LIFU/MMP-2 dual-responsive release of repurposed drug disulfiram from nanodroplets for inhibiting vasculogenic mimicry and lung metastasis in triple-negative breast cancer.

BACKGROUND: Vasculogenic mimicry (VM), when microvascular channels are formed by cancer cells independent of endothelial cells, often occurs in deep hypoxic areas of tumors and contributes to the aggressiveness and metastasis of triple-negative breast cancer (TNBC) cells. However, well-developed VM inhibitors exhibit inadequate efficacy due to their low drug utilization rate and limited deep penetration. Thus, a cost-effective VM inhibition strategy needs to be designed for TNBC treatment. RESULTS: Herein, we designed a low-intensity focused ultrasound (LIFU) and matrix metalloproteinase-2 (MMP-2) dual-responsive nanoplatform termed PFP@PDM-PEG for the cost-effective and efficient utilization of the drug disulfiram (DSF) as a VM inhibitor. The PFP@PDM-PEG nanodroplets effectively penetrated tumors and exhibited substantial accumulation facilitated by PEG deshielding in a LIFU-mediated and MMP-2-sensitive manner. Furthermore, upon exposure to LIFU irradiation, DSF was released controllably under ultrasound imaging guidance. This secure and controllable dual-response DSF delivery platform reduced VM formation by inhibiting COL1/pro-MMP-2 activity, thereby significantly inhibiting tumor progression and metastasis. CONCLUSIONS: Considering the safety of the raw materials, controlled treatment process, and reliable repurposing of DSF, this dual-responsive nanoplatform represents a novel and effective VM-based therapeutic strategy for TNBC in clinical settings.

Palladium-Catalyzed Iodine Assisted Carbonylation of Indoles with ClCF2CO2Na and Alcohols.

A palladium-catalyzed iodine-assisted carbonylation reaction of indoles with readily available ClCF2CO2Na and alcohols has been developed. This protocol provides a practical and efficient approach to highly regioselective indole-3-carboxylates via a preiodination strategy of indoles. Different from classic carbonylation using toxic and difficult-to-handle carbon monoxide, this operationally simple and scalable reaction employed difluorocarbene as the carbonyl surrogate.

Effects of cooking methods on the physical properties and in vitro digestibility of starch isolated from Chinese yam.

The objective of this study was to compare the structural and functional attributes of Chinese yam starches obtained via different domestic cooking methods. Cooking changed the crystalline type from the C type to the CB type, and disrupted the short- and long-range molecular order of Chinese yam starch. The average chain length of amylopectin in BOS (boiling starch) was the smallest at 22.78, while RWS had the longest average chain length, reaching 24.24. These alterations in molecular structure resulted in variations in functional properties such as solubility, swelling power (SP), pasting characteristics, and rheological properties. Among these alterations, boiling was the most effective method for increasing the water-binding capacity and SP of starch. Specifically, its water holding capacity was 2.12 times that of RWS. In vitro digestion experiments indicated that BOS has a higher digestion rate (k = 0.0272 min-1) and lower RDS (rapidly digestible starch), which may be related to its amylopectin chain length distribution. This study can guide us to utilize yam starch through suitable cooking methods, which is relevant for the processing and application of Chinese yam starch.

Identification of a gene expression signature associated with brain metastasis in colorectal cancer.

PURPOSE: Brain metastasis (BM) in colorectal cancer (CRC) is a rare event with poor prognosis. Apart from (K)RAS status and lung and bone metastasis no biomarkers exist to identify patients at risk. This study aimed to identify a gene expression signature associated with colorectal BM. METHODS: Three patient groups were formed: 1. CRC with brain metastasis (BRA), 2. exclusive liver metastasis (HEP) and, 3. non-metastatic disease (M0). RNA was extracted from primary tumors and mRNA expression was measured using a NanoString Panel (770 genes). Expression was confirmed by qPCR in a validation cohort. Statistical analyses including multivariate logistic regression followed by receiver operating characteristic (ROC) analysis were performed. RESULTS: EMILIN3, MTA1, SV2B, TMPRSS6, ACVR1C, NFAT5 and SMC3 were differentially expressed in BRA and HEP/M0 groups. In the validation cohort, differential NFAT5, ACVR1C and SMC3 expressions were confirmed. BRA patients showed highest NFAT5 levels compared to HEP/M0 groups (global p = 0.02). High ACVR1C expression was observed more frequently in the BRA group (42.9%) than in HEP (0%) and M0 (7.1%) groups (global p = 0.01). High SMC3 expressions were only detectable in the BRA group (global p = 0.003). Only patients with BM showed a combined high expression of NFAT5, ACVR1C or SMC3 as well as of all three genes. ROC analysis revealed a good prediction of brain metastasis by the three genes (area under the curve (AUC) = 0.78). CONCLUSIONS: The NFAT5, ACVR1C and SMC3 gene expression signature is associated with colorectal BM. Future studies should further investigate the importance of this biomarker signature.

