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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by lung inflammation and excessive deposition of extracellular matrix components. Transforming growth factor-β1 (TGF-β1) induced epithelial–mesenchymal transformation of type 2 lung epithelial cells leads to excessive extracellular matrix deposition, which plays an important role in fibrosis. Our objective was to evaluate the effects of 3-cyclopropylmethoxy-4-(difluoromethoxy) benzoic acid (DGM) on pulmonary fibrosis and aimed to determine whether EMT plays a key role in the pathogenesis of pulmonary fibrosis and whether EMT can be used as a therapeutic target for DGM therapy to reduce IPF. Firstly, stimulation of in vitro cultured A549 cells to construct EMTs with TGF-β1. DGM treatment inhibited the expression of proteins such as α-SMA, vimentin, and collagen Ⅰ and increased the expression of E-cadherin. Accordingly, Smad2/3 phosphorylation levels were significantly reduced by DGM treatment. Secondly, models of tracheal instillation of bleomycin and DGM were used to treat rats to demonstrate their therapeutic effects, such as improving lung function, reducing lung inflammation and fibrosis, reducing collagen deposition, and reducing the expression of E-cadherin. In conclusion, DGM attenuates TGF-β1-induced EMT in A549 cells and bleomycin-induced pulmonary fibrosis in rats.

Perennial ryegrass (Lolium perenne) is a cool-season turf and forage grass. Heat shock transcription factors (HSFs) play an important role in regulating plant abiotic stress. However, HSFs in perennial ryegrass have rarely been characterized. Here, 25 LpHSFs were identified from the perennial ryegrass genome. Phylogenetic analysis showed that the LpHSFs could be classified into 12 subclasses. Gene structure analysis showed that 22 LpHSFs have only one intron. Cis-acting elements analysis revealed that the promoter of 15 LpHSFs contained hormone responsive and abiotic stress responsive elements. Expression profile analysis indicated that 24 LpHSFs were differentially expressed under submerge, drought, heat and cold stresses. In addition, a subclass C2 gene, LpHSFC2b, was significantly induced by abiotic stresses. The LpHSFC2b protein is localized to the nucleus, and heterologous expression of LpHSFC2b in Arabidopsis improves plant thermotolerance. This study provides insights useful for breeding of stress tolerance in perennial ryegrass. This article is protected by copyright. All rights reserved.

The existence of antibiotics in the environment can trigger a number of issues by fostering the widespread development of antimicrobial resistance. Currently, the most popular techniques for removing antibiotic pollutants from water include physical adsorption, flocculation, and chemical oxidation, however, these processes usually leave a significant quantity of chemical reagents and polymer electrolytes in the water, which can lead to difficulty post-treating unmanageable deposits. Furthermore, though cost-effectiveness, efficiency, reaction conditions, and nontoxicity during the degradation of antibiotics are hurdles to overcome, a variety of photocatalysts can be used to degrade pollutant residuals, allowing for a number of potential solutions to these issues. Thus, the urgent need for effective and rapid processes for photocatalytic degradation leads to an increased interest in finding more sustainable catalysts for antibiotic degradation. In this review, we provide an overview of the removal of pharmaceutical antibiotics through photocatalysis, and detail recent progress using different nanostructure-based photocatalysts. We also review the possible sources of antibiotic pollutants released through the ecological chain and the consequences and damages caused by antibiotics in wastewater on the environment and human health. The fundamental dynamic processes of nanomaterials and the degradation mechanisms of antibiotics are then discussed, and recent studies regarding different photocatalytic materials for the degradation of some typical and commonly used antibiotics are comprehensively summarized. Finally, major challenges and future opportunities for the photocatalytic degradation of commonly used antibiotics are highlighted.

