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1.
T-type Ca2+ channels have been implicated in tremorogenesis and motor coordination. The α1 subunit of the CaV3.1 T-type Ca2+ channel is highly expressed in motor pathways in the brain, but knockout of the CaV3.1 gene (α1G-/-) per se causes no motor defects in mice. Thus, the role of CaV3.1 channels in motor control remains obscure in vivo. Here, we investigated the effect of the CaV3.1 knockout in the null genetic background of α1 GABAA receptor (α1−/−) by generating the double mutants (α1−/−/α1G-/-). α1−/−/α1G-/- mice showed severer motor abnormalities than α1−/− mice as measured by potentiated tremor activities at 20 Hz and impaired motor learning. Propranolol, an anti-ET drug that is known to reduce the pathologic tremor in α1−/− mice, was not effective for suppressing the potentiated tremor in α1−/−/α1G-/- mice. In addition, α1−/−/α1G-/- mice showed an age-dependent loss of cerebellar Purkinje neurons. These results suggest that α1−/−/α1G-/- mice are a novel mouse model for a distinct subtype of ET in human and that CaV3.1 T-type Ca2+ channels play a role in motor coordination under pathological conditions. 相似文献
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3.
Kimihiko Matsusue Daisuke Aibara Risa Hayafuchi Kohei Matsuo Soichi Takiguchi Frank J. Gonzalez Shigeru Yamano 《FEBS letters》2014
The nuclear hormone receptors liver X receptor α (LXRα) and peroxisome proliferator-activated receptor γ (PPARγ) play key roles in the development of fatty liver. To determine the link between hepatic PPARγ and LXRα signaling and the development of fatty liver, a LXRα-specific ligand, T0901317, was administered to normal OB/OB and genetically obese (ob/ob) mice lacking hepatic PPARγ (PparγΔH). In ob/ob-PparγΔH and OB/OB-PparγΔH mice, as well as ob/ob-PparγWT and OB/OB-PparγWT mice, the liver weights and hepatic triglyceride levels were markedly increased in response to T0901317 treatment. These results suggest that hepatic PPARγ and LXRα signals independently contribute to the development of fatty liver. 相似文献
4.
Kenneth R. Wilund Mira Rosenblat Nina Volkova Jeffrey A. Woods 《Biochemical and biophysical research communications》2009,390(1):148-140
Objective
The parasympathetic nervous system regulates inflammation in peripheral tissues through a pathway termed the “cholinergic anti-inflammatory reflex” (CAIR). Mice deficient in the alpha 7 nicotinic acetylcholine receptor (α7−/−) have an impaired CAIR due to decreased signaling through this pathway. The purpose of this study was to determine if the increased inflammation in α7−/− mice is associated with enhanced serum and macrophage atherogenicity.Methods
We measured serum markers of inflammation and oxidative stress, and macrophage atherogenicity in mouse peritoneal macrophages harvested from α7−/− mice on the background of C57BL/6 mice, as well as on the background of the atherosclerotic Apolipoprotein E-deficient (ApoE−/−) mice.Results
α7-Deficiency had no significant effects on serum cholesterol, or on markers of serum oxidative stress (TBARS and paraoxonase1 activities). However, α7-deficiency significantly increased serum CRP and IL-6 (p < 0.05) levels in atherosclerotic mice, confirming an anti-inflammatory role for the α7 receptor. Macrophage cholesterol mass was increased by 25% in both normal and atherosclerotic mice in the absence of the α7 receptor (p < 0.05). This was accompanied by conditional increases in oxidized LDL uptake and in macrophage total peroxide levels. Furthermore, α7-deficiency reduced macrophage paraoxonase2 mRNA and activity by 50-100% in normal and atherosclerotic mice (p < 0.05 for each), indicating a reduction in macrophage anti-oxidant capacity in the α7−/− mice.Conclusion
The above results suggest an anti-atherogenic role for the macrophage α7nAchr, through a mechanism that involves attenuated macrophage oxidative stress and decreased uptake of oxidized LDL. 相似文献5.
