Computational identification of potent inhibitors for Streptomycin 3″-adenylyltransferase of Serratia marcescens.

Science.gov (United States)

Prabhu, Dhamodharan; Vidhyavathi, Ramasamy; Jeyakanthan, Jeyaraman

2017-02-01

Serratia marcescens is an opportunistic pathogen responsible for the respiratory and urinary tract infections in humans. The antibiotic resistance mechanism of S. marcescens is mediated through aminoglycoside modification enzyme that transfer adenyl group from substrate to antibiotic through regiospecific transfers for the inactivation of antibiotics. Streptomycin 3 ″ -adenylyltransferase acts on the 3' position of the antibiotic and considered as a novel drug target to overcome bacterial antibiotic resistance. Till now, there is no experimentally solved crystal structure of Streptomycin 3″-adenylyltransferase in S. marcescens. Hence, the present study was initiated to construct the three dimensional structure of Streptomycin 3″-adenylyltransferase in order to understand the binding mechanism. The modeled structure was subjected to structure-based virtual screening to identify potent compounds from the five chemical structure databases. Furthermore, different computational methods such as molecular docking, molecular dynamics simulations, ADME toxicity assessment, free energy and density functional theory calculations predicted the structural, binding and pharmacokinetic properties of the best five compounds. Overall, the results suggested that stable binding confirmation of the five potent compounds were mediated through hydrophobic, π-π stacking, salt bridges and hydrogen bond interactions. The identified compounds could pave way for the development of anti-pathogenic agents as potential drug entities. Copyright © 2016 Elsevier Ltd. All rights reserved.

Whole-genome sequencing reveals the mechanisms for evolution of streptomycin resistance in Lactobacillus plantarum.

Science.gov (United States)

Zhang, Fuxin; Gao, Jiayuan; Wang, Bini; Huo, Dongxue; Wang, Zhaoxia; Zhang, Jiachao; Shao, Yuyu

2018-04-01

In this research, we investigated the evolution of streptomycin resistance in Lactobacillus plantarum ATCC14917, which was passaged in medium containing a gradually increasing concentration of streptomycin. After 25 d, the minimum inhibitory concentration (MIC) of L. plantarum ATCC14917 had reached 131,072 µg/mL, which was 8,192-fold higher than the MIC of the original parent isolate. The highly resistant L. plantarum ATCC14917 isolate was then passaged in antibiotic-free medium to determine the stability of resistance. The MIC value of the L. plantarum ATCC14917 isolate decreased to 2,048 µg/mL after 35 d but remained constant thereafter, indicating that resistance was irreversible even in the absence of selection pressure. Whole-genome sequencing of parent isolates, control isolates, and isolates following passage was used to study the resistance mechanism of L. plantarum ATCC14917 to streptomycin and adaptation in the presence and absence of selection pressure. Five mutated genes (single nucleotide polymorphisms and structural variants) were verified in highly resistant L. plantarum ATCC14917 isolates, which were related to ribosomal protein S12, LPXTG-motif cell wall anchor domain protein, LrgA family protein, Ser/Thr phosphatase family protein, and a hypothetical protein that may correlate with resistance to streptomycin. After passage in streptomycin-free medium, only the mutant gene encoding ribosomal protein S12 remained; the other 4 mutant genes had reverted to the wild type as found in the parent isolate. Although the MIC value of L. plantarum ATCC14917 was reduced in the absence of selection pressure, it remained 128-fold higher than the MIC value of the parent isolate, indicating that ribosomal protein S12 may play an important role in streptomycin resistance. Using the mobile elements database, we demonstrated that streptomycin resistance-related genes in L. plantarum ATCC14917 were not located on mobile elements. This research offers a way of

Cross-linking of streptomycin to the 16S ribosomal RNA of Escherichia coli

International Nuclear Information System (INIS)

Gravel, M.; Melancon, P.; Barkier-Gingras, L.

1987-01-01

[ 3 H]Dihydrostreptomycin was cross-linked to the 30S ribosomal subunit from Escherichia coli with the bifunctional reagent nitrogen mustard. The cross-linking primarily involved the 16S RNA. To localize the site of cross-linking of streptomycin to the 16S RNA, the authors hybridized RNA labeled with streptomycin to restriction fragments of the 16S RNA gene. Labeled RNA hybridized to DNA fragments corresponding to bases 892-917 and bases 1394-1415. These two segments of the ribosomal RNA must by juxtaposed in the ribosome, since there is a single binding site for streptomycin. This region has been implicated both in the decoding site and in the binding of initiation factor IF-3, indicating its functional importance

76 FR 69734 - Streptomycin Sulfate; Receipt of Application for Emergency Exemption, Solicitation of Public Comment

Science.gov (United States)

2011-11-09

... (NAICS code 111). Animal production (NAICS code 112). Food manufacturing (NAICS code 311). Pesticide... pesticide containing streptomycin sulfate, which is also used in human and animal treatment as an antibiotic... which contains the active ingredient, streptomycin sulfate, also used in humans and animals as an...

The PPARgamma agonist pioglitazone is effective in the MPTP mouse model of Parkinson's disease through inhibition of monoamine oxidase B.

Science.gov (United States)

Quinn, L P; Crook, B; Hows, M E; Vidgeon-Hart, M; Chapman, H; Upton, N; Medhurst, A D; Virley, D J

2008-05-01

The peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist pioglitazone has previously been shown to attenuate dopaminergic cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease, an effect attributed to its anti-inflammatory properties. In the present investigation, we provide evidence that pioglitazone is effective in the MPTP mouse model, not via an anti-inflammatory action, but through inhibition of MAO-B, the enzyme required to biotransform MPTP to its active neurotoxic metabolite 1-methyl-4-phenylpyridinium (MPP+). Mice were treated with pioglitazone (20 mg kg(-1) b.i.d. (twice a day), p.o., for 7 days), prior and post or post-MPTP (30 mg kg(-1) s.c.) treatment. Mice were then assessed for motor impairments on a beam-walking apparatus and for reductions in TH immunoreactivity in the substantia nigra and depletions in striatal dopamine. The effects of pioglitazone on striatal MPP+ levels and MAO-B activity were also assessed. Mice treated with MPTP showed deficits in motor performance, marked depletions in striatal dopamine levels and a concomitant reduction in TH immunoreactivity in the substantia nigra. Pretreatment with pioglitazone completely prevented these effects of MPTP. However, pretreatment with pioglitazone also significantly inhibited the MPTP-induced production of striatal MPP+ and the activity of MAO-B in the striatum. The neuroprotection observed with pioglitazone pretreatment in the MPTP mouse model was due to the blockade of the conversion of MPTP to its active toxic metabolite MPP+, via inhibition of MAO-B.

Probiotic Lactobacillus rhamnosus GG prevents alveolar bone loss in a mouse model of experimental periodontitis.

Science.gov (United States)

Gatej, Simona M; Marino, Victor; Bright, Richard; Fitzsimmons, Tracy R; Gully, Neville; Zilm, Peter; Gibson, Rachel J; Edwards, Suzanne; Bartold, Peter M

2018-02-01

This study investigated the role of Lactobacillus rhamnosus GG (LGG) on bone loss and local and systemic inflammation in an in vivo mouse model of experimental periodontitis (PD). Experimental PD was induced in mice by oral inoculation with Porphyromonas gingivalis and Fusobacterium nucleatum over a period of 44 days. The probiotic LGG was administered via oral inoculation or oral gavage prior to, and during disease induction. The antimicrobial activity of LGG on the inoculum was also tested. Alveolar bone levels and gingival tissue changes were assessed using in vivo microcomputed tomography and histological analysis. Serum levels of mouse homologues for IL-8 were measured using multiplex assays. Pre-treatment with probiotics either via oral gavage or via oral inoculation significantly reduced bone loss (p loss in a mouse model of induced PD irrespective of the mode of administration. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Anaerobic respiration of Escherichia coli in the mouse intestine.

Science.gov (United States)

Jones, Shari A; Gibson, Terri; Maltby, Rosalie C; Chowdhury, Fatema Z; Stewart, Valley; Cohen, Paul S; Conway, Tyrrell

2011-10-01

The intestine is inhabited by a large microbial community consisting primarily of anaerobes and, to a lesser extent, facultative anaerobes, such as Escherichia coli, which we have shown requires aerobic respiration to compete successfully in the mouse intestine (S. A. Jones et al., Infect. Immun. 75:4891-4899, 2007). If facultative anaerobes efficiently lower oxygen availability in the intestine, then their sustained growth must also depend on anaerobic metabolism. In support of this idea, mutants lacking nitrate reductase or fumarate reductase have extreme colonization defects. Here, we further explore the role of anaerobic respiration in colonization using the streptomycin-treated mouse model. We found that respiratory electron flow is primarily via the naphthoquinones, which pass electrons to cytochrome bd oxidase and the anaerobic terminal reductases. We found that E. coli uses nitrate and fumarate in the intestine, but not nitrite, dimethyl sulfoxide, or trimethylamine N-oxide. Competitive colonizations revealed that cytochrome bd oxidase is more advantageous than nitrate reductase or fumarate reductase. Strains lacking nitrate reductase outcompeted fumarate reductase mutants once the nitrate concentration in cecal mucus reached submillimolar levels, indicating that fumarate is the more important anaerobic electron acceptor in the intestine because nitrate is limiting. Since nitrate is highest in the absence of E. coli, we conclude that E. coli is the only bacterium in the streptomycin-treated mouse large intestine that respires nitrate. Lastly, we demonstrated that a mutant lacking the NarXL regulator (activator of the NarG system), but not a mutant lacking the NarP-NarQ regulator, has a colonization defect, consistent with the advantage provided by NarG. The emerging picture is one in which gene regulation is tuned to balance expression of the terminal reductases that E. coli uses to maximize its competitiveness and achieve the highest possible population in

Burn mouse models

DEFF Research Database (Denmark)

Calum, Henrik; Høiby, Niels; Moser, Claus

2014-01-01

Severe thermal injury induces immunosuppression, involving all parts of the immune system, especially when large fractions of the total body surface area are affected. An animal model was established to characterize the burn-induced immunosuppression. In our novel mouse model a 6 % third-degree b......Severe thermal injury induces immunosuppression, involving all parts of the immune system, especially when large fractions of the total body surface area are affected. An animal model was established to characterize the burn-induced immunosuppression. In our novel mouse model a 6 % third...... with infected burn wound compared with the burn wound only group. The burn mouse model resembles the clinical situation and provides an opportunity to examine or develop new strategies like new antibiotics and immune therapy, in handling burn wound victims much....

78 FR 29049 - Streptomycin; Pesticide Tolerances for Emergency Exemptions

Science.gov (United States)

2013-05-17

... determine whether this document applies to them. Potentially affected entities may include: Crop production (NAICS code 111). Animal production (NAICS code 112). Food manufacturing (NAICS code 311). Pesticide....40 ppm. Streptomycin is an antibiotic of the aminoglycoside class and is produced by the bacteria...

Sulphaphenazole, streptomycin and sulphaphenazole combination, trimethoprim, and erythromycin in the treatment of chancroid.

Science.gov (United States)

Kumar, B; Sharma, V K; Bakaya, V

1990-01-01

One hundred and thirty six patients with chancroid were treated with four different treatment regimens; (A) Sulphaphenazole 1 g 12 hourly by mouth x 10 days (B) Inj streptomycin 1 g intramuscularly daily with sulphaphenazole 1 g 12 hourly orally x 10 days; (C) trimethoprim 200 mg 12 hourly by mouth x 7-10 days, and (D) erythromycin 500 mg 6 hourly orally x 7-10 days. Cure rates of 9% with sulphaphenazole alone, 48% with streptomycin and sulphaphenazole combination, 93% with trimethoprim and 100% with erythromycin were obtained. Sulphaphenazole alone or in combination with streptomycin were thus inferior in the treatment of chancroid. There is need for modification of treatment regimens recommended for chancroid in the textbooks of dermatology and venereology. Trimethoprim can be recommended as first line of treatment for chancroid in developing countries like India where resistance to trimethoprim is uncommon and erythromycin is suggested as a second line of therapy because by that time syphilis can be easily ruled out. PMID:2187791

Dantrolene is neuroprotective in Huntington's disease transgenic mouse model

Directory of Open Access Journals (Sweden)

Chen Xi

2011-11-01

Full Text Available Abstract Background Huntington's disease (HD is a progressive neurodegenerative disorder caused by a polyglutamine expansion in the Huntingtin protein which results in the selective degeneration of striatal medium spiny neurons (MSNs. Our group has previously demonstrated that calcium (Ca2+ signaling is abnormal in MSNs from the yeast artificial chromosome transgenic mouse model of HD (YAC128. Moreover, we demonstrated that deranged intracellular Ca2+ signaling sensitizes YAC128 MSNs to glutamate-induced excitotoxicity when compared to wild type (WT MSNs. In previous studies we also observed abnormal neuronal Ca2+ signaling in neurons from spinocerebellar ataxia 2 (SCA2 and spinocerebellar ataxia 3 (SCA3 mouse models and demonstrated that treatment with dantrolene, a ryanodine receptor antagonist and clinically relevant Ca2+ signaling stabilizer, was neuroprotective in experiments with these mouse models. The aim of the current study was to evaluate potential beneficial effects of dantrolene in experiments with YAC128 HD mouse model. Results The application of caffeine and glutamate resulted in increased Ca2+ release from intracellular stores in YAC128 MSN cultures when compared to WT MSN cultures. Pre-treatment with dantrolene protected YAC128 MSNs from glutamate excitotoxicty, with an effective concentration of 100 nM and above. Feeding dantrolene (5 mg/kg twice a week to YAC128 mice between 2 months and 11.5 months of age resulted in significantly improved performance in the beam-walking and gait-walking assays. Neuropathological analysis revealed that long-term dantrolene feeding to YAC128 mice significantly reduced the loss of NeuN-positive striatal neurons and reduced formation of Httexp nuclear aggregates. Conclusions Our results support the hypothesis that deranged Ca2+ signaling plays an important role in HD pathology. Our data also implicate the RyanRs as a potential therapeutic target for the treatment of HD and demonstrate that Ryan

Dantrolene is neuroprotective in Huntington's disease transgenic mouse model.

Science.gov (United States)

Chen, Xi; Wu, Jun; Lvovskaya, Svetlana; Herndon, Emily; Supnet, Charlene; Bezprozvanny, Ilya

2011-11-25

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine expansion in the Huntingtin protein which results in the selective degeneration of striatal medium spiny neurons (MSNs). Our group has previously demonstrated that calcium (Ca2+) signaling is abnormal in MSNs from the yeast artificial chromosome transgenic mouse model of HD (YAC128). Moreover, we demonstrated that deranged intracellular Ca2+ signaling sensitizes YAC128 MSNs to glutamate-induced excitotoxicity when compared to wild type (WT) MSNs. In previous studies we also observed abnormal neuronal Ca2+ signaling in neurons from spinocerebellar ataxia 2 (SCA2) and spinocerebellar ataxia 3 (SCA3) mouse models and demonstrated that treatment with dantrolene, a ryanodine receptor antagonist and clinically relevant Ca2+ signaling stabilizer, was neuroprotective in experiments with these mouse models. The aim of the current study was to evaluate potential beneficial effects of dantrolene in experiments with YAC128 HD mouse model. The application of caffeine and glutamate resulted in increased Ca2+ release from intracellular stores in YAC128 MSN cultures when compared to WT MSN cultures. Pre-treatment with dantrolene protected YAC128 MSNs from glutamate excitotoxicty, with an effective concentration of 100 nM and above. Feeding dantrolene (5 mg/kg) twice a week to YAC128 mice between 2 months and 11.5 months of age resulted in significantly improved performance in the beam-walking and gait-walking assays. Neuropathological analysis revealed that long-term dantrolene feeding to YAC128 mice significantly reduced the loss of NeuN-positive striatal neurons and reduced formation of Httexp nuclear aggregates. Our results support the hypothesis that deranged Ca2+ signaling plays an important role in HD pathology. Our data also implicate the RyanRs as a potential therapeutic target for the treatment of HD and demonstrate that RyanR inhibitors and Ca2+ signaling stabilizers such as

Effects of streptomycin, desiccation, and UV radiation on ice nucleation by Pseudomonas viridiflava

International Nuclear Information System (INIS)

Anderson, J.A.; Ashworth, E.N.

1986-01-01

Streptomycin (100 micrograms per milliliter), desiccation (over CaSO 4 ), and ultraviolet radiation (4500 microwatts per square centimeter at 254 nonometers for 15 minutes) reduced ice nucleation activity by Pseudomonas viridiflava strain W-1 as determined by freezing drops of the bacterial suspensions. Highest residual ice nucleation activity by dead cells was obtained by desiccation, although no freezing above -3.5 0 C was detected. The rate and extent of loss of ice nucleation activity following streptomycin and ultraviolet treatment was affected by preconditioning temperature. At 21 0 C and above, loss of activity by dead cells was rapid and irreversible

Diaphragm Muscle Weakness Following Acute Sustained Hypoxic Stress in the Mouse Is Prevented by Pretreatment with N-Acetyl Cysteine

Directory of Open Access Journals (Sweden)

Andrew J. O’Leary

2018-01-01

Full Text Available Oxygen deficit (hypoxia is a major feature of cardiorespiratory diseases characterized by diaphragm dysfunction, yet the putative role of hypoxic stress as a driver of diaphragm dysfunction is understudied. We explored the cellular and functional consequences of sustained hypoxic stress in a mouse model. Adult male mice were exposed to 8 hours of normoxia, or hypoxia (FiO2 = 0.10 with or without antioxidant pretreatment (N-acetyl cysteine, 200 mg/kg i.p.. Ventilation and metabolism were measured. Diaphragm muscle contractile function, myofibre size and distribution, gene expression, protein signalling cascades, and oxidative stress (TBARS were determined. Hypoxia caused pronounced diaphragm muscle weakness, unrelated to increased respiratory muscle work. Hypoxia increased diaphragm HIF-1α protein content and activated MAPK, mTOR, Akt, and FoxO3a signalling pathways, largely favouring protein synthesis. Hypoxia increased diaphragm lipid peroxidation, indicative of oxidative stress. FoxO3 and MuRF-1 gene expression were increased. Diaphragm 20S proteasome activity and muscle fibre size and distribution were unaffected by acute hypoxia. Pretreatment with N-acetyl cysteine substantially enhanced cell survival signalling, prevented hypoxia-induced diaphragm oxidative stress, and prevented hypoxia-induced diaphragm dysfunction. Hypoxia is a potent driver of diaphragm weakness, causing myofibre dysfunction without attendant atrophy. N-acetyl cysteine protects the hypoxic diaphragm and may have application as a potential adjunctive therapy.

Investigation of the impacts of thermal pretreatment on waste activated sludge and development of a pretreatment model.

Science.gov (United States)

Burger, Gillian; Parker, Wayne

2013-09-15

This study investigated the impacts of high pressure thermal hydrolysis (HPTH) pretreatment on the distribution of chemical oxygen demand (COD) species in waste activated sludge (WAS). In the first phase of the project, WAS from a synthetically-fed biological reactor (BR) was fed to an aerobic digester (AD). In the second phase, WAS from the BR was pretreated by HPTH at 150 °C and 3 bars for 30 min prior to being fed to the AD. A range of physical, biochemical and biological properties were regularly measured in each process stream in both phases. The COD of the BR WAS consisted of storage products (XSTO), active heterotrophs (XH) and endogenous decay products (XE). Pretreatment did not increase the extent to which the BR WAS was aerobically digested and hence it was concluded that the unbiodegradable COD fraction, i.e. XE, was unchanged by pretreatment. However, pretreatment did increase the rate of degradation as it converted 36% of XH to readily biodegradable COD (SB) and the remaining XH to slowly biodegradable COD (XB). Furthermore, XSTO was fully converted to SB by pretreatment. Although pretreatment did not change the VSS concentration in the downstream aerobic digester, it did decrease the ISS concentration by 46 ± 11%. This reduced the total mass of solids produced by the digester by 21 ± 8%. A COD-based HPTH pretreatment model was developed and calibrated. When this model was integrated into BioWin 3.1(®), it was able to accurately simulate both the steady state performance of the overall system employed in this study as well as dynamic respirometry results. Copyright © 2013 Elsevier Ltd. All rights reserved.

Establishing Streptomycin Epidemiological Cut-Off Values for Salmonella and Escherichia coli

DEFF Research Database (Denmark)

Migura, Lourdes Garcia; Sunde, Marianne; Karlsmose, Susanne

2011-01-01

This study was conducted to elucidate the accuracy of the current streptomycin epidemiological cut-off value (ECOFF) for Escherichia coli and Salmonella spp. A total of 236 Salmonella enterica and 208 E. coli isolates exhibiting MICs between 4 and 32 mg/L were selected from 12 countries. Isolates...

Temperature Modelling of the Biomass Pretreatment Process

DEFF Research Database (Denmark)

Prunescu, Remus Mihail; Blanke, Mogens; Jensen, Jakob M.

2012-01-01

In a second generation biorefinery, the biomass pretreatment stage has an important contribution to the efficiency of the downstream processing units involved in biofuel production. Most of the pretreatment process occurs in a large pressurized thermal reactor that presents an irregular temperature...... that captures the environmental temperature differences inside the reactor using distributed parameters. A Kalman filter is then added to account for any missing dynamics and the overall model is embedded into a temperature soft sensor. The operator of the plant will be able to observe the temperature in any...

Subchronic Arsenic Exposure Induces Anxiety-Like Behaviors in Normal Mice and Enhances Depression-Like Behaviors in the Chemically Induced Mouse Model of Depression

Directory of Open Access Journals (Sweden)

Chia-Yu Chang

2015-01-01

Full Text Available Accumulating evidence implicates that subchronic arsenic exposure causes cerebral neurodegeneration leading to behavioral disturbances relevant to psychiatric disorders. However, there is still little information regarding the influence of subchronic exposure to arsenic-contaminated drinking water on mood disorders and its underlying mechanisms in the cerebral prefrontal cortex. The aim of this study is to assess the effects of subchronic arsenic exposure (10 mg/LAs2O3 in drinking water on the anxiety- and depression-like behaviors in normal mice and in the chemically induced mouse model of depression by reserpine pretreatment. Our findings demonstrated that 4 weeks of arsenic exposure enhance anxiety-like behaviors on elevated plus maze (EPM and open field test (OFT in normal mice, and 8 weeks of arsenic exposure augment depression-like behaviors on tail suspension test (TST and forced swimming test (FST in the reserpine pretreated mice. In summary, in this present study, we demonstrated that subchronic arsenic exposure induces only the anxiety-like behaviors in normal mice and enhances the depression-like behaviors in the reserpine induced mouse model of depression, in which the cerebral prefrontal cortex BDNF-TrkB signaling pathway is involved. We also found that eight weeks of subchronic arsenic exposure are needed to enhance the depression-like behaviors in the mouse model of depression. These findings imply that arsenic could be an enhancer of depressive symptoms for those patients who already had the attribute of depression.

Ribosome slowed by mutation to streptomycin resistance. [Escherichia coli

Energy Technology Data Exchange (ETDEWEB)

Galas, D J; Branscomb, E W

1976-08-12

The effect of mutation to streptomycin resistance on the speed of polypeptide elongation in Escherichia coli was investigated. Translation speed was determined by measuring the time required for the first newly synthesized ..beta..-galactosidase molecules to appear after induction of the lactose operon. The results showed that ribosome speed is not a fixed parameter inherent to the protein synthetic apparatus, but a variable determined by the kinetics of translation and ultimately by the structure of the ribosome. (HLW)

The Mouse Tumor Biology Database: A Comprehensive Resource for Mouse Models of Human Cancer.

Science.gov (United States)

Krupke, Debra M; Begley, Dale A; Sundberg, John P; Richardson, Joel E; Neuhauser, Steven B; Bult, Carol J

2017-11-01

Research using laboratory mice has led to fundamental insights into the molecular genetic processes that govern cancer initiation, progression, and treatment response. Although thousands of scientific articles have been published about mouse models of human cancer, collating information and data for a specific model is hampered by the fact that many authors do not adhere to existing annotation standards when describing models. The interpretation of experimental results in mouse models can also be confounded when researchers do not factor in the effect of genetic background on tumor biology. The Mouse Tumor Biology (MTB) database is an expertly curated, comprehensive compendium of mouse models of human cancer. Through the enforcement of nomenclature and related annotation standards, MTB supports aggregation of data about a cancer model from diverse sources and assessment of how genetic background of a mouse strain influences the biological properties of a specific tumor type and model utility. Cancer Res; 77(21); e67-70. ©2017 AACR . ©2017 American Association for Cancer Research.

Energy consumption modeling during dairy sewage pretreatment

Directory of Open Access Journals (Sweden)

Dąbrowski Wojciech

2017-01-01

Full Text Available The research was conducted in a dairy WWTP located in north-eastern Poland with the average flow of 546 m3d-1 and PE 11500 in 2016. Energy consumption was measured with the help of Lumel 3-phase network parameter transducers installed within the plant. The modeling was conducted based on the quantity and quality of raw sewage, after its screening, averaging and dissolved air flotation. The following parameters were determined: BOD5, COD. N-total and P-total. During the research period. 15 measurement series were carried out. Pollution loads removed in primary treatment varied from 167.0 to 803.5 kgO2d-1 and 1205.9 to 10032 kgO2d-1 for BOD5 and COD respectively. The energy consumption share during dairy pretreatment in relation to the total energy consumption was in the range from 13.8 to 28.5% with the mean value of 18.7% during the research period. Energy consumption indicators relating to removed pollution loads for primary treatment were established with the mean values of 0.74 and 0.83 kWhkg-1d-1 for BOD5 and COD respectively. An attempt was made to determine the influence of raw sewage characteristics and pretreatment efficiency on energy consumption of the object. A model of energy consumption during pretreatment was estimated according to the experimental data obtained in the research period. It was modeled using the linear regression model and principal component analysis.

Mouse Models of Gastric Cancer

Science.gov (United States)

Hayakawa, Yoku; Fox, James G.; Gonda, Tamas; Worthley, Daniel L.; Muthupalani, Sureshkumar; Wang, Timothy C.

2013-01-01

Animal models have greatly enriched our understanding of the molecular mechanisms of numerous types of cancers. Gastric cancer is one of the most common cancers worldwide, with a poor prognosis and high incidence of drug-resistance. However, most inbred strains of mice have proven resistant to gastric carcinogenesis. To establish useful models which mimic human gastric cancer phenotypes, investigators have utilized animals infected with Helicobacter species and treated with carcinogens. In addition, by exploiting genetic engineering, a variety of transgenic and knockout mouse models of gastric cancer have emerged, such as INS-GAS mice and TFF1 knockout mice. Investigators have used the combination of carcinogens and gene alteration to accelerate gastric cancer development, but rarely do mouse models show an aggressive and metastatic gastric cancer phenotype that could be relevant to preclinical studies, which may require more specific targeting of gastric progenitor cells. Here, we review current gastric carcinogenesis mouse models and provide our future perspectives on this field. PMID:24216700

Volatile compounds of Lamiaceae exhibit a synergistic antibacterial activity with streptomycin

Directory of Open Access Journals (Sweden)

Sthéfane G. Araújo

2014-12-01

Full Text Available Bacterial infections cause thousands of deaths in the world every year. In most cases, infections are more serious because the patient is already weakened, and often, the bacteria are already resistant to the antibiotics used. Counterparting this negative scenario, the interest in medicinal plants as an alternative to the synthetic antimicrobial drugs is blossoming worldwide. In the present work, we identified the volatile compounds of ethanol extracts of Melissa officinalis, Mentha sp., Ocimum basilicum, Plectranthus barbatus, and Rosmarinus officinalis by gas chromatography/mass spectrometry (GC/MS. Also was evaluated antimicrobial activity of ethanol extracts against 6 bacteria of clinical interest, and was tested the interaction of these extracts with a commercial antibiotic streptomycin. Phytol was a compound identified in all extracts by GC/MS, being majoritary component in Plectranthus barbatus and Rosmarinus officinalis. The Gram-positive bacteria were more sensitive to ethanol extracts, and Plectranthus barbatus and Rosmarinus officinalis were the most active extracts. Ethanol extracts exhibited a synergetic effect with streptomycin. These results encourage additional studies, in order to evaluate the possibilities of using ethanol extracts of Lamiaceae family as natural source for antibacterial activity.

Culture-independent detection of 'TM7' bacteria in a streptomycin-resistant acidophilic nitrifying process

Energy Technology Data Exchange (ETDEWEB)

Kurogi, T.; Linh, N. T. T.; Kuroki, T.; Yamada, T. [Department of Environmental and Life Science, Toyohashi University of Technology, Toyohashi 441-8580 (Japan); Hiraishi, A. [Department of Environmental and Life Science, Toyohashi University of Technology, Toyohashi 441-8580, Japan and Electronics-inspired Interdisciplinary Institute (EIIRIS), Toyohashi University of Technology, Toyohashi 441-8580 (Japan)

2014-02-20

Nitrification in biological wastewater treatment processes has been believed for long time to take place under neutral conditions and is inhibited under acidic conditions. However, we previously constructed acidophilic nitrifying sequencing-batch reactors (ANSBRs) being capable of nitrification at < pH 4 and harboring bacteria of the candidate phylum 'TM7' as the major constituents of the microbial community. In light of the fact that the 16S rRNA of TM7 bacteria has a highly atypical base substitution possibly responsible for resistance to streptomycin at the ribosome level, this study was undertaken to construct streptomycin-resistant acidophilic nitrifying (SRAN) reactors and to demonstrate whether TM7 bacteria are abundant in these reactors. The SRAN reactors were constructed by seeding with nitrifying sludge from an ANSBR and cultivating with ammonium-containing mineral medium (pH 4.0), to which streptomycin at a concentration of 10, 30 and 50 mg L{sup −1} was added. In all reactors, the pH varied between 2.7 and 4.0, and ammonium was completely converted to nitrate in every batch cycle. PCR-aided denaturing gradient gel electrophoresis (DGGE) targeting 16S rRNA genes revealed that some major clones assigned to TM7 bacteria and Gammaproteobacteria were constantly present during the overall period of operation. Fluorescence in situ hybridization (FISH) with specific oligonucleotide probes also showed that TM7 bacteria predominated in all SRAN reactors, accounting for 58% of the total bacterial population on average. Although the biological significance of the TM7 bacteria in the SRAN reactors are unknown, our results suggest that these bacteria are possibly streptomycin-resistant and play some important roles in the acidophilic nitrifying process.

Field Efficiency Trial of 72% Streptomycin against Konjac Bacterial Soft Rot

Institute of Scientific and Technical Information of China (English)

Huang; Yongsheng; Li; Xiaojun; Zhu; Shijin; Ma; Yongsheng; Wang; Li

2014-01-01

72% Streptomycin soluble powder was used to control konjac bacterial soft rot in the study. The control efficiency and yield of different treatments were investigated,and the benefit was analyzed. The control scheme against konjac bacterial soft rot was as follows: spraying 72% atreptomycinon twice on rotation fields after all the seedlings were strong and uniform,or irrigating roots with 72% atreptomycinon once and spraying twice on continuous cropping fields.

Melatonin receptors: latest insights from mouse models

Science.gov (United States)

Tosini, Gianluca; Owino, Sharon; Guillame, Jean-Luc; Jockers, Ralf

2014-01-01

Summary Melatonin, the neuro-hormone synthesized during the night, has recently seen an unexpected extension of its functional implications towards type 2 diabetes development, visual functions, sleep disturbances and depression. Transgenic mouse models were instrumental for the establishment of the link between melatonin and these major human diseases. Most of the actions of melatonin are mediated by two types of G protein-coupled receptors, named MT1 and MT2, which are expressed in many different organs and tissues. Understanding the pharmacology and function of mouse MT1 and MT2 receptors, including MT1/MT2 heteromers, will be of crucial importance to evaluate the relevance of these mouse models for future therapeutic developments. This review will critically discuss these aspects, and give some perspectives including the generation of new mouse models. PMID:24903552

Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease.

Science.gov (United States)

Bloom, Seth M; Bijanki, Vinieth N; Nava, Gerardo M; Sun, Lulu; Malvin, Nicole P; Donermeyer, David L; Dunne, W Michael; Allen, Paul M; Stappenbeck, Thaddeus S

2011-05-19

The intestinal microbiota is important for induction of inflammatory bowel disease (IBD). IBD is associated with complex shifts in microbiota composition, but it is unclear whether specific bacterial subsets induce IBD and, if so, whether their proportions in the microbiota are altered during disease. Here, we fulfilled Koch's postulates in host-genotype-specific fashion using a mouse model of IBD with human-relevant disease-susceptibility mutations. From screening experiments we isolated common commensal Bacteroides species, introduced them into antibiotic-pretreated mice, and quantitatively reisolated them in culture. The bacteria colonized IBD-susceptible and -nonsusceptible mice equivalently, but induced disease exclusively in susceptible animals. Conversely, commensal Enterobacteriaceae were >100-fold enriched during spontaneous disease, but an Enterobacteriaceae isolate failed to induce disease in antibiotic-pretreated mice despite robust colonization. We thus demonstrate that IBD-associated microbiota alterations do not necessarily reflect underlying disease etiology. These findings establish important experimental criteria and a conceptual framework for understanding microbial contributions to IBD. Copyright © 2011 Elsevier Inc. All rights reserved.

Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease

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Bloom, Seth M.; Bijanki, Vinieth N.; Nava, Gerardo M.; Sun, Lulu; Malvin, Nicole P.; Donermeyer, David L.; Dunne, W. Michael; Allen, Paul M.; Stappenbeck, Thaddeus S.

2011-01-01

SUMMARY The intestinal microbiota is important for induction of inflammatory bowel disease (IBD). IBD is associated with complex shifts in microbiota composition, but it is unclear whether specific bacterial subsets induce IBD and, if so, whether their proportions in the microbiota are altered during disease. Here we fulfilled Koch’s postulates in host-genotype-specific fashion using a mouse model of IBD with human-relevant disease-susceptibility mutations. From screening experiments we isolated common commensal Bacteroides species, introduced them into antibiotic-pretreated mice, and quantitatively re-isolated them in culture. The bacteria colonized IBD-susceptible and non-susceptible mice equivalently, but induced disease exclusively in susceptible animals. Conversely, commensal Enterobacteriaceae were >100-fold enriched during spontaneous disease but an Enterobacteriaceae isolate failed to induce disease in antibiotic-pretreated mice despite robust colonization. We thus demonstrate that IBD-associated microbiota alterations do not necessarily reflect underlying disease etiology. These findings establish important experimental criteria and a conceptual framework for understanding microbial contributions to IBD. PMID:21575910

Rational Design of Mouse Models for Cancer Research

NARCIS (Netherlands)

Landgraf, M.; McGovern, J.A.; Friedl, P.; Hutmacher, D.W.

2018-01-01

The laboratory mouse is widely considered as a valid and affordable model organism to study human disease. Attempts to improve the relevance of murine models for the investigation of human pathologies led to the development of various genetically engineered, xenograft and humanized mouse models.

Reduced antimicrobial potencies of Oxytetracycline, tylosin, sulfadiazine, streptomycin, ciprofloxacin and olaquindox due to environmental processes

DEFF Research Database (Denmark)

Halling-Sørensen, Bent; Sengeløv, G.; Ingerslev, Flemming

2003-01-01

The stability of oxytetracycline (OTC), tylosin (TYL), sulfadiazin (SDZ), streptomycin (ST), ciprofloxacin (CF) and olaquindox (O) was examined in environmentally relevant matrices, such as soil interstitial water and sewage sludge water. Compounds were assessed in both aerobic (OTC, TYL, SDZ, ST...

Mouse models of Fanconi anemia

International Nuclear Information System (INIS)

Parmar, Kalindi; D'Andrea, Alan; Niedernhofer, Laura J.

2009-01-01

Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis of proliferating cells. To date, 13 complementation groups of Fanconi anemia were identified. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability.

Mouse models of Fanconi anemia

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Parmar, Kalindi; D' Andrea, Alan [Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115 (United States); Niedernhofer, Laura J., E-mail: niedernhoferl@upmc.edu [Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine and Cancer Institute, 5117 Centre Avenue, Hillman Cancer Center, Research Pavilion 2.6, Pittsburgh, PA 15213-1863 (United States)

2009-07-31

Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis of proliferating cells. To date, 13 complementation groups of Fanconi anemia were identified. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability.

Gastroprotective effect of Desmodium gangeticum roots on gastric ulcer mouse models

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Ayyavu Mahesh

2012-06-01

Full Text Available In the present study, the ethanolic root extract of Desmodium gangeticum (L. DC., Fabaceae, (EDG, have been studied in various acute and chronic ulcer mouse models. Oral administration of root extract, significantly decrease the ulcer index and lesion number in a dose dependent manner against ethanol induced acute gastric ulcer in mice. In gastric ulcerated animal that received high dose of 150 mg/kg EDG, the mucosa showed no ulceration with slight focal congestion and the glands appeared normal. Pylorus ligated mice, pretreated with EDG showed significant decrease in ulcerous activity under chronic condition. The highest dose (150 mg/kg of the extract provoked a marked increase in protein and glutathione levels, when compare to control. Furthermore, gastric juice, free acidity and total acid output were inhibited in a dose-dependent manner at p<0.05 level. Our results indicate that the EDG possess gastroprotective activity and increasing regeneration of damaged gastric mucosa and thus safe for human use.

The Mouse Genome Database (MGD): facilitating mouse as a model for human biology and disease.

Science.gov (United States)

Eppig, Janan T; Blake, Judith A; Bult, Carol J; Kadin, James A; Richardson, Joel E

2015-01-01

The Mouse Genome Database (MGD, http://www.informatics.jax.org) serves the international biomedical research community as the central resource for integrated genomic, genetic and biological data on the laboratory mouse. To facilitate use of mouse as a model in translational studies, MGD maintains a core of high-quality curated data and integrates experimentally and computationally generated data sets. MGD maintains a unified catalog of genes and genome features, including functional RNAs, QTL and phenotypic loci. MGD curates and provides functional and phenotype annotations for mouse genes using the Gene Ontology and Mammalian Phenotype Ontology. MGD integrates phenotype data and associates mouse genotypes to human diseases, providing critical mouse-human relationships and access to repositories holding mouse models. MGD is the authoritative source of nomenclature for genes, genome features, alleles and strains following guidelines of the International Committee on Standardized Genetic Nomenclature for Mice. A new addition to MGD, the Human-Mouse: Disease Connection, allows users to explore gene-phenotype-disease relationships between human and mouse. MGD has also updated search paradigms for phenotypic allele attributes, incorporated incidental mutation data, added a module for display and exploration of genes and microRNA interactions and adopted the JBrowse genome browser. MGD resources are freely available to the scientific community. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

The wobbler mouse, an ALS animal model

DEFF Research Database (Denmark)

Moser, Jakob Maximilian; Bigini, Paolo; Schmitt-John, Thomas

2013-01-01

This review article is focused on the research progress made utilizing the wobbler mouse as animal model for human motor neuron diseases, especially the amyotrophic lateral sclerosis (ALS). The wobbler mouse develops progressive degeneration of upper and lower motor neurons and shows striking...

Mouse Models of the Skin: Models to Define Mechanisms of Skin Carcinogenesis

International Nuclear Information System (INIS)

Wheeler, D. L.; Verma, A. K.; Denning, M. F.

2013-01-01

The multistep model of mouse skin carcinogenesis has facilitated identification of irreversible genetic events of initiation and progression, and epigenetic events of tumor promotion. Mouse skin tumor initiation can be accomplished by a single exposure to a sufficiently small dose of a carcinogen, and this step is rapid and irreversible. However, promotion of skin tumor formation requires a repeated and prolonged exposure to a promoter, and that tumor promotion is reversible. Investigations focused on the mechanisms of mouse carcinogenesis have resulted in the identifications of potential molecular targets of cancer induction and progression useful in planning strategies for human cancer prevention trials. This special issue contains eight papers that focus on mouse models used to study individual proteins expressed in the mouse skin and the role they play in differentiation, tissue homeostasis, skin carcinogenesis, and chemo prevention of skin cancer.

A Humanized Mouse Model Generated Using Surplus Neonatal Tissue

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Matthew E. Brown

2018-04-01

Full Text Available Summary: Here, we describe the NeoThy humanized mouse model created using non-fetal human tissue sources, cryopreserved neonatal thymus and umbilical cord blood hematopoietic stem cells (HSCs. Conventional humanized mouse models are made by engrafting human fetal thymus and HSCs into immunocompromised mice. These mice harbor functional human T cells that have matured in the presence of human self-peptides and human leukocyte antigen molecules. Neonatal thymus tissue is more abundant and developmentally mature and allows for creation of up to ∼50-fold more mice per donor compared with fetal tissue models. The NeoThy has equivalent frequencies of engrafted human immune cells compared with fetal tissue humanized mice and exhibits T cell function in assays of ex vivo cell proliferation, interferon γ secretion, and in vivo graft infiltration. The NeoThy model may provide significant advantages for induced pluripotent stem cell immunogenicity studies, while bypassing the requirement for fetal tissue. : Corresponding author William Burlingham and colleagues created a humanized mouse model called the NeoThy. The NeoThy uses human neonatal, rather than fetal, tissue sources for generating a human immune system within immunocompromised mouse hosts. NeoThy mice are an attractive alternative to conventional humanized mouse models, as they enable robust and reproducible iPSC immunogenicity experiments in vivo. Keywords: NeoThy, humanized mouse, iPSC, PSC, immunogenicity, transplantation, immunology, hematopoietic stem cells, induced pluripotent stem cells, thymus

Description of waste pretreatment and interfacing systems dynamic simulation model

International Nuclear Information System (INIS)

Garbrick, D.J.; Zimmerman, B.D.

1995-05-01

The Waste Pretreatment and Interfacing Systems Dynamic Simulation Model was created to investigate the required pretreatment facility processing rates for both high level and low level waste so that the vitrification of tank waste can be completed according to the milestones defined in the Tri-Party Agreement (TPA). In order to achieve this objective, the processes upstream and downstream of the pretreatment facilities must also be included. The simulation model starts with retrieval of tank waste and ends with vitrification for both low level and high level wastes. This report describes the results of three simulation cases: one based on suggested average facility processing rates, one with facility rates determined so that approximately 6 new DSTs are required, and one with facility rates determined so that approximately no new DSTs are required. It appears, based on the simulation results, that reasonable facility processing rates can be selected so that no new DSTs are required by the TWRS program. However, this conclusion must be viewed with respect to the modeling assumptions, described in detail in the report. Also included in the report, in an appendix, are results of two sensitivity cases: one with glass plant water recycle steams recycled versus not recycled, and one employing the TPA SST retrieval schedule versus a more uniform SST retrieval schedule. Both recycling and retrieval schedule appear to have a significant impact on overall tank usage

Behavioral phenotypes of genetic mouse models of autism.

Science.gov (United States)

Kazdoba, T M; Leach, P T; Crawley, J N

2016-01-01

More than a hundred de novo single gene mutations and copy-number variants have been implicated in autism, each occurring in a small subset of cases. Mutant mouse models with syntenic mutations offer research tools to gain an understanding of the role of each gene in modulating biological and behavioral phenotypes relevant to autism. Knockout, knockin and transgenic mice incorporating risk gene mutations detected in autism spectrum disorder and comorbid neurodevelopmental disorders are now widely available. At present, autism spectrum disorder is diagnosed solely by behavioral criteria. We developed a constellation of mouse behavioral assays designed to maximize face validity to the types of social deficits and repetitive behaviors that are central to an autism diagnosis. Mouse behavioral assays for associated symptoms of autism, which include cognitive inflexibility, anxiety, hyperactivity, and unusual reactivity to sensory stimuli, are frequently included in the phenotypic analyses. Over the past 10 years, we and many other laboratories around the world have employed these and additional behavioral tests to phenotype a large number of mutant mouse models of autism. In this review, we highlight mouse models with mutations in genes that have been identified as risk genes for autism, which work through synaptic mechanisms and through the mTOR signaling pathway. Robust, replicated autism-relevant behavioral outcomes in a genetic mouse model lend credence to a causal role for specific gene contributions and downstream biological mechanisms in the etiology of autism. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Permeation of antigen protein-conjugated nanoparticles and live bacteria through microneedle-treated mouse skin

Science.gov (United States)

Kumar, Amit; Li, Xinran; Sandoval, Michael A; Rodriguez, B Leticia; Sloat, Brian R; Cui, Zhengrong

2011-01-01

Background: The present study was designed to evaluate the extent to which pretreatment with microneedles can enhance skin permeation of nanoparticles in vitro and in vivo. Permeation of live bacteria, which are physically nanoparticles or microparticles, through mouse skin pretreated with microneedles was also studied to evaluate the potential risk of microbial infection. Methods and results: It was found that pretreatment of mouse skin with microneedles allowed permeation of solid lipid nanoparticles, size 230 nm, with ovalbumin conjugated on their surface. Transcutaneous immunization in a mouse skin area pretreated with microneedles with ovalbumin nanoparticles induced a stronger antiovalbumin antibody response than using ovalbumin alone. The dose of ovalbumin antigen determined whether microneedle-mediated transcutaneous immunization with ovalbumin nanoparticles induced a stronger immune response than subcutaneous injection of the same ovalbumin nanoparticles. Microneedle treatment permitted skin permeation of live Escherichia coli, but the extent of the permeation was not greater than that enabled by hypodermic injection. Conclusion: Transcutaneous immunization on a microneedle-treated skin area with antigens carried by nanoparticles can potentially induce a strong immune response, and the risk of bacterial infection associated with microneedle treatment is no greater than that with a hypodermic injection. PMID:21753877

Delayed brain ischemia tolerance induced by electroacupuncture pretreatment is mediated via MCP-induced protein 1

Science.gov (United States)

2013-01-01

Background Emerging studies have demonstrated that pretreatment with electroacupuncture (EA) induces significant tolerance to focal cerebral ischemia. The present study seeks to determine the involvement of monocyte chemotactic protein-induced protein 1 (MCPIP1), a recently identified novel modulator of inflammatory reactions, in the cerebral neuroprotection conferred by EA pretreatment in the animal model of focal cerebral ischemia and to elucidate the mechanisms of EA pretreatment-induced ischemic brain tolerance. Methods Twenty-four hours after the end of the last EA pretreatment, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 90 minutes in male C57BL/6 mice and MCPIP1 knockout mice. Transcription and expression of MCPIP1 gene was monitored by qRT-PCR, Western blot and immunohistochemistry. The neurobehavioral scores, infarction volumes, proinflammatory cytokines and leukocyte infiltration in brain and NF-κB signaling were evaluated after ischemia/reperfusion. Results MCPIP1 protein and mRNA levels significantly increased specifically in mouse brain undergoing EA pretreatment. EA pretreatment significantly attenuated the infarct volume, neurological deficits, upregulation of proinflammatory cytokines and leukocyte infiltration in the brain of wild-type mice after MCAO compared with that of the non-EA group. MCPIP1-deficient mice failed to evoke EA pretreatment-induced tolerance compared with that of the control MCPIP1 knockout group without EA treatment. Furthermore, the activation of NF-κB signaling was significantly reduced in EA-pretreated wild-type mice after MCAO compared to that of the non-EA control group and MCPIP1-deficient mice failed to confer the EA pretreatment-induced inhibition of NF-κB signaling after MCAO. Conclusions Our data demonstrated that MCPIP1 deficiency caused significant lack of EA pretreatment-induced cerebral protective effects after MCAO compared with the control group and that MCPIP1 is

Alpha-1 antitrypsin protein and gene therapies decrease autoimmunity and delay arthritis development in mouse model

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Atkinson Mark A

2011-02-01

Full Text Available Abstract Background Alpha-1 antitrypsin (AAT is a multi-functional protein that has anti-inflammatory and tissue protective properties. We previously reported that human AAT (hAAT gene therapy prevented autoimmune diabetes in non-obese diabetic (NOD mice and suppressed arthritis development in combination with doxycycline in mice. In the present study we investigated the feasibility of hAAT monotherapy for the treatment of chronic arthritis in collagen-induced arthritis (CIA, a mouse model of rheumatoid arthritis (RA. Methods DBA/1 mice were immunized with bovine type II collagen (bCII to induce arthritis. These mice were pretreated either with hAAT protein or with recombinant adeno-associated virus vector expressing hAAT (rAAV-hAAT. Control groups received saline injections. Arthritis development was evaluated by prevalence of arthritis and arthritic index. Serum levels of B-cell activating factor of the TNF-α family (BAFF, antibodies against both bovine (bCII and mouse collagen II (mCII were tested by ELISA. Results Human AAT protein therapy as well as recombinant adeno-associated virus (rAAV8-mediated hAAT gene therapy significantly delayed onset and ameliorated disease development of arthritis in CIA mouse model. Importantly, hAAT therapies significantly reduced serum levels of BAFF and autoantibodies against bCII and mCII, suggesting that the effects are mediated via B-cells, at least partially. Conclusion These results present a new drug for arthritis therapy. Human AAT protein and gene therapies are able to ameliorate and delay arthritis development and reduce autoimmunity, indicating promising potential of these therapies as a new treatment strategy for RA.

Mouse Model of Burn Wound and Infection

DEFF Research Database (Denmark)

Calum, Henrik; Høiby, Niels; Moser, Claus

2017-01-01

The immunosuppression induced by thermal injury renders the burned victim susceptible to infection. A mouse model was developed to examine the immunosuppression, which was possible to induce even at a minor thermal insult of 6% total body surface area. After induction of the burn (48 hr) a depres......The immunosuppression induced by thermal injury renders the burned victim susceptible to infection. A mouse model was developed to examine the immunosuppression, which was possible to induce even at a minor thermal insult of 6% total body surface area. After induction of the burn (48 hr...

Evaluation of high-level waste pretreatment processes with an approximate reasoning model

International Nuclear Information System (INIS)

Bott, T.F.; Eisenhawer, S.W.; Agnew, S.F.

