Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose.

Immune recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors often activates proinflammatory NF-κB signalling1. Recent studies indicate that the bacterial metabolite D-glycero-ß-D-manno-heptose 1,7-bisphosphate (HBP) can activate NF-κB signalling in host cytosol2-4, but it is unclear whether HBP is a genuine PAMP and the cognate pattern recognition receptor has not been identified. Here we combined a transposon screen in Yersinia pseudotuberculosis with biochemical analyses and identified ADP-ß-D-manno-heptose (ADP-Hep), which mediates type III secretion system-dependent NF-κB activation and cytokine expression. ADP-Hep, but not other heptose metabolites, could enter host cytosol to activate NF-κB. A CRISPR-Cas9 screen showed that activation of NF-κB by ADP-Hep involves an ALPK1 (alpha-kinase 1)-TIFA (TRAF-interacting protein with forkhead-associated domain) axis. ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. The crystal structure of the N-terminal domain of ALPK1 and ADP-Hep in complex revealed the atomic mechanism of this ligand-receptor recognition process. HBP was transformed by host adenylyltransferases into ADP-heptose 7-P, which could activate ALPK1 to a lesser extent than ADP-Hep. ADP-Hep (but not HBP) alone or during bacterial infection induced Alpk1-dependent inflammation in mice. Our findings identify ALPK1 and ADP-Hep as a pattern recognition receptor and an effective immunomodulator, respectively.

Cooperative Action between SALL4A and TET Proteins in Stepwise Oxidation of 5-Methylcytosine.

TET family enzymes successively oxidize 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine, leading to eventual demethylation. 5hmC and TET enzymes occupy distinct chromatin regions, suggesting unknown mechanisms controlling the fate of 5hmC within diverse chromatin environments. Here, we report that SALL4A preferentially associates with 5hmC in vitro and occupies enhancers in mouse embryonic stem cells in a largely TET1-dependent manner. Although most 5hmC at SALL4A peaks undergoes further oxidation, this process is abrogated upon deletion of Sall4 gene, with a concomitant reduction of TET2 at these regions. Thus, SALL4A facilitates further oxidation of 5hmC at its binding sites, which requires its 5hmC-binding activity and TET2, supporting a collaborative action between SALL4A and TET proteins in regulating stepwise oxidation of 5mC at enhancers. Our study identifies SALL4A as a 5hmC binder, which facilitates 5hmC oxidation by stabilizing TET2 association, thereby fine-tuning expression profiles of developmental genes in mouse embryonic stem cells.

Value Analysis of Four-Dimensional Color Ultrasound Combined with Maternal Serological Index in Prenatal Screening for Fetal Anomalies.

Objective: This study aimed to assess the efficacy of combining four-dimensional (4D) color ultrasound with maternal serological index testing in prenatal screening for fetal anomalies. Methods: A retrospective analysis was conducted on data from 864 pregnant women who underwent prenatal checkups at the hospital between January 2020 and January 2021. During the mid-pregnancy period, serological tests were performed to determine levels of alpha-fetoprotein (AFP), free ß-subunit of human chorionic gonadotropin (Free-HCG ß), pregnancy-associated plasma protein A (PAPP-A), and vitamin B12 (VitB12). Additionally, 4D color ultrasound examinations were conducted. The gold standard for evaluation was the results of delivery or labor induction. AFP, Free-HCG ß, PAPP-A, and VitB12 levels were compared between the anomaly group and the normal group. The diagnostic efficacy of single and combined detection of serological indexes and 4D color ultrasound was analyzed, with the calculation of the areas under the curve (AUC) for different detection methods. Results: Among the 864 pregnant women, 44 cases (5.09%) exhibited fetal anomalies, while 820 cases (94.91%) did not. The anomaly group showed significantly higher multiples of the median (MOM) values for AFP and Free-HCG ß (P < .001) and significantly lower PAPP-A MOM and VitB12 levels (P < .001) compared to the normal group. The sensitivity of single detections for AFP MOM, Free-HCG ß MOM, PAPP-A MOM, VitB12, 4D color ultrasound, and combined detection were 63.64%, 68.18%, 65.91%, 54.55%, 77.27%, and 97.93%, respectively. The corresponding AUC values were 0.805, 0.829, 0.818, 0.761, 0.885, and 0.974. Conclusions: The combination of 4D color ultrasound with maternal serological index testing demonstrated high sensitivity in prenatal screening for fetal anomalies.

