HypDB: A functionally annotated web-based database of the proline hydroxylation proteome.

Proline hydroxylation (Hyp) regulates protein structure, stability, and protein-protein interaction. It is widely involved in diverse metabolic and physiological pathways in cells and diseases. To reveal functional features of the Hyp proteome, we integrated various data sources for deep proteome profiling of the Hyp proteome in humans and developed HypDB (https://www.HypDB.site), an annotated database and web server for Hyp proteome. HypDB provides site-specific evidence of modification based on extensive LC-MS analysis and literature mining with 14,413 nonredundant Hyp sites on 5,165 human proteins including 3,383 Class I and 4,335 Class II sites. Annotation analysis revealed significant enrichment of Hyp on key functional domains and tissue-specific distribution of Hyp abundance across 26 types of human organs and fluids and 6 cell lines. The network connectivity analysis further revealed a critical role of Hyp in mediating protein-protein interactions. Moreover, the spectral library generated by HypDB enabled data-independent analysis (DIA) of clinical tissues and the identification of novel Hyp biomarkers in lung cancer and kidney cancer. Taken together, our integrated analysis of human proteome with publicly accessible HypDB revealed functional diversity of Hyp substrates and provides a quantitative data source to characterize Hyp in pathways and diseases.

Rapid in situ RNA imaging based on Cas12a thrusting strand displacement reaction.

RNA In situ imaging through DNA self-assembly is advantaged in illustrating its structures and functions with high-resolution, while the limited reaction efficiency and time-consuming operation hinder its clinical application. Here, we first proposed a new strand displacement reaction (SDR) model (Cas12a thrusting SDR, CtSDR), in which Cas12a could overcome the inherent reaction limitation and dramatically enhance efficiency through energy replenishment and by-product consumption. The target-initiated CtSDR amplification was established for RNA analysis, with order of magnitude lower limit of detection (LOD) than the Cas13a system. The CtSDR-based RNA in situ imaging strategy was developed to monitor intra-cellular microRNA expression change and delineate the landscape of oncogenic RNA in 66 clinic tissue samples, possessing a clear advantage over classic in situ hybridization (ISH) in terms of operation time (1 h versus 14 h) while showing comparable sensitivity and specificity. This work presents a promising approach to developing advanced molecular diagnostic tools.

Lysosome-targeted ruthenium(II) complex encapsulated with pluronic® F-127 induces oncosis in A549 cells.

Transition metal complexes with characteristics of unique packaging in nanoparticles and remarkable cancer cell cytotoxicity have emerged as potential alternatives to platinum-based antitumor drugs. Here we report the synthesis, characterization, and antitumor activities of three new Ruthenium complexes that introduce 5-fluorouracil-derived ligands. Notably, encapsulation of one such metal complex, Ru3, within pluronic® F-127 micelles (Ru3-M) significantly enhanced Ru3 cytotoxicity toward A549 cells by a factor of four. To determine the mechanisms underlying Ru3-M cytotoxicity, additional in vitro experiments were conducted that revealed A549 cell treatment with lysosome-targeting Ru3-M triggered oxidative stress, induced mitochondrial membrane potential depolarization, and drastically reduced intracellular ATP levels. Taken together, these results demonstrated that Ru3-M killed cells mainly via a non-apoptotic pathway known as oncosis, as evidenced by observed Ru3-M-induced cellular morphological changes including cytosolic flushing, cell swelling, and cytoplasmic vacuolation. In turn, these changes together caused cytoskeletal collapse and activation of porimin and calpain1 proteins with known oncotic functions that distinguished this oncotic process from other cell death processes. In summary, Ru3-M is a potential anticancer agent that kills A549 cells via a novel mechanism involving Ru(II) complex triggering of cell death via oncosis.

Endothelial mesenchymal transition promotes pannus formation in ankylosing spondylitis by activation of TGF-ß/SMAD signalling pathway.