1999-01-01

The development of an approximate-reasoning (AR)-based model to analyze pretreatment options for high-level waste is presented. AR methods are used to emulate the processes used by experts in arriving at a judgment. In this paper, the authors first consider two specific issues in applying AR to the analysis of pretreatment options. They examine how to combine quantitative and qualitative evidence to infer the acceptability of a process result using the example of cesium content in low-level waste. They then demonstrate the use of simple physical models to structure expert elicitation and to produce inferences consistent with a problem involving waste particle size effects

Pretreatment of Mice with Oligonucleotide prop5 Protects Them from Influenza Virus Infections

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Kang Li

2014-02-01

Full Text Available Influenza A virus is a successful parasite and requires host factors to complete its life cycle. Prop5 is an antisense oligonucleotide, targeting programmed cell death protein 5 (PDCD5. In this study, we tested the antiviral activity of prop5 against mouse-adapted A/FM/1/47 strain of influenza A virus in a mouse model. Prop5 intranasally administered the mice at dosages of 10 and 20 mg/kg/d at 24 h and 30 min before infection, provided 80% and 100% survival rates and prolonged mean survival days in comparison with influenza virus-infected mice (both p < 0.01. Moreover, viral titres in mice pretreated with prop5, at dose of 10 and 20 mg/kg/d, had declined significantly on day two, four, and six post-infection compared with the yields in infected mice (p < 0.05 or p < 0.01; lung index in mice pretreated with prop5 (20 mg/kg/d had been inhibited on day six post-infection (p < 0.05. Western blotting and immunohistochemistry showed that prop5 could down-regulate the PDCD5 protein expression levels in lung tissues of infected mice. These data indicate that antisense oligonucleotide prop5 is a promising drug for prophylaxis and control influenza virus infections and provides an insight into the host-pathogen interaction.

A Mouse Model of Chronic West Nile Virus Disease.

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Jessica B Graham

2016-11-01

Full Text Available Infection with West Nile virus (WNV leads to a range of disease outcomes, including chronic infection, though lack of a robust mouse model of chronic WNV infection has precluded identification of the immune events contributing to persistent infection. Using the Collaborative Cross, a population of recombinant inbred mouse strains with high levels of standing genetic variation, we have identified a mouse model of persistent WNV disease, with persistence of viral loads within the brain. Compared to lines exhibiting no disease or marked disease, the F1 cross CC(032x013F1 displays a strong immunoregulatory signature upon infection that correlates with restraint of the WNV-directed cytolytic response. We hypothesize that this regulatory T cell response sufficiently restrains the immune response such that a chronic infection can be maintained in the CNS. Use of this new mouse model of chronic neuroinvasive virus will be critical in developing improved strategies to prevent prolonged disease in humans.

Esophageal Cancer: Insights from Mouse Models

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Marie-Pier Tétreault

2015-01-01

Full Text Available Esophageal cancer is the eighth leading cause of cancer and the sixth most common cause of cancer-related death worldwide. Despite recent advances in the development of surgical techniques in combination with the use of radiotherapy and chemotherapy, the prognosis for esophageal cancer remains poor. The cellular and molecular mechanisms that drive the pathogenesis of esophageal cancer are still poorly understood. Hence, understanding these mechanisms is crucial to improving outcomes for patients with esophageal cancer. Mouse models constitute valuable tools for modeling human cancers and for the preclinical testing of therapeutic strategies in a manner not possible in human subjects. Mice are excellent models for studying human cancers because they are similar to humans at the physiological and molecular levels and because they have a shorter gestation time and life cycle. Moreover, a wide range of well-developed technologies for introducing genetic modifications into mice are currently available. In this review, we describe how different mouse models are used to study esophageal cancer.

Using the mouse to model human disease: increasing validity and reproducibility

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Monica J. Justice

2016-02-01

Full Text Available Experiments that use the mouse as a model for disease have recently come under scrutiny because of the repeated failure of data, particularly derived from preclinical studies, to be replicated or translated to humans. The usefulness of mouse models has been questioned because of irreproducibility and poor recapitulation of human conditions. Newer studies, however, point to bias in reporting results and improper data analysis as key factors that limit reproducibility and validity of preclinical mouse research. Inaccurate and incomplete descriptions of experimental conditions also contribute. Here, we provide guidance on best practice in mouse experimentation, focusing on appropriate selection and validation of the model, sources of variation and their influence on phenotypic outcomes, minimum requirements for control sets, and the importance of rigorous statistics. Our goal is to raise the standards in mouse disease modeling to enhance reproducibility, reliability and clinical translation of findings.

The effect of antibiotics on associated bacterial community of stored product mites.

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Jan Kopecky

Full Text Available Bacteria are associated with the gut, fat bodies and reproductive organs of stored product mites (Acari: Astigmata. The mites are pests due to the production of allergens. Addition of antibiotics to diets can help to characterize the association between mites and bacteria.Ampicillin, neomycin and streptomycin were added to the diets of mites and the effects on mite population growth (Acarus siro, Lepidoglyphus destructor and Tyrophagus putrescentiae and associated bacterial community structure were assessed. Mites were treated by antibiotic supplementation (1 mg g(-1 of diet for 21 days and numbers of mites and bacterial communities were analyzed and compared to the untreated control. Bacterial quantities, determined by real-time PCR, significantly decreased in antibiotic treated specimens from 5 to 30 times in A. siro and T. putrescentiae, while no decline was observed in L. destructor. Streptomycin treatment eliminated Bartonella-like bacteria in the both A. siro and T. putrescentiae and Cardinium in T. putrescentiae. Solitalea-like bacteria proportion increased in the communities of neomycin and streptomycin treated A. siro specimens. Kocuria proportion increased in the bacterial communities of ampicillin and streptomycin treated A. siro and neomycin and streptomycin treated L. destructor.The work demonstrated the changes of mite associated bacterial community under antibiotic pressure in pests of medical importance. Pre-treatment of mites by 1 mg g(-1 antibiotic diets improved mite fitness as indicated accelerated population growth of A. siro pretreated streptomycin and neomycin and L. destructor pretreated by neomycin. All tested antibiotics supplemented to diets caused the decrease of mite growth rate in comparison to the control diet.

Effects of lithium chloride as a potential radioprotective agent on radiation response of DNA synthesis in mouse germinal cells.

Science.gov (United States)

Bhattacharjee, D; Rajan, R; Krishnamoorthy, L; Singh, B B

1997-06-01

Mouse spermatogonial germ cells are highly sensitive to ionizing radiation. Lithium salts are reported to stimulate the postirradiation recovery of hematopoietic marrow cells. We have, therefore, examined whether administered lithium chloride (LiCl) would also be able to protect the mouse germinal cells against radiation injury. Taking DNA synthesis as an endpoint, our results show that the testicular DNA-specific activity in irradiated mice was higher by 61% on average when they had been pretreated with LiCl both 24 h and 1 h prior to gamma-irradiation (2.0 Gy). It was also observed that the DNA synthetic activity in the germinal cells fully recovered after LiCl pretreatment at doses of 40 mg per kg body weight prior to total body irradiation of 0.05-0.25 Gy, whereas at doses of 0.5-6.0 Gy, following the same procedure of LiCl pretreatment, only an incomplete recovery was observed. The dose reduction factor for LiCl is 1.84. The current findings indicate that pretreatment with LiCl provides considerable protection against radiation damage in mouse spermatogonia.

Experimental photoallergic contact dermatitis: a mouse model

International Nuclear Information System (INIS)

Maguire, H.C. Jr.; Kaidbey, K.

1982-01-01

We have induced photoallergic contact dermatitis in mice to 3,3',4',5 tetrachlorosalicylanilide (TCSA), chlorpromazine and 6-methylcoumarin. These compounds are known to produce photoallergic contact dermatitis in humans. The photoallergic contact dermatitis reaction in the mouse is immunologically specific viz. mice photosensitized to TCSA react, by photochallenge, to that compound and not to chlorpromazine, and conversely. The reaction requires UVA at both sensitization and challenge. It appears to be T-cell mediated in that it can be passively transferred to syngeneic mice by lymph node cells from actively sensitized mice, the histology of the reactions resembles that of classic allergic contact dermatitis in mice, challenge reactions are seen at 24 but not at 4 hr, and photoallergic contact dermatitis can be induced in B-cell deficient mice. The availability of a mouse model for the study of photo-ACD will facilitate the identification of pertinent control mechanisms and may aid in the management of the disease. It is likely that a bioassay for photoallergens of humans can be based on this mouse model

Effect of Ampicillin, Streptomycin, Penicillin and Tetracycline on Metal Resistant and Non-Resistant Staphylococcus aureus

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Dagmar Chudobova

2014-03-01

Full Text Available There is an arising and concerning issue in the field of bacterial resistance, which is confirmed by the number of deaths associated with drug-resistant bacterial infections. The aim of this study was to compare the effects of antibiotics on Staphylococcus aureus non-resistant strain and strains resistant to cadmium or lead ions. Metal resistant strains were created by the gradual addition of 2 mM solution of metal ions (cadmium or lead to the S. aureus culture. An increasing antimicrobial effect of ampicillin, streptomycin, penicillin and tetracycline (0, 10, 25, 50, 75, 150, 225 and 300 µM on the resistant strains was observed using a method of growth curves. A significant growth inhibition (compared to control of cadmium resistant cells was observed in the presence of all the four different antibiotics. On the other hand, the addition of streptomycin and ampicillin did not inhibit the growth of lead resistant strain. Other antibiotics were still toxic to the bacterial cells. Significant differences in the morphology of cell walls were indicated by changes in the cell shape. Our data show that the presence of metal ions in the urban environment may contribute to the development of bacterial strain resistance to other substances including antibiotics, which would have an impact on public health.

Effect of Ampicillin, Streptomycin, Penicillin and Tetracycline on Metal Resistant and Non-Resistant Staphylococcus aureus

Science.gov (United States)

Chudobova, Dagmar; Dostalova, Simona; Blazkova, Iva; Michalek, Petr; Ruttkay-Nedecky, Branislav; Sklenar, Matej; Nejdl, Lukas; Kudr, Jiri; Gumulec, Jaromir; Tmejova, Katerina; Konecna, Marie; Vaculovicova, Marketa; Hynek, David; Masarik, Michal; Kynicky, Jindrich; Kizek, Rene; Adam, Vojtech

2014-01-01

There is an arising and concerning issue in the field of bacterial resistance, which is confirmed by the number of deaths associated with drug-resistant bacterial infections. The aim of this study was to compare the effects of antibiotics on Staphylococcus aureus non-resistant strain and strains resistant to cadmium or lead ions. Metal resistant strains were created by the gradual addition of 2 mM solution of metal ions (cadmium or lead) to the S. aureus culture. An increasing antimicrobial effect of ampicillin, streptomycin, penicillin and tetracycline (0, 10, 25, 50, 75, 150, 225 and 300 µM) on the resistant strains was observed using a method of growth curves. A significant growth inhibition (compared to control) of cadmium resistant cells was observed in the presence of all the four different antibiotics. On the other hand, the addition of streptomycin and ampicillin did not inhibit the growth of lead resistant strain. Other antibiotics were still toxic to the bacterial cells. Significant differences in the morphology of cell walls were indicated by changes in the cell shape. Our data show that the presence of metal ions in the urban environment may contribute to the development of bacterial strain resistance to other substances including antibiotics, which would have an impact on public health. PMID:24651395

Transgenic mouse models of hormonal mammary carcinogenesis: advantages and limitations.

Science.gov (United States)

Kirma, Nameer B; Tekmal, Rajeshwar R

2012-09-01

Mouse models of breast cancer, especially transgenic and knockout mice, have been established as valuable tools in shedding light on factors involved in preneoplastic changes, tumor development and malignant progression. The majority of mouse transgenic models develop estrogen receptor (ER) negative tumors. This is seen as a drawback because the majority of human breast cancers present an ER positive phenotype. On the other hand, several transgenic mouse models have been developed that produce ER positive mammary tumors. These include mice over-expressing aromatase, ERα, PELP-1 and AIB-1. In this review, we will discuss the value of these models as physiologically relevant in vivo systems to understand breast cancer as well as some of the pitfalls involving these models. In all, we argue that the use of transgenic models has improved our understanding of the molecular aspects and biology of breast cancer. Copyright © 2011 Elsevier Ltd. All rights reserved.

Effects of lithium chloride as a potential radioprotective agent on radiation response of DNA synthesis in mouse germinal cells

Energy Technology Data Exchange (ETDEWEB)

Bhattacharjee, D. [Radiation Biology and Biochemistry Division, Bhabha Atomic Research Centre, Mumbai 400 085 (India); Rajan, R. [Radiation Biology and Biochemistry Division, Bhabha Atomic Research Centre, Mumbai 400 085 (India); Krishnamoorthy, L. [Kidwai Memorial Institute of Oncology, Bangalore 560 029 (India); Singh, B.B. [Radiation Biology and Biochemistry Division, Bhabha Atomic Research Centre, Mumbai 400 085 (India)

1997-06-01

Mouse spermatogonial germ cells are highly sensitive to ionizing radiation. Lithium salts are reported to stimulate the postirradiation recovery of hematopoietic marrow cells. We have, therefore, examined whether administered lithium chloride (LiCl) would also be able to protect the mouse germinal cells against radiation injury. Taking DNA synthesis as an endpoint, our results show that the testicular DNA-specific activity in irradiated mice was higher by 61% on average when they had been pretreated with LiCl both 24 h and 1 h prior to {gamma}-irradiation (2.0 Gy). It was also observed that the DNA synthetic activity in the germinal cells fully recovered after LiCl pretreatment at doses of 40 mg per kg body weight prior to total body irradiation of 0.05-0.25 Gy, whereas at doses of 0.5-6.0 Gy, following the same procedure of LiCl pretreatment, only an incomplete recovery was observed. The dose reduction factor for LiCl is 1.84. The current findings indicate that pretreatment with LiCl provides considerable protection against radiation damage in mouse spermatogonia. (orig.). With 3 tabs.

A metabolomic comparison of mouse models of the Neuronal Ceroid Lipofuscinoses

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Salek, Reza M.; Pears, Michael R. [University of Cambridge, Department of Biochemistry and Cambridge Systems Biology Centre (United Kingdom); Cooper, Jonathan D. [King' s College London, Pediatric Storage Disorders Laboratory, Department of Neuroscience, Institute of Psychiatry (United Kingdom); Mitchison, Hannah M. [Royal Free and University College Medical School, Department of Paediatrics and Child Health (United Kingdom); Pearce, David A. [Sanford School of Medicine of the University of South Dakota, Department of Pediatrics (United States); Mortishire-Smith, Russell J. [Johnson and Johnson PR and D (Belgium); Griffin, Julian L., E-mail: jlg40@mole.bio.cam.ac.uk [University of Cambridge, Department of Biochemistry and the Cambridge Systems Biology Centre (United Kingdom)

2011-04-15

The Neuronal Ceroid Lipofuscinoses (NCL) are a group of fatal inherited neurodegenerative diseases in humans distinguished by a common clinical pathology, characterized by the accumulation of storage body material in cells and gross brain atrophy. In this study, metabolic changes in three NCL mouse models were examined looking for pathways correlated with neurodegeneration. Two mouse models; motor neuron degeneration (mnd) mouse and a variant model of late infantile NCL, termed the neuronal ceroid lipofuscinosis (nclf) mouse were investigated experimentally. Both models exhibit a characteristic accumulation of autofluorescent lipopigment in neuronal and non neuronal cells. The NMR profiles derived from extracts of the cortex and cerebellum from mnd and nclf mice were distinguished according to disease/wildtype status. In particular, a perturbation in glutamine and glutamate metabolism, and a decrease in {gamma}-amino butyric acid (GABA) in the cerebellum and cortices of mnd (adolescent mice) and nclf mice relative to wildtype at all ages were detected. Our results were compared to the Cln3 mouse model of NCL. The metabolism of mnd mice resembled older (6 month) Cln3 mice, where the disease is relatively advanced, while the metabolism of nclf mice was more akin to younger (1-2 months) Cln3 mice, where the disease is in its early stages of progression. Overall, our results allowed the identification of metabolic traits common to all NCL subtypes for the three animal models.

A metabolomic comparison of mouse models of the Neuronal Ceroid Lipofuscinoses

International Nuclear Information System (INIS)

Salek, Reza M.; Pears, Michael R.; Cooper, Jonathan D.; Mitchison, Hannah M.; Pearce, David A.; Mortishire-Smith, Russell J.; Griffin, Julian L.

2011-01-01

The Neuronal Ceroid Lipofuscinoses (NCL) are a group of fatal inherited neurodegenerative diseases in humans distinguished by a common clinical pathology, characterized by the accumulation of storage body material in cells and gross brain atrophy. In this study, metabolic changes in three NCL mouse models were examined looking for pathways correlated with neurodegeneration. Two mouse models; motor neuron degeneration (mnd) mouse and a variant model of late infantile NCL, termed the neuronal ceroid lipofuscinosis (nclf) mouse were investigated experimentally. Both models exhibit a characteristic accumulation of autofluorescent lipopigment in neuronal and non neuronal cells. The NMR profiles derived from extracts of the cortex and cerebellum from mnd and nclf mice were distinguished according to disease/wildtype status. In particular, a perturbation in glutamine and glutamate metabolism, and a decrease in γ-amino butyric acid (GABA) in the cerebellum and cortices of mnd (adolescent mice) and nclf mice relative to wildtype at all ages were detected. Our results were compared to the Cln3 mouse model of NCL. The metabolism of mnd mice resembled older (6 month) Cln3 mice, where the disease is relatively advanced, while the metabolism of nclf mice was more akin to younger (1-2 months) Cln3 mice, where the disease is in its early stages of progression. Overall, our results allowed the identification of metabolic traits common to all NCL subtypes for the three animal models.

Permeation of antigen protein-conjugated nanoparticles and live bacteria through microneedle-treated mouse skin

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Kumar A

2011-06-01

Full Text Available Amit Kumar, Xinran Li, Michael A Sandoval, B Leticia Rodriguez, Brian R Sloat, Zhengrong CuiUniversity of Texas at Austin, College of Pharmacy, Pharmaceutics Division, Austin, TX, USABackground: The present study was designed to evaluate the extent to which pretreatment with microneedles can enhance skin permeation of nanoparticles in vitro and in vivo. Permeation of live bacteria, which are physically nanoparticles or microparticles, through mouse skin pretreated with microneedles was also studied to evaluate the potential risk of microbial infection.Methods and results: It was found that pretreatment of mouse skin with microneedles allowed permeation of solid lipid nanoparticles, size 230 nm, with ovalbumin conjugated on their surface. Transcutaneous immunization in a mouse skin area pretreated with microneedles with ovalbumin nanoparticles induced a stronger antiovalbumin antibody response than using ovalbumin alone. The dose of ovalbumin antigen determined whether microneedle-mediated transcutaneous immunization with ovalbumin nanoparticles induced a stronger immune response than subcutaneous injection of the same ovalbumin nanoparticles. Microneedle treatment permitted skin permeation of live Escherichia coli, but the extent of the permeation was not greater than that enabled by hypodermic injection.Conclusion: Transcutaneous immunization on a microneedle-treated skin area with antigens carried by nanoparticles can potentially induce a strong immune response, and the risk of bacterial infection associated with microneedle treatment is no greater than that with a hypodermic injection.Keywords: antibody responses, safety of microneedles, transepidermal water loss

Anti-colitis and -adhesion effects of daikenchuto via endogenous adrenomedullin enhancement in Crohn's disease mouse model.

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Kono, Toru; Kaneko, Atsushi; Hira, Yoshiki; Suzuki, Tatsuya; Chisato, Naoyuki; Ohtake, Nobuhiro; Miura, Naoko; Watanabe, Tsuyoshi

2010-06-01

Adrenomedullin (ADM) is a member of the calcitonin family of regulatory peptides, and is reported to have anti-inflammatory effects in animal models of Crohn's disease (CD). We investigated the therapeutic effects of daikenchuto (DKT), an extracted Japanese herbal medicine, on the regulation of endogenous ADM in the gastrointestinal tract in a CD mouse model. Colitis was induced in mice by intrarectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS); afterwards, DKT was given orally. Colonic damage was assessed on day 3 by macroscopic and microscopic observation, enzyme immunoassays of proinflammatory cytokines in the colonic mucosa, and serum amyloid A (SAA), a hepatic acute-phase protein. To determine the involvement of ADM, an ADM antagonist was instilled intrarectally before DKT administration. The effect of DKT on ADM production by intestinal epithelial cells was evaluated by enzyme immunoassay and real-time PCR. DKT significantly attenuated mucosal damage and colonic inflammatory adhesions, and inhibited elevations of SAA in plasma and the proinflammatory cytokines TNFα and IFNγ in the colon. Small and large intestinal epithelial cells produced higher levels of ADM after DKT stimulation. A DKT-treated IEC-6 cell line also showed enhanced ADM production at protein and mRNA levels. Abolition of this effect by pretreatment with an ADM antagonist shows that DKT appears to exert its anti-colitis effect via up-regulation of endogenous ADM in the intestinal tract. DKT exerts beneficial effects in a CD mouse model through endogenous release and production of ADM. Endogenous ADM may be a therapeutic target for CD. Copyright © 2009 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

A single cell model for pretreatment of wood by microwave explosion

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Xianjun Li; Yongdong Zhou; Yonglin Yan; Zhiyong Cai; Fu Feng

2010-01-01

A theoretical model was developed to better understand the process of microwave explosion treatment of wood cells. The cell expansion and critical conditions concerning pressure and temperature of ray parenchyma cells in Eucalyptus urophylla were simulated during microwave pretreatment. The results indicate that longitudinal and circumferential stresses were generated...

Humanized mouse models: Application to human diseases.

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Ito, Ryoji; Takahashi, Takeshi; Ito, Mamoru

2018-05-01

Humanized mice are superior to rodents for preclinical evaluation of the efficacy and safety of drug candidates using human cells or tissues. During the past decade, humanized mouse technology has been greatly advanced by the establishment of novel platforms of genetically modified immunodeficient mice. Several human diseases can be recapitulated using humanized mice due to the improved engraftment and differentiation capacity of human cells or tissues. In this review, we discuss current advanced humanized mouse models that recapitulate human diseases including cancer, allergy, and graft-versus-host disease. © 2017 Wiley Periodicals, Inc.

Mouse models of estrogen receptor-positive breast cancer

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Shakur Mohibi

2011-01-01

Full Text Available Breast cancer is the most frequent malignancy and second leading cause of cancer-related deaths among women. Despite advances in genetic and biochemical analyses, the incidence of breast cancer and its associated mortality remain very high. About 60 - 70% of breast cancers are Estrogen Receptor alpha (ER-α positive and are dependent on estrogen for growth. Selective estrogen receptor modulators (SERMs have therefore provided an effective targeted therapy to treat ER-α positive breast cancer patients. Unfortunately, development of resistance to endocrine therapy is frequent and leads to cancer recurrence. Our understanding of molecular mechanisms involved in the development of ER-α positive tumors and their resistance to ER antagonists is currently limited due to lack of experimental models of ER-α positive breast cancer. In most mouse models of breast cancer, the tumors that form are typically ER-negative and independent of estrogen for their growth. However, in recent years more attention has been given to develop mouse models that develop different subtypes of breast cancers, including ER-positive tumors. In this review, we discuss the currently available mouse models that develop ER-α positive mammary tumors and their potential use to elucidate the molecular mechanisms of ER-α positive breast cancer development and endocrine resistance.

Ethanol induced antidepressant-like effect in the mouse forced swimming test: modulation by serotonergic system.

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Jain, Nishant S; Kannamwar, Uday; Verma, Lokesh

2017-02-01

The present investigation explored the modulatory role of serotonergic transmission in the acute ethanol-induced effects on immobility time in the mouse forced swim test (FST). Acute i.p. administration of ethanol (20% w/v, 2 or 2.5 g/kg, i.p.) decreased the immobility time in FST of mice, indicating its antidepressant-like effect while lower doses of ethanol (1, 1.5 g/kg, i.p.) were devoid of any effect in the FST. The mice pre-treated with a sub-effective dose of 5-HT 2A agonist, DOI (10 μg/mouse, i.c.v.) or 5-HT 1A receptor antagonist, WAY 100635 (0.1 μg/mouse, i.c.v.) but not with the 5-HT 2A/2C antagonist, ketanserin (1.5 μg/mouse, i.c.v.) exhibited a synergistic reduction in the immobility time induced by sub-effective dose of ethanol (1.5 g/kg, i.p.). On the other hand, ethanol (2.5 g/kg, i.p.) failed to decrease the immobility time in mice, pre-treated with 5-HT 1A agonist, 8-OH-DPAT (0.1 μg/mouse, i.c.v.) or ketanserin (1.5 μg/mouse, i.c.v.). In addition, pre-treatment with a 5-HT neuronal synthesis inhibitor, p-CPA (300 mg/kg, i.p. × 3 days) attenuated the anti-immobility effect ethanol (2.5 g/kg, i.p.) in mouse FST. Thus, the results of the present study points towards the essentiality of the central 5-HT transmission at the synapse for the ethanol-induced antidepressant-like effect in the FST wherein the regulatory role of the 5-HT 1A receptor or contributory role of the 5-HT 2A/2C receptor-mediated mechanism is proposed in the anti-immobility effect of acute ethanol in mouse FST.

Microwave pretreatment of switchgrass for bioethanol production

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Keshwani, Deepak Radhakrishin

conditions, 82% glucose and 63% xylose yields were achieved for switchgrass, and 87% glucose and 59% xylose yields were achieved for coastal bermudagrass following enzymatic hydrolysis of the pretreated biomass. The optimum enzyme loadings were 15 FPU/g and 20 CBU/g for switchgrass and 10 FPU/g and 20 CBU/g for coastal bermudagrass. Dielectric properties for dilute sodium hydroxide solutions were measured and compared to solid loss, lignin reduction and reducing sugar levels in hydrolyzates. Results indicate that the dielectric loss tangent of alkali solutions is a potential indicator of the severity of microwave-based pretreatments. Modeling of pretreatment processes can be a valuable tool in process simulations of bioethanol production from lignocellulosic biomass. Chapter 4 discusses three different approaches that were used to model delignification and carbohydrate loss during microwave-based pretreatment of switchgrass: statistical linear regression modeling, kinetic modeling using a time-dependent rate coefficient, and a Mamdani-type fuzzy inference system. The dielectric loss tangent of the alkali reagent and pretreatment time were used as predictors in all models. The statistical linear regression model for delignification gave comparable root mean square error (RMSE) values for training and testing data and predictions were approximately within 1% of experimental values. The kinetic model for delignification and xylan loss gave comparable RMSE values for training and testing data sets and predictions were approximately within 2% of experimental values. The kinetic model for cellulose loss was not as effective and predictions were only within 5-7% of experimental values. The time-dependent rate coefficients of the kinetic models calculated from experimental data were consistent with the heterogeneity (or lack thereof) of individual biomass components. The Mamdani-type fuzzy inference system was shown to be an effective means to model pretreatment processes and gave

Regulatory Forum commentary: alternative mouse models for future cancer risk assessment.

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Morton, Daniel; Sistare, Frank D; Nambiar, Prashant R; Turner, Oliver C; Radi, Zaher; Bower, Nancy

2014-07-01

International regulatory and pharmaceutical industry scientists are discussing revision of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) S1 guidance on rodent carcinogenicity assessment of small molecule pharmaceuticals. A weight-of-evidence approach is proposed to determine the need for rodent carcinogenicity studies. For compounds with high human cancer risk, the product may be labeled appropriately without conducting rodent carcinogenicity studies. For compounds with minimal cancer risk, only a 6-month transgenic mouse study (rasH2 mouse or p53+/- mouse) or a 2-year mouse study would be needed. If rodent carcinogenicity testing may add significant value to cancer risk assessment, a 2-year rat study and either a 6-month transgenic mouse or a 2-year mouse study is appropriate. In many cases, therefore, one rodent carcinogenicity study could be sufficient. The rasH2 model predicts neoplastic findings relevant to human cancer risk assessment as well as 2-year rodent models, produces fewer irrelevant neoplastic outcomes, and often will be preferable to a 2-year rodent study. Before revising ICH S1 guidance, a prospective evaluation will be conducted to test the proposed weight-of-evidence approach. This evaluation offers an opportunity for a secondary analysis comparing the value of alternative mouse models and 2-year rodent studies in the proposed ICH S1 weight-of-evidence approach for human cancer risk assessment. © 2014 by The Author(s).

Mouse models of long QT syndrome

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Salama, Guy; London, Barry

2007-01-01

Congenital long QT syndrome is a rare inherited condition characterized by prolongation of action potential duration (APD) in cardiac myocytes, prolongation of the QT interval on the surface electrocardiogram (ECG), and an increased risk of syncope and sudden death due to ventricular tachyarrhythmias. Mutations of cardiac ion channel genes that affect repolarization cause the majority of the congenital cases. Despite detailed characterizations of the mutated ion channels at the molecular level, a complete understanding of the mechanisms by which individual mutations may lead to arrhythmias and sudden death requires study of the intact heart and its modulation by the autonomic nervous system. Here, we will review studies of molecularly engineered mice with mutations in the genes (a) known to cause long QT syndrome in humans and (b) specific to cardiac repolarization in the mouse. Our goal is to provide the reader with a comprehensive overview of mouse models with long QT syndrome and to emphasize the advantages and limitations of these models. PMID:17038432

Defining the role of polyamines in colon carcinogenesis using mouse models

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Natalia A Ignatenko

2011-01-01

Full Text Available Genetics and diet are both considered important risk determinants for colorectal cancer, a leading cause of death in the US and worldwide. Genetically engineered mouse (GEM models have made a significant contribution to the characterization of colorectal cancer risk factors. Reliable, reproducible, and clinically relevant animal models help in the identification of the molecular events associated with disease progression and in the development of effictive treatment strategies. This review is focused on the use of mouse models for studying the role of polyamines in colon carcinogenesis. We describe how the available mouse models of colon cancer such as the multiple intestinal neoplasia (Min mice and knockout genetic models facilitate understanding of the role of polyamines in colon carcinogenesis and help in the development of a rational strategy for colon cancer chemoprevention.

Streptomycin, Schatz v. Waksman, and the balance of credit for discovery.

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Kingston, William

2004-07-01

A recent article in Nature, arguing that "the misallocation of credit is endemic in science," used Selman Waksman as an illustration, claiming that the true discoverer of streptomycin was one of his graduate students. The article received wide publicity and seriously damaged Waksman's great reputation. What actually happened was that the success of penicillin stimulated Merck to fund research by Waksman, a soil scientist, into the collection of actinomycetes that he had assembled over thirty years. He applied the systematic, uncreative testing techniques that had made the German pharmaceutical industry so successful to these, and streptomycin was discovered within a matter of months. Work in the Mayo Institute then showed that it was marvelously effective against tuberculosis, and Waksman received the Nobel Prize for it in 1952. The test that turned out to be the crucial one could have been carried out by any of several students, but the lucky one was Albert Schatz. He then sued the university for a share of the royalties payable by Merck and also petitioned the Nobel committee to include him in the award. Although he obtained a very substantial out-of-court settlement, this probably damaged his subsequent academic career, and he has never ceased to argue his case for recognition, of which the Nature article is a reflection. To claim that Waksman took credit properly due to Schatz is to fail to understand that once pharmaceutical research had become primarily a matter of large-scale, routine testing, little individual creativity was left in this work. Credit for any successful results must therefore be given to whoever is the originator or director of a particular program. Nature refused to publish evidence that this case could not be used as an example of misallocation of credit for discovery. This in itself illustrates that editors of scientific journals should be every bit as mindful of scientists' reputations as they are of scientific facts.

Mass spectrometry analysis of hepcidin peptides in experimental mouse models.

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Harold Tjalsma

Full Text Available The mouse is a valuable model for unravelling the role of hepcidin in iron homeostasis, however, such studies still report hepcidin mRNA levels as a surrogate marker for bioactive hepcidin in its pivotal function to block ferroportin-mediated iron transport. Here, we aimed to assess bioactive mouse Hepcidin-1 (Hep-1 and its paralogue Hepcidin-2 (Hep-2 at the peptide level. To this purpose, Fourier transform ion cyclotron resonance (FTICR and tandem-MS was used for hepcidin identification, after which a time-of-flight (TOF MS-based methodology was exploited to routinely determine Hep-1 and -2 levels in mouse serum and urine. This method was biologically validated by hepcidin assessment in: i 3 mouse strains (C57Bl/6; DBA/2 and BABL/c upon stimulation with intravenous iron and LPS, ii homozygous Hfe knock out, homozygous transferrin receptor 2 (Y245X mutated mice and double affected mice, and iii mice treated with a sublethal hepatotoxic dose of paracetamol. The results showed that detection of Hep-1 was restricted to serum, whereas Hep-2 and its presumed isoforms were predominantly present in urine. Elevations in serum Hep-1 and urine Hep-2 upon intravenous iron or LPS were only moderate and varied considerably between mouse strains. Serum Hep-1 was decreased in all three hemochromatosis models, being lowest in the double affected mice. Serum Hep-1 levels correlated with liver hepcidin-1 gene expression, while acute liver damage by paracetamol depleted Hep-1 from serum. Furthermore, serum Hep-1 appeared to be an excellent indicator of splenic iron accumulation. In conclusion, Hep-1 and Hep-2 peptide responses in experimental mouse agree with the known biology of hepcidin mRNA regulators, and their measurement can now be implemented in experimental mouse models to provide novel insights in post-transcriptional regulation, hepcidin function, and kinetics.

Modelling the Thin-Layer Drying Kinetics of Untreated and Blanch-Osmotic Pre-treated Tomato Slices

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Samuel Enahoro Agarry

2016-10-01

Full Text Available The objective of this study was to investigate the effect of pre-treatment and drying temperature on the drying kinetics and nutritional quality of tomato (Lycopersicon esculantum L. under hot air drying. Tomato samples were blanched at 80oC and osmotically dehydrated using 20% w/w sodium chloride solutions at 30oC for 20 min. The blanch-osmotic pre-treated and untreated tomato slices were dried at temperature of 40, 50, 60, 70 and 80oC, respectively in a hot air-dryer. The results showed that blanch-osmotic pre-treatment offered a higher drying rate and lower or faster drying time than untreated condition. The tomato drying regime was characteristically in the constant and falling rate period. The tomato drying rate curve showed characteristics of porous hygroscopic solids. The optimum drying temperature for tomato was found to be 60oC. Four semi-empirical drying models of Newton, Page, Henderson and Pabis, and Logarithmic were fitted to the drying data using non-linear regression analysis. The most appropriate model was selected using the coefficient of determination (R2 and root mean square error (RMSE. The Page model has shown a better fit to the drying kinetics data of tomato in comparison with other tested models. Transport of moisture during drying was described by Fick’s diffusion model application and the effective moisture diffusivity (Deff thus estimated. The Deff at 60oC was 4.43 × 10-11m2/s and 6.33 × 10-11m2/s for blanch-osmotic pre-treated and untreated tomato slices, respectively.

L-carnitine pretreatment protects slow-twitch skeletal muscles in a rat model of ischemia-reperfusion injury.

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Demirel, Mert; Kaya, Burak; Cerkez, Cem; Ertunc, Mert; Sara, Yildirim

2013-10-01

Ischemia-reperfusion (I/R) injury negatively affects the outcome of surgical interventions for amputated or severely traumatized extremities. This study aimed to evaluate the protective role of l-carnitine on the contractile properties of fast-twitch (extensor digitorum longus [EDL]) and slow-twitch (soleus [SOL]) skeletal muscles following I/R-induced injury in a rat model. Rats were divided into 4 groups (1) saline pretreatment, (2) l-carnitine pretreatment, (3) saline pretreatment and I/R, and (4) l-carnitine pretreatment and I/R. Twitch and tetanic contractions in the EDL and SOL muscles in each group were recorded. Additionally, a fatigue protocol was performed in these muscles. Twitch and tetanic contraction amplitudes were lower in the EDL and SOL muscles in which I/R was induced (P contraction amplitude in the SOL muscles following I/R (P muscles. l-Carnitine pretreatment did not alter the fatigue response in any of the muscles.

Mouse Models as Predictors of Human Responses: Evolutionary Medicine.

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Uhl, Elizabeth W; Warner, Natalie J

Mice offer a number of advantages and are extensively used to model human diseases and drug responses. Selective breeding and genetic manipulation of mice have made many different genotypes and phenotypes available for research. However, in many cases, mouse models have failed to be predictive. Important sources of the prediction problem have been the failure to consider the evolutionary basis for species differences, especially in drug metabolism, and disease definitions that do not reflect the complexity of gene expression underlying disease phenotypes. Incorporating evolutionary insights into mouse models allow for unique opportunities to characterize the effects of diet, different gene expression profiles, and microbiomics underlying human drug responses and disease phenotypes.

From penicillin-streptomycin to amikacin-vancomycin: antibiotic decontamination of cardiovascular homografts in Singapore.

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Wee Ling Heng

Full Text Available BACKGROUND: In February 2012, the National Cardiovascular Homograft Bank (NCHB became the first tissue bank outside of North America to receive accreditation from the American Association of Tissue Banks. From 2008 to 2009, NCHB had been decontaminating its cardiovascular homografts with penicillin and streptomycin. The antibiotic decontamination protocol was changed in January 2010 as amikacin and vancomycin were recommended, in order to cover bacteria isolated from post-recovery and post- antibiotic incubation tissue cultures. AIM: The objective of this study is to determine the optimal incubation conditions for decontamination of homografts by evaluating the potencies of amikacin and vancomycin in different incubation conditions. Retrospective reviews of microbiological results were also performed for homografts recovered from 2008 to 2012, to compare the effectiveness of penicillin-streptomycin versus the amikacin-vancomycin regimens. METHODS: Based on microbiological assays stated in United States Pharmacopeia 31, potency of amikacin was evaluated by turbidimetric assay using Staphylococcus aureus, while vancomycin was by diffusion assay using Bacillus subtilis sporulate. Experiments were performed to investigate the potencies of individual antibiotic 6-hours post incubation at 4°C and 37°C and 4°C for 24 hours, after the results suggested that amikacin was more potent at lower temperature. FINDINGS: Tissue incubation at 4°C for 24 hours is optimal for both antibiotics, especially for amikacin, as its potency falls drastically at 37°C. CONCLUSION: The decontamination regimen of amikacin-vancomycin at 4°C for 24 hours is effective. Nevertheless, it is imperative to monitor microbiological trends closely and evaluate the efficacy of current antibiotics regimen against emerging strains of micro-organisms.

Simple and rapid method on High Performance Liquid Chromatography for simultaneous determination of benzylpenicillin potassium, streptomycin sulphate and related substances in Ascomicin – a veterinary use ointment

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Neagu Maria

2015-06-01

Full Text Available A new simple, rapid, accurate and precise High – Performance Liquid Chromatography (HPLC method for determination of benzylpenicillin potassium and streptomycin sulphate in Ascomicin ointment was developed and validated. The method can be used for the detection and quantification of known and unknown impurities and degradation products in this pharmaceutical product during routine analysis and also for stability studies in view of its capability to separate degradation products. The method was validated for accuracy, precision, specificity, robustness and quantification limits according to ICH Guidelines. The estimation of benzylpenicillin potassium and streptomycin sulphate was done by Waters HPLC 2695. The chromatographic conditions comprised a reverse-phased C18 column (5 µm particle size, 250 mm×4.6 mm i.d. with a mobile phase consisting of a mixture of solution in water containing 0.025 M of sodium phosphate dibasic and 0.02 of sodium hexansulfonate adjusted to pH 6.0 with 22.5 g/lsolution of phosphoric acid and acetonitrile in gradient elution. The flow rate was 0.8 ml/min. Standard curves were linear over the concentration range of 5.00 µg/ml to 5.00 mg/ml for streptomycin sulphate and 3.26 µg/ml to 3.26 mg/ml for benzylpenicillin potassium. Statistical analyses proved the method was precise, reproducible, selective, specific and accurate for analysis of benzylpenicillin potassium, streptomycin sulphate and related substances.

Mouse models for gastric cancer: Matching models to biological questions

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Poh, Ashleigh R; O'Donoghue, Robert J J

2016-01-01

Abstract Gastric cancer is the third leading cause of cancer‐related mortality worldwide. This is in part due to the asymptomatic nature of the disease, which often results in late‐stage diagnosis, at which point there are limited treatment options. Even when treated successfully, gastric cancer patients have a high risk of tumor recurrence and acquired drug resistance. It is vital to gain a better understanding of the molecular mechanisms underlying gastric cancer pathogenesis to facilitate the design of new‐targeted therapies that may improve patient survival. A number of chemically and genetically engineered mouse models of gastric cancer have provided significant insight into the contribution of genetic and environmental factors to disease onset and progression. This review outlines the strengths and limitations of current mouse models of gastric cancer and their relevance to the pre‐clinical development of new therapeutics. PMID:26809278

Histologic scoring of gastritis and gastric cancer in mouse models.

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Rogers, Arlin B

2012-01-01

Histopathology is a defining endpoint in mouse models of experimental gastritis and gastric adenocarcinoma. Presented here is an overview of the histology of gastritis and gastric cancer in mice experimentally infected with Helicobacter pylori or H. felis. A modular histopathologic scoring scheme is provided that incorporates relevant disease-associated changes. Whereas the guide uses Helicobacter infection as the prototype challenge, features may be applied to chemical and genetically engineered mouse models of stomach cancer as well. Specific criteria included in the combined gastric histologic activity index (HAI) include inflammation, epithelial defects, oxyntic atrophy, hyperplasia, pseudopyloric metaplasia, and dysplasia or neoplasia. Representative photomicrographs accompany descriptions for each lesion grade. Differentiation of genuine tumor invasion from pseudoinvasion is highlighted. A brief comparison of normal rodent versus human stomach anatomy and physiology is accompanied by an introduction to mouse-specific lesions including mucous metaplasia and eosinophilic droplets (hyalinosis). In conjunction with qualified pathology support, this guide is intended to assist research scientists, postdoctoral fellows, graduate students, and medical professionals from affiliated disciplines in the interpretation and histologic grading of chronic gastritis and gastric carcinoma in mouse models.

Soaking assisted thermal pretreatment of cassava peels wastes for fermentable sugar production: Process modelling and optimization

International Nuclear Information System (INIS)

Aruwajoye, Gabriel S.; Faloye, Funmilayo D.; Kana, Evariste Gueguim

2017-01-01

Highlights: • Soaking Assisted Thermal Pretreatment (SATP) of Cassava Peels’ waste is reported. • Maximum fermentable sugar of 0.93 g/g and 90.90% sugar recovery was achieved. • This technique gave a 31% sugar yield improvement over enzymatic pretreatment. • SEM and FTIR analysis confirms the efficiency of SATP. - Abstract: This study reports a hybrid pretreatment strategy for optimum fermentable sugar (FS) release from cassava peels waste. The Response Surface design method was used to investigate the effect of soaking temperature, soaking duration, autoclave duration, acid concentration and solid loading on reducing sugar yield. The model gave a coefficient of determination (R 2 ) of 0.87. The optimum pretreatment conditions of 69.62 °C soaking temperature, 2.57 h soaking duration, 5 min autoclave duration, 3.68 v/v acid concentration and 9.65% w/v solid loading were obtained. Maximum reducing sugar of 89.80 ± 2.87 g/L corresponding to a fermentable sugar yield of 0.93 ± 0.03 g/g cassava peels was achieved upon model validation. A percentage sugar recovery of 90.79% was achieved with a 31% improvement in the FS yield from the enzyme pretreatment. The combined severity factor (CSF) of 0.77 and the low concentration of inhibitory compounds achieved further demonstrates the efficiency of this technique.

Development of a Representative Mouse Model with Nonalcoholic Steatohepatitis.

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Verbeek, Jef; Jacobs, Ans; Spincemaille, Pieter; Cassiman, David

2016-06-01

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the Western world. It represents a disease spectrum ranging from isolated steatosis to non-alcoholic steatohepatitis (NASH). In particular, NASH can evolve to fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. The development of novel treatment strategies is hampered by the lack of representative NASH mouse models. Here, we describe a NASH mouse model, which is based on feeding non-genetically manipulated C57BL6/J mice a 'Western style' high-fat/high-sucrose diet (HF-HSD). HF-HSD leads to early obesity, insulin resistance, and hypercholesterolemia. After 12 weeks of HF-HSD, all mice exhibit the complete spectrum of features of NASH, including steatosis, hepatocyte ballooning, and lobular inflammation, together with fibrosis in the majority of mice. Hence, this model closely mimics the human disease. Implementation of this mouse model will lead to a standardized setup for the evaluation of (i) underlying mechanisms that contribute to the progression of NAFLD to NASH, and (ii) therapeutic interventions for NASH. © 2016 by John Wiley & Sons, Inc. Copyright © 2016 John Wiley & Sons, Inc.

Anticonvulsant profile of a balanced ketogenic diet in acute mouse seizure models.

Science.gov (United States)

Samala, Ramakrishna; Willis, Sarah; Borges, Karin

2008-10-01

Anticonvulsant effects of the ketogenic diet (KD) have been reported in the mouse, although previous studies did not control for intake of vitamins, minerals and antioxidants. The aim of this study was to examine the effects of balanced ketogenic and control diets in acute mouse seizure models. The behavior in four mouse seizure models, plasma d-beta-hydroxybutyrate (d-BHB) and glucose levels were determined after feeding control diet, 4:1 and 6:1 KDs with matched vitamins, minerals and antioxidants. Feeding 4:1 and 6:1 KDs ad lib to 3-week-old (adolescent) mice resulted in 1.2-2.2mM d-BHB in plasma, but did not consistently change glucose levels. The 6:1 KD reproducibly elevated the CC50 (current that initiates seizures in 50% mice tested) in the 6-Hz model after 14 days of feeding to adolescent CD1 mice. Higher plasma d-BHB levels correlated with anticonvulsant effects. Despite ketosis, no consistent anticonvulsant effects of KDs were found in the fluorothyl or pentylenetetrazole CD1 mouse models. The 4:1 KD was neither anticonvulsant nor neuroprotective in hippocampus in the C3H mouse kainate model. Taken together, the KD's anticonvulsant effect was limited to the 6-Hz model, required chronic feeding with 6:1 fat content, and was independent from lowering plasma glucose.

The STR/ort mouse model of spontaneous osteoarthritis - an update.

Science.gov (United States)

Staines, K A; Poulet, B; Wentworth, D N; Pitsillides, A A

2017-06-01

Osteoarthritis is a degenerative joint disease and a world-wide healthcare burden. Characterized by cartilage degradation, subchondral bone thickening and osteophyte formation, osteoarthritis inflicts much pain and suffering, for which there are currently no disease-modifying treatments available. Mouse models of osteoarthritis are proving critical in advancing our understanding of the underpinning molecular mechanisms. The STR/ort mouse is a well-recognized model which develops a natural form of osteoarthritis very similar to the human disease. In this Review we discuss the use of the STR/ort mouse in understanding this multifactorial disease with an emphasis on recent advances in its genetics and its bone, endochondral and immune phenotypes. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Decerebrate mouse model for studies of the spinal cord circuits

DEFF Research Database (Denmark)

Meehan, Claire Francesca; Mayr, Kyle A; Manuel, Marin

2017-01-01

The adult decerebrate mouse model (a mouse with the cerebrum removed) enables the study of sensory-motor integration and motor output from the spinal cord for several hours without compromising these functions with anesthesia. For example, the decerebrate mouse is ideal for examining locomotor be......, which is ample time to perform most short-term procedures. These protocols can be modified for those interested in cardiovascular or respiratory function in addition to motor function and can be performed by trainees with some previous experience in animal surgery....

Mathematical modeling of drying of pretreated and untreated pumpkin.

Science.gov (United States)

Tunde-Akintunde, T Y; Ogunlakin, G O

2013-08-01

In this study, drying characteristics of pretreated and untreated pumpkin were examined in a hot-air dryer at air temperatures within a range of 40-80 °C and a constant air velocity of 1.5 m/s. The drying was observed to be in the falling-rate drying period and thus liquid diffusion is the main mechanism of moisture movement from the internal regions to the product surface. The experimental drying data for the pumpkin fruits were used to fit Exponential, General exponential, Logarithmic, Page, Midilli-Kucuk and Parabolic model and the statistical validity of models tested were determined by non-linear regression analysis. The Parabolic model had the highest R(2) and lowest χ(2) and RMSE values. This indicates that the Parabolic model is appropriate to describe the dehydration behavior for the pumpkin.

The Event Coordination Notation: Behaviour Modelling Beyond Mickey Mouse

DEFF Research Database (Denmark)

Jepsen, Jesper; Kindler, Ekkart

2015-01-01

The Event Coordination Notation (ECNO) allows modelling the desired behaviour of a software system on top of any object-oriented software. Together with existing technologies from Model-based Software Engineering (MBSE) for automatically generating the software for the structural parts, ECNO allows...... special aspect of ECNO or another; and it would be fair to call them “Mickey Mouse examples”. In this paper, we give a concise overview of the motivation, ideas, and concepts of ECNO. More importantly, we discuss a larger system, which was completely generated from the underlying models: a workflow...... management system. This way, we demonstrate that ECNO can be used for modelling software beyond the typical Mickey Mouse examples. This example demonstrates that the essence of workflow management – including its behaviour – can be captured in ECNO: in a sense, it is a domain model of workflow management...

Genetically engineered Lactococcus lactis protect against house dust mite allergy in a BALB/c mouse model.