A new species, Aster yaoshanensis (Asteracae, Astereae), from Guangxi (China), based on morphology and molecular phylogenetic data.

Aster yaoshanensis sp. nov., a new species of the family Asteraceae is here described and illustrated. The species is presently known only from rock crevices of mountain valleys in Dayaoshan National Nature Reserve, Guangxi autonomous region, China. Phylogenetic analyses based on ITS sequences and complete plastome data have shown that this new species is a member of genus Aster with high support. Morphologically, it mostly resembles A. jishouensis, but it can be easily distinguished from the latter by bract indumentum (glabrous except margin ciliate vs. villous especially on veins abaxially, glabrous adaxially) and color (green vs. purple), shorter corolla (3.2-3.5 mm vs. 4.5-5.3 mm), bract stalk (obvious, ca.1.2 mm vs. sessile), and different distribution (Guangxi vs. Hunan). The detailed description, distribution map, and photos are provided. This study further elucidates the species identification, phylogeny and characteristic evolution of Aster.

Bilateral intertrochanteric fractures in an elderly patient following high-energy trauma: a case report.

BACKGROUND: Cases of bilateral hip fractures are rare, and even more so are cases of bilateral intertrochanteric fractures. Common causes include trauma, internal diseases, and primary or secondary bone diseases. We report a case of bilateral intertrochanteric fractures in an elderly patient following a severe car accident, a scenario not extensively reported in existing literature. CASE PRESENTATION: We report on an 84-year-old male who suffered severe trauma from a car accident, resulting in multiple injuries and shock state, with pain and limited mobility in both hip joints. After examination and imaging studies, the patient was diagnosed with multiple injuries and bilateral intertrochanteric fractures. Following emergency resuscitation, he was admitted to the orthopedic ward. A pre-surgical multidisciplinary team (MDT) consultation was convened to optimize surgical conditions. The patient underwent successful one-stage bilateral intramedullary nailing. The patient was assisted to stand with a walker on the third day after surgery. Six months post-surgery, the patient resumed outdoor activities. CONCLUSION: Managing bilateral intertrochanteric fractures, particularly in the elderly with severe trauma, is notably challenging due to their rarity. However, a coordinated multidisciplinary approach and one-stage bilateral internal fixation can lead to effective treatment outcomes and favorable prognoses.

The effect analysis of shape design of different charging piles based on Human physiological characteristics using the MF-DFA.

With the rapid development of new energy vehicles, the users have an increasing demand for charging piles. It is generally believed that the charging pile is a kind of practical product, and it only needs to realize the charging function. However, as a product, the shape design of the charging pile will directly affect the user experience, thus affecting product sales. Therefore, in the face of increasingly fierce market competition, when designing the shape of charging piles, it is necessary to adopt the traditional evaluation method and human physiological cognitive characteristics to evaluate the shape of charging piles more objectively. From the user's point of view, using the electroencephalogram (EEG) of the user, with the help of the multifractal detrended fluctuation analysis (MF-DFA) method, this paper comprehensively analyzes the differences in emotional cognitive characteristics between two kinds of charging piles, namely, the charging pile with a curved appearance design and the charging pile with square appearance design. The results show that there are significant differences in human physiological cognitive characteristics between two kinds of charging piles with different shapes. And different shapes of charging piles have different physiological cognitive differences for users. When designing charging pile product shapes, human beings can objectively evaluate the product shape design according to the physiological cognition differences of users, so as to optimize the charging pile product shape design.

Synthesis, Herbicidal Activity, and Molecular Mode of Action Evaluation of Novel Aryloxyphenoxypropionate/Amide Derivatives Containing a Quinazolinone Moiety.

