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The novel potassium competitive acid blocker, KFP-H008, developed to overcome the shortcomings of proton pump inhibitors. In this study, KFP-H008 was administered by oral gavage at doses of 0 (control), 15, 45, and 150 mg/kg to Sprague-Dawley rats (24 animals per sex per group). Body weight, food consumption, mortality, sexual cycle, mating behavior, pregnancy, sperm motility, and relative organ weights were evaluated. In a concomitant toxicokinetic (TK) study (10 animals per sex per group), plasma TK parameters and tissue distribution of KFP-H008 were tested. There were obvious effects at the dosage of 150 mg/kg to male rats with decreases of prostate weight and lower weight gain; to female rats with lower weight gain, hair off, and lower corpus luteum count. There were no effects on litter parameters. Time to reach maximum plasma concentrations for KFP-H008 was between 0.5 and 1.0 hr for the 15 and 45 mg/kg groups, while for the 150 mg/kg group it had a delay to 2 hr. Overall, the NOAEL of KFP-H008 was considered to be 45 mg/kg in both genders and the TK study shows that exposure (area under the curve) of male rats was about 1,091.0 ± 530.8 μg/Lhr and to female rats was 1,030.5 ± 512.5 μg/Lhr. Administration of KFP-H008although reaches the reproductive organs, it demonstrated no significant effects on reproductive organs, it did not affect mating, fertility, pregnancy, growth, or morphologic development.

Maternally inherited diabetes and deafness is a rare genetic disease mainly caused by a point mutation in mitochondrial deoxyribonucleic acid. Lipoprotein lipase gene mutations are associated with familial dyslipidemias, which are difficult to manage. We reported for the first time a case that had both maternally inherited diabetes and severe hyperlipidemia caused by lipoprotein lipase gene mutation (C.347(exon3)G>C) that was resistant to fenofibrate and atorvastatin. We were able to manage the patient’s hyperlipidemia with bezafibrate, and her diabetes was well controlled with insulin. In conclusion, genetic testing is helpful in identifying rare and interesting cases when clinicians suspect inheritable diseases. Additionally, when one fibrate drug is ineffective in treating hyperlipidemia, it might be worthwhile trying another fibrate.

The early diversification of angiosperms is thought to have been a rapid process, which may complicate phylogenetic analyses of early angiosperm relationships. Plastid and nuclear phylogenomic studies have raised several conflicting hypotheses regarding overall angiosperm phylogeny, but mitochondrial genomes have been largely ignored as a relevant source of information. Here we sequenced mitochondrial genomes from 18 angiosperms to fill taxon-sampling gaps in Austrobaileyales, magnoliids, Chloranthales, Ceratophyllales, and major lineages of eudicots and monocots. We assembled a data matrix of 38 mitochondrial genes from 107 taxa to assess how well mitochondrial genomic data address current uncertainties in angiosperm relationships. Although we recovered conflicting phylogenies based on different data sets and analytical methods, we also observed congruence regarding deep relationships of several major angiosperm lineages: Chloranthales were always inferred to be the sister group of Ceratophyllales, Austrobaileyales to mesangiosperms, and the unplaced Dilleniales was consistently resolved as the sister to superasterids. Substitutional saturation, GC compositional heterogeneity, and codon-usage bias are possible reasons for the noise/conflict that may impact phylogenetic reconstruction; and angiosperm mitochondrial genes may not be substantially affected by these factors. The third codon positions of the mitochondrial genes appear to contain more parsimony-informative sites than the first and second codon positions, and therefore produced better resolved phylogenetic relationships with generally strong support. The relationships among these major lineages remain incompletely resolved, perhaps as a result of the rapidity of early radiations. Nevertheless, data from mitochondrial genomes provide additional evidence and alternative hypotheses for exploring the early evolution and diversification of the angiosperms. Jiangsu Key Laboratory for the Research and Utilization of Plant Resources (Institute of Botany, Jiangsu Province) [KSPKLB201835]; Jiangsu Key Laboratory for the Research and Utilization of Plant Resources (Chinese Academy of Sciences) [KSPKLB201835]; Shenzhen Key Laboratory of Southern Subtropical Plant Diversity [SLPD-2018-3]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31470314, 31471200, 31470448]; Public Welfare Forestry Industry Project of State Forestry Administration, China [201504322]; Special Research Fund of Ghent UniversityGhent University [BOFPDO2018001701]; Strategic Priority Research Program of Chinese Academy of SciencesChinese Academy of Sciences [XDA13020603]; Shenzhen Fairy Lake Botanical Garden Science Foundation [FLSF-2019-02]; Ghent UniversityGhent University; FWOFWO; Flemish Government-department EWI info:eu-repo/semantics/publishedVersion

