MLRDFM: a multi-view Laplacian regularized DeepFM model for predicting miRNA-disease associations.

MOTIVATION: MicroRNAs (miRNAs), as critical regulators, are involved in various fundamental and vital biological processes, and their abnormalities are closely related to human diseases. Predicting disease-related miRNAs is beneficial to uncovering new biomarkers for the prevention, detection, prognosis, diagnosis and treatment of complex diseases. RESULTS: In this study, we propose a multi-view Laplacian regularized deep factorization machine (DeepFM) model, MLRDFM, to predict novel miRNA-disease associations while improving the standard DeepFM. Specifically, MLRDFM improves DeepFM from two aspects: first, MLRDFM takes the relationships among items into consideration by regularizing their embedding features via their similarity-based Laplacians. In this study, miRNA Laplacian regularization integrates four types of miRNA similarity, while disease Laplacian regularization integrates two types of disease similarity. Second, to judiciously train our model, Laplacian eigenmaps are utilized to initialize the weights in the dense embedding layer. The experimental results on the latest HMDD v3.2 dataset show that MLRDFM improves the performance and reduces the overfitting phenomenon of DeepFM. Besides, MLRDFM is greatly superior to the state-of-the-art models in miRNA-disease association prediction in terms of different evaluation metrics with the 5-fold cross-validation. Furthermore, case studies further demonstrate the effectiveness of MLRDFM.

Predicting drug-drug interactions by graph convolutional network with multi-kernel.

Drug repositioning is proposed to find novel usages for existing drugs. Among many types of drug repositioning approaches, predicting drug-drug interactions (DDIs) helps explore the pharmacological functions of drugs and achieves potential drugs for novel treatments. A number of models have been applied to predict DDIs. The DDI network, which is constructed from the known DDIs, is a common part in many of the existing methods. However, the functions of DDIs are different, and thus integrating them in a single DDI graph may overlook some useful information. We propose a graph convolutional network with multi-kernel (GCNMK) to predict potential DDIs. GCNMK adopts two DDI graph kernels for the graph convolutional layers, namely, increased DDI graph consisting of 'increase'-related DDIs and decreased DDI graph consisting of 'decrease'-related DDIs. The learned drug features are fed into a block with three fully connected layers for the DDI prediction. We compare various types of drug features, whereas the target feature of drugs outperforms all other types of features and their concatenated features. In comparison with three different DDI prediction methods, our proposed GCNMK achieves the best performance in terms of area under receiver operating characteristic curve and area under precision-recall curve. In case studies, we identify the top 20 potential DDIs from all unknown DDIs, and the top 10 potential DDIs from the unknown DDIs among breast, colorectal and lung neoplasms-related drugs. Most of them have evidence to support the existence of their interactions. fangxiang.wu@usask.ca.

ACP_MS: prediction of anticancer peptides based on feature extraction.

Anticancer peptides (ACPs) are bioactive peptides with antitumor activity and have become the most promising drugs in the treatment of cancer. Therefore, the accurate prediction of ACPs is of great significance to the research of cancer diseases. In the paper, we developed a more efficient prediction model called ACP_MS. Firstly, the monoMonoKGap method is used to extract the characteristic of anticancer peptide sequences and form the digital features. Then, the AdaBoost model is used to select the most discriminating features from the digital features. Finally, a stochastic gradient descent algorithm is introduced to identify anticancer peptide sequences. We adopt 7-fold cross-validation and independent test set validation, and the final accuracy of the main dataset reached 92.653% and 91.597%, respectively. The accuracy of the alternate dataset reached 98.678% and 98.317%, respectively. Compared with other advanced prediction models, the ACP_MS model improves the identification ability of anticancer peptide sequences. The data of this model can be downloaded from the public website for free https://github.com/Zhoucaimao1998/Zc.

EGFR/TKIs induce excessive apoptosis of bladder carcinoma cells by arresting cell cycle and promoting mitochondrial peroxidation damage.