OBJECTIVES: To explore the role of endothelial-mesenchymal transition (EndMT) mediated by the TGF-ß/SMAD signalling pathway in the pathogenesis of ankylosing spondylitis (AS). METHODS: Serum levels of TGF-ß1 were measured by enzyme-linked immunosorbent assay (ELISA) in 48 patients with AS and 15 healthy subjects. The expression levels of TGF-ß1, SMAD7, CTGF, CD34 and EndMT-related markers (α-SMA, vimentin, FSP-1, VE-cadherin) in the sacroiliac joint (SIJ) of three AS patients were detected by immunohistochemistry, and three non-spondyloarthritis (SpA) autopsy samples were used as controls. RESULTS: Serum TGF-ß1 level of AS patients was significantly higher than that of healthy controls (22971 ± 7667 pg/ml vs. 14837±4653 pg/ml, p<0.01). Compared with the non-SpA control group, the microvascular density (MVD) at the pannus formation site of SIJ in AS patients was significantly increased, accompanied by respectively increased expressions of TGF-ß1, CTGF, α-SMA, vimentin, and FSP-1 (all p<0.05), whereas respectively decreased expressions of VE-cadherin and SMAD7 (p<0.01). The expression level of FSP-1 was positively correlated with levels of TGF-ß1 and MVD, and negatively correlated with SMAD7. CONCLUSIONS: Our findings show that EndMT is involved in the promotion of pannus formation by TGF-ß/SMAD signalling pathway activation in AS.

PD-L1 siRNA hitched polyethyleneimine-elastase constituting nanovesicle induces tumor immunogenicity and PD-L1 silencing for synergistic antitumor immunotherapy.

BACKGROUND: PD-1/PD-L1 blockade has become a powerful method to treat malignant tumors. However, a large proportion of patients still do not benefit from this treatment, due to low tumor immunogenicity and low tumor penetration of the agents. Recently, neutrophil elastase has been shown to induce robust tumor immunogenicity, while the insufficient enzyme activity at the tumor site restricted its anti-tumor application. Here, we designed polyethyleneimine-modified neutrophil elastase (PEI-elastase) loaded with PD-L1small interfering RNA (PD-L1 siRNA) for improving enzymatic activity and delivering siRNA to tumor, which was expected to solve the above-mentioned problems. RESULTS: We first demonstrated that PEI-elastase possessed high enzymatic activity, which was also identified as an excellent gene-delivery material. Then, we synthesized anti-tumor lipopolymer (P-E/S Lip) by encapsulating PEI-elastase and PD-L1siRNA with pH-responsive anionic liposomes. The P-E/S Lip could be rapidly cleaved in tumor acidic environment, leading to exposure of the PEI-elastase/PD-L1 siRNA. Consequently, PEI-elastase induced powerful tumor immunogenicity upon direct tumor killing with minimal toxicity to normal cells. In parallel, PEI-elastase delivered PD-L1siRNA into the tumor and reduced PD-L1 expression. Orthotopic tumor administration of P-E/S Lip not only attenuated primary tumor growth, but also produced systemic anti-tumor immune response to inhibit growth of distant tumors and metastasis. Moreover, intravenous administration of P-E/S Lip into mice bearing subcutaneous tumors leaded to an effective inhibition of established B16-F10 tumor and 4T1 tumor, with histological analyses indicating an absence of detectable toxicity. CONCLUSIONS: In our study, a protease-based nanoplatform was used to cooperatively provoke robust tumor immunogenicity and down-regulate PD-L1 expression, which exhibited great potential as a combination therapy for precisely treating solid tumors.

UbE3-APA: a bioinformatic strategy to elucidate ubiquitin E3 ligase activities in quantitative proteomics study.