BACKGROUND AND AIMS About 20% of patients receiving nucleos(t)ide analogues treatment experienced low-level viraemia (LLV), which is associated with progression of liver fibrosis and high risk of hepatocellular carcinoma. We aimed to evaluate the effectiveness and safety of switching from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) in ETV-treated patients with LLV. METHODS In this prospective study, ETV-treated patients with LLV, presented to our hospital from December 2018 to October 2019, were enrolled. Switching to TAF or continuing ETV was given. The primary effectiveness endpoint was complete virological response (CVR) at 24 weeks, and the safety endpoint was the first occurrence of any clinical adverse event during the treatment. RESULTS Totally, 211 patients were recruited and propensity score matching (PSM) generated 75 patients in either TAF or ETV group. After PSM, baseline characteristics were balanced in two groups. After 24-week treatment, the CVR and ALT normalization in TAF group were 62.7% and 47.6%, which were higher than 9.3% and 10.5% in ETV group (OR 16.4, 95% CI 6.6-40.0, P

Hydrophobic deep eutectic solvents (DESs) emerge as candidates to extract organic substrates from aqueous solutions. The DES-aqueous liquid-liquid interface plays a vital role in the extraction ability of hydrophobic DES because the non-bulk structure of molecules at the interface could cause thermodynamic and kinetic barriers. One question is how the DES compositions affect the structural features of the DES-aqueous liquid-liquid interface. We investigate the density profile, dipole moment and hydrogen bonds of eight hydrophobic DES-aqueous liquid-liquid interfaces using molecular dynamics simulations. The eight DESs are composed of four organic compounds: decanoic acid, menthol, thymol, and lidocaine. The simulation results show the variations of dipole moment and hydrogen bond structure and dynamics at the liquid-liquid interfaces. Such variations could influence the extraction ability of DES through adjusting the partition and kinetics of organic substrates in the DES-aqueous biphasic systems.

Background There is increasing evidence that the eradication of Helicobacter pylori leads to the regression of gastric hyperplastic polyps (GHPs). We performed a systematic review with a meta-analysis of randomized controlled trials and observational studies that assessed the effects of eradication. Materials and methods We searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases for relevant studies with a combination of the terms "Helicobacter pylori" and "polyps." The risk ratio was used to compare the effect of H. pylori eradication/treatment on GHP. We also calculated the pooled disappearance rate of GHP in the H. pylori eradication/treatment group and persistent infection group. Results We analyzed data from 6 studies, including 3 RCTs. A total of 58/394 patients were included in the H. pylori treatment/successful eradication group, and 57/302 patients were included in the H. pylori untreated/persistent infection group. The pooled rate of GHP elimination after H. pylori treatment/successful eradication was 59% (95% CI, 43%-75%)/79% (95% CI, 72%-86%). H. pylori treatment/successful eradication significantly increased the GHP elimination rate [ITT: (pooled rate: 58% vs. 0%, RR =22.24, 95% CI, 4.51- 109.78, p = 0.0001), PP: (pooled rate: 65% vs. 0%, RR =22.25, 95% CI, 4.52- 109.37, p = 0.0001)/(pooled rate: 79% vs. 9%, RR =26.87, 95% CI, 1.34-540.5, p = 0.03)]. Conclusions Our meta-analysis showed that after the eradication of H. pylori, most GHPs are eliminated. Moreover, the treatment/successful eradication of H. pylori increased the GHP elimination rate by more than 20 times that in the control group.