In recent years, bladder carcinoma (BC) has shown an increasing incidence, with poor patient outcomes. In clinical practice, BC is still mainly treated by surgery combined with chemoradiotherapy. However, as chemotherapy resistance of tumor cells becomes more and more obvious, it is urgent to find more effective BC treatment regimes. With the increasing application and growing attention paid to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in various neoplastic diseases, EGFR-TKIs have been considered as a new treatment direction in the future. In this study, the research team used AG1478, an EGFR-TKI, to intervene with the BC cell line T24. It was found that the cell activity was statistically decreased, the apoptosis was enhanced, and the cells were dominantly arrested in the G0/G1 phase, confirming the future therapeutic potential of EGFR-TKIs in BC. Besides, the research team further observed that AG1478 also promoted pyroptosis in T24 cells, and its mechanism is related to the induction of mitochondrial oxidative stress damage. The findings lay a more reliable foundation for the future application of EGFR-TKIs in BC.

Switching from Thermally Activated Delayed Fluorescence in Single Crystals for Low-Threshold Laser to Room-temperature Phosphorescence in Amorphous-Film for Highly Efficient OLEDs.

Metal-organic phosphorescent complexes containing Ir or Pt are work horse in organic light-emitting diode (OLED) technology, which can harvest both singlet and triplet excitons in electroluminescence (EL) owing to strong heavy-atom effect. Recently, organic room-temperature phosphorescence (ORTP) have achieved high photoluminescence quantum yield (PLQY) in rigid crystalline state, which, however, is unsuitable for OLED fabrication, therefore leading to an EL efficiency far low behind those of metal-organic phosphorescent complexes. Here, we reported a luminescence mechanism switch from thermally activated delayed fluorescence (TADF) in single crystal microwires to ORTP in amorphous thin-films, based on a tert-butylcarbazole difluoroboron ß-diketonate derivative of DtCzBF2. Tightly packed and well-faceted single-crystal microwires exhibit aggregation induced emission (AIE), enabling TADF microlasers at 473 nm with an optical gain coefficient as high as 852 cm-1 . In contrast, loosely packed dimers of DtCzBF2 formed in guest-host amorphous thin-films decrease the oscillator strength of fluorescence transition but stabilize triplets for ORTP with a PLQY up to 61 %, leading to solution-processed OLEDs with EQE approaching 20 %. This study opens possibilities of low-cost ORTP emitters for high performance OLEDs and future low-threshold electrically injected organic semiconductor lasers (OSLs).

Identification of Inflammatory Endotypes by Clinical Characteristics and Nasal Secretion Biomarkers in Chronic Rhinosinusitis with Nasal Polyps.

INTRODUCTION: The emergency of biologics and surgical techniques targeting the specific inflammatory endotype in chronic rhinosinusitis with nasal polyps (CRSwNP) asks for efficient identification of patients with different endotypes. Although mucosal IL-4, IL-5, IL-13, and IgE have been used to define type 2 (T2) inflammation, the optimal one remains unclear. In this study, we aimed to determine the optimal anchor for T2 inflammation and identify clinical characteristics and nasal secretion biomarkers predicting different endotypes in CRSwNP. METHODS: Six mediators in sinonasal tissue and 36 mediators in nasal secretion samples were detected by the Bio-Plex suspension array system. Mucosal IFN-γ and IL-17A levels were used to define the T1 and T3 endotype, respectively. The efficacy of mucosal IL-4, IL-5, IL-13, and IgE to define the T2 endotype was compared. The power of clinical characteristics and nasal secretion biomarkers to predict the T1, T2, and T3 endotype was analyzed. RESULTS: Among mucosal IL-4, IL-5, IL-13, and IgE, IL-13 was the best one to coincide with the expression of other T2 biomarkers. A combination of atopy, facial pain symptom score, ethmoid/maxillary computed tomography score ratio, and blood eosinophil percentage had a moderate predictive performance for T2 endotype (area under the receiver operating curve [AUC] = 0.815), comparable to that of nasal secretion IL-5 (AUC = 0.819). For the T3 endotype, nasal secretion IL-1Rα identified it with an AUC value of 0.756. No efficient marker for the T1 endotype was found. CONCLUSION: IL-13 is a primary anchor for the T2 endotype in CRSwNP. Clinical characteristics and nasal secretion biomarkers are helpful for identifying the T2 and T3 endotype of CRSwNP.