Directory of Open Access Journals (Sweden)

Chunqing Ai

Full Text Available Mucosal vaccine based on lactic acid bacteria is an attractive concept for the prevention and treatment of allergic diseases, but their mechanisms of action in vivo are poorly understood. Therefore, we sought to investigate how recombinant major dust mite allergen Der p2-expressing Lactococcus lactis as a mucosal vaccine induced the immune tolerance against house dust mite allergy in a mouse model.Three strains of recombinant L. lactis producing Der p2 in different cell components (extracellular, intracellular and cell wall were firstly constructed. Their prophylactic potential was evaluated in a Der p2-sensitised mouse model, and immunomodulation properties at the cellular level were determined by measuring cytokine production in vitro.Der p2 expressed in the different recombinant L. lactis strains was recognized by a polyclonal anti-Der p2 antibody. Oral treatment with the recombinant L. lactis prior sensitization significantly prevented the development of airway inflammation in the Der p2-sensitized mice, as determined by the attenuation of inflammatory cells infiltration in the lung tissues and decrease of Th2 cytokines IL-4 and IL-5 levels in bronchoalveolar lavage. In addition, the serum allergen-specific IgE levels were significantly reduced, and the levels of IL-4 in the spleen and mesenteric lymph nodes cell cultures were also markedly decreased upon allergen stimulation in the mice fed with the recombinant L. lactis strains. These protective effects correlated with a significant up-regulation of regulatory T cells in the mesenteric lymph nodes.Oral pretreatment with live recombinant L. lactis prevented the development of allergen-induced airway inflammation primarily by the induction of specific mucosal immune tolerance.

The neuroinflammatory phenotype in a mouse model of Gulf War Illness is unrelated to brain regional levels of acetylcholine as measured by quantitative HILIC-UPLC-MS/MS.

Science.gov (United States)

Miller, Julie V; LeBouf, Ryan F; Kelly, Kimberly A; Michalovicz, Lindsay T; Ranpara, Anand; Locker, Alicia R; Miller, Diane B; O'Callaghan, James P

2018-05-28

Many veterans of the 1991 Persian Gulf War (GW) returned with a chronic multisymptom illness that has been termed Gulf War Illness (GWI). Previous GWI studies have suggested that exposure to acetylcholinesterase inhibitors (AChEIs) in theater, such as sarin and/or pesticides, may have contributed to the symptomatology of GWI. Additionally, concomitant high physiological stress experienced during the war may have contributed to the initiation of the GWI phenotype. While inhibition of AChE leading to accumulation of acetylcholine (ACh) will activate the cholinergic anti-inflammatory pathway, the signature symptomatology of GWI has been shown to be associated with neuroinflammation. To investigate the relationship between ACh and neuroinflammation in discrete brain regions, we used our previously established mouse model of GWI, which combines an exposure to a high physiological stress mimic, corticosterone (CORT), with GW-relevant AChEIs. The AChEIs used in this study were diisopropyl fluorophosphate (DFP), chlorpyrifos oxon (CPO), and physostigmine (PHY). After AChEI exposure, ACh concentrations for cortex (CTX), hippocampus (HIP), and striatum (STR) were determined using hydrophilic interaction liquid chromatography (HILIC) with ultra-performance liquid chromatography (UPLC)-tandem-mass spectrometry (MS/MS). CORT pretreatment ameliorated the DFP-induced ACh increase in HIP and STR, but not CTX. CORT pretreatment did not significantly alter ACh levels for CPO and PHY. Further analysis of STR neuroinflammatory biomarkers revealed an exacerbated CORT+AChEI response, which does not correspond to measured brain ACh. By utilizing this new analytical method for discrete brain region analysis of ACh, this work suggests the exacerbated neuroinflammatory effects in our mouse model of GWI are not driven by the accumulation of brain region-specific ACh.

Biorefining of wheat straw: accounting for the distribution of mineral elements in pretreated biomass by an extended pretreatment-severity equation.

Science.gov (United States)

Le, Duy Michael; Sørensen, Hanne R; Knudsen, Niels Ole; Schjoerring, Jan K; Meyer, Anne S

2014-01-01

Mineral elements present in lignocellulosic biomass feedstocks may accumulate in biorefinery process streams and cause technological problems, or alternatively can be reaped for value addition. A better understanding of the distribution of minerals in biomass in response to pretreatment factors is therefore important in relation to development of new biorefinery processes. The objective of the present study was to examine the levels of mineral elements in pretreated wheat straw in response to systematic variations in the hydrothermal pretreatment parameters (pH, temperature, and treatment time), and to assess whether it is possible to model mineral levels in the pretreated fiber fraction. Principal component analysis of the wheat straw biomass constituents, including mineral elements, showed that the recovered levels of wheat straw constituents after different hydrothermal pretreatments could be divided into two groups: 1) Phosphorus, magnesium, potassium, manganese, zinc, and calcium correlated with xylose and arabinose (that is, hemicellulose), and levels of these constituents present in the fiber fraction after pretreatment varied depending on the pretreatment-severity; and 2) Silicon, iron, copper, aluminum correlated with lignin and cellulose levels, but the levels of these constituents showed no severity-dependent trends. For the first group, an expanded pretreatment-severity equation, containing a specific factor for each constituent, accounting for variability due to pretreatment pH, was developed. Using this equation, the mineral levels could be predicted with R(2) > 0.75; for some with R(2) up to 0.96. Pretreatment conditions, especially pH, significantly influenced the levels of phosphorus, magnesium, potassium, manganese, zinc, and calcium in the resulting fiber fractions. A new expanded pretreatment-severity equation is proposed to model and predict mineral composition in pretreated wheat straw biomass.

Pathology of Mouse Models of Accelerated Aging

NARCIS (Netherlands)

Harkema, L.; Youssef, S. A.; de Bruin, A.

Progeroid mouse models display phenotypes in multiple organ systems that suggest premature aging and resemble features of natural aging of both mice and humans. The prospect of a significant increase in the global elderly population within the next decades has led to the emergence of geroscience,

Pathology of Mouse Models of Accelerated Aging

NARCIS (Netherlands)

Harkema, L; Youssef, S A; de Bruin, A

2016-01-01

Progeroid mouse models display phenotypes in multiple organ systems that suggest premature aging and resemble features of natural aging of both mice and humans. The prospect of a significant increase in the global elderly population within the next decades has led to the emergence of "geroscience,"

Genome-Wide Expression Profiling of Five Mouse Models Identifies Similarities and Differences with Human Psoriasis

Science.gov (United States)

Swindell, William R.; Johnston, Andrew; Carbajal, Steve; Han, Gangwen; Wohn, Christian; Lu, Jun; Xing, Xianying; Nair, Rajan P.; Voorhees, John J.; Elder, James T.; Wang, Xiao-Jing; Sano, Shigetoshi; Prens, Errol P.; DiGiovanni, John; Pittelkow, Mark R.; Ward, Nicole L.; Gudjonsson, Johann E.

2011-01-01

Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psoriasis mouse models (K5-Tie2, imiquimod, K14-AREG, K5-Stat3C and K5-TGFbeta1). While the cutaneous gene expression profiles associated with each mouse phenotype exhibited statistically significant similarity to the expression profile of psoriasis in humans, each model displayed distinctive sets of similarities and differences in comparison to human psoriasis. For all five models, correspondence to the human disease was strong with respect to genes involved in epidermal development and keratinization. Immune and inflammation-associated gene expression, in contrast, was more variable between models as compared to the human disease. These findings support the value of all five models as research tools, each with identifiable areas of convergence to and divergence from the human disease. Additionally, the approach used in this paper provides an objective and quantitative method for evaluation of proposed mouse models of psoriasis, which can be strategically applied in future studies to score strengths of mouse phenotypes relative to specific aspects of human psoriasis. PMID:21483750

[Streptomycin--an activator of persisting tick-borne encephalitis virus].

Science.gov (United States)

Malenko, G V; Pogodina, V V; Karmysheva, V Ia

1984-01-01

The effect of streptomycin (C) on persistence of tick-borne encephalitis (TBE) virus in Syrian hamsters infected with 3 strains of the virus (41/65, Aina/1448, Vasilchenko ) intracerebrally or subcutaneously was studied. In the animals not given C the infectious virus could be detected in the brain for 8-14 days but not later although their organs (mostly brains and spleens) contained the hemagglutinating antigen and viral antigen detectable by immunofluorescence. Intramuscularly C was given twice daily for 13-35 days in a daily dose of 200 mg/kg. The C-treated hamsters yielded 7 virulent TBE virus strains: 3 from the brain, 3 from the spleen, and one from the blood. No virus could be isolated from the liver, kidneys, or lungs despite the use of various methods for isolation including tissue explantation. The activating effect of C was observed against the background of 4-fold decrease in the titre of complement-fixing and antihemagglutinating antibodies. C exerted its activating effect both at early (70 days) and late (9 months) stages of TBE virus persistence. The activating effect of C appears to be due to its immunosuppressive properties and neurotoxic action on the CNS.

An inducible mouse model of late onset Tay-Sachs disease.

Science.gov (United States)

Jeyakumar, Mylvaganam; Smith, David; Eliott-Smith, Elena; Cortina-Borja, Mario; Reinkensmeier, Gabriele; Butters, Terry D; Lemm, Thorsten; Sandhoff, Konrad; Perry, V Hugh; Dwek, Raymond A; Platt, Frances M

2002-08-01

Mouse models of the G(M2) gangliosidoses, Tay-Sachs and Sandhoff disease, are null for the hexosaminidase alpha and beta subunits respectively. The Sandhoff (Hexb-/-) mouse has severe neurological disease and mimics the human infantile onset variant. However, the Tay-Sachs (Hexa-/-) mouse model lacks an overt phenotype as mice can partially bypass the blocked catabolic pathway and escape disease. We have investigated whether a subset of Tay-Sachs mice develop late onset disease. We have found that approximately 65% of the mice develop one or more clinical signs of the disease within their natural life span (n = 52, P disease at an earlier age (n = 21, P Tay-Sachs mice confirmed that pregnancy induces late onset Tay-Sachs disease. Onset of symptoms correlated with reduced up-regulation of hexosaminidase B, a component of the bypass pathway.

Dynamic Modeling and Validation of a Biomass Hydrothermal Pretreatment Process - A Demonstration Scale Study

DEFF Research Database (Denmark)

Prunescu, Remus Mihail; Blanke, Mogens; Jakobsen, Jon Geest

2015-01-01

for the enzymatic hydrolysis process. Several by-products are also formed, which disturb and act as inhibitors downstream. The objective of this study is to formulate and validate a large scale hydrothermal pretreatment dynamic model based on mass and energy balances, together with a complex conversion mechanism......Hydrothermal pretreatment of lignocellulosic biomass is a cost effective technology for second generation biorefineries. The process occurs in large horizontal and pressurized thermal reactors where the biomatrix is opened under the action of steam pressure and temperature to expose cellulose...... and kinetics. The study includes a comprehensive sensitivity and uncertainty analysis, with parameter estimation from real-data in the 178-185° range. To highlight the application utility of the model, a state estimator for biomass composition is developed. The predictions capture well the dynamic trends...

Ultrastructural study of Rift Valley fever virus in the mouse model

Energy Technology Data Exchange (ETDEWEB)

Reed, Christopher; Steele, Keith E.; Honko, Anna; Shamblin, Joshua; Hensley, Lisa E. [United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD (United States); Smith, Darci R., E-mail: darci.smith1@us.army.mil [United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD (United States)

2012-09-15

Detailed ultrastructural studies of Rift Valley fever virus (RVFV) in the mouse model are needed to develop and characterize a small animal model of RVF for the evaluation of potential vaccines and therapeutics. In this study, the ultrastructural features of RVFV infection in the mouse model were analyzed. The main changes in the liver included the presence of viral particles in hepatocytes and hepatic stem cells accompanied by hepatocyte apoptosis. However, viral particles were observed rarely in the liver; in contrast, particles were extremely abundant in the CNS. Despite extensive lymphocytolysis, direct evidence of viral replication was not observed in the lymphoid tissue. These results correlate with the acute-onset hepatitis and delayed-onset encephalitis that are dominant features of severe human RVF, but suggest that host immune-mediated mechanisms contribute significantly to pathology. The results of this study expand our knowledge of RVFV-host interactions and further characterize the mouse model of RVF.

Ultrastructural study of Rift Valley fever virus in the mouse model

International Nuclear Information System (INIS)

Reed, Christopher; Steele, Keith E.; Honko, Anna; Shamblin, Joshua; Hensley, Lisa E.; Smith, Darci R.

2012-01-01

Detailed ultrastructural studies of Rift Valley fever virus (RVFV) in the mouse model are needed to develop and characterize a small animal model of RVF for the evaluation of potential vaccines and therapeutics. In this study, the ultrastructural features of RVFV infection in the mouse model were analyzed. The main changes in the liver included the presence of viral particles in hepatocytes and hepatic stem cells accompanied by hepatocyte apoptosis. However, viral particles were observed rarely in the liver; in contrast, particles were extremely abundant in the CNS. Despite extensive lymphocytolysis, direct evidence of viral replication was not observed in the lymphoid tissue. These results correlate with the acute-onset hepatitis and delayed-onset encephalitis that are dominant features of severe human RVF, but suggest that host immune-mediated mechanisms contribute significantly to pathology. The results of this study expand our knowledge of RVFV–host interactions and further characterize the mouse model of RVF.

Engineering a new mouse model for vitiligo.

Science.gov (United States)

Manga, Prashiela; Orlow, Seth J

2012-07-01

Although the precise mechanisms that trigger vitiligo remain elusive, autoimmune responses mediate its progression. The development of therapies has been impeded by a paucity of animal models, since mice lack interfollicular melanocytes, the primary targets in vitiligo. In this issue, Harris et al. describe a mouse model in which interfollicular melanocytes are retained by Kit ligand overexpression and an immune response is initiated by transplanting melanocyte-targeting CD8+ T cells.

Taltirelin alleviates fatigue-like behavior in mouse models of cancer-related fatigue.

Science.gov (United States)

Dougherty, John P; Wolff, Brian S; Cullen, Mary J; Saligan, Leorey N; Gershengorn, Marvin C

2017-10-01

Fatigue affects most cancer patients and has numerous potential causes, including cancer itself and cancer treatment. Cancer-related fatigue (CRF) is not relieved by rest, can decrease quality of life, and has no FDA-approved therapy. Thyrotropin-releasing hormone (TRH) has been proposed as a potential novel treatment for CRF, but its efficacy against CRF remains largely untested. Thus, we tested the TRH analog, taltirelin (TAL), in mouse models of CRF. To model fatigue, we used a mouse model of chemotherapy, a mouse model of radiation therapy, and mice bearing colon 26 carcinoma tumors. We used the treadmill fatigue test to assess fatigue-like behavior after treatment with TAL. Additionally, we used wild-type and TRH receptor knockout mice to determine which TRH receptor was necessary for the actions of TAL. Tumor-bearing mice displayed muscle wasting and all models caused fatigue-like behavior, with mice running a shorter distance in the treadmill fatigue test than controls. TAL reversed fatigue-like behavior in all three models and the mouse TRH 1 receptor was necessary for the effects of TAL. These data suggest that TAL may be useful in alleviating fatigue in all cancer patients and provide further support for evaluating TAL as a potential therapy for CRF in humans. Published by Elsevier Ltd.

Cardiac disease and arrhythmogenesis: Mechanistic insights from mouse models

Directory of Open Access Journals (Sweden)

Lois Choy

2016-09-01

Full Text Available The mouse is the second mammalian species, after the human, in which substantial amount of the genomic information has been analyzed. With advances in transgenic technology, mutagenesis is now much easier to carry out in mice. Consequently, an increasing number of transgenic mouse systems have been generated for the study of cardiac arrhythmias in ion channelopathies and cardiomyopathies. Mouse hearts are also amenable to physical manipulation such as coronary artery ligation and transverse aortic constriction to induce heart failure, radiofrequency ablation of the AV node to model complete AV block and even implantation of a miniature pacemaker to induce cardiac dyssynchrony. Last but not least, pharmacological models, despite being simplistic, have enabled us to understand the physiological mechanisms of arrhythmias and evaluate the anti-arrhythmic properties of experimental agents, such as gap junction modulators, that may be exert therapeutic effects in other cardiac diseases. In this article, we examine these in turn, demonstrating that primary inherited arrhythmic syndromes are now recognized to be more complex than abnormality in a particular ion channel, involving alterations in gene expression and structural remodelling. Conversely, in cardiomyopathies and heart failure, mutations in ion channels and proteins have been identified as underlying causes, and electrophysiological remodelling are recognized pathological features. Transgenic techniques causing mutagenesis in mice are extremely powerful in dissecting the relative contributions of different genes play in producing disease phenotypes. Mouse models can serve as useful systems in which to explore how protein defects contribute to arrhythmias and direct future therapy.

Olfaction in three genetic and two MPTP-induced Parkinson's disease mouse models.

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Stefan Kurtenbach

Full Text Available Various genetic or toxin-induced mouse models are frequently used for investigation of early PD pathology. Although olfactory impairment is known to precede motor symptoms by years, it is not known whether it is caused by impairments in the brain, the olfactory epithelium, or both. In this study, we investigated the olfactory function in three genetic Parkinson's disease (PD mouse models and mice treated with MPTP intraperitoneally and intranasally. To investigate olfactory function, we performed electro-olfactogram recordings (EOGs and an olfactory behavior test (cookie-finding test. We show that neither a parkin knockout mouse strain, nor intraperitoneal MPTP treated animals display any olfactory impairment in EOG recordings and the applied behavior test. We also found no difference in the responses of the olfactory epithelium to odorants in a mouse strain over-expressing doubly mutated α-synuclein, while this mouse strain was not suitable to test olfaction in a cookie-finding test as it displays a mobility impairment. A transgenic mouse expressing mutated α-synuclein in dopaminergic neurons performed equal to control animals in the cookie-finding test. Further we show that intranasal MPTP application can cause functional damage of the olfactory epithelium.

A streptomycin resistance marker in H. parasuis based on site-directed mutations in rpsL gene to perform unmarked in-frame mutations and to verify natural transformation

Directory of Open Access Journals (Sweden)

Ke Dai

2018-01-01

Full Text Available Haemophilus parasuis is a member of the family Pasteurellaceae and a major causative agent of Glässer’s disease. This bacterium is normally a benign swine commensal but may become a deadly pathogen upon penetration into multiple tissues, contributing to severe lesions in swine. We have established a successive natural transformation-based markerless mutation system in this species. However, the two-step mutation system requires screening of natural competent cells, and cannot delete genes which regulate natural competence per se. In this study, we successfully obtained streptomycin-resistant derivatives from H. parasuis wild type strain SC1401 by using ethyl methane sulfonate (EMS, CH3SO2OC2H5. Upon sequencing and site-directed mutations, we uncovered that the EMS-induced point mutation in rpsL at codon 43rd (AAA → AGA; K43R or at 88th (AAA → AGA; K88R confers a much higher streptomycin resistance than clinical isolates. We have applied the streptomycin resistance marker as a positive selection marker to perform homologous recombination through conjugation and successfully generated a double unmarked in-frame targeted mutant 1401D88△tfox△arcA. Combined with a natural transformation-based knockout system and this genetic technique, multiple deletion mutants or attenuated strains of H. parasuis can be easily constructed. Moreover, the mutant genetic marker rpsL and streptomycin resistant phenotypes can serve as an effective tool to select naturally competent strains, and to verify natural transformation quantitatively.

Detrimental effects of rat mesenchymal stromal cell pre-treatment in a model of acute kidney rejection

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Martina eSeifert

2012-07-01

Full Text Available Mesenchymal stromal cells (MSC have shown immunomodulatory and tissue repair potential including partial tolerance induction by pre-treatment of donor-specific cells in a rat heart transplantation model. Very recently, we could show that autologous MSC attenuated ischemia reperfusion injury in a highly mismatched donor-recipient rat kidney transplant model. Therefore, we investigated donor-specific MSC pre-treatment in this rat kidney transplantation model to study whether graft function could be improved, or if tolerance could be induced.Donor- and recipient-type MSC or PBS as a control were injected i.v. four days before kidney transplantation. Mycophenolate mofetil (MMF immunosuppression (20 mg/kg body weight was applied for 7 days. Kidney grafts and spleens were harvested between days 8-10 and analyzed by quantitative RT-PCR and immunohistology. In addition, creatinine levels in the blood were measured and serum was screened for the presence of donor-specific antibodies.Surprisingly, application of both donor- and recipient-specific MSC resulted in enhanced humoral immune responses verified by intragraft B cell infiltration and complement factor C4d deposits. Moreover, signs of inflammation and rejection were generally enhanced in both MSC-treated groups relative to PBS control group. Additionally, pre-treatment with donor-specific MSC significantly enhanced the level of donor-specific antibody formation when compared with PBS- or recipient-MSC-treated groups. Pre-treatment with both MSC types resulted in a higher degree of kidney cortex tissue damage and elevated creatinine levels at the time point of rejection. Thus, MSC pre-sensitization in this model impairs the allograft outcome.Our data from this pre-clinical kidney transplantation model indicate that pre-operative MSC administration may not be optimal in kidney transplantation and caution must be exerted before moving forward with clinical studies in order to avoid adverse effects.

Quantitative trait loci affecting phenotypic variation in the vacuolated lens mouse mutant, a multigenic mouse model of neural tube defects

NARCIS (Netherlands)

Korstanje, Ron; Desai, Jigar; Lazar, Gloria; King, Benjamin; Rollins, Jarod; Spurr, Melissa; Joseph, Jamie; Kadambi, Sindhuja; Li, Yang; Cherry, Allison; Matteson, Paul G.; Paigen, Beverly; Millonig, James H.

Korstanje R, Desai J, Lazar G, King B, Rollins J, Spurr M, Joseph J, Kadambi S, Li Y, Cherry A, Matteson PG, Paigen B, Millonig JH. Quantitative trait loci affecting phenotypic variation in the vacuolated lens mouse mutant, a multigenic mouse model of neural tube defects. Physiol Genomics 35:

Nonspecific airway reactivity in a mouse model of asthma

Energy Technology Data Exchange (ETDEWEB)

Collie, D.D.; Wilder, J.A.; Bice, D.E.

1995-12-01

Animal models are indispensable for studies requiring an intact immune system, especially for studying the pathogenic mechanisms in atopic diseases, regulation of IgE production, and related biologic effects. Mice are particularly suitable and have been used extensively for such studies because their immune system is well characterized. Further, large numbers of mutants or inbred strains of mice are available that express deficiencies of individual immunologic processes, inflammatory cells, or mediator systems. By comparing reactions in such mice with appropriate control animals, the unique roles of individual cells or mediators may be characterized more precisely in the pathogenesis of atopic respiratory diseases including asthma. However, given that asthma in humans is characterized by the presence of airway hyperresponsiveness to specific and nonspecific stimuli, it is important that animal models of this disease exhibit similar physiologic abnormalities. In the past, the size of the mouse has limited its versatility in this regard. However, recent studies indicate the feasibility of measuring pulmonary responses in living mice, thus facilitating the physiologic evaluation of putative mouse models of human asthma that have been well charcterized at the immunologic and patholigic level. Future work will provide details of the morphometry of the methacholine-induced bronchoconstriction and will further seek to determine the relationship between cigarette smoke exposure and the development of NS-AHR in the transgenic mouse model.

Mouse Models Recapitulating Human Adrenocortical Tumors: What is lacking?

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Felicia Leccia

2016-07-01

Full Text Available Adrenal cortex tumors are divided into benign forms such as primary hyperplasias and adrenocortical adenomas (ACAs, and malignant forms or adrenocortical carcinomas (ACCs. Primary hyperplasias are rare causes of ACTH-independent hypercortisolism. ACAs are the most common type of adrenal gland tumors and they are rarely functional, i.e producing steroids. When functional, adenomas result in endocrine disorders such as Cushing’s syndrome (hypercortisolism or Conn’s syndrome (hyperaldosteronism. In contrast, ACCs are extremely rare but highly aggressive tumors that may also lead to hypersecreting syndromes. Genetic analyses of patients with sporadic or familial forms of adrenocortical tumors led to the identification of potentially causative genes, most of them being involved in PKA, Wnt/β-catenin and P53 signaling pathways. Development of mouse models is a crucial step to firmly establish the functional significance of candidate genes, to dissect mechanisms leading to tumors and endocrine disorders and in fine to provide in vivo tools for therapeutic screens. In this article we will provide an overview on the existing mouse models (xenografted and genetically engineered of adrenocortical tumors by focusing on the role of PKA and Wnt/β-catenin pathways in this context. We will discuss the advantages and limitations of models that have been developed heretofore and we will point out necessary improvements in the development of next generation mouse models of adrenal diseases.

Spallanzani's mouse: a model of restoration and regeneration.

Science.gov (United States)

Heber-Katz, E; Leferovich, J M; Bedelbaeva, K; Gourevitch, D

2004-01-01

The ability to regenerate is thought to be a lost phenotype in mammals, though there are certainly sporadic examples of mammalian regeneration. Our laboratory has identified a strain of mouse, the MRL mouse, which has a unique capacity to heal complex tissue in an epimorphic fashion, i.e., to restore a damaged limb or organ to its normal structure and function. Initial studies using through-and-through ear punches showed rapid full closure of the ear holes with cartilage growth, new hair follicles, and normal tissue architecture reminiscent of regeneration seen in amphibians as opposed to the scarring usually seen in mammals. Since the ear hole closure phenotype is a quantitative trait, this has been used to show-through extensive breeding and backcrossing--that the trait is heritable. Such analysis reveals that there is a complex genetic basis for this trait with multiple loci. One of the major phenotypes of the MRL mouse is a potent remodeling response with the absence or a reduced level of scarring. MRL healing is associated with the upregulation of the metalloproteinases MMP-2 and MMP-9 and the downregulation of their inhibitors TIMP-2 and TIMP-3, both present in inflammatory cells such as neutrophils and macrophages. This model has more recently been extended to the heart. In this case, a cryoinjury to the right ventricle leads to near complete scarless healing in the MRL mouse whereas scarring is seen in the control mouse. In the MRL heart, bromodeoxyuridine uptake by cardiomyocytes filling the wound site can be seen 60 days after injury. This does not occur in the control mouse. Function in the MRL heart, as measured by echocardiography, returns to normal.

A chimeric human-mouse model of Sjögren's syndrome.

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Young, Nicholas A; Wu, Lai-Chu; Bruss, Michael; Kaffenberger, Benjamin H; Hampton, Jeffrey; Bolon, Brad; Jarjour, Wael N

2015-01-01

Despite recent advances in the understanding of Sjögren's Syndrome (SjS), the pathogenic mechanisms remain elusive and an ideal model for early drug discovery is not yet available. To establish a humanized mouse model of SjS, peripheral blood mononuclear cells (PBMCs) from healthy volunteers or patients with SjS were transferred into immunodeficient NOD-scid IL-2rγ(null) mouse recipients to produce chimeric mice. While no difference was observed in the distribution of cells, chimeric mice transferred with PBMCs from SjS patients produced enhanced cytokine levels, most significantly IFN-γ and IL-10. Histological examination revealed enhanced inflammatory responses in the lacrimal and salivary glands of SjS chimeras, as measured by digital image analysis and blinded histopathological scoring. Infiltrates were primarily CD4+, with minimal detection of CD8+ T-cells and B-cells. These results demonstrate a novel chimeric mouse model of human SjS that provides a unique in vivo environment to test experimental therapeutics and investigate T-cell disease pathology. Copyright © 2014. Published by Elsevier Inc.

Rapid genetic algorithm optimization of a mouse computational model: Benefits for anthropomorphization of neonatal mouse cardiomyocytes

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Corina Teodora Bot

2012-11-01

Full Text Available While the mouse presents an invaluable experimental model organism in biology, its usefulness in cardiac arrhythmia research is limited in some aspects due to major electrophysiological differences between murine and human action potentials (APs. As previously described, these species-specific traits can be partly overcome by application of a cell-type transforming clamp (CTC to anthropomorphize the murine cardiac AP. CTC is a hybrid experimental-computational dynamic clamp technique, in which a computationally calculated time-dependent current is inserted into a cell in real time, to compensate for the differences between sarcolemmal currents of that cell (e.g., murine and the desired species (e.g., human. For effective CTC performance, mismatch between the measured cell and a mathematical model used to mimic the measured AP must be minimal. We have developed a genetic algorithm (GA approach that rapidly tunes a mathematical model to reproduce the AP of the murine cardiac myocyte under study. Compared to a prior implementation that used a template-based model selection approach, we show that GA optimization to a cell-specific model results in a much better recapitulation of the desired AP morphology with CTC. This improvement was more pronounced when anthropomorphizing neonatal mouse cardiomyocytes to human-like APs than to guinea pig APs. CTC may be useful for a wide range of applications, from screening effects of pharmaceutical compounds on ion channel activity, to exploring variations in the mouse or human genome. Rapid GA optimization of a cell-specific mathematical model improves CTC performance and may therefore expand the applicability and usage of the CTC technique.

Combination radiotherapy in an orthotopic mouse brain tumor model.

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Kramp, Tamalee R; Camphausen, Kevin

2012-03-06

Glioblastoma multiforme (GBM) are the most common and aggressive adult primary brain tumors. In recent years there has been substantial progress in the understanding of the mechanics of tumor invasion, and direct intracerebral inoculation of tumor provides the opportunity of observing the invasive process in a physiologically appropriate environment. As far as human brain tumors are concerned, the orthotopic models currently available are established either by stereotaxic injection of cell suspensions or implantation of a solid piece of tumor through a complicated craniotomy procedure. In our technique we harvest cells from tissue culture to create a cell suspension used to implant directly into the brain. The duration of the surgery is approximately 30 minutes, and as the mouse needs to be in a constant surgical plane, an injectable anesthetic is used. The mouse is placed in a stereotaxic jig made by Stoetling (figure 1). After the surgical area is cleaned and prepared, an incision is made; and the bregma is located to determine the location of the craniotomy. The location of the craniotomy is 2 mm to the right and 1 mm rostral to the bregma. The depth is 3 mm from the surface of the skull, and cells are injected at a rate of 2 μl every 2 minutes. The skin is sutured with 5-0 PDS, and the mouse is allowed to wake up on a heating pad. From our experience, depending on the cell line, treatment can take place from 7-10 days after surgery. Drug delivery is dependent on the drug composition. For radiation treatment the mice are anesthetized, and put into a custom made jig. Lead covers the mouse's body and exposes only the brain of the mouse. The study of tumorigenesis and the evaluation of new therapies for GBM require accurate and reproducible brain tumor animal models. Thus we use this orthotopic brain model to study the interaction of the microenvironment of the brain and the tumor, to test the effectiveness of different therapeutic agents with and without

Immunocompromised and immunocompetent mouse models for head and neck squamous cell carcinoma

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Lei ZG

2016-01-01

Full Text Available Zhen-ge Lei,1,* Xiao-hua Ren,2,* Sha-sha Wang,3 Xin-hua Liang,3,4 Ya-ling Tang3,5 1Department of Oral and Maxillofacial Surgery, Stomatological Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, 2Department of Stomatology, Sichuan Medical Science Academy and Sichuan Provincial People’s Hospital, 3State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, 4Department of Oral and Maxillofacial Surgery, West China College of Stomatology, Sichuan University, 5Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China *These authors contributed equally to this work Abstract: Mouse models can closely mimic human oral squamous epithelial carcinogenesis, greatly expand the in vivo research possibilities, and play a critical role in the development of diagnosis, monitoring, and treatment of head and neck squamous cell carcinoma. With the development of the recent research on the contribution of immunity/inflammation to cancer initiation and progression, mouse models have been divided into two categories, namely, immunocompromised and immunocompetent mouse models. And thus, this paper will review these two kinds of models applied in head and neck squamous cell carcinoma to provide a platform to understand the complicated histological, molecular, and genetic changes of oral squamous epithelial tumorigenesis. Keywords: head and neck squamous cell carcinoma, HNSCC, mouse models, immunocompromised models, immunocompetent models, transgenic models

ADM1-based modeling of anaerobic digestion of swine manure fibers pretreated with aqueous ammonia soaking

DEFF Research Database (Denmark)

Jurado, Esperanza; Gavala, Hariklia N.; Skiadas, Ioannis

2012-01-01

fibers. In the present study, mesophilic anaerobic digestion of AAS pretreated manure fibers was tested in CSTR-type digesters fed with swine manure and/or a mixture of swine manure and AAS pretreated manure fibers. The Anaerobic Digestion Model No.1 (ADM1) was used for the prediction of the effect......Anaerobic digestion of manure fibers present challenges due to their low biodegradability. Aqueous ammonia soaking (AAS) and subsequent ammonia removal has been tested as a simple and cheap method to disrupt the lignocellulose and increase the methane potential and the biogas productivity of manure...... that the AAS had on the efficiency of the anaerobic digestion of manure. Kinetic parameters were estimated by fitting of the model to data from manure fed digesters. The model was able to satisfactorily simulate the behaviour of digesters fed with manure. However, the model predictions were poorer...

Centralized mouse repositories.

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Donahue, Leah Rae; Hrabe de Angelis, Martin; Hagn, Michael; Franklin, Craig; Lloyd, K C Kent; Magnuson, Terry; McKerlie, Colin; Nakagata, Naomi; Obata, Yuichi; Read, Stuart; Wurst, Wolfgang; Hörlein, Andreas; Davisson, Muriel T

2012-10-01

Because the mouse is used so widely for biomedical research and the number of mouse models being generated is increasing rapidly, centralized repositories are essential if the valuable mouse strains and models that have been developed are to be securely preserved and fully exploited. Ensuring the ongoing availability of these mouse strains preserves the investment made in creating and characterizing them and creates a global resource of enormous value. The establishment of centralized mouse repositories around the world for distributing and archiving these resources has provided critical access to and preservation of these strains. This article describes the common and specialized activities provided by major mouse repositories around the world.

A Mouse Model for Human Anal Cancer

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Stelzer, Marie K.; Pitot, Henry C.; Liem, Amy; Schweizer, Johannes; Mahoney, Charles; Lambert, Paul F.

2010-01-01

Human anal cancers are associated with high-risk human papillomaviruses (HPVs) that cause other anogenital cancers and head and neck cancers. As with other cancers, HPV16 is the most common high-risk HPV in anal cancers. We describe the generation and characterization of a mouse model for human anal cancer. This model makes use of K14E6 and K14E7 transgenic mice in which the HPV16 E6 and E7 genes are directed in their expression to stratified squamous epithelia. HPV16 E6 and E7 possess oncogenic properties including but not limited to their capacity to inactivate the cellular tumor suppressors p53 and pRb, respectively. Both E6 and E7 were found to be functionally expressed in the anal epithelia of K14E6/K14E7 transgenic mice. To assess the susceptibility of these mice to anal cancer, mice were treated topically with dimethylbenz[a]anthracene (DMBA), a chemical carcinogen that is known to induce squamous cell carcinomas in other sites. Nearly 50% of DMBA-treated HPV16 E6/E7 transgenic mice showed overt signs of tumors; whereas, none of the like treated non-transgenic mice showed tumors. Histopathological analyses confirmed that the HPV16 transgenic mice were increased in their susceptibility to anal cancers and precancerous lesions. Biomarker analyses demonstrated that these mouse anal cancers exhibit properties that are similar to those observed in HPV-positive precursors to human anal cancer. This is the first mouse model for investigating the contributions of viral and cellular factors in anal carcinogenesis, and should provide a platform for assessing new therapeutic modalities for treating and/or preventing this type of cancer. PMID:20947489

A consensus definition of cataplexy in mouse models of narcolepsy.

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Scammell, Thomas E; Willie, Jon T; Guilleminault, Christian; Siegel, Jerome M

2009-01-01

People with narcolepsy often have episodes of cataplexy, brief periods of muscle weakness triggered by strong emotions. Many researchers are now studying mouse models of narcolepsy, but definitions of cataplexy-like behavior in mice differ across labs. To establish a common language, the International Working Group on Rodent Models of Narcolepsy reviewed the literature on cataplexy in people with narcolepsy and in dog and mouse models of narcolepsy and then developed a consensus definition of murine cataplexy. The group concluded that murine cataplexy is an abrupt episode of nuchal atonia lasting at least 10 seconds. In addition, theta activity dominates the EEG during the episode, and video recordings document immobility. To distinguish a cataplexy episode from REM sleep after a brief awakening, at least 40 seconds of wakefulness must precede the episode. Bouts of cataplexy fitting this definition are common in mice with disrupted orexin/hypocretin signaling, but these events almost never occur in wild type mice. It remains unclear whether murine cataplexy is triggered by strong emotions or whether mice remain conscious during the episodes as in people with narcolepsy. This working definition provides helpful insights into murine cataplexy and should allow objective and accurate comparisons of cataplexy in future studies using mouse models of narcolepsy.

Development and function of human innate immune cells in a humanized mouse model.

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Rongvaux, Anthony; Willinger, Tim; Martinek, Jan; Strowig, Till; Gearty, Sofia V; Teichmann, Lino L; Saito, Yasuyuki; Marches, Florentina; Halene, Stephanie; Palucka, A Karolina; Manz, Markus G; Flavell, Richard A

2014-04-01

Mice repopulated with human hematopoietic cells are a powerful tool for the study of human hematopoiesis and immune function in vivo. However, existing humanized mouse models cannot support development of human innate immune cells, including myeloid cells and natural killer (NK) cells. Here we describe two mouse strains called MITRG and MISTRG, in which human versions of four genes encoding cytokines important for innate immune cell development are knocked into their respective mouse loci. The human cytokines support the development and function of monocytes, macrophages and NK cells derived from human fetal liver or adult CD34(+) progenitor cells injected into the mice. Human macrophages infiltrated a human tumor xenograft in MITRG and MISTRG mice in a manner resembling that observed in tumors obtained from human patients. This humanized mouse model may be used to model the human immune system in scenarios of health and pathology, and may enable evaluation of therapeutic candidates in an in vivo setting relevant to human physiology.

Development of a transgenic mouse model to study the immunogenicity of recombinant human insulin

NARCIS (Netherlands)

Torosantucci, Riccardo; Brinks, Vera; Kijanka, Grzegorz; Halim, Liem Andhyk; Sauerborn, Melody; Schellekens, Huub; Jiskoot, Wim

2014-01-01

Mouse models are commonly used to assess the immunogenicity of therapeutic proteins and to investigate the immunological processes leading to antidrug antibodies. The aim of this work was to develop a transgenic (TG) Balb/c mouse model for evaluating the immunogenicity of recombinant human insulin

Evaluation of synthetic vascular grafts in a mouse carotid grafting model.

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Chan, Alex H P; Tan, Richard P; Michael, Praveesuda L; Lee, Bob S L; Vanags, Laura Z; Ng, Martin K C; Bursill, Christina A; Wise, Steven G

2017-01-01

Current animal models for the evaluation of synthetic grafts are lacking many of the molecular tools and transgenic studies available to other branches of biology. A mouse model of vascular grafting would allow for the study of molecular mechanisms of graft failure, including in the context of clinically relevant disease states. In this study, we comprehensively characterise a sutureless grafting model which facilitates the evaluation of synthetic grafts in the mouse carotid artery. Using conduits electrospun from polycaprolactone (PCL) we show the gradual development of a significant neointima within 28 days, found to be greatest at the anastomoses. Histological analysis showed temporal increases in smooth muscle cell and collagen content within the neointima, demonstrating its maturation. Endothelialisation of the PCL grafts, assessed by scanning electron microscopy (SEM) analysis and CD31 staining, was near complete within 28 days, together replicating two critical aspects of graft performance. To further demonstrate the potential of this mouse model, we used longitudinal non-invasive tracking of bone-marrow mononuclear cells from a transgenic mouse strain with a dual reporter construct encoding both luciferase and green fluorescent protein (GFP). This enabled characterisation of mononuclear cell homing and engraftment to PCL using bioluminescence imaging and histological staining over time (7, 14 and 28 days). We observed peak luminescence at 7 days post-graft implantation that persisted until sacrifice at 28 days. Collectively, we have established and characterised a high-throughput model of grafting that allows for the evaluation of key clinical drivers of graft performance.

Evaluation of synthetic vascular grafts in a mouse carotid grafting model.

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Alex H P Chan

Full Text Available Current animal models for the evaluation of synthetic grafts are lacking many of the molecular tools and transgenic studies available to other branches of biology. A mouse model of vascular grafting would allow for the study of molecular mechanisms of graft failure, including in the context of clinically relevant disease states. In this study, we comprehensively characterise a sutureless grafting model which facilitates the evaluation of synthetic grafts in the mouse carotid artery. Using conduits electrospun from polycaprolactone (PCL we show the gradual development of a significant neointima within 28 days, found to be greatest at the anastomoses. Histological analysis showed temporal increases in smooth muscle cell and collagen content within the neointima, demonstrating its maturation. Endothelialisation of the PCL grafts, assessed by scanning electron microscopy (SEM analysis and CD31 staining, was near complete within 28 days, together replicating two critical aspects of graft performance. To further demonstrate the potential of this mouse model, we used longitudinal non-invasive tracking of bone-marrow mononuclear cells from a transgenic mouse strain with a dual reporter construct encoding both luciferase and green fluorescent protein (GFP. This enabled characterisation of mononuclear cell homing and engraftment to PCL using bioluminescence imaging and histological staining over time (7, 14 and 28 days. We observed peak luminescence at 7 days post-graft implantation that persisted until sacrifice at 28 days. Collectively, we have established and characterised a high-throughput model of grafting that allows for the evaluation of key clinical drivers of graft performance.

Role of Stat in Skin Carcinogenesis: Insights Gained from Relevant Mouse Models

International Nuclear Information System (INIS)

Macias, E.; Rao, D.; DiGiovanni, J.; DiGiovanni, J.; DiGiovanni, J.

2013-01-01

Signal transducer and activator of transcription 3 (Stat) is a cytoplasmic protein that is activated in response to cytokines and growth factors and acts as a transcription factor. Stat plays critical roles in various biological activities including cell proliferation, migration, and survival. Studies using keratinocyte-specific Stat-deficient mice have revealed that Stat plays an important role in skin homeostasis including keratinocyte migration, wound healing, and hair follicle growth. Use of both constitutive and inducible keratinocyte-specific Stat-deficient mouse models has demonstrated that Stat is required for both the initiation and promotion stages of multistage skin carcinogenesis. Further studies using a transgenic mouse model with a gain of function mutant of Stat (Stat3C) expressed in the basal layer of the epidermis revealed a novel role for Stat in skin tumor progression. Studies using similar Stat-deficient and gain-of-function mouse models have indicated its similar roles in ultraviolet B (UVB) radiation-mediated skin carcinogenesis. This paper summarizes the use of these various mouse models for studying the role and underlying mechanisms for the function of Stat in skin carcinogenesis. Given its significant role throughout the skin carcinogenesis process, Stat is an attractive target for skin cancer prevention and treatment.

[Effect of Shouwu Shudi Yin on dopaminegic neurons in MPTP induced Parkinson's disease mouse model].

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Tunje, Reginachizi; Ye, Yang-Lie; Sonauddin, Ahmed; Hansraj, Bhugun; Ngawang, Sangye; Shivani, Sharma; Zhang, Xiong; Zhu, Jian-Hong; Liu, Rong-Pei

2016-09-01

In order to investigate the effect of Shouwu Shudi Yin on dopaminegic neurons in MPTP induced Parkinson's disease mouse model and the possible mechamism, the experimental mice were randomly divided into 4 groups: control, Shouwu Shudi Yin, MPTP and the treatment (MPTP+Shouwu Shudi Yin) groups. The number of tyrosine hydroxylase (TH) positive cells in the substantia nigra was measured by immunohistochemistry, and mRNA expression of TH and glutathione peroxidase (GPX) were detected by PCR. The results showed that the number of TH positive cells and mRNA expression of TH were significantly reduced in MPTP group compared with the control (PYin didn't show protective effect. Compared to MPTP group, the mRNA expression of four subtypes of GPX were increased in various degrees in the treatment group pretreated with Shouwu Shudi Yin, although the difference was not statistically significant. These indicated that the preventive medication of Shouwu Shudi Yin don't have protective effect on the mice with Parkinson' s disease induced by MPTP, but it may enhance the antioxidant capacity through increasing the expression of GPX. Copyright© by the Chinese Pharmaceutical Association.

One-tube loop-mediated isothermal amplification combined with restriction endonuclease digestion and ELISA for colorimetric detection of resistance to isoniazid, ethambutol and streptomycin in Mycobacterium tuberculosis isolates.

Science.gov (United States)

Lee, Mei-Feng; Chen, Yen-Hsu; Hsu, Hui-Jine; Peng, Chien-Fang

2010-10-01

In this study, we designed a simple and rapid colorimetric detection method, a one-tube loop-mediated isothermal amplification (LAMP)-PCR-hybridization-restriction endonuclease-ELISA [one-tube LAMP-PCR-HY-RE-ELISA] system, to detect resistance to isoniazid, ethambutol and streptomycin in strains of Mycobacterium tuberculosis isolated from clinical specimens. The clinical performance of this method for detecting isoniazid-resistant, ethambutol-resistant and streptomycin-resistant isolates of M. tuberculosis showed 98.9%, 94.3% and 93.8%, respectively. This assay is rapid and convenient that can be performed within one working day. One-tube LAMP-PCR-HY-RE-ELISA system was designed based on hot spot point mutations in target drug-resistant genes, using LAMP-PCR, hybridization, digestion with restriction endonuclease and colorimetric method of ELISA. In this study, LAMP assay was used to amplify DNA from drug-resistant M. tuberculosis, and ELISA was used for colorimetrical determination. This assay will be a useful tool for rapid diagnosis of mutant codons in strains of M. tuberculosis for isoniazid at katG 315 and katG 463, ethambutol at embB 306 and embB 497, and streptomycin at rpsL 43. Crown Copyright © 2010. Published by Elsevier B.V. All rights reserved.

Macrophage colony-stimulating factor augments Tie2-expressing monocyte differentiation, angiogenic function, and recruitment in a mouse model of breast cancer.

Science.gov (United States)

Forget, Mary A; Voorhees, Jeffrey L; Cole, Sara L; Dakhlallah, Duaa; Patterson, Ivory L; Gross, Amy C; Moldovan, Leni; Mo, Xiaokui; Evans, Randall; Marsh, Clay B; Eubank, Tim D

2014-01-01

Reports demonstrate the role of M-CSF (CSF1) in tumor progression in mouse models as well as the prognostic value of macrophage numbers in breast cancer patients. Recently, a subset of CD14+ monocytes expressing the Tie2 receptor, once thought to be predominantly expressed on endothelial cells, has been characterized. We hypothesized that increased levels of CSF1 in breast tumors can regulate differentiation of Tie2- monocytes to a Tie2+ phenotype. We treated CD14+ human monocytes with CSF1 and found a significant increase in CD14+/Tie2+ positivity. To understand if CSF1-induced Tie2 expression on these cells improved their migratory ability, we pre-treated CD14+ monocytes with CSF1 and used Boyden chemotaxis chambers to observe enhanced response to angiopoietin-2 (ANG2), the chemotactic ligand for the Tie2 receptor. We found that CSF1 pre-treatment significantly augmented chemotaxis and that Tie2 receptor upregulation was responsible as siRNA targeting Tie2 receptor abrogated this effect. To understand any augmented angiogenic effect produced by treating these cells with CSF1, we cultured human umbilical vein endothelial cells (HUVECs) with conditioned supernatants from CSF1-pre-treated CD14+ monocytes for a tube formation assay. While supernatants from CSF1-pre-treated TEMs increased HUVEC branching, a neutralizing antibody against the CSF1R abrogated this activity, as did siRNA against the Tie2 receptor. To test our hypothesis in vivo, we treated PyMT tumor-bearing mice with CSF1 and observed an expansion in the TEM population relative to total F4/80+ cells, which resulted in increased angiogenesis. Investigation into the mechanism of Tie2 receptor upregulation on CD14+ monocytes by CSF1 revealed a synergistic contribution from the PI3 kinase and HIF pathways as the PI3 kinase inhibitor LY294002, as well as HIF-1α-deficient macrophages differentiated from the bone marrow of HIF-1αfl/fl/LysMcre mice, diminished CSF1-stimulated Tie2 receptor expression.

Escherichia coli EDL933 Requires Gluconeogenic Nutrients To Successfully Colonize the Intestines of Streptomycin-Treated Mice Precolonized with E. coli Nissle 1917

Science.gov (United States)

Schinner, Silvia A. C.; Mokszycki, Matthew E.; Adediran, Jimmy; Leatham-Jensen, Mary; Conway, Tyrrell

2015-01-01

Escherichia coli MG1655, a K-12 strain, uses glycolytic nutrients exclusively to colonize the intestines of streptomycin-treated mice when it is the only E. coli strain present or when it is confronted with E. coli EDL933, an O157:H7 strain. In contrast, E. coli EDL933 uses glycolytic nutrients exclusively when it is the only E. coli strain in the intestine but switches in part to gluconeogenic nutrients when it colonizes mice precolonized with E. coli MG1655 (R. L. Miranda et al., Infect Immun 72:1666–1676, 2004, http://dx.doi.org/10.1128/IAI.72.3.1666-1676.2004). Recently, J. W. Njoroge et al. (mBio 3:e00280-12, 2012, http://dx.doi.org/10.1128/mBio.00280-12) reported that E. coli 86-24, an O157:H7 strain, activates the expression of virulence genes under gluconeogenic conditions, suggesting that colonization of the intestine with a probiotic E. coli strain that outcompetes O157:H7 strains for gluconeogenic nutrients could render them nonpathogenic. Here we report that E. coli Nissle 1917, a probiotic strain, uses both glycolytic and gluconeogenic nutrients to colonize the mouse intestine between 1 and 5 days postfeeding, appears to stop using gluconeogenic nutrients thereafter in a large, long-term colonization niche, but continues to use them in a smaller niche to compete with invading E. coli EDL933. Evidence is also presented suggesting that invading E. coli EDL933 uses both glycolytic and gluconeogenic nutrients and needs the ability to perform gluconeogenesis in order to colonize mice precolonized with E. coli Nissle 1917. The data presented here therefore rule out the possibility that E. coli Nissle 1917 can starve the O157:H7 E. coli strain EDL933 of gluconeogenic nutrients, even though E. coli Nissle 1917 uses such nutrients to compete with E. coli EDL933 in the mouse intestine. PMID:25733524

Establishment of mouse neuron and microglial cell co-cultured models and its action mechanism.

