Physical Grinding of Prefabricated Co3O4 and MCM-22 Zeolite for Fischer-Tropsch Synthesis: Impact of Pretreatment Procedure on the Dispersion and Catalytic Performance.

To improve the mess-specific activity of Co supported on zeolite catalysts in Fischer-Tropsch (FT) synthesis, the Co-MCM-22 catalyst was prepared by simply grinding the MCM-22 with nanosized Co3O4 prefabricated by the thermal decomposition of the Co(II)-glycine complex. It is found that this novel strategy is effective for improving the mess-specific activity of Co catalysts in FT synthesis compared to the impregnation method. Moreover, the ion exchange and calcination sequence of MCM-22 has a significant influence on the dispersion, particle size distribution, and reduction degree of Co. The Co-MCM-22 prepared by the physical grinding of prefabricated Co3O4 and H+-type MCM-22 without a further calcination process exhibits a moderate interaction between Co3O4 and MCM-22, which results in the higher reduction degree, higher dispersion, and higher mess-specific activity of Co. Thus, the newly developed method is more controllable and promising for the synthesis of metal-supported catalysts.

Structure-directed linker optimization of novel HEPTs as non-nucleoside inhibitors of HIV-1 reverse transcriptase.

1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymines (HEPTs) have been previously described as an important class of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). In our continuously pursuing HEPT optimization efforts, a series of novel HEPTs, featuring -C(OH)CH2R, -CC, or -CHCH2R linker at the benzylic α-methylene unit, were developed as NNRTIs. Among these new HEPTs, the compound C20 with -CHCH3 group at the benzylic α-methylene unit conferred the highest potency toward WT HIV-1 and selectivity (EC50 = 0.23 µM, SI = 150.20), which was better than the lead compound HEPT (EC50 = 7 µM, SI = 106). Also, C20 was endowed with high efficacy against clinically relevant mutant strains (EC50(L100I) = 1.07 µM; EC50(K103N) = 4.33 µM; EC50(Y181C) = 5.57 µM; EC50(E138K) = 1.06 µM; EC50(F227L+V106A) = 5.45 µM) and wild-type HIV-1 reverse transcriptase (RT) with an IC50 value of 0.55 µM. Molecular docking and molecular dynamics simulations, as well as preliminary structure-activity relationship (SAR) analysis of these new compounds, provided a deeper insight into the key structural features of the interactions between HEPT analogs and HIV-1 RT and laid the foundation for further modification on HEPT scaffold.

Cochlear morphology in the developing inner ear of the porcine model of spontaneous deafness.

BACKGROUND: Auditory function and cochlear morphology have previously been described in a porcine model with spontaneous WS2-like phenotype. In the present study, cochlear histopathology was further investigated in the inner ear of the developing spontaneous deafness pig. RESULTS: We found that the stria vascularis transformed into a complex tri-laminar tissue at embryonic 85 days (E85) in normal pigs, but not in the MITF-/- pigs. As the neural crest (NC) of cochlea was derived by melanocytes. MITF mutation caused failure of development of melanocytes which caused a subsequent collapse of cochlear duct and deficits of the epithelium after E100. Furthermore, the spiral ganglion neurons of cochlea in the MITF-/- pigs began to degenerate at postnatal 30 days (P30). Thus, our histopathological results indicated that the malformation of the stria vascularis was a primary defect in MITF-/- induced WT pigs which was resulted from the loss of NC-derived melanocytes. Subsequently, the cochleae underwent secondary degeneration of the vestibular organs. As the degeneration of spiral ganglion neurons happened after P30, it suggests that WS patients should be considered as candidates for cochlear implant. CONCLUSIONS: Our porcine model of MITF-M mutation may provide a crucial animal model for cochlear implant, cell therapy in patients with congenital hereditary hearing loss.