MOTIVATION: Ubiquitination is widely involved in protein homeostasis and cell signaling. Ubiquitin E3 ligases are critical regulators of ubiquitination that recognize and recruit specific ubiquitination targets for the final rate-limiting step of ubiquitin transfer reactions. Understanding the ubiquitin E3 ligase activities will provide knowledge in the upstream regulator of the ubiquitination pathway and reveal potential mechanisms in biological processes and disease progression. Recent advances in mass spectrometry-based proteomics have enabled deep profiling of ubiquitylome in a quantitative manner. Yet, functional analysis of ubiquitylome dynamics and pathway activity remains challenging. RESULTS: Here, we developed a UbE3-APA, a computational algorithm and stand-alone python-based software for Ub E3 ligase Activity Profiling Analysis. Combining an integrated annotation database with statistical analysis, UbE3-APA identifies significantly activated or suppressed E3 ligases based on quantitative ubiquitylome proteomics datasets. Benchmarking the software with published quantitative ubiquitylome analysis confirms the genetic manipulation of SPOP enzyme activity through overexpression and mutation. Application of the algorithm in the re-analysis of a large cohort of ubiquitination proteomics study revealed the activation of PARKIN and the co-activation of other E3 ligases in mitochondria depolarization-induced mitophagy process. We further demonstrated the application of the algorithm in the DIA (data-independent acquisition)-based quantitative ubiquitylome analysis. AVAILABILITY AND IMPLEMENTATION: Source code and binaries are freely available for download at URL: https://github.com/Chenlab-UMN/Ub-E3-ligase-Activity-Profiling-Analysis, implemented in python and supported on Linux and MS Windows. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Cyclometalated iridium(III) complexes induce immunogenic cell death in HepG2 cells via paraptosis.

Immunotherapy has been shown to provide superior antitumor efficacy by activating the innate immune system to recognize, attack and eliminate tumor cells without seriously harming normal cells. Herein, we designed and synthesized three new cyclometalated iridium(III) complexes (Ir1, Ir2, Ir3) then evaluated their antitumor activity. When co-incubated with HepG2 cells, the complex Ir1 localized in the lysosome, where it induced paraptosis and endoplasmic reticulum stress (ER stress). Notably, Ir1 also induced immunogenic cell death (ICD), promoted dendritic cell maturation that enhanced effector T cell chemotaxis to tumor tissues, down-regulated proportions of immunosuppressive regulatory T cells within tumor tissues and triggered activation of antitumor immunity throughout the body. To date, Ir1 is the first reported iridium(III) complex-based paraptosis inducer to successfully induce tumor cell ICD. Furthermore, Ir1 induced ICD of HepG2 cells without affecting cell cycle or reactive oxygen species levels.

The first Chinese with Hb Chile leading to chronic anemia and methemoglobinemia: a case report.

BACKGROUND: Hemoglobin (Hb) Chile [ß28(B10) Leu > Met; HBB: c.85 C > A] is a rare hemoglobin variant caused by a missense mutation in the HBB gene. Only one case of Hb Chile has been reported worldwide so far. It is an unstable hemoglobin, characterized by cyanosis associated with chronic methemoglobinemia and hemolytic anemia induced by sulfonamides or methylene blue. CASE PRESENTATION: A 9-year-3-month-old girl had mild anemia of unknown etiology for more than 6 years. She had a slight pallor without other symptoms or signs. The complete blood count revealed normocytic normochromic anemia with a sometimes-elevated reticulocyte count, and the bone marrow cytology showed marked erythroid hyperplasia, but the tests related to hemolysis were normal. Therefore, the whole exome sequencing was performed and showed a heterozygous mutation for HBB: c.85 C > A. With asymptomatic methemoglobinemia confirmed later, she was eventually diagnosed with Hb Chile. CONCLUSIONS: This is the first report of Hb Chile in China and the second worldwide. This case shows that Hb Chile is clinically heterogeneous and difficult to diagnose and expands our understanding on the clinical and hematological traits of the disease.

Acoustofluidic sonoporation for gene delivery to human hematopoietic stem and progenitor cells.

Advances in gene editing are leading to new medical interventions where patients' own cells are used for stem cell therapies and immunotherapies. One of the key limitations to translating these treatments to the clinic is the need for scalable technologies for engineering cells efficiently and safely. Toward this goal, microfluidic strategies to induce membrane pores and permeability have emerged as promising techniques to deliver biomolecular cargo into cells. As these technologies continue to mature, there is a need to achieve efficient, safe, nontoxic, fast, and economical processing of clinically relevant cell types. We demonstrate an acoustofluidic sonoporation method to deliver plasmids to immortalized and primary human cell types, based on pore formation and permeabilization of cell membranes with acoustic waves. This acoustofluidic-mediated approach achieves fast and efficient intracellular delivery of an enhanced green fluorescent protein-expressing plasmid to cells at a scalable throughput of 200,000 cells/min in a single channel. Analyses of intracellular delivery and nuclear membrane rupture revealed mechanisms underlying acoustofluidic delivery and successful gene expression. Our studies show that acoustofluidic technologies are promising platforms for gene delivery and a useful tool for investigating membrane repair.