The capability in spatially resolving the interactions between components in lithium (Li)-ion battery cathodes, especially correlating chemistry and electronic structure, is challenging but critical for a better understanding of complex degradation mechanisms for rational developments. X-ray spectro-ptychography and conventional synchrotron-based scanning transmission X-ray microscopy image stacks are the most powerful probes for studying the distribution and chemical state of cations in degraded Li-rich cathodes. Herein, we propose a chemical approach with a spatial resolution of around 5.6 nm to imaging degradation heterogeneities and interplay among components in degraded Li-rich cathodes. Through the chemical imaging reconstruction of the degraded Li-rich cathodes, fluorine (F) ions incorporated into the lattice during charging/discharging processes are proved and strongly correlate with the manganese (Mn) dissolution and oxygen loss within the secondary particles and impact the electronic structure. Otherwise, the electrode-electrolyte interphase component, scattered LiF particles (100-500 nm) along with the MnF2 layer, is also visualized between the primary particles inside the secondary particles of the degraded cathodes. The results provide direct visual evidence for the Li-rich cathode degradation mechanisms and demonstrate that the low-energy ptychography technique offers a superior approach for high-resolution battery material characterization.

Oxygen reduction/evolution reactions (ORR/OERs) catalysts play a key role in the metal‐air battery and water‐splitting process. Herein, we developed a facile template‐free method to fabricate a new type of non–noble metal‐based hybrid catalyst which consists of binary FeNi alloy/nitride nanocrystals with graphitic‐shell and biomass‐derived N‐doped carbon (NC) (FexNiyN@C/NC). This novel nanostructure exhibits superior performance for ORR/OER, which can be attributed to the strong interactions between the graphitic‐shell encapsulated FeNi alloy/nitride nanocrystals and the N‐doped porous carbon substrate. The X‐ray absorption spectroscopy technique was employed to reveal the underlying mechanisms for the excellent performance. The assembled Zn‐air battery device exhibits outstanding charging/discharging performance and cycling stability, indicating the great potential of this type of novel catalysts.

Characterizing relationships between Zn 2+ , insulin, and insulin vesicles is of vital importance to the study of pancreatic beta cells. However, the precise content of Zn 2+ and the specific location of insulin inside insulin vesicles are not clear, which hinders a thorough understanding of the insulin secretion process and diseases caused by blood sugar dysregulation. Here, we demonstrated the colocalization of Zn 2+ and insulin in both single extracellular insulin vesicles and pancreatic beta cells by using an X-ray scanning coherent diffraction imaging (ptychography) technique. We also analyzed the elemental Zn 2+ and Ca 2+ contents of insulin vesicles using electron microscopy and energy dispersive spectroscopy (EDS) mapping. We found that the presence of Zn 2+ is an important characteristic that can be used to distinguish insulin vesicles from other types of vesicles in pancreatic beta cells and that the content of Zn 2+ is proportional to the size of insulin vesicles. By using dual-energy contrast X-ray microscopy and scanning transmission X-ray microscopy (STXM) image stacks, we observed that insulin accumulates in the off-center position of extracellular insulin vesicles. Furthermore, the spatial distribution of insulin vesicles and their colocalization with other organelles inside pancreatic beta cells were demonstrated using three-dimensional (3D) imaging by combining X-ray ptychography and an equally sloped tomography (EST) algorithm. This study describes a powerful method to univocally describe the location and quantitative analysis of intracellular insulin, which will be of great significance to the study of diabetes and other blood sugar diseases.

To investigate the effect of eupatilin in asthma treatment, we evaluated its therapeutic effect and related signal transduction in OVA-induced asthmatic mice and LPS-stimulated RAW264.7 cells. The BALF was tested for changes in lung inflammatory cells. Th2 cytokines in the BALF and OVA-IgE in the serum were measured by ELISA. H&E and PAS staining were used to evaluate histopathological changes in mouse lungs. The key proteins NF-κB, MAPK, and Nrf2 in lung tissues were quantitatively analyzed by Western blotting. Finally, we evaluated the effect of eupatilin on cytokines and related protein expression in LPS-stimulated RAW 264.7 cells in vitro. In OVA-induced asthmatic mice, eupatilin reduced the numbers of inflammatory cells, especially neutrophils and eosinophils. Eupatilin also decreased the levels of IL-5, IL-13 in the BALF and OVA-IgE in the serum. Furthermore, eupatilin inhibited the activation of NF-κB and MAPK pathways and increased the expression of Nrf2 in OVA-induced asthmatic mice. In vitro, eupatilin significantly reduced LPS-stimulated NO, IL-6, and ROS production. Additionally, the NF-κB, MAPK, and Nrf2 protein expression in LPS-stimulated RAW264.7 cells was consistent with that in OVA-induced asthmatic lung tissues. In summary, eupatilin attenuated OVA-induced asthma by regulating NF-κB, MAPK, and Nrf2 signaling pathways. These results suggest the utility of eupatilin as an anti-inflammatory drug for asthma treatment.