To develop aryloxyphenoxypropionate herbicides with a novel structure and improved activity, a total of 39 aryloxyphenoxypropionate/amide derivatives containing quinazolinone moiety were synthesized and further bioevaluated. The bioassay results in the greenhouse showed that most of the target compounds had good herbicidal activity under postemergence conditions, of which, QPP-I-6 displayed excellent herbicidal activity against Echinochloa crusgalli, Digitaria sanguinalis, Spartina alterniflora, Eleusine indica, and Pennisetum alopecuroides with inhibition rates >90% at a dosage of 187.5 g ha-1. More importantly, QPP-I-6 displayed higher crop safety to Gossypium hirsutum, Glycine max, and Arachis hypogaea than the commercial herbicide quizalofop-p-ethyl. Studying the molecular mode of action by phenotypic observation, membrane permeability evaluation, transcriptomic analysis, and in vivo ACCase activity evaluation reveals that QPP-I-6 is a novel ACCase inhibitor. The present work demonstrates that QPP-I-6 can serve as a lead compound for further developing novel ACCase-inhibiting herbicides.

Pathological progression of osteoarthritis: a perspective on subchondral bone.

Osteoarthritis (OA) is a degenerative bone disease associated with aging. The rising global aging population has led to a surge in OA cases, thereby imposing a significant socioeconomic burden. Researchers have been keenly investigating the mechanisms underlying OA. Previous studies have suggested that the disease starts with synovial inflammation and hyperplasia, advancing toward cartilage degradation. Ultimately, subchondral-bone collapse, sclerosis, and osteophyte formation occur. This progression is deemed as "top to bottom." However, recent research is challenging this perspective by indicating that initial changes occur in subchondral bone, precipitating cartilage breakdown. In this review, we elucidate the epidemiology of OA and present an in-depth overview of the subchondral bone's physiological state, functions, and the varied pathological shifts during OA progression. We also introduce the role of multifunctional signal pathways (including osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B ligand (RANKL)/receptor activator of nuclear factor-kappa B (RANK), and chemokine (CXC motif) ligand 12 (CXCL12)/CXC motif chemokine receptor 4 (CXCR4)) in the pathology of subchondral bone and their role in the "bottom-up" progression of OA. Using vivid pattern maps and clinical images, this review highlights the crucial role of subchondral bone in driving OA progression, illuminating its interplay with the condition.

Bilateral Sensorimotor Impairments in Individuals with Unilateral Chronic Ankle Instability: A Systematic Review and Meta-Analysis.

BACKGROUND: Chronic ankle instability (CAI) is manifested by sensorimotor impairments in the sprained ankle, including deficits in sensation, motor function, and central integration or processing. These impairments have a significant impact on physical activities and daily life. Recently, some studies have suggested that bilateral deficits were observed in unilateral CAI, but contradictory evidence disputes this finding. Therefore, the objective of this study was to investigate whether bilateral sensorimotor deficits presented in individuals with unilateral CAI. METHODS: Without language restriction, the following databases were retrieved from database inception up until 3 November 2023, including PubMed, WOS, EMBASE, Cochrane, SPORTDiscus and CINAHL. Case-control and cross-sectional studies that investigated bilateral sensorimotor functions in individuals with unilateral CAI were included. Sensorimotor functions contained static and dynamic balance, functional performance, muscle strength and activation, as well as sensation. Outcome measures contained centre-of-pressure parameters, normalised reach distance, activation time and magnitude of muscle, sensory errors and threshold. The risk of bias and quality assessment of included studies were evaluated using a standardised tool recommended by the Cochrane Collaboration and the Epidemiological Appraisal Instrument, respectively. To explore the potential bilateral deficits associated with unilateral CAI, a comprehensive meta-analysis was conducted using Review Manager version 5.4. The analysis compared the injured limb of unilateral CAI with healthy controls and the uninjured limb with healthy controls. The main focus of this study was to investigate the differences between the uninjured limb and healthy controls. A random-effects model was employed and effect sizes were estimated using the standardised mean difference (SMD) with 95% confidence intervals (CIs). Effect sizes were deemed as weak (0.2-0.5), moderate (0.5-0.8), or large (> 0.8). RESULTS: A total of 11,442 studies were found; 30 studies were contained in the systematic review and 20 studies were included in the meta-analysis. Compared with healthy controls, those with unilateral CAI presented weak to moderate impairments in their uninjured limbs in static balance with eyes open (SMD = 0.32, 95% CI: 0.08 to 0.56), functional performance (SMD = 0.37; 95% CI: 0.08 to 0.67), kinesthesia (SMD = 0.52; 95% CI: 0.09 to 0.95) and tibialis anterior activation (SMD = 0.60, 95% CI: 0.19 to 1.01). There were no significant differences in other comparisons between the uninjured limb and healthy controls. CONCLUSIONS: Patients with unilateral CAI may present bilateral deficits in static balance with eyes open, functional performance and kinaesthesia. However, further evidence is required to confirm this point due to limited studies included in some analyses and small effect size. REGISTRATION: The protocol was registered in the International Prospective Register of Systematic Reviews platform (CRD: 42,022,375,855).