Quantitative Proteome and Transcriptome Dynamics Analysis Reveals Iron Deficiency Response Networks and Signature in Neuronal Cells.

Iron and oxygen deficiencies are common features in pathophysiological conditions, such as ischemia, neurological diseases, and cancer. Cellular adaptive responses to such deficiencies include repression of mitochondrial respiration, promotion of angiogenesis, and cell cycle control. We applied a systematic proteomics analysis to determine the global proteomic changes caused by acute hypoxia and chronic and acute iron deficiency (ID) in hippocampal neuronal cells. Our analysis identified over 8600 proteins, revealing similar and differential effects of each treatment on activation and inhibition of pathways regulating neuronal development. In addition, comparative analysis of ID-induced proteomics changes in cultured cells and transcriptomic changes in the rat hippocampus identified common altered pathways, indicating specific neuronal effects. Transcription factor enrichment and correlation analysis identified key transcription factors that were activated in both cultured cells and tissue by iron deficiency, including those implicated in iron regulation, such as HIF1, NFY, and NRF1. We further identified MEF2 as a novel transcription factor whose activity was induced by ID in both HT22 proteome and rat hippocampal transcriptome, thus linking iron deficiency to MEF2-dependent cellular signaling pathways in neuronal development. Taken together, our study results identified diverse signaling networks that were differentially regulated by hypoxia and ID in neuronal cells.

The long-term urinary dysfunction after type C2 radical hysterectomy in patients with cervical cancer.

Radical hysterectomy (RH) may cause lower urinary tract symptoms (LUTS) for patients with cervical cancer. Few data are available on the long-term LUTS of these patients and whether the symptoms relate to the route of surgery remain unclear. Here, we assessed the long-term urinary dysfunction in cervical cancer patients after RH based on a self-reported questionnaire. A total of 168 patients after type C2 RH, either by laparoscopy (LRH) or laparotomy (ARH), were analysed. The median length of follow-up was 54 ± 8.35 months. The total incidence of urinary dysfunction was around 40%. Patients with LRH had more intermittent stream and feeling of incomplete emptying than those in ARH group. Our data indicate the irreversible damage of RH to urinary function of cervical cancer patients, who should be informed of the long-term and high incidence of urinary dysfunction after RH when they choose surgical treatment.Impact StatementWhat is already known on this subject? Radical hysterectomy (RH) with pelvic lymphadenectomy is standard surgical care for patients with cervical cancer. RH could induce urinary dysfunction, including bladder sensation loss, hypertonic and hypotonic bladder, urinary incontinence, etc. Studies mainly focus on short- or mid-term urinary dysfunction and stated that spontaneous recovery of urinary function is to be expected within 6-12 months after surgery.What the results of this study add? The lower urinary tract symptoms last for years after type C2 RH, indicating the irreversible damage of RH to urinary function of cervical cancer patients. The incidence of bladder dysfunction is increased in patients submitted to laparoscopic RH compared to abdominal RH.What the implications are of these findings for clinical practice and/or further research? Cervical cancer patients should be informed of the long-term and high incidence of urinary dysfunction after RH when they choose surgical treatment.

Tunable Symmetry-Breaking-Induced Dual Functions in Stable and Photoswitched Single-Molecule Junctions.

The aim of molecular electronics is to miniaturize active electronic devices and ultimately construct single-molecule nanocircuits using molecules with diverse structures featuring various functions, which is extremely challenging. Here, we realize a gate-controlled rectifying function (the on/off ratio reaches ∼60) and a high-performance field effect (maximum on/off ratio >100) simultaneously in an initially symmetric single-molecule photoswitch comprising a dinuclear ruthenium-diarylethene (Ru-DAE) complex sandwiched covalently between graphene electrodes. Both experimental and theoretical results consistently demonstrate that the initially degenerated frontier molecular orbitals localized at each Ru fragment in the open-ring Ru-DAE molecule can be tuned separately and shift asymmetrically under gate electric fields. This symmetric orbital shifting (AOS) lifts the degeneracy and breaks the molecular symmetry, which is not only essential to achieve a diode-like behavior with tunable rectification ratio and controlled polarity, but also enhances the field-effect on/off ratio at the rectification direction. In addition, this gate-controlled symmetry-breaking effect can be switched on/off by isomerizing the DAE unit between its open-ring and closed-ring forms with light stimulus. This new scheme offers a general and efficient strategy to build high-performance multifunctional molecular nanocircuits.

