Poly(vinylpyridine-co-vinylpyridine N-oxide) Excipients Mediate Rapid Dissolution and Sustained Supersaturation of Posaconazole Amorphous Solid Dispersions.

The chemical structure of excipients molecularly mixed in an amorphous solid dispersion (ASD) has a significant impact on properties of the ASD including dissolution behavior, physical stability, and bioavailability. Polymers used in ASDs require a balance between hydrophobic and hydrophilic functionalities to ensure rapid dissolution of the amorphous dispersion as well as sustained supersaturation of the drug in solution. This work demonstrates the use of postpolymerization functionalization of poly(vinylpyridine) excipients to elucidate the impact of polymer properties on the dissolution behavior of amorphous dispersions containing posaconazole. It was found that N-oxidation of pyridine functionalities increased the solubility of poly(vinylpyridine) derivatives in neutral aqueous conditions and allowed for nanoparticle formation which supplied posaconazole into solution at concentrations exceeding those achieved by more conventional excipients such as hydroxypropyl methylcellulose acetate succinate (HPMCAS) or Eudragit E PO. By leveraging these functional modifications of the parent poly(vinylpyridine) excipient to increase polymer hydrophilicity and minimize the effect of polymer on pH, a new polymeric excipient was optimized for rapid dissolution and supersaturation maintenance for a model compound.

Linear Block Copolymer Synthesis.

Block copolymers form the basis of the most ubiquitous materials such as thermoplastic elastomers, bridge interphases in polymer blends, and are fundamental for the development of high-performance materials. The driving force to further advance these materials is the accessibility of block copolymers, which have a wide variety in composition, functional group content, and precision of their structure. To advance and broaden the application of block copolymers will depend on the nature of combined segmented blocks, guided through the combination of polymerization techniques to reach a high versatility in block copolymer architecture and function. This review provides the most comprehensive overview of techniques to prepare linear block copolymers and is intended to serve as a guideline on how polymerization techniques can work together to result in desired block combinations. As the review will give an account of the relevant procedures and access areas, the sections will include orthogonal approaches or sequentially combined polymerization techniques, which increases the synthetic options for these materials.

Spironolactone alleviates myocardial fibrosis via inhibition of Ets-1 in mice with experimental autoimmune myocarditis.

Spironolactone improves cardiac structure, function and prognosis in patients with heart failure and delays the progression of cardiac fibrosis. However, the exact underlying mechanism of this process remains to be elucidated. The present study therefore aimed to explore the protective effect and underlying mechanism of the aldosterone receptor antagonist, spironolactone, on myocardial fibrosis in mice with experimental autoimmune myocarditis (EAM). The EAM model was induced in BALB/c mice via immunization with murine cardiac α-myosin heavy chain sequence polypeptides. The cardiac function of the mice was assessed using echocardiography and the levels of inflammatory cytokines were quantified using ELISA. E26 transformation-specific sequence-1 (Ets-1) expression was knocked down using lentivirus-mediated small interference RNA. Total collagen deposition was assessed using Masson's trichrome and Ets-1, TGF-ß1, Smad2/3, collagen I and III protein expression levels were detected using immunohistochemistry and western blotting. MMP-2 and MMP-9 mRNA expression levels and activity was determined using reverse transcription-quantitative PCR and gelatin zymography, respectively. The results of the present study demonstrated that spironolactone significantly improved myocardium hypertrophy, diastolic cardiac function and decreased myocardial inflammation and collagen deposition induced by EAM. Spironolactone treatment significantly inhibited Ets-1 and smad2/3 phosphorylation. In addition, inhibition of Ets-1 reduced the expression and activity of MMP-2 and MMP-9 and decreased cardiac fibrosis in EAM mice. The results indicated that the improvement of myocardial fibrosis by spironolactone may be associated with the TGF-ß1/Smad-2/3/Ets-1 signaling pathway in EAM mice.