ACE2 and Ang-(1-7) protect endothelial cell function and prevent early atherosclerosis by inhibiting inflammatory response.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is a counter-regulator against ACE by converting angiotensin II (Ang-II) to Ang-(1-7), but the effect of ACE2 and Ang-(1-7) on endothelial cell function and atherosclerotic evolution is unknown. We hypothesized that ACE2 overexpression and Ang-(1-7) may protect endothelial cell function by counterregulation of angiotensin II signaling and inhibition of inflammatory response. METHODS: We used a recombinant adenovirus vector to locally overexpress ACE2 gene (Ad-ACE2) in human endothelial cells in vitro and in apoE-deficient mice in vivo. The Ang II-induced MCP-1, VCAM-1 and E-selectin expression, endothelial cell migration and adhesion of human monocytic cells (U-937) to HUVECs by ACE2 gene transfer were evaluated in vitro. Accelerated atherosclerosis was studied in vivo, and atherosclerosis was induced in apoE-deficient mice which were divided randomly into four groups that received respectively a ACE2 gene transfer, Ad-ACE2, Ad-EGFP, Ad-ACE2 + A779, an Ang-(1-7) receptor antagonist, control group. After a gene transfer for 4 weeks, atherosclerotic pathology was evaluated. RESULTS: ACE2 gene transfer not only promoted HUVECs migration, inhibited adhesion of monocyte to HUVECs and decreased Ang II-induced MCP-1, VCAM-1 and E-selectin protein production in vitro, but also decreased the level of MCP-1, VCAM-1 and interleukin 6 and inhibit atherosclerotic plaque evolution in vivo. Further, administration of A779 increased the level of MCP-1, VCAM-1 and interleukin 6 in vivo and led to further advancements in atherosclerotic extent. CONCLUSIONS: ACE2 and Ang-(1-7) significantly inhibit early atherosclerotic lesion formation via protection of endothelial function and inhibition of inflammatory response.

Development of novel S-N3-DABO derivatives as potent non-nucleoside reverse transcriptase inhibitors with improved potency and selectivity.

Following on our initial discovery of S-CN-DABOs as non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel S-N3-DABO derivatives F1-F31 were developed by substituting the cyano group of S-CN-DABOs with azide group. Some of these compounds were conferred significantly increased potency against wild-type HIV-1 and clinically observed mutant strains. Remarkably, the best compound F10 exerted a 7-fold improvement in potency (EC50 = 0.053 µM) and 12.5-fold higher selectivity (SI = 6818) in MT-4 cells infected with wild-type HIV-1, compared to that of the parent compound B1 (EC50 = 370 nM, SI = 547). The anti-HIV-1 activity of F10 against the tested mutant strains was prominently enhanced. For wild-type reverse transcriptase, it was approximately 19-fold more potent (IC50 = 0.080 µM) than B1 (IC50 = 1.51 µM). It was not found that this analog had significant inhibition of hERG, CYP, and acute toxicity after a single dose of F10 (1.0 g/kg).

Expansion of the S-CN-DABO scaffold to exploit the impact on inhibitory activities against the non-nucleoside HIV-1 reverse transcriptase.

The α-cyanoarylmethyl-3, 4-dihydropyrimidin-4(3H)-ones (S-CN-DABOs) were reported as a kind of reverse transcriptase inhibitors of human immunodeficiency virus type-1 (HIV-1) by our group in 2007. In this paper, we proposed to expand the S-CN-DABO scaffold to enrich the structure-activity relationship (SAR) of the phenyl ring that was predicted to be located in the W229 hydrophobic pocket. Thirty-nine S-CN-DABO derivatives were manufactured to explore the impact on inhibitory activities against the non-nucleoside HIV-1 reverse transcriptase. These analogues displayed up to low nanomolar activity against wild-type (WT) HIV-1 and good activity against several clinically relevant resistant mutant viruses, especially rilpivirine-associated resistant mutant E138K strain. The inhibitory ability toward the RT enzyme was significantly improved. Compound B23 with a 2, 6-difluoro-phenyl group showed inhibitory effects with an EC50 value of 20.8 nM against HIV-1 WT strain, and an EC50 of 50 nM targeting mutant E138K, which were about 20-fold better than the lead compound B1. Molecular docking analysis elucidated the biological activity and offered a structural insight for follow-up research. In addition, compound B23 also showed favorable drug-like properties in vitro and in vivo. There was no significant inhibition of hERG (IC50 > 40 µM), no apparent CYP enzymatic inhibitory activity and acute toxicity in mouse models. Perfect oral bioavailability of compound B23 was revealed (F = 164%, SD rats). In summary, these S-CN-DABOs compounds could be further optimized and modified for promising drug candidates in anti-HIV clinical therapy.