Charge-Assisted Hydrogen-Bonded Organic Frameworks with Inorganic Ammonium Regulated Switchable Open Polar Sites.

Surface open polar sites within the voids of porous molecular crystals define the localized physicochemical environment for critical functions such as gas separation and molecular recognition. This study presents a new charge-assisted hydrogen bonding (H-bonding) motif, by exploiting inorganic ammonium (NH4 + ) cations as H-bond donors, to regulate the assembly of C2 -symmetric carboxylic tectons for building robust H-bonded frameworks with permanent ultra-micropores and open oxygen sites. Diverse building blocks are bridged by tetrahedral NH4 + to expand distinctive H-bonded networks with varied pore architectures. Particularly, the open polar oxygen sites can be switched by altering NH4 + sources to tune the deprotonation of carboxyl-containing tectons. The activated porous PTBA·NH4 ·DMF preserves the pore architecture and open polar oxygen sites, exhibiting remarkably selective sorption of CO2 (107.8 cm3 g-1 ,195 K) over N2 (11.2 cm3 g-1 , 77 K) and H2 (1.4 cm3 g-1 , 77 K).

Hydrogen-Bonded Organic Frameworks: Structural Design and Emerging Applications.

Constructing well-organized organic frameworks with tailor-made functionalities potentially boost multi-domain applications. Hydrogen bonding (H-bonding) is a category of general and weak intermolecular interactions when compared with covalent bonding or metal-ligand coordination. Porous frameworks mainly assembled by H-bonding (named hydrogen-bonded organic frameworks, HOFs) are intrinsically capable of decomposing and regenerating, a distinctive advantage to improve their processability while expanding the applicability. This paper summarizes the basic building concepts of HOFs, including feasible hydrogen bonded motifs, effective molecular structures, and their emerging applications.

A Cone Beam Computed Tomography Analysis of Bone Volume Variations of Extra-alveolar Region Based on Sex, Age, Vertical and Sagittal Facial Patterns.

OBJECTIVES: The goal of this study is to measure mandibular buccal shelf (MBS) concerning angulation, bone volume, and cortical bone volume as well as bone depth and cortical bone depth of infrazygomatic crest (IZC) via cone beam computed tomography and evaluate the measurements according to sex, age, vertical, and sagittal facial types. MATERIALS AND METHODS: This study collected lateral cephalograms and cone beam computed tomography scans from 100 individuals, which were used to observe angulation, bone and cortical bone volume entailing width and depth of MBS as well as the depth of IZC. FH-MP (mandibular plane angle) and A point-Nasion-B point were adopted to determine vertical and sagittal facial patterns respectively. RESULTS: Bone widths at 6 mm and 11 mm to cementoenamel junction (CEJ) and cortical bone width at 6 mm to CEJ in MBS showed significant sex differences, while bone depths and cortical bone depths in IZC show significant age difference( P <0.05). Bone width and cortical bone width at 6 mm to CEJ at the mesial root and 11 mm to CEJ at both roots as well as angulations of MBS in the mandibular first molar region, bone depth and cortical bone depth at the maxillary first molar distal buccal root, and the proximity region were all correlated to FH-MP ( P <0.05). CONCLUSIONS: Short-faced individuals of Asian ethnicity tend to have greater bone width, greater projection in MBS, and greater bone depth in the posterior region of IZC. The optimal implant sites are 11 mm apical to CEJ at the mandibular second molar distal root and 65° at the maxillary first molar mesial root.

Hydrogen-Bonding Assembly Meets Anion Coordination Chemistry: Framework Shaping and Polarity Tuning for Xenon/Krypton Separation.

