Insight into Accelerating Polysulfides Redox Kinetics by BN@MXene Heterostructure for Li-S Batteries.

Sluggish redox kinetics and shuttle effect of polysulfides hinder the extensive application of the lithium-sulfur batteries (LSBs). Herein a functional heterostructure of boron nitride (BN) and MXene with an alternately layered structure (BN@MXene) is designed as separator interlayer. High efficiency Li+ transmission, uniform lithium deposition, strong adsorption, and efficient catalytic conversion activities of lithium polysulfides (LiPSs) realized by this heterostructure are confirmed by experiments and theoretical calculations. The alternately layered structure provides unblocked ion transmission channels and abundant active sites to accelerate the polysulfides redox kinetics with reduced energy barriers of oxidation and reduction reactions. As a result, the LSBs deliver an initial discharge capacity of up to 1273.9 mAh g-1 at 0.2 °C and a low decay of 0.058% per cycle in long-term cycling up to 700 cycles at 1 °C. This work provides an effective designing strategy to accelerate the polysulfides redox kinetics for advanced Li-S electrochemical system.

Highly Deformable High-Strength SiO2 Aerogel Designed with an Alternating Structure of Hard Cores and Flexible Chains for Thermal Insulation.

Thermally insulating aerogels can now be prepared from ceramics, polymers, carbon, and metals and composites between them. However, it is still a great challenge to make aerogels with high strength and excellent deformability. We propose a design concept of hard cores and flexible chains that alternately construct the aerogel skeleton structure. The approach gives the designed SiO2 aerogel excellent compressive (fracture strain 83.32%), tensile. and shear deformabilities, corresponding to maximum strengths of 22.15, 1.18, and 1.45 MPa, respectively. Also, the SiO2 aerogel can stably perform 100 load-unload cycles at a 70% large compression strain, demonstrating an excellent resilient compressibility. In addition, the low density of 0.226 g/cm3, the high porosity of 88.7%, and the average pore size of 45.36 nm effectively inhibit heat conduction and heat convection, giving the SiO2 aerogel outstanding thermal insulation properties [0.02845 W/(m·K) at 25 °C and 0.04895 W/(m·K) at 300 °C], and the large number of hydrophobic groups itself also gives it excellent hydrophobicity and hydrophobic stability (hydrophobic angle of 158.4° and saturated mass moisture absorption rate of about 0.327%). The successful practice of this concept has provided different insights into the preparation of high-strength aerogels with high deformability.

Plasma and magnetron sputtering constructed dual-functional polysulfides barrier separator for high-performance lithium-sulfur batteries.

In order to fundamentally suppress the shuttle effect, N2 Plasma & Al2O3 magnetron sputtered separators (Al2O3@N-PP) are proposed for lithium-sulfur batteries (LSBs). Such a dual-functional polysulfides (LiPSs) barrier separator greatly inhibits the shuttle effect from the perspective of physical and chemical interaction. Physically, the inherently electronegative amorphous Al2O3 first achieves the repulsion of LiPSs to the sulfur cathode through the electrostatic repulsive effect, effectively preventing a large amount of soluble LiPSs from accumulating at the separator. At the same time, the Al2O3 film seals the shuttle channel of LiPSs to a certain extent. Chemically, N2 plasma-doped N heteroatoms form a lithium bond with Li+ in LiPSs to achieve the first step chemical adsorption and anchoring of LiPSs. When the LiPSs reaches the amorphous Al2O3 film, more stable chemical bonds are formed between Al3+ and S2-, Li+ and O2- to achieve more effective adsorption and anchoring of LiPSs. At 1C with a high sulfur loading up to 3-5 mg cm-2 the LSB contributes a specific charge capacity of 717.4 mAh g-1, with high retention rate up to 75.49 % after 450 cycles. The U-shaped electrolytic cell experiment and ultraviolet-visible spectrum experiment confirmed the LiPSs barrier function of the functional separator.

Lead zirconate titanate aerogel piezoelectric composite designed with a biomimetic shell structure for underwater acoustic transducers.

In this study, we used lead zirconate titanate (PZT) aerogels prepared by a solvothermal assisted sol-gel method as raw materials to synthesize PZT aerogel/PVDF composite coatings and PZT aerogel sintered sheets through natural annealing and PVDF composite and hot pressing, respectively, and then combined them with the design principle of a biomimetic shell structure to prepare an alternate coating/sheet structured PZT aerogel piezoelectric composite with natural distinguished mechanical properties. It had excellent piezoelectric properties with a piezoelectric coefficient d33 of 435.15 pC N-1 and d31 of -144.55 pC N-1, excellent electromechanical coupling properties with a planar electromechanical coupling coefficient of 60.14%, low dielectric loss of 0.76% at 40 Hz and low density of 3.04 g cm-3. When used as the piezoelectric material in underwater acoustic transducers (UATs), compared with all kinds of piezoelectric ceramics, it achieved higher piezoelectric and comprehensive mechanical properties, lower dielectric loss, lower density, and electromechanical coupling properties similar to that of Pb-containing piezoelectric ceramics, thus showing extremely promising application prospects in UATs.

