How to avoid a local epidemic becoming a global pandemic.

Here, we combine international air travel passenger data with a standard epidemiological model of the initial 3 mo of the COVID-19 pandemic (January through March 2020; toward the end of which the entire world locked down). Using the information available during this initial phase of the pandemic, our model accurately describes the main features of the actual global development of the pandemic demonstrated by the high degree of coherence between the model and global data. The validated model allows for an exploration of alternative policy efficacies (reducing air travel and/or introducing different degrees of compulsory immigration quarantine upon arrival to a country) in delaying the global spread of SARS-CoV-2 and thus is suggestive of similar efficacy in anticipating the spread of future global disease outbreaks. We show that a lesson from the recent pandemic is that reducing air travel globally is more effective in reducing the global spread than adopting immigration quarantine. Reducing air travel out of a source country has the most important effect regarding the spreading of the disease to the rest of the world. Based upon our results, we propose a digital twin as a further developed tool to inform future pandemic decision-making to inform measures intended to control the spread of disease agents of potential future pandemics. We discuss the design criteria for such a digital twin model as well as the feasibility of obtaining access to the necessary online data on international air travel.

Prediction of blood-brain barrier penetrating peptides based on data augmentation with Augur.

BACKGROUND: The blood-brain barrier serves as a critical interface between the bloodstream and brain tissue, mainly composed of pericytes, neurons, endothelial cells, and tightly connected basal membranes. It plays a pivotal role in safeguarding brain from harmful substances, thus protecting the integrity of the nervous system and preserving overall brain homeostasis. However, this remarkable selective transmission also poses a formidable challenge in the realm of central nervous system diseases treatment, hindering the delivery of large-molecule drugs into the brain. In response to this challenge, many researchers have devoted themselves to developing drug delivery systems capable of breaching the blood-brain barrier. Among these, blood-brain barrier penetrating peptides have emerged as promising candidates. These peptides had the advantages of high biosafety, ease of synthesis, and exceptional penetration efficiency, making them an effective drug delivery solution. While previous studies have developed a few prediction models for blood-brain barrier penetrating peptides, their performance has often been hampered by issue of limited positive data. RESULTS: In this study, we present Augur, a novel prediction model using borderline-SMOTE-based data augmentation and machine learning. we extract highly interpretable physicochemical properties of blood-brain barrier penetrating peptides while solving the issues of small sample size and imbalance of positive and negative samples. Experimental results demonstrate the superior prediction performance of Augur with an AUC value of 0.932 on the training set and 0.931 on the independent test set. CONCLUSIONS: This newly developed Augur model demonstrates superior performance in predicting blood-brain barrier penetrating peptides, offering valuable insights for drug development targeting neurological disorders. This breakthrough may enhance the efficiency of peptide-based drug discovery and pave the way for innovative treatment strategies for central nervous system diseases.

iRice-MS: An integrated XGBoost model for detecting multitype post-translational modification sites in rice.

Post-translational modification (PTM) refers to the covalent and enzymatic modification of proteins after protein biosynthesis, which orchestrates a variety of biological processes. Detecting PTM sites in proteome scale is one of the key steps to in-depth understanding their regulation mechanisms. In this study, we presented an integrated method based on eXtreme Gradient Boosting (XGBoost), called iRice-MS, to identify 2-hydroxyisobutyrylation, crotonylation, malonylation, ubiquitination, succinylation and acetylation in rice. For each PTM-specific model, we adopted eight feature encoding schemes, including sequence-based features, physicochemical property-based features and spatial mapping information-based features. The optimal feature set was identified from each encoding, and their respective models were established. Extensive experimental results show that iRice-MS always display excellent performance on 5-fold cross-validation and independent dataset test. In addition, our novel approach provides the superiority to other existing tools in terms of AUC value. Based on the proposed model, a web server named iRice-MS was established and is freely accessible at http://lin-group.cn/server/iRice-MS.

Targeted ablation of the left middle cervical ganglion prevents ventricular arrhythmias and cardiac injury induced by AMI.

