1.059). In the updated meta-analysis of this study and 9 existing cohorts, we estimated a pooled HR of 1.043 (95% CI: 1.023-1.063) for each 10-μg/m 3 growth in NO 2 . Reaching a 10-μg/m 3 counterfactual target of NO 2 concentration in China could avoid 0.33 (95% empirical CI: 0.19-0.49) million premature deaths and an LLE of 0.40 (95% empirical CI: 0.23-0.59) years in 2010, which greatly dropped to 0.24 (95% empirical CI: 0.14-0.36) million deaths and 0.21 (95% empirical CI: 0.12-0.31) years of LLE in 2020. The net fall in NO 2 -attributable deaths (-26.8%) between 2010 and 2020 was primarily driven by the declines in both NO 2 concentration (-41.6%) and mortality rate (-27.1%) under population growth (+41.0%) and age structure transition (+0.9%)., Conclusions: Our findings provide national evidence for increased risk of premature death and loss of life expectancy attributed to later-life NO 2 exposure among the elderly in China. In an accelerated aging society, strengthened clean air actions should be formulated to minimize the health burden and regional inequality in NO 2 -attributable mortality., 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 Inc. All rights reserved.)

Background: The influence of genetic variants on the glucose-lowering effects of dapagliflozin remains unclear. This study aims to investigate the impact of polymorphisms in solute carrier family 5 member 2 ( SLC5A2 ), uridine diphosphate glucuronosyltransferase 1A9 ( UGT1A9 ), solute carrier family 2 member 2 ( SLC2A2 ) and member 4 ( SLC2A4 ) on the anti-hyperglycemic effect of dapagliflozin in patients with type-2 diabetes mellitus (T2DM)., Methods: A total of 141 patients with T2DM were included in this prospective cohort study. Twenty-nine single nucleotide polymorphisms (SNPs) were selected and genotyped using the Sequenom MassArray platform or Sanger sequencing. Glycated hemoglobin (HbA1c) and fasting blood glucose (FBG) levels were compared before and after the treatment with dapagliflozin., Results: Among the 29 SNPs selected, 27 were successfully analyzed. After three months of dapagliflozin treatment, FBG levels were significantly reduced (8.00 mmol/L (5.45-10.71) mmol/L vs 6.40 mmol/L (5.45-9.20) mmol/L, p = 0.003) in patients with T2DM. However, there was no significant change in HbA1c levels (8.10% (6.88-10.00)% vs 8.10% (6.83-10.00)%, p = 0.452). Analysis of covariance showed that patients with the minor allele homozygote or heterozygote of rs12471030 (CT/TT), rs12988520 (AC/CC) or rs2602381 (TC/CC) had higher FBG levels compared to those with the major allele homozygote ( p = 0.014, p = 0.024, and p = 0.044, respectively). After adjusting for baseline FBG level, age, gender, body mass index, use of insulin and use of metformin, three SNPs-rs12471030, rs12988520 and rs2602381-were associated with the anti-hyperglycemic effect of dapagliflozin. However, using a stringent significance threshold ( p < 0.002 with Bonferroni correction), none of these selected SNPs were significantly associated with FBG and HbA1c levels after dapagliflozin treatment., Conclusion: After adjusting for confounding variables, polymorphisms in SLC5A2, UGT1A9, SLC2A2 and SLC2A4 genes were not associated with the anti-hyperglycemic effect of dapagliflozin in the Chinese population., Clinical Trial Registration Number: ChiCTR2200059645., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Wang et al.)