A new species and a key to eleven species of the genus Conophyma Zubovsky, 1898 (Orthoptera, Acridoidea, Catantopidae, Conophyminae) from China.

A new species and a key to eleven species of of the genus Conophyma Zobovsky, 1898 from China is described in this paper. The new species Conophyma lini sp. nov. is similar to C. xiai Zhang et al, 2015, but differs from latter by: vertex longer, apex narrower; minimum width of interspace 1.6 times length in mesosternum; posterior margin of epiproct waved, with angular projection in the middle, furculae small and width of Epiphallus 2.5 times high. Type specimens are deposited in the Northwest Plateau Institute of Biology, Chinese Academy of Sciences, Xining, Qinghai 810001, China.

Distorted Sandwich α-Diimine PdII Catalyst: Linear Polyethylene and Synthesis of Ethylene/Acrylate Elastomers.

The introduction of m-xylyl substituents to α-diimine PdII catalyst promotes living ethylene polymerization at room temperature and low pressure to yield high molecular weight polyethylene (PE) with low branching (<17/1000 C). m-Xylyl groups provide a highly effective blockage to the axial sites of the catalytic center and form a distorted sandwich geometry. The shielding prevents chain-transfer and easy accessibility of polar monomers, leading to a living polymerization. Conducting a light irradiation as part of the one-step metal-organic insertion light initiated radical (MILRad) process leads to diblock copolymers of ethylene and acrylates. Incorporation of different acrylate block sequences can significantly modify the mechanical and chemical properties of block copolymers which can be modulated to be a hard plastic, elastomer, or semi-amorphous polymer.

Establishment and Social Impacts of the Red Imported Fire Ant, Solenopsis invicta, (Hymenoptera: Formicidae) in Taiwan.

The first report of the red imported fire ant (RIFA), Solenopsis invicta Buren, in Taiwan was in the city of Taoyuan in 2003. The government has made great efforts to bring RIFA-infested areas under control. RIFA has gradually spread outward since its discovery, but it is still confined in northern Taiwan, in part due to the control efforts. RIFA is well established in densely populated environments (i.e., urban areas), causing damage to public utilities and significantly affects the inhabitants of Taiwan. Out of 10,127 human encounters with RIFA reported by the Plant Pest Information Management System in the Bureau of Animal and Plant Health Inspection and Quarantine, Council of Agriculture, Executive Yuan, 3819 (37.71%) persons were stung, with 834 (21.8%) persons exhibiting wheal-and-flare reaction (swelling and redness of the skin). Among the victims, 288 (7.5%) sought medical care, and about 21 (0.6%) developed severe cellulitis and urticaria. Unexpectedly, 2.8% (106) of the victims exhibited anaphylactic shock, which was higher than previously reported cases (1%). The high anaphylactic shock percentage was probably because most victims were elderly farmers or because Asian people have higher sensitivity to the RIFA sting. RIFA is well adapted to the environmental conditions in Taiwan, which makes it extremely difficult (if not impossible) to eradicate. The management of RIFA in the future should focus on lowering the speed of spread to mitigate possible dangers to the inhabitants. Six major challenges of RIFA management in Taiwan are also discussed.

Lattice QCD Calculations of Transverse-Momentum-Dependent Soft Function through Large-Momentum Effective Theory.

The transverse-momentum-dependent (TMD) soft function is a key ingredient in QCD factorization of Drell-Yan and other processes with relatively small transverse momentum. We present a lattice QCD study of this function at moderately large rapidity on a 2+1 flavor CLS dynamic ensemble with a=0.098 fm. We extract the rapidity-independent (or intrinsic) part of the soft function through a large-momentum-transfer pseudoscalar meson form factor and its quasi-TMD wave function using leading-order factorization in large-momentum effective theory. We also investigate the rapidity-dependent part of the soft function-the Collins-Soper evolution kernel-based on the large-momentum evolution of the quasi-TMD wave function.

Identification of microRNAs that Regulate the MAPK Pathway in Human Cumulus Cells from PCOS Women with Insulin Resistance.