Synthesis of hierarchical nanocrystalline ß zeolite as efficient catalyst for alkylation of benzene with benzyl alcohol.

To develop an efficient solid acid catalysts for the Friedel-Crafts alkylation reaction, especially for involving bulky molecules, the direct synthesis of hierarchical nanocrystalline ß zeolites were achieved by using amphiphilic organosilane ([(CH3O)3SiC3H6N(CH3)2C18H37]Cl, TPOAC) as collaborative structure-directing agent (SDA). The growth evolution of ß crystals and the influence of TPOAC/SiO2 molar ratio on the mesoporous structure, crystal size, and acidic properties of ß zeolites were investigated and discussed in detail. The characterization results reveal that intracrystalline mesopores and intercrystalline mesopores/macropores via the stacking of ß nanocrystals were generated over the hierarchical ß zeolites. Moreover, most of the strong acid sites were well remained compared with the conventional microporous ß zeolite. Consequently, the hierarchical nanocrystalline ß zeolite synthesized under the optimized synthesis conditions shows improved specific catalytic activity of acid sites (turnover number, TON) in alkylation of benzene with benzyl alcohol, which can be attributed to the integrated balance of considerable mesoporosity, accessibility of the acid sites, and well-remained strong acid sites in the hierarchical ß zeolite.

Controlled direct synthesis of single- to multiple-layer MWW zeolite.

The minimized diffusion limitation and completely exposed strong acid sites of the ultrathin zeolites make it an industrially important catalyst especially for converting bulky molecules. However, the structure-controlled and large-scale synthesis of the material is still a challenge. In this work, the direct synthesis of the single-layer MWW zeolite was demonstrated by using hexamethyleneimine and amphiphilic organosilane as structure-directing agents. Characterization results confirmed the formation of the single-layer MWW zeolite with high crystallinity and excellent thermal/hydrothermal stability. The formation mechanism was rigorously revealed as the balanced rates between the nucleation/growth of the MWW nanocrystals and the incorporation of the organosilane into the MWW unit cell, which is further supported by the formation of MWW nanosheets with tunable thickness via simply changing synthesis conditions. The commercially available reagents, well-controlled structure and the high catalytic stability for the alkylation of benzene with 1-dodecene make it an industrially important catalyst.

Effect of tirofiban plus clopidogrel and aspirin on primary percutaneous coronary intervention via transradial approach in patients with acute myocardial infarction.

BACKGROUND: Aspirin and clopidogrel can improve myocardial reperfusion and alleviate myocardial injury during percutaneous coronary intervention (PCI). Whether the addition of intravenous tirofiban during this procedure produces further benefit has not been clarified in ST segment elevation myocardial infarction (STEMI) patients. We evaluated this on STEMI patients who underwent primary PCI (p-PCI) via transradial artery approach. METHODS: Consecutive patients were randomized into tirofiban group (n=72) or placebo group (n=78). Angiographic analysis included initial and final thrombolysis in myocardial infarction (TIMI) flow grade (TFG), corrected TIMI frame count (CTFC) and TIMI myocardial perfusion grade (TMPG) of the thrombotic vessel. Platelet aggregation rate (PAR), creatine phosphokinase (CPK), CPK isoenzyme MB (CPK-MB) and troponin I levels were measured and TIMI definitions were used to assess bleeding complications. Left ventricular performance parameters were investigated with equilibrium radionuclide ventriculography. Major adverse cardiac events (MACE) were followed up for 6 months. RESULTS: The cases of TFG 0 and 1 before PCI, TFG 0 when first crossing of guide wire were less, and the cases of TFG 3 after PCI was more in tirofiban group than those in placebo group. The final CTFC was fewer and the incidence of no reflow phenomenon was lower, as well the percentage of final TFG 3 was higher in tirofiban group than those in placebo group (all P<0.05). Mean peak CPK-MB was significantly lower, while the left ventricular performance parameters 1 week after PCI were much more improved in tirofiban group than those in the placebo group. PAR was significantly decreased shortly after tirofiban infusion. The incidence of 6-month MACE in tirofiban group was obviously lower than that in the placebo group. No statistical difference was noted between the two groups with regard to bleeding complications. CONCLUSIONS: Intravenous tirofiban infusion, in addition to aspirin and clopidogrel in STEMI patients with p-PCI via transradial artery access, can quickly inhibit platelet aggregation, loosen occlusive thrombus, improve myocardial reperfusion and reduce incidence of MACE with few complications of vessel access and bleeding.