Kamari Y Shaish A Shemesh S Vax E Grosskopf I Dotan S White M Voronov E Dinarello CA Apte RN Harats D 《Biochemical and biophysical research communications》2011,(2):197-203
Objective
Interleukin (IL)-1α and IL-1β are products of macrophages, endothelial cells and vascular smooth muscle cells; moreover, each of these cell types is affected by the pro-inflammatory properties of both IL-1’s. Whereas several studies demonstrate the proatherogenic properties of IL-1β, the role of IL-1α in atherogenesis remains unclear. We assessed whether IL-1α and IL-1β from tissue resident vascular cells or emigrating bone marrow-derived cells promote the development of atherosclerosis in apoE−/− mice and determined the effect of selective macrophage IL-1α or IL-1β deficiency on degradation of LDL and cytokine production.Methods
We generated strains of double knock-out (KO) mice (apoE−/−/IL-1α−/− and apoE−/−/IL-1β−/−) and created chimeras consisting of apoE−/− mice reconstituted with bone marrow-derived cells from apoE−/−/IL-1+/+, apoE−/−/IL-1α−/− and apoE−/−/IL-1β−/−.Results
The areas of aortic sinus lesions were lower in either double KO mice compared to solely apoE−/− mice, despite higher non-HDL cholesterol levels. Importantly, selective deficiency of IL-1α or IL-1β in bone marrow-derived cells inhibited atherogenesis to the same extent as in double KO mice without affecting plasma lipids. Aortic sinus lesions in apoE−/− mice transplanted with IL-1β−/− or IL-1α−/− cells were 32% and 52% lower, respectively, than in IL-1+/+ transplanted mice. Ex vivo, isolated IL-1α−/− macrophages from atherosclerotic mice degraded LDL and secreted IL-6, TNFα and IL-12 similarly to IL-1+/+ macrophages; however, IL-1α deficient macrophages secreted reduced levels of IL-1β (−50%) and 2–3-fold higher levels of the anti-inflammatory cytokine IL-10.Conclusion
We show for the first time that it is IL-1α from bone marrow-derived cells that accelerates atherogenesis in apoE-deficient mice rather than constitutive IL-1α in vascular cells, possibly by increasing the inflammatory cytokine profile of macrophages. 相似文献6.
Hsiu-Ting Tseng Young Joo Park Yoon Kwang Lee David D Moore 《Journal of biomedical science》2015,22(1)
Background
Small heterodimer partner (SHP, NR0B2) is involved in diverse metabolic pathways, including hepatic bile acid, lipid and glucose homeostasis, and has been implicated in effects on the peroxisome proliferator-activated receptor γ (PPARγ), a master regulator of adipogenesis and the receptor for antidiabetic drugs thiazolidinediones (TZDs). In this study, we aim to investigate the role of SHP in TZD response by comparing TZD-treated leptin-deficient (ob/ob) and leptin-, SHP-deficient (ob/ob;Shp−/−) double mutant mice.Results
Both ob/ob and double mutant ob/ob;Shp−/− mice developed hyperglycemia, insulin resistance, and hyperlipidemia, but hepatic fat accumulation was decreased in the double mutant ob/ob;Shp−/− mice. PPARγ2 mRNA levels were markedly lower in ob/ob;Shp−/− liver and decreased to a lesser extent in adipose tissue. The TZD troglitazone did not reduce glucose or circulating triglyceride levels in ob/ob;Shp−/− mice. Expression of the adipocytokines, such as adiponectin and resistin, was not stimulated by troglitazone treatment. Expression of hepatic lipogenic genes was also reduced in ob/ob;Shp−/− mice. Moreover, overexpression of SHP by adenovirus infection increased PPARγ2 mRNA levels in mouse primary hepatocytes.Conclusions
Our results suggest that SHP is required for both antidiabetic and hypolipidemic effects of TZDs in ob/ob mice through regulation of PPARγ expression. 相似文献7.