Warm- and cool-season turfgrasses were originated from different locations with contrasting heat tolerance. The molecular mechanisms of heat tolerance have not been extensively studied in turfgrass species. In this study, transcriptomic analysis showed that bermudagrass was more tolerant to heat stress as evidenced by lower contents of H

The rational design for transition metals-based carbon nano-materials as efficient electrocatalysts still remains a crucial challenge for economical electrochemical hydrogen production. Carbon nanotubes (CNTs) as attractive electrocatalysts are typically activated by non-metal dopant to promote catalytic performance. Metals doping or metal/non-metal co-doping of CNTs, however, are rarely explored. Herein, this work rationally designs bimetal oxide templates of ZnCo

The development of highly efficient bifunctional catalysts for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) is of paramount importance for rechargeable Zn-air batteries. Herein, cobalt (II) oxide (L-CoO) nanosheets with hierarchical nanostructures were grown on the stainless steel (SS) substrate via the facile heat treatment of 2D layered Co(OH)2; and this binder-free 3D air electrode exhibits superior ORR/OER activity and stability (over 1000 h) in the rechargeable Zn-air flow battery. Importantly, X-ray absorption spectroscopy (XAS) and X-ray photoelectron spectroscopy (XPS) were employed to reveal the origins of the excellent bifunctional catalytic performance of this catalyst. Moreover, the evolution of the atomic-scale structures revealed by operando XAS strongly supports the excellent stability of L-CoO during electrocatalytic operation. Our work suggests a facile strategy to construct oxygen vacancy active sites; meanwhile, it offers a deep understanding at the atomic level on the excellent cycling stability in the Zn-air flow battery through X-ray spectroscopy.

The primary objective of early drug discovery is to associate druggable target space with a desired phenotype. The inability to efficiently associate these often leads to failure early in the drug discovery process. In this proof-of-concept study, the most tractable starting points for drug discovery within the NF-κB pathway model system were identified by integrating affinity selection-mass spectrometry (AS-MS) with functional cellular assays. The AS-MS platform Automated Ligand Identification System (ALIS) was used to rapidly screen 15 NF-κB proteins in parallel against large-compound libraries. ALIS identified 382 target-selective compounds binding to 14 of the 15 proteins. Without any chemical optimization, 22 of the 382 target-selective compounds exhibited a cellular phenotype consistent with the respective target associated in ALIS. Further studies on structurally related compounds distinguished two chemical series that exhibited a preliminary structure-activity relationship and confirmed target-driven cellular activity to NF-κB1/p105 and TRAF5, respectively. These two series represent new drug discovery opportunities for chemical optimization. The results described herein demonstrate the power of combining ALIS with cell functional assays in a high-throughput, target-based approach to determine the most tractable drug discovery opportunities within a pathway.

Perennial ryegrass (Lolium perenne L.) is a cool-season forage and turf grass species cultivated world-wide. Natural variations of stress tolerance of perennial ryegrass varieties and mechanisms of stress tolerance are of great interest for breeders. In this study, stress tolerances of seventeen varieties and function of HSFC1b have been characterized. The results showed seventeen varieties exhibited contrasting tolerance to drought, heat and cold stresses. Tolerant varieties had higher proline than sensitive ones after stress treatments. Drought, heat and cold stresses extensively reprogrammed transcriptome of perennial ryegrass and modulated expression of 4797, 4329 and 4635 genes, respectively. LpHSFC1b was significantly induced after stress treatments and characterized as the core regulators through protein interaction network analysis. Ectopic expression of LpHSFC1b in Arabidopsis improved plant thermotolerance, but not drought and cold tolerances. Transgenic Arabidopsis had decreased electrolyte leakage (EL), malondialdehyde (MDA) content and chlorosis⁄necrosis severity indices, and increased expression of heat stress responsive genes. These data indicated that perennial ryegrass exhibited divergent stress tolerances, and HSFC1b likely functioned as a positive regulator in heat stress response, that may provide detailed insight for understanding of abiotic stress response clues in perennial ryegrass.