Long-term Consequences of COVID-19: Chemosensory Disorders.

PURPOSE OF REVIEW: A number of sequelae after acute coronavirus disease 2019 (COVID-19) significantly affect the quality of life of patients. The chemosensory disorders including olfactory dysfunction (OD) and gustatory dysfunction (GD) are two of the commonest symptoms complained by patients with COVID-19. Although chemosensory function has been reported improved in over 60% of COVID-19 patients in a short time after acute infection, it may last as a major symptom for patients with long COVID-19. This narrative review discussed current literatures on OD and GD in long COVID-19 including the prevalence, risk factors, possible mechanisms, and potential therapies. RECENT FINDINGS: Although the prevalence of OD and GD has declined continuously after acute COVID-19, a considerable number of patients had persistent chemosensory disorders 3 months to 2 years after symptom onset. Female gender, initial severity of dysfunction, nasal congestion, emotional distress and depression, and SARS-CoV-2 variants have been identified as risk factors for persistent OD and GD in long COVID-19. The pathogenesis of OD and GD in long COVID-19 remains unknown, but may be analogous to the persistent OD and GD post common respiratory viral infection. Corticosteroids and olfactory training might be a potential choice regarding the treatment of lasting OD and GD after SARS-CoV-2 infection; however, more studies are needed to prove it. OD and GD are common long-term consequences of COVID-19 and influenced by gender, initial severity of dysfunction, emotional distress and depression, and SARS-CoV-2 variants. More studies are needed to illustrate their pathogenesis and to establish therapeutic strategies.

FAM177A1 Inhibits IL-1ß-Induced Signaling by Impairing TRAF6-Ubc13 Association.

The proinflammatory cytokine IL-1ß is a crucial mediator of inflammatory responses. IL-1ß-induced signaling is finely regulated by various mechanisms, and its imbalance is involved in a variety of diseases. In this study, we identified FAM177A1, a protein of unknown function, as a negative regulator of IL-1ß-induced signaling in human cells. Overexpression of FAM177A1 inhibited IL-1ß-triggered activation of NF-κB and transcription of inflammatory genes, whereas knockdown of FAM177A1 showed the opposite effects. Mechanistically, FAM177A1 competitively bound to the E3 ubiquitin ligase TRAF6 and impaired its interaction with the E2-conjugating enzyme Ubc13; therefore, it inhibited TRAF6-mediated polyubiquitination and recruitment of downstream signaling molecules. These findings reveal a function of FAM177A1 and promote our understanding of the regulatory mechanisms of IL-1ß-induced inflammatory responses.

Indocyanine green fluorescent cholangiography improves the clinical effects of difficult laparoscopic cholecystectomy.