Cardiac sympathetic overactivation is a critical driver in the progression of acute myocardial infarction (AMI). The left middle cervical ganglion (LMCG) is an important extracardiac sympathetic ganglion. However, the regulatory effects of LMCG on AMI have not yet been fully documented. In the present study, we detected that the LMCG was innervated by abundant sympathetic components and exerted an excitatory effect on the cardiac sympathetic nervous system in response to stimulation. In canine models of AMI, targeted ablation of LMCG reduced the sympathetic indexes of heart rate variability and serum norepinephrine, resulting in suppressed cardiac sympathetic activity. Moreover, LMCG ablation could improve ventricular electrophysiological stability, evidenced by the prolonged ventricular effective refractory period, elevated action potential duration, increased ventricular fibrillation threshold, and enhanced connexin43 expression, consequently showing antiarrhythmic effects. Additionally, compared with the control group, myocardial infarction size, circulating cardiac troponin I, and myocardial apoptosis were significantly reduced, accompanied by preserved cardiac function in canines subjected to LMCG ablation. Finally, we performed the left stellate ganglion (LSG) ablation and compared its effects with LMCG destruction. The results indicated that LMCG ablation prevented ventricular electrophysiological instability, cardiac sympathetic activation, and AMI-induced ventricular arrhythmias with similar efficiency as LSG denervation. In conclusion, this study demonstrated that LMCG ablation suppressed cardiac sympathetic activity, stabilized ventricular electrophysiological properties and mitigated cardiomyocyte death, resultantly preventing ischemia-induced ventricular arrhythmias, myocardial injury, and cardiac dysfunction. Neuromodulation therapy targeting LMCG represented a promising strategy for the treatment of AMI.

Study on 2D Molecular Networks of Flexible Pentacarboxylic Acid Ligands Induced by Ether Bonds in Response to Selective Guest Inclusion.

The flexibility of ligands allows for their bending, twisting, or rotation to adopt various conformations, leading to distinct symmetries during the self-assembled process. Flexible aromatic acid ligands modified by ether bonds are a promising type of self-assembled module when it comes to surfaces. Here, two pentacarboxylic acid ligands (H5L1 and H5L2) with minor skeleton differences have successfully self-assembled into disparate porous networks on the graphite surface and demonstrated excellent potential for the inclusion of guest molecules. The H5L1 molecule's network structure only accommodates coronene (COR) molecules. With fewer COR molecules, H5L1 molecules act as a host template to accommodate the COR molecules. When there are too many COR molecules, COR molecules will induce H5L1 molecules to transform into a new host-guest nanostructure. Additionally, H5L2 molecules showed the ability to capture C70 molecules and exhibited cavity selectivity. However, the assembled network of H5L2 was slightly deformed in attempts to trap the COR molecules. To understand these phenomena more deeply, various assembled mechanisms were analyzed in combination with building theoretical models and energy analysis. These results reveal the great potential of flexible aromatic acid ligands in two-dimensional self-assembly and host-guest systems for their application in related fields.

The E3 Ligase TRIM16 Is a Key Suppressor of Pathological Cardiac Hypertrophy.

BACKGROUND: Pathological cardiac hypertrophy is one of the leading causes of heart failure with highly complicated pathogeneses. The E3 ligase TRIM16 (tripartite motif-containing protein 16) has been recognized as a pivotal regulator to control cell survival, immune response, and oxidativestress. However, the role of Trim16 in cardiac hypertrophy is unknown. METHODS: We generated cardiac-specific knockout mice and adeno-associated virus serotype 9-Trim16 mice to evaluate the function of Trim16 in pathological myocardial hypertrophy. The direct effect of TRIM16 on cardiomyocyte enlargement was examined using an adenovirus system. Furthermore, we combined RNA-sequencing and interactome analysis that was followed by multiple molecular biological methodologies to identify the direct target and corresponding molecular events contributing to TRIM16 function. RESULTS: We found an intimate correlation of Trim16 expression with hypertrophy-related heart failure in both human and mouse. Our functional investigations and unbiased transcriptomic analyses clearly demonstrated that Trim16 deficiency markedly exacerbated cardiomyocyte enlargement in vitro and in transverse aortic constriction-induced cardiac hypertrophy mouse model, whereas Trim16 overexpression attenuated cardiac hypertrophy and remodeling. Mechanistically, Prdx1 (peroxiredoxin 1) is an essential target of Trim16 in cardiac hypertrophy. We found that Trim16 interacts with Prdx1 and inhibits its phosphorylation, leading to a robust enhancement of its downstream Nrf2 (nuclear factor-erythroid 2-related factor 2) pathway to block cardiac hypertrophy. Trim16-blocked Prdx1 phosphorylation was largely dependent on a direct interaction between Trim16 and Src and the resultant Src ubiquitinational degradation. Notably, Prdx1 knockdown largely abolished the anti-hypertrophic effects of Trim16 overexpression. CONCLUSIONS: Our findings provide the first evidence supporting Trim16 as a novel suppressor of pathological cardiac hypertrophy and indicate that targeting the Trim16-Prdx1 axis represents a promising therapeutic strategy for hypertrophy-related heart failure.