Hybrid hydrogen-bonded (H-bonded) frameworks built from charged components or metallotectons offer diverse guest-framework interactions for target-specific separations. We present here a study to systematically explore the coordination chemistry of monovalent halide anions, i.e., F- , Cl- , Br- , and I- , with the aim to develop hybrid H-bond synthons that enable the controllable construction of microporous H-bonded frameworks exhibiting fine-tunable surface polarity within the adaptive cavities for realistic xenon/krypton (Xe/Kr) separation. The spherical halide anions, especially Cl- , Br- , and I- , are found to readily participate in the charge-assisted H-bonding assembly with well-defined coordination behaviors, resulting in robust frameworks bearing open halide anions within the distinctive 1D pore channels. The activated frameworks show preferential binding towards Xe (IAST Xe/Kr selectivity ca. 10.5) because of the enhanced polarizability and the pore confinement effect. Specifically, dynamic column Xe/Kr separation with a record-high separation factor (SF=7.0) among H-bonded frameworks was achieved, facilitating an efficient Xe/Kr separation in dilute, CO2 -containing gas streams exactly mimicking the off-gas of spent nuclear fuel (SNF) reprocessing.

Nanosheet-Assembled Zirconium-Porphyrin Frameworks Enabling Surface-Confined, Initiator-Free Photosynthesis of Ultrahigh Molecular Weight Polymers.

Metal-organic frameworks with well-organized low-dimensional architectures provide significant thermodynamic and/or kinetic benefits for diverse applications. We present here the controlled synthesis of a novel class of hierarchical zirconium-porphyrin frameworks (ZrPHPs) with nanosheet-assembled hexagonal prism morphology. The crystal growth behaviors and structural evolution of ZrPHPs in an additive-modulated solvothermal synthesis are examined, showing an "assembly-hydrolysis-reassembly" mechanism towards the formation of 2D nanosheets with ordered arrangement. Because of the highly-accessible active sites harvesting broadband photons, ZrPHPs serve as adaptable photocatalysts to regulate macromolecular synthesis under full-range visible light and natural sunlight. An initiator-free, oxygen-tolerant photopolymerization system is established, following a distinctive mechanism involving direct photo-induced electron transfer to dormant species and hole-mediated reversible deactivation. Specifically, ZrPHPs provide a surface-confined effect towards the propagating chains which inhibits their recombination termination, enabling the highly-efficient synthesis of ultrahigh molecular weight polymers (Mn >1,500,000) with relatively low dispersity (D≈1.5).

obaDIA: one-step biological analysis pipeline for data-independent acquisition and other quantitative proteomics data.

MOTIVATION: Data mining and data quality evaluation are indispensable constituents of quantitative proteomics, but few integrated tools available. RESULTS: We introduced obaDIA, a one-step pipeline to generate visualizable and comprehensive results for quantitative proteomics data. obaDIA supports fragment-level, peptide-level and protein-level abundance matrices from DIA technique, as well as protein-level abundance matrices from other quantitative proteomic techniques. The result contains abundance matrix statistics, differential expression analysis, protein functional annotation and enrichment analysis. Additionally, enrichment strategies which use total proteins or expressed proteins as background are optional, and HTML based interactive visualization for differentially expressed proteins in the KEGG pathway is offered, which helps biological significance mining. In short, obaDIA is an automatic tool for bioinformatics analysis for quantitative proteomics. AVAILABILITY AND IMPLEMENTATION: obaDIA is freely available from https://github.com/yjthu/obaDIA.git. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Consequences of Preoperative Oral Carbohydrate Consumption in Septal Deviation Patients Undergoing Endoscopic Septoplasty: A Retrospective Cohort Study.