Science.gov (United States)

Zhang, Bo; Yang, Yunfeng; Tang, Jun; Tao, Yihao; Jiang, Bing; Chen, Zhi; Feng, Hua; Yang, Liming; Zhu, Gang

2017-06-27

The objective of this study is to establish a co-culture model of mouse neurons and microglial cells, and to analyze the mechanism of action of oxygen glucose deprivation (OGD) and transient oxygen glucose deprivation (tOGD) preconditioning cell models. Mouse primary neurons and BV2 microglial cells were successfully cultured, and the OGD and tOGD models were also established. In the co-culture of mouse primary neurons and microglial cells, the cell number of tOGD mouse neurons and microglial cells was larger than the OGD cell number, observed by a microscope. CCK-8 assay result showed that at 1h after treatment, the OD value in the control group is lower compared to all the other three groups (P control group compared to other three groups (P neurons cells were cultured. In the meantime mouse BV2 microglia cells were cultured. Two types of cells were co-cultured, and OGD and tOGD cell models were established. There were four groups in the experiment: control group (OGD), treatment group (tOGD+OGD), placebo group (tOGD+OGD+saline) and minocycline intervention group (tOGD+OGD+minocycline). CCK-8 kit was used to detect cell viability and flow cytometry was used to detect apoptosis. In this study, mouse primary neurons and microglial cells were co-cultured. The OGD and tOGD models were established successfully. tOGD was able to effectively protect neurons and microglial cells from damage, and inhibit the apoptosis caused by oxygen glucose deprivation.

Modelling and L1 Adaptive Control of Temperature in Biomass Pretreatment

DEFF Research Database (Denmark)

Prunescu, Remus Mihail; Blanke, Mogens; Sin, Gürkan

2013-01-01

Biomass steam pretreatment is a key process in converting agricultural wastes to bioethanol. The pretreatment occurs in a large pressurized tank called a thermal reactor. Two key parameters influence the successfulness of the process: the reactor temperature, and the retention time. A particle pu...

Biomass pretreatment

Science.gov (United States)

Hennessey, Susan Marie; Friend, Julie; Elander, Richard T; Tucker, III, Melvin P

2013-05-21

A method is provided for producing an improved pretreated biomass product for use in saccharification followed by fermentation to produce a target chemical that includes removal of saccharification and or fermentation inhibitors from the pretreated biomass product. Specifically, the pretreated biomass product derived from using the present method has fewer inhibitors of saccharification and/or fermentation without a loss in sugar content.

Conditional Expression of Human 15-Lipoxygenase-1 in Mouse Prostate Induces Prostatic Intraepithelial Neoplasia: The FLiMP Mouse Model

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Uddhav P. Kelavkar

2006-06-01

Full Text Available The incidence and mortality of prostate cancer (PCa vary greatly in different geographic regions, for which lifestyle factors, such as dietary fat intake, have been implicated. Human 15-lipoxygenase-1 (h15-LO-1, which metabolizes polyunsaturated fatty acids, is a highly regulated, tissue-specific, lipid-peroxidating enzyme that functions in physiological membrane remodeling and in the pathogenesis of atherosclerosis, inflammation, and carcinogenesis. We have shown that aberrant overexpression of 15-LO-1 occurs in human PCa, particularly high-grade PCa, and in high-grade prostatic intraepithelial neoplasia (HGPIN, and that the murine orthologue is increased in SV40-based genetically engineered mouse (GEM models of PCa, such as LADY and TRansgenic Adenocarcinoma of Mouse Prostate. To further define the role of 15-LO-1 in prostate carcinogenesis, we established a novel GEM model with targeted overexpression of h15-LO-1 in the prostate [human fifteen lipoxygenase-1 in mouse prostate (FLiMP]. We used a Cre- mediated and a loxP-mediated recombination strategy to target h15-LO-1 specifically to the prostate of C57BL/6 mice. Wild-type (wt, FLiMP+/-, and FLiMP+/+ mice aged 7 to 21, 24 to 28, and 35 weeks were characterized by histopathology, immunohistochemistry (IHC, and DNA/RNA and enzyme analyses. Compared to wt mice, h15-LO-1 enzyme activity was increased similarly in both homozygous FLiMP+/+ and hemizygous FLiMP+/- prostates. Dorsolateral and ventral prostates of FLiMP mice showed focal and progressive epithelial hyperplasia with nuclear atypia, indicative of the definition of mouse prostatic intraepithelial neoplasia (mPIN according to the National Cancer Institute. These foci showed increased proliferation by Ki-67 IHC. No progression to invasive PCa was noted up to 35 weeks. By IHC, h15-LO-1 expression was limited to luminal epithelial cells, with increased expression in mPIN foci (similar to human HGPIN. In summary, targeted overexpression of h

Mouse Models for Drug Discovery. Can New Tools and Technology Improve Translational Power?

Science.gov (United States)

Zuberi, Aamir; Lutz, Cathleen

2016-01-01

Abstract The use of mouse models in biomedical research and preclinical drug evaluation is on the rise. The advent of new molecular genome-altering technologies such as CRISPR/Cas9 allows for genetic mutations to be introduced into the germ line of a mouse faster and less expensively than previous methods. In addition, the rapid progress in the development and use of somatic transgenesis using viral vectors, as well as manipulations of gene expression with siRNAs and antisense oligonucleotides, allow for even greater exploration into genomics and systems biology. These technological advances come at a time when cost reductions in genome sequencing have led to the identification of pathogenic mutations in patient populations, providing unprecedented opportunities in the use of mice to model human disease. The ease of genetic engineering in mice also offers a potential paradigm shift in resource sharing and the speed by which models are made available in the public domain. Predictively, the knowledge alone that a model can be quickly remade will provide relief to resources encumbered by licensing and Material Transfer Agreements. For decades, mouse strains have provided an exquisite experimental tool to study the pathophysiology of the disease and assess therapeutic options in a genetically defined system. However, a major limitation of the mouse has been the limited genetic diversity associated with common laboratory mice. This has been overcome with the recent development of the Collaborative Cross and Diversity Outbred mice. These strains provide new tools capable of replicating genetic diversity to that approaching the diversity found in human populations. The Collaborative Cross and Diversity Outbred strains thus provide a means to observe and characterize toxicity or efficacy of new therapeutic drugs for a given population. The combination of traditional and contemporary mouse genome editing tools, along with the addition of genetic diversity in new modeling

Mouse Models for Drug Discovery. Can New Tools and Technology Improve Translational Power?

Science.gov (United States)

Zuberi, Aamir; Lutz, Cathleen

2016-12-01

The use of mouse models in biomedical research and preclinical drug evaluation is on the rise. The advent of new molecular genome-altering technologies such as CRISPR/Cas9 allows for genetic mutations to be introduced into the germ line of a mouse faster and less expensively than previous methods. In addition, the rapid progress in the development and use of somatic transgenesis using viral vectors, as well as manipulations of gene expression with siRNAs and antisense oligonucleotides, allow for even greater exploration into genomics and systems biology. These technological advances come at a time when cost reductions in genome sequencing have led to the identification of pathogenic mutations in patient populations, providing unprecedented opportunities in the use of mice to model human disease. The ease of genetic engineering in mice also offers a potential paradigm shift in resource sharing and the speed by which models are made available in the public domain. Predictively, the knowledge alone that a model can be quickly remade will provide relief to resources encumbered by licensing and Material Transfer Agreements. For decades, mouse strains have provided an exquisite experimental tool to study the pathophysiology of the disease and assess therapeutic options in a genetically defined system. However, a major limitation of the mouse has been the limited genetic diversity associated with common laboratory mice. This has been overcome with the recent development of the Collaborative Cross and Diversity Outbred mice. These strains provide new tools capable of replicating genetic diversity to that approaching the diversity found in human populations. The Collaborative Cross and Diversity Outbred strains thus provide a means to observe and characterize toxicity or efficacy of new therapeutic drugs for a given population. The combination of traditional and contemporary mouse genome editing tools, along with the addition of genetic diversity in new modeling systems

A preclinical mouse model of invasive lobular breast cancer metastasis

NARCIS (Netherlands)

Doornebal, Chris W.; Klarenbeek, Sjoerd; Braumuller, Tanya M.; Klijn, Christiaan N.; Ciampricotti, Metamia; Hau, Cheei-Sing; Hollmann, Markus W.; Jonkers, Jos; de Visser, Karin E.

2013-01-01

Metastatic disease accounts for more than 90% of cancer-related deaths, but the development of effective antimetastatic agents has been hampered by the paucity of clinically relevant preclinical models of human metastatic disease. Here, we report the development of a mouse model of spontaneous

Resveratrol protects mouse embryonic stem cells from ionizing radiation by accelerating recovery from DNA strand breakage.

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Denissova, Natalia G; Nasello, Cara M; Yeung, Percy L; Tischfield, Jay A; Brenneman, Mark A

2012-01-01

Resveratrol has elicited many provocative anticancer effects in laboratory animals and cultured cells, including reduced levels of oxidative DNA damage, inhibition of tumor initiation and progression and induction of apoptosis in tumor cells. Use of resveratrol as a cancer-preventive agent in humans will require that its anticancer effects not be accompanied by damage to normal tissue stem or progenitor cells. In mouse embryonic stem cells (mESC) or early mouse embryos exposed to ethanol, resveratrol has been shown to suppress apoptosis and promote survival. However, in cells exposed to genotoxic stress, survival may come at the expense of genome stability. To learn whether resveratrol can protect stem cells from DNA damage and to study its effects on genomic integrity, we exposed mESC pretreated with resveratrol to ionizing radiation (IR). Forty-eight hours pretreatment with a comparatively low concentration of resveratrol (10 μM) improved survival of mESC >2-fold after exposure to 5 Gy of X-rays. Cells pretreated with resveratrol sustained the same levels of reactive oxygen species and DNA strand breakage after IR as mock-treated controls, but repaired DNA damage more rapidly and resumed cell division sooner. Frequencies of IR-induced mutation at a chromosomal reporter locus were not increased in cells pretreated with resveratrol as compared with controls, indicating that resveratrol can improve viability in mESC after DNA damage without compromising genomic integrity.

Biology and therapy of inherited retinal degenerative disease: insights from mouse models

Science.gov (United States)

Veleri, Shobi; Lazar, Csilla H.; Chang, Bo; Sieving, Paul A.; Banin, Eyal; Swaroop, Anand

2015-01-01

Retinal neurodegeneration associated with the dysfunction or death of photoreceptors is a major cause of incurable vision loss. Tremendous progress has been made over the last two decades in discovering genes and genetic defects that lead to retinal diseases. The primary focus has now shifted to uncovering disease mechanisms and designing treatment strategies, especially inspired by the successful application of gene therapy in some forms of congenital blindness in humans. Both spontaneous and laboratory-generated mouse mutants have been valuable for providing fundamental insights into normal retinal development and for deciphering disease pathology. Here, we provide a review of mouse models of human retinal degeneration, with a primary focus on diseases affecting photoreceptor function. We also describe models associated with retinal pigment epithelium dysfunction or synaptic abnormalities. Furthermore, we highlight the crucial role of mouse models in elucidating retinal and photoreceptor biology in health and disease, and in the assessment of novel therapeutic modalities, including gene- and stem-cell-based therapies, for retinal degenerative diseases. PMID:25650393

Transcranial magnetic stimulation of mouse brain using high-resolution anatomical models

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Crowther, L. J.; Hadimani, R. L.; Kanthasamy, A. G.; Jiles, D. C.

2014-05-01

Transcranial magnetic stimulation (TMS) offers the possibility of non-invasive treatment of brain disorders in humans. Studies on animals can allow rapid progress of the research including exploring a variety of different treatment conditions. Numerical calculations using animal models are needed to help design suitable TMS coils for use in animal experiments, in particular, to estimate the electric field induced in animal brains. In this paper, we have implemented a high-resolution anatomical MRI-derived mouse model consisting of 50 tissue types to accurately calculate induced electric field in the mouse brain. Magnetic field measurements have been performed on the surface of the coil and compared with the calculations in order to validate the calculated magnetic and induced electric fields in the brain. Results show how the induced electric field is distributed in a mouse brain and allow investigation of how this could be improved for TMS studies using mice. The findings have important implications in further preclinical development of TMS for treatment of human diseases.

Hypothalamic food intake regulation in a cancer-cachectic mouse model

NARCIS (Netherlands)

Dwarkasing, J.T.; Dijk, van M.; Dijk, F.J.; Boekschoten, M.V.; Faber, J.; Argiles, J.M.; Laviano, A.; Müller, M.R.; Witkamp, R.F.; Norren, van K.

2014-01-01

Background Appetite is frequently affected in cancer patients leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer-cachectic mouse model with increased food intake. In this model, mice bearing C26 tumour have an

Impaired spatial processing in a mouse model of fragile X syndrome.

Science.gov (United States)

Ghilan, Mohamed; Bettio, Luis E B; Noonan, Athena; Brocardo, Patricia S; Gil-Mohapel, Joana; Christie, Brian R

2018-05-17

Fragile X syndrome (FXS) is the most common form of inherited intellectual impairment. The Fmr1 -/y mouse model has been previously shown to have deficits in context discrimination tasks but not in the elevated plus-maze. To further characterize this FXS mouse model and determine whether hippocampal-mediated behaviours are affected in these mice, dentate gyrus (DG)-dependent spatial processing and Cornu ammonis 1 (CA1)-dependent temporal order discrimination tasks were evaluated. In agreement with previous findings of long-term potentiation deficits in the DG of this transgenic model of FXS, the results reported here demonstrate that Fmr1 -/y mice perform poorly in the DG-dependent metric change spatial processing task. However, Fmr1 -/y mice did not present deficits in the CA1-dependent temporal order discrimination task, and were able to remember the order in which objects were presented to them to the same extent as their wild-type littermate controls. These data suggest that the previously reported subregional-specific differences in hippocampal synaptic plasticity observed in the Fmr1 -/y mouse model may manifest as selective behavioural deficits in hippocampal-dependent tasks. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.

Neuropathological assessment and validation of mouse models for Alzheimer's disease: applying NIA-AA guidelines

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C. Dirk Keene

2016-06-01

Full Text Available Dozens of transgenic mouse models, generally based on mutations associated with familial Alzheimer's disease (AD, have been developed, in part, for preclinical testing of candidate AD therapies. However, none of these models has successfully predicted the clinical efficacy of drugs for treating AD patients. Therefore, development of more translationally relevant AD mouse models remains a critical unmet need in the field. A concept not previously implemented in AD preclinical drug testing is the use of mouse lines that have been validated for neuropathological features of human AD. Current thinking suggests that amyloid plaque and neurofibrillary tangle deposition is an essential component for accurate modeling of AD. Therefore, the AD translational paradigm would require pathologic Aβ and tau deposition, a disease-relevant distribution of plaques and tangles, and a pattern of disease progression of Aβ and tau isoforms similar to the neuropathological features found in the brains of AD patients. Additional parameters useful to evaluate parallels between AD and animal models would include 1 cerebrospinal fluid (CSF AD biomarker changes with reduced Aβ and increased phospho-tau/tau; 2 structural and functional neuroimaging patterns including MRI hippocampal atrophy, fluorodeoxyglucose (FDG, and amyloid/tau PET alterations in activity and/or patterns of pathologic peptide deposition and distribution; and 3 cognitive impairment with emphasis on spatial learning and memory to distinguish presymptomatic and symptomatic mice at specific ages. A validated AD mouse model for drug testing would likely show tau-related neurofibrillary degeneration following Aβ deposition and demonstrate changes in pathology, CSF analysis, and neuroimaging that mirror human AD. Development of the ideal model would revolutionize the ability to establish the translational value of AD mouse models and serve as a platform for discussions about national phenotyping guidelines

A dystrophic Duchenne mouse model for testing human antisense oligonucleotides.

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Marcel Veltrop

Full Text Available Duchenne muscular dystrophy (DMD is a severe muscle-wasting disease generally caused by reading frame disrupting mutations in the DMD gene resulting in loss of functional dystrophin protein. The reading frame can be restored by antisense oligonucleotide (AON-mediated exon skipping, allowing production of internally deleted, but partially functional dystrophin proteins as found in the less severe Becker muscular dystrophy. Due to genetic variation between species, mouse models with mutations in the murine genes are of limited use to test and further optimize human specific AONs in vivo. To address this we have generated the del52hDMD/mdx mouse. This model carries both murine and human DMD genes. However, mouse dystrophin expression is abolished due to a stop mutation in exon 23, while the expression of human dystrophin is abolished due to a deletion of exon 52. The del52hDMD/mdx model, like mdx, shows signs of muscle dystrophy on a histological level and phenotypically mild functional impairment. Local administration of human specific vivo morpholinos induces exon skipping and dystrophin restoration in these mice. Depending on the number of mismatches, occasional skipping of the murine Dmd gene, albeit at low levels, could be observed. Unlike previous models, the del52hDMD/mdx model enables the in vivo analysis of human specific AONs targeting exon 51 or exon 53 on RNA and protein level and muscle quality and function. Therefore, it will be a valuable tool for optimizing human specific AONs and genome editing approaches for DMD.

The impact of mouse passaging of Mycobacterium tuberculosis strains prior to virulence testing in the mouse and guinea pig aerosol models.

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Paul J Converse

2010-04-01

Full Text Available It has been hypothesized that the virulence of lab-passaged Mycobacterium tuberculosis and recombinant M. tuberculosis mutants might be reduced due to multiple in vitro passages, and that virulence might be augmented by passage of these strains through mice before quantitative virulence testing in the mouse or guinea pig aerosol models.By testing three M. tuberculosis H37Rv samples, one deletion mutant, and one recent clinical isolate for survival by the quantitative organ CFU counting method in mouse or guinea pig aerosol or intravenous infection models, we could discern no increase in bacterial fitness as a result of passaging of M. tuberculosis strains in mice prior to quantitative virulence testing in two animal models. Surface lipid expression as assessed by neutral red staining and thin-layer chromatography for PDIM analysis also failed to identify virulence correlates.These results indicate that animal passaging of M. tuberculosis strains prior to quantitative virulence testing in mouse or guinea pig models does not enhance or restore potency to strains that may have lost virulence due to in vitro passaging. It is critical to verify virulence of parental strains before genetic manipulations are undertaken and comparisons are made.

Mouse Chromosome Engineering for Modeling Human Disease

OpenAIRE

van der Weyden, Louise; Bradley, Allan

2006-01-01

Chromosomal rearrangements occur frequently in humans and can be disease-associated or phenotypically neutral. Recent technological advances have led to the discovery of copy-number changes previously undetected by cytogenetic techniques. To understand the genetic consequences of such genomic changes, these mutations need to be modeled in experimentally tractable systems. The mouse is an excellent organism for this analysis because of its biological and genetic similarity to humans, and the e...

Ultrasound Pretreatment as an Useful Tool to Enhance Egg White Protein Hydrolysis: Kinetics, Reaction Model, and Thermodinamics.

Science.gov (United States)

Jovanović, Jelena R; Stefanović, Andrea B; Šekuljica, Nataša Ž; Tanasković, Sonja M Jakovetić; Dojčinović, Marina B; Bugarski, Branko M; Knežević-Jugović, Zorica D

2016-09-28

The impact of ultrasound waves generated by probe-type sonicator and ultrasound cleaning bath on egg white protein susceptibility to hydrolysis by alcalase compared to both thermal pretreatment and conventional enzymatic hydrolysis was quantitatively investigated. A series of hydrolytic reactions was carried out in a stirred tank reactor at different substrate concentrations, enzyme concentrations, and temperatures using untreated, and pretreated egg white proteins (EWPs). The kinetic model based on substrate inhibition and second-order enzyme deactivation successfully predicts the experimental behavior providing an effective tool for comparison and optimization. The ultrasound pretreatments appear to greatly improve the enzymatic hydrolysis of EWPs under different conditions when compare to other methods. The apparent reaction rate constants for proteolysis (k 2 ) are 0.009, 0.011, 0.053, and 0.045 min -1 for untreated EWPs, and those pretreated with heat, probe-type sonicator, and ultrasound cleaning bath technologies, respectively. The ultrasound pretreatment also decreases hydrolysis activation (E a ) and enzyme deactivation (E d ) energy, enthalpy (ΔH), and entropy (ΔS) of activation and for the probe-type sonication this decrease is 61.7%, 61.6%, 63.6%, and 32.2%, respectively, but ultrasound has little change in Gibbs free energy value in the temperature range of 318 to 338 K. The content of sulfhydryl groups and ζ potential show a significant increase (P < 0.05) for both applied ultrasound pretreatments and the reduction of particle size distribution are achieved, providing some evidence that the ultrasound causes EWP structural changes affecting the proteolysis rate. © 2016 Institute of Food Technologists®

Revisiting the mouse model of oxygen-induced retinopathy

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Kim CB

2016-05-01

Full Text Available Clifford B Kim,1,2 Patricia A D’Amore,2–4 Kip M Connor1,2 1Angiogenesis Laboratory, Massachusetts Eye and Ear, 2Department of Ophthalmology, Harvard Medical School, 3Schepens Eye Research Institute, Massachusetts Eye and Ear, 4Department of Pathology, Harvard Medical School, Boston, MA, USA Abstract: Abnormal blood vessel growth in the retina is a hallmark of many retinal diseases, such as retinopathy of prematurity (ROP, proliferative diabetic retinopathy, and the wet form of age-related macular degeneration. In particular, ROP has been an important health concern for physicians since the advent of routine supplemental oxygen therapy for premature neonates more than 70 years ago. Since then, researchers have explored several animal models to better understand ROP and retinal vascular development. Of these models, the mouse model of oxygen-induced retinopathy (OIR has become the most widely used, and has played a pivotal role in our understanding of retinal angiogenesis and ocular immunology, as well as in the development of groundbreaking therapeutics such as anti-vascular endothelial growth factor injections for wet age-related macular degeneration. Numerous refinements to the model have been made since its inception in the 1950s, and technological advancements have expanded the use of the model across multiple scientific fields. In this review, we explore the historical developments that have led to the mouse OIR model utilized today, essential concepts of OIR, limitations of the model, and a representative selection of key findings from OIR, with particular emphasis on current research progress. Keywords: ROP, OIR, angiogenesis

[Role of hippocampal neuronal intracellular calcium overload in modulating cognitive dysfunction and the neuronprotective effect of mematine in a mouse model of chronic intermittent hypoxia].

Science.gov (United States)

Ming, Hong; Chen, Rui; Wang, Jing; Ju, Jingmei; Sun, Li; Zhang, Guoxing

2014-12-01

To investigate the role of hippocampal intracellular calcium overload in modulating cognitive dysfunction and the neuronprotective effect of mematine in a mouse model of chronic intermittent hypoxia. 45 ICR male mice were randomly divided into 3 groups: the unhandled control group (UC group, n = 15), the chronic intermittent hypoxia (CIH group, n = 15) and the pretreatment memantine group (MEM group, n = 15). CIH and MEM mice were subjected to intermittent hypoxia while UC mice to room air for 8 h per day during 4 weeks. Mice in the MEM group were pretreated with memantine (5 mg/kg) by intraperitoneal injection before the cycle started, and those in the UC group and the CIH group were treated with same volume of physiological saline. Neurobehavioral assessments were performed by Open filed and Morris water maze, [Ca²⁺]i in hippocampal neurons was evaluate by flow cytometry, and the expression of cleaved caspase-3, phospho-ERK1/2 in hippocampus were detected by Western blotting. Compared with the UC group, CIH mice displayed markedly more locomotor activity (P overload, neuron apoptosis, dephosphorylation of ERK1/2, which can be attenuated by memantine. Memantine may have a therapeutic effect in the neurocognitive impairment associated with OSAHS.

Mouse Xenograft Model for Mesothelioma | NCI Technology Transfer Center | TTC

Science.gov (United States)

The National Cancer Institute is seeking parties interested in collaborative research to co-develop, evaluate, or commercialize a new mouse model for monoclonal antibodies and immunoconjugates that target malignant mesotheliomas. Applications of the technology include models for screening compounds as potential therapeutics for mesothelioma and for studying the pathology of mesothelioma.

HUPO BPP Workshop on Mouse Models for Neurodegeneration--Choosing the right models.

Science.gov (United States)

Hamacher, Michael; Marcus, Katrin; Stephan, Christian; van Hall, Andre; Meyer, Helmut E

2005-09-01

The HUPO Brain Proteome Project met during the 4th Dutch Endo-Neuro-Psycho Meeting in Doorwerth, The Netherlands, on June 1, 2005, in order to discuss appropriate (mouse) models for neurodegenerative diseases as well as to conceptualise sophisticated proteomics analyses strategies. Here, the topics of the meeting are summarised.

Evaluation of an in vitro toxicogenetic mouse model for hepatotoxicity

International Nuclear Information System (INIS)

Martinez, Stephanie M.; Bradford, Blair U.; Soldatow, Valerie Y.; Kosyk, Oksana; Sandot, Amelia; Witek, Rafal; Kaiser, Robert; Stewart, Todd; Amaral, Kirsten; Freeman, Kimberly; Black, Chris; LeCluyse, Edward L.; Ferguson, Stephen S.; Rusyn, Ivan

2010-01-01

Numerous studies support the fact that a genetically diverse mouse population may be useful as an animal model to understand and predict toxicity in humans. We hypothesized that cultures of hepatocytes obtained from a large panel of inbred mouse strains can produce data indicative of inter-individual differences in in vivo responses to hepato-toxicants. In order to test this hypothesis and establish whether in vitro studies using cultured hepatocytes from genetically distinct mouse strains are feasible, we aimed to determine whether viable cells may be isolated from different mouse inbred strains, evaluate the reproducibility of cell yield, viability and functionality over subsequent isolations, and assess the utility of the model for toxicity screening. Hepatocytes were isolated from 15 strains of mice (A/J, B6C3F1, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/EiJ, DBA/2J, FVB/NJ, BALB/cByJ, AKR/J, MRL/MpJ, NOD/LtJ, NZW/LacJ, PWD/PhJ and WSB/EiJ males) and cultured for up to 7 days in traditional 2-dimensional culture. Cells from B6C3F1, C57BL/6J, and NOD/LtJ strains were treated with acetaminophen, WY-14,643 or rifampin and concentration-response effects on viability and function were established. Our data suggest that high yield and viability can be achieved across a panel of strains. Cell function and expression of key liver-specific genes of hepatocytes isolated from different strains and cultured under standardized conditions are comparable. Strain-specific responses to toxicant exposure have been observed in cultured hepatocytes and these experiments open new opportunities for further developments of in vitro models of hepatotoxicity in a genetically diverse population.

Biology and therapy of inherited retinal degenerative disease: insights from mouse models

Directory of Open Access Journals (Sweden)

Shobi Veleri

2015-02-01

Full Text Available Retinal neurodegeneration associated with the dysfunction or death of photoreceptors is a major cause of incurable vision loss. Tremendous progress has been made over the last two decades in discovering genes and genetic defects that lead to retinal diseases. The primary focus has now shifted to uncovering disease mechanisms and designing treatment strategies, especially inspired by the successful application of gene therapy in some forms of congenital blindness in humans. Both spontaneous and laboratory-generated mouse mutants have been valuable for providing fundamental insights into normal retinal development and for deciphering disease pathology. Here, we provide a review of mouse models of human retinal degeneration, with a primary focus on diseases affecting photoreceptor function. We also describe models associated with retinal pigment epithelium dysfunction or synaptic abnormalities. Furthermore, we highlight the crucial role of mouse models in elucidating retinal and photoreceptor biology in health and disease, and in the assessment of novel therapeutic modalities, including gene- and stem-cell-based therapies, for retinal degenerative diseases.

Mouse models in liver cancer research: A review of current literature

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Leenders, Martijn WH; Nijkamp, Maarten W; Rinkes, Inne HM Borel

2008-01-01

Primary liver cancer remains one of the most lethal malignancies worldwide. Due to differences in prevalence of etiological factors the incidence of primary liver cancer varies among the world, with a peak in East-Asia. As this disease is still lethal in most of the cases, research has to be done to improve our understanding of the disease, offering insights for possible treatment options. For this purpose, animal models are widely used, especially mouse models. In this review, we describe the different types of mouse models used in liver cancer research, with emphasis on genetically engineered mice used in this field. We focus on hepatocellular carcinoma (HCC), as this is by far the most common type of primary liver cancer, accounting for 70%-85% of cases. PMID:19058325

Distinctive serum miRNA profile in mouse models of striated muscular pathologies.

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Nicolas Vignier

Full Text Available Biomarkers are critically important for disease diagnosis and monitoring. In particular, close monitoring of disease evolution is eminently required for the evaluation of therapeutic treatments. Classical monitoring methods in muscular dystrophies are largely based on histological and molecular analyses of muscle biopsies. Such biopsies are invasive and therefore difficult to obtain. The serum protein creatine kinase is a useful biomarker, which is however not specific for a given pathology and correlates poorly with the severity or course of the muscular pathology. The aim of the present study was the systematic evaluation of serum microRNAs (miRNAs as biomarkers in striated muscle pathologies. Mouse models for five striated muscle pathologies were investigated: Duchenne muscular dystrophy (DMD, limb-girdle muscular dystrophy type 2D (LGMD2D, limb-girdle muscular dystrophy type 2C (LGMD2C, Emery-Dreifuss muscular dystrophy (EDMD and hypertrophic cardiomyopathy (HCM. Two-step RT-qPCR methodology was elaborated, using two different RT-qPCR miRNA quantification technologies. We identified miRNA modulation in the serum of all the five mouse models. The most highly dysregulated serum miRNAs were found to be commonly upregulated in DMD, LGMD2D and LGMD2C mouse models, which all exhibit massive destruction of striated muscle tissues. Some of these miRNAs were down rather than upregulated in the EDMD mice, a model without massive myofiber destruction. The dysregulated miRNAs identified in the HCM model were different, with the exception of one dysregulated miRNA common to all pathologies. Importantly, a specific and distinctive circulating miRNA profile was identified for each studied pathological mouse model. The differential expression of a few dysregulated miRNAs in the DMD mice was further evaluated in DMD patients, providing new candidates of circulating miRNA biomarkers for DMD.

A mouse model of mitochondrial complex III dysfunction induced by myxothiazol

Energy Technology Data Exchange (ETDEWEB)

Davoudi, Mina [Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185 (Sweden); Kallijärvi, Jukka; Marjavaara, Sanna [Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, 00014 (Finland); Kotarsky, Heike; Hansson, Eva [Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185 (Sweden); Levéen, Per [Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185 (Sweden); Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, 00014 (Finland); Fellman, Vineta, E-mail: Vineta.Fellman@med.lu.se [Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185 (Sweden); Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, 00014 (Finland); Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki 00029 (Finland)

2014-04-18

Highlights: • Reversible chemical inhibition of complex III in wild type mouse. • Myxothiazol causes decreased complex III activity in mouse liver. • The model is useful for therapeutic trials to improve mitochondrial function. - Abstract: Myxothiazol is a respiratory chain complex III (CIII) inhibitor that binds to the ubiquinol oxidation site Qo of CIII. It blocks electron transfer from ubiquinol to cytochrome b and thus inhibits CIII activity. It has been utilized as a tool in studies of respiratory chain function in in vitro and cell culture models. We developed a mouse model of biochemically induced and reversible CIII inhibition using myxothiazol. We administered myxothiazol intraperitoneally at a dose of 0.56 mg/kg to C57Bl/J6 mice every 24 h and assessed CIII activity, histology, lipid content, supercomplex formation, and gene expression in the livers of the mice. A reversible CIII activity decrease to 50% of control value occurred at 2 h post-injection. At 74 h only minor histological changes in the liver were found, supercomplex formation was preserved and no significant changes in the expression of genes indicating hepatotoxicity or inflammation were found. Thus, myxothiazol-induced CIII inhibition can be induced in mice for four days in a row without overt hepatotoxicity or lethality. This model could be utilized in further studies of respiratory chain function and pharmacological approaches to mitochondrial hepatopathies.

The Mouse Lemur, a Genetic Model Organism for Primate Biology, Behavior, and Health.

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Ezran, Camille; Karanewsky, Caitlin J; Pendleton, Jozeph L; Sholtz, Alex; Krasnow, Maya R; Willick, Jason; Razafindrakoto, Andriamahery; Zohdy, Sarah; Albertelli, Megan A; Krasnow, Mark A

2017-06-01

Systematic genetic studies of a handful of diverse organisms over the past 50 years have transformed our understanding of biology. However, many aspects of primate biology, behavior, and disease are absent or poorly modeled in any of the current genetic model organisms including mice. We surveyed the animal kingdom to find other animals with advantages similar to mice that might better exemplify primate biology, and identified mouse lemurs ( Microcebus spp.) as the outstanding candidate. Mouse lemurs are prosimian primates, roughly half the genetic distance between mice and humans. They are the smallest, fastest developing, and among the most prolific and abundant primates in the world, distributed throughout the island of Madagascar, many in separate breeding populations due to habitat destruction. Their physiology, behavior, and phylogeny have been studied for decades in laboratory colonies in Europe and in field studies in Malagasy rainforests, and a high quality reference genome sequence has recently been completed. To initiate a classical genetic approach, we developed a deep phenotyping protocol and have screened hundreds of laboratory and wild mouse lemurs for interesting phenotypes and begun mapping the underlying mutations, in collaboration with leading mouse lemur biologists. We also seek to establish a mouse lemur gene "knockout" library by sequencing the genomes of thousands of mouse lemurs to identify null alleles in most genes from the large pool of natural genetic variants. As part of this effort, we have begun a citizen science project in which students across Madagascar explore the remarkable biology around their schools, including longitudinal studies of the local mouse lemurs. We hope this work spawns a new model organism and cultivates a deep genetic understanding of primate biology and health. We also hope it establishes a new and ethical method of genetics that bridges biological, behavioral, medical, and conservation disciplines, while

Primary amines protect against retinal degeneration in mouse models of retinopathies.

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Maeda, Akiko; Golczak, Marcin; Chen, Yu; Okano, Kiichiro; Kohno, Hideo; Shiose, Satomi; Ishikawa, Kaede; Harte, William; Palczewska, Grazyna; Maeda, Tadao; Palczewski, Krzysztof

2011-12-25

Vertebrate vision is initiated by photoisomerization of the visual pigment chromophore 11-cis-retinal and is maintained by continuous regeneration of this retinoid through a series of reactions termed the retinoid cycle. However, toxic side reaction products, especially those involving reactive aldehyde groups of the photoisomerized product, all-trans-retinal, can cause severe retinal pathology. Here we lowered peak concentrations of free all-trans-retinal with primary amine-containing Food and Drug Administration (FDA)-approved drugs that did not inhibit chromophore regeneration in mouse models of retinal degeneration. Schiff base adducts between all-trans-retinal and these amines were identified by MS. Adducts were observed in mouse eyes only when an experimental drug protected the retina from degeneration in both short-term and long-term treatment experiments. This study demonstrates a molecular basis of all-trans-retinal-induced retinal pathology and identifies an assemblage of FDA-approved compounds with protective effects against this pathology in a mouse model that shows features of Stargardt's disease and age-related retinal degeneration.

The impacts of pretreatment on the fermentability of pretreated lignocellulosic biomass: a comparative evaluation between ammonia fiber expansion and dilute acid pretreatment

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Dale Bruce E

2009-12-01

Full Text Available Abstract Background Pretreatment chemistry is of central importance due to its impacts on cellulosic biomass processing and biofuels conversion. Ammonia fiber expansion (AFEX and dilute acid are two promising pretreatments using alkaline and acidic pH that have distinctive differences in pretreatment chemistries. Results Comparative evaluation on these two pretreatments reveal that (i AFEX-pretreated corn stover is significantly more fermentable with respect to cell growth and sugar consumption, (ii both pretreatments can achieve more than 80% of total sugar yield in the enzymatic hydrolysis of washed pretreated solids, and (iii while AFEX completely preserves plant carbohydrates, dilute acid pretreatment at 5% solids loading degrades 13% of xylose to byproducts. Conclusion The selection of pretreatment will determine the biomass-processing configuration, requirements for hydrolysate conditioning (if any and fermentation strategy. Through dilute acid pretreatment, the need for hemicellulase in biomass processing is negligible. AFEX-centered cellulosic technology can alleviate fermentation costs through reducing inoculum size and practically eliminating nutrient costs during bioconversion. However, AFEX requires supplemental xylanases as well as cellulase activity. As for long-term sustainability, AFEX has greater potential to diversify products from a cellulosic biorefinery due to lower levels of inhibitor generation and lignin loss.

Adipose-derived Stem Cells Stimulated with n-Butylidenephthalide Exhibit Therapeutic Effects in a Mouse Model of Parkinson's Disease.

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Chi, Kang; Fu, Ru-Huei; Huang, Yu-Chuen; Chen, Shih-Yin; Hsu, Ching-Ju; Lin, Shinn-Zong; Tu, Chi-Tang; Chang, Li-Hsun; Wu, Ping-An; Liu, Shih-Ping

2018-03-01

Parkinson's disease (PD) causes motor dysfunction and dopaminergic cell death. Drug treatments can effectively reduce symptoms but often cause unwanted side effects. Stem cell therapies using cell replacement or indirect beneficial secretomes have recently emerged as potential therapeutic strategies. Although various types of stem cells have been proposed as possible candidates, adipose-derived stem cells (ADSCs) are easily obtainable, more abundant, less ethically disputed, and able to differentiate into multiple cell lineages. However, treatment of PD using adult stem cells is known to be less efficacious than neuron or embryonic stem cell transplantation. Therefore, improved therapies are urgently needed. n-Butylidenephthalide (BP), which is extracted from Angelica sinensis, has been shown to have anti-inflammatory and neuroprotective effects. Indeed, we previously demonstrated that BP treatment of ADSCs enhances the expression of neurogenesis and homing factors such as nuclear receptor related 1 protein, stromal-derived factor 1, and brain-derived neurotrophic factor. In the present study, we examined the ability of BP-pretreated ADSC transplantation to improve PD motor symptoms and protect dopamine neurons in a mouse model of PD. We evaluated the results using neuronal behavior tests such as beam walking, rotarod, and locomotor activity tests. ADSCs with or without BP pretreatment were transplanted into the striatum. Our findings demonstrated that ADSC transplantation improved motor abilities with varied efficacies and that BP stimulation improved the therapeutic effects of transplantation. Dopaminergic cell numbers returned to normal in ADSC-transplanted mice after 22 d. In summary, stimulating ADSCs with BP improved PD recovery efficiency. Thus, our results provide important new strategies to improve stem cell therapies for neurodegenerative diseases in future studies.

Effects of Pretreatments in Convective Dehydration of Rosehip (Rosa eglanteria

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Alejandra Mabellini

2012-04-01

Full Text Available The aim of this work was to experimentally determine drying curves for thin layer and bed drying of rosehip fruits, with and without pretreatments, to reduce processing times as a function of drying air operating variables, to propose dehydration kinetics of fruits and to determine its kinetic parameters for further use within drying simulation software. Fruits were pre-treated both chemically and mechanically, which included dipping the fruits in NaOH and ethyl oleate solutions; and cutting or perforating the fruit cuticle, respectively. Simulation models were then adopted to fit the kinetics drying data considering fruit volume shrinkage. These simple models minimized the calculation time during the simulation of deep-bed driers. Results show that pre-treatments reduced processing times up to 57%, and evaluated models satisfactorily predicted the drying of rosehip fruit. Effective mass diffusion coefficients were up to 4-fold greater when fruit was submitted to mechanical pretreatments.

Macrophage colony-stimulating factor augments Tie2-expressing monocyte differentiation, angiogenic function, and recruitment in a mouse model of breast cancer.

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Mary A Forget

Full Text Available Reports demonstrate the role of M-CSF (CSF1 in tumor progression in mouse models as well as the prognostic value of macrophage numbers in breast cancer patients. Recently, a subset of CD14+ monocytes expressing the Tie2 receptor, once thought to be predominantly expressed on endothelial cells, has been characterized. We hypothesized that increased levels of CSF1 in breast tumors can regulate differentiation of Tie2- monocytes to a Tie2+ phenotype. We treated CD14+ human monocytes with CSF1 and found a significant increase in CD14+/Tie2+ positivity. To understand if CSF1-induced Tie2 expression on these cells improved their migratory ability, we pre-treated CD14+ monocytes with CSF1 and used Boyden chemotaxis chambers to observe enhanced response to angiopoietin-2 (ANG2, the chemotactic ligand for the Tie2 receptor. We found that CSF1 pre-treatment significantly augmented chemotaxis and that Tie2 receptor upregulation was responsible as siRNA targeting Tie2 receptor abrogated this effect. To understand any augmented angiogenic effect produced by treating these cells with CSF1, we cultured human umbilical vein endothelial cells (HUVECs with conditioned supernatants from CSF1-pre-treated CD14+ monocytes for a tube formation assay. While supernatants from CSF1-pre-treated TEMs increased HUVEC branching, a neutralizing antibody against the CSF1R abrogated this activity, as did siRNA against the Tie2 receptor. To test our hypothesis in vivo, we treated PyMT tumor-bearing mice with CSF1 and observed an expansion in the TEM population relative to total F4/80+ cells, which resulted in increased angiogenesis. Investigation into the mechanism of Tie2 receptor upregulation on CD14+ monocytes by CSF1 revealed a synergistic contribution from the PI3 kinase and HIF pathways as the PI3 kinase inhibitor LY294002, as well as HIF-1α-deficient macrophages differentiated from the bone marrow of HIF-1αfl/fl/LysMcre mice, diminished CSF1-stimulated Tie2 receptor

Emission model for landfills with mechanically-biologically pretreated waste, with the emphasis on modelling the gas balance; Emissionsprognosemodell fuer Deponien mit mechanisch-biologisch vorbehandelten Abfaellen - Schwerpunkt: Modellierung des Gashaushaltes

Energy Technology Data Exchange (ETDEWEB)

Danhamer, H.

2001-07-01

The objective of this work was to determine influence factors on processes going on in landfills with mechanically-biologically pretreated waste (MBP-landfills) in order to predict emissions. For this purpose a computer based model has been developed. The model allows to simulate the gas, water and heat balance as well as settlement processes and was called DESIM2005 (version MB). It is based on theoretical modeling approaches as well as data from lab and reactor experiments. The main focus of model application was to determine factors influencing the gas phase and the emissions of landfill gas and methane during operation and aftercare of MBP-landfills. By performing simulations the effects of changing parameters for the processes gas transport and biological degradation as well as the effects of different qualities in waste pretreatment and of varying landfill operation techniques were investigated. Possibilities for increasing the environmental sustainability of landfills containing mechanically-biologically pretreated waste were shown. (orig.)

The Oak Ridge Polycystic Kidney mouse: modeling ciliopathies of mice and men.

Energy Technology Data Exchange (ETDEWEB)

Lehman, J M [University of Alabama, Birmingham; Michaud III, Edward J [ORNL; Schoeb, T [University of Alabama, Birmingham; Aydin Son, Yesim [University of Tennessee, Knoxville (UTK); Miller, M [University of Alabama, Birmingham; Yoder, Bradley [University of Alabama, Birmingham

2008-08-01

The Oak Ridge Polycystic Kidney (ORPK) mouse was described nearly 14 years ago as a model for human recessive polycystic kidney disease. The ORPK mouse arose through integration of a transgene into an intron of the Ift88 gene resulting in a hypomorphic allele (Ift88Tg737Rpw). The Ift88Tg737Rpw mutation impairs intraflagellar transport (IFT), a process required for assembly of motile and immotile cilia. Historically, the primary immotile cilium was thought to have minimal importance for human health; however, a rapidly expanding number of human disorders have now been attributed to ciliary defects. Importantly, many of these phenotypes are present and can be analyzed using the ORPK mouse. In this review, we highlight the research conducted using the OPRK mouse and the phenotypes shared with human cilia disorders. Furthermore, we describe an additional follicular dysplasia phenotype in the ORPK mouse, which alongside the ectodermal dysplasias seen in human Ellis-van Creveld and Sensenbrenner's syndromes, suggests an unappreciated role for primary cilia in the skin and hair follicle.

Influence of caffeine on the protective activity of gabapentin and topiramate in a mouse model of generalized tonic-clonic seizures.

Science.gov (United States)

Jargiełło-Baszak, Małgorzata; Chrościńska-Krawczyk, Magdalena; Andres-Mach, Marta; Łuszczki, Jarogniew J; Czuczwar, Stanisław J

2016-08-01

Caffeine may interact with classical antiepileptic drugs (AEDs), reducing their anticonvulsant effects in basic seizure models. The aim of the present study was to ascertain whether intraperitoneal caffeine (acute or chronic for 15 days) could attenuate the anticonvulsant effect of some newer AEDs: gabapentin (GBP) and topiramate (TPM) against electroconvulsions in mice. Maximal electroshock (MES)-induced mouse seizure model was used for the estimation of the anticonvulsant activity of TPM whilst the protective activity of GBP was evaluated in the threshold test for maximal (tonic) convulsions. Adverse effects were evaluated by measurement of long-term memory (the step-through passive avoidance task) and motor coordination (chimney test). Plasma AED concentrations were also measured to determinate any pharmacokinetic contribution to the observed effects. Caffeine (both acute and chronic at 23.1 and 46.2mg/kg) significantly reduced the protective effects of TPM against MES. As regards GBP, caffeine (acutely at 46.2mg/kg and chronically at 23.1 or 46.2mg/kg) significantly diminished the GBP-induced increases in the electroconvulsive threshold. In addition, caffeine did not affect the free plasma concentrations of TPM or GBP. Acute and chronic caffeine (23.1 and 46.2mg/kg) enhanced the impairment of motor coordination in mice pretreated with GBP whilst an opposite effect was observed in TPM injected mice and pretreated with chronic caffeine at 46.2mg/kg. The results indicate that newer AEDs, GBP or TPM behave in the exactly same way as classical antiepileptics in mice challenged with caffeine. This hazardous effect of caffeine is not subject to tolerance. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Long-Term Blocking of Calcium Channels in mdx Mice Results in Differential Effects on Heart and Skeletal Muscle

DEFF Research Database (Denmark)

Jørgensen, Louise Helskov; Blain, Alison; Greally, Elizabeth

2011-01-01

in older mice. However, streptomycin treatment did not show positive effects in diaphragm or heart muscle, and heart pathology was worsened. Thus, blocking calcium channels even before disease onset does not prevent dystrophy, making this an unlikely treatment for DMD. These findings highlight......The disease mechanisms underlying dystrophin-deficient muscular dystrophy are complex, involving not only muscle membrane fragility, but also dysregulated calcium homeostasis. Specifically, it has been proposed that calcium channels directly initiate a cascade of pathological events by allowing...... calcium ions to enter the cell. The objective of this study was to investigate the effect of chronically blocking calcium channels with the aminoglycoside antibiotic streptomycin from onset of disease in the mdx mouse model of Duchenne muscular dystrophy (DMD). Treatment in utero onwards delayed onset...

USING OF MOUSE MODEL TO ANALYZE IMMUNE RESPONSE TO INFECTIOUS PATHOGENS BY THE METHODS OF CLASSICAL GENETICS

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A. Poltorak

2011-01-01

Full Text Available Abstract. Identification and studying of numerous functions of all genes of the human beings is one of the main objects of modern biological science. Due to high level of homology between mouse and human genomes the important role to reach above mentioned goal belongs to the mouse model which using in the classical genetics increase in connection with appearance of different inbred mouse lines. For instance, the differences in immune response to infectious pathogens in various mouse lines were used many times to determine immunologically competent genes. That is why the contribution of mouse model in understanding of the mechanisms of immune response to infectious pathogens is difficult to overestimate. In the current review some of the most successful and well known examples of mouse using in studies of anti-infectious response are described.

Cholinergic anti-inflammatory pathway in the non-obese diabetic mouse model

NARCIS (Netherlands)

Koopman, F. A.; Vosters, J. L.; Roescher, N.; Broekstra, N.; Tak, P. P.; Vervoordeldonk, M. J.

2015-01-01

Activation of the cholinergic anti-inflammatory pathway (CAP) has been shown to reduce inflammation in animal models, while abrogation of the pathway increases inflammation. We investigated whether modulation of CAP influences inflammation in the non-obese diabetic (NOD) mouse model for Sjögren's

EFFECT OF AQUEOUS PRETREATMENT ON PYROLYSIS CHARACTERISTICS OF NAPIER GRASS

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ISAH YAKUB MOHAMMED

2015-11-01

Full Text Available Effect of non-catalytic aqueous pretretment on pyrolysis characteristics of Napier grass was investigated using thermogravimetric analyser. Increasing pretreatment severity (0.0-2.0 improved pyrolysis process. The residual mass at the end of pyrolysis for the pretreated sample was about 50% less compared to the untreated sample. Kinetics of the process was evaluated using order based model and both pretreated and untreated samples followed first order reaction. The activation energy of the pretreated samples was similar and higher than that of the raw sample which was attributed to faster rate of decomposition due removal of hetromaterials (ash, extractives and some hemicellulose in the pretreatment stage. Finally, this pretreatment method has demonstrated effectiveness for the removal of pyrolysis retardants and will improve the quantity and quality of bio-oil yield.

Development of a unilaterally-lesioned 6-OHDA mouse model of Parkinson's disease.

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Thiele, Sherri L; Warre, Ruth; Nash, Joanne E

2012-02-14

The unilaterally lesioned 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD) has proved to be invaluable in advancing our understanding of the mechanisms underlying parkinsonian symptoms, since it recapitulates the changes in basal ganglia circuitry and pharmacology observed in parkinsonian patients(1-4). However, the precise cellular and molecular changes occurring at cortico-striatal synapses of the output pathways within the striatum, which is the major input region of the basal ganglia remain elusive, and this is believed to be site where pathological abnormalities underlying parkinsonian symptoms arise(3,5). In PD, understanding the mechanisms underlying changes in basal ganglia circuitry following degeneration of the nigro-striatal pathway has been greatly advanced by the development of bacterial artificial chromosome (BAC) mice over-expressing green fluorescent proteins driven by promoters specific for the two striatal output pathways (direct pathway: eGFP-D1; indirect pathway: eGFP-D2 and eGFP-A2a)(8), allowing them to be studied in isolation. For example, recent studies have suggested that there are pathological changes in synaptic plasticity in parkinsonian mice(9,10). However, these studies utilised juvenile mice and acute models of parkinsonism. It is unclear whether the changes described in adult rats with stable 6-OHDA lesions also occur in these models. Other groups have attempted to generate a stable unilaterally-lesioned 6-OHDA adult mouse model of PD by lesioning the medial forebrain bundle (MFB), unfortunately, the mortality rate in this study was extremely high, with only 14% surviving the surgery for 21 days or longer(11). More recent studies have generated intra-nigral lesions with both a low mortality rate >80% loss of dopaminergic neurons, however expression of L-DOPA induced dyskinesia(11,12,13,14) was variable in these studies. Another well established mouse model of PD is the MPTP-lesioned mouse(15). Whilst this

A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis.