Impact of enhanced recovery after surgery protocol compliance on patients' outcome in benign hysterectomy and establishment of a predictive nomogram model.

BACKGROUND: Enhanced recovery after surgery (ERAS) pathways have been shown to improve clinical outcomes after surgery. Considering the importance of patient experience for patients with benign surgery, this study evaluated whether improved compliance with ERAS protocol modified for gynecological surgery which recommended by the ERAS Society is associated with better clinical outcomes and patient experience, and to determine the influence of compliance with each ERAS element on patients' outcome after benign hysterectomy. METHODS: A prospective observational study was performed on the women who underwent hysterectomy between 2019 and 2020. A total of 475 women greater 18 years old were classified into three groups according to their per cent compliance with ERAS protocols: Group I: < 60% (148 cases); Group II:≥60 and < 80% (160 cases); Group III: ≥80% (167 cases). Primary outcome was the 30-day postoperative complications. Second outcomes included QoR-15 questionnaire scores, patient satisfaction on a scale from 1 to 7, and length of stay after operation. After multivariable binary logistic regression analyse, a nomogram model was established to predict the incidence of having a postoperative complication with individual ERAS element compliance. RESULTS: The study enrolled 585 patients, and 475 completed the follow-up assessment. Patients with compliance over 80% had a significant reduction in postoperative complications (20.4% vs 41.2% vs 38.1%, P < 0.001) and length of stay after surgery (4 vs 5 vs 4, P < 0.001). Increased compliance was also associated with higher patient satisfaction and QoR-15 scores (P < 0.001),. Among the five dimensions of the QoR-15, physical comfort (P < 0.05), physical independence (P < 0.05), and pain dimension (P < 0.05) were better in the higher compliance groups. Minimally invasive surgery (MIS) (P < 0.001), postoperative nausea and vomiting (PONV) prophylaxis (P < 0.001), early mobilization (P = 0.031), early oral nutrition (P = 0.012), and early removal of urinary drainage (P < 0.001) were significantly associated with less complications. Having a postoperative complication was better predicted by the proposed nomogram model with high AUC value (0.906) and sensitivity (0.948) in the cohort. CONCLUSIONS: Improved compliance with the ERAS protocol was associated with improved recovery and better patient experience undergoing hysterectomy. MIS, PONV prophylaxis, early mobilization, early oral intake, and early removal of urinary drainage were of concern in reducing postoperative complications. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800019178 . Registered on 30/10/2018.

EGFL6 expression in hair follicle central isthmus is dependent on the presence of terminal Schwann cells.

Hair follicle central isthmus is surrounded by dense nerve endings and terminal Schwann cells (TSCs), forming a specialized sensory structure called lanceolate complexes. Extracellular matrix protein EGFL6 expressed from epidermis has been found closely associated with lanceolate complexes and important for proper alignment of nerve fibres and TSCs processes, and for proper response to light touch. However, how EGFL6 itself is specifically induced/deposited/maintained at the central isthmus remains to be elucidated. Previous reports and our results showed that nerve endings and TSCs docking at the central isthmus during hair follicle development occur before the specific depositing of EGFL6 protein. Furthermore, we found nude mice rarely maintain the lanceolate complex, and EGFL6 is lost in their aberrant hair follicle. Instead, reconstituted hair follicle in nude mice by stem cells chamber grafting assay expresses EGFL6 at the central isthmus area after hair follicle innervation. At last, long-term but not short-term cutaneous denervation leads to degeneration of TSCs and loss of EGFL6 expression. Together, our results demonstrate that EGFL6 expression in the central isthmus is dependent on the presence of TSCs, proposing that the interplay of epidermis and neuronal components is important for maintaining functional structure of lanceolate complexes.