Selection of different surgical methods for uterine fibroids: Protocol for a retrospective clinical study.

INTRODUCTION: Uterine fibroids is a common benign tumor disease of the female reproductive system. The main methods of current clinical treatment of uterine fibroids are conservative treatment and surgical treatment. With the rise of the concept of minimally invasive surgery in gynecology, laparoscopic myomectomy, and vaginal myomectomy have been widely used. METHODS/DESIGN: This study plans to retrospectively analyze 150 patients with uterine fibroids. They will be divided into laparoscopic myomectomy, vaginal myomectomy group, and open hysteromyoma resection group. This study will compare the intraoperative blood loss, operation time, postoperative exhaust time, postoperative hospital stay and postoperative complications of different surgical methods. DISCUSSION: This study will compare the clinical efficacy of these 3 common surgical methods through retrospective medical record analysis, and provide more reliable evidence-based medical evidence for clinical treatment choices.

Discovery and structure-activity relationships of a novel series of benzopyran-based K(ATP) openers for urge urinary incontinence.

A novel series of benzopyran derivatives were synthesized and evaluated as K(ATP) channel openers. Structure-activity relationships were investigated around 4-position of the benzopyran nucleus. Optimization of 4-substituent with some heterocyclic rings led to compound 13b bearing a benzo[d]isoxazol-3-one moiety as a potent and selective K(ATP) channel opener in vitro. In two anesthetized rat models of myogenic bladder overactivity, compound 13b was found to inhibit spontaneous bladder contractions.

Long-Term Safety Follow-Up of Subjects Previously Treated with Non-Replicating Retroviral Vector-Based Gene Therapies.

OBJECTIVE: Our objective was to evaluate the life-long safety profile of gene therapy using retroviral (non-replicating) vectors (nRCR), or cell products in 127 subjects with hemophilia, human immunodeficiency virus (HIV), or cancer, previously treated with such gene therapy. METHODS: We assessed the occurrence of serious adverse events (SAEs), deaths and presence of replication competent retrovirus (RCR). RESULTS: A total of 23 subjects remained until the data cut-off date of 31 July 2013 and provided safety information of up to 18 years. Of the 104 subjects who discontinued, the primary reason was loss to follow-up (47.2 %; n = 60). The follow-up period for the 60 subjects lost to follow-up was 7-10 years. A total of 41 subjects experienced at least one SAE, and 15 subjects died. We reviewed SAEs and cause of death (none related to the active therapy), but no evidence was found for safety signals related to new malignancy or neurologic, rheumatological, autoimmune, or hematologic disorder. RCR results were negative, indicating no evidence for in vivo vector persistence. CONCLUSION: Despite the loss of follow-up, which is the limiting factor in this long-term safety trial, the findings from this long-term follow-up study are encouraging.

Pyrroloquinolone PDE5 inhibitors with improved pharmaceutical profiles for clinical studies on erectile dysfunction.

We previously reported a series of potent and selective pyrimidinyl pyrroloquinolone PDE5 inhibitors such as 2a for potential use in male erectile dysfunction (MED) (Sui, Z.; Guan, J.; Macielag, M. J.; Jiang, W.; Zhang, S.; Qiu, Y.; Kraft, P., Bhattacharjee, S.; John, T. M.; Craig, E.; Haynes-Johnson, D.; Clancy, J. J. Med. Chem. 2002, 45, 4094-4096). Unfortunately, the low aqueous solubility and poor oral bioavailability rendered them undesirable development candidates. To address this issue, we designed a series of analogues using two approaches: increasing the overall basicity and reducing molecular weight of the lead. Through earlier SAR studies, we discovered that the PDE5 potency of the pyrroloquinolones is insensitive to substitution on the pyrrole nitrogen. Basic functional groups such as pyridines and benzimidazoles were appended via the aromatic ring connected to the pyrrole nitrogen. Several truncated analogues were also designed and synthesized to improve oral absorption. These modifications allowed us to identify analogues with good oral bioavailability in rats, dogs, and monkeys while the high potency against PDE5 and desirable selectivity versus other PDE isozymes were maintained. Compounds R-11e and R-11l were selected as development candidates for MED and other indications.

Expression of PDE11A in normal and malignant human tissues.