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Nina Fransén-Pettersson

Full Text Available Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders.

Dmdmdx/Largemyd: a new mouse model of neuromuscular diseases useful for studying physiopathological mechanisms and testing therapies

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Poliana C. M. Martins

2013-09-01

Although muscular dystrophies are among the most common human genetic disorders, there are few treatment options available. Animal models have become increasingly important for testing new therapies prior to entering human clinical trials. The Dmdmdx mouse is the most widely used animal model for Duchenne muscular dystrophy (DMD, presenting the same molecular and protein defect as seen in humans with the disease. However, this mouse is not useful for clinical trials because of its very mild phenotype. The mouse model for congenital myodystrophy type 1D, Largemyd, harbors a mutation in the glycosyltransferase Large gene and displays a severe phenotype. To help elucidate the role of the proteins dystrophin and LARGE in the organization of the dystrophin-glycoprotein complex in muscle sarcolemma, we generated double-mutant mice for the dystrophin and LARGE proteins. The new Dmdmdx/Largemyd mouse model is viable and shows a severe phenotype that is associated with the lack of dystrophin in muscle. We tested the usefulness of our new mouse model for cell therapy by systemically injecting them with normal murine mesenchymal adipose stem cells (mASCs. We verified that the mASCs were hosted in the dystrophic muscle. The new mouse model has proven to be very useful for the study of several other therapies, because injected cells can be screened both through DNA and protein analysis. Study of its substantial muscle weakness will also be very informative in the evaluation of functional benefits of these therapies.

Towards a mouse model of depression : a psychoneuroendocrine approach

NARCIS (Netherlands)

Dalm, Sergiu

2012-01-01

Chronic stress is considered a vulnerability factor for depression. A key symptom is anhedonia; a reduced response to positive stimuli. Drugs are effective for only 20-40% of the patients and new drugs are urgently needed. The objective of the research was to develop a mouse model of depression that

Sparse Statistical Deformation Model for the Analysis of Craniofacial Malformations in the Crouzon Mouse

DEFF Research Database (Denmark)

Ólafsdóttir, Hildur; Hansen, Michael Sass; Sjöstrand, Karl

2007-01-01

Crouzon syndrome is characterised by the premature fusion of cranial sutures. Recently the first genetic Crouzon mouse model was generated. In this study, Micro CT skull scannings of wild-type mice and Crouzon mice were investigated. Using nonrigid registration, a wild-type mouse atlas was built...

Longitudinal Multiplexed Measurement of Quantitative Proteomic Signatures in Mouse Lymphoma Models Using Magneto-Nanosensors.

Science.gov (United States)

Lee, Jung-Rok; Appelmann, Iris; Miething, Cornelius; Shultz, Tyler O; Ruderman, Daniel; Kim, Dokyoon; Mallick, Parag; Lowe, Scott W; Wang, Shan X

2018-01-01

Cancer proteomics is the manifestation of relevant biological processes in cancer development. Thus, it reflects the activities of tumor cells, host-tumor interactions, and systemic responses to cancer therapy. To understand the causal effects of tumorigenesis or therapeutic intervention, longitudinal studies are greatly needed. However, most of the conventional mouse experiments are unlikely to accommodate frequent collection of serum samples with a large enough volume for multiple protein assays towards single-object analysis. Here, we present a technique based on magneto-nanosensors to longitudinally monitor the protein profiles in individual mice of lymphoma models using a small volume of a sample for multiplex assays. Methods: Drug-sensitive and -resistant cancer cell lines were used to develop the mouse models that render different outcomes upon the drug treatment. Two groups of mice were inoculated with each cell line, and treated with either cyclophosphamide or vehicle solution. Serum samples taken longitudinally from each mouse in the groups were measured with 6-plex magneto-nanosensor cytokine assays. To find the origin of IL-6, experiments were performed using IL-6 knock-out mice. Results: The differences in serum IL-6 and GCSF levels between the drug-treated and untreated groups were revealed by the magneto-nanosensor measurement on individual mice. Using the multiplex assays and mouse models, we found that IL-6 is secreted by the host in the presence of tumor cells upon the drug treatment. Conclusion: The multiplex magneto-nanosensor assays enable longitudinal proteomic studies on mouse tumor models to understand tumor development and therapy mechanisms more precisely within a single biological object.

Mouse neuroblastoma cell based model and the effect of epileptic events on calcium oscillations and neural spikes

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Kim, Suhwan; Baek, Juyeong; Jung, Unsang; Lee, Sangwon; Jung, Woonggyu; Kim, Jeehyun; Kang, Shinwon

2013-05-01

Recently, Mouse neuroblastoma cells are considered as an attractive model for the study of human neurological and prion diseases, and intensively used as a model system in different areas. Among those areas, differentiation of neuro2a (N2A) cells, receptor mediated ion current, and glutamate induced physiological response are actively investigated. The reason for the interest to mouse neuroblastoma N2A cells is that they have a fast growing rate than other cells in neural origin with a few another advantages. This study evaluated the calcium oscillations and neural spikes recording of mouse neuroblastoma N2A cells in an epileptic condition. Based on our observation of neural spikes in mouse N2A cell with our proposed imaging modality, we report that mouse neuroblastoma N2A cells can be an important model related to epileptic activity studies. It is concluded that the mouse neuroblastoma N2A cells produce the epileptic spikes in vitro in the same way as produced by the neurons or the astrocytes. This evidence advocates the increased and strong level of neurotransmitters release by enhancement in free calcium using the 4-aminopyridine which causes the mouse neuroblastoma N2A cells to produce the epileptic spikes and calcium oscillation.

[Effect of topical application of a recombinant adenovirus carrying promyelocytic leukemia gene in a psoriasis-like mouse model].

Science.gov (United States)

Wang, Qiongyu; Zhang, Aijun; Ma, Huiqun; Wang, Shijie; Ma, Yunyun; Zou, Xingwei; Li, Ruilian

2013-03-01

To investigate the effects of topical treatment with adenovirus-mediated promyelocytic leukemia gene (PML) gene in a psoriasis-like mouse model. The effect of adenovirus-mediated PML gene on the granular layer of mouse tail scale epidermis and epithelial mitosis were observed on longitudinal histological sections prepared from the tail skin and vaginal epithelium of the mice. Adenovirus-mediated PML gene significantly inhibited mitosis of mouse vaginal epithelial cells and promoted the formation of granular layer in mouse tail scale epidermis. The therapeutic effect of PML gene in the psoriasis-like mouse model may be associated with increased granular cells and suppressed epidemic cell proliferation.

Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy.

Science.gov (United States)

Nash, Kevin R; Lee, Daniel C; Hunt, Jerry B; Morganti, Josh M; Selenica, Maj-Linda; Moran, Peter; Reid, Patrick; Brownlow, Milene; Guang-Yu Yang, Clement; Savalia, Miloni; Gemma, Carmelina; Bickford, Paula C; Gordon, Marcia N; Morgan, David

2013-06-01

Alzheimer's disease is characterized by amyloid plaques, neurofibrillary tangles, glial activation, and neurodegeneration. In mouse models, inflammatory activation of microglia accelerates tau pathology. The chemokine fractalkine serves as an endogenous neuronal modulator to quell microglial activation. Experiments with fractalkine receptor null mice suggest that fractalkine signaling diminishes tau pathology, but exacerbates amyloid pathology. Consistent with this outcome, we report here that soluble fractalkine overexpression using adeno-associated viral vectors significantly reduced tau pathology in the rTg4510 mouse model of tau deposition. Furthermore, this treatment reduced microglial activation and appeared to prevent neurodegeneration normally found in this model. However, in contrast to studies with fractalkine receptor null mice, parallel studies in an APP/PS1 model found no effect of increased fractalkine signaling on amyloid deposition. These data argue that agonism at fractalkine receptors might be an excellent target for therapeutic intervention in tauopathies, including those associated with amyloid deposition. Copyright © 2013 Elsevier Inc. All rights reserved.

Construction of a mouse model of factor VIII deficiency by gene targeting

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Bi, L.; Lawler, A.; Gearhart, J. [Univ. of Pennsylvania School of Medicine, Philadelphia, PA (United States)] [and others

1994-09-01

To develop a small animal model of hemophilia A for gene therapy experiments, we set out to construct a mouse model for factor VIII deficiency by gene targeting. First, we screened a mouse liver cDNA library using a human FVIII cDNA probe. We cloned a 2.6 Kb partial mouse factor VIII cDNA which extends from 800 base pairs of the 3{prime} end of exon 14 to the 5{prime} end of exon 26. A mouse genomic library made from strain 129 was then screened to obtain genomic fragments covering the exons desired for homologous recombination. Two genomic clones were obtained, and one covering exon 15 through 22 was used for gene targeting. To make gene targeting constructs, a 5.8 Kb genomic DNA fragment covering exons 15 to 19 of the mouse FVIII gene was subcloned, and the neo expression cassette was inserted into exons 16 and 17 separately by different strategies. These two constructs were named MFVIIIC-16 and MFVIIIC-17. The constructs were linearized and transfected into strain 129 mouse ES cells by electroporation. Factor VIII gene-knockout ES cell lines were selected by G-418 and screened by genomic Southern blots. Eight exon 16 targeted cell lines and five exon 17 targeted cell lines were obtained. Three cell lines from each construct were injected into blastocysts and surgically transferred into foster mothers. Multiple chimeric mice with 70-90% hair color derived from the ES-cell genotype were seen with both constructs. Germ line transmission of the ES-cell genotype has been obtained for the MFVIIIC-16 construct, and multiple hemophilia A carrier females have been identified. Factor VIII-deficient males will be conceived soon.

Inhibition of Pyk2 blocks lung inflammation and injury in a mouse model of acute lung injury

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Duan Yingli

2012-01-01

Full Text Available Abstract Background Proline-rich tyrosine kinase 2 (Pyk2 is essential in neutrophil degranulation and chemotaxis in vitro. However, its effect on the process of lung inflammation and edema formation during LPS induced acute lung injury (ALI remains unknown. The goal of the present study was to determine the effect of inhibiting Pyk2 on LPS-induced acute lung inflammation and injury in vivo. Methods C57BL6 mice were given either 10 mg/kg LPS or saline intratracheally. Inhibition of Pyk2 was effected by intraperitoneal administration TAT-Pyk2-CT 1 h before challenge. Bronchoalveolar lavage analysis of cell counts, lung histology and protein concentration in BAL were analyzed at 18 h after LPS treatment. KC and MIP-2 concentrations in BAL were measured by a mouse cytokine multiplex kit. The static lung compliance was determined by pressure-volume curve using a computer-controlled small animal ventilator. The extravasated Evans blue concentration in lung homogenate was determined spectrophotometrically. Results Intratracheal instillation of LPS induced significant neutrophil infiltration into the lung interstitium and alveolar space, which was attenuated by pre-treatment with TAT-Pyk2-CT. TAT-Pyk2-CT pretreatment also attenuated 1 myeloperoxidase content in lung tissues, 2 vascular leakage as measured by Evans blue dye extravasation in the lungs and the increase in protein concentration in bronchoalveolar lavage, and 3 the decrease in lung compliance. In each paradigm, treatment with control protein TAT-GFP had no blocking effect. By contrast, production of neutrophil chemokines MIP-2 and keratinocyte-derived chemokine in the bronchoalveolar lavage was not reduced by TAT-Pyk2-CT. Western blot analysis confirmed that tyrosine phosphorylation of Pyk2 in LPS-challenged lungs was reduced to control levels by TAT-Pyk2-CT pretreatment. Conclusions These results suggest that Pyk2 plays an important role in the development of acute lung injury in mice and

Riluzole does not improve lifespan or motor function in three ALS mouse models.

Science.gov (United States)

Hogg, Marion C; Halang, Luise; Woods, Ina; Coughlan, Karen S; Prehn, Jochen H M

2017-12-08

Riluzole is the most widespread therapeutic for treatment of the progressive degenerative disease amyotrophic lateral sclerosis (ALS). Riluzole gained FDA approval in 1995 before the development of ALS mouse models. We assessed riluzole in three transgenic ALS mouse models: the SOD1 G93A model, the TDP-43 A315T model, and the recently developed FUS (1-359) model. Age, sex and litter-matched mice were treated with riluzole (22 mg/kg) in drinking water or vehicle (DMSO) from symptom onset. Lifespan was assessed and motor function tests were carried out twice weekly to determine whether riluzole slowed disease progression. Riluzole treatment had no significant benefit on lifespan in any of the ALS mouse models tested. Riluzole had no significant impact on decline in motor performance in the FUS (1-359) and SOD1 G93A transgenic mice as assessed by Rotarod and stride length analysis. Riluzole is widely prescribed for ALS patients despite questions surrounding its efficacy. Our data suggest that if riluzole was identified as a therapeutic candidate today it would not progress past pre-clinical assessment. This raises questions about the standards used in pre-clinical assessment of therapeutic candidates for the treatment of ALS.

Empirical Modeling on Hot Air Drying of Fresh and Pre-treated Pineapples

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Tanongkankit Yardfon

2016-01-01

Full Text Available This research was aimed to study drying kinetics and determine empirical model of fresh pineapple and pre-treated pineapple with sucrose solution at different concentrations during drying. 3 mm thick samples were immersed into 30, 40 and 50 Brix of sucrose solution before hot air drying at temperatures of 60, 70 and 80°C. The empirical models to predict the drying kinetics were investigated. The results showed that the moisture content decreased when increasing the drying temperatures and times. Increase in sucrose concentration led to longer drying time. According to the statistical values of the highest coefficients (R2, the lowest least of chi-square (χ2 and root mean square error (RMSE, Logarithmic model was the best models for describing the drying behavior of soaked samples into 30, 40 and 50 Brix of sucrose solution.

Genetically engineered mouse models of craniopharyngioma: an opportunity for therapy development and understanding of tumor biology.

Science.gov (United States)

Apps, John Richard; Martinez-Barbera, Juan Pedro

2017-05-01

Adamantinomatous craniopharyngioma (ACP) is the commonest tumor of the sellar region in childhood. Two genetically engineered mouse models have been developed and are giving valuable insights into ACP biology. These models have identified novel pathways activated in tumors, revealed an important function of paracrine signalling and extended conventional theories about the role of organ-specific stem cells in tumorigenesis. In this review, we summarize these mouse models, what has been learnt, their limitations and open questions for future research. We then discussed how these mouse models may be used to test novel therapeutics against potentially targetable pathways recently identified in human ACP. © 2017 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.

Manifestation of Non-Alcoholic Fatty Liver Disease/Non-Alcoholic Steatohepatitis in Different Dietary Mouse Models

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Vera HI Fengler

2016-05-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD and non-alcoholic steatohepatitis (NASH, which are usually associated with obesity and metabolic syndrome, are considerable health and economic issues due to the rapid increase of their prevalence in Western society. Histologically, the diseases are characterised by steatosis, hepatic inflammation, and if further progressed, fibrosis. Dietary-induced mouse models are widely used in investigations of the development and progression of NAFLD and NASH; these models attempt to mimic the histological and metabolic features of the human diseases. However, the majority of dietary mouse models fail to reflect the whole pathophysiological spectrum of NAFLD and NASH. Some models exhibit histological features similar to those seen in humans while lacking the metabolic context, while others resemble the metabolic conditions leading to NAFLD in humans but fail to mimic the whole histological spectrum, including progression from steatosis to liver fibrosis, and thus fail to mimic NASH. This review summarises the advantages and disadvantages of the different dietary-induced mouse models of NAFLD and NASH, with a focus on the genetic background of several commonly used wild-type mouse strains as well as gender and age, which influence the development and progression of these liver diseases.

Mouse Model Resources for Vision Research

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Jungyeon Won

2011-01-01

Full Text Available The need for mouse models, with their well-developed genetics and similarity to human physiology and anatomy, is clear and their central role in furthering our understanding of human disease is readily apparent in the literature. Mice carrying mutations that alter developmental pathways or cellular function provide model systems for analyzing defects in comparable human disorders and for testing therapeutic strategies. Mutant mice also provide reproducible, experimental systems for elucidating pathways of normal development and function. Two programs, the Eye Mutant Resource and the Translational Vision Research Models, focused on providing such models to the vision research community are described herein. Over 100 mutant lines from the Eye Mutant Resource and 60 mutant lines from the Translational Vision Research Models have been developed. The ocular diseases of the mutant lines include a wide range of phenotypes, including cataracts, retinal dysplasia and degeneration, and abnormal blood vessel formation. The mutations in disease genes have been mapped and in some cases identified by direct sequencing. Here, we report 3 novel alleles of Crxtvrm65, Rp1tvrm64, and Rpe65tvrm148 as successful examples of the TVRM program, that closely resemble previously reported knockout models.

Galantamine improves olfactory learning in the Ts65Dn mouse model of Down syndrome.

Science.gov (United States)

de Souza, Fabio M Simoes; Busquet, Nicolas; Blatner, Megan; Maclean, Kenneth N; Restrepo, Diego

2011-01-01

Down syndrome (DS) is the most common form of congenital intellectual disability. Although DS involves multiple disturbances in various tissues, there is little doubt that in terms of quality of life cognitive impairment is the most serious facet and there is no effective treatment for this aspect of the syndrome. The Ts65Dn mouse model of DS recapitulates multiple aspects of DS including cognitive impairment. Here the Ts65Dn mouse model of DS was evaluated in an associative learning paradigm based on olfactory cues. In contrast to disomic controls, trisomic mice exhibited significant deficits in olfactory learning. Treatment of trisomic mice with the acetylcholinesterase inhibitor galantamine resulted in a significant improvement in olfactory learning. Collectively, our study indicates that olfactory learning can be a sensitive tool for evaluating deficits in associative learning in mouse models of DS and that galantamine has therapeutic potential for improving cognitive abilities.

Applications of ribosomal in situ hybridization for the study of bacterial cells in the mouse intestine

DEFF Research Database (Denmark)

Licht, Tine Rask; Poulsen, Lars Kongsbak; Molin, Søren

1997-01-01

Localization of E. coli and S. typhimurium in the large and small intestine of streptomycin-treated mice was visualized by in situ hybridization with specific rRNA target probes and epi-fluorescence microscopy. Growth rates of E. coli BJ4 colonizing the large intestine of streptomycin-treated mic...

Moringin activates Wnt canonical pathway by inhibiting GSK3β in a mouse model of experimental autoimmune encephalomyelitis

Directory of Open Access Journals (Sweden)

Giacoppo S

2016-10-01

Full Text Available Sabrina Giacoppo,1 Thangavelu Soundara Rajan,1 Gina Rosalinda De Nicola,2 Renato Iori,2 Placido Bramanti,1 Emanuela Mazzon1 1IRCCS Centre Neurolesi “Bonino-Pulejo”, Messina, Italy; 2Council for Agricultural Research and Economics, Research Centre for Industrial Crops (CREA-CIN, Bologna, Italy Abstract: Aberrant canonical Wnt–β-catenin signaling has been reported in multiple sclerosis (MS, although the results are controversial. The present study aimed to examine the role of the Wnt–β-catenin pathway in experimental MS and also to test moringin (4-[α-L-rhamnopyranosyloxy]-benzyl isothiocyanate, resulting from exogenous myrosinase hydrolysis of the natural phytochemical glucomoringin 4(α-L-rhamnosyloxy-benzyl glucosinolate as a modulator of neuroinflammation via the β-catenin–PPARγ axis. Experimental autoimmune encephalomyelitis (EAE, the most common model of MS, was induced in C57BL/6 mice by immunization with MOG35–55. Released moringin (10 mg/kg glucomoringin +5 µL myrosinase/mouse was administered daily for 1 week before EAE induction and continued until mice were killed on day 28 after EAE induction. Our results clearly showed that the Wnt–β-catenin pathway was downregulated in the EAE model, whereas moringin pretreatment was able to avert this. Moringin pretreatment normalizes the aberrant Wnt–β-catenin pathway, resulting in GSK3β inhibition and β-catenin upregulation, which regulates T-cell activation (CD4 and FoxP3, suppresses the main inflammatory mediators (IL-1β, IL-6, and COX2, through activation of PPARγ. In addition, moringin attenuates apoptosis by reducing the expression of the Fas ligand and cleaved caspase 9, and in parallel increases antioxidant Nrf2 expression in EAE mice. Taken together, our results provide an interesting discovery in identifying moringin as a modulator of the Wnt–β-catenin signaling cascade and as a new potential therapeutic target for MS treatment. Keywords: Wnt�

Characterization of a mouse-adapted Staphylococcus aureus strain.

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Silva Holtfreter

Full Text Available More effective antibiotics and a protective vaccine are desperately needed to combat the 'superbug' Staphylococcus aureus. While in vivo pathogenicity studies routinely involve infection of mice with human S. aureus isolates, recent genetic studies have demonstrated that S. aureus lineages are largely host-specific. The use of such animal-adapted S. aureus strains may therefore be a promising approach for developing more clinically relevant animal infection models. We have isolated a mouse-adapted S. aureus strain (JSNZ which caused a severe outbreak of preputial gland abscesses among male C57BL/6J mice. We aimed to extensively characterize this strain on a genomic level and determine its virulence potential in murine colonization and infection models. JSNZ belongs to the MLST type ST88, rare among human isolates, and lacks an hlb-converting phage encoding human-specific immune evasion factors. Naive mice were found to be more susceptible to nasal and gastrointestinal colonization with JSNZ than with the human-derived Newman strain. Furthermore, naïve mice required antibiotic pre-treatment to become colonized with Newman. In contrast, JSNZ was able to colonize mice in the absence of antibiotic treatment suggesting that this strain can compete with the natural flora for space and nutrients. In a renal abscess model, JSNZ caused more severe disease than Newman with greater weight loss and bacterial burden. In contrast to most other clinical isolates, JSNZ can also be readily genetically modified by phage transduction and electroporation. In conclusion, the mouse-adapted strain JSNZ may represent a valuable tool for studying aspects of mucosal colonization and for screening novel vaccines and therapies directed at preventing colonization.

A Mathematical Model of Skeletal Muscle Disease and Immune Response in the mdx Mouse

Directory of Open Access Journals (Sweden)

Abdul Salam Jarrah

2014-01-01

Full Text Available Duchenne muscular dystrophy (DMD is a genetic disease that results in the death of affected boys by early adulthood. The genetic defect responsible for DMD has been known for over 25 years, yet at present there is neither cure nor effective treatment for DMD. During early disease onset, the mdx mouse has been validated as an animal model for DMD and use of this model has led to valuable but incomplete insights into the disease process. For example, immune cells are thought to be responsible for a significant portion of muscle cell death in the mdx mouse; however, the role and time course of the immune response in the dystrophic process have not been well described. In this paper we constructed a simple mathematical model to investigate the role of the immune response in muscle degeneration and subsequent regeneration in the mdx mouse model of Duchenne muscular dystrophy. Our model suggests that the immune response contributes substantially to the muscle degeneration and regeneration processes. Furthermore, the analysis of the model predicts that the immune system response oscillates throughout the life of the mice, and the damaged fibers are never completely cleared.

Effect of CPAP in a Mouse Model of Hyperoxic Neonatal Lung Injury

Science.gov (United States)

Reyburn, Brent; Fiore, Juliann M. Di; Raffay, Thomas; Martin, Richard J.; Y.S., Prakash; Jafri, Anjum; MacFarlane, Peter M.

2015-01-01

Background Continuous positive airway pressure [CPAP] and supplemental oxygen have become the mainstay of neonatal respiratory support in preterm infants. Although oxygen therapy is associated with respiratory morbidities including bronchopulmonary dysplasia [BPD], the long-term effects of CPAP on lung function are largely unknown. We used a hyperoxia-induced mouse model of BPD to explore the effects of daily CPAP during the first week of life on later respiratory system mechanics. Objective To test the hypothesis that daily CPAP in a newborn mouse model of BPD improves longer term respiratory mechanics. Methods Mouse pups from C57BL/6 pregnant dams were exposed to room air [RA] or hyperoxia [50% O2, 24hrs/day] for the first postnatal week with or without exposure to daily CPAP [6cmH2O, 3hrs/day]. Respiratory system resistance [Rrs] and compliance [Crs] were measured following a subsequent 2 week period of room RA recovery. Additional measurements included radial alveolar counts and macrophage counts. Results Mice exposed to hyperoxia had significantly elevated Rrs, decreased Crs, reduced alveolarization, and increased macrophage counts at three weeks compared to RA treated mice. Daily CPAP treatment significantly improved Rrs, Crs and alveolarization, and decreased lung macrophage infiltration in hyperoxia-exposed pups. Conclusions We have demonstrated that daily CPAP had a longer term benefit on baseline respiratory system mechanics in a neonatal mouse model of BPD. We speculate that this beneficial effect of CPAP was the consequence of a decrease in the inflammatory response and resultant alveolar injury associated with hyperoxic newborn lung injury. PMID:26394387

Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments

Science.gov (United States)

Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B.; Wang, Ya

2016-06-01

Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

Impact of pretreatment on colour and texture of watermelon rind

Science.gov (United States)

Athmaselvi, K.; Alagusundaram, K.; Kavitha, C.; Arumuganathan, T.

2012-07-01

The effect of osmotic dehydration pretreatment on water loss, solid gain, colour and textural change was investigated. Watermelon rind 1 x 1 cm size was immersed in sucrose solution of 40, 50 and 60° Brix after pretreatment with microwave and conventional boiling in water for 1, 3, and 5 min, respectively. Water loss and solid gain increased with the time of cooking and sugar concentration. Microwave pretreated samples showed higher water loss and solid gain. Increase in the time of cooking decreased the brightness of all the samples. Microwave pretreated samples showed higher `b' values than conventionally pretreated ones. There was no significant difference (P≤0.05) in texture profile analysis parameters except for hardness. Hardness decreased with increase in time of cooking and sugar concentration. Second order regression model was developed for water loss and solid gain of microwave and conventional pretreated watermelon rind.

Automatic Assessment of Craniofacial Growth in a Mouse Model of Crouzon Syndrome

DEFF Research Database (Denmark)

Thorup, Signe Strann; Larsen, Rasmus; Darvann, Tron Andre

2009-01-01

for each mouse-type; growth models were created using linear interpolation and visualized as 3D animations. Spatial regions of significantly different growth were identified using the local False Discovery Rate method, estimating the expected percentage of false predictions in a set of predictions. For all......-rigid volumetric image registration was applied to micro-CT scans of ten 4-week and twenty 6-week euthanized mice for growth modeling. Each age group consisted of 50% normal and 50% Crouzon mice. Four 3D mean shapes, one for each mouse-type and age group were created. Extracting a dense field of growth vectors...... a tool for spatially detailed automatic phenotyping. MAIN OBJECTIVES OF PRESENTATION: We will present a 3D growth model of normal and Crouzon mice, and differences will be statistically and visually compared....

Molecular Alterations in a Mouse Cardiac Model of Friedreich Ataxia

DEFF Research Database (Denmark)

Anzovino, Amy; Chiang, Shannon; Brown, Bronwyn E

2017-01-01

mechanisms. Using a mouse conditional frataxin knockout (KO) model in the heart and skeletal muscle, we examined the Nrf2 pathway in these tissues. Frataxin KO results in fatal cardiomyopathy, whereas skeletal muscle was asymptomatic. In the KO heart, protein oxidation and a decreased glutathione...

Thymoquinone inhibits phorbol ester-induced activation of NF-κB and expression of COX-2, and induces expression of cytoprotective enzymes in mouse skin in vivo

International Nuclear Information System (INIS)

Kundu, Joydeb Kumar; Liu, Lijia; Shin, Jun-Wan; Surh, Young-Joon

2013-01-01

Highlights: •Thymoquinone inhibits phorbol ester-induced COX-2 expression in mouse skin. •Thymoquinone attenuates phosphorylation of IκBα and DNA binding of NF-κB in mouse skin. •Thymoquinone inhibits phosphorylation of p38 MAP kinase, JNK and Akt in mouse skin. •Thymoquinone induces the expression of cytoprotective proteins in mouse skin. -- Abstract: Thymoquinone (TQ), the active ingredient of Nigella sativa, has been reported to possess anti-inflammatory and chemopreventive properties. The present study was aimed at elucidating the molecular mechanisms of anti-inflammatory and antioxidative activities of thymoquinone in mouse skin. Pretreatment of female HR-1 hairless mouse skin with TQ attenuated 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced expression of cyclooxygenase-2 (COX-2). TQ diminished nuclear translocation and the DNA binding of nuclear factor-kappaB (NF-κB) via the blockade of phosphorylation and subsequent degradation of IκBα in TPA-treated mouse skin. Pretreatment with TQ attenuated the phosphorylation of Akt, c-Jun-N-terminal kinase and p38 mitogen-activated protein kinase, but not that of extracellular signal-regulated kinase-1/2. Moreover, topical application of TQ induced the expression of heme oxygenase-1, NAD(P)H-quinoneoxidoreductase-1, glutathione-S-transferase and glutamate cysteine ligase in mouse skin. Taken together, the inhibitory effects of TQ on TPA-induced COX-2 expression and NF-κB activation, and its ability to induce the expression of cytoprotective proteins provide a mechanistic basis of anti-inflammatory and antioxidative effects of TQ in hairless mouse skin

Using Bioluminescence To Monitor Treatment Response in Real Time in Mice with Mycobacterium ulcerans Infection▿

OpenAIRE

Zhang, Tianyu; Li, Si-Yang; Converse, Paul J.; Almeida, Deepak V.; Grosset, Jacques H.; Nuermberger, Eric L.

2010-01-01

Mycobacterium ulcerans causes Buruli ulcer, a potentially disabling ulcerative skin disease. Only recently was antimicrobial therapy proven effective. Treatment for 2 months with rifampin plus streptomycin was first proposed after experiments in the mouse footpad model demonstrated bactericidal activity. This treatment is now considered the treatment of choice, although larger ulcers may require adjunctive surgery. Shorter, oral regimens are desired, but evaluating drug activity in mice is ha...

Hypothalamic food intake regulation in a cancer-cachectic mouse model

OpenAIRE

Dwarkasing, Jvalini T.; van Dijk, Miriam; Dijk, Francina J.; Boekschoten, Mark V.; Faber, Joyce; Argilès, Josep M.; Laviano, Alessandro; Müller, Michael; Witkamp, Renger F.; van Norren, Klaske

2013-01-01

Background Appetite is frequently affected in cancer patients leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer-cachectic mouse model with increased food intake. In this model, mice bearing C26 tumour have an increased food intake subsequently to the loss of body weight. We hypothesise that in this model, appetite-regulating systems in the hypothalamus, which apparently fail in anorexia, are still able t...

Recent technological advances in using mouse models to study ovarian cancer.

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House, Carrie Danielle; Hernandez, Lidia; Annunziata, Christina Messineo

2014-01-01

Serous epithelial ovarian cancer (SEOC) is the most lethal gynecological cancer in the United States with disease recurrence being the major cause of morbidity and mortality. Despite recent advances in our understanding of the molecular mechanisms responsible for the development of SEOC, the survival rate for women with this disease has remained relatively unchanged in the last two decades. Preclinical mouse models of ovarian cancer, including xenograft, syngeneic, and genetically engineered mice, have been developed to provide a mechanism for studying the development and progression of SEOC. Such models strive to increase our understanding of the etiology and dissemination of ovarian cancer in order to overcome barriers to early detection and resistance to standard chemotherapy. Although there is not a single model that is most suitable for studying ovarian cancer, improvements have led to current models that more closely mimic human disease in their genotype and phenotype. Other advances in the field, such as live animal imaging techniques, allow effective monitoring of the microenvironment and therapeutic efficacy. New and improved preclinical mouse models, combined with technological advances to study such models, will undoubtedly render success of future human clinical trials for patients with SEOC.

A recombinant lentiviral PDGF-driven mouse model of proneural glioblastoma.

Science.gov (United States)

Rahme, Gilbert J; Luikart, Bryan W; Cheng, Chao; Israel, Mark A

2018-02-19

Mouse models of glioblastoma (GBM), the most aggressive primary brain tumor, are critical for understanding GBM pathology and can contribute to the preclinical evaluation of therapeutic agents. Platelet-derived growth factor (PDGF) signaling has been implicated in the development and pathogenesis of GBM, specifically the proneural subtype. Although multiple mouse models of PDGF-driven glioma have been described, they require transgenic mice engineered to activate PDGF signaling and/or impair tumor suppressor genes and typically represent lower-grade glioma. We designed recombinant lentiviruses expressing both PDGFB and a short hairpin RNA targeting Cdkn2a to induce gliomagenesis following stereotactic injection into the dentate gyrus of adult immunocompetent mice. We engineered these viruses to coexpress CreERT2 with PDGFB, allowing for deletion of floxed genes specifically in transduced cells, and designed another version of this recombinant lentivirus in which enhanced green fluorescent protein was coexpressed with PDGFB and CreERT2 to visualize transduced cells. The dentate gyrus of injected mice showed hypercellularity one week post-injection and subsequently developed bona fide tumors with the pathologic hallmarks of GBM leading to a median survival of 77 days post-injection. Transcriptomic analysis of these tumors revealed a proneural gene expression signature. Informed by the genetic alterations observed in human GBM, we engineered a novel mouse model of proneural GBM. While reflecting many of the advantages of transgenic mice, this model allows for the facile in vivo testing of gene function in tumor cells and makes possible the rapid production of large numbers of immunocompetent tumor-bearing mice for preclinical testing of therapeutics. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Arrhythmia phenotype in mouse models of human long QT.

Science.gov (United States)

Salama, Guy; Baker, Linda; Wolk, Robert; Barhanin, Jacques; London, Barry

2009-03-01

Enhanced dispersion of repolarization (DR) was proposed as a unifying mechanism, central to arrhythmia genesis in the long QT (LQT) syndrome. In mammalian hearts, K(+) channels are heterogeneously expressed across the ventricles resulting in 'intrinsic' DR that may worsen in long QT. DR was shown to be central to the arrhythmia phenotype of transgenic mice with LQT caused by loss of function of the dominant mouse K(+) currents. Here, we investigated the arrhythmia phenotype of mice with targeted deletions of KCNE1 and KCNH2 genes which encode for minK/IsK and Merg1 (mouse homolog of human ERG) proteins resulting in loss of function of I(Ks) and I(Kr), respectively. Both currents are important human K(+) currents associated with LQT5 and LQT2. Loss of minK, a protein subunit that interacts with KvLQT1, results in a marked reduction of I(Ks) giving rise to the Jervell and Lange-Nielsen syndrome and the reduced KCNH2 gene reduces MERG and I(Kr). Hearts were perfused, stained with di-4-ANEPPS and optically mapped to compare action potential durations (APDs) and arrhythmia phenotype in homozygous minK (minK(-/-)) and heterozygous Merg1 (Merg(+/-)) deletions and littermate control mice. MinK(-/-) mice has similar APDs and no arrhythmias (n = 4). Merg(+/-) mice had prolonged APDs (from 20 +/- 6 to 32 +/- 9 ms at the base, p mice (60% vs. 10%). A comparison of mouse models of LQT based on K(+) channel mutations important to human and mouse repolarization emphasizes DR as a major determinant of arrhythmia vulnerability.

Enhanced Reconstitution of Human Erythropoiesis and Thrombopoiesis in an Immunodeficient Mouse Model with KitWv Mutations

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Ayano Yurino

2016-09-01

Full Text Available In human-to-mouse xenograft models, reconstitution of human hematopoiesis is usually B-lymphoid dominant. Here we show that the introduction of homozygous KitWv mutations into C57BL/6.Rag2nullIl2rgnull mice with NOD-Sirpa (BRGS strongly promoted human multi-lineage reconstitution. After xenotransplantation of human CD34+CD38− cord blood cells, these newly generated C57BL/6.Rag2nullIl2rgnullNOD-Sirpa KitWv/Wv (BRGSKWv/Wv mice showed significantly higher levels of human cell chimerism and long-term multi-lineage reconstitution compared with BRGS mice. Strikingly, this mouse displayed a robust reconstitution of human erythropoiesis and thrombopoiesis with terminal maturation in the bone marrow. Furthermore, depletion of host macrophages by clodronate administration resulted in the presence of human erythrocytes and platelets in the circulation. Thus, attenuation of mouse KIT signaling greatly enhances the multi-lineage differentiation of human hematopoietic stem and progenitor cells (HSPCs in mouse bone marrow, presumably by outcompeting mouse HSPCs to occupy suitable microenvironments. The BRGSKWv/Wv mouse model is a useful tool to study human multi-lineage hematopoiesis.

A mouse model of mammary hyperplasia induced by oral hormone ...

African Journals Online (AJOL)

Methods and Materials: To address the mechanism, we developed a mouse model of mammary hyperplasia. We gave mice estradiol valerate tablets and progesterone capsules sequentially for one month by intragastric administration. Results: Mice treated by this method had a series of pathological changes which are ...

Biologically Pre-Treated Habitation Waste Water as a Sustainable Green Urine Pre-Treat Solution

Science.gov (United States)

Jackson, W. Andrew; Thompson, Bret; Sevanthi, Ritesh; Morse, Audra; Meyer, Caitlin; Callahan, Michael

2017-01-01

The ability to recover water from urine and flush water is a critical process to allow long term sustainable human habitation in space or bases on the moon or mars. Organic N present as urea or similar compounds can hydrolyze producing free ammonia. This reaction results in an increase in the pH converting ammonium to ammonia which is volatile and not removed by distillation. The increase in pH will also cause precipitation reactions to occur. In order to prevent this, urine on ISS is combined with a pretreat solution. While use of a pretreatment solution has been successful, there are numerous draw backs including: storage and use of highly hazardous solutions, limitations on water recovery (less than 85%), and production of brine with pore dewatering characteristics. We evaluated the use of biologically treated habitation wastewaters (ISS and early planetary base) to replace the current pretreat solution. We evaluated both amended and un-amended bioreactor effluent. For the amended effluent, we evaluated "green" pretreat chemicals including citric acid and citric acid amended with benzoic acid. We used a mock urine/air separator modeled after the urine collection assembly on ISS. The urine/air separator was challenged continually for >6 months. Depending on the test point, the separator was challenged daily with donated urine and flushed with amended or un-amended reactor effluent. We monitored the pH of the urine, flush solution and residual pH in the urine/air separator after each urine event. We also evaluated solids production and biological growth. Our results support the use of both un-amended and amended bioreactor effluent to maintain the operability of the urine /air separator. The ability to use bioreactor effluent could decrease consumable cost, reduce hazards associated with current pre-treat chemicals, allow other membrane based desalination processes to be utilized, and improve brine characteristics.

Animal models for studying neural crest development: is the mouse different?

Science.gov (United States)

Barriga, Elias H; Trainor, Paul A; Bronner, Marianne; Mayor, Roberto

2015-05-01

The neural crest is a uniquely vertebrate cell type and has been well studied in a number of model systems. Zebrafish, Xenopus and chick embryos largely show consistent requirements for specific genes in early steps of neural crest development. By contrast, knockouts of homologous genes in the mouse often do not exhibit comparable early neural crest phenotypes. In this Spotlight article, we discuss these species-specific differences, suggest possible explanations for the divergent phenotypes in mouse and urge the community to consider these issues and the need for further research in complementary systems. © 2015. Published by The Company of Biologists Ltd.

Microbial pretreatment of cotton stalks by Phanerochaete chrysosporium for bioethanol production

Science.gov (United States)

Shi, Jian

.04% for SmC and SSC pretreated samples, respectively) compared with untreated cotton stalk samples (17.93%). Washing of pretreated cotton stalks alone caused no significant increase in cellulose conversion. However, a heat treatment (autoclaving) followed by washing remarkably improved (Pconversion to 14.94% and 17.81% for SmC and SSC pretreatment, respectively. Mathematical models describing holocellulose consumption, lignin degradation, cellulase and ligninolytic enzyme production, and oxygen uptake associated with the growth of P. chrysosporium during 14 days fungal pretreatment were developed. For SmC pretreatment, model parameters were estimated by nonlinear regression and validated using an independent set of experimental data. Models yielded sufficiently accurate predictions for holocellulose consumption (R2=0.9772 and 0.9837, 1d and 3d oxygen flushing, respectively), lignin degradation (R2=0.9879 and 0.8682) and ligninolytic enzyme production (R2=0.8135 and 0.9693) under both 1 and 3d oxygen flushing conditions. However, the prediction capabilities for fungal growth (1d and 3d), cellulase production (3d) and oxygen uptake (3d) were limited. For SSC, the models were established in three phases (I: day 0-4, II: day 4-7, III: day 7-14). After validation it was shown that the developed models can yield sufficiently accurate predictions for fungal growth (R 2=0.9724), holocellulose consumption (R2=0.9686), lignin degradation (R2=0.9309) and ligninolytic enzyme production (R2=0.9203); however predictions of cellulase production were fair (R2=0.6133). Although significant delignification occurred during fungal pretreatment indicating the presence of ligninolytic enzymes, common spectrophotometric enzyme assays failed to detect lignin peroxidase (LiP) and manganese peroxidase (MnP) activities in fungal pretreatment cultures. Efforts were made to overcome the drawbacks of standardized assays by performing protein gel electrophoresis and crude enzyme delignification studies

Iontophoresis of monomeric insulin analogues in vitro: effects of insulin charge and skin pretreatment.

Science.gov (United States)

Langkjaer, L; Brange, J; Grodsky, G M; Guy, R H

1998-01-23

The aim of this study was to investigate the influence of association state and net charge of human insulin analogues on the rate of iontophoretic transport across hairless mouse skin, and the effect of different skin pretreatments on said transport. No insulin flux was observed with anodal delivery probably because of degradation at the Ag/AgCl anode. The flux during cathodal iontophoresis through intact skin was insignificant for human hexameric insulin, and only low and variable fluxes were observed for monomeric insulins. Using stripped skin on the other hand, the fluxes of monomeric insulins with two extra negative charges were 50-100 times higher than that of hexameric human insulin. Introducing three additional charges led to a further 2-3-fold increase in flux. Wiping the skin gently with absolute alcohol prior to iontophoresis resulted in a 1000-fold increase in transdermal transport of insulin relative to that across untreated skin, i.e. to almost the same level as stripping the skin. The alcohol pretreatment reduced the electrical resistance of the skin, presumably by lipid extraction. In conclusion, monomeric insulin analogues with at least two extra negative charges can be iontophoretically delivered across hairless mouse skin, whereas insignificant flux is observed with human, hexameric insulin. Wiping the skin with absolute alcohol prior to iontophoresis gave substantially improved transdermal transport of monomeric insulins resulting in clinically relevant delivery rates for basal treatment.

HMGB1 Contributes to the Expression of P-Glycoprotein in Mouse Epileptic Brain through Toll-Like Receptor 4 and Receptor for Advanced Glycation End Products.

Directory of Open Access Journals (Sweden)

Yan Chen

Full Text Available The objective of the present study was to investigate the role of high-mobility group box-1 (HMGB1 in the seizure-induced P-glycoprotein (P-gp overexpression and the underlying mechanism. Kainic acid (KA-induced mouse seizure model was used for in vivo experiments. Male C57BL/6 mice were divided into four groups: normal saline control (NS group, KA-induced epileptic seizure (EP group, and EP group pretreated with HMGB1 (EP+HMGB1 group or BoxA (HMGB1 antagonist, EP+BoxA group. Compared to the NS group, increased levels of HMGB1 and P-gp in the brain were observed in the EP group. Injection of HMGB1 before the induction of KA further increased the expression of P-gp while pre-treatment with BoxA abolished this up-regulation. Next, the regulatory role of HMGB1 and its potential involved signal pathways were investigated in mouse microvascular endothelial bEnd.3 cells in vitro. Cells were treated with HMGB1, HMGB1 plus lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS [toll-like receptor 4 (TLR4 antagonist], HMGB1 plus FPS-ZM1 [receptor for advanced glycation end products (RAGE inhibitor], HMGB1 plus SN50 [nuclear factor-kappa B (NF-κB inhibitor], or vehicle. Treatment with HMGB1 increased the expression levels of P-gp, TLR4, RAGE and the activation of NF-κB in bEnd.3 cells. These effects were inhibited by the pre-treatment with either LPS-RS or FPS-ZM1, and were abolished by the pre-treatment of SN50 or a combination treatment of both LPS-RS and FPS-ZM1. Luciferase reporter assays showed that exogenous expression of NF-κB p65 increased the promoter activity of multidrug resistance 1a (P-gp-encoding gene in endothelial cells. These data indicate that HMGB1 contributes to the overexpression of P-gp in mouse epileptic brain tissues via activation of TLR4/RAGE receptors and the downstream transcription factor NF-κB in brain microvascular endothelial cells.

Bioenergetic Defects and Oxidative Damage in Transgenic Mouse Models of Neurodegenerative Disorders

National Research Council Canada - National Science Library

Brown, Susan

1999-01-01

... (HE) and familial amyotrophic lateral sclerosis (FALS), using transgenic mouse models. Studies in this first year employed C-14-2-deoxyglucose in vivo autoradiography and spectrophotometric metabolic enzyme assays...

Methods for pretreating biomass

Science.gov (United States)

Balan, Venkatesh; Dale, Bruce E; Chundawat, Shishir; Sousa, Leonardo

2017-05-09

A method for pretreating biomass is provided, which includes, in a reactor, allowing gaseous ammonia to condense on the biomass and react with water present in the biomass to produce pretreated biomass, wherein reactivity of polysaccharides in the biomass is increased during subsequent biological conversion as compared to the reactivity of polysaccharides in biomass which has not been pretreated. A method for pretreating biomass with a liquid ammonia and recovering the liquid ammonia is also provided. Related systems which include a biochemical or biofuel production facility are also disclosed.

High-fertility phenotypes: two outbred mouse models exhibit substantially different molecular and physiological strategies warranting improved fertility.

Science.gov (United States)

Langhammer, Martina; Michaelis, Marten; Hoeflich, Andreas; Sobczak, Alexander; Schoen, Jennifer; Weitzel, Joachim M

2014-01-01

Animal models are valuable tools in fertility research. Worldwide, there are more than 400 transgenic or knockout mouse models available showing a reproductive phenotype; almost all of them exhibit an infertile or at least subfertile phenotype. By contrast, animal models revealing an improved fertility phenotype are barely described. This article summarizes data on two outbred mouse models exhibiting a 'high-fertility' phenotype. These mouse lines were generated via selection over a time period of more than 40 years and 161 generations. During this selection period, the number of offspring per litter and the total birth weight of the entire litter nearly doubled. Concomitantly with the increased fertility phenotype, several endocrine parameters (e.g. serum testosterone concentrations in male animals), physiological parameters (e.g. body weight, accelerated puberty, and life expectancy), and behavioral parameters (e.g. behavior in an open field and endurance fitness on a treadmill) were altered. We demonstrate that the two independently bred high-fertility mouse lines warranted their improved fertility phenotype using different molecular and physiological strategies. The fertility lines display female- as well as male-specific characteristics. These genetically heterogeneous mouse models provide new insights into molecular and cellular mechanisms that enhance fertility. In view of decreasing fertility in men, these models will therefore be a precious information source for human reproductive medicine. Translated abstract A German translation of abstract is freely available at http://www.reproduction-online.org/content/147/4/427/suppl/DC1.

Benefits of hyperbaric oxygen pretreatment for decompression sickness in Bama pigs.

Science.gov (United States)

Qing, Long; Yi, Hong-Jie; Wang, Ye-Wei; Zhou, Quan; Ariyadewa, Dinesh K; Xu, Wei-Gang

2018-03-07

Decompression sickness (DCS) occurs when ambient pressure is severely reduced during diving and aviation. Hyperbaric oxygen (HBO) pretreatment has been shown to exert beneficial effects on DCS in rats via heat-shock proteins (HSPs). We hypothesized that HBO pretreatment will also reduce DCS via HSPs in swine models. In the first part of our investigation, six swine were subjected to a session of HBO treatment. HSP32, 60, 70 and 90 were detected, before and at 6, 12, 18, 24 and 30 h following exposure in lymphocytes. In the second part of our investigation, another 10 swine were randomly assigned into two groups (five per group). All swine were subjected to two simulated air dives in a hyperbaric chamber with an interval of 7 days. Eighteen hours before each dive, the swine were pretreated with HBO or air: the first group received air pretreatment prior to the first dive and HBO pretreatment prior to the second; the second group were pretreated with HBO first and then air. Bubble loads, skin lesions, inflammation and endothelial markers were detected after each dive. In lymphocytes, all HSPs increased significantly ( P <0.05), with the greatest expression appearing at 18 h for HSP32 and 70. HBO pretreatment significantly reduced all the determined changes compared with air pretreatment. The results demonstrate that a single exposure to HBO 18 h prior to diving effectively protects against DCS in the swine model, possibly via induction of HSPs. © 2018. Published by The Company of Biologists Ltd.

Culture-independent detection of 'TM7' bacteria in a streptomycin-resistant acidophilic nitrifying process

International Nuclear Information System (INIS)

Kurogi, T.; Linh, N. T. T.; Kuroki, T.; Yamada, T.; Hiraishi, A.