Recent research showed that invariant natural killer T (iNKT) cells take part in the regulation of osteoclastogenesis. While the role of iNKT cells in myeloma bone disease (MBD) remains unclear. In our study, the quantity of iNKT cells and the levels of cytokines produced by them were measured by flow cytometry. iNKT cells and osteoclasts were induced from peripheral blood mononuclear cells after activation by α‐GalCer or RANKL in vitro. Then, gene expressions and the levels of cytokines were determined by RT‐PCR and ELISA, respectively. The results showed that the quantity of iNKT and production of IFN‐γ by iNKT cells were significantly decreased in newly diagnosed MM (NDMM), and both negatively related with severity of bone disease. Then, the osteoclasts from healthy controls were cultured in vitro and were found to be down‐regulated after α‐GalCer‐stimulated, while there was no significant change with or without α‐GalCer in NDMM patients, indicating that the regulation of osteoclastogenesis by iNKT cells was impaired. Furthermore, the inhibition of osteoclastogenesis by iNKT cells was regulated by IFN‐γ production, which down‐regulated osteoclast‐associated genes. In conclusion, the role of α‐GalCer‐stimulated iNKT cells in regulation of osteoclastogenesis was impaired in MBD, as a result of iNKT cell dysfunction.

Aims Because of concerns about the safety of aliskiren in patients with diabetes, study treatment was stopped prematurely in the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE). We examined outcomes and treatment effect in these patients compared with those without diabetes. Methods and results ATMOSPHERE included 7016 patients with heart failure and a reduced ejection fraction (HFrEF) randomly assigned to enalapril plus aliskiren, aliskiren alone, or enalapril. At baseline, 1944 (27.7%) patients had diabetes. Median follow-up was shorter in patients with diabetes compared with those without (24 months vs. 46 months). Among patients with diabetes, the primary endpoint of cardiovascular death or hospitalization for heart failure occurred in 216 patients (33.1%) in the enalapril group (reference), 172 (27.4%) in the aliskiren group [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.67–1.00; P = 0.053], and 196 (29.5%) in the combination group (HR 0.86, 95% CI 0.71–1.04; P = 0.13). The effects of the treatments studied did not differ significantly compared with patients without diabetes. In patients with diabetes, aliskiren monotherapy was associated with a lower risk of symptomatic hypotension compared to enalapril [42 (6.7%) vs. 65 (10.0%); P = 0.04], whereas other adverse events were generally balanced between the three groups. Conclusion In patients with HFrEF and diabetes, there was no signal of harm and a trend towards benefit when direct renin inhibition monotherapy was compared with an angiotensin-converting enzyme inhibitor, whereas combined aliskiren and enalapril treatment led to more adverse events with no improvement in outcomes. Treatment effects did not differ in patients with diabetes compared with those without. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00853658.

We present for the first time the generation of induced pluripotent stem cells (iPSCs) from a patient with a connexin-linked disease. The importance of gap junctional intercellular communication in bone homeostasis is exemplified by the autosomal dominant developmental disorder oculodentodigital dysplasia (ODDD), which is linked to mutations in the GJA1 (Cx43) gene. ODDD is characterized by craniofacial malformations, ophthalmic deficits, enamel hypoplasia, and syndactyly. In addition to harboring a Cx43 p.V216L mutation, ODDD iPSCs exhibit reduced Cx43 mRNA and protein abundance when compared to control iPSCs and display impaired channel function. Osteogenic differentiation involved an early, and dramatic downregulation of Cx43 followed by a slight upregulation during the final stages of differentiation. Interestingly, osteoblast differentiation was delayed in ODDD iPSCs. Moreover, Cx43 subcellular localization was altered during chondrogenic differentiation of ODDD iPSCs compared to controls and this may have contributed to the more compact cartilage pellet morphology found in differentiated ODDD iPSCs. These studies highlight the importance of Cx43 expression and function during osteoblast and chondrocyte differentiation, and establish a potential mechanism for how ODDD-associated Cx43 mutations may have altered cell lineages involved in bone and cartilage development. © 2017 American Society for Bone and Mineral Research.