Jun Ren Feng Dong Guo-Jun Cai Peng Zhao Jennifer M. Nunn Loren E. Wold Jianming Pei 《PloS one》2010,5(4)
Objectives
This study was designed to evaluate the interaction between aging and obesity on cardiac contractile and intracellular Ca2+ properties.Methods
Cardiomyocytes from young (4-mo) and aging (12- and 18-mo) male lean and the leptin deficient ob/ob obese mice were treated with leptin (0.5, 1.0 and 50 nM) for 4 hrs in vitro. High fat diet (45% calorie from fat) and the leptin receptor mutant db/db obesity models at young and older age were used for comparison. Cardiomyocyte contractile and intracellular Ca2+ properties were evaluated including peak shortening (PS), maximal velocity of shortening/relengthening (± dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR90), intracellular Ca2+ levels and decay. O2 − levels were measured by dihydroethidium fluorescence.Results
Our results revealed reduced survival in ob/ob mice. Aging and obesity reduced PS, ± dL/dt, intracellular Ca2+ rise, prolonged TR90 and intracellular Ca2+ decay, enhanced O2 − production and p 47phox expression without an additive effect of the two, with the exception of intracellular Ca2+ rise. Western blot analysis exhibited reduced Ob-R expression and STAT-3 phosphorylation in both young and aging ob/ob mice, which was restored by leptin. Aging and obesity reduced phosphorylation of Akt, eNOS and p38 while promoting pJNK and pIκB. Low levels of leptin reconciled contractile, intracellular Ca2+ and cell signaling defects as well as O2 − production and p 47phox upregulation in young but not aging ob/ob mice. High level of leptin (50 nM) compromised contractile and intracellular Ca2+ response as well as O2 − production and stress signaling in all groups. High fat diet-induced and db/db obesity displayed somewhat comparable aging-induced mechanical but not leptin response.Conclusions
Taken together, our data suggest that aging and obesity compromise cardiac contractile function possibly via phosphorylation of Akt, eNOS and stress signaling-associated O2 − release. 相似文献8.
Motohiro Sekiya Yoshiaki Tamura Masaki Igarashi Mikio Takanashi Satoru Takase Yoshinori Takeuchi Midori Kubota Yoko Iizuka Takanari Gotoda Hitoshi Shimano Takashi Kadowaki Shun Ishibashi 《Biochemical and biophysical research communications》2009,387(3):511-515
It has long been a matter of debate whether the hormone-sensitive lipase (HSL)-mediated lipolysis in pancreatic β-cells can affect insulin secretion through the alteration of lipotoxicity. We generated mice lacking both leptin and HSL (Lepob/ob/HSL−/−) and explored the role of HSL in pancreatic β-cells in the setting of obesity. Lepob/ob/HSL−/− developed elevated blood glucose levels and reduced plasma insulin levels compared with Lepob/ob/HSL+/+ in a fed state, while the deficiency of HSL did not affect glucose homeostasis in Lep+/+ background. The deficiency of HSL exacerbated the accumulation of triglycerides in Lepob/ob islets, leading to reduced glucose-stimulated insulin secretion. The deficiency of HSL also diminished the islet mass in Lepob/ob mice due to decreased cell proliferation. In conclusion, HSL affects insulin secretary capacity especially in the setting of obesity. 相似文献
9.
Kathrin Ikels Stefanie Kuschel Julia Fischer Wolfgang Kaisers Daniel Eberhard Ulrich Rüther 《PloS one》2014,9(8)
The metabolic syndrome is a worldwide problem mainly caused by obesity. FTO was found to be a obesity-risk gene in humans and FTO deficiency in mice led to reduction in adipose tissue. Thus, FTO is an important factor for the development of obesity. Leptin-deficient mice are a well characterized model for analysing the metabolic syndrome. To determine the relevance of FTO for the development of the metabolic syndrome we analysed different parameters in combined homozygous deficient mice (Lepob/ob;Fto−/−). Lepob/ob;Fto−/− mice showed an improvement in analysed hallmarks of the metabolic syndrome in comparison to leptin-deficient mice wild type or heterozygous for Fto. Lepob/ob;Fto−/− mice did not develop hyperglycaemia and showed an improved glucose tolerance. Furthermore, extension of beta-cell mass was prevented in Lepob/ob;Fto−/−mice and accumulation of ectopic fat in the liver was reduced. In conclusion this study demonstrates that FTO deficiency has a protective effect not only on the development of obesity but also on the metabolic syndrome. Thus, FTO plays an important role in the development of metabolic disorders and is an interesting target for therapeutic agents. 相似文献
10.