Polycystic ovary syndrome (PCOS) is one of the most common gynaecological endocrine disorders, and more than 60% of PCOS patients have varying degrees of insulin resistance (IR). The regulatory role of microRNAs (miRNAs) at post-transcriptional levels in human cumulus cells relating to IR in PCOS remains unclear. In this case-control study, 26 PCOS patients with IR (PCOS-IR) and 24 patients without IR (PCOS-control) were enrolled. We determined the differentially expressed miRNA and mRNA using next-generation sequencing technology, and these miRNAs and mRNAs were validated by quantitative real-time polymerase chain reaction (PCR). These miRNA regulating pathways (e.g., MAPK pathway) were analysed by bioinformatics analysis, and the Rap1b was demonstrated to be targeted by miR-612 based on quantitative real-time PCR, western blot and luciferase activity assay. A total of 59 known miRNAs and 617 differentially expressed genes were identified that differentially expressed between PCOS-IR and PCOS-control cumulus cells. Moreover, the potential regulating roles of miRNAs and their targeting genes in pathophysiology of IR and PCOS were analysed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation, and several key processes were enriched, such as MAPK activity. Furthermore, Rap1b, a regulator of the MAPK pathway, was demonstrated to be suppressed directly by miR-612 in PCOS-IR cumulus cells based on negative expression correlation validation, dual luciferase activity assay and reduction of Rap1b expression after miR-612 mimics transfection. Our results suggested that miRNAs and their targeted pathways in ovarian cumulus cells may play important roles in the aetiology and pathophysiology of PCOS with IR.

Olefins and Vinyl Polar Monomers: Bridging the Gap for Next Generation Materials.

The inherent differences in reactivity between activated and non-activated alkenes prevents copolymerization using established polymer synthesis techniques. Research over the past 20 years has greatly advanced the copolymerization of polar vinyl monomers and olefins. This Review highlights the challenges associated with conventional polymerization systems and evaluates the most relevant methods which have been developed to "bridge the gap" between polar vinyl monomers and olefins. We discuss advancements in heteroatom tolerant coordination-insertion polymerizations, methods of controlling radical polymerizations to incorporate olefinic monomers, as well as combined approaches employing sequential polymerizations. Finally, we discuss state-of-the-art stimuli-responsive systems capable of facile switching between catalytic pathways and provide an outlook towards applications in which tailored copolymers are ideally suited.

Vitamin D level affects IVF outcome partially mediated via Th/Tc cell ratio.

PROBLEM: The role of vitamin D (VD) in IVF outcome and immune parameters has not been elucidated well. METHOD OF STUDY: Women undergoing IVF treatment with GnRH agonist (Agonist) and progestin-primed ovarian stimulation (PPOS) protocols were divided into VD lower (VDL, 25(OH)VD ≤20 ng/mL) and VD higher (VDH, 25(OH)VD >20 ng/mL) groups. Follicular fluid (FF) VD level, IVF outcomes, and peripheral blood immunophenotypes by flow cytometry were analyzed. RESULTS: FF VD levels of the whole subjects were positively correlated with peripheral blood VD level (r = 0.86, P < 0.001). The number of mature oocytes and the blastocyst formation rate were significantly higher in women with VDH group as compared with those of VDL group in both Agonist and PPOS groups (P < 0.05, respectively). In women with PPOS protocol, peripheral blood NK and B-cell proportions and T helper/T cytotoxic (Th/Tc) cell ratios of VDL group were significantly higher than those of VDH group (P < 0.05, respectively). In women with Agonist protocol, peripheral blood B-cell proportion and Th/Tc ratios of VDL group were significantly higher than those of VDH group (P < 0.05, respectively). CONCLUSION: VD level is associated with IVF outcomes possibly derived by T-cell immunity, particularly Th/Tc ratios.

Feasibility analysis of treating severe intrauterine adhesions by transplanting menstrual blood-derived stem cells.