Nuclear m6 A reader YTHDC1 suppresses proximal alternative polyadenylation sites by interfering with the 3' processing machinery.

N6-methyladenosine (m6 A) and alternative polyadenylation (APA) are important regulators of gene expression in eukaryotes. Recently, it was found that m6 A is closely related to APA. However, the molecular mechanism of this new APA regulation remains elusive. Here, we show that YTHDC1, a nuclear m6 A reader, can suppress proximal APA sites and produce longer 3' UTR transcripts by binding to their upstream m6 A sites. YTHDC1 can directly interact with the 3' end processing factor FIP1L1 and interfere with its ability to recruit CPSF4. Binding to the m6 A sites can promote liquid-liquid phase separation of YTHDC1 and FIP1L1, which may play an important role in their interaction and APA regulation. Collectively, YTHDC1 as an m6 A "reader" links m6 A modification with pre-mRNA 3' end processing, providing a new mechanism for APA regulation.

Long-term efficacy of microwave ablation for multifocal papillary thyroid microcarcinoma: a 5-year follow-up study.

OBJECTIVES: Microwave ablation (MWA) has achieved excellent long-term efficacy in treating unifocal papillary thyroid microcarcinoma (UPTMC). The therapeutic effect of this treatment on multifocal papillary thyroid microcarcinoma (MPTMC) is unknown. Therefore, we evaluated the long-term efficacy of MWA for low-risk MPTMC and to provide evidence-based medicine for the revision of clinical guidelines. METHODS: This study included 66 MPTMC patients with a total of 158 lesions, all of whom received MWA. We collected and retrospectively analyzed the patients' follow-up data before MWA, at 1, 3, 6, and 12 months posttreatment and every 6 months thereafter until 5 years posttreatment. We evaluated the MWA complication rate, technical success rate (TSR), lesion volume reduction rate (VRR), and complete disappearance rate (CDR) during follow-up and in those patients with tumor progression and delayed surgery. RESULTS: After 60 months of follow-up, all 158 lesions disappeared in 66 patients, and the volume was reduced from 43.82 mm3 to 0.00 mm3. The TSR and VRR were both 100%. The CDRs at 1 year, 2 years, and 3 years were 57.59%, 93.67%, and 100%, respectively. The complication rate was 3.03% (2/66), and the incidence of tumor progression was 3.03% (2/66), including one new intrathyroidal lesion and one cervical lymph node metastasis (LNM). These lesions were retreated with MWA, and the lesions disappeared during the follow-up period. CONCLUSIONS: Ultrasound-guided MWA for low-risk MPTMC is safe and effective and may serve as an alternative option for patients who refuse surgery or active surveillance (AS). CLINICAL RELEVANCE STATEMENT: This study concludes that ultrasound-guided microwave ablation for low-risk multifocal papillary thyroid microcarcinoma is safe and effective and may serve as an alternative option for patients who refuse surgery or active surveillance. KEY POINTS: • Ultrasound-guided microwave ablation for low-risk multifocal papillary thyroid microcarcinoma is safe and effective. • During 5 years of follow-up, multifocal papillary thyroid microcarcinoma patients treated with microwave ablation had a favorable prognosis. • To provide evidence-based medicine for the revision of clinical guidelines.

