Relationship between Indel Variants within the JAK2 Gene and Growth Traits in Goats.

Janus kinase 2 (JAK2) plays a critical role in myoblast proliferation and fat deposition in animals. Our previous RNA-Seq analyses identified a close association between the JAK2 gene and muscle development. To date, research delving into the relationship between the JAK2 gene and growth traits has been sparse. In this study, we sought to investigate the relationship between novel mutations within the JAK2 gene and goat growth traits. Herein, two novel InDel (Insertion/Deletion) polymorphisms within the JAK2 gene were detected in 548 goats, and only two genotypes were designated as ID (Insertion/Deletion) and DD (Deletion/Deletion). The results indicate that the two InDels, the del19008 locus in intron 2 and del72416 InDel in intron 6, showed significant associations with growth traits (p < 0.05). Compared to Nubian and Jianzhou Daer goats, the del72416 locus displayed a more pronounced effect in the Fuqing breed group. In the Nubian breed (NB) group, both InDels showed a marked influence on body height (BH). There were strong linkages observed for these two InDels between the Fuqing (FQ) and Jianzhou (JZ) populations. The DD-ID diplotype was associated with inferior growth traits in chest width (ChW) and cannon circumference (CaC) in the FQ goats compared to the other diplotypes. In the NB population, the DD-DD diplotype exhibited a marked negative impact on BH and HuWI (hucklebone width index), in contrast to the other diplotypes. In summary, our findings suggest that the two InDel polymorphisms within the JAK2 gene could serve as valuable molecular markers for enhancing goat growth traits in breeding programs.

Diagnostic model for hepatocellular carcinoma using small extracellular vesicle-propagated miRNA signatures.

Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Small extracellular vesicles (sEVs) are bilayer lipid membrane vesicles containing RNA that exhibit promising diagnostic and prognostic potential as cancer biomarkers. Aims: To establish a miRNA panel from peripheral blood for use as a noninvasive biomarker for the diagnosis of HCC. Methods: sEVs obtained from plasma were profiled using high-throughput sequencing. The identified differential miRNA expression patterns were subsequently validated using quantitative real-time polymerase chain reaction analysis. Results: The random forest method identified ten distinct miRNAs distinguishing HCC plasma from non-HCC plasma. During validation, miR-140-3p (p = 0.0001) and miR-3200-3p (p = 0.0017) exhibited significant downregulation. Enrichment analysis uncovered a notable correlation between the target genes of these miRNAs and cancer development. Utilizing logistic regression, we developed a diagnostic model incorporating these validated miRNAs. Receiver operating characteristic (ROC) curve analysis revealed an area under the curve (AUC) of 0.951, with a sensitivity of 90.1% and specificity of 87.8%. Conclusion: These aberrantly expressed miRNAs delivered by sEVs potentially contribute to HCC pathology and may serve as diagnostic biomarkers for HCC.

Generic and facile mechanochemical access to versatile lattice-confined Pd(ii)-based heterometallic sites.

Metal-organic frameworks (MOFs) show remarkable potential in a broad array of applications given their physical and chemical versatility. Classical synthesis of MOFs is performed using solution chemistry at elevated temperatures to achieve reversible metal-ligand bond formation. These harsh conditions may not be suitable for chemical species sensitive to high temperature or prone to deleterious reactions with solvents. For instance, Pd(ii) is susceptible to reduction under solvothermal conditions and is not a common metal node of MOFs. We report a generic and facile mechanochemical strategy that directly incorporates a series of Pd(ii)-based heterobimetallic clusters into MOFs as metal nodes without Pd(ii) being reduced to Pd(0). Mechanochemistry features advantages of short reaction time, minimum solvent, high reaction yield, and high degree of synthetic control. Catalytic performances of lattice-confined heterobimetallic sites are examined for nitrene transfer reactions and we demonstrate that the chemoselectivity for allylic amination versus olefin aziridination is readily tuned by the identity of the first-row metal ion in Pd(ii)-based heterobimetallic clusters.

Efficacy of tibial cortex transverse transport in treating diabetic foot ulcer and its effect on serum omentin-1 and irisin levels.