Intrauterine adhesions (IUA) are associated with the loss of stem cells in the endometrium. Menstrual blood­derived stem cells (MenSCs) can be isolated from the menstrual blood and differentiated into endometrial cells. To check the transplantation feasibility of MenSCs for the treatment of severe IUA, MenSCs were isolated from menstrual blood, cultured in Dulbecco's modified Eagle's medium (DMEM), identified by immunocytochemistry and flow cytometry, differentiated into endometrial cells in vitro, and finally transplanted into the axillary subcutaneous tissue of non­obese diabetic/severe combined immunodeficiency (NOD­SCID) mice to create endometrial tissue. Additionally, the cloning efficiency and POU domain class 5 transcription factor 1 (OCT­4) positivity of MenSCs from patients with severe IUA were compared with those from healthy women. Immunocytochemistry and flow cytometry results showed that 95.1±0.8% cells were OCT­4­positive, 0.9±0.4% were cluster of differentiation (CD)45­positive, 1.8±0.9% were STRO­1­positive and 1.0±0.4% were human leukocyte antigen­antigen D related­positive. Following differentiation in vitro, the results of immunocytochemistry, reverse transcription­polymerase chain reaction and western blot analysis showed that the expression of cytokeratin (CK) and vimentin (VIM) was increased in MenSCs compared with that in control subjects. Subsequent to transplantation in mice administered with sequential 17ß­estradiol and progesterone, CK, VIM, estrogen receptor and progesterone receptor were expressed in the transplantation regions, suggesting that MenSCs could differentiate into endometrial tissues in vivo. The cloning efficiency and OCT­4 positivity of MenSCs from patients with severe IUA was significantly decreased. In conclusion, to the best of our knowledge, this is the first study in which MenSCs could differentiate into endometrial cells in vitro and create endometrial tissue in NOD­SCID mice in vivo, with impaired cloning efficiency and OCT­4 expression of MenSCs from patients with IUA. This study will provide a theoretical basis for the treatment of IUA with MenSCs.

Efficient Quantum-Dot Light-Emitting Diodes Employing Thermally Activated Delayed Fluorescence Emitters as Exciton Harvesters.

Utilization of triplet excitons plays a key role in obtaining highly efficient quantum-dot light-emitting diodes (QD-LEDs). However, to date, only phosphorescent materials have been implemented to harvest triplet excitons in QD-LEDs. In this work, we introduced a thermally activated delayed fluorescence (TADF) emitter, 4,5-di(9H-carbazol-9-yl)phthalonitrile (2CzPN), doped into poly(N-vinylcarbazole) (PVK) as an exciton harvester in red QD-LEDs by solution processing. As a result, electrons leaking to the PVK layer will be trapped by 2CzPN to form long-lifetime TADF excitons in the 2CzPN:PVK layer, and then this harvested exciton energy can be effectively transferred to the adjacent QDs by the Förster resonance energy-transfer process. The fabricated red CdSe/CdS core/shell QD-LEDs show a maximum luminescence efficiency of 17.33 cd/A and longer lifetime. Our results demonstrate that the TADF sensitizer would be a promising candidate to develop highly efficient QD-LEDs.

Proton Isovector Helicity Distribution on the Lattice at Physical Pion Mass.

We present a state-of-the-art calculation of the isovector quark-helicity Bjorken-x distribution in the proton using lattice-QCD ensembles at the physical pion mass. We compute quasidistributions at proton momenta P_{z}∈{2.2,2.6,3.0} GeV on the lattice and match them systematically to the physical parton distribution using the large-momentum effective theory. We reach an unprecedented precision through high statistics in simulations, large-momentum proton matrix elements, and control of excited-state contamination. The resulting distribution with combined statistical and systematic errors is in agreement with the latest phenomenological analysis of the spin-dependent experimental data, in particular, Δu[over ¯](x)>Δd[over ¯](x).

IL-7/IL-7R signaling pathway might play a role in recurrent pregnancy losses by increasing inflammatory Th17 cells and decreasing Treg cells.