Tumor necrosis factor receptor-associated factor 5 protects against intimal hyperplasia by regulation of macrophage polarization via directly targeting PPARγ.

OBJECTIVES: Intimal hyperplasia is a serious clinical problem associated with the failure of therapeutic methods in multiple atherosclerosis-related coronary heart diseases, which are initiated and aggravated by the polarization of infiltrating macrophages. The present study aimed to determine the effect and underlying mechanism by which tumor necrosis factor receptor-associated factor 5 (TRAF5) regulates macrophage polarization during intimal hyperplasia. METHODS: TRAF5 expression was detected in mouse carotid arteries subjected to wire injury. Bone marrow-derived macrophages, mouse peritoneal macrophages and human myeloid leukemia mononuclear cells were also used to test the expression of TRAF5 in vitro. Bone marrow-derived macrophages upon to LPS or IL-4 stimulation were performed to examine the effect of TRAF5 on macrophage polarization. TRAF5-knockout mice were used to evaluate the effect of TRAF5 on intimal hyperplasia. RESULTS: TRAF5 expression gradually decreased during neointima formation in carotid arteries in a time-dependent manner. In addition, the results showed that TRAF5 expression was reduced in classically polarized macrophages (M1) subjected to LPS stimulation but was increased in alternatively polarized macrophages (M2) in response to IL-4 administration, and these changes were demonstrated in three different types of macrophages. An in vitro loss-of-function study with TRAF5 knockdown plasmids or TRAF5-knockout mice revealed high expression of markers associated with M1 macrophages and reduced expression of genes related to M2 macrophages. Subsequently, we incubated vascular smooth muscle cells with conditioned medium of polarized macrophages in which TRAF5 expression had been downregulated or ablated, which promoted the proliferation, migration and dedifferentiation of VSMCs. Mechanistically, TRAF5 knockdown inhibited the activation of anti-inflammatory M2 macrophages by directly inhibiting PPARγ expression. More importantly, TRAF5-deficient mice showed significantly aggressive intimal hyperplasia. CONCLUSIONS: Collectively, this evidence reveals an important role of TRAF5 in the development of intimal hyperplasia through the regulation of macrophage polarization, which provides a promising target for arterial restenosis-related disease management.

Anemoside B4, a new pyruvate carboxylase inhibitor, alleviates colitis by reprogramming macrophage function.

OBJECTIVES: Colitis is a global disease usually accompanied by intestinal epithelial damage and intestinal inflammation, and an increasing number of studies have found natural products to be highly effective in treating colitis. Anemoside B4 (AB4), an abundant saponin isolated from Pulsatilla chinensis (Bunge), which was found to have strong anti-inflammatory activity. However, the exact molecular mechanisms and direct targets of AB4 in the treatment of colitis remain to be discovered. METHODS: The anti-inflammatory activities of AB4 were verified in LPS-induced cell models and 2, 4, 6-trinitrobenzene sulfonic (TNBS) or dextran sulfate sodium (DSS)-induced colitis mice and rat models. The molecular target of AB4 was identified by affinity chromatography analysis using chemical probes derived from AB4. Experiments including proteomics, molecular docking, biotin pull-down, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA) were used to confirm the binding of AB4 to its molecular target. Overexpression of pyruvate carboxylase (PC) and PC agonist were used to study the effects of PC on the anti-inflammatory and metabolic regulation of AB4 in vitro and in vivo. RESULTS: AB4 not only significantly inhibited LPS-induced NF-κB activation and increased ROS levels in THP-1 cells, but also suppressed TNBS/DSS-induced colonic inflammation in mice and rats. The molecular target of AB4 was identified as PC, a key enzyme related to fatty acid, amino acid and tricarboxylic acid (TCA) cycle. We next demonstrated that AB4 specifically bound to the His879 site of PC and altered the protein's spatial conformation, thereby affecting the enzymatic activity of PC. LPS activated NF-κB pathway and increased PC activity, which caused metabolic reprogramming, while AB4 reversed this phenomenon by inhibiting the PC activity. In vivo studies showed that diisopropylamine dichloroacetate (DADA), a PC agonist, eliminated the therapeutic effects of AB4 by changing the metabolic rearrangement of intestinal tissues in colitis mice. CONCLUSION: We identified PC as a direct cellular target of AB4 in the modulation of inflammation, especially colitis. Moreover, PC/pyruvate metabolism/NF-κB is crucial for LPS-driven inflammation and oxidative stress. These findings shed more light on the possibilities of PC as a potential new target for treating colitis.