Endothelial TFEB (Transcription Factor EB) Restrains IKK (IκB Kinase)-p65 Pathway to Attenuate Vascular Inflammation in Diabetic db/db Mice.

Objective- TFEB (transcription factor EB) was recently reported to be induced by atheroprotective laminar flow and play an anti-atherosclerotic role by inhibiting inflammation in endothelial cells (ECs). This study aims to investigate whether TFEB regulates endothelial inflammation in diabetic db/db mice and the molecular mechanisms involved. Approach and Results- Endothelial denudation shows that TFEB is mainly expressed in ECs in mouse aortas. Western blotting shows TFEB total protein level decreases whereas the p-TFEB S142 (phosphorylated form of TFEB) increases in db/db mouse aortas, suggesting a decreased TFEB activity. Adenoviral TFEB overexpression reduces endothelial inflammation as evidenced by decreased expression of vascular inflammatory markers in db/db mouse aortas, and reduced expression of a wide range of adhesion molecules and chemokines in human umbilical vein ECs. Monocyte attachment assay shows TFEB suppresses monocyte adhesion to human umbilical vein ECs. RNA sequencing of TFEB-overexpressed human umbilical vein ECs suggested TFEB inhibits NF-κB (nuclear factor-kappa B) signaling. Indeed, luciferase assay shows TFEB suppresses NF-κB transcriptional activity. Mechanistically, TFEB suppresses IKK (IκB kinase) activity to protect IκB-α from degradation, leading to reduced p65 nuclear translocation. Inhibition of IKK by PS-1145 abolished TFEB silencing-induced inflammation in human umbilical vein ECs. Lastly, we identified KLF2 (Krüppel-like factor 2) upregulates TFEB expression and promoter activity. Laminar flow experiment showed that KLF2 is required for TFEB induction by laminar flow and TFEB is an anti-inflammatory effector downstream of laminar flow-KLF2 signaling in ECs. Conclusions- These findings suggest that TFEB exerts anti-inflammatory effects in diabetic mice and such function in ECs is achieved by inhibiting IKK activity and increasing IκBα level to suppress NF-κB activity. KLF2 mediates TFEB upregulation in response to laminar flow.

Long noncoding RNAs C2dat1 enhances vascular smooth muscle cell proliferation and migration by targeting MiR-34a-5p.

Deregulated proliferation of vascular smooth muscle cells (VSMCs) is one common phenomenon of atherosclerosis progression. Long noncoding RNAs (lncRNAs) are one group of noncoding RNAs that play essential roles in many cell biological processes, including cell development, growth, and migration. However, the role of a novel calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D)-associated lncRNA, CAMK2D-associated transcript 1 (C2dat1), in VSMCs is still uncovered. In this study, we showed that the expression level of C2dat1 was higher in coronary artery disease (CAD) tissues than in normal arterial tissues and the C2dat1 expression level was upregulated in the proliferating VSMC after being treated with PDGF-bb or TNF-α. In addition, we indicated that overexpression of C2dat1 promoted VSMC growth and enhanced proliferating cell nuclear antigen (PCNA) expression in VSMC. Moreover, ectopic expression of C2dat1 increased VSMC migration. Furthermore, we showed that elevated expression of C2dat1 suppressed microRNA-34a (miR-34a) expression and promoted sirtuin 1 (SIRT1) expression, which was a direct target gene of miR-34a. We demonstrated that the expression level of miR-34a was lower in CAD tissues than in normal arterial tissues and the expression of miR-34a was negatively correlated with C2dat1 expression. Restored expression of C2dat1 increased VSMC proliferation and migration through promoting SIRT1 expression. These data suggested that lncRNA C2dat1 might be a potential therapeutic target to promote VSMC growth and migration in CAD.

DRMDA: deep representations-based miRNA-disease association prediction.