PURPOSE: Multiple reports have demonstrated the benefits of preoperative oral carbohydrates (CHO) in patients receiving open abdominal, thoracic, and orthopedic surgeries. However, thus far, no reports have investigated the benefits of CHO in patients undergoing nasal endoscopic surgery. Our goal was to evaluate the outcome of preoperative oral of administration of CHO in septal deviation patients, undergoing endoscopic septoplasty, under general anesthesia. DESIGN: A retrospective cohort study from a prospectively collected database. METHODS: Consecutive 400 septal deviation patients, undergoing endoscopic septoplasty, were randomly assigned to receive CHO or plain water (80 CHO cohort vs. 320 control cohort) before general anesthesia. The primary outcome was the risk of acute postoperative hypertension (APH). The secondary outcomes included length of hospital stay (LOS), hospitalization cost, sleep time the day before surgery, fluid infusion volume on surgical day, as well the incidence of postoperative nausea and vomiting (PONV) and aspiration. FINDINGS: Patients in the CHO cohort experienced a lower risk of both diastolic blood pressure (DBP)-based APH (OR, 0.49; 95% CI, 0.25 to 0.96; P = 0.0375) and total APH (OR, 0.49; 95% CI, 0.26 to 0.92; P = 0.0258), lower LOS, lower hospitalization cost, longer sleep time and less fluid infusion volume after adjusting for gender, age, BMI, preoperative blood pressure and pulse. Besides, data showed no significant differences in the incidence of (P = 0.4173) and aspiration (P > 0.99). CONCLUSIONS: Preoperative CHO administration can reduce APH risk in patients undergoing endoscopic septoplasty under general anesthesia. Besides, preoperative CHO administration can improve other clinical outcomes, such as, LOS, hospitalization cost, sleep time, and fluid infusion volume. Moreover, CHO safety was confirmed in our study. In the future, additional investigation is necessary to confirm our results.

Binary Solvent Regulated Architecture of Ultra-Microporous Hydrogen-Bonded Organic Frameworks with Tunable Polarization for Highly-Selective Gas Separation.

A binary solvent synthetic strategy is proposed for the construction of C2 -symmetric molecule-based hydrogen-bonded organic frameworks (HOFs) with permanent ultra-micropores and surface polarization derived from tunable coplanar open oxygen atoms. The activated HOFs BTBA-1 a and PTBA-1 a show highly selective separation of CO2 /N2 with a record high ideal adsorbed solution theory (IAST) selectivity >2000 under ambient temperature and pressure.

Development of an immunogenomic landscape for the competing endogenous RNAs network of peri-implantitis.

BACKGROUND: Peri-implantitis is an inflammation that occurs around the implant, resulting in varying degrees of inflammatory damage to the soft and hard tissues. The characteristic criterion is the loss of the supporting bone in an inflammatory environment. However, the specific mechanisms and biomarkers involved in peri-implantitis remain to be further studied. Recently, competing endogenous RNAs (ceRNA) and immune microenvironment have been found to play a more important role in the inflammatory process. In our study, we analyzed the expression of immune related microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and message RNAs (mRNAs) in peri-implantitis by analyzing GSE33774 and GSE57631. METHODS: In this study, we explored the expression profile data of immune-related lncRNAs, miRNAs and mRNAs, and constructed immune-related ceRNA network involved in the pathogenesis of peri-implantitis. In addition, the CIBERSORT was used to evaluate the content of immune cells in normal tissues and peri-implantitis to detect the immune microenvironment of peri-implantitis. RESULTS: In the analysis, 14 DElncRNAs, 16 DEmiRNAs, and 18 DEmRNAs were used to establish an immune related ceRNA network and the immune infiltration patterns associated with peri-implantitis was discovered. Through the mutual verification of the two datasets, we found that GSK3B and miR-1297 may have important significance in the immune microenvironment and pathogenesis of peri-implantitis and GSK3B was closely related to four types of immune cells, especially with the highest correlation with resting mast cells (P = 0.0003). CONCLUSIONS: Through immune-related ceRNA network, immune-related genes (IRGs) and immune cell infiltration can further comprehensively understand the pathogenesis of peri-implantitis, which built up an immunogenomic landscape with clinical significance for peri-implantitis.

A mammalian autophagosome maturation mechanism mediated by TECPR1 and the Atg12-Atg5 conjugate.