BACKGROUND: Near-infrared fluorescent cholangiography (NIRFC) with indocyanine green (ICG) as the developer yields clear visualization of the extrahepatic bile ducts and is effective in identifying key structures. Here, we analyzed and compared the surgical outcomes of fluorescent and conventional laparoscopy in cholecystectomy of various difficulties and then assessed the value of NIRFC. MATERIALS AND METHODS: This retrospective study collected clinical data from partial patients who underwent laparoscopic cholecystectomy (LC) at the Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University between 2020 and 2021. The study subjects were classified into ICG-assisted and white-light laparoscopy. Two cohorts with homogeneous baseline status were selected based on 1:1 ratio propensity score matching (PSM). Multivariate logistic regression analysis was performed to predict independent risk factors for LC difficulty. Thereafter, the matched cases were classified into difficult and easy subgroups by combining difficulty score and gallbladder disease type, and then the surgical outcomes of the two groups were compared. RESULTS: This study included a total of 624 patients. The patients were classified into the ICG group (n = 218) and the non-ICG group (n = 218) after a 1:1 ratio PSM. Our data showed significant differences between the groups in operative time (P = 0.020), blood loss (P = 0.016), length of stay (P = 0.036), and adverse reaction (P = 0.023). Stratified analysis demonstrated that ICG did not significantly improve the surgical outcomes in simple cases (n = 208). On the other hand, in difficult cases (n = 228), NIRFC shortened operative time (P = 0.003) and length of stay (P = 0.015), reduced blood loss (P = 0.028) and drain placement rate (P = 0.015), and had fewer adverse reactions (P = 0.023). The data showed that five cases were converted to laparotomy while two cases had minor bile leaks in the non-ICG group. There was no bile duct injury (BDI) in all the cases. Furthermore, high BMI, history of urgent admission and abdominal surgery, palpable gallbladder, thickened wall, and pericholecystic collection were risk factors for surgical difficulty. CONCLUSION: ICG-assisted NIRFC provides real-time biliary visualization. In complicated conditions such as acute severe inflammation, dense adhesions, and biliary variants, the navigating ability of fluorescence can enhance the operation progress, reduce the possibility of conversion or serious complications, and improve the efficiency and safety of difficult LC.

Nickel oxide morphology synthesized with a hydrothermal method for inverted perovskite solar cells.

In this paper, a hydrothermal method is used to synthesize a nickel oxide nanostructure (nano-NiO) for its application to inverted perovskite solar cells. These pore nanostructures were employed to increase both the contact and channel between the hole transport and perovskite layers of an ITO/nano-N i O/C H 3 N H 3 P b I 3/P C B M/A g device. The purpose of this research is twofold. First, three different nano-NiO morphologies were synthesized at temperatures of 140°C, 160°C, and 180°C. Then, a Raman spectrometer was used to check the phonon vibration and magnon scattering characteristics after an annealing temperature of 500°C. Second, nano-NiO powders were dispersed in isopropanol for subsequent spin coating on the inverted solar cells. The nano-NiO morphologies were multi-layer flakes, microspheres, and particles at synthesis temperatures of 140°C, 160°C, and 180°C, respectively. When the microsphere nano-NiO was used as the hole transport layer, the perovskite layer had a larger coverage of 83.9%. The grain size of the perovskite layer was analyzed by x-ray diffraction, and strong crystal orientations of (110) and (220) peaks were found. Despite this, the power conversion efficiency could affect the promotion, which is 1.37 times higher than the poly(3,4-ethylenedioxythiophene) polystyrene sulfonate element conversion efficiency of the planar structure.

Can a Nomogram Predict Survival After Treatment for an Ankylosing Spondylitis Cervical Fracture in a Patient With Neurologic Impairment? A National, Multicenter Study.