Plant genomes harbor dozens to hundreds of nucleotide-binding site-leucine-rich repeat (NBS-LRR) genes; however, the long-term evolutionary history of these resistance genes has not been fully understood. This study focuses on five Brassicaceae genomes and the Carica papaya genome to explore changes in NBS-LRR genes that have taken place in this Rosid II lineage during the past 72 million years. Various numbers of NBS-LRR genes were identified from Arabidopsis lyrata (198), A. thaliana (165), Brassica rapa (204), Capsella rubella (127), Thellungiella salsuginea (88), and C. papaya (51). In each genome, the identified NBS-LRR genes were found to be unevenly distributed among chromosomes and most of them were clustered together. Phylogenetic analysis revealed that, before and after Brassicaceae speciation events, both toll/interleukin-1 receptor-NBS-LRR (TNL) genes and non-toll/interleukin-1 receptor-NBS-LRR (nTNL) genes exhibited a pattern of first expansion and then contraction, suggesting that both subclasses of NBS-LRR genes were responding to pathogen pressures synchronically. Further, by examining the gain/loss of TNL and nTNL genes at different evolutionary nodes, this study revealed that both events often occurred more drastically in TNL genes. Finally, the phylogeny of nTNL genes suggested that this NBS-LRR subclass is composed of two separate ancient gene types: RPW8-NBS-LRR and Coiled-coil-NBS-LRR.

A sensitive LC-MS/MS method was developed and validated for simultaneous quantification of 11 constituents, ginsenoside Rg1, Re, Rf, Rg2, Rb1, Rd, Rc, ophiopogonin D, schisandrin, schisandrol B and schizandrin B, in rat serum using digoxin as the internal standard (IS). The serum samples were pretreated and extracted with a two-step liquid-liquid extraction. Chromatographic separation was achieved on a C18 analytical column with a proper gradient elution using 0.02% acetic acid aqueous solution and 0.02% acetic acid-acetonitrile as mobile phase at a flow rate of 0.5 mL/min. MS detection was performed using multiple reaction monitoring via an electrospray ionization source. Good linearity was observed in the validated concentration range for every analyte (r(2) ≥0.9929), and the lower limits of quantitation of the analytes were in the range of 0.044-1.190 ng/mL in rat serum. Intra- and inter-day precisions were 75.8%.The validated method was successfully applied to a pharmacokinetic study of all analytes in rats after single intravenous administration of Shengmai injection.

Here, a set of novel and personalized nanocarriers are presented for controlled nucleus-targeted antitumor drug delivery and real-time imaging of intracellular drug molecule trafficking by integrating an enzyme activatable cell penetrating peptide (CPP) with mesoporous silica coated quantum dots nanoparticles. Upon loading of antitumor drug, doxorubicin (DOX) and further exposure to proteases in tumor cell environment, the enzymatic cleavage of peptide sequence activates oligocationic TAT residues on the QDs@mSiO2 surface and direct the DOX delivery into cellular nucleus. The systematic cell imaging and cytotoxicity studies confirm that the enzyme responsive DOX-loaded CPP-QDs@mSiO2 nanoparticles can selectively release DOX in the tumor cells with high cathepsin B enzyme expression and greatly facilitate DOX accumulation in targeted nucleus, thus exhibiting enhanced antitumor activity in these cells. As contrast, there is limited nuclear-targeted drug accumulation and lower tumor cytotoxicity observed in the cells without enzyme expression. More importantly, significant antitumor DOX accumulation and higher tumor inactivation is also found in the drug resistant tumor cells with targeted enzyme expression. Such simple and specific enzyme responsive mesoporous silica-QDs nanoconjugates provide great promise for rational design of targeted drug delivery into biological system, and may thus greatly facilitate the medical theranostics in the near future.