This study aimed to investigate the impact of the drug-drug interaction between rivaroxaban and amiodarone on the clinical outcomes in patients with non-valvular atrial fibrillation (NVAF), focusing on pharmacokinetic and pharmacodynamic (PK/PD) aspects. A prospective study enrolling 174 patients with NVAF who were treated with rivaroxaban was conducted. The patients were divided into two groups based on postoperative antiarrhythmic and anticoagulation strategies: the rivaroxaban group (Control group) and the rivaroxaban plus amiodarone group (Riv/Amio group). The trough plasma concentrations (C trough ) of rivaroxaban, activated partial thromboplastin time (APTT), prothrombin time (PT), and the clinical outcomes between the two groups were compared. Patients receiving 20 mg of rivaroxaban in the Riv/Amio group had a higher concentration of rivaroxaban C trough than those in the Control group ( p = 0.009). Furthermore, in patients with moderate to severe renal impairment, rivaroxaban C trough was significantly increased in the Riv/Amio group. There was no significant difference in PT and APTT between the two groups. Regarding the clinical outcomes, the combination of rivaroxaban and amiodarone medication was associated with a higher incidence of bleeding events ( p = 0.041; HR = 2.83, 95% CI 1.05-7.66) and clinically relevant non-major bleeding ( p = 0.021; HR = 3.65, 95% CI 1.21-10.94). Finally, independent risk factors for bleeding in NAVF patients treated with rivaroxaban were identified as its combination with amiodarone ( p = 0.044; OR = 2.871, 95% CI 1.028-8.023). The combination of rivaroxaban and amiodarone led to changes in rivaroxaban pharmacokinetics and an elevated risk of bleeding events. Therefore, physicians prescribing rivaroxaban medications should assess the potential bleeding risk associated with the concurrent use of amiodarone, particularly in patients with renal impairment.

In recent years, with the increasing awareness of consumers about the relationship between excessive fat intake and chronic diseases, such as obesity, heart disease, diabetes, etc., the demand for low-fat foods has increased year by year. However, a simple reduction of fat content in food will cause changes in physical and chemical properties, physiological properties, and sensory properties of food. Therefore, developing high-quality fat replacers to replace natural fats has become an emerging trend, and it is still a technical challenge to completely simulate the special function of natural fat in low-fat foods. This review aims to provide an overview of development trends of fat replacers, and the different types of fat replacers, the potential fat replacement mechanisms, sensory evaluation methods, and their consumer acceptance are discussed and compared, which may provide a theoretical guidance to produce fat replacers and develop more healthy low-fat products favored by consumers., Competing Interests: Declaration of competing interest No conflict of interest exits in the submission of this manuscript., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Early ambulation is an important step in accelerating post-joint replacement surgery recovery. However, there is limited research on populations who are unable to walk immediately after the operation. The purpose of this study was to determine the factors influencing postoperative ambulation in total knee arthroplasty (TKA) patients., Methods: Primary TKA patients were included in this retrospective study. All patients were divided into two groups. Patients who began walking within 24 h were categorized as the early ambulation group, while patients who began walking after 24 h were classified as the late ambulation group. Recorded demographic data included age, gender, body mass index (BMI), clinical diagnosis, and comorbidities. Hematological parameters potentially affecting patients' preoperative physical condition were also documented. Additionally, intraoperative metrics such as surgical time, surgical side, tourniquet time, intraoperative blood loss, the placement of drains, and prosthetic model were recorded., Results: A total of 453 patients (79.0% female, 21.0% male) were included in this study. The average age of all patients was 68.5±7.9 years, ranging from 36 to 87 years, with an average BMI of 27.2±9.9 kg/ m 2 . The mean postoperative ambulation time was 1.6 days, with a range of 0-4 days. In univariate group comparisons, an increase in postoperative time to ambulation was significantly associated with a history of heart disease ( P < 0.001 ), stroke history ( P = 0.003 ), and prior surgeries ( P = 0.003 ). Patients who delayed ambulation also exhibited significantly higher coagulation-related parameters including PT ( P < 0.001 ), APTT ( P = 0.002 ), TT ( P = 0.039 ) before surgery compared to those who mobilized early. Furthermore, prolonged surgical time ( P = 0.030 ), increased intraoperative blood loss ( P < 0.001 ), and the placement of intraoperative drains ( P < 0.001 ) also significantly extended the time to postoperative ambulation. However, after multivariate logistic regression analysis, only PT (OR 1.86, 95% CI 1.32 - 2.61, P < 0.001 ), TT (OR 1.30, 95% CI 1.09 - 1.55, P = 0.004 ) intraoperative blood loss (OR 1.01, 95% CI 1.00 - 1.01, P = 0.008 ) and the placement of intraoperative drains (OR 11.39, 95% CI 6.59 - 19.69, P < 0.001 ) were identified as predictive factors for late ambulation in patients after TKA., Conclusion: In this study, preoperative coagulation function, intraoperative blood loss and the placement of intraoperative drains were factors contributing to delay ambulation time. Therefore, it is believed that properly improving preoperative coagulation function, effective intraoperative hemostasis, and reducing the placement of drains have a positive impact on early postoperative ambulation in patients undergoing TKA., (© 2024. The Author(s).)