BACKGROUND: Ankylosing spondylitis-related cervical spine fracture with neurologic impairment (ASCF-NI) is a rare but often lethal injury. Factors independently associated with survival after treatment remain poorly defined, and identifying patients who are likely to survive the injury remains challenging. QUESTIONS/PURPOSES: (1) What factors are independently associated with survival after treatment among patients with ASCF-NI? (2) Can a nomogram be developed that is sufficiently simple for clinicians to use that can identify patients who are the most likely to survive after injury? METHODS: This retrospective study was conducted based on a multi-institutional group of patients admitted and treated at one of 29 tertiary hospitals in China between March 1, 2003, and July 31, 2019. A total of 363 patients with a mean age of 53 ± 12 years were eventually included, 343 of whom were male. According to the National Household Registration Management System, 17% (61 of 363) died within 5 years of injury. Patients were treated using nonsurgical treatment or surgery, including procedures using the anterior approach, posterior approach, or combined anterior and posterior approaches. Indications for surgery included three-column injury, unstable fracture displacement, neurologic impairment or continuous progress, and intervertebral disc incarceration. By contrast, patients generally received nonsurgical treatment when they had a relatively stable fracture or medical conditions that did not tolerate surgery. Demographic, clinical, and treatment data were collected. The primary study goal was to identify which factors are independently associated with death within 5 years of injury, and the secondary goal was the development of a clinically applicable nomogram. We developed a multivariable Cox hazards regression model, and independent risk factors were defined by backward stepwise selection with the Akaike information criterion. We used these factors to create a nomogram using a multivariate Cox proportional hazards regression analysis. RESULTS: After controlling for potentially confounding variables, we found the following factors were independently associated with a lower likelihood of survival after injury: lower fracture site, more-severe peri-injury complications, poorer American Spinal Injury Association (ASIA) Impairment Scale, and treatment methods. We found that a C5 to C7 or T1 fracture (ref: C1 to C4 and 5; hazard ratio 1.7 [95% confidence interval 0.9 to 3.5]; p = 0.12), moderate peri-injury complications (ref: absence of or mild complications; HR 6.0 [95% CI 2.3 to 16.0]; p < 0.001), severe peri-injury complications (ref: absence of or mild complications; HR 30.0 [95% CI 11.5 to 78.3]; p < 0.001), ASIA Grade A (ref: ASIA Grade D; HR 2.8 [95% CI 1.1 to 7.0]; p = 0.03), anterior approach (ref: nonsurgical treatment; HR 0.5 [95% CI 0.2 to 1.0]; p = 0.04), posterior approach (ref: nonsurgical treatment; HR 0.4 [95% CI 0.2 to 0.8]; p = 0.006), and combined anterior and posterior approach (ref: nonsurgical treatment; HR 0.4 [95% CI 0.2 to 0.9]; p = 0.02) were associated with survival. Based on these factors, a nomogram was developed to predict the survival of patients with ASCF-NI after treatment. Tests revealed that the developed nomogram had good performance (C statistic of 0.91). CONCLUSION: The nomogram developed in this study will allow us to classify patients with different mortality risk levels into groups. This, coupled with the factors we identified, was independently associated with survival, and can be used to guide more appropriate treatment and care strategies for patients with ASCF-NI. LEVEL OF EVIDENCE: Level III, therapeutic study.

Extrafollicular PD-1highCXCR5-CD4+ T cells participate in local immunoglobulin production in nasal polyps.

BACKGROUND: Local immunoglobulin hyperproduction is observed in nasal polyps (NPs) with and without ectopic lymphoid tissues (eLTs). OBJECTIVE: Our aim was to identify the T-cell subsets involved in local immunoglobulin production independent of eLTs in NPs. METHODS: The localization, abundance, and phenotype of CD4+ T-cell subsets were studied by immunofluorescence, flow cytometry, and single-cell RNA sequencing. Purified nasal T-cell subsets were cultured with autologous peripheral naive B cells to explore their function. Programmed death ligand 1 and programmed death ligand 2 expression in NPs was investigated by immunofluorescence staining and flow cytometry. RESULTS: Accumulation of PD-1highCXCR5-CD4+ T cells outside lymphoid aggregates was found in NPs. Nasal PD-1highCXCR5-CD4+ T cells were characterized by a unique phenotype that was related to B-cell help and tissue residency and distinct from PD-1-/intCXCR5- and CXCR5+ CD4+ T cells in NPs as well as PD-1highCXCR5highCD4+ follicular helper T cells in tonsils. Compared with the frequencies of PD-1highCXCR5-CD4+ T cells and their IFN-γ+, IL-17A+, and IL-21+ subsets in the control inferior turbinate tissues, the frequencies of these cells and their subsets were increased in both eosinophilic and noneosinophilic NPs, whereas the frequencies of the IL-4+ and IL-4+IL-21+ subsets were increased only in eosinophilic NPs. Nasal PD-1highCXCR5-CD4+ T cells induced immunoglobulin production from B cells in a potency comparable to that induced by tonsillar follicular helper T cells. PD-1highCXCR5-CD4+ T-cell frequencies were correlated with IgE levels in eosinophilic NPs. PD-L1 and PD-L2 suppressed the function of PD-1highCXCR5-CD4+ T cells, and their levels were reduced in NPs. PD-1highCXCR5-CD4+ T-cell abundance was associated with the postsurgical relapse of NPs. CONCLUSION: PD-1highCXCR5-CD4+ T cells participate in local immunoglobulin production independent of eLTs in NPs.