Pasteurella multocida activates apoptosis via the FAK-AKT-FOXO1 axis to cause pulmonary integrity loss, bacteremia, and eventually a cytokine storm.

Pasteurella multocida is an important zoonotic respiratory pathogen capable of infecting a diverse range of hosts, including humans, farm animals, and wild animals. However, the precise mechanisms by which P. multocida compromises the pulmonary integrity of mammals and subsequently induces systemic infection remain largely unexplored. In this study, based on mouse and rabbit models, we found that P. multocida causes not only lung damage but also bacteremia due to the loss of lung integrity. Furthermore, we demonstrated that bacteremia is an important aspect of P. multocida pathogenesis, as evidenced by the observed multiorgan damage and systemic inflammation, and ultimately found that this systemic infection leads to a cytokine storm that can be mitigated by IL-6-neutralizing antibodies. As a result, we divided the pathogenesis of P. multocida into two phases: the pulmonary infection phase and the systemic infection phase. Based on unbiased RNA-seq data, we discovered that P. multocida-induced apoptosis leads to the loss of pulmonary epithelial integrity. These findings have been validated in both TC-1 murine lung epithelial cells and the lungs of model mice. Conversely, the administration of Ac-DEVD-CHO, an apoptosis inhibitor, effectively restored pulmonary epithelial integrity, significantly mitigated lung damage, inhibited bacteremia, attenuated the cytokine storm, and reduced mortality in mouse models. At the molecular level, we demonstrated that the FAK-AKT-FOXO1 axis is involved in P. multocida-induced lung epithelial cell apoptosis in both cells and animals. Thus, our research provides crucial information with regard to the pathogenesis of P. multocida as well as potential treatment options for this and other respiratory bacterial diseases.

Early proactive monitoring of DNA-thioguanine in patients with Crohn's disease predicts thiopurine-induced late leucopenia in NUDT15/TPMT normal metabolizers.

BACKGROUND: Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines. Dose optimization guided by nudix hydrolase 15 (NUDT15) has significantly reduced the early leucopenia rate, but there are no definitive biomarkers for late risk leucopenia prediction. AIM: To determine the predictive value of early monitoring of DNA-thioguanine (DNATG) or 6-thioguanine nucleotides (6TGN) for late leucopenia under a NUDT15-guided thiopurine dosing strategy in patients with Crohn's disease (CD). METHODS: Blood samples were collected within two months after thiopurine initiation for detection of metabolite concentrations. Late leucopenia was defined as a leukocyte count < 3.5 × 109/L over two months. RESULTS: Of 148 patients studied, late leucopenia was observed in 15.6% (17/109) of NUDT15/thiopurine methyltransferase (TPMT) normal and 64.1% (25/39) of intermediate metabolizers. In patients suffering late leucopenia, early DNATG levels were significantly higher than in those who did not develop late leucopenia (P = 4.9 × 10-13). The DNATG threshold of 319.43 fmol/µg DNA could predict late leucopenia in the entire sample with an area under the curve (AUC) of 0.855 (sensitivity 83%, specificity 81%), and in NUDT15/TPMT normal metabolizers, the predictive performance of a threshold of 315.72 fmol/µg DNA was much more remarkable with an AUC of 0.902 (sensitivity 88%, specificity 85%). 6TGN had a relatively poor correlation with late leucopenia whether in the entire sample (P = 0.021) or NUDT15/TPMT normal or intermediate metabolizers (P = 0.018, P = 0.55, respectively). CONCLUSION: Proactive therapeutic drug monitoring of DNATG could be an effective strategy to prevent late leucopenia in both NUDT15/TPMT normal and intermediate metabolizers with CD, especially the former.

Attenuated vaccine PmCQ2Δ4555-4580 effectively protects mice against Pasteurella multocida infection.