2014-01-01

Nitrification in biological wastewater treatment processes has been believed for long time to take place under neutral conditions and is inhibited under acidic conditions. However, we previously constructed acidophilic nitrifying sequencing-batch reactors (ANSBRs) being capable of nitrification at −1 was added. In all reactors, the pH varied between 2.7 and 4.0, and ammonium was completely converted to nitrate in every batch cycle. PCR-aided denaturing gradient gel electrophoresis (DGGE) targeting 16S rRNA genes revealed that some major clones assigned to TM7 bacteria and Gammaproteobacteria were constantly present during the overall period of operation. Fluorescence in situ hybridization (FISH) with specific oligonucleotide probes also showed that TM7 bacteria predominated in all SRAN reactors, accounting for 58% of the total bacterial population on average. Although the biological significance of the TM7 bacteria in the SRAN reactors are unknown, our results suggest that these bacteria are possibly streptomycin-resistant and play some important roles in the acidophilic nitrifying process

The common parasite Toxoplasma gondii induces prostatic inflammation and microglandular hyperplasia in a mouse model.

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Colinot, Darrelle L; Garbuz, Tamila; Bosland, Maarten C; Wang, Liang; Rice, Susan E; Sullivan, William J; Arrizabalaga, Gustavo; Jerde, Travis J

2017-07-01

Inflammation is the most prevalent and widespread histological finding in the human prostate, and associates with the development and progression of benign prostatic hyperplasia and prostate cancer. Several factors have been hypothesized to cause inflammation, yet the role each may play in the etiology of prostatic inflammation remains unclear. This study examined the possibility that the common protozoan parasite Toxoplasma gondii induces prostatic inflammation and reactive hyperplasia in a mouse model. Male mice were infected systemically with T. gondii parasites and prostatic inflammation was scored based on severity and focality of infiltrating leukocytes and epithelial hyperplasia. We characterized inflammatory cells with flow cytometry and the resulting epithelial proliferation with bromodeoxyuridine (BrdU) incorporation. We found that T. gondii infects the mouse prostate within the first 14 days of infection and can establish parasite cysts that persist for at least 60 days. T. gondii infection induces a substantial and chronic inflammatory reaction in the mouse prostate characterized by monocytic and lymphocytic inflammatory infiltrate. T. gondii-induced inflammation results in reactive hyperplasia, involving basal and luminal epithelial proliferation, and the exhibition of proliferative inflammatory microglandular hyperplasia in inflamed mouse prostates. This study identifies the common parasite T. gondii as a new trigger of prostatic inflammation, which we used to develop a novel mouse model of prostatic inflammation. This is the first report that T. gondii chronically encysts and induces chronic inflammation within the prostate of any species. Furthermore, T. gondii-induced prostatic inflammation persists and progresses without genetic manipulation in mice, offering a powerful new mouse model for the study of chronic prostatic inflammation and microglandular hyperplasia. © 2017 Wiley Periodicals, Inc.

Effects of environmental enrichment on the amyotrophic lateral sclerosis mouse model.

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Sorrells, A D; Corcoran-Gomez, K; Eckert, K A; Fahey, A G; Hoots, B L; Charleston, L B; Charleston, J S; Roberts, C R; Markowitz, H

2009-04-01

The manner in which an animal's environment is furnished may have significant implications for animal welfare as well as research outcomes. We evaluated four different housing conditions to determine the effects of what has been considered standard rodent enrichment and the exercise opportunities those environments allow on disease progression in the amyotrophic lateral sclerosis mouse model. Forty-eight copper/zinc superoxide dismutase mice (strain: B6SJL-TgN [SOD1-G931]1Gur) (SOD1) and 48 control (C) (strain: B6SJL-TgN[SOD1]2Gur) male mice were randomly assigned to four different conditions where 12 SOD1 and 12 C animals were allotted to each condition (n = 96). Conditions tested the effects of standard housing, a forced exercise regime, access to a mouse house and opportunity for ad libitum exercise on a running wheel. In addition to the daily all-occurrence behavioural sampling, mice were weighed and tested twice per week on gait and Rotor-Rod performance until the mice reached the age of 150 days (C) or met the criteria for our humane endpoint (SOD1). The SOD1 mice exposed to the forced exercise regime and wheel access did better in average lifespan and Rotor-Rod performance, than SOD1 mice exposed to the standard cage and mouse house conditions. In SOD1 mice, stride length remained longest throughout the progression of the disease in mice exposed to the forced exercise regime compared with other SOD1 conditions. Within the control group, mice in the standard cage and forced exercise regime conditions performed significantly less than the mice with the mouse house and wheels on the Rotor-Rod. Alpha motor neuron counts were highest in mice with wheels and in mice exposed to forced exercise regime in both mouse strains. All SOD1 mice had significantly lower alpha neuron counts than controls (P model, and may have implications for the effects of these strategies on experimental outcomes.

From Immunodeficiency to Humanization: The Contribution of Mouse Models to Explore HTLV-1 Leukemogenesis

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Eléonore Pérès

2015-12-01

Full Text Available The first discovered human retrovirus, Human T-Lymphotropic Virus type 1 (HTLV-1, is responsible for an aggressive form of T cell leukemia/lymphoma. Mouse models recapitulating the leukemogenesis process have been helpful for understanding the mechanisms underlying the pathogenesis of this retroviral-induced disease. This review will focus on the recent advances in the generation of immunodeficient and human hemato-lymphoid system mice with a particular emphasis on the development of mouse models for HTLV-1-mediated pathogenesis, their present limitations and the challenges yet to be addressed.

Effects of cartap on isolated mouse phrenic nerve diaphragm and its related mechanism.

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Liao, J W; Kang, J J; Liu, S H; Jeng, C R; Cheng, Y W; Hu, C M; Tsai, S F; Wang, S C; Pang, V F

2000-06-01

Cartap, a nereistoxin analogue pesticide, is reported to have no irritation to eyes in rabbits. However, we have demonstrated recently that cartap could actually cause acute death in rabbits via ocular exposure. Our preliminary study with isolated mouse phrenic nerve diaphragms has shown that instead of neuromuscular blockade, cartap caused muscular contracture. The objective of the study was to examine the effect of cartap on the neuromuscular junction in more detail and to investigate its possible underlying mechanism with isolated mouse phrenic nerve diaphragms and sarcoplasmic reticulum (SR) vesicles. Cartap or nereistoxin at various concentrations was added in the organ bath with isolated mouse phrenic nerve diaphragm and both nerve- and muscle-evoked twitches were recorded. Instead of blocking the neuromuscular transmission as nereistoxin did, cartap caused contracture in stimulated or quiescent isolated mouse phrenic nerve diaphragm. Both the cartap-induced muscular contracture force and the time interval to initiate the contracture were dose-dependent. The contracture induced by cartap was not affected by the pretreatment of the diaphragm with the acetylcholine receptor blocker alpha-bungarotoxin; the Na(+) channel blocker tetrodotoxin; or various Ca(2+) channel blockers, NiCl(2), verapamil, and nifedipine. On the contrary, the contracture was significantly inhibited when the diaphragm was pretreated with ryanodine or EGTA containing Ca(2+)-free Krebs solution or in combination. This suggested that both internal and extracellular Ca(2+) might participate in cartap-induced skeletal muscle contracture. Moreover, cartap inhibited the [(3)H]-ryanodine binding to the Ca(2+) release channel of SR in a dose-dependent manner. Additionally, cartap could induce a significant reduction in Ca(2+)-ATPase activity of SR vesicles at a relatively high dose. The results suggested that cartap might cause the influx of extracellular Ca(2+) and the release of internal Ca(2

Ultrasonic vocalizations: a tool for behavioural phenotyping of mouse models of neurodevelopmental disorders

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Scattoni, Maria Luisa; Crawley, Jacqueline; Ricceri, Laura

2008-01-01

In neonatal mice ultrasonic vocalizations have been studied both as an early communicative behavior of the pup-mother dyad and as a sign of an aversive affective state. Adult mice of both sexes produce complex ultrasonic vocalization patterns in different experimental/social contexts. All these vocalizations are becoming an increasingly valuable assay for behavioral phenotyping throughout the mouse life-span and alterations of the ultrasound patterns have been reported in several mouse models...

Transformation of Starchy Lignocellulosic Biomass to Ethanol using Ragi Tapai Synergized with Microwave Irradiation Pretreatment

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Kok Cheang Diong

2016-01-01

Full Text Available Ethanol production strategy was studied using multiple strain microbes from microwave irradiation (MI pretreated sago waste. Sago waste (SW was MI-pretreated for reducing sugars production using 2 heating media (water and sulfuric acid under pretreatment conditions including MI power, pretreatment duration, and solid loading. When water was used, the pretreatment parameters were optimized using Box-Behnken Design (BBD. However, gelatinized starch and charring of SW led to an insignificant quadratic model. To mitigate the gelatinization problem while determining the best MI pretreatment conditions, water was substituted by sulfuric acid using single factor method. The highest reducing sugar yield of 261.5 mg/g SW was achieved at 7.5% solid loading, 6 min pretreatment duration, and 300 W MI power. The effectiveness of the pretreatment was ascertained by field-emission scanning electron microscopy (FESEM and chemical-composition analysis. When fermenting MI-pretreated SW using ragi tapai, simultaneous saccharification of starch and ethanol production was evidenced from the sugar/ethanol profile. A resulted yield of 7.24 g ethanol/100 g SW confirmed the fermentability of MI-pretreated SW. The ethanol production was well fitted into the modified Gompertz model.

Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments.

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Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B; Wang, Ya

2016-06-01

Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk. Copyright © 2016 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.

Rasagiline ameliorates olfactory deficits in an alpha-synuclein mouse model of Parkinson's disease.

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Géraldine H Petit

Full Text Available Impaired olfaction is an early pre-motor symptom of Parkinson's disease. The neuropathology underlying olfactory dysfunction in Parkinson's disease is unknown, however α-synuclein accumulation/aggregation and altered neurogenesis might play a role. We characterized olfactory deficits in a transgenic mouse model of Parkinson's disease expressing human wild-type α-synuclein under the control of the mouse α-synuclein promoter. Preliminary clinical observations suggest that rasagiline, a monoamine oxidase-B inhibitor, improves olfaction in Parkinson's disease. We therefore examined whether rasagiline ameliorates olfactory deficits in this Parkinson's disease model and investigated the role of olfactory bulb neurogenesis. α-Synuclein mice were progressively impaired in their ability to detect odors, to discriminate between odors, and exhibited alterations in short-term olfactory memory. Rasagiline treatment rescued odor detection and odor discrimination abilities. However, rasagiline did not affect short-term olfactory memory. Finally, olfactory changes were not coupled to alterations in olfactory bulb neurogenesis. We conclude that rasagiline reverses select olfactory deficits in a transgenic mouse model of Parkinson's disease. The findings correlate with preliminary clinical observations suggesting that rasagiline ameliorates olfactory deficits in Parkinson's disease.

Genetic mouse models of brain ageing and Alzheimer's disease.

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Bilkei-Gorzo, Andras

2014-05-01

Progression of brain ageing is influenced by a complex interaction of genetic and environmental factors. Analysis of genetically modified animals with uniform genetic backgrounds in a standardised, controlled environment enables the dissection of critical determinants of brain ageing on a molecular level. Human and animal studies suggest that increased load of damaged macromolecules, efficacy of DNA maintenance, mitochondrial activity, and cellular stress defences are critical determinants of brain ageing. Surprisingly, mouse lines with genetic impairment of anti-oxidative capacity generally did not show enhanced cognitive ageing but rather an increased sensitivity to oxidative challenge. Mouse lines with impaired mitochondrial activity had critically short life spans or severe and rapidly progressing neurodegeneration. Strains with impaired clearance in damaged macromolecules or defects in the regulation of cellular stress defences showed alterations in the onset and progression of cognitive decline. Importantly, reduced insulin/insulin-like growth factor signalling generally increased life span but impaired cognitive functions revealing a complex interaction between ageing of the brain and of the body. Brain ageing is accompanied by an increased risk of developing Alzheimer's disease. Transgenic mouse models expressing high levels of mutant human amyloid precursor protein showed a number of symptoms and pathophysiological processes typical for early phase of Alzheimer's disease. Generally, therapeutic strategies effective against Alzheimer's disease in humans were also active in the Tg2576, APP23, APP/PS1 and 5xFAD lines, but a large number of false positive findings were also reported. The 3xtg AD model likely has the highest face and construct validity but further studies are needed. Copyright © 2013 Elsevier Inc. All rights reserved.

Inhibiting Effects of Achyranthes Bidentata Polysaccharide and Lycium Barbarum Polysaccharide on Nonenzyme Glycation in D-galactose Induced Mouse Aging Model

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HONG-BIN DENG; DA-PENG CUI; JIAN-MING JIANG; YAN-CHUN FENG; NIAN-SHENG CAI; DIAN-DONG LI

2003-01-01

To investigate the inhibiting effects and mechanism of achyranthes bidentata polysaccharide (ABP) and lycium barbarum polysaccharide (LBP) on nonenzyme glycation in D-galactose induced mouse aging model. Methods Serum AGE levels were determined by AGE-ELISA, MTT method was used to determine lymphocyte proliferation, IL-2 activity was determined by a bioassay method. Spontaneous motor activity was used to detect mouse's neuromuscular movement, latency of step-through method was used to examine learning and memory abilities of mouse, colormetric assay was used to determine hydroxyproline concentration in mouse skin, pyrogallol autoxidation method was used to determine superoxide dismutase (SOD) activity of erythrocytes. Results Decreased levels of serum AGE, hydroxyproline concentration in mouse skin and spontaneous motor activity in D-galactose mouse aging model were detected after treated with ABP or LBP, while lymphocyte proliferation and IL-2 activity, learning and memory abilities,SOD activity of erythrocytes, were enhanced. Conclusions ABP and LBP could inhibit nonenzyme glycation in D-galactose induced mouse aging model in vivo and ABP has a better inhibiting effect than LBP.

Injurious Effects of Curcumin on Maturation of Mouse Oocytes, Fertilization and Fetal Development via Apoptosis

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Wen-Hsiung Chan

2012-04-01

Full Text Available Curcumin, a common dietary pigment and spice, is a hydrophobic polyphenol derived from the rhizome of the herb Curcuma longa. Previously, we reported a cytotoxic effect of curcumin on mouse embryonic stem cells and blastocysts and its association with defects in subsequent development. In the present study, we further investigated the effects of curcumin on oocyte maturation and subsequent pre- and post-implantation development, both in vitro and in vivo. Notably, curcumin induced a significant reduction in the rate of oocyte maturation, fertilization, and in vitro embryonic development. Treatment of oocytes with curcumin during in vitro maturation (IVM led to increased resorption of postimplantation embryos and decreased fetal weight. Experiments with an in vivo mouse model disclosed that consumption of drinking water containing 40 μM curcumin led to decreased oocyte maturation and in vitro fertilization as well as early embryonic developmental injury. Finally, pretreatment with a caspase-3-specific inhibitor effectively prevented curcumin-triggered injury effects, suggesting that embryo impairment by curcumin occurs mainly via a caspase-dependent apoptotic process.

Mouse neuroblastoma cell-based model and the effect of epileptic events on calcium oscillations and neural spikes

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Kim, Suhwan; Jung, Unsang; Baek, Juyoung; Lee, Sangwon; Jung, Woonggyu; Kim, Jeehyun; Kang, Shinwon

2013-01-01

Recently, mouse neuroblastoma cells have been considered as an attractive model for the study of human neurological and prion diseases, and they have been intensively used as a model system in different areas. For example, the differentiation of neuro2a (N2A) cells, receptor-mediated ion current, and glutamate-induced physiological responses have been actively investigated with these cells. These mouse neuroblastoma N2A cells are of interest because they grow faster than other cells of neural origin and have a number of other advantages. The calcium oscillations and neural spikes of mouse neuroblastoma N2A cells in epileptic conditions are evaluated. Based on our observations of neural spikes in these cells with our proposed imaging modality, we reported that they can be an important model in epileptic activity studies. We concluded that mouse neuroblastoma N2A cells produce epileptic spikes in vitro in the same way as those produced by neurons or astrocytes. This evidence suggests that increased levels of neurotransmitter release due to the enhancement of free calcium from 4-aminopyridine causes the mouse neuroblastoma N2A cells to produce epileptic spikes and calcium oscillations.

Effect of angiotensin II on proliferation and differentiation of mouse induced pluripotent stem cells into mesodermal progenitor cells

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Ishizuka, Toshiaki, E-mail: tishizu@ndmc.ac.jp [Department of Pharmacology, National Defense Medical College, Tokorozawa, Saitama 359-8513 (Japan); Goshima, Hazuki; Ozawa, Ayako; Watanabe, Yasuhiro [Department of Pharmacology, National Defense Medical College, Tokorozawa, Saitama 359-8513 (Japan)

2012-03-30

Highlights: Black-Right-Pointing-Pointer Treatment with angiotensin II enhanced LIF-induced DNA synthesis of mouse iPS cells. Black-Right-Pointing-Pointer Angiotensin II may enhance the DNA synthesis via induction of superoxide. Black-Right-Pointing-Pointer Treatment with angiotensin II significantly increased JAK/STAT3 phosphorylation. Black-Right-Pointing-Pointer Angiotensin II enhanced differentiation into mesodermal progenitor cells. Black-Right-Pointing-Pointer Angiotensin II may enhance the differentiation via activation of p38 MAPK. -- Abstract: Previous studies suggest that angiotensin receptor stimulation may enhance not only proliferation but also differentiation of undifferentiated stem/progenitor cells. Therefore, in the present study, we determined the involvement of the angiotensin receptor in the proliferation and differentiation of mouse induced pluripotent stem (iPS) cells. Stimulation with angiotensin II (Ang II) significantly increased DNA synthesis in mouse iPS cells cultured in a medium with leukemia inhibitory factor (LIF). Pretreatment of the cells with either candesartan (a selective Ang II type 1 receptor [AT{sub 1}R] antagonist) or Tempol (a cell-permeable superoxide scavenger) significantly inhibited Ang II-induced DNA synthesis. Treatment with Ang II significantly increased JAK/STAT3 phosphorylation. Pretreatment with candesartan significantly inhibited Ang II- induced JAK/STAT3 phosphorylation. In contrast, induction of mouse iPS cell differentiation into Flk-1-positive mesodermal progenitor cells was performed in type IV collagen (Col IV)- coated dishes in a differentiation medium without LIF. When Col IV-exposed iPS cells were treated with Ang II for 5 days, the expression of Flk-1 was significantly increased compared with that in the cells treated with the vehicle alone. Pretreatment of the cells with both candesartan and SB203580 (a p38 MAPK inhibitor) significantly inhibited the Ang II- induced increase in Flk-1 expression

Effect of angiotensin II on proliferation and differentiation of mouse induced pluripotent stem cells into mesodermal progenitor cells

International Nuclear Information System (INIS)

Ishizuka, Toshiaki; Goshima, Hazuki; Ozawa, Ayako; Watanabe, Yasuhiro

2012-01-01

Highlights: ► Treatment with angiotensin II enhanced LIF-induced DNA synthesis of mouse iPS cells. ► Angiotensin II may enhance the DNA synthesis via induction of superoxide. ► Treatment with angiotensin II significantly increased JAK/STAT3 phosphorylation. ► Angiotensin II enhanced differentiation into mesodermal progenitor cells. ► Angiotensin II may enhance the differentiation via activation of p38 MAPK. -- Abstract: Previous studies suggest that angiotensin receptor stimulation may enhance not only proliferation but also differentiation of undifferentiated stem/progenitor cells. Therefore, in the present study, we determined the involvement of the angiotensin receptor in the proliferation and differentiation of mouse induced pluripotent stem (iPS) cells. Stimulation with angiotensin II (Ang II) significantly increased DNA synthesis in mouse iPS cells cultured in a medium with leukemia inhibitory factor (LIF). Pretreatment of the cells with either candesartan (a selective Ang II type 1 receptor [AT 1 R] antagonist) or Tempol (a cell-permeable superoxide scavenger) significantly inhibited Ang II-induced DNA synthesis. Treatment with Ang II significantly increased JAK/STAT3 phosphorylation. Pretreatment with candesartan significantly inhibited Ang II- induced JAK/STAT3 phosphorylation. In contrast, induction of mouse iPS cell differentiation into Flk-1-positive mesodermal progenitor cells was performed in type IV collagen (Col IV)- coated dishes in a differentiation medium without LIF. When Col IV-exposed iPS cells were treated with Ang II for 5 days, the expression of Flk-1 was significantly increased compared with that in the cells treated with the vehicle alone. Pretreatment of the cells with both candesartan and SB203580 (a p38 MAPK inhibitor) significantly inhibited the Ang II- induced increase in Flk-1 expression. Treatment with Ang II enhanced the phosphorylation of p38 MAPK in Col IV- exposed iPS cells. These results suggest that the stimulation

DISC1 mouse models as a tool to decipher gene-environment interactions in psychiatric disorders

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Tyler eCash-Padgett

2013-09-01

Full Text Available DISC1 was discovered in a Scottish pedigree in which a chromosomal translocation that breaks this gene segregates with psychiatric disorders, mainly depression and schizophrenia. Linkage and association studies in diverse populations support DISC1 as a susceptibility gene to a variety of neuropsychiatric disorders. Many Disc1 mouse models have been generated to study its neuronal functions. These mouse models display variable phenotypes, some of them relevant to schizophrenia, others to depression.The Disc1 mouse models are popular genetic models for studying gene-environment interactions in schizophrenia. Five different Disc1 models have been combined with environmental factors. The environmental stressors employed can be classified as either early immune activation or later social paradigms. These studies cover major time points along the neurodevelopmental trajectory: prenatal, early postnatal, adolescence, and adulthood. Various combinations of molecular, anatomical and behavioral methods have been used to assess the outcomes. Additionally, three of the studies sought to rescue the resulting abnormalities.Here we provide background on the environmental paradigms used, summarize the results of these studies combining Disc1 mouse models with environmental stressors and discuss what we can learn and how to proceed. A major question is how the genetic and environmental factors determine which psychiatric disorder will be clinically manifested. To address this we can take advantage of the many Disc1 models available and expose them to the same environmental stressor. The complementary experiment would be to expose the same model to different environmental stressors. DISC1 is an ideal gene for this approach, since in the Scottish pedigree the same chromosomal translocation results in different psychiatric conditions.

The mthA mutation conferring low-level resistance to streptomycin enhances antibiotic production in Bacillus subtilis by increasing the S-adenosylmethionine pool size.

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Tojo, Shigeo; Kim, Ji-Yun; Tanaka, Yukinori; Inaoka, Takashi; Hiraga, Yoshikazu; Ochi, Kozo

2014-04-01

Certain Str(r) mutations that confer low-level streptomycin resistance result in the overproduction of antibiotics by Bacillus subtilis. Using comparative genome-sequencing analysis, we successfully identified this novel mutation in B. subtilis as being located in the mthA gene, which encodes S-adenosylhomocysteine/methylthioadenosine nucleosidase, an enzyme involved in the S-adenosylmethionine (SAM)-recycling pathways. Transformation experiments showed that this mthA mutation was responsible for the acquisition of low-level streptomycin resistance and overproduction of bacilysin. The mthA mutant had an elevated level of intracellular SAM, apparently acquired by arresting SAM-recycling pathways. This increase in the SAM level was directly responsible for bacilysin overproduction, as confirmed by forced expression of the metK gene encoding SAM synthetase. The mthA mutation fully exerted its effect on antibiotic overproduction in the genetic background of rel(+) but not the rel mutant, as demonstrated using an mthA relA double mutant. Strikingly, the mthA mutation activated, at the transcription level, even the dormant ability to produce another antibiotic, neotrehalosadiamine, at concentrations of 150 to 200 μg/ml, an antibiotic not produced (antibiotic production, by introducing either the rsmG mutation to Streptomyces or the mthA mutation to eubacteria, since many eubacteria have mthA homologues.

Kinetic study of enzymatic hydrolysis of acid-pretreated coconut coir

Science.gov (United States)

Fatmawati, Akbarningrum; Agustriyanto, Rudy

2015-12-01

Biomass waste utilization for biofuel production such as bioethanol, has become more prominent currently. Coconut coir is one of lignocellulosic food wastes, which is abundant in Indonesia. Bioethanol production from such materials consists of more than one step. Pretreatment and enzymatic hydrolysis is crucial steps to produce sugar which can then be fermented into bioethanol. In this research, ground coconut coir was pretreated using dilute sulfuric acid at 121°C. This pretreatment had increased the cellulose content and decreased the lignin content of coconut coir. The pretreated coconut coir was hydrolyzed using a mix of two commercial cellulase enzymes at pH of 4.8 and temperature of 50°C. The enzymatic hydrolysis was conducted at several initial coconut coir slurry concentrations (0.1-2 g/100 mL) and reaction times (2-72 hours). The reducing sugar concentration profiles had been produced and can be used to obtain reaction rates. The highest reducing sugar concentration obtained was 1,152.567 mg/L, which was produced at initial slurry concentration of 2 g/100 mL and 72 hours reaction time. In this paper, the reducing sugar concentrations were empirically modeled as a function of reaction time using power equations. Michaelis-Menten kinetic model for enzymatic hydrolysis reaction is adopted. The kinetic parameters of that model for sulfuric acid-pretreated coconut coir enzymatic hydrolysis had been obtained which are Vm of 3.587×104 mg/L.h, and KM of 130.6 mg/L.

A novel film-pore-surface diffusion model to explain the enhanced enzyme adsorption of corn stover pretreated by ultrafine grinding.

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Zhang, Haiyan; Chen, Longjian; Lu, Minsheng; Li, Junbao; Han, Lujia

2016-01-01

Ultrafine grinding is an environmentally friendly pretreatment that can alter the degree of polymerization, the porosity and the specific surface area of lignocellulosic biomass and can, thus, enhance cellulose hydrolysis. Enzyme adsorption onto the substrate is a prerequisite for the enzymatic hydrolysis process. Therefore, it is necessary to investigate the enzyme adsorption properties of corn stover pretreated by ultrafine grinding. The ultrafine grinding pretreatment was executed on corn stover. The results showed that ultrafine grinding pretreatment can significantly decrease particle size [from 218.50 μm of sieve-based grinding corn stover (SGCS) to 17.45 μm of ultrafine grinding corn stover (UGCS)] and increase the specific surface area (SSA), pore volume (PV) and surface composition (SSA: from 1.71 m(2)/g of SGCS to 2.63 m(2)/g of UGCS, PV: from 0.009 cm(3)/g of SGCS to 0.024 m(3)/g of UGCS, cellulose surface area: from 168.69 m(2)/g of SGCS to 290.76 m(2)/g of UGCS, lignin surface area: from 91.46 m(2)/g of SGCS to 106.70 m(2)/g of UGCS). The structure and surface composition changes induced by ultrafine grinding increase the enzyme adsorption capacity from 2.83 mg/g substrate of SGCS to 5.61 mg/g substrate of UGCS. A film-pore-surface diffusion model was developed to simultaneously predict the enzyme adsorption kinetics of both the SGCS and UGCS. Satisfactory predictions could be made with the model based on high R (2) and low RMSE values (R (2) = 0.95 and RMSE = 0.16 mg/g for the UGCS, R (2) = 0.93 and RMSE = 0.09 mg/g for the SGCS). The model was further employed to analyze the rate-limiting steps in the enzyme adsorption process. Although both the external-film and internal-pore mass transfer are important for enzyme adsorption on the SGCS and UGCS, the UGCS has a lower internal-pore resistance compared to the SGCS. Ultrafine grinding pretreatment can enhance the enzyme adsorption onto corn stover by altering structure and

Selenium Pretreatment Alleviated LPS-Induced Immunological Stress Via Upregulation of Several Selenoprotein Encoding Genes in Murine RAW264.7 Cells.

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Wang, Longqiong; Jing, Jinzhong; Yan, Hui; Tang, Jiayong; Jia, Gang; Liu, Guangmang; Chen, Xiaoling; Tian, Gang; Cai, Jingyi; Shang, Haiying; Zhao, Hua

2018-04-18

This study was conducted to profile selenoprotein encoding genes in mouse RAW264.7 cells upon lipopolysaccharide (LPS) challenge and integrate their roles into immunological regulation in response to selenium (Se) pretreatment. LPS was used to develop immunological stress in macrophages. Cells were pretreated with different levels of Se (0, 0.5, 1.0, 1.5, 2.0 μmol Se/L) for 2 h, followed by LPS (100 ng/mL) stimulation for another 3 h. The mRNA expression of 24 selenoprotein encoding genes and 9 inflammation-related genes were investigated. The results showed that LPS (100 ng/mL) effectively induced immunological stress in RAW264.7 cells with induced inflammation cytokines, IL-6 and TNF-α, mRNA expression, and cellular secretion. LPS increased (P immunological stress in RAW264.7 cells accompanied with the global downregulation of selenoprotein encoding genes and Se pretreatment alleviated immunological stress via upregulation of a subset of selenoprotein encoding genes.

Effect of induced peritoneal endometriosis on oocyte and embryo quality in a mouse model.

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Cohen, J; Ziyyat, A; Naoura, I; Chabbert-Buffet, N; Aractingi, S; Darai, E; Lefevre, B

2015-02-01

To assess the impact of peritoneal endometriosis on oocyte and embryo quality in a mouse model. Peritoneal endometriosis was surgically induced in 33 B6CBA/F1 female mice (endometriosis group, N = 17) and sham-operated were used as control (sham group, N = 16). Mice were superovulated 4 weeks after surgery and mated or not, to collect E0.5-embryos or MII-oocytes. Evaluation of oocyte and zygote quality was done by immunofluorescence under spinning disk confocal microscopy. Endometriosis-like lesions were observed in all mice of endometriosis group. In both groups, a similar mean number of MII oocytes per mouse was observed in non-mated mice (30.2 vs 32.6), with a lower proportion of normal oocytes in the endometriosis group (61 vs 83 %, p endometriosis group (21 vs 35.5, p = 0.02) without difference in embryo quality. Our results support that induced peritoneal endometriosis in a mouse model is associated with a decrease in oocyte quality and embryo number. This experimental model allows further studies to understand mechanisms of endometriosis-associated infertility.

Lignocellulosic Biomass Pretreatment Using AFEX

Science.gov (United States)

Balan, Venkatesh; Bals, Bryan; Chundawat, Shishir P. S.; Marshall, Derek; Dale, Bruce E.

Although cellulose is the most abundant organic molecule, its susceptibility to hydrolysis is restricted due to the rigid lignin and hemicellulose protection surrounding the cellulose micro fibrils. Therefore, an effective pretreatment is necessary to liberate the cellulose from the lignin-hemicellulose seal and also reduce cellulosic crystallinity. Some of the available pretreatment techniques include acid hydrolysis, steam explosion, ammonia fiber expansion (AFEX), alkaline wet oxidation, and hot water pretreatment. Besides reducing lignocellulosic recalcitrance, an ideal pretreatment must also minimize formation of degradation products that inhibit subsequent hydrolysis and fermentation. AFEX is an important pretreatment technology that utilizes both physical (high temperature and pressure) and chemical (ammonia) processes to achieve effective pretreatment. Besides increasing the surface accessibility for hydrolysis, AFEX promotes cellulose decrystallization and partial hemicellulose depolymerization and reduces the lignin recalcitrance in the treated biomass. Theoretical glucose yield upon optimal enzymatic hydrolysis on AFEX-treated corn stover is approximately 98%. Furthermore, AFEX offers several unique advantages over other pretreatments, which include near complete recovery of the pretreatment chemical (ammonia), nutrient addition for microbial growth through the remaining ammonia on pretreated biomass, and not requiring a washing step during the process which facilitates high solid loading hydrolysis. This chapter provides a detailed practical procedure to perform AFEX, design the reactor, determine the mass balances, and conduct the process safely.

Neuroglobin overexpression inhibits oxygen-glucose deprivation-induced mitochondrial permeability transition pore opening in primary cultured mouse cortical neurons.

Science.gov (United States)

Yu, Zhanyang; Liu, Ning; Li, Yadan; Xu, Jianfeng; Wang, Xiaoying

2013-08-01

Neuroglobin (Ngb) is an endogenous neuroprotective molecule against hypoxic/ischemic brain injury, but the underlying mechanisms remain largely undefined. Our recent study revealed that Ngb can bind to voltage-dependent anion channel (VDAC), a regulator of mitochondria permeability transition (MPT). In this study we examined the role of Ngb in MPT pore (mPTP) opening following oxygen-glucose deprivation (OGD) in primary cultured mouse cortical neurons. Co-immunoprecipitation (Co-IP) and immunocytochemistry showed that the binding between Ngb and VDAC was increased after OGD compared to normoxia, indicating the OGD-enhanced Ngb-VDAC interaction. Ngb overexpression protected primary mouse cortical neurons from OGD-induced neuronal death, to an extent comparable to mPTP opening inhibitor, cyclosporine A (CsA) pretreatment. We further measured the role of Ngb in OGD-induced mPTP opening using Ngb overexpression and knockdown approaches in primary cultured neurons, and recombinant Ngb exposure to isolated mitochondria. Same as CsA pretreatment, Ngb overexpression significantly reduced OGD-induced mPTP opening markers including mitochondria swelling, mitochondrial NAD(+) release, and cytochrome c (Cyt c) release in primary cultured neurons. Recombinant Ngb incubation significantly reduced OGD-induced NAD(+) release and Cyt c release from isolated mitochondria. In contrast, Ngb knockdown significantly increased OGD-induced neuron death, and increased OGD-induced mitochondrial NAD(+) release and Cyt c release as well, and these outcomes could be rescued by CsA pretreatment. In summary, our results demonstrated that Ngb overexpression can inhibit OGD-induced mPTP opening in primary cultured mouse cortical neurons, which may be one of the molecular mechanisms of Ngb's neuroprotection. Copyright © 2013 Elsevier Inc. All rights reserved.

Effects of gypenosides on anxiety disorders in MPTP-lesioned mouse model of Parkinson's disease.

Science.gov (United States)

Shin, Keon Sung; Zhao, Ting Ting; Choi, Hyun Sook; Hwang, Bang Yeon; Lee, Chong Kil; Lee, Myung Koo

2014-06-03

Ethanol extract (GP-EX) of Gynostemma pentaphyllum (GP) ameliorates chronic stress-induced anxiety in mice. The present study investigated the effects of gypenoside-enriched components (GPS), GP-EX and water extract of GP (GP-WX) on MPTP lesion-induced affective disorders in C57BL/6 mice. GPS (50mg/kg) and GP-EX (50mg/kg) for 21 day-treatment period improved the symptom of anxiety disorders in the MPTP-lesioned mouse model of PD with or without L-DOPA treatment, which was examined by the elevated plus-maze and marble burying tests. In these states, treatments with GPS (50mg/kg) and GP-EX (50mg/kg) significantly increased the brain levels of dopamine and serotonin in the MPTP-lesioned mouse model of PD with or without l-DOPA treatment. In addition, treatments with GPS (50mg/kg) and GP-EX (50mg/kg) showed protective effects on dopaminergic neurons in MPTP-lesioned mouse model of PD with or without L-DOPA treatment. In contrast, GPS (30 mg/kg) and GP-WX (50mg/kg) showed anxiolytic effects in the same animal models, but it was not significant. These results suggest that GPS (50mg/kg) and GP-EX (50mg/kg) showed anxiolytic effects on affective disorders and protective effects on dopaminergic neurons by modulating the brain levels of dopamine and serotonin in the MPTP-lesioned mouse model of PD with or without l-DOPA treatment. Clinical trials of GPS and GP-EX need to be conducted further so as to develop adjuvant therapeutic agents for PD patients. Copyright © 2014 Elsevier B.V. All rights reserved.

Food withdrawal lowers energy expenditure and induces inactivity in long-chain fatty acid oxidation-deficient mouse models.

Science.gov (United States)

Diekman, Eugene F; van Weeghel, Michel; Wanders, Ronald J A; Visser, Gepke; Houten, Sander M

2014-07-01

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inherited disorder of mitochondrial long-chain fatty acid β-oxidation (FAO). Patients with VLCAD deficiency may present with hypoglycemia, hepatomegaly, cardiomyopathy, and myopathy. Although several mouse models have been developed to aid in the study of the pathogenesis of long-chain FAO defects, the muscular phenotype is underexposed. To address the muscular phenotype, we used a newly developed mouse model on a mixed genetic background with a more severe defect in FAO (LCAD(-/-); VLCAD(+/-)) in addition to a validated mouse model (LCAD(-/-); VLCAD(+/+)) and compared them with wild-type (WT) mice. We found that both mouse models show a 20% reduction in energy expenditure (EE) and a 3-fold decrease in locomotor activity in the unfed state. In addition, we found a 1.7°C drop in body temperature in unfed LCAD(-/-); VLCAD(+/+) mice compared with WT body temperature. We conclude that food withdrawal-induced inactivity, hypothermia, and reduction in EE are novel phenotypes associated with FAO deficiency in mice. Unexpectedly, inactivity was not explained by rhabdomyolysis, but rather reflected the overall reduced capacity of these mice to generate heat. We suggest that mice are partly protected against the negative consequence of an FAO defect.-Diekman, E. F., van Weeghel, M., Wanders, R. J. A., Visser, G., Houten, S. M. Food withdrawal lowers energy expenditure and induces inactivity in long-chain fatty acid oxidation-deficient mouse models. © FASEB.

A Longitudinal Motor Characterisation of the HdhQ111 Mouse Model of Huntington's Disease.

Science.gov (United States)

Yhnell, Emma; Dunnett, Stephen B; Brooks, Simon P

2016-05-31

Huntington's disease (HD) is a rare, incurable neurodegenerative disorder caused by a CAG trinucleotide expansion with the first exon of the huntingtin gene. Numerous knock-in mouse models are currently available for modelling HD. However, before their use in scientific research, these models must be characterised to determine their face and predictive validity as models of the disease and their reliability in recapitulating HD symptoms. Manifest HD is currently diagnosed upon the onset of motor symptoms, thus we sought to longitudinally characterise the progression and severity of motor signs in the HdhQ111 knock-in mouse model of HD, in heterozygous mice. An extensive battery of motor tests including: rotarod, inverted lid test, balance beam, spontaneous locomotor activity and gait analysis were applied longitudinally to a cohort of HdhQ111 heterozygous mice in order to progressively assess motor function. A progressive failure to gain body weight was demonstrated from 11 months of age and motor problems in all measures of balance beam performance were shown in HdhQ111 heterozygous animals in comparison to wild type control animals from 9 months of age. A decreased latency to fall from the rotarod was demonstrated in HdhQ111 heterozygous animals in comparison to wild type animals, although this was not progressive with time. No genotype specific differences were demonstrated in any of the other motor tests included in the test battery. The HdhQ111 heterozygous mouse demonstrates a subtle and progressive motor phenotype that begins at 9 months of age. This mouse model represents an early disease stage and would be ideal for testing therapeutic strategies that require elongated lead-in times, such as viral gene therapies or striatal transplantation.

A Bone-Implant Interaction Mouse Model for Evaluating Molecular Mechanism of Biomaterials/Bone Interaction.

Science.gov (United States)

Liu, Wenlong; Dan, Xiuli; Wang, Ting; Lu, William W; Pan, Haobo

2016-11-01

The development of an optimal animal model that could provide fast assessments of the interaction between bone and orthopedic implants is essential for both preclinical and theoretical researches in the design of novel biomaterials. Compared with other animal models, mice have superiority in accessing the well-developed transgenic modification techniques (e.g., cell tracing, knockoff, knockin, and so on), which serve as powerful tools in studying molecular mechanisms. In this study, we introduced the establishment of a mouse model, which was specifically tailored for the assessment of bone-implant interaction in a load-bearing bone marrow microenvironment and could potentially allow the molecular mechanism study of biomaterials by using transgenic technologies. The detailed microsurgery procedures for developing a bone defect (Φ = 0.8 mm) at the metaphysis region of the mouse femur were recorded. According to our results, the osteoconductive and osseointegrative properties of a well-studied 45S5 bioactive glass were confirmed by utilizing our mouse model, verifying the reliability of this model. The feasibility and reliability of the present model were further checked by using other materials as objects of study. Furthermore, our results indicated that this animal model provided a more homogeneous tissue-implant interacting surface than the rat at the early stage of implantation and this is quite meaningful for conducting quantitative analysis. The availability of transgenic techniques to mechanism study of biomaterials was further testified by establishing our model on Nestin-GFP transgenic mice. Intriguingly, the distribution of Nestin + cells was demonstrated to be recruited to the surface of 45S5 glass as early as 3 days postsurgery, indicating that Nestin + lineage stem cells may participate in the subsequent regeneration process. In summary, the bone-implant interaction mouse model could serve as a potential candidate to evaluate the early stage tissue

Bioethanol from lignocellulose - pretreatment, enzyme immobilization and hydrolysis kinetics

DEFF Research Database (Denmark)

Tsai, Chien Tai

, the cost of enzyme is still the bottle neck, re-using the enzyme is apossible way to reduce the input of enzyme in the process. In the point view of engineering, the prediction of enzymatic hydrolysis kinetics under different substrate loading, enzyme combination is usful for process design. Therefore...... lignocellulose is the required high cellulase enzyme dosages that increase the processing costs. One method to decrease the enzyme dosage is to re-use BG, which hydrolyze the soluble substrate cellobiose. Based on the hypothesis that immobilized BG can be re-used, how many times the enzyme could be recycled...... liquid and pretreatment time can be reduced, the influence of substrate concentration, pretreatment time and temperature were investigated and optimized. Pretreatment of barley straw by [EMIM]Ac, correlative models were constructed using 3 different pretreatment parameters (temperature, time...

Use of mouse thigh as a radiobiological model of radiation-induced skin reactions

International Nuclear Information System (INIS)

Smith, A.J.; Hagkyriakou, H.; Martin, R.F.

2000-01-01

Full text: The effects of radiation exposure on skin have been widely studied. One of the most useful and relatively easy methods for evaluating radiation-induced skin reactions is the mouse thigh model. This model is non-invasive and has the advantage of not requiring the use of anaesthetic. In the current adaptation of the mouse thigh model, female C3H/HeJ ARC mice (from the Animal Resource Centre, W.A.) were used. The mice were restrained in specially designed jigs where the right leg was held in place by a metal hook. Lead shielding ensured that only the right ventral thigh was exposed to the radiation beam. A 6MeV electron beam from a Varian 2100 Linac (20Gy / minute) was used, thus minimising the time for which the mice were restrained. Eight to twelve days after exposure to the radiation, the first skin reactions can be seen. These are scored according to a scale ranging from 0 (no visible reaction) to 3.5 (breakdown of the entire area with severe exudation). The skin reactions (erythema and moist desquamation) peak approximately 18-22 days after radiation exposure and may remain at peak for only 1-3 days. Therefore, the reactions need to be scored daily and this continues, generally until day 35, or until all moist desquamation has healed. The maximum score in a score versus time profile for each mouse in a group of 5-6 animals are averaged. Radiation-dose response data will be presented. Using the mouse thigh model, hair loss can also be measured (usually on about day 30-35) using a scale from 0-4, where 0 depicts no evident hair loss and 4 represents complete epilation. Leg contraction can also be measured as a late effect by comparison with the length of the unirradiated leg

Imaging noradrenergic influence on amyloid pathology in mouse models of Alzheimer's disease

International Nuclear Information System (INIS)

Winkeler, A.; Waerzeggers, Y.; Klose, A.; Monfared, P.; Thomas, A.V.; Jacobs, A.H.; Schubert, M.; Heneka, M.T.

2008-01-01

Molecular imaging aims towards the non-invasive characterization of disease-specific molecular alterations in the living organism in vivo. In that, molecular imaging opens a new dimension in our understanding of disease pathogenesis, as it allows the non-invasive determination of the dynamics of changes on the molecular level. The imaging technology being employed includes magnetic resonance imaging (MRI) and nuclear imaging as well as optical-based imaging technologies. These imaging modalities are employed together or alone for disease phenotyping, development of imaging-guided therapeutic strategies and in basic and translational research. In this study, we review recent investigations employing positron emission tomography and MRI for phenotyping mouse models of Alzheimers' disease by imaging. We demonstrate that imaging has an important role in the characterization of mouse models of neurodegenerative diseases. (orig.)

Intermittent Fasting Pretreatment Prevents Cognitive Impairment in a Rat Model of Chronic Cerebral Hypoperfusion.

Science.gov (United States)

Hu, Yuan; Yang, Ying; Zhang, Miao; Deng, Min; Zhang, Jun-Jian

2017-07-01

Background: Whether intermittent fasting (IF) pretreatment can prevent vascular cognitive dysfunction remains unknown to our knowledge. Objective: We investigated the effects and underlying mechanisms of IF pretreatment on cognitive dysfunction in a permanent 2-vessel occlusion (2VO) vascular dementia rat model. Methods: Male Wistar rats weighing 200 g were subjected to either IF or ad libitum feeding for 12 wk before 2VO surgery. Rats in the IF protocol underwent alternative-day feed deprivation (FD). Memory of the animals was assessed by using the Morris water maze (MWM) and the novel object recognition (NOR) test 6 wk after the surgery. After behavioral testing, malondialdehyde and glutathione concentrations, superoxide dismutase (SOD) activity, gene expression of antioxidative enzymes, inflammatory protein concentrations, and microglia density were determined in the hippocampus of rats. Results: 2-vessel occlusion operation ad libitum (2VO-AL) rats had significantly longer escape latencies on day 4 of the training phase and spent a lower percentage of time in the target quadrant (25% compared with 38% and 41%) in the MWM, and had lower discrimination ratios (47% compared with 65% and 67%) in the NOR test than 2-vessel operation and alternate-day feed deprivation (2VO-FD) and sham operation ad libitum (Sham-AL) rats, respectively ( P < 0.05). This indicates that IF helps to prevent vascular cognitive deficits. 2VO-AL rats also had higher malondialdehyde (3.54 compared with 2.15 and 1.66 nmol/mg protein) and lower glutathione concentrations (53.25 compared with 66.41 and 91.71 nmol/mg protein), lower SOD activity (100.1 compared with 133.3 and 138.5 U/mg protein), lower gene expression of antioxidative enzymes, higher expression of inflammatory proteins, and higher microglia density in the hippocampus than 2VO-FD and Sham-AL rats, respectively ( P < 0.05). This suggests that IF has antioxidative and anti-inflammatory effects. Conclusions: IF pretreatment provided

Effect of Fibroblast Co-culture on In Vitro Maturation and Fertilization of Mouse Preantral Follicles

Directory of Open Access Journals (Sweden)

Mahmoud Heidari

2011-01-01

Full Text Available Background: The aim of this study was to evaluate fibroblast co-culture on in vitro maturation andfertilization of prepubertal mouse preantral follicles.Materials and Methods: The ovaries of 12-14 day old mice were dissected and 120-150 μmintact preantral follicles with one or two layers of granulosa cells, and round oocytes were culturedindividually in α-minimal essential medium (α-MEM supplemented with 5% fetal bovine serum(FBS, 100 mIU/ml recombinant follicle stimulating hormone, 1% insulin, transferrin, seleniummix, 100 μg/ml penicillin and 50 μg/ml streptomycin as base medium for 12 days. A total number of226 follicules were cultured under two conditions: i base medium as control group (n=113; ii basemedium co-cultured with mouse embryonic fibroblast (MEF (n=113. Follicular diameters, alone,in addition to other factors were analyzed by student’s t-test and chi-square test, respectively.Results: The co-culture group showed significant differences (p<0.05 in growth rate (days 4, 6 and8 of the culture period and survival rate. However, there was no significant difference in antrumformation, ovulation rate and embryonic development of released oocytes. There were significantdifferences (p<0.05 in the estradiol and progesterone secretion at all days between the co-cultureand control groups.Conclusion: Fibroblast co-culture increased survival rate and steroid production of preantralfollicles by promoting granulosa cell proliferation.

An athymic mouse model to mimic cobalt-60 cutaneous radiation injury

Energy Technology Data Exchange (ETDEWEB)

Mosca, Rodrigo Crespo; Ferreira, Danilo Cardenuto; Napolitano, Celia Marina; Santin, Stefany Plumeri; Dornelles, Leonardo Dalla Porta; Alvarenga, Eluara Ortigoso; Mathor, Monica Beatriz, E-mail: rcmosca@usp.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

2013-07-01

Propose: Cutaneous wound from irradiation is the most common complication in radiotherapy treatment, and can be lead to mortality. We describe an athymic mouse model to mimic cutaneous radiation injury by Cobalt-60. Methods: A protocol was including dosimetry with silicon diodes,10x10x5 cm arrangement made by four lead bricks and PVC pipe designed to immobilize the athymic mouse in order to irradiate one clamped back skin point that was subdivided in four parts. To get the measurements of dose rates on the arrangement in Panoramic Irradiator, it was used a silicon diode encased in an opaque protection for ambient light and connected to an electric cable, forming a dosing probe. The currents generated in diode sensitive volume as a function of time of exposure to gamma radiation coming from the radiator, with dose rate of 0,015 Gy/min in positions 1, 0,021 Gy/min in position 2, 0,55 Gy/min in position 3 and 1,45 Gy/min in position four. After the dosimetry, each athymic mouse was anesthetized using Xylazine and Ketamine dilution and entered into a PVC pipe and a small portion of skin (1 cm{sup 3}) was clamped. This tube was then fixed to arrangement and the athymic mouse was irradiate for 60 min, than it was being returned to its cage. Results: The wound was visualized in all animals and photographed after 5 days of irradiation, with the emergence of ulceration after 9 days. No systemic or lethal sequelae occurred or visualized in any animals. Late clinical signs included a wound healing after 22 days. Conclusion: While still being a baseline study, we created a new functional preclinical animal model that can be used for new therapies and may improve radiotherapy management. (author)

An athymic mouse model to mimic cobalt-60 cutaneous radiation injury

International Nuclear Information System (INIS)

Mosca, Rodrigo Crespo; Ferreira, Danilo Cardenuto; Napolitano, Celia Marina; Santin, Stefany Plumeri; Dornelles, Leonardo Dalla Porta; Alvarenga, Eluara Ortigoso; Mathor, Monica Beatriz

2013-01-01

Propose: Cutaneous wound from irradiation is the most common complication in radiotherapy treatment, and can be lead to mortality. We describe an athymic mouse model to mimic cutaneous radiation injury by Cobalt-60. Methods: A protocol was including dosimetry with silicon diodes,10x10x5 cm arrangement made by four lead bricks and PVC pipe designed to immobilize the athymic mouse in order to irradiate one clamped back skin point that was subdivided in four parts. To get the measurements of dose rates on the arrangement in Panoramic Irradiator, it was used a silicon diode encased in an opaque protection for ambient light and connected to an electric cable, forming a dosing probe. The currents generated in diode sensitive volume as a function of time of exposure to gamma radiation coming from the radiator, with dose rate of 0,015 Gy/min in positions 1, 0,021 Gy/min in position 2, 0,55 Gy/min in position 3 and 1,45 Gy/min in position four. After the dosimetry, each athymic mouse was anesthetized using Xylazine and Ketamine dilution and entered into a PVC pipe and a small portion of skin (1 cm 3 ) was clamped. This tube was then fixed to arrangement and the athymic mouse was irradiate for 60 min, than it was being returned to its cage. Results: The wound was visualized in all animals and photographed after 5 days of irradiation, with the emergence of ulceration after 9 days. No systemic or lethal sequelae occurred or visualized in any animals. Late clinical signs included a wound healing after 22 days. Conclusion: While still being a baseline study, we created a new functional preclinical animal model that can be used for new therapies and may improve radiotherapy management. (author)

Pretreatment of the macroalgae Chaetomorpha linum for the production of bioethanol - Comparison of five pretreatment technologies

DEFF Research Database (Denmark)

Schultz-Jensen, Nadja; Thygesen, Anders; Thomsen, Sune Tjalfe

2013-01-01

-assisted pretreatment (PAP) and ball milling (BM), to determine effects of the pretreatment methods on the conversion of C. linum into ethanol by simultaneous saccharification and fermentation (SSF). WO and BM showed the highest ethanol yield of 44. g ethanol/100. g glucan, which was close to the theoretical ethanol......A qualified estimate for pretreatment of the macroalgae Chaetomorpha linum for ethanol production was given, based on the experience of pretreatment of land-based biomass. C. linum was subjected to hydrothermal pretreatment (HTT), wet oxidation (WO), steam explosion (STEX), plasma...... yield of 57. g ethanol/100. g glucan. A 64% higher ethanol yield, based on raw material, was reached after pretreatment with WO and BM compared with unpretreated C. linum, however 50% of the biomass was lost during WO. Results indicated that the right combination of pretreatment and marine macroalgae...