Recently, microRNAs (miRNAs) are confirmed to be important molecules within many crucial biological processes and therefore related to various complex human diseases. However, previous methods of predicting miRNA-disease associations have their own deficiencies. Under this circumstance, we developed a prediction method called deep representations-based miRNA-disease association (DRMDA) prediction. The original miRNA-disease association data were extracted from HDMM database. Meanwhile, stacked auto-encoder, greedy layer-wise unsupervised pre-training algorithm and support vector machine were implemented to predict potential associations. We compared DRMDA with five previous classical prediction models (HGIMDA, RLSMDA, HDMP, WBSMDA and RWRMDA) in global leave-one-out cross-validation (LOOCV), local LOOCV and fivefold cross-validation, respectively. The AUCs achieved by DRMDA were 0.9177, 08339 and 0.9156 ± 0.0006 in the three tests above, respectively. In further case studies, we predicted the top 50 potential miRNAs for colon neoplasms, lymphoma and prostate neoplasms, and 88%, 90% and 86% of the predicted miRNA can be verified by experimental evidence, respectively. In conclusion, DRMDA is a promising prediction method which could identify potential and novel miRNA-disease associations.

Stereoelectronic Effect-Induced Conductance Switching in Aromatic Chain Single-Molecule Junctions.

Biphenyl, as the elementary unit of organic functional materials, has been widely used in electronic and optoelectronic devices. However, over decades little has been fundamentally understood regarding how the intramolecular conformation of biphenyl dynamically affects its transport properties at the single-molecule level. Here, we establish the stereoelectronic effect of biphenyl on its electrical conductance based on the platform of graphene-molecule single-molecule junctions, where a specifically designed hexaphenyl aromatic chain molecule is covalently sandwiched between nanogapped graphene point contacts to create stable single-molecule junctions. Both theoretical and temperature-dependent experimental results consistently demonstrate that phenyl twisting in the aromatic chain molecule produces different microstates with different degrees of conjugation, thus leading to stochastic switching between high- and low-conductance states. These investigations offer new molecular design insights into building functional single-molecule electrical devices.

Detection and characterization of the accessory mental foramen using cone-beam computed tomography.

OBJECTIVE: This study aimed to investigate the frequency and characteristics of accessory mental foramina (AMFs) and their bony canals in a selected Chinese population using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: Reconstructed CBCT images of the mandible in 784 Chinese patients (305 males and 479 females) were retrospectively analysed to identify the AMF. The presence, dimension and location of the AMF as well as the origin and course of the associated bony canal were evaluated and classified. Variations in these characteristics were analysed according to gender, side and age. RESULTS: A total of 66 AMFs were found in 57 (7.3%) of the 784 patients. The frequency of AMFs was significantly influenced by gender and side of the mandible (p < .05). Most AMFs were located apically between apices of the first and second premolars. The high-position AMFs (above the mental foramen) accounted for 54.5% of the total. The mean horizontal and vertical diameters of the AMF were 1.38 ± 0.47 and 1.23 ± 0.37 mm, respectively. Two typical types of the bony canal leading to the AMF were identified according to their bifurcation site from the mandibular canal. Most bony canals originated from the anterior loop of the mental canal (56.1%) and coursed posterosuperiorly (36.3%). The mean length of the bony canals was 5.78 ± 2.31 mm. CONCLUSIONS: This study presents a considerable frequency of AMFs in a Chinese population. The high-position AMF and the associated bony canal coursing in the oblique upward direction appear frequently. Thus, clinicians should be alert to the presence of the AMF to avoid neurovascular complications especially when dental procedures require periosteum detachment and implant insertion in the mental region.

Tuning Charge Transport in Aromatic-Ring Single-Molecule Junctions via Ionic-Liquid Gating.

Achieving gate control with atomic precision, which is crucial to the transistor performance on the smallest scale, remains a challenge. Herein we report a new class of aromatic-ring molecular nanotransistors based on graphene-molecule-graphene single-molecule junctions by using an ionic-liquid gate. Experimental phenomena and theoretical calculations confirm that this ionic-liquid gate can effectively modulate the alignment between molecular frontier orbitals and the Fermi energy level of graphene electrodes, thus tuning the charge-transport properties of the junctions. In addition, with a small gate voltage (|VG |≤1.5 V) ambipolar charge transport in electrochemically inactive molecular systems (EG >3.5 eV) is realized. These results offer a useful way to build high-performance single-molecule transistors, thus promoting the prospects for molecularly engineered electronic devices.