Pasteurella multocida type A (PmA) mainly causes respiratory diseases such as pneumonia in bovines, leading to great economic losses to the breeding industry. At present, there is still no effective commercial vaccine against PmA infection. In this study, a mutant strain (PmCQ2Δ4555-4580) with brand-new phenotypes was obtained after serially passaging at 42 °C. Whole genome resequencing and PCR analysis showed that PmCQ2Δ4555-4580 missed six genes, including PmCQ2_004555, PmCQ2_004560, PmCQ2_004565, PmCQ2_004570, PmCQ2_004575, and PmCQ2_004580. Importantly, the virulence of PmCQ2Δ4555-4580 was reduced by approximately 2.8 × 109 times in mice. Notably, live PmCQ2Δ4555-4580 could provide 100%, 100% and 40% protection against PmA, PmB and PmF, respectively; and inactivated PmCQ2Δ4555-4580 could provide 100% and 87.5% protection against PmA and PmB. Interestingly, immune protection-related proteins were significantly upregulated in PmCQ2Δ4555-4580 based on RNA-seq and bioinformatics analysis. Meaningfully, by in vitro expression, purification and in vivo immunization, 12 proteins had different degrees of immune protective effects. Among them, PmCQ2_008205, PmCQ2_010435, PmCQ2_008190, and PmCQ2_004170 had the best protective effect, the protection rates against PmA were 50%, 40%, 30%, and 30%, respectively, and the protective rates against PmB were 62.5%, 42.9%, 37.5%, and 28.6%, respectively. Collectively, PmCQ2Δ4555-4580 is a potential vaccine candidate for the prevention of Pasteurellosis involving in high expression of immune protective related proteins.

Design and development of a personalized virtual reality-based training system for vascular intervention surgery.

BACKGROUND AND OBJECTIVES: Virtual training has emerged as an exceptionally effective approach for training healthcare practitioners in the field of vascular intervention surgery. By providing a simulated environment and blood vessel model that enables repeated practice, virtual training facilitates the acquisition of surgical skills in a safe and efficient manner for trainees. However, the current state of research in this area is characterized by limitations in the fidelity of blood vessel and guidewire models, which restricts the effectiveness of training. Additionally, existing approaches lack the necessary real-time responsiveness and precision, while the blood vessel models suffer from incompleteness and a lack of scientific rigor. METHODS: To address these challenges, this paper integrates position-based dynamics (PBD) and its extensions, shape matching, and Cosserat elastic rods. By combining these approaches within a unified particle framework, accurate and realistic deformation simulation of personalized blood vessel and guidewire models is achieved, thereby enhancing the training experience. Furthermore, a multi-level progressive continuous collision detection method, leveraging spatial hashing, is proposed to improve the accuracy and efficiency of collision detection. RESULTS: Our proposed blood vessel model demonstrated acceptable performance with the reduced deformation simulation response times of 7 ms, improving the real-time capability at least of 43.75 %. Experimental validation confirmed that the guidewire model proposed in this paper can dynamically adjust the density of its elastic rods to alter the degree of bending and torsion. It also exhibited a deformation process comparable to that of real guidewires, with an average response time of 6 ms. In the interaction of blood vessel and guidewire models, the simulator blood vessel model used for coronary vascular intervention training exhibited an average response time of 15.42 ms, with a frame rate of approximately 64 FPS. CONCLUSIONS: The method presented in this paper achieves deformation simulation of both vascular and guidewire models, demonstrating sufficient real-time performance and accuracy. The interaction efficiency between vascular and guidewire models is enhanced through the unified simulation framework and collision detection. Furthermore, it can be integrated with virtual training scenarios within the system, making it suitable for developing more advanced vascular interventional surgery training systems.

The catalytic subunit of type 2A protein phosphatase negatively regulates conidiation and melanin biosynthesis in Setosphaeria turcica.