Streptomycin-lidocaine injections for the treatment of postherpetic neuralgia: Report of three cases with literature review.

Science.gov (United States)

Waghray, Shefali; Asif, Shaik Mohammed; Duddu, Mahesh Kumar; Arakeri, Gururaj

2013-09-01

The sudden, stabbing, paroxysmal pain of neuralgia is the fiercest agony that a patient may experience in his life. Many varied medical treatments and surgical procedures have been suggested in the literature for neuralgic pain. Most of the patients fail to respond to medical treatments or succumb to complications of total anesthesia owing to surgical procedures. Herein, we tried a new treatment modality in patients suffering from postherpetic neuralgia with appreciable success in all the three cases that are presented in this paper. Streptomycin sulfate dissolved in 2% lidocaine solution was deposited at the peripheral branches on the involved nerves targeting the trigger zones, given weekly once for a maximum of 6 week period and continued once in 2 weeks if symptoms persisted. All patients were followed-up for 1 year and there was a marked improvement on follow-up.

A two-compartment model of VEGF distribution in the mouse.

Directory of Open Access Journals (Sweden)

Phillip Yen

Full Text Available Vascular endothelial growth factor (VEGF is a key regulator of angiogenesis--the growth of new microvessels from existing microvasculature. Angiogenesis is a complex process involving numerous molecular species, and to better understand it, a systems biology approach is necessary. In vivo preclinical experiments in the area of angiogenesis are typically performed in mouse models; this includes drug development targeting VEGF. Thus, to quantitatively interpret such experimental results, a computational model of VEGF distribution in the mouse can be beneficial. In this paper, we present an in silico model of VEGF distribution in mice, determine model parameters from existing experimental data, conduct sensitivity analysis, and test the validity of the model. The multiscale model is comprised of two compartments: blood and tissue. The model accounts for interactions between two major VEGF isoforms (VEGF(120 and VEGF(164 and their endothelial cell receptors VEGFR-1, VEGFR-2, and co-receptor neuropilin-1. Neuropilin-1 is also expressed on the surface of parenchymal cells. The model includes transcapillary macromolecular permeability, lymphatic transport, and macromolecular plasma clearance. Simulations predict that the concentration of unbound VEGF in the tissue is approximately 50-fold greater than in the blood. These concentrations are highly dependent on the VEGF secretion rate. Parameter estimation was performed to fit the simulation results to available experimental data, and permitted the estimation of VEGF secretion rate in healthy tissue, which is difficult to measure experimentally. The model can provide quantitative interpretation of preclinical animal data and may be used in conjunction with experimental studies in the development of pro- and anti-angiogenic agents. The model approximates the normal tissue as skeletal muscle and includes endothelial cells to represent the vasculature. As the VEGF system becomes better characterized in

A novel minimal invasive mouse model of extracorporeal circulation.

Science.gov (United States)

Luo, Shuhua; Tang, Menglin; Du, Lei; Gong, Lina; Xu, Jin; Chen, Youwen; Wang, Yabo; Lin, Ke; An, Qi

2015-01-01

Extracorporeal circulation (ECC) is necessary for conventional cardiac surgery and life support, but it often triggers systemic inflammation that can significantly damage tissue. Studies of ECC have been limited to large animals because of the complexity of the surgical procedures involved, which has hampered detailed understanding of ECC-induced injury. Here we describe a minimally invasive mouse model of ECC that may allow more extensive mechanistic studies. The right carotid artery and external jugular vein of anesthetized adult male C57BL/6 mice were cannulated to allow blood flow through a 1/32-inch external tube. All animals (n = 20) survived 30 min ECC and subsequent 60 min observation. Blood analysis after ECC showed significant increases in levels of tumor necrosis factor α, interleukin-6, and neutrophil elastase in plasma, lung, and renal tissues, as well as increases in plasma creatinine and cystatin C and decreases in the oxygenation index. Histopathology showed that ECC induced the expected lung inflammation, which included alveolar congestion, hemorrhage, neutrophil infiltration, and alveolar wall thickening; in renal tissue, ECC induced intracytoplasmic vacuolization, acute tubular necrosis, and epithelial swelling. Our results suggest that this novel, minimally invasive mouse model can recapitulate many of the clinical features of ECC-induced systemic inflammatory response and organ injury.

A Novel Minimal Invasive Mouse Model of Extracorporeal Circulation

Directory of Open Access Journals (Sweden)

Shuhua Luo

2015-01-01

Full Text Available Extracorporeal circulation (ECC is necessary for conventional cardiac surgery and life support, but it often triggers systemic inflammation that can significantly damage tissue. Studies of ECC have been limited to large animals because of the complexity of the surgical procedures involved, which has hampered detailed understanding of ECC-induced injury. Here we describe a minimally invasive mouse model of ECC that may allow more extensive mechanistic studies. The right carotid artery and external jugular vein of anesthetized adult male C57BL/6 mice were cannulated to allow blood flow through a 1/32-inch external tube. All animals (n=20 survived 30 min ECC and subsequent 60 min observation. Blood analysis after ECC showed significant increases in levels of tumor necrosis factor α, interleukin-6, and neutrophil elastase in plasma, lung, and renal tissues, as well as increases in plasma creatinine and cystatin C and decreases in the oxygenation index. Histopathology showed that ECC induced the expected lung inflammation, which included alveolar congestion, hemorrhage, neutrophil infiltration, and alveolar wall thickening; in renal tissue, ECC induced intracytoplasmic vacuolization, acute tubular necrosis, and epithelial swelling. Our results suggest that this novel, minimally invasive mouse model can recapitulate many of the clinical features of ECC-induced systemic inflammatory response and organ injury.

Induction of micronuclei in human and mouse lymphocytes irradiated with gamma radiation and effect of panax ginseng C. A. Meyer

Energy Technology Data Exchange (ETDEWEB)

Kim, Sung Ho; Oh, Heon; Lee, Song Eun [Chonnam National Univ., Kwangju (Korea, Republic of); Lee, Yun Sil; Kim, Tae Hwan [Korea Cancer Center Hospital, Seoul (Korea, Republic of); Jeong, Kyu Sik [Korea Research Institute of Bioscience and Biotechnology, Taejon (Korea, Republic of); Ryu, Si Yun [Chungnam National Univ., Taejon (Korea, Republic of)

1997-09-01

The frequencies of {gamma}-ray-induced micronuclei (MN) in Cytokinesis-Blocked (CB) lymphocytes at several doses were measured in three donors of human and C57BL/6 mice. Measurements performed after irradiation showed a dose-related increases in MN frequency in each of the donors studied. The relative sensitivity of mouse in Spleen Lymphocytes (SLs) compared with human Peripheral Blood Lymphocytes (PBLs) was estimated by best fitting linear-quadratic model based on the radiation-induced MN data over the range from 0 cGy to 400 cGy. In the case of MN frequency with 0.2 per CB cell, the relative sensitivity of mouse SLs was 1.67. Compared with the radiation-induced MN formation in the PBLs of human, the SLs of mouse were more radiosensitive. Using this MN assay with human PBLs and mouse SLs, studies were performed to determine whether the water fraction of ginseng (Panax ginseng C.A.Meyer)against radiation-induced MN in human PBLs after in vitro irradiation (3Gy) and in SLs of C57BL/6 mice after in vivo irradiation (3Gy). The frequency of MN in human PBLs was reduced by water fraction of ginseng (0.5mg/ml of medium) both pre-and post treatment (p<0.01) in vitro. In addition, the frequency of MN in mouse SLs was also reduced by pretreatment of ginseng (2mg/ml of drinking water for 7 days) in vivo.

Mouse models: the ketogenic diet and polyunsaturated fatty acids.

Science.gov (United States)

Borges, Karin

2008-11-01

Literature on the anticonvulsant effects of the ketogenic diet (KD) in mouse seizure models is summarized. Recent data show that a KD balanced in vitamin, mineral, and antioxidant content is anticonvulsant in mice, confirming that the KD's effect in mice can be attributed to the composition of the diet and not other dietary factors. Given that the anticonvulsant mechanism of the KD is still unknown, the anticonvulsant profile of the diet in different seizure models may help to decipher this mechanism. The implications of the findings that the KD is anticonvulsant in electrical seizure models are indicated. Further, the potential involvement of polyunsaturated fatty acids (PUFA) in the KD's anticonvulsant mechanism is discussed.

Enzymatic hydrolsis of pretreated rice straw

Energy Technology Data Exchange (ETDEWEB)

Vlasenko, E.Y.; Shoemaker, S.P. [California Inst. of Food and Agricultural Research, Davis, CA (United States); Ding, H. [California Univ., Davis (Canada). Dept. of Food Science and Technology; Labavitch, J.M. [California Univ., Davis, CA (United States). Dept. of Pomology

1997-02-01

California rice straw is being evaluated as a feedstock for production of power and fuel. This paper examines the initial steps in the process: pretreatment of rice straw and enzymatic hydrolysis of the polysaccharides in the pretreated material to soluble sugars. Rice straw was subjected to three distinct pretreatment procedures: acid-catalyzed steam explosion (Swan Biomass Company), acid hydrolysis (U.S. DOE National Renewable Energy Laboratory), and ammonia fiber explosion or AFEX (Texas A and M University). Standard conditions for each pretreatment were used, but none was optimized for rice straw specifically. Six commercial cellulases, products of Genencor International (USA), Novo (Denmark), Iogen (Canada) and Fermtech (Russia) were used for hydrolysis. The Swan- and the acid-pretreatments effectively removed hemicellulose from rice straw, providing high yields of fermentable sugars. The AFEX-pretreatment was distinctly different from other pretreatments in that it did not significantly solubilize hemicellulose. All three pretreatment procedures substantially increased enzymatic digestibility of rice straw. Three commercial Trichoderma-reesei-derived enzyme preparations: Cellulase 100L (Iogen), Spezyme CP (Genencor), and Al (Fermtech), were more active on pretreated rice straw compared than others tested. Conditions for hydrolysis of rice straw using Cellulase 100L were evaluated. The supplementation of this enzyme preparation with cellobiase (Novozyme 188) significantly improved the parameters of hydrolysis for the Swan- and the acid-pretreated materials, but did not affect the hydrolysis of the AFEX-pretreated rice straw. (Author)

The calm mouse: an animal model of stress reduction.

Science.gov (United States)

Gurfein, Blake T; Stamm, Andrew W; Bacchetti, Peter; Dallman, Mary F; Nadkarni, Nachiket A; Milush, Jeffrey M; Touma, Chadi; Palme, Rupert; Di Borgo, Charles Pozzo; Fromentin, Gilles; Lown-Hecht, Rachel; Konsman, Jan Pieter; Acree, Michael; Premenko-Lanier, Mary; Darcel, Nicolas; Hecht, Frederick M; Nixon, Douglas F

2012-05-09

Chronic stress is associated with negative health outcomes and is linked with neuroendocrine changes, deleterious effects on innate and adaptive immunity, and central nervous system neuropathology. Although stress management is commonly advocated clinically, there is insufficient mechanistic understanding of how decreasing stress affects disease pathogenesis. Therefore, we have developed a "calm mouse model" with caging enhancements designed to reduce murine stress. Male BALB/c mice were divided into four groups: control (Cntl), standard caging; calm (Calm), large caging to reduce animal density, a cardboard nest box for shelter, paper nesting material to promote innate nesting behavior, and a polycarbonate tube to mimic tunneling; control exercise (Cntl Ex), standard caging with a running wheel, known to reduce stress; and calm exercise (Calm Ex), calm caging with a running wheel. Calm, Cntl Ex and Calm Ex animals exhibited significantly less corticosterone production than Cntl animals. We also observed changes in spleen mass, and in vitro splenocyte studies demonstrated that Calm Ex animals had innate and adaptive immune responses that were more sensitive to acute handling stress than those in Cntl. Calm animals gained greater body mass than Cntl, although they had similar food intake, and we also observed changes in body composition, using magnetic resonance imaging. Together, our results suggest that the Calm mouse model represents a promising approach to studying the biological effects of stress reduction in the context of health and in conjunction with existing disease models.

Tissue specific mutagenic and carcinogenic responses in NER defective mouse models.

NARCIS (Netherlands)

Wijnhoven, Susan W P; Hoogervorst, Esther M; Waard, Harm de; Horst, Gijsbertus T J van der; Steeg, Harry van

2007-01-01

Several mouse models with defects in genes encoding components of the nucleotide excision repair (NER) pathway have been developed. In NER two different sub-pathways are known, i.e. transcription-coupled repair (TC-NER) and global-genome repair (GG-NER). A defect in one particular NER protein can

Efficacy of Enrofloxacin in a Mouse Model of Sepsis

OpenAIRE

Slate, Andrea R; Bandyopadhyay, Sheila; Francis, Kevin P; Papich, Mark G; Karolewski, Brian; Hod, Eldad A; Prestia, Kevin A

2014-01-01

We examined the efficacy of enrofloxacin administered by 2 different routes in a mouse model of sepsis. Male CD1 mice were infected with a bioluminescent strain of enteropathogenic Escherichia coli and treated with enrofloxacin either by injection or in drinking water. Peak serum levels were evaluated by using HPLC. Mice were monitored for signs of clinical disease, and infections were monitored by using bioluminescence imaging. Serum levels of enrofloxacin and the active metabolite ciproflox...

Immunotropic aspect of the Bacillus coagulans probiotic action.

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Bomko, Tatiana V; Nosalskaya, Tatiana N; Kabluchko, Tatiana V; Lisnyak, Yury V; Martynov, Artur V

2017-08-01

Currently, probiotics are increasingly used as the alternative to antibiotics as well as the preventive measures in humans. In particular, probiotics occupy a key position in the treatment of antibiotics-associated intestinal dysbiosis. A spore-forming microorganism lactobacillus Bacillus coagulans is one of the most promising probiotics. However, some of its pharmacological effects remain poorly understood. This study was aimed at investigation of the effect of B. coagulans (Laktovit Forte) on the intestinal dysbiosis syndrome in mice caused by streptomycin against the background of cyclophosphamide-induced cellular immunodeficiency. Pharmacological method: mouse model in vivo with immunodeficiency caused by cyclophosphamide. In mice with colitis caused by streptomycin treatment, the administration of B. coagulans (Laktovit Forte medicinal product) resulted in an antidiarrhoeal effect, normalisation of gastrointestinal motility and prevention of the animals' weight loss. Given the cyclophosphamide-induced immunosuppression and streptomycin-associated diarrhoea, the immunity was completely restored only under the action of B. coagulans. According to all parameters, B. coagulans has been proved to be more effective as compared to the Linex Forte reference product containing lacto- and bifidobacteria. © 2017 Royal Pharmaceutical Society.

Validation of a mouse xenograft model system for gene expression analysis of human acute lymphoblastic leukaemia

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Francis Richard W

2010-04-01

Full Text Available Abstract Background Pre-clinical models that effectively recapitulate human disease are critical for expanding our knowledge of cancer biology and drug resistance mechanisms. For haematological malignancies, the non-obese diabetic/severe combined immunodeficient (NOD/SCID mouse is one of the most successful models to study paediatric acute lymphoblastic leukaemia (ALL. However, for this model to be effective for studying engraftment and therapy responses at the whole genome level, careful molecular characterisation is essential. Results Here, we sought to validate species-specific gene expression profiling in the high engraftment continuous ALL NOD/SCID xenograft. Using the human Affymetrix whole transcript platform we analysed transcriptional profiles from engrafted tissues without prior cell separation of mouse cells and found it to return highly reproducible profiles in xenografts from individual mice. The model was further tested with experimental mixtures of human and mouse cells, demonstrating that the presence of mouse cells does not significantly skew expression profiles when xenografts contain 90% or more human cells. In addition, we present a novel in silico and experimental masking approach to identify probes and transcript clusters susceptible to cross-species hybridisation. Conclusions We demonstrate species-specific transcriptional profiles can be obtained from xenografts when high levels of engraftment are achieved or with the application of transcript cluster masks. Importantly, this masking approach can be applied and adapted to other xenograft models where human tissue infiltration is lower. This model provides a powerful platform for identifying genes and pathways associated with ALL disease progression and response to therapy in vivo.

A Transgenic Mouse Model of Poliomyelitis.

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Koike, Satoshi; Nagata, Noriyo

2016-01-01

Transgenic mice (tg mice) that express the human poliovirus receptor (PVR), CD155, are susceptible to poliovirus and develop a neurological disease that resembles human poliomyelitis. Assessment of the neurovirulence levels of poliovirus strains, including mutant viruses produced by reverse genetics, circulating vaccine-derived poliovirus, and vaccine candidates, is useful for basic research of poliovirus pathogenicity, the surveillance of circulating polioviruses, and the quality control of oral live poliovirus vaccines, and does not require the use of monkeys. Furthermore, PVR-tg mice are useful for studying poliovirus tissue tropism and host immune responses. PVR-tg mice can be bred with mice deficient in the genes involved in viral pathogenicity. This report describes the methods used to analyze the pathogenicity and immune responses of poliovirus using the PVR-tg mouse model.

A mouse model of prenatal ethanol exposure using a voluntary drinking paradigm.

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Allan, Andrea M; Chynoweth, Julie; Tyler, Lani A; Caldwell, Kevin K

2003-12-01

The incidence of fetal alcohol spectrum disorders is estimated to be as high as 1 in 100 births. Efforts to better understand the basis of prenatal ethanol-induced impairments in brain functioning, and the mechanisms by which ethanol produces these defects, will rely on the use of animal models of fetal alcohol exposure (FAE). Using a saccharin-sweetened alcohol solution, we developed a free-choice, moderate alcohol access model of prenatal alcohol exposure. Stable drinking of a saccharin solution (0.066%) was established in female mice. Ethanol then was added to the saccharin in increasing concentrations (2%, 5%, 10% w/v) every 2 days. Water was always available, and mice consumed standard pellet chow. Control mice drank saccharin solution without ethanol. After a stable baseline of ethanol consumption (14 g/kg/day) was obtained, females were impregnated. Ethanol consumption continued throughout pregnancy and then was decreased to 0% in a step-wise fashion over a period of 6 days after pups were delivered. Characterization of the model included measurements of maternal drinking patterns, blood alcohol levels, food consumption, litter size, pup weight, pup retrieval times for the dams, and effects of FAE on performance in fear-conditioned learning and novelty exploration. Maternal food consumption, maternal care, and litter size and number were all found to be similar for the alcohol-exposed and saccharin control animals. FAE did not alter locomotor activity in an open field but did increase the time spent inspecting a novel object introduced into the open field. FAE mice displayed reduced contextual fear when trained using a delay fear conditioning procedure. The mouse model should be a useful tool in testing hypotheses about the neural mechanisms underlying the learning deficits present in fetal alcohol spectrum disorders. Moreover, a mouse prenatal ethanol model should increase the opportunity to use the power of genetically defined and genetically altered mouse

Generation of a mouse model for studying the role of upregulated RTEL1 activity in tumorigenesis.

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Wu, Xiaoli; Sandhu, Sumit; Nabi, Zinnatun; Ding, Hao

2012-10-01

Regulator of telomere length 1 (RTEL1) is a DNA helicase protein that has been demonstrated to be required for the maintenance of telomere length and genomic stability. It has also been found to be essential for DNA homologous recombination during DNA repairing. Human RTEL1 genomic locus (20q13.3) is frequently amplified in multiple types of human cancers, including hepatocellular carcinoma and gastrointestinal tract tumors, indicating that upregulated RTEL1 activity could be important for tumorigenesis. In this study, we have developed a conditional transgenic mouse model that overexpress mouse Rtel1 in a Cre-excision manner. By crossing with a ubiquitous Cre mouse line, we further demonstrated that these established Rtel1 conditional transgenic mice allow to efficiently and highly express a functional Rtel1 that is able to rescue the embryonic defects of Rtel1 null mouse allele. Furthermore, we demonstrated that more than 70% transgenic mice that widely overexpress Rtel1 developed liver tumors that recapitulate many malignant features of human hepatocellular carcinoma (HCC). Our work not only generated a valuable mouse model for determining the role of RTEL1 in the development of cancers, but also provided the first genetic evidence to support that amplification of RTEL1, as observed in several types of human cancers, is tumorigenic.

A mouse model for MERS coronavirus-induced acute respiratory distress syndrome.

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Cockrell, Adam S; Yount, Boyd L; Scobey, Trevor; Jensen, Kara; Douglas, Madeline; Beall, Anne; Tang, Xian-Chun; Marasco, Wayne A; Heise, Mark T; Baric, Ralph S

2016-11-28

Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel virus that emerged in 2012, causing acute respiratory distress syndrome (ARDS), severe pneumonia-like symptoms and multi-organ failure, with a case fatality rate of ∼36%. Limited clinical studies indicate that humans infected with MERS-CoV exhibit pathology consistent with the late stages of ARDS, which is reminiscent of the disease observed in patients infected with severe acute respiratory syndrome coronavirus. Models of MERS-CoV-induced severe respiratory disease have been difficult to achieve, and small-animal models traditionally used to investigate viral pathogenesis (mouse, hamster, guinea-pig and ferret) are naturally resistant to MERS-CoV. Therefore, we used CRISPR-Cas9 gene editing to modify the mouse genome to encode two amino acids (positions 288 and 330) that match the human sequence in the dipeptidyl peptidase 4 receptor, making mice susceptible to MERS-CoV infection and replication. Serial MERS-CoV passage in these engineered mice was then used to generate a mouse-adapted virus that replicated efficiently within the lungs and evoked symptoms indicative of severe ARDS, including decreased survival, extreme weight loss, decreased pulmonary function, pulmonary haemorrhage and pathological signs indicative of end-stage lung disease. Importantly, therapeutic countermeasures comprising MERS-CoV neutralizing antibody treatment or a MERS-CoV spike protein vaccine protected the engineered mice against MERS-CoV-induced ARDS.

Musical Electroacupuncture May Be a Better Choice than Electroacupuncture in a Mouse Model of Alzheimer's Disease

OpenAIRE

Jiang, Jing; Liu, Gang; Shi, Suhua; Li, Zhigang

2016-01-01

Objectives. To compare musical electroacupuncture and electroacupuncture in a mouse model of Alzheimer's disease. Methods. In this study, 7.5-month-old male senescence-accelerated mouse prone 8 (SAMP8) mice were used as an Alzheimer's disease animal model. In the normal control paradigm, 7.5-month-old male SAMR1 mice were used as the blank control group (N group). After 15 days of treatment, using Morris water maze test, micro-PET, and immunohistochemistry, the differences among the musical e...

An antibiotic-responsive mouse model of fulminant ulcerative colitis.

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Silvia S Kang

2008-03-01

Full Text Available BACKGROUND: The constellation of human inflammatory bowel disease (IBD includes ulcerative colitis and Crohn's disease, which both display a wide spectrum in the severity of pathology. One theory is that multiple genetic hits to the host immune system may contribute to the susceptibility and severity of IBD. However, experimental proof of this concept is still lacking. Several genetic mouse models that each recapitulate some aspects of human IBD have utilized a single gene defect to induce colitis. However, none have produced pathology clearly distinguishable as either ulcerative colitis or Crohn's disease, in part because none of them reproduce the most severe forms of disease that are observed in human patients. This lack of severe IBD models has posed a challenge for research into pathogenic mechanisms and development of new treatments. We hypothesized that multiple genetic hits to the regulatory machinery that normally inhibits immune activation in the intestine would generate more severe, reproducible pathology that would mimic either ulcerative colitis or Crohn's disease. METHODS AND FINDINGS: We generated a novel mouse line (dnKO that possessed defects in both TGFbetaRII and IL-10R2 signaling. These mice rapidly and reproducibly developed a disease resembling fulminant human ulcerative colitis that was quite distinct from the much longer and more variable course of pathology observed previously in mice possessing only single defects. Pathogenesis was driven by uncontrolled production of proinflammatory cytokines resulting in large part from T cell activation. The disease process could be significantly ameliorated by administration of antibodies against IFNgamma and TNFalpha and was completely inhibited by a combination of broad-spectrum antibiotics. CONCLUSIONS: Here, we develop to our knowledge the first mouse model of fulminant ulcerative colitis by combining multiple genetic hits in immune regulation and demonstrate that the resulting

Development of A Mouse Model of Menopausal Ovarian Cancer

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Elizabeth R. Smith

2014-02-01

Full Text Available Despite significant understanding of the genetic mutations involved in ovarian epithelial cancer and advances in genomic approaches for expression and mutation profiling of tumor tissues, several key questions in ovarian cancer biology remain enigmatic: the mechanism for the well-established impact of reproductive factors on ovarian cancer risk remains obscure; questions of the cell of origin of ovarian cancer continue to be debated; and the precursor lesion, sequence, or events in progression remain to be defined. Suitable mouse models should complement the analysis of human tumor tissues and may provide clues to these questions currently perplexing ovarian cancer biology.A potentially useful model is the germ cell-deficient Wv (white spotting variant mutant mouse line, which may be used to study the impact of menopausal physiology on the increased risk of ovarian cancer. The Wv mice harbor a point mutation in c-Kit that reduces the receptor tyrosine kinase activity to about 1-5% (it is not a null mutation. Homozygous Wv mutant females have a reduced ovarian germ cell reservoir at birth and the follicles are rapidly depleted upon reaching reproductive maturity, but other biological phenotypes are minimal and the mice have a normal life span. The loss of ovarian function precipitates changes in hormonal and metabolic activity that model features of menopause in humans. As a consequence of follicle depletion, the Wv ovaries develop ovarian tubular adenomas, a benign epithelial tumor corresponding to surface epithelial invaginations and papillomatosis that mark human ovarian aging. Ongoing work will test the possibility of converting the benign epithelial tubular adenomas into neoplastic tumors by addition of an oncogenic mutation, such as of Tp53, to model the genotype and biology of serous ovarian cancer.Model based on the Wv mice may have the potential to gain biological and etiological insights into ovarian cancer development and prevention.

LBH589, A Hydroxamic Acid-Derived HDAC Inhibitor, is Neuroprotective in Mouse Models of Huntington's Disease.

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Chopra, Vanita; Quinti, Luisa; Khanna, Prarthana; Paganetti, Paolo; Kuhn, Rainer; Young, Anne B; Kazantsev, Aleksey G; Hersch, Steven

2016-12-15

Modulation of gene transcription by HDAC inhibitors has been shown repeatedly to be neuroprotective in cellular, invertebrate, and rodent models of Huntington's disease (HD). It has been difficult to translate these treatments to the clinic, however, because existing compounds have limited potency or brain bioavailability. In the present study, we assessed the therapeutic potential of LBH589, an orally bioavailable hydroxamic acid-derived nonselective HDAC inhibitor in mouse models of HD. The efficacy of LBH589 is tested in two HD mouse models using various biochemical, behavioral and neuropathological outcome measures. We show that LBH589 crosses the blood brain barrier; induces histone hyperacetylation and prevents striatal neuronal shrinkage in R6/2 HD mice. In full-length knock-in HD mice LBH589-treatment improves motor performance and reduces neuronal atrophy. Our efficacious results of LBH589 in fragment and full-length mouse models of HD suggest that LBH589 is a promising candidate for clinical assessment in HD patients and provides confirmation that non-selective HDAC inhibitors can be viable clinical candidates.

Attenuation of Morphine Withdrawal Syndrome by Various Dosages of Curcumin in Comparison with Clonidine in Mouse: Possible Mechanism

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Majid Motaghinejad

2015-03-01

Full Text Available Background: Herbal medical compounds and their major constituent have been used in the management and treatment of opioid withdrawal syndrome and pain. This study was carried out to clarify the effect of curcumin, the major compound of turmeric, on morphine withdrawal syndrome in mouse model and its possible mechanisms of pain relieving activity by assessing in writhing test as a model of visceral pain. Methods: Due to two separate protocols (withdrawal syndrome and pain, 144 male albino mice were divided in two major groups. In withdrawal syndrome group, test effect of various dosages of curcumin (10, 20, and 40 mg/kg was assessed on withdrawal signs and compared with positive and negative control and standard treatment (clonidine 0.4 mg/kg groups. In pain groups, to determine the mechanism of pain relieving activity of curcumin, various dosages of curcumin (10, 20, and 40 mg/kg in three separated groups, were used against acetic acid induced writhing (which is a constriction test. The most effective dose (40 mg/kg was used in writhing test and compared with groups pretreated with antagonist of major neurotransmitters involved in pain; and compared with group pretreated with vehicle (DMSO, 0.05% as control. Results: Curcumin attenuates withdrawal syndrome in a dose dependent manner in comparison with the dependent positive control group (P<0.05. It also indicated that pretreatment with naloxone and cyproheptadine significantly attenuate antinociception effect of curcumin (P<0.05. Conclusion: This study advocate that antinociception of curcumin was mediated by opioidergic and adrenergic system.

Inhibition of Inflammation-Associated Olfactory Loss by Etanercept in an Inducible Olfactory Inflammation Mouse Model.

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Jung, Yong Gi; Lane, Andrew P

2016-06-01

To determine the effect of a soluble human tumor necrosis factor alpha (TNF-α) receptor blocker (etanercept) on an inducible olfactory inflammation (IOI) mouse model. An in vivo study using a transgenic mouse model. Research laboratory. To study the impact of chronic inflammation on the olfactory system, a transgenic mouse model of chronic rhinosinusitis-associated olfactory loss was utilized (IOI mouse), expressing TNF-α in a temporally controlled fashion within the olfactory epithelium. In one group of mice (n = 4), etanercept was injected intraperitoneally (100 μg/dose, 3 times/week) concurrent with a 2-week period of TNF-α expression. A second group of mice (n = 2) underwent induction of TNF-α expression for 8 weeks, with etanercept treatment administered during the final 2 weeks of inflammation. Olfactory function was assayed by elecro-olfactogram (EOG), and olfactory tissue was processed for histology and immunohistochemical staining. Each group was compared with an equal-number control group. Compared with nontreated IOI mice, etanercept-treated IOI mice showed significantly improved EOG responses after 2 weeks (P loss of olfactory epithelium and no EOG response in nontreated IOI mice. However, in etanercept-treated mice, regeneration of olfactory epithelium was observed. Concomitant administration of etanercept in IOI mice results in interruption of TNF-α-induced olfactory loss and induction of neuroepithelial regeneration. This demonstrates that etanercept has potential utility as a tool for elucidating the role of TNF-α in other olfactory inflammation models. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.

Pretreatment Solution for Water Recovery Systems

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Muirhead, Dean (Inventor)

2018-01-01

Chemical pretreatments are used to produce usable water by treating a water source with a chemical pretreatment that contains a hexavalent chromium and an acid to generate a treated water source, wherein the concentration of sulfate compounds in the acid is negligible, and wherein the treated water source remains substantially free of precipitates after the addition of the chemical pretreatment. Other methods include reducing the pH in urine to be distilled for potable water extraction by pretreating the urine before distillation with a pretreatment solution comprising one or more acid sources selected from a group consisting of phosphoric acid, hydrochloric acid, and nitric acid, wherein the urine remains substantially precipitate free after the addition of the pretreatment solution. Another method described comprises a process for reducing precipitation in urine to be processed for water extraction by mixing the urine with a pretreatment solution comprising hexavalent chromium compound and phosphoric acid.

The mouse as a model organism in aging research: usefulness, pitfalls and possibilities.

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Vanhooren, Valerie; Libert, Claude

2013-01-01

The mouse has become the favorite mammalian model. Among the many reasons for this privileged position of mice is their genetic proximity to humans, the possibilities of genetically manipulating their genomes and the availability of many tools, mutants and inbred strains. Also in the field of aging, mice have become very robust and reliable research tools. Since laboratory mice have a life expectancy of only a few years, genetic approaches and other strategies for intervening in aging can be tested by examining their effects on life span and aging parameters during the relatively short period of, for example, a PhD project. Moreover, experiments on mice with an extended life span as well as on mice demonstrating signs of (segmental) premature aging, together with genetic mapping strategies, have provided novel insights into the fundamental processes that drive aging. Finally, the results of studies on caloric restriction and pharmacological anti-aging treatments in mice have a high degree of relevance to humans. In this paper, we review a number of recent genetic mapping studies that have yielded novel insights into the aging process. We discuss the value of the mouse as a model for testing interventions in aging, such as caloric restriction, and we critically discuss mouse strains with an extended or a shortened life span as models of aging. Copyright © 2012 Elsevier B.V. All rights reserved.

Phage Therapy Is Effective in a Mouse Model of Bacterial Equine Keratitis.

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Furusawa, Takaaki; Iwano, Hidetomo; Hiyashimizu, Yutaro; Matsubara, Kazuki; Higuchi, Hidetoshi; Nagahata, Hajime; Niwa, Hidekazu; Katayama, Yoshinari; Kinoshita, Yuta; Hagiwara, Katsuro; Iwasaki, Tomohito; Tanji, Yasunori; Yokota, Hiroshi; Tamura, Yutaka

2016-09-01

Bacterial keratitis of the horse is mainly caused by staphylococci, streptococci, and pseudomonads. Of these bacteria, Pseudomonas aeruginosa sometimes causes rapid corneal corruption and, in some cases, blindness. Antimicrobial resistance can make treatment very difficult. Therefore, new strategies to control bacterial infection are required. A bacteriophage (phage) is a virus that specifically infects and kills bacteria. Since phage often can lyse antibiotic-resistant bacteria because the killing mechanism is different, we examined the use of phage to treat horse bacterial keratitis. We isolated Myoviridae or Podoviridae phages, which together have a broad host range. They adsorb efficiently to host bacteria; more than 80% of the ΦR18 phage were adsorbed to host cells after 30 s. In our keratitis mouse model, the administration of phage within 3 h also could kill bacteria and suppress keratitis. A phage multiplicity of infection of 100 times the host bacterial number could kill host bacteria effectively. A cocktail of two phages suppressed bacteria in the keratitis model mouse. These data demonstrated that the phages in this study could completely prevent the keratitis caused by P. aeruginosa in a keratitis mouse model. Furthermore, these results suggest that phage may be a more effective prophylaxis for horse keratitis than the current preventive use of antibiotics. Such treatment may reduce the use of antibiotics and therefore antibiotic resistance. Further studies are required to assess phage therapy as a candidate for treatment of horse keratitis. Antibiotic-resistant bacteria are emerging all over the world. Bacteriophages have great potential for resolution of this problem. A bacteriophage, or phage, is a virus that infects bacteria specifically. As a novel therapeutic strategy against racehorse keratitis caused by Pseudomonas aeruginosa, we propose the application of phages for treatment. Phages isolated in this work had in vitro effectiveness for a broad

Pretreatment with Fish Oil-Based Lipid Emulsion Modulates Muscle Leukocyte Chemotaxis in Murine Model of Sublethal Lower Limb Ischemia

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Yao-Ming Shih

2017-01-01

Full Text Available This study investigated the effects of a fish oil- (FO- based lipid emulsion on muscle leukocyte chemotaxis and inflammatory responses in a murine model of limb ischemia-reperfusion (IR injury. Mice were assigned randomly to 1 sham (sham group, 2 ischemic groups, and 2 IR groups. The sham group did not undergo the ischemic procedure. The mice assigned to the ischemic or IR groups were pretreated intraperitoneally with either saline or FO-based lipid emulsion for 3 consecutive days. The IR procedure was induced by applying a 4.5 oz orthodontic rubber band to the left thigh above the greater trochanter for 120 min and then cutting the band to allow reperfusion. The ischemic groups were sacrificed immediately while the IR groups were sacrificed 24 h after reperfusion. Blood, IR-injured gastrocnemius, and lung tissues were collected for analysis. The results showed that FO pretreatment suppressed the local and systemic expression of several IR-induced proinflammatory mediators. Also, the FO-pretreated group had lower blood Ly6ChiCCR2hi monocyte percentage and muscle M1/M2 ratio than the saline group at 24 h after reperfusion. These findings suggest that FO pretreatment may have a protective role in limb IR injury by modulating the expression of proinflammatory mediators and regulating the polarization of macrophage.

Human immune system mouse models of Ebola virus infection.

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Spengler, Jessica R; Prescott, Joseph; Feldmann, Heinz; Spiropoulou, Christina F

2017-08-01

Human immune system (HIS) mice, immunodeficient mice engrafted with human cells (with or without donor-matched tissue), offer a unique opportunity to study pathogens that cause disease predominantly or exclusively in humans. Several HIS mouse models have recently been used to study Ebola virus (EBOV) infection and disease. The results of these studies are encouraging and support further development and use of these models in Ebola research. HIS mice provide a small animal model to study EBOV isolates, investigate early viral interactions with human immune cells, screen vaccines and therapeutics that modulate the immune system, and investigate sequelae in survivors. Here we review existing models, discuss their use in pathogenesis studies and therapeutic screening, and highlight considerations for study design and analysis. Finally, we point out caveats to current models, and recommend future efforts for modeling EBOV infection in HIS mice. Published by Elsevier B.V.

A novel brain trauma model in the mouse : effects of dexamethasone treatment

NARCIS (Netherlands)

Hortobágyi, Tibor; Hortobagyi, S; Gorlach, C; Harkany, T; Benbyo, Z; Gorogh, T; Nagel, W; Wahl, M

2000-01-01

We describe a novel methodological approach for inducing cold lesion in the mouse as a model of human cortical contusion trauma. To validate its reproducibility and reliability, dexamethasone (Dxm) was repeatedly applied to demonstrate possible antioedematous drug effects. Following tho induction of

Enhancing biogas production of corn stover by fast pyrolysis pretreatment.

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Wang, Fang; Zhang, Deli; Wu, Houkai; Yi, Weiming; Fu, Peng; Li, Yongjun; Li, Zhihe

2016-10-01

A new thermo-chemical pretreatment by a lower temperature fast pyrolysis (LTFP) was applied to promote anaerobic digestion (AD) efficiency of corn stover (CS). The pretreatment experiment was performed by a fluidized bed pyrolysis reactor at 180, 200 and 220°C with a carrier gas flow rate of 4 and 3m(3)/h. The components characteristics, Scanning Electron Microscope (SEM) images and Crystal Intensity (CrI) of the pretreated CS were tested to explore effectiveness of the pretreatment. The results showed that the cumulative methane production at 180°C for 4 and 3m(3)/h were 199.8 and 200.3mL/g TS, respectively. As compared to the untreated CS, the LTFP pretreatment significantly (a<0.05) increased the methane production by 18.07% and 18.33%, respectively. Methane production was well fitted by the Gompertz models, and the maximum methane potential and AD efficiency was obtained at 180°C for 3m(3)/h. Copyright © 2016 Elsevier Ltd. All rights reserved.

Abnormal notochord branching is associated with foregut malformations in the adriamycin treated mouse model.

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Hajduk, Piotr; Sato, Hideaki; Puri, Prem; Murphy, Paula

2011-01-01

Oesophageal atresia (OA) and tracheooesophageal fistula (TOF) are relatively common human congenital malformations of the foregut where the oesophagus does not connect with the stomach and there is an abnormal connection between the stomach and the respiratory tract. They require immediate corrective surgery and have an impact on the future health of the individual. These abnormalities are mimicked by exposure of rat and mouse embryos in utero to the drug adriamycin. The causes of OA/TOF during human development are not known, however a number of mouse mutants where different signalling pathways are directly affected, show similar abnormalities, implicating multiple and complex signalling mechanisms. The similarities in developmental outcome seen in human infants and in the adriamycin treated mouse model underline the potential of this model to unravel the early embryological events and further our understanding of the processes disturbed, leading to such abnormalities. Here we report a systematic study of the foregut and adjacent tissues in embryos treated with adriamycin at E7 and E8 and analysed between E9 and E12, comparing morphology in 3D in 149 specimens. We describe a spectrum of 8 defects, the most common of which is ventral displacement and branching of the notochord (in 94% of embryos at E10) and a close spatial correspondence between the site of notochord branching and defects of the foregut. In addition gene expression analysis shows altered dorso-ventral foregut patterning in the vicinity of notochord branches. This study shows a number of features of the adriamycin mouse model not previously reported, implicates the notochord as a primary site of disturbance in such abnormalities and underlines the importance of the model to further address the mechanistic basis of foregut congenital abnormalities.

Translational Mouse Models of Autism: Advancing Toward Pharmacological Therapeutics

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Kazdoba, Tatiana M.; Leach, Prescott T.; Yang, Mu; Silverman, Jill L.; Solomon, Marjorie

2016-01-01

Animal models provide preclinical tools to investigate the causal role of genetic mutations and environmental factors in the etiology of autism spectrum disorder (ASD). Knockout and humanized knock-in mice, and more recently knockout rats, have been generated for many of the de novo single gene mutations and copy number variants (CNVs) detected in ASD and comorbid neurodevelopmental disorders. Mouse models incorporating genetic and environmental manipulations have been employed for preclinical testing of hypothesis-driven pharmacological targets, to begin to develop treatments for the diagnostic and associated symptoms of autism. In this review, we summarize rodent behavioral assays relevant to the core features of autism, preclinical and clinical evaluations of pharmacological interventions, and strategies to improve the translational value of rodent models of autism. PMID:27305922

Halofuginone suppresses growth of human uterine leiomyoma cells in a mouse xenograft model.

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Koohestani, Faezeh; Qiang, Wenan; MacNeill, Amy L; Druschitz, Stacy A; Serna, Vanida A; Adur, Malavika; Kurita, Takeshi; Nowak, Romana A

2016-07-01

Does halofuginone (HF) inhibit the growth of human uterine leiomyoma cells in a mouse xenograft model? HF suppresses the growth of human uterine leiomyoma cells in a mouse xenograft model through inhibiting cell proliferation and inducing apoptosis. Uterine leiomyomas are the most common benign tumors of the female reproductive tract. HF can suppress the growth of human uterine leiomyoma cells in vitro. The mouse xenograft model reflects the characteristics of human leiomyomas. Primary leiomyoma smooth muscle cells from eight patients were xenografted under the renal capsule of adult, ovariectomized NOD-scid IL2Rγ(null) mice (NSG). Mice were treated with two different doses of HF or vehicle for 4 weeks with six to eight mice per group. Mouse body weight measurements and immunohistochemical analysis of body organs were carried out to assess the safety of HF treatment. Xenografted tumors were measured and analyzed for cellular and molecular changes induced by HF. Ovarian steroid hormone receptors were evaluated for possible modulation by HF. Treatment of mice carrying human UL xenografts with HF at 0.25 or 0.50 mg/kg body weight for 4 weeks resulted in a 35-40% (P leiomyoma cells in an in vivo model, HF was administered to mice whose tolerance and metabolism of the drug may differ from that in humans. Also, the longer term effects of HF treatment are yet unclear. The results of this study showing the effectiveness of HF in reducing UL tumor growth by interfering with the main cellular processes regulating cell proliferation and apoptosis are in agreement with previous studies on the effects of HF on other fibrotic diseases. HF can be considered as a candidate for reducing the size of leiomyomas, particularly prior to surgery. This project was funded by NIH PO1HD057877 and R01 HD064402. Authors report no competing interests. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights

A mouse model for inherited renal fibrosis associated with endoplasmic reticulum stress

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Sian E. Piret

2017-06-01

Full Text Available Renal fibrosis is a common feature of renal failure resulting from multiple etiologies, including diabetic nephropathy, hypertension and inherited renal disorders. However, the mechanisms of renal fibrosis are incompletely understood and we therefore explored these by establishing a mouse model for a renal tubular disorder, referred to as autosomal dominant tubulointerstitial kidney disease (ADTKD due to missense uromodulin (UMOD mutations (ADTKD-UMOD. ADTKD-UMOD, which is associated with retention of mutant uromodulin in the endoplasmic reticulum (ER of renal thick ascending limb cells, is characterized by hyperuricemia, interstitial fibrosis, inflammation and renal failure, and we used targeted homologous recombination to generate a knock-in mouse model with an ADTKD-causing missense cysteine to arginine uromodulin mutation (C125R. Heterozygous and homozygous mutant mice developed reduced uric acid excretion, renal fibrosis, immune cell infiltration and progressive renal failure, with decreased maturation and excretion of uromodulin, due to its retention in the ER. The ER stress marker 78 kDa glucose-regulated protein (GRP78 was elevated in cells expressing mutant uromodulin in heterozygous and homozygous mutant mice, and this was accompanied, both in vivo and ex vivo, by upregulation of two unfolded protein response pathways in primary thick ascending limb cells from homozygous mutant mice. However, this did not lead to an increase in apoptosis in vivo. Thus, we have developed a novel mouse model for renal fibrosis, which will be a valuable resource to decipher the mechanisms linking uromodulin mutations with ER stress and renal fibrosis.

Comparative efficacies of candidate antibiotics against Yersinia pestis in an in vitro pharmacodynamic model.

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Louie, Arnold; Vanscoy, Brian; Liu, Weiguo; Kulawy, Robert; Brown, David; Heine, Henry S; Drusano, George L

2011-06-01

Yersinia pestis, the bacterium that causes plague, is a potential agent of bioterrorism. Streptomycin is the "gold standard" for the treatment of plague infections in humans, but the drug is not available in many countries, and resistance to this antibiotic occurs naturally and has been generated in the laboratory. Other antibiotics have been shown to be active against Y. pestis in vitro and in vivo. However, the relative efficacies of clinically prescribed regimens of these antibiotics with streptomycin and with each other for the killing of Yersinia pestis are unknown. The efficacies of simulated pharmacokinetic profiles for human 10-day clinical regimens of ampicillin, meropenem, moxifloxacin, ciprofloxacin, and gentamicin were compared with the gold standard, streptomycin, for killing of Yersinia pestis in an in vitro pharmacodynamic model. Resistance amplification with therapy was also assessed. Streptomycin killed the microbe in one trial but failed due to resistance amplification in the second trial. In two trials, the other antibiotics consistently reduced the bacterial densities within the pharmacodynamic systems from 10⁸ CFU/ml to undetectable levels (pestis and deserve further evaluation.

Mouse Models Applied to the Research of Pharmacological Treatments in Asthma.

Science.gov (United States)

Marqués-García, Fernando; Marcos-Vadillo, Elena

2016-01-01

Models developed for the study of asthma mechanisms can be used to investigate new compounds with pharmacological activity against this disease. The increasing number of compounds requires a preclinical evaluation before starting the application in humans. Preclinical evaluation in animal models reduces the number of clinical trials positively impacting in the cost and in safety. In this chapter, three protocols for the study of drugs are shown: a model to investigate corticoids as a classical treatment of asthma; a protocol to test the effects of retinoic acid (RA) on asthma; and a mouse model to test new therapies in asthma as monoclonal antibodies.

Process and technoeconomic analysis of leading pretreatment technologies for lignocellulosic ethanol production using switchgrass.

Science.gov (United States)

Tao, Ling; Aden, Andy; Elander, Richard T; Pallapolu, Venkata Ramesh; Lee, Y Y; Garlock, Rebecca J; Balan, Venkatesh; Dale, Bruce E; Kim, Youngmi; Mosier, Nathan S; Ladisch, Michael R; Falls, Matthew; Holtzapple, Mark T; Sierra, Rocio; Shi, Jian; Ebrik, Mirvat A; Redmond, Tim; Yang, Bin; Wyman, Charles E; Hames, Bonnie; Thomas, Steve; Warner, Ryan E

2011-12-01

Six biomass pretreatment processes to convert switchgrass to fermentable sugars and ultimately to cellulosic ethanol are compared on a consistent basis in this technoeconomic analysis. The six pretreatment processes are ammonia fiber expansion (AFEX), dilute acid (DA), lime, liquid hot water (LHW), soaking in aqueous ammonia (SAA), and sulfur dioxide-impregnated steam explosion (SO(2)). Each pretreatment process is modeled in the framework of an existing biochemical design model so that systematic variations of process-related changes are consistently captured. The pretreatment area process design and simulation are based on the research data generated within the Biomass Refining Consortium for Applied Fundamentals and Innovation (CAFI) 3 project. Overall ethanol production, total capital investment, and minimum ethanol selling price (MESP) are reported along with selected sensitivity analysis. The results show limited differentiation between the projected economic performances of the pretreatment options, except for processes that exhibit significantly lower monomer sugar and resulting ethanol yields. Copyright © 2011 Elsevier Ltd. All rights reserved.