A green approach to the synthesis of biologically important indeno[2,1-e]pyrazolo[5,4-b]pyridines was successfully realized via multi-component reactions of aldehyde, 3-methyl-1-phenyl-1H-pyrazol-5-amine and 1,3-indanedione in water under microwave irradiation without catalyst. This protocol has the prominent advantages of environmental-friendliness, short reaction time, excellent yields, low cost, easy operation as well as broad scope of applicability.

Radix Ophiopogonis is a widely used traditional Chinese medicine. The quality of Radix Ophiopogonis available in the market varies, and some confusing or fake herbs exist. In order to improve the quality control of Radix Ophiopogonis, a novel fingerprinting method was established using HPLC coupled with UV and evaporative light-scattering detectors (ELSDs). Extraction with methanol and liquid-liquid extraction with water-saturated n-butanol were employed for the preparation of the sample solution. Chromatographic separation was performed on a Lichrospher C(18) column (250x4.6 mm id, 5.0 microm particle size) with a linear gradient elution program. UV detection at 280 nm and evaporative light-scattering detection were utilized to obtain two subfingerprinting chromatograms. A novel protocol for data processing was proposed, in order to identify and remove redundant data obtained by the two detectors, and balance the weight of the two subfingerprints on the similarity values. The method was validated and applied to quality evaluation of 16 samples of Radix Ophiopogonis and related herbs.

The catalytic activity of a series of indenylnickel(II) halides: (1-R-Ind)Ni(PPh3)X (R=ethyl, cyclopentyl and benzyl, while X=Cl, Br and I), towards styrene polymerization was studied in the presence of NaBPh4 and PPh3. The catalytic property of these halides was related to the substituent group on the indenyl ligand and the halogen atom bonded to the metal atom. Among them, the (1-Et-Ind)Ni(PPh3)Cl/NaBPh4/PPh3 system showed the highest activity for the polymerization of styrene, and the polystyrene obtained was a syndio-rich (rr triad) atactic polymer with Mn values in the range of 103–104. The mechanism of the styrene polymerization initiated by the (1-Et-Ind)Ni(PPh3)Cl/NaBPh4/PPh3 system was studied.

BACKGROUND The connexin 43 gene (cx43, GJA1) mediates gap junctional intercellular communication (GJIC), which regulates tissue homeostasis. cx43 is frequently downregulated in prostate cancer. We investigated the role of a histone deacetylase (HDAC)-dependent mechanism in the transcriptional repression of cx43 in a panel of prostate cancer cells. METHODS The impact of Trichostatin A (TSA), an inhibitor of HDAC, on exogenous and endogenous cx43 gene transcription was examined by the luciferase assay, Northern blot, nuclear run-on, Western blot, and chromatin immunoprecipitation assays. RESULTS Trichostatin A induces transcription of cx43 gene and GJIC. The co-activator p300/CBP synergizes with TSA for cx43 promoter activation. We identified a promoter region where cooperation between Ap1 and Sp1 elements was essential for TSA-induced cx43 transcription. TSA increased the level of hyperacetylated histones bound to cx43 promoter. CONCLUSION Our results highlight the potential utility of inhibitors of HDAC to restore cx43 gene expression in prostate cancer. Prostate © 2006 Wiley-Liss, Inc.