Autophagy is a major catabolic pathway in eukaryotes associated with a broad spectrum of human diseases. In autophagy, autophagosomes carrying cellular cargoes fuse with lysosomes for degradation. However, the molecular mechanism underlying autophagosome maturation is largely unknown. Here we report that TECPR1 binds to the Atg12-Atg5 conjugate and phosphatidylinositol 3-phosphate (PtdIns[3]P) to promote autophagosome-lysosome fusion. TECPR1 and Atg16 form mutually exclusive complexes with the Atg12-Atg5 conjugate, and TECPR1 binds PtdIns(3)P upon association with the Atg12-Atg5 conjugate. Strikingly, TECPR1 localizes to and recruits Atg5 to autolysosome membrane. Consequently, elimination of TECPR1 leads to accumulation of autophagosomes and blocks autophagic degradation of LC3-II and p62. Finally, autophagosome maturation marked by GFP-mRFP-LC3 is defective in TECPR1-deficient cells. Thus, we propose that the concerted interactions among TECPR1, Atg12-Atg5, and PtdIns(3)P provide the fusion specificity between autophagosomes and lysosomes and that the assembly of this complex initiates the autophagosome maturation process.

Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains.

The tumour necrosis factor (TNF) family is crucial for immune homeostasis, cell death and inflammation. These cytokines are recognized by members of the TNF receptor (TNFR) family of death receptors, including TNFR1 and TNFR2, and FAS and TNF-related apoptosis-inducing ligand (TRAIL) receptors. Death receptor signalling requires death-domain-mediated homotypic/heterotypic interactions between the receptor and its downstream adaptors, including TNFR1-associated death domain protein (TRADD) and FAS-associated death domain protein (FADD). Here we discover that death domains in several proteins, including TRADD, FADD, RIPK1 and TNFR1, were directly inactivated by NleB, an enteropathogenic Escherichia coli (EPEC) type III secretion system effector known to inhibit host nuclear factor-κB (NF-κB) signalling. NleB contained an unprecedented N-acetylglucosamine (GlcNAc) transferase activity that specifically modified a conserved arginine in these death domains (Arg 235 in the TRADD death domain). NleB GlcNAcylation (the addition of GlcNAc onto a protein side chain) of death domains blocked homotypic/heterotypic death domain interactions and assembly of the oligomeric TNFR1 complex, thereby disrupting TNF signalling in EPEC-infected cells, including NF-κB signalling, apoptosis and necroptosis. Type-III-delivered NleB also blocked FAS ligand and TRAIL-induced cell death by preventing formation of a FADD-mediated death-inducing signalling complex (DISC). The arginine GlcNAc transferase activity of NleB was required for bacterial colonization in the mouse model of EPEC infection. The mechanism of action of NleB represents a new model by which bacteria counteract host defences, and also a previously unappreciated post-translational modification.

Analysis of clinical and electrophysiological characteristics of 150 patients with amyotrophic lateral sclerosis in China.

OBJECTIVE: To explore the relationship between the clinical onset locations and the electrophysiological characteristics of different spinal segments in amyotrophic lateral sclerosis (ALS) patients. To develop a rapid examination method using electromyographs (EMGs) for the diagnosis of ALS. METHODS: The clinical symptoms and electrodiagnostic examination results of 150 patients with definite or probable ALS were retrospectively analyzed. The patients were divided into four groups according to the primary onset locations (arms and legs onset, arms onset, legs onset, and bulbar onset groups). The differences between the onset locations and the electrophysiological characteristics revealed the lower motor neuron dysfunction in EMGs. RESULTS: The most affected onset location was the lower limbs (36.7%), particularly in the distal muscles. Nerve conduction showed that the sensory system was damaged in 22 patients (14.7%). The positive diagnostic rate of EMGs varied due to different onset locations. EMG abnormalities were seen in approximately 40% of asymptomatic limb muscles. Distal limb muscles showed higher electrodiagnostic sensitivity (78.4%) than proximal limb muscles. Cervical muscles showed the highest electrodiagnostic sensitivity (86.3%). CONCLUSIONS: The sensory system in ALS patients was commonly impaired. Cervical muscles showed the highest electrodiagnostic sensitivity. The highest positive rate was generated from detecting the spinal segment onset and the special distal muscles onset ALS in our optimized test method. Through this improved examination based on the most affected individual muscles, physicians can greatly optimize the test duration and significantly reduce patient discomfort.