Evaluating the prognostic value of tumor deposits in non-metastatic lymph node-positive colon adenocarcinoma using Cox regression and machine learning.

BACKGROUND: The 8th AJCC TNM staging for non-metastatic lymph node-positive colon adenocarcinoma patients(NMLP-CA) stages solely by lymph node status, irrespective of the positivity of tumor deposits (TD). This study uses machine learning and Cox regression to predict the prognostic value of tumor deposits in NMLP-CA. METHODS: Patient data from the SEER registry (2010-2019) was used to develop CSS nomograms based on prognostic factors identified via multivariate Cox regression. Model performance was evaluated by c-index, dynamic calibration, and Schmid score. Shapley additive explanations (SHAP) were used to explain the selected models. RESULTS: The study included 16,548 NMLP-CA patients, randomized 7:3 into training (n = 11,584) and test (n = 4964) sets. Multivariate Cox analysis identified TD, age, marital status, primary site, grade, pT stage, and pN stage as prognostic for cancer-specific survival (CSS). In the test set, the gradient boosting machine (GBM) model achieved the best C-index (0.733) for CSS prediction, while the Cox model and GAMBoost model optimized dynamic calibration(6.473) and Schmid score (0.285), respectively. TD ranked among the top 3 most important features in the models, with increasing predictive significance over time. CONCLUSIONS: Positive tumor deposit status confers worse prognosis in NMLP-CA patients. Tumor deposits may confer higher TNM staging. Furthermore, TD could play a more significant role in the staging system.

Diagnostic accuracy of salivary active matrix metalloproteinase (aMMP)-8 point-of-care test for detecting periodontitis in adults: A systematic review and meta-analysis.

OBJECTIVE: To determine the accuracy of salivary active matrix metalloproteinase (aMMP)-8 point-of-care test (POCT) for detecting periodontitis in adults, through meta-analysis. MATERIALS AND METHODS: Diagnostic studies evaluating the accuracy of salivary/oral rinse aMMP-8 POCT for detecting periodontitis in adults, when compared with clinical examination, were considered eligible. A comprehensive search was performed up to 31 August 2023 through five databases. Quality Assessment of Diagnostic Accuracy Studies 2 was utilized to evaluate the methodological quality of the included articles. Meta-analysis was performed using Bayesian bivariate hierarchical model and subgroup analysis. RESULTS: From 368 screened studies, 6 studies (4 cross-sectional and 2 longitudinal studies) were included in the meta-analysis. Overall, the pooled sensitivity and specificity of salivary aMMP-8-POCT for detecting periodontitis were 0.63 (95% CI: 0.41-0.82) and 0.84 (95% CI: 0.65-0.95), respectively. Subgroup analyses revealed that the 95% CI for oral fluid types, predefined diagnostic thresholds and the POCT systems largely overlapped, indicating that the differences between them may not be significant. CONCLUSION: Salivary aMMP-8 POCT shows fair accuracy for detecting periodontitis. The diagnostic accuracy cannot be significantly influenced by the types of oral fluids, predefined diagnostic thresholds or the specific POCT systems used. More research is needed to confirm the clinical utility and implementation of aMMP-8 POCT in the diagnosis of periodontitis.

Enhanced control of periodontitis by an artificial intelligence-enabled multimodal-sensing toothbrush and targeted mHealth micromessages: A randomized trial.