OBJECTIVE: Diabetic foot ulcer (DFU) is a common and debilitating complication of diabetes that is associated with an increased risk of lower-limb amputation and a reduced life expectancy. Tibial cortex transverse transport (TTT) has become a newly alternative surgical method to facilitate ulcer healing and prevent lower limb amputation. Herein, we investigated the efficacy of TTT in treating DFU and changes of serum omentin-1 and irisin levels. METHODS: This study prospectively recruited 52 consecutive patients with DFU who were treated with TTT. The follow-up was performed weekly during the first 12 weeks postoperatively and every 3 months until 1 year after TTT. The serum levels of vascular endothelial growth factor (VEGF), omentin-1, and irisin in DFU patients undergoing TTT were determined by ELISA methods on the preoperative 1st day, postoperative 2nd week and 4th week. RESULTS: The wound healing rate was 92.3% (48/52) at the 1-year follow-up. The visual analog scale (VAS) pain scores of patients showed a significant reduction at the 4th week after TTT (p < 0.001). The dorsal foot skin temperature, ankle brachial index, and dorsal foot blood flow of patients were significantly increased at the 4th week after TTT (p < 0.001). Results of ELISA methods showed the serum levels of VEGF, omentin-1, and irisin on the 2nd week and 4th week after TTT were notably elevated compared to the levels determined on the preoperative 1st day (p < 0.001). The serum levels of VEGF, omentin-1, and irisin on the 4th week after TTT were also significantly higher than the levels determined on the 2nd week after TTT (p < 0.001). CONCLUSION: TTT could promote the wound healing and reduce the risk of lower limb amputation, demonstrating promising clinical benefits in the treatment of DFU. Increased expressions of serum proangiogenic factors including VEGF, omentin-1, and irisin were noted in the early stage after TTT, which may provide a new mechanism of TTT promoting wound heal.

Research situation, hot spots, and global trends of melasma therapy: Bibliometric insights and visual analysis from 2000 to 2023.

BACKGROUND: Melasma is a prevalent pigmented disease, yet its pathogenesis remains unclear, posing challenges for effective treatment. Bibliometric analysis, a novel approach to literature research, offers the opportunity to evaluate research trends through qualitative and quantitative methods. This study utilizes bibliometric methods to analyze the existing literature on melasma treatment, examining influential publications, institutions, countries, and authors through statistical analysis. METHODS: In order to retrieve manuscripts related to the topic of melasma treatment, we conducted a search using the search formula: (TS = (melasma or Chloasma or "mask of pregnancy")) AND TS = (treatment or therapy). We searched through the Web of Science Core Collection database, covering publications from 2000 to 2023. VOSviewer, CiteSpace and the Bibliometric online site (https://bibliometric.com/app) were used to conduct this bibliometric analysis. Our analysis focused on various factors including publications, authors co-authorship, institutions, countries, citation analysis, keywords co-occurrence, references co-citation and journal co-citation. RESULTS: A total of 943 articles and 200 reviews were published between 2000 and 2023, accumulating a total of 8628 citations. The average number of citations per item was 18.85, and the average number of citations per year was 292.69. The most prolific author, Sungeun Chang, contributed a total of 9 articles. Cario University emerged as the top research institution. The United States led in terms of article publications with a count of 276. In the past 5 years, the research trends in this field have primarily focused on tranexamic acid and epidermal melasma, as indicated by the burst analysis of publications and keywords. CONCLUSIONS: The United States continues to lead in terms of institutions and research output. The current emphasis is on the meticulous implementation of tranexamic acid and laser therapy. It is crucial to foster enhanced collaboration among countries, institutions, and authors to facilitate improved research.

Vascular clips for preventing lymphocele and symptomatic lymphocele in patients with gynecologic malignancies after laparoscopic pelvic lymphadenectomy.

STUDY OBJECTIVE: To evaluate the effectiveness of using vascular clips to seal targeted lymphatics in gynecological malignancies for the prevention of postoperative pelvic lymphocele and symptomatic lymphocele after laparoscopic pelvic lymphadenectomy. DESIGN: Retrospective analysis. SETTING: Single-center academic hospital. PATIENTS: In total, 217 patients with gynecological malignancies were included. INTERVENTIONS: Patients were classified into two groups: group 1 (vascular clips were used to seal the targeted lymphatics) and group 2 (electrothermal instruments were used to seal the targeted lymphatics). The patients were followed up 4-6 weeks after surgery to evaluate the incidence of lymphoceles by ultrasound or CT. Symptomatic lymphoceles are defined as those that cause infection, deep vein thrombosis with or without swelling of the extremities, edema (swelling) of the extremities or perineum, hydronephrosis and/or moderate to severe pain. MEASUREMENT AND MAIN RESULTS: One hundred and thirteen patients were enrolled in group 1, and 104 patients were enrolled in group 2. Lymphoceles were observed in 46 (21.2%) patients. Fewer lymphoceles occurred in group 1 than in group 2 [8 (7.1%) vs. 38 (36.5%), p < 0.001]. The percentage of significantly sized lymphoceles was lower in group 1 than that in group 2 [4 (3.5%) vs. 30 (28.8%), p < 0.001]. Symptomatic lymphoceles occurred in 18 patients (8.3%), and only one (1.0%) occurred in group 1, while 17 (16.3%) occurred in group 2 (p < 0.001). A multivariate analysis revealed that vascular clips were the only independent factor for preventing lymphocele (OR = 7.65, 95% CI = [3.30, 17.13], p < 0.001) and symptomatic lymphocele (OR = 22.03, 95% CI = [2.84, 170.63], p = 0.003). CONCLUSIONS: The results indicate that the use of vascular clips may be useful for the prevention of the development of lymphocele and symptomatic lymphocele secondary to pelvic lymphadenectomy performed via laparoscopy.