Cone-Beam Computed Tomography Study on Morphologic Characteristics of the Posterior Region in Hard Palate.

BACKGROUND: The goal of this study is to evaluate the morphologic characteristics of the posterior palatine region among the Chinese population, more specifically, the greater palatine grooves, crests, bridges, and torus palatinus structures and make comparisons between different ethnic groups and minorities. METHODS: A total of 323 cone-beam computed tomography (CBCT) scans were collected for analysis on the presence of grooves, crests, bridges, or torus palatinus (TP). Data were collected through recognizing the grooves, crests, bridges, and TPs and calculating the number of those anatomy structures. The statistics index, including average, standard deviation, were adopted to describe the subjects and Wilcoxon test, Mann-Whitney test, and Chi-squared test were all carried out by SPSS. RESULTS: Three different morphologic manifestations of the greater palatine groove (GPG) found in the upper 1st and 2nd molar regions are as follows: no groove, 1 groove, and 2 grooves. The number of crests ranged from 0 to 3. And the incidence of torus palatines was 29%. Moreover, a positive correlation was found between the presence of crests/GPGs and age in the 2nd molar region. CONCLUSION: The results in this study reveal that GPGs in the upper 1st and 2nd molar regions have 3 different morphologic manifestations among Chinese people and the number of crests can vary from 0 to 3 crests. Although the proportion of GPG or crest and the incidence of TP are different from the proportions of other studies, this may be due to the fact that different ethnic groups and sample sizes were used in the course of this study. Information about the anatomy structures of the posterior region in hard palate directly contributed to a decrease in potential complications during palatal implant surgery and periodontal surgery.

A Multi-Module Electrodynamic Exciter with a Variable Pole-Arc Ratio Disk Halbach Array for a High-Bandwidth Dynamic Torsional Stiffness Test.

In this paper, a multi-module electrodynamic exciter based on moving-magnet disk voice coil motor is presented to meet the demands of high torque and high bandwidth in a dynamic torsional stiffness test. A variable pole-arc ratio disk Halbach array (VPAR-DHA) is proposed, so that both high torque density and low rotor inertia can be obtained through enhancing the magnetic field in the working range. The analytical quasi-3-D model of VPAR-DHA was set up by using the harmonic function method, with the consideration of end-effects by a correction function. Electromagnetic structure optimization was carried out with the analytical model, and verified by 3-D finite-element (FEM) results. The proposed design was experimentally tested and verified with a prototype that achieved a peak dynamic torque output of 40 Nm at a frequency of 120 Hz, and a stroke of ±1°. The proposed method can also be easily extended to satisfy various demands of dynamic torsional stiffness test.

SB-216763, a GSK-3ß inhibitor, protects against aldosterone-induced cardiac, and renal injury by activating autophagy.

Cardiovascular and renal inflammation induced by Aldosterone (Aldo) plays a pivotal role in the pathogenesis of hypertension and renal fibrosis. GSK-3ß contributes to inflammatory cardiovascular and renal diseases, but its role in Aldo-induced hypertension, and renal damage is not clear. In the present study, rats were treated with Aldo combined with SB-216763 (a GSK-3ß inhibitor) for 4 weeks. Hemodynamic, cardiac, and renal parameters were assayed at the indicated time. Here we found that rats treated with Aldo presented cardiac and renal hypertrophy and dysfunction. Cardiac and renal expression levels of molecular markers attesting inflammation and fibrosis were increased by Aldo infusion, whereas the treatment of SB-216763 reversed these alterations. SB-216763 suppressed cardiac and renal inflammatory cytokines levels (TNF-a, IL-1ß, and MCP-1). Meanwhile, SB-216763 increased the protein levels of LC3-II in the cardiorenal tissues as well as p62 degradation, indicating that SB-216763 induced autophagy activation in cardiac, and renal tissues. Importantly, inhibition of autophagy by 3-MA attenuated the role of SB-216763 in inhibiting perivascular fibrosis, and tubulointerstitial injury. These data suggest that SB-216763 protected against Aldo-induced cardiac and renal injury by activating autophagy, and might be a therapeutic option for salt-sensitive hypertension and renal fibrosis.