Optical coherence tomography guided successful treatment without stent implantation in a patient with non-ST-segment elevation myocardial infarction caused by plaque rapture: A case report.

RATIONALE: Primary percutaneous coronary intervention (PPCI) with immediate stenting provides effective revascularization. While the risks of no-reflow, stent thrombosis, stent undersizing, and malapposition reduced the benefits in patients with high burden thrombosis. Intravascular imaging, especially optical coherence tomography (OCT), offers potential in optimization of percutaneous coronary intervention. PATIENT CONCERNS: A 51-year-old male underwent coronary angiography (CAG) due to chest pain with minimal ST-segment depression of the electrocardiogram. DIAGNOSES: Urgent CAG revealed burden thrombus in the mid left anterior descending coronary artery (LAD) with TIMI grade I distal flow. INTERVENTIONS: After aspiration thrombectomy, OCT was used to evaluate the target lesion of non-ST-segment elevation myocardial infarction (NSTEMI) and conservative treatment without stent implantation was selected. OUTCOMES: CAG repeated 1 month after PPCI revealed TIMI grade III blood flow in LAD and only minimal stenosis in the target lesion. OCT showed a cavity formation due to plaque rupture and MLA increased after thrombus dissolution. Follow-up was uneventful at 6 months. LESSONS: OCT may be useful imaging modality to identify the characteristic of culprit lesion of acute myocardial infarction and subsequently guide individual treatment.

Effect of template removal using plasma treatment on the structure and catalytic performance of MCM-22.

To investigate the effect of template removal methods on the structure, properties and catalytic performance of the MCM-22 zeolite, dielectric-barrier discharge (DBD) plasma treatment and thermal calcination have been comparatively studied for the removal of hexamethyleneimine (HMI) from the two-dimensional layered precursor of MCM-22 (MCM-22(P)). The materials were characterized using FT-IR, TG, XRD, N2 adsorption at low temperature, NH3-TPD, and 27Al and 29Si MAS NMR. The results revealed that the seven-membered heterocyclic compound HMI can be effectively removed from the MCM-22 zeolite, and the condensation of silanol groups on the neighboring surface of MWW nanosheets can be induced by DBD treatment. Compared with calcination, DBD treatment could preserve the structure well and decrease the formation of extra-framework aluminum. Consequently, the concentration of acidic sites over MCM-22 treated by DBD (MCM-22(DBD)) is higher than that over calcined MCM-22 (MCM-22(C)). Moreover, MCM-22(DBD) possesses a certain amount of external surface area derived from the intercrystal pores due to the inhibiting effect of the condensation of the silanol groups on the external surface of the MCM-22 crystals. The activity and product selectivity of the Fischer-Tropsch (FT) synthesis was investigated over cobalt supported on the obtained MCM-22 zeolites. Compared with Co/MCM-22(C), Co/MCM-22(DBD) shows a higher catalytic activity in the FT synthesis reaction. Moreover, Co/MCM-22(DBD) can effectively decrease CH4 selectivity and increase C5-C20 liquid fuel selectivity.

Familial nonsyndromic hearing loss with incomplete partition type II caused by novel DSPP gene mutations.