Preoperative chemoradiotherapy in older patients with rectal cancer guided by comprehensive geriatric assessment within a multidisciplinary team-a multicenter phase II trial.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as "fit" by comprehensive geriatric assessment (CGA). METHODS: A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of "fit" (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22). RESULTS: One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47). CONCLUSION: This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA. TRIAL REGISTRATION: The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).

Enhancing Zinc Electrode Stability Through Pre-Desolvation and Accelerated Charge Transfer via a Polyimide Interface for Zinc-Ion Batteries.

Aqueous zinc-based energy storage devices possess superior safety, cost-effectiveness, and high energy density; however, dendritic growth and side reactions on the zinc electrode curtail their widespread applications. In this study, these issues are mitigated by introducing a polyimide (PI) nanofabric interfacial layer onto the zinc substrate. Simulations reveal that the PI nanofabric promotes a pre-desolvation process, effectively desolvating hydrated zinc ions from Zn(H2O)6 2+ to Zn(H2O)4 2+ before approaching the zinc surface. The exposed zinc ion in Zn(H2O)4 2+ provides an accelerated charge transfer process and reduces the activation energy for zinc deposition from 40 to 21 kJ mol-1. The PI nanofabric also acts as a protective barrier, reducing side reactions at the electrode. As a result, the PI-Zn symmetric cell exhibits remarkable cycling stability over 1200 h, maintaining a dendrite-free morphology and minimal byproduct formation. Moreover, the cell exhibits high stability and low voltage hysteresis even under high current densities (20 mA cm-2, 10 mAh cm-2) thanks to the 3D porous structure of PI nanofabric. When integrated into full cells, the PI-Zn||AC hybrid zinc-ion capacitor and PI-Zn||MnVOH@SWCNT zinc-ion battery achieve impressive lifespans of 15000 and 600 cycles with outstanding capacitance retention. This approach paves a novel avenue for high-performance zinc metal electrodes.

Characteristics of advanced anaerobic digestion sludge-based biochar and its application for sewage sludge conditioning.

The utilization of sludge-based biochar, characterized by abundant pore structures, proves advantageous in enhancing sludge dewatering performance. In this study, advanced anaerobic digestion sludge underwent pyrolysis to produce biochar, subsequently employed for sludge conditioning. Results revealed that biochar, obtained at 800 °C, exhibited the highest specific surface area (105.3 m2/g) and pore volume (0.17 cm3/g). As the pyrolysis temperature increased, the sludge's functional groups tended to aromatize. When used to condition sludge, particularly at a 20 % (dry solid) dosage, biochar significantly reduced sludge capillary suction time and floc size. The addition of biochar enhanced the conditioning effect of cationic polyacrylamide by absorbing extracellular polymeric substances, creating water molecule channels, and forming skeletons for sludge flocs. These findings introduce a novel approach to sludge reuse and provide valuable data supporting the use of biochar as a sludge conditioner.

Minimal residual disease profiling predicts pathological complete response in esophageal squamous cell carcinoma.