Gebhard C Stähli BE Shi Y Camici GG Akhmedov A Hoegger L Lohmann C Matter CM Hassa PO Hottiger MO Malinski T Lüscher TF Tanner FC 《Biochemical and biophysical research communications》2011,(4):641-646
Background
Generation of reactive oxygen species (ROS) is a key feature of vascular disease. Activation of the nuclear enzyme poly (adenosine diphosphate [ADP]-ribose) polymerase-1 (PARP-1) is a downstream effector of oxidative stress.Methods
PARP-1(−/−) and PARP-1(+/+) mice were injected with paraquat (PQ; 10 mg/kg i.p.) to induce intracellular oxidative stress. Aortic rings were suspended in organ chambers for isometric tension recording to analyze vascular function.Results
PQ treatment markedly impaired endothelium-dependent relaxations to acetylcholine in PARP-1(−/−), but not PARP-1(+/+) mice (p < 0.0001). Maximal relaxation was 45% in PQ treated PARP-1(−/−) mice compared to 79% in PARP-1(+/+) mice. In contrast, endothelium-independent relaxations to sodium nitroprusside (SNP) were not altered. After PQ treatment, l-NAME enhanced contractions to norepinephrine by 2.0-fold in PARP-1(−/−) mice, and those to acetylcholine by 3.3-fold, respectively, as compared to PARP-1(+/+) mice. PEG-superoxide dismutase (SOD) and PEG-catalase prevented the effect of PQ on endothelium-dependent relaxations to acetylcholine in PARP-1(−/−) mice (p < 0.001 vs. PQ treated PARP-1(+/+) mice. Indomethacin restored endothelium-dependent relaxations to acetylcholine in PQ treated PARP-1(−/−) mice (p < 0.05 vs. PQ treated PARP-1(+/+).Conclusion
PARP-1 protects from acute intracellular oxidative stress induced endothelial dysfunction by inhibiting ROS induced production of vasoconstrictor prostanoids. 相似文献11.
12.
Changhyun Lee Jaeyoung Chun Sung Wook Hwang Seung Joo Kang Jong Pil Im Joo Sung Kim 《Life sciences》2014
Aims
Intestinal alkaline phosphatase (IAP) is an intestinal brush border enzyme that is shown to function as a gut mucosal defense factor, but its defensive mechanism remains unclear. The aims of this study were to evaluate the effect of IAP on intestinal epithelial cells and macrophages, and on chronic colitis in interleukin-10-deficient (IL-10−/−) mice.Main methods
Human intestinal epithelial cells COLO 205 and peritoneal macrophages from IL-10−/− mice were pretreated with IAP and then stimulated with lipopolysaccharide (LPS). IL-8 secretion from COLO205 cells and TNF-α, IL-6, IL-12 from peritoneal macrophages were measured by ELISA. Electrophoretic mobility shift assay was used to assess the DNA binding activity of NF-κB and IκBα phosphorylation/degradation was evaluated by immunoblot assay in COLO 205. For the in vivo study, colitis was induced in IL-10−/− mice with piroxicam, the mice were then treated with 100 or 300 units of IAP by oral gavage for 2 weeks. Colitis was quantified by histopathologic scoring, and the phosphorylation of IκBα in the colonic mucosa was assessed using immunohistochemistry.Key findings
IAP significantly inhibited LPS-induced inflammatory cytokine production in both IECs and peritoneal macrophages. IAP also attenuated LPS-induced NF-κB binding activity and IκBα phosphorylation/degradation in IECs. Oral administration of IAP significantly reduced the severity of colitis and down-regulated colitis-induced IκBα phosphorylation in IL-10−/− mice.Significance
IAP may inhibit the activation of intestinal epithelial cells and peritoneal macrophages, and may attenuate chronic murine colitis. This finding suggests that IAP supplementation is a potential therapeutic option for inflammatory bowel disease. 相似文献13.