A Biological Feature and Heterogeneous Network Representation Learning-Based Framework for Drug-Target Interaction Prediction.

The prediction of drug-target interaction (DTI) is crucial to drug discovery. Although the interactions between the drug and target can be accurately verified by traditional biochemical experiments, the determination of DTI through biochemical experiments is a time-consuming, laborious, and expensive process. Therefore, we propose a learning-based framework named BG-DTI for drug-target interaction prediction. Our model combines two main approaches based on biological features and heterogeneous networks to identify interactions between drugs and targets. First, we extract original features from the sequence to encode each drug and target. Later, we further consider the relationships among various biological entities by constructing drug-drug similarity networks and target-target similarity networks. Furthermore, a graph convolutional network and a graph attention network in the graph representation learning module help us learn the features representation of drugs and targets. After obtaining the features from graph representation learning modules, these features are combined into fusion descriptors for drug-target pairs. Finally, we send the fusion descriptors and labels to a random forest classifier for predicting DTI. The evaluation results show that BG-DTI achieves an average AUC of 0.938 and an average AUPR of 0.930, which is better than those of five existing state-of-the-art methods. We believe that BG-DTI can facilitate the development of drug discovery or drug repurposing.

Reversal of pancreatic desmoplasia by a tumour stroma-targeted nitric oxide nanogel overcomes TRAIL resistance in pancreatic tumours.

OBJECTIVE: Stromal barriers, such as the abundant desmoplastic stroma that is characteristic of pancreatic ductal adenocarcinoma (PDAC), can block the delivery and decrease the tumour-penetrating ability of therapeutics such as tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), which can selectively induce cancer cell apoptosis. This study aimed to develop a TRAIL-based nanotherapy that not only eliminated the extracellular matrix barrier to increase TRAIL delivery into tumours but also blocked antiapoptotic mechanisms to overcome TRAIL resistance in PDAC. DESIGN: Nitric oxide (NO) plays a role in preventing tissue desmoplasia and could thus be delivered to disrupt the stromal barrier and improve TRAIL delivery in PDAC. We applied an in vitro-in vivo combinatorial phage display technique to identify novel peptide ligands to target the desmoplastic stroma in both murine and human orthotopic PDAC. We then constructed a stroma-targeted nanogel modified with phage display-identified tumour stroma-targeting peptides to co-deliver NO and TRAIL to PDAC and examined the anticancer effect in three-dimensional spheroid cultures in vitro and in orthotopic PDAC models in vivo. RESULTS: The delivery of NO to the PDAC tumour stroma resulted in reprogramming of activated pancreatic stellate cells, alleviation of tumour desmoplasia and downregulation of antiapoptotic BCL-2 protein expression, thereby facilitating tumour penetration by TRAIL and substantially enhancing the antitumour efficacy of TRAIL therapy. CONCLUSION: The co-delivery of TRAIL and NO by a stroma-targeted nanogel that remodels the fibrotic tumour microenvironment and suppresses tumour growth has the potential to be translated into a safe and promising treatment for PDAC.

USP44 positively regulates innate immune response to DNA viruses through deubiquitinating MITA.