PROBLEM: We aim to investigate a possible role of IL-7/IL-7R signaling pathway in recurrent pregnancy losses (RPL). MATERIAL AND METHODS: Using the abortion-prone (AP) and non-abortion-prone (NP) mice model, fetal resorption rates (FRR), Th17 and Treg cells-related factors, and the effect of IL-7 and IL-7R antagonist were investigated by flow cytometry, quantitative real-time PCR, and immunohistochemistry. IL-7 and IL-7R expressions in human decidua were investigated by immunohistochemistry. RESULTS: In the AP mice, IL-7R antagonist treatment significantly decreased FRR by downregulating Th17 and upregulating Treg-related factors. When the NP mice were treated with IL-7, FRR was significantly increased by upregulating Th17 and downregulating Treg-related factors. In decidual stromal cells of women with RPL, increased IL-7 and decreased IL-7R expressions were present when compared to normal controls. CONCLUSION: IL-7/IL-7R signaling pathway plays a possible role in RPL by upregulating Th17 immunity, meanwhile downregulating Treg immunity. Regulation of IL-7/IL-7R may be a new therapeutic strategy for RPL.

Electrophobic Scalar Boson and Muonic Puzzles.

A new scalar boson which couples to the muon and proton can simultaneously solve the proton radius puzzle and the muon anomalous magnetic moment discrepancy. Using a variety of measurements, we constrain the mass of this scalar and its couplings to the electron, muon, neutron, and proton. Making no assumptions about the underlying model, these constraints and the requirement that it solve both problems limit the mass of the scalar to between about 100 keV and 100 MeV. We identify two unexplored regions in the coupling constant-mass plane. Potential future experiments and their implications for theories with mass-weighted lepton couplings are discussed.

Expression Profile of microRNAs and Their Targeted Pathways in Human Ovaries Detected by Next-Generation Small RNA Sequencing.

Recently, post-transcriptional gene regulation by microRNAs (miRNAs) has been reported to play a key role during ovary development and differentiation. However, there are no published studies identifying miRNA profiles of human ovarian tissues directly using next-generation sequencing technology. In the human ovary, a total of 762 known and 21 novel human miRNAs were detected, indicating that human ovaries have a complex population of small RNAs. To confirm the miRNA profile in human ovaries, quantitative real-time polymerase chain reaction was used to validate the expression of known miRNAs and novel miRNAs. The potential regulating roles of miRNA in physiological function of ovaries were analyzed by gene ontology and Kyoto encyclopedia of genes and genomes pathway annotation, and several important processes were identified to be targeted by the most abundantly expressed miRNAs, for example, antral ovarian follicle growth, ovarian follicle rupture, and fertilization. Our current findings extend the knowledge of the regulatory role of miRNAs and their targeted processes in human ovaries, suggesting that miRNAs play important roles in development and physiological function of ovaries. In this study, we provide a useful resource for further research of the regulatory role of miRNAs in the ovaries, which may also provide novel candidates for molecular biomarkers or treatment targets in the research of female infertility.

Distinct CPT-induced deaths in lung cancer cells caused by clathrin-mediated internalization of CP micelles.