Ulrich E. Grauer 《Plant and Soil》1993,157(2):319-331
There is good evidence for the ameliorating effect of SO4
2- and F- on the expression of Al phytotoxicity in acidic solutions. The role of OH-, in both shifting Al speciation towards hydroxy-Al species and decreasing activities of H+ with increasing pH, is still controversially discussed. Grauer and Horst (1992) proposed a model based on the assumption that Al phytotoxicity is a function of the Al saturation (AlS) of exchange sites in the root apoplast and analyzed the predictions of the model in the case of cation amelioration, with special emphasis on H+. In this study the model is further developed by considering, in addition to Al3+, the complexation of Al with the anions OH-, F-, SO4
2-, and Cl- to form potentially toxic Al species. Association constants of these Al complexes with a ligand (L
-) which is assumed to simulate the cation exchange sites in the root apoplast, were estimated. Affinity factors for binding to L
- compared to Al3+ were derived from these estimated association constants, and values were, in a first approach, 0.79 for AlOH2+, 0.02 for Al(OH)2
+, and 0.13 for Al(OH)3
0 (or 0.03 choosing another hydrolysis constant). High toxicity of Al13 (AlO4Al12(OH)24(H2O)12
7+) could be explained by diminished H+ amelioration and a high association constant to L
-. From estimated association constants for Al-Cl complexes, low affinity factors for L
- for these complexes were derived. Since the formation of these Al-Cl complexes is not favoured, Cl- is predicted to have very little ameliorating effect. In the case of SO4
2– and F- complexes with Al, the derived affinity factors never exceeded 0.05 and, since formation of these complexes is favoured by high association constants, are thus in agreement with experimental results on ameliorating effects. The ranking of the anions for ameliorative effectiveness was estimated to be in the order of OH->F->SO4
2–>Cl-. Hydroxy amelioration in this context is restricted to the speciation effect, which is only significant above pH 4. 相似文献
14.
Joanna Kotyńska Izabela Dobrzyńska Zbigniew Artur Figaszewski 《Journal of bioenergetics and biomembranes》2008,40(6):637-641
We examined the effect of adsorbed monovalent ions on the surface charge of phosphatidylcholine (PC) – decylamine (DA) liposomal
membranes. Surface charge density values were determined from electrophoretic mobility measurements of lipid vesicles performed
at various pH levels. The interaction between solution ions and the PC-DA liposomal surface was described by a six component
equilibrium model. The previously determined association constants of the -PO(-) and –N(+)(CH3)3 groups of PC with H+, OH-, Na+ and Cl- ions (K
A1H, K
B1OH, K
A1Na, K
B1C1) were used to calculate K
B2OH, and K
B2C1, the association constants of the –N(+)H3 group of DA with OH- and Cl- ions, providing an experimental verification for the proposed model. 相似文献
15.
Alton G. Sutter Arun P. Palanisamy Nichole Kurtz Demetri D. Spyropoulos Kenneth D. Chavin 《PloS one》2013,8(11)
Objective
Direct health care costs of obesity continue to grow throughout the world and research on obesity disease models are on the rise. The ob/ob mouse is a well-characterized model of obesity and associated risk factors. Successful breeding and backcrossing onto different backgrounds are essential to create knockout models. Ob/ob mice are sterile and heterozygotes must be identified by genotyping to maintain breeding colonies. Several methods are employed to detect the ob mutant allele, a single nucleotide polymorphism (SNP). Gel based methods are time consuming and inconsistent, and non-gel based assays rely upon expensive and complex reagents or instruments. A fast, high-throughput, cost effective, and consistent method to identify Lepob mutation is much needed.Design and Methods
Primers to produce an amplicon for High Resolution Melting Analysis (HRM) of the Lepob SNP were designed and validated.Results
Fluorescence normalized high resolution melting curve plots delineated ob/+, ob/ob, and WT genotypes. Genotypes were also confirmed phenotypically.Conclusions
HRM of the Lepob SNP allows closed-tube identification of the Lepob mutation using a real-time PCR machine now common to most labs/departments. Advantages of this method include assay sensitivity/accuracy, low cost dyes, less optimization, and cost effectiveness as compared to other genotyping techniques. 相似文献16.
17.