Accurate presurgical prediction of pathological complete response (pCR) can guide treatment decisions, potentially avoiding unnecessary surgeries and improving the quality of life for cancer patients. We developed a minimal residual disease (MRD) profiling approach with enhanced sensitivity and specificity for detecting minimal tumor DNA from cell-free DNA (cfDNA). The approach was validated in two independent esophageal squamous cell carcinoma (ESCC) cohorts. In a cohort undergoing neoadjuvant, surgical, and adjuvant therapy (NAT cohort), presurgical MRD status precisely predicted pCR. All MRD-negative cases (10/10) were confirmed as pCR by pathological evaluation on the resected tissues. In contrast, MRD-positive cases included all the 27 non-pCR cases and only one pCR case (10/10 vs 1/28, P < 0.0001, Fisher's exact test). In a definitive radiotherapy cohort (dRT cohort), post-dRT MRD status was closely correlated with patient prognosis. All MRD-negative patients (25/25) remained progression-free during the follow-up period, while 23 of the 26 MRD-positive patients experienced disease progression (25/25 vs 3/26, P < 0.0001, Fisher's exact test; progression-free survival, P < 0.0001, log-rank test). The MRD profiling approach effectively predicted the ESCC patients who would achieve pCR with surgery and those likely to remain progression-free without surgery. This suggests that the cancer cells in these MRD-negative patients have been effectively eliminated and they could be suitable candidates for a watch-and-wait strategy, potentially avoiding unnecessary surgery.

Unsupervised Bidirectional Contrastive Reconstruction and Adaptive Fine-Grained Channel Attention Networks for image dehazing.

Recently, Unsupervised algorithms has achieved remarkable performance in image dehazing. However, the CycleGAN framework can lead to confusion in generator learning due to inconsistent data distributions, and the DisentGAN framework lacks effective constraints on generated images, resulting in the loss of image content details and color distortion. Moreover, Squeeze and Excitation channel attention employs only fully connected layers to capture global information, lacking interaction with local information, resulting in inaccurate feature weight allocation for image dehazing. To solve the above problems, in this paper, we propose an Unsupervised Bidirectional Contrastive Reconstruction and Adaptive Fine-Grained Channel Attention Networks (UBRFC-Net). Specifically, an Unsupervised Bidirectional Contrastive Reconstruction Framework (BCRF) is proposed, aiming to establish bidirectional contrastive reconstruction constraints, not only to avoid the generator learning confusion in CycleGAN but also to enhance the constraint capability for clear images and the reconstruction ability of the unsupervised dehazing network. Furthermore, an Adaptive Fine-Grained Channel Attention (FCA) is developed to utilize the correlation matrix to capture the correlation between global and local information at various granularities promotes interaction between them, achieving more efficient feature weight assignment. Experimental results on challenging benchmark datasets demonstrate the superiority of our UBRFC-Net over state-of-the-art unsupervised image dehazing methods. This study successfully introduces an enhanced unsupervised image dehazing approach, addressing limitations of existing methods and achieving superior dehazing results. The source code is available at https://github.com/Lose-Code/UBRFC-Net.

[Effect of Thermal Hydrolysis Pretreatment Time on Microbial Community Structure in Sludge Anaerobic Digestion System].

To evaluate the effect of thermal hydrolysis pretreatment time on the sludge anaerobic digestion system of wastewater treatment plants (WWTPs) in Daxing district, Beijing, the structure and diversity of microbial communities in primary sludge and an activated sludge anaerobic digestion system with different thermal hydrolysis pretreatment times (15 min, 30 min, and 45 min) were analyzed using Illumina MiSeq high-throughput sequencing. The results showed that the dominant groups of digested sludge were mainly distributed in Firmicutes, Cloacimonadota, Chloroflexi, and Synergistota, with W5 being the most common genus. The sum of relative abundance of the dominant phylum was greater than 60%, and W5 accounted for 20.8%-54.5%, showing a high abundance of a few dominant species. During the anaerobic digestion of thermo-hydrolyzed sludge, the relative abundance of acetogenic methanogens decreased due to high levels of volatile fatty acids (VFAs) and ammonia nitrogen (NH4+-N) concentrations, which suggested that the hydrogenophilic methanogenic pathway was more than that of the acetogenic methanogenic pathway. Correlation analysis showed that the soluble protein and pH of thermo-hydrolyzed sludge, NH4+-N of digested sludge, and thermal hydrolysis pretreatment time were the four main environmental factors affecting microbial community structure, and NH4+-N of digested sludge had the largest negative correlation with methanogens. The thermal hydrolysis pretreatment time was negatively correlated with both the Chao index and Shannon index, so longer thermal hydrolysis pretreatment time was not conducive to microbial flora during anaerobic digestion.

Nonisospectral water wave field: Fast and adaptive modal identification and prediction via reduced-order nonlinear solutions.