BACKGROUND: Familial nonsyndromic hearing loss (NSHL) with incomplete partition type II (IP-II) is a very rare condition. AIMS/OBJECTIVES: To determine the audiological feature, inheritance patterns and genetic etiology of familial NSHL with IP-II in a Chinese family with eight family members. MATERIAL AND METHODS: Clinical data were collected from all eight family members, selected deafness genes were sequenced in proband and whole genome sequencing of seven family members was performed. RESULTS: The proband were a pair of male nonidentical twins (III:1, III:2). Three patients in this family, including the twins and their father (II:1), were diagnosed with bilateral NSHL with IP-II, and no mutation was found in the genes of SLC26A4, GJB2, GJB3, mitochondrial 12S rRNA, and MITF. Whole genome sequencing data indicated de novo mutations of the gene DSPP, c.3085A > G and c.3087C > T, which resulted in p.N1029D and co-segregated with deafness phenotype, were the underlying genetic etiology. CONCLUSION AND SIGNIFICANCE: Familial NSHL with IP-II is extremely rare. In this family, de novo DSPP gene mutations, were considered to be the most probable genetic etiology. And this is the first report to reveal DSPP gene mutations leading to familial NSHL with IP-II.

Inner ear structure of miniature pigs measured by multi-planar reconstruction techniques.

To study the structures of the scala vestibuli and tympani of miniature pigs in order to evaluate the feasibility of using miniature pigs as the animal model for cochlear implant. The temporal bones of three miniature pigs with normal hearing were scanned by micro-CT. With the aid of the Mimics software, we reconstructed the 3D structure of inner ear basing on the serial images of the miniature pig, and obtained dimensions of the scala vestibuli and tympani with multi-planar reconstruction (MPR) technique. The constructed slicing images displayed the fine structures of the cochlea. The results of our study showed that the cross-sectional areas of the scala tympani were greatest at 2.67 ± 0.90 mm2 when the circumferential length from the starting point of basal turn of the cochlea reached to 1.16 mm. The scala vestibuli has a largest width and height at the starting point of basal turn. The width and the height were 2.65 ± 0.45 mm and 2.43 ± 0.2 mm respectively. The largest width and height of the scala tympani were 2.17 ± 0.30 mm and 1.83 ± 0.42 mm. The result of our study suggests that the cochlea of miniature pigs is highly consistent with human's. Miniature pigs may be used as a new model for cochlear implant. MPR technique may be used as a new approach to obtain further information of patient's cochlea in surgeons which is helpful to select suitable cochlear implant devices and surgery approach.

Key Genes and Pathways Associated With Inner Ear Malformation in SOX10  p.R109W Mutation Pigs.

SRY-box 10 (SOX10) mutation may lead to inner ear deformities. However, its molecular mechanisms on inner ear development are not clear. In this work, the inner ear morphology was investigated at different embryonic stages of the SOX10 mutation miniature porcine model with sensorineural hearing loss, and high-throughput RNA-seq and bioinformatics analyses were applied. Our results indicated that the SOX10 mutation in the miniature pigs led to an incomplete partition (IP) of the cochlea, a cystic apex caused by fusion from middle and apical turns, cochlear modiolar defects and a shortened cochlear duct. The model demonstrated 173 differentially expressed genes (DEGs) and 185 differentially expressed long non-coding RNAs (lncRNAs). The down-regulated DEGs most significantly enriched the inflammatory mediator regulation of the TRP channels, arachidonic acid metabolism, and the salivary secretion pathways, while the up-regulated DEGs most significantly enriched the systemic lupus erythematosus and alcoholism pathways. Based on gene cluster analysis, we selected four gene groups: WNT1, KCNQ4, STRC and PAX6.

Molecular docking, 3D-QSAR and structural optimization on imidazo-pyridine derivatives dually targeting AT1 and PPARg.