Effect of Intensive Personalized "5As+5Rs" Intervention on Smoking Cessation in Hospitalized Acute Coronary Syndrome Patients Not Ready to Quit Immediately: A Randomized Controlled Trial.

Introduction: The acute coronary syndrome (ACS) patients who are not ready to quit smoking immediately have an extremely low rate of cessation. This study aims to investigate the efficacy of intensive personalized '5As+5Rs'intervention (IPANR intervention) on smoking cessation in this population. Methods: A parallel-group randomized controlled trial was carried out, which compared IPANR intervention with routine 5Rs (control) at Fu Xing Hospital, Capital Medical University, Bei Jing, China. Three hundred and twenty hospitalized ACS smokers who were not ready to quit were randomly distributed to IPANR intervention group comprising three individual counseling during hospitalization and 15 intensive follow-up sessions (weekly during months 1, 2, 3, and monthly thereafter until month 6) or 5Rs group in a 1:1 fashion by 8 cardiologists who were blinded to the allocation sequence. Primary end point was carbon monoxide-confirmed continuous abstinence rate (CAR) through week 9 to week 12. Secondary outcome included abstinence rate at 24 weeks. Results: Overall, 97.5% (312/320) participants completed the trial. An intention-to-treat analysis showed statistically significant advantage of IPANR compared with control group at 4 weeks CAR (27.5% vs. 17.5%, RR = 1.571, 95% CI = 1.032-2.392, p = 0.032, number needed to treat (NNT) = 10), and abstinence rate at 24 weeks (23.8% vs.15.0%, RR 1.583, 95% CI = 0.998-2.512, p = 0.048, NNT: 11.36). At 24 weeks, cigarettes smoked per day by the patients who failed to quit were significant lower in IPANR group than 5Rs group (13.21 ± 8.23 vs. 17.45 ± 10.71; p < 0.001). Conclusions: The IPANR initiated during hospitalization, is a feasible and effective approach for smoking cessation in ACS patients not ready to quit immediately. Implications: Smoking has a major impact on acute stages of ACS for recurrent ischemic events and long-term outcomes. However, there are few evidence-based treatments for smokers who are not ready to quit. This study described a cessation intervention initiated during hospitalization and included 15 intensive follow-up aimed at enabling ACS smokers who were not ready to quit immediately to deliver adequate motivational and behavior change counseling. Given its effectiveness demonstrated in this prospective study, this intervention in hospitalized ACS smokers might have the potential to substantially improve the cessation rate of ACS patients who are not ready to quit smoking immediately.

DOK1/PPARgamma pathway mediates anti-tumor ability of all-trans retinoic acid in breast cancer MCF-7 cells.

Previous studies have showed the anticancer effect of the all-trans retinoic acid (ATRA) in many tumors including breast cancer; however, the underlying molecular mechanism is still poorly understood. This study experimentally revealed that ATRA treatment inhibited MCF-7 cell proliferation and promoted its apoptosis, along with an enhanced expression of docking protein 1 (DOK1). ATRA's effects on cell proliferation and apoptosis were prevented by DOK1 knockdown. In addition, the genetic silence of DOK1 can inhibit PPARγ expression and its activity. Moreover, inactivation of PPARγ by its specific inhibitor GW9662 reversed the impacts of ATRA on cell proliferation and apoptosis. Taken together, these results indicate that ATRA-enhanced expression of DOK1 activates PPARγ leading to inhibition of cell proliferation and enhancement of cell apoptosis in MCF-7 cell.