Cyclic nucleotide phosphodiesterase 11A (PDE11A) is the newest member in the PDE family. Although the tissue distribution of PDE11A mRNA has been shown, its protein expression pattern has not been well studied. The goal of this report is to investigate the distribution of PDE11A proteins in a wide range of normal and malignant human tissues. We utilized a polyclonal antibody that recognized all four PDE11A isoforms. Its specificity was demonstrated by Western blot analysis on a recombinant human PDE11A protein and native PDE11A proteins in various human tissues. Immunohistochemistry showed that PDE11A is widely expressed. Various degrees of immunoreactivity were observed in the epithelial cells, endothelial cells, and smooth muscle cells of all tissues examined. The highest expression was in the epithelial, endothelial, and smooth muscle cells of the prostate, Leydig, and spermatogenic cells of the testis, the tubule epithelial cells in the kidney, the epithelial and endothelial cells in the adrenal, the epithelial cells and macrophages in the colon, and the epidermis in the skin. Furthermore, PDE11A expression was also detected in several human carcinomas. Our results suggest that PDE11A might be involved in multiple physiological processes in various organs via its ability to modulate intracellular cAMP and cGMP levels.

Altered activities of cyclic nucleotide phosphodiesterases and soluble guanylyl cyclase in cultured RFL-6 cells.

We utilized rat fetal lung fibroblasts (RFL-6) to evaluate our PDE5 inhibitors at cellular level and observed a decrease in cGMP accumulation induced by sodium nitroprusside (SNP) and PDE5 inhibitors with passage. To further investigate this observation, we examined cGMP synthesis via soluble guanylyl cyclase (sGC) and degradation via phosphodiesterases (PDEs) at different passages. At passage (p)4, p9, p14, major cGMP and cAMP degradation activities were contributed by PDE5 and PDE4, respectively. The PDE5 activity decreased 50% from p4 to p14, while PDE4 activity doubled. The cGMP accumulation was evaluated in the presence of sodium nitroprusside (SNP) and/or PDE inhibitors in p4 and p14 cells. SNP together with sildenafil, a PDE5 inhibitor, induced dose-dependent increase in cGMP levels in cells at p4, but showed little effect on cells at p14. The possible down regulation of sGC at mRNA level was explored using real-time RT-PCR. The result showed the mRNA level of the alpha1 subunit of sGC decreased about 98% by p9, while the change on beta1 mRNA was minimal. Consistently, sGC activities in cell lysate decreased by 94% at p9. Forskolin stimulated a dramatic increase in cAMP levels in cells at all passages examined. Our results show that sGC activity decreased significantly and rapidly with passage due to a down regulation of the alpha1 subunit mRNA, yet the adenylyl cyclase activity was not compromised. This study further emphasized the importance of considering passage number when using cell culture as a model system to study NO/cGMP pathway.

Pyrimidinylpyrroloquinolones as highly potent and selective PDE5 inhibitors for treatment of erectile dysfunction.

A series of N-pyrimidinylpyrroloquinolones were discovered as extremely potent and selective PDE5 inhibitors. Representative compounds demonstrated in vivo efficacy in dog erectile dysfunction models and are orally bioavailable.

Structure-activity relationships of N-acyl pyrroloquinolone PDE-5 inhibitors.

The discovery of the potent and selective PDE-5 inhibitory activity of a pyrroloquinolone scaffold prompted us to explore the SAR of its acyl derivatives. During the course of these studies, three structural series were found with K(i) values for PDE-5 in the subnanomolar range. Systematic modification of one of these leads produced a compound with excellent selectivity for PDE-5 over other phosphodiesterases and oral bioavailability of 15% in male rats. This compound also displayed in vivo efficacy in an anesthetized canine model of erection when dosed intravenously.

Furoyl and benzofuroyl pyrroloquinolones as potent and selective PDE5 inhibitors for treatment of erectile dysfunction.

Synthesis of furoyl and benzofuroyl pyrroloquinolones as potent and selective PDE5 inhibitors was reported. Their in vitro potencies in inhibiting PDE5 and selectivity in inhibiting other PDE isozymes (PDE1-4 and PDE6) were evaluated. Some of these compounds are more potent than sildenafil with better selectivity toward PDE1 and PDE6. Incorporation of solublizing groups resulted in bioavailable analogues. Selected compounds showed in vivo efficacy in anesthetized dog model for penile erection.

Characterization of a novel phosphodiesterase type 5 inhibitor: JNJ-10258859.

We have characterized a novel, potent, and selective phosphodiesterase type 5 inhibitor, JNJ-10258859 ((R)-(-)-3-(2,3-dihydro-benzofuran-5-yl)-2-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one). Its inhibitory effects on phosphodiesterase 1-6 were determined using enzymes partially purified from human tissues. The compound inhibited phosphodiesterase type 5 with a K(i) of 0.23 nM and displayed excellent selectivity versus phosphodiesterase types 1-4 (>/=22,000 fold compared to phosphodiesterase type 5). It had 27-fold selectivity over phosphodiesterase type 6 as well. In a cell-based assay, JNJ-10258859 was more potent than sildenafil in potentiating nitric oxide (NO) induced accumulation of intracellular cGMP. The in vivo effect of JNJ-10258859 was evaluated in an anesthetized dog model via intravenous administration. The compound had similar efficacy to sildenafil in enhancing both the amplitude and duration of intracavernosal pressure increase induced by electrical stimulation to the pelvic nerve. No significant effects on either mean aortic pressure or heart rate were observed during the course of the experiments. This data suggests that JNJ-10258859 could be a useful treatment for erectile dysfunction.