Based on the Experimental Physics and Industrial Control System, a portable data-collection system for soft x-ray absorption spectroscopy has been developed at the BL02B and BL08U beamlines of the Shanghai Synchrotron Radiation Facility. The data-collection system can be used to carry out total electron yield (TEY) and total fluorescence yield (TFY) experiments simultaneously. The hardware consists of current preamplifiers, voltage-to-frequency converters, and a multi-channel counter, which are aimed at improving the signal-to-noise ratio. The control logic is developed using Python and Java. The novelty of this control system is its designed portability while being extensible and readable and having low noise and high real-time capabilities. The oxygen K-edge absorption spectra of SrTiO3 were obtained using the TEY and TFY technology at the BL02B beamline. Furthermore, the TEY and TFY spectra of the relaxor ferroelectric single-crystal of lead magnesium niobate-lead titanate measured by the present data-collection system have lower peak-to-peak noise amplitude than the ones measured by using a picoammeter. The experimental results show that the spectral signal-to-noise ratio recorded by the present system is 5.7–12.4 dB higher than that with the picoammeter detector.

Modern literature on the physical property of the

We study the smooth structure of convex functions by generalizing a powerful concept so-called self-concordance introduced by Nesterov and Nemirovskii in the early 1990s to a broader class of convex functions, which we call generalized self-concordant functions. This notion allows us to develop a unified framework for designing Newton-type methods to solve convex optimiza- tion problems. The proposed theory provides a mathematical tool to analyze both local and global convergence of Newton-type methods without imposing unverifiable assumptions as long as the un- derlying functionals fall into our generalized self-concordant function class. First, we introduce the class of generalized self-concordant functions, which covers standard self-concordant functions as a special case. Next, we establish several properties and key estimates of this function class, which can be used to design numerical methods. Then, we apply this theory to develop several Newton-type methods for solving a class of smooth convex optimization problems involving the generalized self- concordant functions. We provide an explicit step-size for the damped-step Newton-type scheme which can guarantee a global convergence without performing any globalization strategy. We also prove a local quadratic convergence of this method and its full-step variant without requiring the Lipschitz continuity of the objective Hessian. Then, we extend our result to develop proximal Newton-type methods for a class of composite convex minimization problems involving generalized self-concordant functions. We also achieve both global and local convergence without additional assumption. Finally, we verify our theoretical results via several numerical examples, and compare them with existing methods., Comment: 47 pages, 2 figures

Focal stack (FS) is an effective technique for fast 3D imaging in high-resolution scanning transmission X-ray microscopy. Its crucial issue is to assign each object within the sample to the correct position along the optical axis according to a proper focus measure. There is probably information loss with previous algorithms for FS reconstruction because the old algorithms can only detect one focused object along each optical-axial pixel line (OAPL). In this study, we present an improved FS algorithm, which utilizes an elaborately calculated threshold for normalized local variances to extract multiple focused objects in each OAPL. Simulation and experimental results show its feasibility and high efficiency for 3D imaging of high contrast, sparse samples. It is expected that our advanced approach has potential applications in 3D X-ray microscopy for more complex samples.