Real-world water wave fields exhibit significant nonlinear and nonisospectral characteristics, making it challenging to predict their evolution by relying solely on numerical simulation or exact solutions using integrable system theory. Hence, this paper introduces a fast and adaptive method of modal identification and prediction in nonisospectral water wave fields using the reduced-order nonlinear solution (RONS) scheme. Specifically, we discuss the coarse graining and mode extraction of wave field snapshots from the data-driven and physics-driven perspectives and utilize the RONS method for principle modal prediction of nonisospectral water wave fields. This is achieved by investigating the standard and nonisospectral Gardner system describing nonlinear water waves as a demonstration. Through detailed comparison and analysis, the fundamental solitary behaviors and dispersive effects in the Gardner system are discussed. Subsequently, a neighbor approximation is developed that combines the essences of symbolic precomputation and numerical computation in the RONS procedure, which exploits the locality of nonlinear interactions in water wave fields.

A Quadrivalent mRNA Immunization Elicits Potent Immune Responses against Multiple Orthopoxviral Antigens and Neutralization of Monkeypox Virus in Rodent Models.

The global outbreak of the 2022 monkeypox virus infection of humans and the 2023 documentation of a more virulent monkeypox in the Democratic Republic of the Congo raised public health concerns about the threat of human-to-human transmission of zoonotic diseases. Currently available vaccines may not be sufficient to contain outbreaks of a more transmissible and pathogenic orthopoxvirus. Development of a safe, effective, and scalable vaccine against orthopoxviruses to stockpile for future emergencies is imminent. In this study, we have developed an mRNA vaccine candidate, ALAB-LNP, expressing four vaccinia viral antigens A27, L1, A33, and B5 in tandem in one molecule, and evaluated the vaccine immunogenicity in rodent models. Immunization of animals with the candidate mRNA vaccine induced a potent cellular immune response and long-lasting antigen-specific binding antibody and neutralizing antibody responses against vaccinia virus. Strikingly, the sera from the vaccine-immunized mice cross-reacted with all four homologous antigens of multiple orthopoxviruses and neutralized monkeypox virus in vitro, holding promise for this mRNA vaccine candidate to be used for protection of humans from the infection of monkeypox and other orthopoxvirus.

Bifunctional Metal-Organic Nanoballs Featuring Lewis Acidic and Basic Sites as a New Platform for One-Pot Tandem Catalysis.

The design and synthesis of polyhedra using coordination-driven self-assembly has been an intriguing research area for synthetic chemists. Metal-organic polyhedra are a class of intricate molecular architectures that have garnered significant attention in the literature due to their diverse structures and potential applications. Hereby, we report Cu-MOP, a bifunctional metal-organic cuboctahedra built using 2,6-dimethylpyridine-3,5-dicarboxylic acid and copper acetate at room temperature. The presence of both Lewis basic pyridine groups and Lewis acidic copper sites imparts catalytic activity to Cu-MOP for the tandem one-pot deacetalization-Knoevenagel/Henry reactions. The effect of solvent system and time duration on the yields of the reactions was studied, and the results illustrate the promising potential of these metal-organic cuboctahedra, also known as nanoballs for applications in catalysis.

Biomechanical and clinical outcomes of 3D-printed versus modular hemipelvic prostheses for limb-salvage reconstruction following periacetabular tumor resection: a mid-term retrospective cohort study.

BACKGROUND: Debates persist over optimal pelvic girdle reconstruction after acetabular tumor resection, with surgeons grappling between modular and 3D-printed hemipelvic endoprostheses. We hypothesize superior outcomes with 3D-printed versions, yet scarce comparative research exists. This study fills the gap, examining biomechanics and clinical results retrospectively. METHODS: From February 2017 to June 2021, we retrospectively assessed 32 patients undergoing en bloc resection for malignant periacetabular tumors at a single institution. PRIMARY OUTCOME: limb function. SECONDARY OUTCOMES: implant precision, hip joint rotation center restoration, prosthesis-bone osteointegration, and complications. Biomechanical characteristics were evaluated through finite element analysis on pelvic defect models. RESULTS: In the 3D-printed group, stress distribution mirrored a normal pelvis, contrasting the modular group with elevated overall stress, unstable transitions, and higher stress peaks. The 3D-printed group exhibited superior functional scores (MSTS: 24.3 ± 1.8 vs. 21.8 ± 2.0, p < 0.05; HHS: 79.8 ± 5.2 vs. 75.3 ± 3.5, p < 0.05). Prosthetic-bone interface osteointegration, measured by T-SMART, favored 3D-printed prostheses, but surgery time (426.2 ± 67.0 vs. 301.7 ± 48.6 min, p < 0.05) and blood loss (2121.1 ± 686.8 vs. 1600.0 ± 505.0 ml, p < 0.05) were higher. CONCLUSIONS: The 3D-printed hemipelvic endoprosthesis offers precise pelvic ring defect matching, superior stress transmission, and function compared to modular endoprostheses. However, complexity, fabrication expertise, and challenging surgical implantation result in prolonged operation times and increased blood loss. A nuanced consideration of functional outcomes, complexity, and patient conditions is crucial for informed treatment decisions. LEVEL OF EVIDENCE: Level III, therapeutic study (Retrospective comparative study).