AIM: Treatment of periodontitis, a chronic inflammatory disease driven by biofilm dysbiosis, remains challenging due to patients' poor performance and adherence to the necessary oral hygiene procedures. Novel, artificial intelligence-enabled multimodal-sensing toothbrushes (AI-MST) can guide patients' oral hygiene practices in real-time and transmit valuable data to clinicians, thus enabling effective remote monitoring and guidance. The aim of this trial was to assess the effect of such a system as an adjunct to clinical practice guideline-conform treatment. MATERIALS AND METHODS: This was a single-centre, double-blind, standard-of-care controlled, randomized, parallel-group, superiority trial. Male and female adults with generalized Stage II/III periodontitis were recruited at the Shanghai Ninth People's Hospital, China. Subjects received a standard-of-care oral hygiene regimen or a technology-enabled, theory-based digital intervention consisting of an AI-MST and targeted doctor's guidance by remote micromessaging. Additionally, both groups received guideline-conform periodontal treatment. The primary outcome was the resolution of inflamed periodontal pockets (≥4 mm with bleeding on probing) at 6 months. The intention-to-treat (ITT) analysis included all subjects who received the allocated treatment and at least one follow-up. RESULTS: One hundred patients were randomized and treated (50 tests/controls) between 1 February and 30 November 2022. Forty-eight tests (19 females) and 47 controls (16 females) were analysed in the ITT population. At 6 months, the proportion of inflamed periodontal pockets decreased from 80.7% (95% confidence interval [CI] 76.5-84.8) to 52.3% (47.7-57.0) in the control group, and from 81.4% (77.1-85.6) to 44.4% (39.9-48.9) in the test group. The inter-group difference was 7.9% (1.6-14.6, p < .05). Test subjects achieved better levels of oral hygiene (p < .001). No significant adverse events were observed. CONCLUSIONS: The tested digital health intervention significantly improved the outcome of periodontal therapy by enhancing the adherence and performance of self-performed oral hygiene. The model breaks the traditional model of oral health care and has the potential to improve efficiency and reduce costs (NCT05137392).

Detection of cryptic balanced chromosomal rearrangements using high-resolution optical genome mapping.

BACKGROUND: Chromosomal rearrangements have profound consequences in diverse human genetic diseases. Currently, the detection of balanced chromosomal rearrangements (BCRs) mainly relies on routine cytogenetic G-banded karyotyping. However, cryptic BCRs are hard to detect by karyotyping, and the risk of miscarriage or delivering abnormal offspring with congenital malformations in carrier couples is significantly increased. In the present study, we aimed to investigate the potential of single-molecule optical genome mapping (OGM) in unravelling cryptic chromosomal rearrangements. METHODS: Eleven couples with normal karyotypes that had abortions/affected offspring with unbalanced rearrangements were enrolled. Ultra-high-molecular-weight DNA was isolated from peripheral blood cells and processed via OGM. The genome assembly was performed followed by variant calling and annotation. Meanwhile, multiple detection strategies, including FISH, long-range-PCR amplicon-based next-generation sequencing and Sanger sequencing were implemented to confirm the results obtained from OGM. RESULTS: High-resolution OGM successfully detected cryptic reciprocal translocation in all recruited couples, which was consistent with the results of FISH and sequencing. All high-confidence cryptic chromosomal translocations detected by OGM were confirmed by sequencing analysis of rearrangement breakpoints. Moreover, OGM revealed additional complex rearrangement events such as inverted aberrations, further refining potential genetic interpretation. CONCLUSION: To the best of our knowledge, this is the first study wherein OGM facilitate the rapid and robust detection of cryptic chromosomal reciprocal translocations in clinical practice. With the excellent performance, our findings suggest that OGM is well qualified as an accurate, comprehensive and first-line method for detecting cryptic BCRs in routine clinical testing.

Ill-fitting prosthesis is associated with an increased risk of elevated blood pressures.