Northern corn leaf blight caused by Setosphaeria turcica is a major fungal disease responsible for significant reductions in maize yield worldwide. Eukaryotic type 2A protein phosphatase (PP2A) influences growth and virulence in a number of pathogenic fungi, but little is known about its roles in S. turcica. Here, we functionally characterized S. turcica StPP2A-C, which encodes the catalytic C subunit of StPP2A. StPP2A-C deletion slowed colony growth, conidial germination, and appressorium formation but increased conidiation, melanin biosynthesis, glycerol content, and disease lesion size on maize. These effects were associated with expression changes in genes related to calcium signaling, conidiation, laccase activity, and melanin and glycerol biosynthesis, as well as changes in intra- and extracellular laccase activity. A pull-down screen for candidate StPP2A-c interactors revealed an interaction between StPP2A-c and StLac1. Theoretical modeling and yeast two-hybrid experiments confirmed that StPP2A-c interacted specifically with the copper ion binding domain of StLac1 and that Cys267 of StPP2A-c was required for this interaction. StPP2A-C expression thus appears to promote hyphal growth and reduce pathogenicity in S. turcica, at least in part by altering melanin synthesis and laccase activity; these insights may ultimately support the development of novel strategies for biological management of S. turcica.

Preparation and characterization of furfural residue derived char-based catalysts for biomass tar cracking.

This study proposed an innovative strategy of catalytic cracking of tar during biomass pyrolysis/gasification using furfural residue derived biochar-based catalysts. Fe, Co, and Ni modified furfural residue char (FRC-Fe, FRC-Co, and FRC-Ni) were prepared by one-step impregnation method. The influences of cracking temperature and metal species on the tar cracking characteristics were investigated. The results showed that the tar conversion efficiency for all catalysts were improved with the cracking temperature increasing, the higher tar conversion efficiency achieved at 800 °C were 66.72 %, 89.58 %, 84.58 %, and 94.70 % for FRC, FRC-Fe, FRC-Co, and FRC-Ni respectively. FRC-Ni achieved the higher gas (H2, CO, CH4, CO2) yield 681.81 mL/g. At 800 °C, the catalyst (FRC-Ni) still reached a high tar conversion efficiency over 85.90 % after 5 cycles. SEM-EDS results showed that the distribution of Ni particles on the biochar support was uniform. TGA results demonstrated that FRC-Ni exhibited better thermal stability. XRD results indicated that there was no significant change in the grain size of Ni before and after the reaction. The FRC-Ni catalyst was reasonably stable due to its better anti-sintering and coke-resistant capabilities.

Dioxane promoted photochemical O-alkylation of 1,3-dicarbonyl compounds beyond carbene insertion into C-H and C-C bonds.

A photochemical synthesis of enol ethers and furan-3(2H)-ones from 1,3-dicarbonyl compounds and aryl diazoacetates has been developed. Significantly, 1,4-dioxane promoted O-alkylation of various 1,3-dicarbonyl compounds beyond previous carbene insertion into C-H and C-C bonds has been disclosed.

Pasteurella multocida activates Rassf1-Hippo-Yap pathway to induce pulmonary epithelial apoptosis.

Pasteurella multocida is an opportunistic zoonotic pathogen that primarily causes fatal respiratory diseases, such as pneumonia and respiratory syndromes. However, the precise mechanistic understanding of how P. multocida disrupts the epithelial barrier in mammalian lung remains largely unknown. In this study, using unbiased RNA-seq analysis, we found that the evolutionarily conserved Hippo-Yap pathway was dysregulated after P. multocida infection. Given the complexity of P. multocida infection associated with lung injury and systemic inflammatory processes, we employed a combination of cell culture models, mouse models, and rabbit models to investigate the dynamics of the Hippo-Yap pathway during P. multocida infection. Our findings reveal that P. multocida infection activates the Hippo-Yap pathway both in vitro and in vivo, by upregulating the upstream factors p-Mst1/2, p-Lats1, and p-Yap, and downregulating the downstream effectors Birc5, Cyr61, and Slug. Conversely, pharmacological inhibition of the Hippo pathway by XMU-MP-1 significantly rescued pulmonary epithelial cell apoptosis in vitro and reduced lung injury, systemic inflammation, and mouse mortality in vivo. Mechanistic studies revealed that P. multocida induced up-regulation of Rassf1 expression, and Rassf1 enhanced Hippo-Yap pathway through phosphorylation. Accordingly, in vitro knockdown of Rassf1 significantly enhanced Yap activity and expression of Yap downstream factors and reduced apoptosis during P. multocida infection. P. multocida-infected rabbit samples also showed overexpression of Rassf1, p-Lats1, and p-Yap, suggesting that P. multocida activates the Rassf1-Hippo-Yap pathway. These results elucidate the pathogenic role of the Rassf1-Hippo-Yap pathway in P. multocida infection and suggest that this pathway has the potential to be a drug target for the treatment of pasteurellosis.