Bayesian hypernetwork collaborates with time-difference evolutional network for temporal knowledge prediction.

A Temporal Knowledge Graph (TKG) is a sequence of Knowledge Graphs (KGs) attached with time information, in which each KG contains the facts that co-occur at the same timestamp. Temporal knowledge prediction (TKP) aims to predict future events given observed historical KGs in TKGs, which is essential for many applications to provide intelligent analysis services. However, most existing TKP methods focus on entity and relation prediction tasks but ignore the importance of time prediction tasks. Furthermore, there is uncertainty in time prediction, and it is difficult for prediction models to model it completely. In this work, we propose a collaboration framework with Bayesian Hypernetwork and Time-Difference Evolutional Network (BH-TDEN) to address these problems. First, we begin with the time prediction task, and we present a Bayesian hypernetwork to model the uncertainty of events time. For the input of Bayesian hypernetwork, we design a novel time-difference evolutional network to obtain the entities and relations embedding. Specifically, we propose an auto-regressive time gate parameterized by the time difference of adjacent KGs in entity and relation encoder to learn the time-sensitive TKG embedding, which not only learns the relationship between the given time information and TKG embedding but also provides more expressive TKG embedding for Bayesian hypernetwork to accurately predict the time of future events. Furthermore, we also present a novel relation updating mechanism that employs the neighbor relations of the subject corresponding to the current relation to learn more adaptive relation embedding. Extensive experiments demonstrate that the proposed method obtains considerable time prediction and link prediction performance on four TKG benchmark datasets.

Nicorandil-Pretreated Mesenchymal Stem Cell-Derived Exosomes Facilitate Cardiac Repair After Myocardial Infarction via Promoting Macrophage M2 Polarization by Targeting miR-125a-5p/TRAF6/IRF5 Signaling Pathway.

Background: Exosomes derived from bone marrow mesenchymal stem cells (MSC-exo) have been considered as a promising cell-free therapeutic strategy for ischemic heart disease. Cardioprotective drug pretreatment could be an effective approach to improve the efficacy of MSC-exo. Nicorandil has long been used in clinical practice for cardioprotection. This study aimed to investigate whether the effects of exosomes derived from nicorandil pretreated MSC (MSCNIC-exo) could be enhanced in facilitating cardiac repair after acute myocardial infarction (AMI). Methods: MSCNIC-exo and MSC-exo were collected and injected into the border zone of infarcted hearts 30 minutes after coronary ligation in rats. Macrophage polarization was detected 3 days post-infarction, cardiac function as well as histological pathology were measured on the 28th day after AMI. Macrophages were separated from the bone marrow of rats for in vitro model. Exosomal miRNA sequencing was conducted to identify differentially expressed miRNAs between MSCNIC-exo and MSC-exo. MiRNA mimics and inhibitors were transfected to MSCs or macrophages to explore the specific mechanism. Results: Compared to MSC-exo, MSCNIC-exo showed superior therapeutic effects on cardiac functional and structural recovery after AMI and markedly elevated the ratio of CD68+ CD206+/ CD68+cells in infarcted hearts 3 days post-infarction. The notable ability of MSCNIC-exo to promote macrophage M2 polarization was also confirmed in vitro. Exosomal miRNA sequencing and both in vivo and in vitro experiments identified and verified that miR-125a-5p was an effector of the roles of MSCNIC-exo in vivo and in vitro. Furthermore, we found miR-125a-5p promoted macrophage M2 polarization by inhibiting TRAF6/IRF5 signaling pathway. Conclusion: This study suggested that MSCNIC-exo could markedly facilitate cardiac repair post-infarction by promoting macrophage M2 polarization by upregulating miR-125a-5p targeting TRAF6/IRF5 signaling pathway, which has great potential for clinical translation.