OBJECTIVE: Previous studies focused on the benefits of adequate prosthodontic treatment, while few studies have investigated the prosthodontic-related risks to health. As a modifiable oral health indicator, the association of ill-fitting prosthesis (IFP) with hypertension has not been fully explored. METHODS: This cross-sectional study involved 158,659 adults in Beijing (2009-2017) receiving intra-oral examinations and blood pressure measurements. Logistic regression models were applied to assess the association of IFP with the prevalence of hypertension, systolic blood pressure (SBP) ≧ 140 mmHg and diastolic blood pressure (DBP) ≧ 90 mmHg, as well as subgroup analyses by different fixed IFP subgroups (according to involved teeth number) and removable IFP subgroup. We further investigated effect modifications among stratified populations. RESULTS: 158,659 individuals were included for analysis, 346 (26.86%) in IFP group and 27,380 (17.40%) in non-IFP group (p < 0.001) were hypertensive. After adjustment of sex, age, obesity, dyslipidaemia, diabetes, hsCRP, family history of CVD, self-reported smoking, self-reported drinking and WC, ORs of hypertension, SBP ≧ 140 mmHg and DBP ≧ 90 mmHg were 1.330 (95% CI: 1.162-1.522), 1.277 (95% CI: 1.098-1.486) and 1.376 (95% CI: 1.186-1.596), respectively (p < 0.05). Furthermore, after full adjustment, the number of involved teeth showed a significant incremental trend with hypertension risk in the population with and without IFP (p for trend <0.001). The IFP-blood pressure associations were more pronounced in females, 18-60 years, non-obese and diabetic participants. CONCLUSION: As a modifiable oral indicator, IFP was significantly associated with a higher risk of hypertension.

Smooth-Muscle-Cell-Specific Deletion of CD38 Protects Mice from AngII-Induced Abdominal Aortic Aneurysm through Inhibiting Vascular Remodeling.

Abdominal aortic aneurysm (AAA) is a serious vascular disease which is associated with vascular remodeling. CD38 is a main NAD+-consuming enzyme in mammals, and our previous results showed that CD38 plays the important roles in many cardiovascular diseases. However, the role of CD38 in AAA has not been explored. Here, we report that smooth-muscle-cell-specific deletion of CD38 (CD38SKO) significantly reduced the morbidity of AngII-induced AAA in CD38SKOApoe-/- mice, which was accompanied with a increases in the aortic diameter, medial thickness, collagen deposition, and elastin degradation of aortas. In addition, CD38SKO significantly suppressed the AngII-induced decreases in α-SMA, SM22α, and MYH11 expression; the increase in Vimentin expression in VSMCs; and the increase in VCAM-1 expression in smooth muscle cells and macrophage infiltration. Furthermore, we demonstrated that the role of CD38SKO in attenuating AAA was associated with the activation of sirtuin signaling pathways. Therefore, we concluded that CD38 plays a pivotal role in AngII-induced AAA through promoting vascular remodeling, suggesting that CD38 may serve as a potential therapeutic target for the prevention of AAA.

Impact of periodontitis on type 2 diabetes: a bioinformatic analysis.

BACKGROUND: Periodontitis is strongly associated with type 2 diabetes (T2D) that results in serious complications and mortality. However, the pathogenic role of periodontitis in the development of T2D and the underlain mechanism have not been fully elucidated. METHODS: A Mendelian randomization (MR) was performed to estimate the causality between two diseases. Bioinformatics tools, including gene ontology and pathway enrichment analyses, were employed to analyze the common differentially expressed genes (DEGs) in periodontitis and T2D. MR and colocalization analyses were then utilized to investigate the causal associations between potential pathogenic gene expression and the risk of T2D. Single cell-type expression analysis was further performed to detect the cellular localization of these genes. RESULTS: Genetically predicted periodontitis was associated with a higher risk of T2D (OR, 1.469; 95% CI, 1.117-1.930; P = 0.006) and insulin resistance (OR 1.034; 95%CI 1.001-1.068; P = 0.041). 79 common DEGs associated with periodontitis and T2D were then identified and demonstrated enrichment mainly in CXC receptor chemokine receptor binding and interleutin-17 signaling pathway. The integration of GWAS with the expression quantitative trait locis of these genes from the peripheral blood genetically prioritized 6 candidate genes, including 2 risk genes (RAP2A, MCUR1) and 4 protective genes (WNK1, NFIX, FOS, PANX1) in periodontitis-related T2D. Enriched in natural killer cells, RAP2A (OR 4.909; 95% CI 1.849-13.039; P = 0.001) demonstrated high risk influence on T2D, and exhibited strong genetic evidence of colocalization (coloc.abf-PPH4 = 0.632). CONCLUSIONS: This study used a multi-omics integration method to explore causality between periodontitis and T2D, and revealed molecular mechanisms using bioinformatics tools. Periodontitis was associated with a higher risk of T2D. MCUR1, RAP2A, FOS, PANX1, NFIX and WNK1 may play important roles in the pathogenesis of periodontitis-related T2D, shedding light on the development of potential drug targets.