Pedro Gili Alfredo MederosEduardo Medina de la Rosa Alfonso Muñoz 《Inorganica chimica acta》2002,331(1):16-24
A computational study of chromium(VI) and (V) peroxides, which exhibit important genotoxic and mutagenic activity, is reported. Energies and equilibrium geometries for [CrVI(O)(O2)2(OH)]−, [CrVI(O)(O2)2(OH2)], [CrVI(O)(O2)2(py)], [CrVI(OH)(O2)2(OH2)]+, [CrV(O)(O2)2(OH2)]− and species were calculated using molecular mechanics calculations (MMFF94 and MM+), quantum calculations with semi-empirical methods (RHF and UHF/PM3) and density functional theory (pBP86/DN* or pBP/DN* and B3LYP/6-31G(d). Equilibrium geometries for the compounds [CrV(O2)3(OH)]2− and [CrV(O2)4]3− were determined by molecular mechanics. Vibrational frequencies, standard thermodynamic quantities and electronic spectra were calculated using B3LYP/6-31G(d). The structural relationship between all these species and an explanation of the formation of peroxo species in the acid-basic pH range are given. An experimental study of peroxo species in basic medium was also performed (synthesis, X-ray powder diffraction patterns and infrared spectra of the peroxo complexes isolated) but did not confirm the existence of a tri-peroxo complex in the solid phase. 相似文献
18.
Hiroyasu Kumamoto Yoshiharu Matsubara Yoshitomi Iizuka Kozo Okamoto Katsumi Yokoi 《Bioscience, biotechnology, and biochemistry》2013,77(9):2613-2618
An attempt was made to isolate the hypotensive substances from a hot water extract of kinkan. Eight flavonoid glycosides were isolated by repeated chromatography and by gel filtration after extracting with n-butanol and treating with lead subacetate. Their structures were established to be 6,8-di-C-glucosylapigenin (1), 3,6-di-C-glucosylacacetin (2), 2″-O-α-l-rhamnosyl-4′-O-methyl-vitexin (3), 2″-O-α-l-rhamnosyl-4′-O-methylisovitexin (4), 2″-O-α-l-rhamnosylvitexin (5), 2″-O-α-l-rhamnosylorientin (6), 2″-O-α-l-rhamnosyl-4′-O-methylorientin (7) and ponicilin (8) by UV. MS, 1-NMR and 13C-NMR spectroscopy, and by sugar analysis. Each component was intravenously injected in SHR-SP (0.5 ~ 1.0 mg/100 g of body weight), 1, 2, 5 and 6 were found to lower the rat blood pressure.Among these compounds, 2, 3, 4, 6 and 7 were new flavone glycosides. 相似文献
19.
Junitsu Ito Noriyuki Otsuki Xuhong Zhang Tasuku Konno Toshihiro Kurahashi Motoko Takahashi Mayumi Yamato Yuta Matsuoka Ken-ichi Yamada Satoshi Miyata Junichi Fujii 《Life sciences》2014
Aims
Aldehyde reductase (AKR1A), a member of the aldo-keto reductase superfamily, is highly expressed in the liver and is involved in both the detoxification of carbonyl compounds and ascorbic acid biosynthesis. By comparison with wild-type mice, Akr1a-knockout (Akr1a−/−) mice and human Akrla-transgenic (Akr1atg/+) mice experience different anesthetic actions from pentobarbital—prolonged in Akr1a-knockout (Akr1a−/−) mice and shortened in human Akrla-transgenic (Akr1atg/+) mice.Main methods
We investigated this alteration in the anesthetic efficacy of pentobarbital in Akr1a genetically modified mice.Key findings
Neither the cytosolic protein of wild-type mouse liver nor purified rat AKR1A directly reduced pentobarbital. Ascorbic acid administration neutralized the prolonged duration of the loss of the righting reflex (LORR) in Akr1a−/− mice, but preincubation of pentobarbital with ascorbic acid prior to administration did not change the anesthetic effect. Those results indicated that ascorbic acid does not directly reduce pentobarbital. Enzymatic activities and levels of the proteins of some cytochrome P450s that make up a potent detoxification system for pentobarbital showed no changes in the genetically modified mice examined. Thus, ascorbic acid also had no effect on the detoxification system in the liver. The prolonged duration of LORR in the Akr1a−/− mice caused by pentobarbital and the neutralization of the anesthetic effect by ascorbic acid together with other results imply that ascorbic acid alters the responses of the neuronal system to anesthetics.Significance
Pentobarbital action is increased under conditions of ascorbic acid deficiency, and this may have to be taken into account when anesthetizing malnourished patients. 相似文献20.
Jianchang Zhou Paul C. Dimayuga Xiaoning Zhao Juliana YanoWai Man Lio Portia TrinidadTomoyuki Honjo Bojan CercekPrediman K. Shah Kuang-Yuh Chyu 《Biochemical and biophysical research communications》2014