We previously synthesized a chondroitin sulfate-graft-poly(ε-caprolactone) copolymer (H-CP) with a high content of poly(ε-caprolactone) (18.7 mol%), which self-assembled in water into a rod-like micelle to encapsulate hydrophobic camptothecin (CPT) in the core (micelle/CPT) for tumor-targeted drug delivery. As a result of the recognition of the micelle by CD44, the micelle/CPT entered CRL-5802 cells efficiently and released CPT efficaciously, resulting in higher tumor suppression than commercial CPT-11. In this study, H1299 cells were found to have a higher CD44 expression than CRL-5802 cells. However, the lower CD44-expressing CRL-5802 cells had a higher percentage of cell death and higher cellular uptake of the micelle/CPT than the higher CD44-expressing H1299 cells. Examination of the internalization pathway of the micelle/CPT in the presence of different endocytic chemical inhibitors showed that the CRL-5802 cells involved clathrin-mediated endocytosis, which was not found in the H1299 cells. Analysis of the cell cycle of the two cell lines exposed to the micelle/CPT revealed that the CRL-5802 cells arrested mainly in the S phase and the H1299 cells arrested mainly in the G2-M phase. A consistent result was also found in the evaluation of γ-H2AX expression, which was about three-fold higher in the CRL-5802 cells than in the H1299 cells. A near-infrared dye, IR780, was encapsulated into the micelle to observe the in vivo biodistribution of the micelle/IR780 in tumor-bearing mice. The CRL-5802 tumor showed a higher fluorescence intensity than the H1299 tumor at any tracing time after 1 h. Thus we tentatively concluded that CRL-5802 cells utilized the clathrin-mediated internalization pathway and arrested in the S phase on exposure to the micelle/CPT; all are possible reasons for the better therapeutic outcome in CRL-5802 cells than in H1299 cells.

Atorvastatin counteracts high glucose-induced Krüppel-like factor 2 suppression in human umbilical vein endothelial cells.

OBJECTIVE: Krüppel-like factor 2 (KLF2) is a transcription factor that regulates endothelial function and atorvastatin can stabilize atherosclerotic plaque and inhibit inflammation on endothelial cells by attenuating the role of cytokines. The aim of this study is to investigate the effect of high glucose (HG) on KLF2 expression in human umbilical vein endothelial cells (HUVECs) and the underlying mechanisms. METHODS: HUVECs were isolated from the human umbilical cords from normal pregnancies and exposed to medium containing 25.5 mM D-glucose for 24 hours as the HG induction model (HG group). In the HG plus atorvastatin groups or KLF2 gene transduction, the medium then was collected for the nitric oxide (NO) assay and the cells were harvested for Western blot and for the real-time polymerase chain reaction to observe the expression of KLF2, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, total and phosphorylated endothelial NO synthase (eNOS), p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2, caspase-3 and cleaved caspase-3 and the role of the p38MAPK and ERK1/2 intracellular signal pathway. The cells' apoptosis was analyzed by flow cytometry. RESULTS: HG dose-dependently increased apoptosis. The presence of HG inhibited the expression of KLF2 mRNA and protein in HUVECs and atorvastatin treatment increased KLF2 expression, thus counteracted HG-induced suppression of KLF2 expression, and overexpression of KLF2 might protect the cells from apoptosis. HG increased the expression of VCAM-1, ICAM-1, but decreased the nitric oxide release and the expression of p-eNOs/eNos in HUVECs. However, atorvastatin reversed these changes and also attenuated high-glucose induced p38 MAPK and ERK1/2 phosphorylation. CONCLUSIONS: HG suppressed the KLF2 expression in HUVECs. The suppression was counteracted by atorvastatin treatment, probably via attenuating the activation of the signal pathyway p38 MAPK and ERK1/2.

Oocyte quality is decreased in women with minimal or mild endometriosis.

Endometriosis, a pathological condition in which the endometrium grows outside the uterus, is one of the most common causes of female infertility; it is diagnosed in 25-40% of infertile women. The mechanism by which endometriosis affects the fertility of females remains largely unknown. We examined the ultrastructure of oocytes from patients with minimal or mild endometriosis and control females undergoing in vitro fertilization (IVF) treatment by transmission electron microscopy (TEM) to investigate the physiological significance of oocyte quality for patients with minimal or mild endometriosis. The TEM results revealed that the oocytes from women with minimal or mild endometriosis exhibited abnormal mitochondrial structure and decreased mitochondria mass. Quantitative real time PCR analysis revealed that the mitochondrial DNA copy number was significantly reduced in the oocytes from women with minimal or mild endometriosis compared with those of the control subjects. Our results suggest that decreased oocyte quality because of impaired mitochondrial structure and functions probably an important factor affecting the fertility of endometriosis patients.