Mediator of IRF3 activation (MITA, also known as stimulator of interferon genes, STING) senses the second messenger cyclic GMP-AMP (cGAMP) which is synthesized upon DNA virus infection and activates innate antiviral immune response. It has been demonstrated that the activity of MITA is delicately regulated by various post-translational modifications including polyubiquitination. In this study, we identified the deubiquitinating enzyme USP44 as a positive regulator of MITA. USP44 is recruited to MITA following DNA virus infection and removes K48-linked polyubiquitin moieties from MITA at K236, therefore prevents MITA from proteasome mediated degradation. USP44-deficiency results in acceleration of HSV-1-induced degradation of MITA and reduced induction of type I interferons (IFNs) and proinflammatory cytokines. Consistently, Usp44-/- mice are more susceptible to HSV-1 infection as indicated by higher tissue viral titers, greater tissue damage and lower survival rate. These findings suggest that USP44 plays a specific and critical role in the regulation of innate immune response against DNA viruses.

Reversible light-controlled fluorescence switch of block polymer-grafted carbon dots and cellular imaging.

A novel type of aggregation-induced emission (AIE) nanoparticles, which are carbon dots (CDs) grafted with block polymer of tetraphenylethylene, spiropyran and N-isopropylacrylamide (CD-g-poly((TPE-co-SPA)-block-NIPAM)), was synthesized. The CD-g-poly((TPE-co-SPA)-block-NIPAM) nanoparticles can emit weak cyan fluorescence in tetrahydrofuran, while showing AIE-enhanced cyan fluorescence in water and solid film. The fluorescence of the CD-g-poly((TPE-co-SPA)-block-NIPAM) nanoparticles can reversibly transform cyan to red with UV/visible light irradiation, and functioned as a reversible fluorescence photoswitch. Importantly, the CD-g-poly((TPE-co-SPA)-block-NIPAM) nanoparticles have low cytotoxicity and, therefore, can be used for imaging in living cells.

Preparation of chitosan-tannic acid coating and its anti-osteoclast and antibacterial activities in titanium implants.

INTRODUCTION: Bacterial infection and aseptic loosening caused by bone resorption at the implant interface are major clinical complications during bone defect implantation surgery, and surface modification of the implant to address the aforementioned problems has long been a research focus. MATERIALS AND METHODS: In this paper, a chitosan (CTS)-tannic acid (TA) colloid coating with a negative charge and excellent hydrophilicity was prepared on a Ti6Al4V (TC4) surface using a layer-by-layer assembly method. The physical properties, anti-osteoclast activity, and antimicrobial activity of the coatings were investigated. RESULTS: The findings showed that when the pH value was 5 and the ratio of CTS:TA was 0.8, the carrying rate of TA was the best. Furthermore, the CTS-TA coating had no cytotoxicity on the morphology and proliferation of BMSCs cells and effectively inhibited the differentiation of RAW264.7 cells into osteoclasts and the proliferation of Staphylococcus aureus and Escherichia coli. With the increase in the immersion time of TC4 in CTS-TA colloid solution, the inhibitory effects will also enhance. CONCLUSION: Therefore, the preparation of the CTS-TA coating provides a revolutionary technique for implant surface modification to avoid postoperative bacterial infection and aseptic loosening.

Variational graph auto-encoders for miRNA-disease association prediction.

Cumulative experimental studies have demonstrated the critical roles of microRNAs (miRNAs) in the diverse fundamental and important biological processes, and in the development of numerous complex human diseases. Thus, exploring the relationships between miRNAs and diseases is helpful with understanding the mechanisms, the detection, diagnosis, and treatment of complex diseases. As the identification of miRNA-disease associations via traditional biological experiments is time-consuming and expensive, an effective computational prediction method is appealing. In this study, we present a deep learning framework with variational graph auto-encoder for miRNA-disease association prediction (VGAE-MDA). VGAE-MDA first gets the representations of miRNAs and diseases from the heterogeneous networks constructed by miRNA-miRNA similarity, disease-disease similarity, and known miRNA-disease associations. Then, VGAE-MDA constructs two sub-networks: miRNA-based network and disease-based network. Combining the representations based on the heterogeneous network, two variational graph auto-encoders (VGAE) are deployed for calculating the miRNA-disease association scores from two sub-networks, respectively. Lastly, VGAE-MDA obtains the final predicted association score for a miRNA-disease pair by integrating the scores from these two trained networks. Unlike the previous model, the VGAE-MDA can mitigate the effect of noises from random selection of negative samples. Besides, the use of graph convolutional neural (GCN) network can naturally incorporate the node features from the graph structure while the variational autoencoder (VAE) makes use of latent variables to predict associations from the perspective of data distribution. The experimental results show that VGAE-MDA outperforms the state-of-the-art approaches in miRNA-disease association prediction. Besides, the effectiveness of our model has been further demonstrated by case studies.