Telmisartan, a bifunctional agent of blood pressure lowering and glycemia reduction, was previously reported to antagonize angiotensin II type 1 (AT1) receptor and partially activate peroxisome proliferator-activated receptor γ (PPARγ) simultaneously. Through the modification to telmisartan, researchers designed and obtained imidazo-\pyridine derivatives with the IC50s of 0.49~94.1 nM against AT1 and EC50s of 20~3640 nM towards PPARγ partial activation. For minutely inquiring the interaction modes with the relevant receptor and analyzing the structure-activity relationships, molecular docking and 3D-QSAR (Quantitative structure-activity relationships) analysis of these imidazo-\pyridines on dual targets were conducted in this work. Docking approaches of these derivatives with both receptors provided explicit interaction behaviors and excellent matching degree with the binding pockets. The best CoMFA (Comparative Molecular Field Analysis) models exhibited predictive results of q2=0.553, r2=0.954, SEE=0.127, r2pred=0.779 for AT1 and q2=0.503, r2=1.00, SEE=0.019, r2pred=0.604 for PPARγ, respectively. The contour maps from the optimal model showed detailed information of structural features (steric and electrostatic fields) towards the biological activity. Combining the bioisosterism with the valuable information from above studies, we designed six molecules with better predicted activities towards AT1 and PPARγ partial activation. Overall, these results could be useful for designing potential dual AT1 antagonists and partial PPARγ agonists.

One-stage coclear implantation via a facial recess approach in children with otitis media with effusion.

OBJECTIVE: To investigate surgical indications, operative techniques, complications and auditory and speech rehabilitation for cochlear implant (CI) in children with otitis media with effusion (OME). MATERIAL AND METHODS: This is a retrospective review of records of 24children with bilateral profound sensorineural hearing loss and OME who were implanted during January 2011 to November 2014 in the Department of Otorhinolaryngology and Head and Neck Surgery at the PLA Hospital, using one-stage implantation via the facial recess approach and round window insertion. The incus was removed in 8 cases during the implantation procedure. Local infiltration of dexamethasone and adrenaline in the middle ear was also performed. Postoperative complications were examined. Preoperative and postoperative questionnaires including Categories of Auditory Performance (CAP), Speech Intelligibility Rating (SIR), and the Meaningful Auditory Integration Scale (MAIS) were collected. RESULTS: All electrodes were implanted successfully without any immediate or delayed complications. Inflammatory changes of middle ear mucosa with effusion were noted in all implanted ears. The scores of post-implant CAP and SIR increased significantly in all 24 cases (t = -25.95 and -14.09, respectively for CAP and SIR, p < 0.05). CONCLUSIONS: One-stage CI via the facial recess approach with round window insertion is safe and effective in cochlear implant candidates with OME, as seen in the 24 children in our study who achieved improved auditory performance and speech intelligibility after CI.

ACE2 activity was increased in atherosclerotic plaque by losartan: Possible relation to anti-atherosclerosis.

INTRODUCTION: Angiotensin-converting enzyme 2 (ACE2) is a new member of the renin-angiotensin system (RAS) and it has been proposed that ACE2 is a potential therapeutic target for the control of cardiovascular disease. The effect of losartan on the ACE2 activity in atherosclerosis was studied. METHODS: Atherosclerosis was induced in New Zealand white rabbits by high-cholesterol diet for 3 months. An Angiotensin II (Ang II) receptor blocker (losartan, 25 mg/kg/d) was given for 3 months. ACE2 activity was measured by fluorescence assay and the extent of atherosclerosis was evaluated by H&E and Oil Red O staining. In addition, the effect of losartan on ACE2 activity in smooth muscle cells (SMCs) in vitro was also evaluated. RESULTS: Losartan increased ACE2 activity in atherosclerosis in vivo and SMCs in vitro. Losartan inhibited atherosclerotic evolution. Addition of losartan blocked Ang II-induced down-regulation of ACE2 activity, and blockade of extracellular signal-regulated kinase (ERK1/2) with PD98059 prevented Ang II-induced down-regulation of ACE2 activity. CONCLUSIONS: The results showed that ACE2 activity was regulated in atherosclerotic plaque by losartan, which may play an important role in treatment of atherosclerosis. The mechanism involves Ang II-AT1R-mediated mitogen-activated protein kinases, MAPKs (MAPKs) signaling pathway.