Acupoint catgut embedding (ACE) was applied widely to antiweight in China. The aim of this review is to estimate the effectiveness and safety of ACE on obesity. A literature search was conducted in PubMed, Cochrane Library, EBASE, CNKI, and so forth, using combination subject terms of obesity (or overweight, weight loss, etc.) and acupoint catgut embedding (or catgut implantation, catgut embedding). Improvement rate, reduction of body weight and body mass index (BMI), and so forth were analyzed. 43 studies were included for systematic review and meta-analysis. Although with poor methodological quality, ACE was superior to manual acupuncture (MA), sham, and cupping in improvement rate and presented a better tendency (OR>1) compared with drugs and electroacupuncture (EA). Mean values of weight loss by ACE were 1.14 kg, 1.26 kg, 1.79 kg, and 3.01 kg comparing with MA, drugs, EA, and sham, respectively. Mean of BMI reduced to 0.56 kg/m2, 0.83 kg/m2, 0.79 kg/m2, and 1.63 kg/m2 comparing with MA, drugs, EA, and sham. Less adverse effects were reported. Pooled outcomes presented a tendency of equal or superior effects to other interventions and fewer side effects. Future high quality trials with rigorous design and positive FDA approved drug as control are urgent to assess the effect of ACE for obesity. PROSPERO registration number is as follows: CRD42015016006.

Vintafolide (also known as EC145 or MK-8109), is a small molecule drug conjugate for the treatment of cancers expressing high affinity folate receptor (FR). Vintafolide consists of the anti-mitotic vinca alkaloid desacetylvinblastine monohydrazide (DAVLBH) chemically linked to folic acid. Binding of vintafolide to FR located on the cell surface delivers the chemotherapy payload directly to the tumor cell. Clinical investigations of vintafolide are underway in ovarian and lung cancer, indications with a high prevalence of FR expression. Triple negative breast cancer (TNBC) may represent an additional indication for vintafolide due to the prevalence of FR expression (∼30%), sensitivity to vinca alkaloids, and unmet medical need. Vintafolide and/or DAVLBH were evaluated in preclinical models of TNBC as monotherapies and in combination with taxanes (paclitaxel or docetaxel). Taxanes represent a commonly used standard of care therapy for TNBC. A panel of TNBC cell lines was generally sensitive to DAVLBH, with IC50s ranging from 4-67 nM. In the majority of cell lines tested, DAVLBH in combination with paclitaxel provided combination benefit and induced more cell death than either single agent. Vintafolide and DAVLBH were further evaluated in vivo in the FR-high MDA-MB-231 and FR-low CAL51 TNBC xenograft models. Vintafolide was dosed at its MTD of 9.6 mg/kg three times per week (TIW), and at 1.5 mg/kg TIW. DAVLBH was dosed at its MTD of 0.77 mg/kg TIW. Mice were dosed for 3 weeks followed by a 6 week follow-up. Both vintafolide doses resulted in marked MDA-MB-231 tumor regressions of 56-78% at the end of therapy (Day 21) and 75% cures (6 of 8 mice) over the 6 week follow-up period. In the CAL51 model, vintafolide produced 8% and 76% tumor growth inhibition (TGI), respectively, at the 1.5 and 9.6 mg/kg doses, and no cures. DAVLBH was less efficacious compared to vintafolide, giving 96% TGI in the MDA-MB-231 model and 46% TGI in the CAL51 model. In mechanism of action studies in the MDA-MB-231 xenograft model, a dose of vintafolide that gave tumor regressions/cures was associated with increased phospho-histone H3 staining, indicative of a mitotic block of tumor cells, and consistent with the mechanism of action of vinca alkaloids. In combination therapy experiments in vivo, docetaxel (20 mg/kg weekly) monotherapy achieved near tumor stasis (98% TGI) of MDA-MB-231 tumors over 3 weeks of therapy, but all tumors re-grew upon cessation of treatment. Since vintafolide monotherapy at 1.5 mg/kg TIW gave significant regressions and cures, a combination benefit with docetaxel could not be determined. However, DAVLBH and docetaxel combination therapy delayed tumor re-growth over single agents upon follow-up, suggesting benefit of a vinca alkaloid / taxane combination. Taken together, these preclinical data support further investigation of vintafolide monotherapy and in combination with taxane therapy in TNBC. Citation Format: Brian B. Haines, Jennifer O'Neil, Marlene C. Hinton, Christopher Ware, Tammie C. Yeh, Tianxiao Sun, Kristen L. Picard, Theresa Zhang, Emmett V. Schmidt, Isabelle Dussault. Preclinical activity of Vintafolide/MK-8109 monotherapy and in combination with standard of care therapy in triple-negative breast cancer models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1677. doi:10.1158/1538-7445.AM2014-1677