Zebrafish Klf4 maintains the ionocyte progenitor population by regulating epidermal stem cell proliferation and lateral inhibition.

In the skin and gill epidermis of fish, ionocytes develop alongside keratinocytes and maintain body fluid ionic homeostasis that is essential for adaptation to environmental fluctuations. It is known that ionocyte progenitors in zebrafish embryos are specified from p63+ epidermal stem cells through a patterning process involving DeltaC (Dlc)-Notch-mediated lateral inhibition, which selects scattered dlc+ cells into the ionocyte progenitor fate. However, mechanisms by which the ionocyte progenitor population is modulated remain unclear. Krüppel-like factor 4 (Klf4) transcription factor was previously implicated in the terminal differentiation of mammalian skin epidermis and is known for its bifunctional regulation of cell proliferation in a tissue context-dependent manner. Here, we report novel roles for zebrafish Klf4 in the ventral ectoderm during embryonic skin development. We found that Klf4 was expressed in p63+ epidermal stem cells of the ventral ectoderm from 90% epiboly onward. Knockdown or knockout of klf4 expression reduced the proliferation rate of p63+ stem cells, resulting in decreased numbers of p63+ stem cells, dlc-p63+ keratinocyte progenitors and dlc+ p63+ ionocyte progenitor cells. These reductions subsequently led to diminished keratinocyte and ionocyte densities and resulted from upregulation of the well-known cell cycle regulators, p53 and cdkn1a/p21. Moreover, mutation analyses of the KLF motif in the dlc promoter, combined with VP16-klf4 or engrailed-klf4 mRNA overexpression analyses, showed that Klf4 can bind the dlc promoter and modulate lateral inhibition by directly repressing dlc expression. This idea was further supported by observing the lateral inhibition outcomes in klf4-overexpressing or knockdown embryos. Overall, our experiments delineate novel roles for zebrafish Klf4 in regulating the ionocyte progenitor population throughout early stem cell stage to initiation of terminal differentiation, which is dependent on Dlc-Notch-mediated lateral inhibition.

Differential expression and localization of immunity-related factors in main immune organs of yak.

The yak is an agricultural animal with strong disease resistance in Qinghai-Tibet Plateau. Immune organs are directly involved in the body's immune response and protect it from external aggression. In this study, we characterized and evaluated the main markers of interleukin (IL)-1ß, IL-17a, hypoxia inducer factor-1 (HIF-1)α, and heat shock protein 90 (HSP90) in the lymph nodes, spleen, thymus, and hemal nodes of adult yaks using network informatics, molecular cloning, immunohistochemistry, real-time quantitative polymerase chain reaction (RT-qPCR), and western blotting. We first cloned the IL-1ß and IL-17a mRNA of yaks. A significant feature was the higher IL-1ß and IL-17a expression in the lymph nodes than in the spleen, hemal nodes, and thymus. Immunohistochemistry and immunofluorescence revealed that IL-1ß and IL-17a cells were mainly located in the paracortex area of the lymph nodes and the T-cell-dependent area in the hemal nodes and spleen. Several HIF-1α proteins were detected in the cortex of the hemal nodes mantle, while HSP90 was detected in the lymphoid nodules of the hemal nodes and lymph nodes. This study sheds light on the relationship between the morphology and function of these organs and provides an important reference for studies on the participation of yak immune organs in immune responses.