As part of a wider research program related to polycarbonate embrittlement, the effects of heat-aging on mechanical relaxation behavior have been studied by examining the relationship between secondary transitions and stress relaxation behavior. In this Part I, the differences in response between two molecular weight polycarbonates (PC) are compared for injection molded samples. Dynamic mechanical spectra showed that the presence of an intermediate β transition (∼ 80°C) is strongly dependent on molecular weight and heat-aging. However, the β 1 (35°C) and the γ (-100°C) peaks are generally insensitive to either effect. The study also attempted to interpret the similarities and differences in relaxation response using free volume and conformational change arguments, which have been subject to much scrutiny. Using the KWW stretched exponential to characterize stress relaxation, it appeared that bulk free volume recovery concepts could explain differences in stress relaxation response but not the corresponding losses in toughness. Hence, it is proposed that changes in relaxation response are most likely due to an interplay of relatively large scale molecular volume and molecular conformation processes that affect intermolecular cooperativity. These high-activation processes are related to the broad β region (β 1 < T < T g ).

The effects of high hydrostatic pressure on the structure and biological activity of infectious bursal disease virus (IBDV), a commercially important pathogen of chickens, were investigated. IBDV was completely dissociated into subunits at a pressure of 240 MPa and 0 °C revealed by the change in intrinsic fluorescence spectrum and light scattering. The dissociation of IBDV showed abnormal concentration dependence as observed for some other viruses. Electron microscopy study showed that morphology of IBDV had an obvious change after pressure treatment at 0 °C. It was found that elevating pressure destroyed the infectivity of IBDV, and a completely pressure-inactivated IBDV could be obtained under proper conditions. The pressure-inactivated IBDV retained the original immunogenic properties and could elicit high titers of virus neutralizing antibodies. These results indicate that hydrostatic pressure provides a potential physical means to prepare antiviral vaccine.

Photoactive technology has proven successful for non-invasive regulation of biological activities and processes in living cells. With the light-directed generation of biomaterials or signals, mechanisms in cell biology can be investigated at the molecular level with spatial and temporal resolution. In this tutorial review, we aim to introduce the important applications of photoactive molecules for elucidating cell biology on aspects of protein engineering, fluorescence labelling, gene regulation and cell physiological functions.

Coordinated differentiation of the ameloblast cell layer is essential to enamel matrix protein deposition and subsequent mineralization. It has been hypothesized that this process is governed by Cx43-based gap junctional intercellular communication as oculodentodigital dysplasia (ODDD) patients harboring autosomal-dominant mutations in Cx43 exhibit enamel defects typically resulting in early adulthood tooth loss. To assess the role of Cx43 in tooth development we employ a mouse model of ODDD that harbors a G60S Cx43 mutant, Gja1(Jrt)/+, and appears to exhibit tooth abnormalities that mimic the human disease. We found that total Cx43 plaques at all stages of ameloblast differentiation, as well as within the supporting cell layers, were greatly reduced in Gja1(Jrt)/+ incisors compared to wild-type littermate controls. To characterize the Gja1(Jrt)/+ mouse tooth phenotype, mice were sacrificed prior to tooth eruption (postnatal day 7), weaning (postnatal day 21), and adulthood (2 months postnatal). A severely disorganized Gja1(Jrt)/+ mouse ameloblast layer and abnormal accumulation of amelogenin were observed at stages when the cells were active in secretion and mineralization. Differences in enamel thickness became more apparent after tooth eruption and incisor exposure to the oral cavity suggesting that enamel integrity is compromised, leading to rapid erosion. Additional analysis of incisors from mutant mice revealed that they were longer with a thicker dentin layer than their wild-type littermates, which may reflect a mechanical stress response to the depleted enamel layer. Together, these data show that reduced levels of Cx43 gap junctions result in ameloblast dysregulation, enamel hypoplasia, and secondary tissue responses.

A set of stable and efficient photoactivable bioluminescent probes for imaging luciferase activity has been developed, which displayed robust bioluminescent signals upon brief UV illumination in buffer, cells and living animals.

The first α-diimine nickel(I) complex having a chloro bridge is reported. The centrosymmetric dinuclear structure of {[ArNC(Me)C(Me)NAr]NiCl}2[Ar2,6−C6H3(i-Pr)2] features two chelating α-diimine ligands and two bridged chlorine atoms, so that a distorted tetrahedral N2Cl2 coordination geometry for nickel results. Copyright © 2004 John Wiley & Sons, Ltd.