Comparison of endothelin-1-mediated tissue tension and calcium mobilization effects in isolated rabbit corpus cavernosum.

OBJECTIVES: To directly compare and contrast the effects of endothelin-1 (ET-1) and adrenoreceptor agonists norepinephrine and phenylephrine on eliciting calcium influx in primary rabbit corpus cavernosum cells and their ability to elicit tissue contractions. The potent vasoconstrictor peptide ET-1 and the alpha-adrenoreceptor agonists are important modulators of smooth muscle tone in the penile corpus cavernosum. However, the mechanisms involved in maintaining smooth muscle tone and contraction are not clearly understood. METHODS: Intracellular calcium mobilization was measured in cultured corpus cavernosum smooth muscle cells using calcium-sensing dyes in conjunction with a fluorometric imaging plate reader. Tissue tension studies on rabbit corpus cavernosum were conducted using organ chambers. RESULTS: ET-1 at concentrations as low as 10 nM was sufficient to induce a transient increase of intracellular calcium in these cells. In contrast, concentrations of 1 mM and greater of norepinephrine and phenylephrine were required to elicit comparable calcium fluxes in cavernosum cells. Tissue bath studies indicated that ET-1 is a potent stimulator of corpus cavernosum smooth muscle contraction, with concentrations as low as 10 nM sufficient to initiate contraction. CONCLUSIONS: The potency of ET-1 in producing contraction on tissue strips and inducing calcium flux suggests that ET-1 might be an important mediator for modulating and maintaining corpus cavernosum smooth muscle tone. Therefore, additional exploration of the role of endothelins and their receptors in the tumescence and detumescence states of the penis would be extremely valuable.

Cyclic nucleotide phosphodiesterases in rabbit detrusor smooth muscle.

OBJECTIVES: To identify the phosphodiesterase (PDE) isoenzymes in the rabbit detrusor and to evaluate their roles in regulating detrusor muscular tone. Cyclic nucleotides are important secondary messengers involved in modulating the contractility of various smooth muscles. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are synthesized by their respective cyclases and degraded by various PDEs. METHODS: PDE isoenzymes from male and female rabbit detrusor were isolated by the Mono-Q anion exchange column and identified with various inhibitors. Detrusor strips from both sexes were precontracted with carbachol and relaxed with PDE inhibitors and adenylate and guanylyl cyclase activators in a tissue bath. Cyclic nucleotide concentrations in strips from male rabbits were determined after the compound treatment. RESULTS: Similar results were obtained from both sexes in the experiments in which both sexes were used. The activities of PDE1, 2, 3, 4, and 5 were identified. Forskolin induced a dramatic rise in the cAMP levels and was the most effective relaxant. Papaverine generated moderate increases in the cAMP and cGMP levels and induced very good relaxation. Vinpocetine produced no detectable changes in the cyclic nucleotide levels but elicited good relaxation. Sildenafil caused an increase in the cGMP levels and had a similar relaxation effect as vinpocetine. Sodium nitroprusside induced some increase in cGMP and had no relaxation effect. Rolipram raised the cAMP levels significantly, yet had a moderate effect on relaxation. CONCLUSIONS: Our results demonstrated the presence of PDE1 through 5 in rabbit detrusor muscle and supported their involvement in regulating detrusor muscle tone. The relaxation of rabbit detrusor was mainly mediated by the cAMP pathway.

Synthesis and SAR of tetracyclic pyrroloquinolones as phosphodiesterase 5 inhibitors.

The synthesis of the fused tetracyclic pyrroloquinolones 9a-i in four steps is described. The PDE5 inhibitory activities of these compounds, their selectivities against PDE1, PDE2, PDE3, PDE4 and PDE6, the preclinical pharmacokinetic assessments and the in vivo efficacy in increasing intracavernosal pressure are presented and discussed.

Synthesis and biological activities of novel beta-carbolines as PDE5 inhibitors.

A series of N(2)-furoyl and N(2)pyrimidinyl beta-carbolines was discovered to possess potent inhibitory activity against PDE5. During the synthesis we developed a tandem resin quenching protocol, which allowed us to synthesize large number of target compounds in a rapid fashion. Representative compounds exhibit superior selectivity to sildenafil versus other isozymes of PDEs, and demonstrated in vivo efficacy in increasing introcavernosal pressure in dogs.