Non-Directed C-H Arylation of Anisole Derivatives via Pd/S,O-Ligand Catalysis.

Non-directed C-H arylation is one of the most efficient methods to synthesize biaryl compounds without the need of the prefuctionalization of starting materials, or the installment and removal of directing groups on the substrate. A direct C-H arylation of simple arenes as limiting reactants remains a challenge. Here we disclose a non-directed C-H arylation of anisole derivatives as limiting reagents with aryl iodides under mild reaction conditions. The arylated products are obtained in synthetically useful yields and the arylation of bioactive molecules is also demonstrated. Key to the success of this methodology is the use of a one-step synthesized S,O-ligand.

MiRACLe: an individual-specific approach to improve microRNA-target prediction based on a random contact model.

Deciphering microRNA (miRNA) targets is important for understanding the function of miRNAs as well as miRNA-based diagnostics and therapeutics. Given the highly cell-specific nature of miRNA regulation, recent computational approaches typically exploit expression data to identify the most physiologically relevant target messenger RNAs (mRNAs). Although effective, those methods usually require a large sample size to infer miRNA-mRNA interactions, thus limiting their applications in personalized medicine. In this study, we developed a novel miRNA target prediction algorithm called miRACLe (miRNA Analysis by a Contact modeL). It integrates sequence characteristics and RNA expression profiles into a random contact model, and determines the target preferences by relative probability of effective contacts in an individual-specific manner. Evaluation by a variety of measures shows that fitting TargetScan, a frequently used prediction tool, into the framework of miRACLe can improve its predictive power with a significant margin and consistently outperform other state-of-the-art methods in prediction accuracy, regulatory potential and biological relevance. Notably, the superiority of miRACLe is robust to various biological contexts, types of expression data and validation datasets, and the computation process is fast and efficient. Additionally, we show that the model can be readily applied to other sequence-based algorithms to improve their predictive power, such as DIANA-microT-CDS, miRanda-mirSVR and MirTarget4. MiRACLe is publicly available at https://github.com/PANWANG2014/miRACLe.

Nek6 knockdown polarized macrophages into a pro-inflammatory phenotype via inhibiting STAT3 expression.

Recently macrophage polarization has emerged as playing an essential role in the oathogenesis of atherosclerosis, which is the most important underlying process in many types of cardiovascular diseases. Although Nek6 has been reported to be involved in various cellular processes, the effect of Nek6 on macrophage polarization remains unknown. Macrophages exposed to lipopolysaccharide (LPS) or IL-4 were used to establish an in vitro model for the study of regulation of classically (M1) or alternatively (M2) activated macrophage. Bone marrow-derived macrophages (BMDMs) transfected with short hairpin RNA-targeting Nek6 were then in functional studies. We observed that Nek6 expression was decreased in both peritoneal macrophages (PMs) and BMDMs stimulated by LPS. This effect was seen at both mRNA and protein level. The opposite results were obtained after administration of IL-4. Macrophage-specific Nek6 knockdown significantly exacerbated pro-inflammatory M1 polarized macrophage gene expression in response to LPS challenge, but the anti-inflammatory response gene expression that is related to M2 macrophages was attenuated by Nek6 silencing followed by treatment with IL-4. Mechanistic studies exhibited that Nek6 knockdown inhibited the phosphorylated STAT3 expression that mediated the effect on macrophage polarization regulated by AdshNek6. Moreover, decreased Nek6 expression was also observed in atherosclerotic plaques. Collectively, these evidences suggested that Nek6 acts as a crucial site in macrophage polarization, and that this operates in a STAT3-dependent manner.