Impact analysis of different chemical pre-treatments on colour of apple discs during drying process

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Jasmina Lukinac

2009-01-01

Full Text Available The main purpose of this study was to compare colour changes of chemically pre-treated dried apple discs. Changes were observed by chromameter in L*a*b* colour model by using Minolta chromameter CR-400 and by image analysis system in RGB colour model. Apple discs variety "Gold Rush" were pre-treated and dried in laboratory tray drier at drying temperature 70 °C and at airflow velocity of 1.5 ms-1. Different chemical pre-treatments were applied on apple discs (dipping in 0.5% ascorbic acid solution; 0.3% L–cysteine solution; 0.1% 4–hexyl resorcinol solution and 1% sodium metabisulphite solution. Mean values of colour parameters, colour changes and correlation coefficients for apple discs were calculated for both colour models. The analysis showed statistically significant influence of pre-treatment method on total colour changes for both chosen colour models of dried apples. Calculated correlation coefficient between colour changes for used models was found to be 0.894. According to colour characteristics the best results were achieved when samples were pre-treated with 0.5% ascorbic acid solution. According to calculated results it was found that image analysis method as well as colorimetric method can be used to observe the colour changes on dried apple discs.

A prenatal nicotine exposure mouse model of methylphenidate responsive ADHD-associated cognitive phenotypes.

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Zhu, Jinmin; Fan, Fangfang; McCarthy, Deirdre M; Zhang, Lin; Cannon, Elisa N; Spencer, Thomas J; Biederman, Joseph; Bhide, Pradeep G

2017-05-01

Prenatal exposure to nicotine via cigarette smoke or other forms of tobacco use is a significant environmental risk factor for attention deficit hyperactivity disorder (ADHD). The neurobiological mechanisms underlying the link between prenatal nicotine exposure (PNE) and ADHD are not well understood. Animal models, especially rodent models, are beginning to bridge this gap in knowledge. Although ADHD is characterized by hyperactivity, inattention, impulsivity and working memory deficits, the majority of the animal models are based on only one or two ADHD associated phenotypes, in particular, hyperactivity or inattention. We report a PNE mouse model that displays the full range of ADHD associated behavioral phenotypes including working memory deficit, attention deficit and impulsive-like behavior. All of the ADHD-associated phenotypes respond to a single administration of a therapeutic equivalent dose of methylphenidate. In an earlier study, we showed that PNE produces hyperactivity, frontal cortical hypodopaminergic state and thinning of the cingulate cortex. Collectively, these data suggest that the PNE mouse model recapitulates key features of ADHD and may be a suitable preclinical model for ADHD research. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

Improvements and Limitations of Humanized Mouse Models for HIV Research: NIH/NIAID “Meet the Experts” 2015 Workshop Summary

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Akkina, Ramesh; Allam, Atef; Balazs, Alejandro B.; Blankson, Joel N.; Burnett, John C.; Casares, Sofia; Garcia, J. Victor; Hasenkrug, Kim J.; Kitchen, Scott G.; Klein, Florian; Kumar, Priti; Luster, Andrew D.; Poluektova, Larisa Y.; Rao, Mangala; Shultz, Leonard D.; Zack, Jerome A.

2016-01-01

Abstract The number of humanized mouse models for the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) and other infectious diseases has expanded rapidly over the past 8 years. Highly immunodeficient mouse strains, such as NOD/SCID/gamma chainnull (NSG, NOG), support better human hematopoietic cell engraftment. Another improvement is the derivation of highly immunodeficient mice, transgenic with human leukocyte antigens (HLAs) and cytokines that supported development of HLA-restricted human T cells and heightened human myeloid cell engraftment. Humanized mice are also used to study the HIV reservoir using new imaging techniques. Despite these advances, there are still limitations in HIV immune responses and deficits in lymphoid structures in these models in addition to xenogeneic graft-versus-host responses. To understand and disseminate the improvements and limitations of humanized mouse models to the scientific community, the NIH sponsored and convened a meeting on April 15, 2015 to discuss the state of knowledge concerning these questions and best practices for selecting a humanized mouse model for a particular scientific investigation. This report summarizes the findings of the NIH meeting. PMID:26670361

The circling mutant Pcdh15roda is a new mouse model for hearing loss.

Science.gov (United States)

Torres, Adriana Amorim; Rzadzinska, Agnieszka K; Ribeiro, Andrea Frozino; Silva, Daniel Almeida da Silva E; Guénet, Jean-Louis; Massironi, Sílvia Maria Gomes; Godard, Ana Lúcia Brunialti

2013-01-01

Mouse mutagenesis is a key tool for studying gene function and several mutant alleles have been described and constitute mouse models for human hereditary diseases. Genetic hearing loss represents over 50% of all hearing loss cases in children and, due to the heterogeneity of the disorder, there is still a demand for the isolation and characterization of new genes and alleles. Here we report phenotypic and molecular characterization of a new mouse model for hereditary hearing loss. The mutant rodador, isolated by Massironi and colleagues in 2006, presents an autosomal recessive disorder characterized by deafness and balance dysfunction associated with abnormal stereocilia in the inner ear. The mutation was mapped to mouse chromosome 10, and characterization of the gene Pcdh15 revealed an AT-to-GC transition in intron 23 of mutant animals. The alteration led to the switch of a dinucleotide ApA for ApG, creating a novel intronic acceptor splice site, which leads to incorporation of eight intronic bases into the processed mRNA and alteration of the downstream reading frame. In silico analysis indicated that the mutated protein is truncated and lacks two cadherin domains, and the transmembrane and cytoplasmic domains. Real Time PCR analyses revealed a significantly reduced Pcdh15 mRNA level in the brain of mutant mice, which might be due to the mechanism of non-sense mediated decay. In man, mutations in the orthologue PCDH15 cause non-syndromic deafness and Usher Syndrome Type 1F, a genetic disorder characterized by hearing loss and retinitis pigmentosa. Rodador mouse constitutes a new model for studying deafness in these conditions and may help in the comprehension of the pathogeneses of the disease, as well as of the mechanisms involved in the morphogenesis and function of inner ear stereocilia. This is a new ENU-induced allele and the first isolated in a BALB/c background. Copyright © 2013 Elsevier B.V. All rights reserved.

Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2.

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Chen, Ying; Hu, Lingxiang; Wang, Xueling; Sun, Changling; Lin, Xin; Li, Lei; Mei, Ling; Huang, Zhiwu; Yang, Tao; Wu, Hao

2016-09-13

The homozygous p.V37I variant in GJB2 is prevalent in East and Southeast Asians and may lead to mild-to-moderate hearing loss with reduced penetrance. To investigate the pathogenic mechanism underlying this variant, we generated a knock-in mouse model of homozygous p.V37I by an embryonic stem cell gene targeting method. Auditory brainstem response test showed that the knock-in mice developed progressive, mild-to-moderate hearing loss over the first 4-9 months. Overall no significant developmental and morphological abnormality was observed in the knock-in mouse cochlea, while confocal immunostaining and electron microscopic scanning revealed minor loss of the outer hair cells. Gene expression microarray analysis identified 105 up-regulated and 43 down-regulated genes in P5 knock-in mouse cochleae (P knock-in mouse modeled the hearing phenotype of the human patients and can serve as a useful animal model for further studies. The differentially expressed genes identified in this study may shed new insights into the understanding of the pathogenic mechanism and the phenotypic modification of homozygous p.V37I.

Combined treatment with atorvastatin and imipenem improves survival and vascular functions in mouse model of sepsis.

Science.gov (United States)

Choudhury, Soumen; Kannan, Kandasamy; Pule Addison, M; Darzi, Sazad A; Singh, Vishakha; Singh, Thakur Uttam; Thangamalai, Ramasamy; Dash, Jeevan Ranjan; Parida, Subhashree; Debroy, Biplab; Paul, Avishek; Mishra, Santosh Kumar

2015-08-01

We have recently reported that pre-treatment, but not the post-treatment with atorvastatin showed survival benefit and improved hemodynamic functions in cecal ligation and puncture (CLP) model of sepsis in mice. Here we examined whether combined treatment with atorvastatin and imipenem after onset of sepsis can prolong survival and improve vascular functions. At 6 and 18h after sepsis induction, treatment with atorvastatin plus imipenem, atorvastatin or imipenem alone or placebo was initiated. Ex vivo experiments were done on mouse aorta to examine the vascular reactivity to nor-adrenaline and acetylcholine and mRNA expressions of α1D AR, GRK2 and eNOS. Atorvastatin plus imipenem extended the survival time to 56.00±4.62h from 20.00±1.66h observed in CLP mice. The survival time with atorvastatin or imipenem alone was 20.50±1.89h and 27.00±4.09h, respectively. The combined treatment reversed the hyporeactivity to nor-adrenaline through preservation of α1D AR mRNA/protein expression and reversal of α1D AR desensitization mediated by GRK2/Gβγ pathway. The treatment also restored endothelium-dependent relaxation to ACh through restoration of aortic eNOS mRNA expression and NO availability. In conclusion, combined treatment with atorvastatin and imipenem exhibited survival benefit and improved vascular functions in septic mice. Copyright © 2015 Elsevier Inc. All rights reserved.

In Vivo Monitoring of Pancreatic β-Cells in a Transgenic Mouse Model

Directory of Open Access Journals (Sweden)

Steven J. Smith

2006-04-01

Full Text Available We generated a transgenic mouse model (RIP-luc for the in vivo monitoring of pancreatic islet mass and function in response to metabolic disease. Using the rat insulin promoter fused to firefly luciferase, and noninvasive technology to detect luciferase activity, we tracked changes in reporter signal during metabolic disease states and correlated the changes in luciferase signal with metabolic status of the mouse. Transgene expression was found to be specific to the pancreatic islets in this transgenic model. Basal transgene expression was tracked in male and female mice fed either a chow or a high-fat diet and in response to treatment with streptozotocin. Pancreatic bioluminescent signal increased in mice fed a high-fat diet compared with chow-fed animals. In a model of chemically induced diabetes, the bioluminescent signal decreased in accordance with the onset of diabetes and reduction of islet β-cell number. Preliminary studies using islets transplanted from this transgenic model suggest that in vivo image analysis can also be used to monitor transplanted islet viability and survival in the host. This transgenic model is a useful tool for in vivo studies of pancreatic β-cells and as a donor for islet transplantation studies.

Long-term exposure to intranasal oxytocin in a mouse autism model.

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Bales, K L; Solomon, M; Jacob, S; Crawley, J N; Silverman, J L; Larke, R H; Sahagun, E; Puhger, K R; Pride, M C; Mendoza, S P

2014-11-11

Oxytocin (OT) is a neuropeptide involved in mammalian social behavior. It is currently in clinical trials for the treatment of autism spectrum disorder (ASD). Previous studies in healthy rodents (prairie voles and C57BL/6J mice) have shown that there may be detrimental effects of long-term intranasal administration, raising the questions about safety and efficacy. To investigate the effects of OT on the aspects of ASD phenotype, we conducted the first study of chronic intranasal OT in a well-validated mouse model of autism, the BTBR T+ Itpr3tf/J inbred strain (BTBR), which displays low sociability and high repetitive behaviors. BTBR and C57BL/6J (B6) mice (N=94) were administered 0.8  IU/kg of OT intranasally, daily for 30 days, starting on day 21. We ran a well-characterized set of behavioral tasks relevant to diagnostic and associated symptoms of autism, including juvenile reciprocal social interactions, three-chambered social approach, open-field exploratory activity, repetitive self-grooming and fear-conditioned learning and memory, some during and some post treatment. Intranasal OT did not improve autism-relevant behaviors in BTBR, except for female sniffing in the three-chambered social interaction test. Male saline-treated BTBR mice showed increased interest in a novel mouse, both in chamber time and sniffing time, whereas OT-treated male BTBR mice showed a preference for the novel mouse in sniffing time only. No deleterious effects of OT were detected in either B6 or BTBR mice, except possibly for the lack of a preference for the novel mouse's chamber in OT-treated male BTBR mice. These results highlight the complexity inherent in understanding the effects of OT on behavior. Future investigations of chronic intranasal OT should include a wider dose range and early developmental time points in both healthy rodents and ASD models to affirm the efficacy and safety of OT.

Hypothalamic gene expression of appetite regulators in a cancer-cachectic mouse model [Dataset 1

NARCIS (Netherlands)

Dwarkasing, Jvalini; Dijk, Francina J.; Boekschoten, Mark; Faber, Joyce; Argilès, Josep M.; Lavianio, Alessandro; Muller, Michael; Witkamp, Renger; Norren, van Klaske

2013-01-01

Appetite is frequently affected in cancer patients, leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer cachectic mouse model with increased food intake. In this model, mice bearing C26 colon adenocarcinoma have

Hypothalamic gene expression of appetite regulators in a cancer-cachectic mouse model [Dataset 2

NARCIS (Netherlands)

Dwarkasing, Jvalini; Dijk, Francina J.; Boekschoten, Mark; Faber, Joyce; Argilès, Josep M.; Lavianio, Alessandro; Muller, Michael; Witkamp, Renger; Norren, van Klaske

2013-01-01

Appetite is frequently affected in cancer patients, leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer cachectic mouse model with increased food intake. In this model, mice bearing C26 colon adenocarcinoma have

A mouse model for binge-like sucrose overconsumption: Contribution of enhanced motivation for sweetener consumption.

Science.gov (United States)

Yasoshima, Yasunobu; Shimura, Tsuyoshi

2015-01-01

Behavioral and neural features of binge-like sugar overconsumption have been studied using rat models. However, few mouse models are available to examine the interaction between neural and genetic underpinnings of bingeing. In the present study, we first aim to establish a simple mouse model of binge-like sucrose overconsumption using daytime limited access training in food-restricted male mice. Trained mice received 4-h limited access to both 0.5M sucrose solution and chow for 10 days. Three control groups received (1) 4-h sucrose and 20-h chow access, (2) 20-h sucrose and 4-h, or (3) 20-h chow access, respectively. Only the trained group showed progressively increased sucrose consumption during brief periods of time and developed binge-like excessive behavior. Next, we examined whether the present mouse model mimicked a human feature of binge eating known as "eating when not physically hungry." Trained mice consumed significantly more sucrose or non-caloric sweetener (saccharin) during post-training days even after they nocturnally consumed substantial chow prior to daytime sweetener access. In other trained groups, both a systemic administration of glucose and substantial chow consumption prior to the daytime limited sucrose access failed to reduce binge-like sucrose overconsumption. Our results suggest that even when caloric consumption is not necessarily required, limited access training shapes and triggers binge-like overconsumption of sweetened solution in trained mice. The binge-like behavior in trained mice may be mainly due to enhanced hedonic motivation for the sweetener's taste. The present study suggests that our mouse model for binge-like sugar overconsumption may mimic some human features of binge eating and can be used to investigate the roles of neural and genetic mechanisms in binge-like overconsumption of sweetened substances in the absence of physical hunger. Copyright © 2014 Elsevier Inc. All rights reserved.

X-ray phase-contrast CT of a pancreatic ductal adenocarcinoma mouse model.

Directory of Open Access Journals (Sweden)

Arne Tapfer

Full Text Available To explore the potential of grating-based x-ray phase-contrast computed tomography (CT for preclinical research, a genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC was investigated. One ex-vivo mouse specimen was scanned with different grating-based phase-contrast CT imaging setups covering two different settings: i high-resolution synchrotron radiation (SR imaging and ii dose-reduced imaging using either synchrotron radiation or a conventional x-ray tube source. These experimental settings were chosen to assess the potential of phase-contrast imaging for two different types of application: i high-performance imaging for virtual microscopy applications and ii biomedical imaging with increased soft-tissue contrast for in-vivo applications. For validation and as a reference, histological slicing and magnetic resonance imaging (MRI were performed on the same mouse specimen. For each x-ray imaging setup, attenuation and phase-contrast images were compared visually with regard to contrast in general, and specifically concerning the recognizability of lesions and cancerous tissue. To quantitatively assess contrast, the contrast-to-noise ratios (CNR of selected regions of interest (ROI in the attenuation images and the phase images were analyzed and compared. It was found that both for virtual microscopy and for in-vivo applications, there is great potential for phase-contrast imaging: in the SR-based benchmarking data, fine details about tissue composition are accessible in the phase images and the visibility of solid tumor tissue under dose-reduced conditions is markedly superior in the phase images. The present study hence demonstrates improved diagnostic value with phase-contrast CT in a mouse model of a complex endogenous cancer, promoting the use and further development of grating-based phase-contrast CT for biomedical imaging applications.

Liquid chromatography-tandem mass spectrometric assay for the quantitative determination of the tyrosine kinase inhibitor quizartinib in mouse plasma using salting-out liquid-liquid extraction

NARCIS (Netherlands)

Retmana, Irene A; Wang, Jing; Schinkel, Alfred H; Schellens, Jan H M; Beijnen, Jos H; Sparidans, Rolf W

2017-01-01

A bioanalytical assay for quizartinib -a potent, and selective FLT3 tyrosine kinase inhibitor- in mouse plasma was developed and validated. Salting-out assisted liquid-liquid extraction (SALLE), using acetonitrile and magnesium sulfate, was selected as sample pretreatment with deuterated quizartinib

Establishment of Early Endpoints in Mouse Total-Body Irradiation Model.

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Amory Koch

Full Text Available Acute radiation sickness (ARS following exposure to ionizing irradiation is characterized by radiation-induced multiorgan dysfunction/failure that refers to progressive dysfunction of two or more organ systems, the etiological agent being radiation damage to cells and tissues over time. Radiation sensitivity data on humans and animals has made it possible to describe the signs associated with ARS. A mouse model of total-body irradiation (TBI has previously been developed that represents the likely scenario of exposure in the human population. Herein, we present the Mouse Intervention Scoring System (MISS developed at the Veterinary Sciences Department (VSD of the Armed Forces Radiobiology Research Institute (AFRRI to identify moribund mice and decrease the numbers of mice found dead, which is therefore a more humane refinement to death as the endpoint. Survival rates were compared to changes in body weights and temperatures in the mouse (CD2F1 male TBI model (6-14 Gy, 60Co γ-rays at 0.6 Gy min-1, which informed improvements to the Scoring System. Individual tracking of animals via implanted microchips allowed for assessment of criteria based on individuals rather than by group averages. From a total of 132 mice (92 irradiated, 51 mice were euthanized versus only four mice that were found dead (7% of non-survivors. In this case, all four mice were found dead after overnight periods between observations. Weight loss alone was indicative of imminent succumbing to radiation injury, however mice did not always become moribund within 24 hours while having weight loss >30%. Only one survivor had a weight loss of greater than 30%. Temperature significantly dropped only 2-4 days before death/euthanasia in 10 and 14 Gy animals. The score system demonstrates a significant refinement as compared to using subjective assessment of morbidity or death as the endpoint for these survival studies.

Optimization of twin gear-based pretreatment of rice straw for bioethanol production

International Nuclear Information System (INIS)

Ahmed, Muhammad Ajaz; Rehman, Muhammd Saif Ur; Terán-Hilares, Ruly; Khalid, Saira; Han, Jong-In

2017-01-01

Highlights: • Twin gear reactor is a continuous high solids pretreatment reactor. • RSM was applied to optimize twin gear pretreatment for enzymatic digestibility. • 89% enzymatic digestibility was achieved under optimum conditions. • Thermomechanical pretreatment altered the structural features of rice straw. - Abstract: A laboratory twin-gear reactor (TGR) was investigated as a new means for the pretreatment of high solid lignocelluloses. Response surface methodology based on Box Behnken Design was used to optimize the enzymatic digestibility with respect to the pretreatment process variables: temperature of 50–90 °C, NaOH concentration of 2–6% and no. of cycles of 30–60. The results revealed that the TGR-based pretreatment led to the significant structural alterations through increases in pore size, pore volume, cellulose crystallinity and surface area. SEM images also confirmed the surface modifications in the pretreated rice straw. A response surface quadratic model predicted 90% of the enzymatic digestibility, and it was confirmed experimentally and through the analysis of variance (ANOVA) as well. The TGR extrusion proved to be an effective means for exceedingly high solids lignocellulose.

Low temperature lignocellulose pretreatment: effects and interactions of pretreatment pH are critical for maximizing enzymatic monosaccharide yields from wheat straw

DEFF Research Database (Denmark)

Pedersen, Mads; Johansen, Katja S.; Meyer, Anne S.

2011-01-01

Background: The recent development of improved enzymes and pentose-using yeast for cellulosic ethanol processes calls for new attention to the lignocellulose pretreatment step. This study assessed the influence of pretreatment pH, temperature, and time, and their interactions on the enzymatic...... alkaline pretreatments. Alkaline pretreatments also solubilized most of the lignin. Conclusions: Pretreatment pH exerted significant effects and factor interactions on the enzymatic glucose and xylose releases. Quite extreme pH values were necessary with mild thermal pretreatment strategies (T...... glucose and xylose yields from mildly pretreated wheat straw in multivariate experimental designs of acid and alkaline pretreatments. Results: The pretreatment pH was the most significant factor affecting both the enzymatic glucose and xylose yields after mild thermal pretreatments at maximum 140 degrees...

Organ dose conversion coefficients based on a voxel mouse model and MCNP code for external photon irradiation.

Science.gov (United States)

Zhang, Xiaomin; Xie, Xiangdong; Cheng, Jie; Ning, Jing; Yuan, Yong; Pan, Jie; Yang, Guoshan

2012-01-01

A set of conversion coefficients from kerma free-in-air to the organ absorbed dose for external photon beams from 10 keV to 10 MeV are presented based on a newly developed voxel mouse model, for the purpose of radiation effect evaluation. The voxel mouse model was developed from colour images of successive cryosections of a normal nude male mouse, in which 14 organs or tissues were segmented manually and filled with different colours, while each colour was tagged by a specific ID number for implementation of mouse model in Monte Carlo N-particle code (MCNP). Monte Carlo simulation with MCNP was carried out to obtain organ dose conversion coefficients for 22 external monoenergetic photon beams between 10 keV and 10 MeV under five different irradiation geometries conditions (left lateral, right lateral, dorsal-ventral, ventral-dorsal, and isotropic). Organ dose conversion coefficients were presented in tables and compared with the published data based on a rat model to investigate the effect of body size and weight on the organ dose. The calculated and comparison results show that the organ dose conversion coefficients varying the photon energy exhibits similar trend for most organs except for the bone and skin, and the organ dose is sensitive to body size and weight at a photon energy approximately <0.1 MeV.

Trypsin digest protocol to analyze the retinal vasculature of a mouse model.

Science.gov (United States)

Chou, Jonathan C; Rollins, Stuart D; Fawzi, Amani A

2013-06-13

Trypsin digest is the gold standard method to analyze the retinal vasculature (1-5). It allows visualization of the entire network of complex three-dimensional retinal blood vessels and capillaries by creating a two-dimensional flat-mount of the interconnected vascular channels after digestion of the non-vascular components of the retina. This allows one to study various pathologic vascular changes, such as microaneurysms, capillary degeneration, and abnormal endothelial to pericyte ratios. However, the method is technically challenging, especially in mice, which have become the most widely available animal model to study the retina because of the ease of genetic manipulations (6,7). In the mouse eye, it is particularly difficult to completely remove the non-vascular components while maintaining the overall architecture of the retinal blood vessels. To date, there is a dearth of literature that describes the trypsin digest technique in detail in the mouse. This manuscript provides a detailed step-by-step methodology of the trypsin digest in mouse retina, while also providing tips on troubleshooting difficult steps.

Metabolic effects of bariatric surgery in mouse models of circadian disruption.

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Arble, D M; Sandoval, D A; Turek, F W; Woods, S C; Seeley, R J

2015-08-01

Mounting evidence supports a link between circadian disruption and metabolic disease. Humans with circadian disruption (for example, night-shift workers) have an increased risk of obesity and cardiometabolic diseases compared with the non-disrupted population. However, it is unclear whether the obesity and obesity-related disorders associated with circadian disruption respond to therapeutic treatments as well as individuals with other types of obesity. Here, we test the effectiveness of the commonly used bariatric surgical procedure, Vertical Sleeve Gastrectomy (VSG), in mouse models of genetic and environmental circadian disruption. VSG led to a reduction in body weight and fat mass in both Clock(Δ19) mutant and constant-light mouse models (Pdisruption. Interestingly, the decrease in body weight occurred without altering diurnal feeding or activity patterns (P>0.05). Within circadian-disrupted models, VSG also led to improved glucose tolerance and lipid handling (Pdisruption, and that the potent effects of bariatric surgery are orthogonal to circadian biology. However, as the effects of bariatric surgery are independent of circadian disruption, VSG cannot be considered a cure for circadian disruption. These data have important implications for circadian-disrupted obese patients. Moreover, these results reveal new information about the metabolic pathways governing the effects of bariatric surgery as well as of circadian disruption.

Xiao-Qing-Long-Tang shows preventive effect of asthma in an allergic asthma mouse model through neurotrophin regulation

Science.gov (United States)

2013-01-01

Background This study investigates the effect of Xiao-Qing-Long-Tang (XQLT) on neurotrophin in an established mouse model of Dermatophagoides pteronyssinus (Der p)-induced acute allergic asthma and in a LA4 cell line model of lung adenoma. The effects of XQLT on the regulation of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), airway hyper-responsiveness (AHR) and immunoglobulin E were measured. Methods LA4 cells were stimulated with 100 μg/ml Der p 24 h and the supernatant was collected for ELISA analysis. Der p-stimulated LA4 cells with either XQLT pre-treatment or XQLT co-treatment were used to evaluate the XQLT effect on neurotrophin. Balb/c mice were sensitized on days 0 and 7 with a base-tail injection of 50 μg Dermatophagoides pteronyssinus (Der p) that was emulsified in 50 μl incomplete Freund’s adjuvant (IFA). On day 14, mice received an intra-tracheal challenge of 50 μl Der p (2 mg/ml). XQLT (1g/Kg) was administered orally to mice either on days 2, 4, 6, 8, 10 and 12 as a preventive strategy or on day 15 as a therapeutic strategy. Results XQLT inhibited expression of those NGF, BDNF and thymus-and activation-regulated cytokine (TARC) in LA4 cells that were subjected to a Der p allergen. Both preventive and therapeutic treatments with XQLT in mice reduced AHR. Preventive treatment with XQLT markedly decreased NGF in broncho-alveolar lavage fluids (BALF) and BDNF in serum, whereas therapeutic treatment reduced only serum BDNF level. The reduced NGF levels corresponded to a decrease in AHR by XQLT treatment. Reduced BALF NGF and TARC and serum BDNF levels may have been responsible for decreased eosinophil infiltration into lung tissue. Immunohistochemistry showed that p75NTR and TrkA levels were reduced in the lungs of mice under both XQLT treatment protocols, and this reduction may have been correlated with the prevention of the asthmatic reaction by XQLT. Conclusion XQLT alleviated allergic inflammation including AHR, Ig

Epidermal growth factor (EGF) inhibits stimulated thyroid hormone secretion in the mouse

International Nuclear Information System (INIS)

Ahren, B.

1987-01-01

It is known that epidermal growth factor (EGF) inhibits iodide uptake in the thyroid follicular cells and lowers plasma levels of thyroid hormones upon infusion into sheep and ewes. In this study, the effects of EGF on basal and stimulated thyroid hormone secretion were investigated in the mouse. Mice were pretreated with 125 I and thyroxine; the subsequent release of 125 I is an estimation of thyroid hormone secretion. It was found that basal radioiodine secretion was not altered by intravenous injection of EGF (5 micrograms/animal). However, the radioiodine secretion stimulated by both TSH (120 microU/animal) and vasoactive intestinal peptide (VIP; 5 micrograms/animal) were inhibited by EGF (5 micrograms/animal). At a lower dose level (0.5 microgram/animal), EGF had no influence on stimulated radioiodine secretion. In conclusion, EGF inhibits stimulated thyroid hormone secretion in the mouse

Development and application of free pretreatment container steel

Science.gov (United States)

Yang, Y.; Liu, Y.; Han, B.; Wei, B.; Wang, S. Z.

2017-12-01

Due to economic and environmental advantages pre-treatment containers have good big development prospects, which can avoid shot blasting processes, and decrease the noise and dust pollution. By analyzing requirements of the container steel surface quality, target oxide scale structure of free pretreatment container steel has been determined. Trial process was carried out, and test results showed that the oxide scale achieved the desired objects, oxide scale with outer thin Fe3O4 layer and inner eutectoid α-Fe+Fe3O4. Salt spray test, second adhesion test, and modeling performance basically corroborated the container feasibility.

Mouse models of ageing and their relevance to disease.

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Kõks, Sulev; Dogan, Soner; Tuna, Bilge Guvenc; González-Navarro, Herminia; Potter, Paul; Vandenbroucke, Roosmarijn E

2016-12-01

Ageing is a process that gradually increases the organism's vulnerability to death. It affects different biological pathways, and the underlying cellular mechanisms are complex. In view of the growing disease burden of ageing populations, increasing efforts are being invested in understanding the pathways and mechanisms of ageing. We review some mouse models commonly used in studies on ageing, highlight the advantages and disadvantages of the different strategies, and discuss their relevance to disease susceptibility. In addition to addressing the genetics and phenotypic analysis of mice, we discuss examples of models of delayed or accelerated ageing and their modulation by caloric restriction. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus

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Crampton, Steve P.; Morawski, Peter A.; Bolland, Silvia

2014-01-01

Systemic lupus erythematosus (SLE) represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics. Both human genome-wide association studies (GWAS) and investigations using a variety of mouse models of SLE have been valuable for the identification of the genes and pathways involved in pathogenesis. In this Review, we link human susceptibility genes for SLE with biological pathways characterized in mouse models of lupus, and discuss how the mechanistic insights gained could advance drug discovery for the disease. PMID:25147296

Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus

Directory of Open Access Journals (Sweden)

Steve P. Crampton

2014-09-01

Full Text Available Systemic lupus erythematosus (SLE represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics. Both human genome-wide association studies (GWAS and investigations using a variety of mouse models of SLE have been valuable for the identification of the genes and pathways involved in pathogenesis. In this Review, we link human susceptibility genes for SLE with biological pathways characterized in mouse models of lupus, and discuss how the mechanistic insights gained could advance drug discovery for the disease.

Enhanced Operant Extinction and Prefrontal Excitability in a Mouse Model of Angelman Syndrome.

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Sidorov, Michael S; Judson, Matthew C; Kim, Hyojin; Rougie, Marie; Ferrer, Alejandra I; Nikolova, Viktoriya D; Riddick, Natallia V; Moy, Sheryl S; Philpot, Benjamin D

2018-03-14

Angelman syndrome (AS), a neurodevelopmental disorder associated with intellectual disability, is caused by loss of maternal allele expression of UBE3A in neurons. Mouse models of AS faithfully recapitulate disease phenotypes across multiple domains, including behavior. Yet in AS, there has been only limited study of behaviors encoded by the prefrontal cortex, a region broadly involved in executive function and cognition. Because cognitive impairment is a core feature of AS, it is critical to develop behavioral readouts of prefrontal circuit function in AS mouse models. One such readout is behavioral extinction, which has been well described mechanistically and relies upon prefrontal circuits in rodents. Here we report exaggerated operant extinction in male AS model mice, concomitant with enhanced excitability in medial prefrontal neurons from male and female AS model mice. Abnormal behavior was specific to operant extinction, as two other prefrontally dependent tasks (cued fear extinction and visuospatial discrimination) were largely normal in AS model mice. Inducible deletion of Ube3a during adulthood was not sufficient to drive abnormal extinction, supporting the hypothesis that there is an early critical period for development of cognitive phenotypes in AS. This work represents the first formal experimental analysis of prefrontal circuit function in AS, and identifies operant extinction as a useful experimental paradigm for modeling cognitive aspects of AS in mice. SIGNIFICANCE STATEMENT Prefrontal cortex encodes "high-level" cognitive processes. Thus, understanding prefrontal function is critical in neurodevelopmental disorders where cognitive impairment is highly penetrant. Angelman syndrome is a neurodevelopmental disorder associated with speech and motor impairments, an outwardly happy demeanor, and intellectual disability. We describe a behavioral phenotype in a mouse model of Angelman syndrome and related abnormalities in prefrontal cortex function. We

Mobile Laser Indirect Ophthalmoscope: For the Induction of Choroidal Neovascularization in a Mouse Model.

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Weinberger, Dov; Bor-Shavit, Elite; Barliya, Tilda; Dahbash, Mor; Kinrot, Opher; Gaton, Dan D; Nisgav, Yael; Livnat, Tami

2017-11-01

This study aims to evaluate and standardize the reliability of a mobile laser indirect ophthalmoscope in the induction of choroidal neovascularization (CNV) in a mouse model. A diode laser indirect ophthalmoscope was used to induce CNV in pigmented male C57BL/6J mice. Standardization of spot size and laser intensity was determined using different aspheric lenses with increasing laser intensities applied around the optic disc. Development of CNV was evaluated 1, 5, and 14 days post laser application using fluorescein angiography (FA), histology, and choroidal flat mounts stained for the endothelial marker CD31 and FITC-dextran. Correlation between the number of laser hits to the number and size of developed CNV lesions was determined using flat mount choroid staining. The ability of intravitreally injected anti-human and anti-mouse VEGF antibodies to inhibit CNV induced by the mobile laser was evaluated. Laser parameters were standardized on 350 mW for 100 msec, using the 90 diopter lens to accomplish the highest incidence of Bruch's membrane rupture. CNV lesions' formation was validated on days 5 and 14 post laser injury, though FA showed leakage on as early as day 1. The number of laser hits was significantly correlated with the CNV area. CNV growth was successfully inhibited by both anti-human and mouse VEGF antibodies. The mobile laser indirect ophthalmoscope can serve as a feasible and a reliable alternative method for the CNV induction in a mouse model.

Mitomycin-treated undifferentiated embryonic stem cells as a safe and effective therapeutic strategy in a mouse model of Parkinson's disease.

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Mariana eAcquarone

2015-04-01

Full Text Available Parkinson’s disease (PD is an incurable progressive neurodegenerative disorder. Clinical presentation of PD stems largely from the loss of dopaminergic neurons in the nigrostriatal dopaminergic pathway, motivating experimental strategies aimed at replacing dopaminergic innervation by cellular therapy. Transplantation of dopaminergic neurons derived from embryonic stem cells significantly improves motor functions in rodent and non-human primate models of PD. However, protocols to generate dopaminergic neurons from embryonic stem cells generally meet with low efficacy and high risk of teratoma development upon transplantation. To address these issues, we have pre-treated undifferentiated mouse embryonic stem cells (mESCs with the DNA alkylating agent mitomycin C (MMC before transplantation. MMC treatment of cultures prevented tumor formation in a 12-week follow-up after mESCs were injected in nude mice. In 6-OH-dopamine-lesioned mice, intrastriatal injection of MMC-treated mESCs markedly improved motor function without tumor formation for as long as 15 months. Furthermore, we show that halting mitotic activity of undifferentiated mESCs induces a four-fold increase in dopamine release following in vitro differentiation. Our findings indicate that treating mESCs with mitomycin C prior to intrastriatal transplant is an effective strategy that could be further investigated as a novel alternative for treatment of Parkinson's disease.

NOD mouse model for Sjögren's syndrome: lack of longitudinal stability

NARCIS (Netherlands)

Lodde, B. M.; Mineshiba, F.; Kok, M. R.; Wang, J.; Zheng, C.; Schmidt, M.; Cotrim, A. P.; Kriete, M.; Tak, P. P.; Baum, B. J.

2006-01-01

OBJECTIVES: The non-obese diabetic (NOD) mouse is not only a widely used model for diabetes mellitus type I, but also for the chronic autoimmune disease Sjögren's syndrome (SS), mainly affecting salivary and lacrimal glands. We studied the efficacy of local recombinant serotype 2 adeno-associated

Generalized glycogen storage and cardiomegaly in a knockout mouse model of Pompe disease

NARCIS (Netherlands)

A.G.A. Bijvoet (Agnes); A.T. van der Ploeg (Ans); E.H. van de Kamp; M.A. Kroos (Marian); J.-H. Ding (Jia-Huan); B.Z. Yang (Bing); P. Visser (Pim); C.E. Bakker (Cathy); M.Ph. Verbeet (Martin); B.A. Oostra (Ben); A.J.J. Reuser (Arnold)

1998-01-01

textabstractGlycogen storage disease type II (GSDII; Pompe disease), caused by inherited deficiency of acid alpha-glucosidase, is a lysosomal disorder affecting heart and skeletal muscles. A mouse model of this disease was obtained by targeted disruption of the

Early life exposure to bisphenol A investigated in mouse models of airway allergy, food allergy and oral tolerance.

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Nygaard, Unni Cecilie; Vinje, Nina Eriksen; Samuelsen, Mari; Andreassen, Monica; Groeng, Else-Carin; Bølling, Anette Kocbach; Becher, Rune; Lovik, Martinus; Bodin, Johanna

2015-09-01

The impact of early life exposure to bisphenol A (BPA) through drinking water was investigated in mouse models of respiratory allergy, food allergy and oral tolerance. Balb/c mice were exposed to BPA (0, 10 or 100 μg/ml), and the offspring were intranasally exposed to the allergen ovalbumin (OVA). C3H/HeJ offspring were sensitized with the food allergen lupin by intragastric gavage, after exposure to BPA (0, 1, 10 or 100 μg/ml). In separate offspring, oral tolerance was induced by gavage of 5 mg lupin one week before entering the protocol for the food allergy induction. In the airway allergy model, BPA (100 μg/ml) caused increased eosinophil numbers in bronchoalveolar lavage fluid (BALF) and a trend of increased OVA-specific IgE levels. In the food allergy and tolerance models, BPA did not alter the clinical anaphylaxis or antibody responses, but induced alterations in splenocyte cytokines and decreased mouse mast cell protease (MMCP)-1 serum levels. In conclusion, early life exposure to BPA through drinking water modestly augmented allergic responses in a mouse model of airway allergy only at high doses, and not in mouse models for food allergy and tolerance. Thus, our data do not support that BPA promotes allergy development at exposure levels relevant for humans. Copyright © 2015 Elsevier Ltd. All rights reserved.

No Effect of NGAL/lipocalin-2 on Aggressiveness of Cancer in the MMTV-PyMT/FVB/N Mouse Model for Breast Cancer

DEFF Research Database (Denmark)

Cramer, Elisabeth P; Glenthøj, Andreas; Häger, Mattias

2012-01-01

tumor volume, or to the number of metastases. Histology and gelatinolytic activity of the mammary tumors did not differ between wild-type and lipocalin-2-deficient mice. We conclude that NGAL/lipocalin-2 does not invariably affect the aggressiveness of breast cancers as assessed in mouse models, thus......NGAL/lipocalin-2 is a siderophore-binding protein that is highly expressed in several cancers. It is suggested to confer a proliferative advantage to cancer cells. Its expression has been correlated with aggressiveness of breast cancer as determined both in patients and in mouse breast cancer...... models. This was recently confirmed in two mouse models of spontaneous breast cancer in wild-type and lipocalin-2-deficient mice. We used a similar strategy using a different mouse strain. Lipocalin-2-deficient mice and mouse mammary tumor virus-polyoma middle T antigen (MMTV-PyMT) mice were crossed...

Bat-mouse bone marrow chimera: a novel animal model for dissecting the uniqueness of the bat immune system.

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Yong, Kylie Su Mei; Ng, Justin Han Jia; Her, Zhisheng; Hey, Ying Ying; Tan, Sue Yee; Tan, Wilson Wei Sheng; Irac, Sergio Erdal; Liu, Min; Chan, Xue Ying; Gunawan, Merry; Foo, Randy Jee Hiang; Low, Dolyce Hong Wen; Mendenhall, Ian Hewitt; Chionh, Yok Teng; Dutertre, Charles-Antoine; Chen, Qingfeng; Wang, Lin-Fa

2018-03-16

Bats are an important animal model with long lifespans, low incidences of tumorigenesis and an ability to asymptomatically harbour pathogens. Currently, in vivo studies of bats are hampered due to their low reproduction rates. To overcome this, we transplanted bat cells from bone marrow (BM) and spleen into an immunodeficient mouse strain NOD-scid IL-2R -/- (NSG), and have successfully established stable, long-term reconstitution of bat immune cells in mice (bat-mice). Immune functionality of our bat-mouse model was demonstrated through generation of antigen-specific antibody response by bat cells following immunization. Post-engraftment of total bat BM cells and splenocytes, bat immune cells survived, expanded and repopulated the mouse without any observable clinical abnormalities. Utilizing bat's remarkable immunological functions, this novel model has a potential to be transformed into a powerful platform for basic and translational research.

GREET Pretreatment Module

Energy Technology Data Exchange (ETDEWEB)

Adom, Felix K. [Argonne National Lab. (ANL), Argonne, IL (United States). Energy Systems Division; Dunn, Jennifer B. [Argonne National Lab. (ANL), Argonne, IL (United States). Energy Systems Division; Han, Jeongwoo [Argonne National Lab. (ANL), Argonne, IL (United States). Energy Systems Division

2014-09-01

A wide range of biofuels and biochemicals can be produced from cellulosic biomass via different pretreatment technologies that yield sugars. Process simulations of dilute acid and ammonia fiber expansion pretreatment processes and subsequent hydrolysis were developed in Aspen Plus for four lignocellulosic feedstocks (corn stover, miscanthus, switchgrass, and poplar). This processing yields sugars that can be subsequently converted to biofuels or biochemical. Material and energy consumption data from Aspen Plus were then compiled in a new Greenhouses Gases, Regulated Emissions, and Energy Use in Transportation (GREET^TM) pretreatment module. The module estimates the cradle-to-gate fossil energy consumption (FEC) and greenhouse gas (GHG) emissions associated with producing fermentable sugars. This report documents the data and methodology used to develop this module and the cradle-to-gate FEC and GHG emissions that result from producing fermentable sugars.

Improving the sludge disintegration efficiency of sonication by combining with alkalization and thermal pre-treatment methods.

Science.gov (United States)

Şahinkaya, S; Sevimli, M F; Aygün, A

2012-01-01

One of the most serious problems encountered in biological wastewater treatment processes is the production of waste activated sludge (WAS). Sonication, which is an energy-intensive process, is the most powerful sludge pre-treatment method. Due to lack of information about the combined pre-treatment methods of sonication, the combined pre-treatment methods were investigated and it was aimed to improve the disintegration efficiency of sonication by combining sonication with alkalization and thermal pre-treatment methods in this study. The process performances were evaluated based on the quantities of increases in soluble chemical oxygen demand (COD), protein and carbohydrate. The releases of soluble COD, carbohydrate and protein by the combined methods were higher than those by sonication, alkalization and thermal pre-treatment alone. Degrees of sludge disintegration in various options of sonication were in the following descending order: sono-alkalization > sono-thermal pre-treatment > sonication. Therefore, it was determined that combining sonication with alkalization significantly improved the sludge disintegration and decreased the required energy to reach the same yield by sonication. In addition, effects on sludge settleability and dewaterability and kinetic mathematical modelling of pre-treatment performances of these methods were investigated. It was proven that the proposed model accurately predicted the efficiencies of ultrasonic pre-treatment methods.

Immunotherapy for choroidal neovascularization in a laser-induced mouse model simulating exudative (wet) macular degeneration

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Bora, Puran S.; Hu, Zhiwei; Tezel, Tongalp H.; Sohn, Jeong-Hyeon; Kang, Shin Goo; Cruz, Jose M. C.; Bora, Nalini S.; Garen, Alan; Kaplan, Henry J.

2003-03-01

Age-related macular degeneration (AMD) is the leading cause of blindness after age 55 in the industrialized world. Severe loss of central vision frequently occurs with the exudative (wet) form of AMD, as a result of the formation of a pathological choroidal neovasculature (CNV) that damages the macular region of the retina. We tested the effect of an immunotherapy procedure, which had been shown to destroy the pathological neovasculature in solid tumors, on the formation of laser-induced CNV in a mouse model simulating exudative AMD in humans. The procedure involves administering an Icon molecule that binds with high affinity and specificity to tissue factor (TF), resulting in the activation of a potent cytolytic immune response against cells expressing TF. The Icon binds selectively to TF on the vascular endothelium of a CNV in the mouse and pig models and also on the CNV of patients with exudative AMD. Here we show that the Icon dramatically reduces the frequency of CNV formation in the mouse model. After laser treatment to induce CNV formation, the mice were injected either with an adenoviral vector encoding the Icon, resulting in synthesis of the Icon by vector-infected mouse cells, or with the Icon protein. The route of injection was i.v. or intraocular. The efficacy of the Icon in preventing formation of laser-induced CNV depends on binding selectively to the CNV. Because the Icon binds selectively to the CNV in exudative AMD as well as to laser-induced CNV, the Icon might also be efficacious for treating patients with exudative AMD.

Optimization of Saccharification Conditions of Lignocellulosic Biomass under Alkaline Pre-Treatment and Enzymatic Hydrolysis

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Rafał Łukajtis

2018-04-01

Full Text Available Pre-treatment is a significant step in the production of second-generation biofuels from waste lignocellulosic materials. Obtaining biofuels as a result of fermentation processes requires appropriate pre-treatment conditions ensuring the highest possible degree of saccharification of the feed material. An influence of the following process parameters were investigated for alkaline pre-treatment of Salix viminalis L.: catalyst concentration (NaOH, temperature, pre-treatment time and granulation. For this purpose, experiments were carried out in accordance to the Box-Behnken design for four factors. In the saccharification process of the pre-treated biomass, cellulolytic enzymes immobilized on diatomaceous earth were used. Based on the obtained results, a mathematical model for the optimal conditions of alkaline pre-treatment prediction is proposed. The optimal conditions of alkaline pre-treatment are established as follows: granulation 0.75 mm, catalyst concentration 7%, pre-treatment time 6 h and temperature 65 °C if the saccharification efficiency and cost analysis are considered. An influence of the optimized pre-treatment on both the chemical composition and structural changes for six various lignocellulosic materials (energetic willow, energetic poplar, beech, triticale, meadow grass, corncobs was investigated. SEM images of raw and pre-treated biomass samples are included in order to follow the changes in the biomass structure during hydrolysis.

Processes for pretreating lignocellulosic biomass: A review

Energy Technology Data Exchange (ETDEWEB)

McMillan, J.D.

1992-11-01

This paper reviews existing and proposed pretreatment processes for biomass. The focus is on the mechanisms by which the various pretreatments act and the influence of biomass structure and composition on the efficacy of particular pretreatment techniques. This analysis is used to identify pretreatment technologies and issues that warrant further research.

Cytomegalovirus-induced embryopathology: mouse submandibular salivary gland epithelial-mesenchymal ontogeny as a model

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Huang Jing

2006-09-01

Full Text Available Abstract Background Human studies suggest, and mouse models clearly demonstrate, that cytomegalovirus (CMV is dysmorphic to early organ and tissue development. CMV has a particular tropism for embryonic salivary gland and other head mesenchyme. CMV has evolved to co-opt cell signaling networks so to optimize replication and survival, to the detriment of infected tissues. It has been postulated that mesenchymal infection is the critical step in disrupting organogenesis. If so, organogenesis dependent on epithelial-mesenchymal interactions would be particularly vulnerable. In this study, we chose to model the vulnerability by investigating the cell and molecular pathogenesis of CMV infected mouse embryonic submandibular salivary glands (SMGs. Results We infected E15 SMG explants with mouse CMV (mCMV. Active infection for up to 12 days in vitro results in a remarkable cell and molecular pathology characterized by atypical ductal epithelial hyperplasia, apparent epitheliomesenchymal transformation, oncocytic-like stromal metaplasia, β-catenin nuclear localization, and upregulation of Nfkb2, Relb, Il6, Stat3, and Cox2. Rescue with an antiviral nucleoside analogue indicates that mCMV replication is necessary to initiate and maintain SMG dysmorphogenesis. Conclusion mCMV infection of embryonic mouse explants results in dysplasia, metaplasia, and, possibly, anaplasia. The molecular pathogenesis appears to center around the activation of canonical and, perhaps more importantly, noncanonical NFκB. Further, COX-2 and IL-6 are important downstream effectors of embryopathology. At the cellular level, there appears to be a consequential interplay between the transformed SMG cells and the surrounding extracellular matrix, resulting in the nuclear translocation of β-catenin. From these studies, a tentative framework has emerged within which additional studies may be planned and performed.

Expression of Caytaxin protein in Cayman Ataxia mouse models correlates with phenotype severity.

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Kristine M Sikora

Full Text Available Caytaxin is a highly-conserved protein, which is encoded by the Atcay/ATCAY gene. Mutations in Atcay/ATCAY have been identified as causative of cerebellar disorders such as the rare hereditary disease Cayman ataxia in humans, generalized dystonia in the dystonic (dt rat, and marked motor defects in three ataxic mouse lines. While several lines of evidence suggest that Caytaxin plays a critical role in maintaining nervous system processes, the physiological function of Caytaxin has not been fully characterized. In the study presented here, we generated novel specific monoclonal antibodies against full-length Caytaxin to examine endogenous Caytaxin expression in wild type and Atcay mutant mouse lines. Caytaxin protein is absent from brain tissues in the two severely ataxic Atcay(jit (jittery and Atcay(swd (sidewinder mutant lines, and markedly decreased in the mildly ataxic/dystonic Atcay(ji-hes (hesitant line, indicating a correlation between Caytaxin expression and disease severity. As the expression of wild type human Caytaxin in mutant sidewinder and jittery mice rescues the ataxic phenotype, Caytaxin's physiological function appears to be conserved between the human and mouse orthologs. Across multiple species and in several neuronal cell lines Caytaxin is expressed as several protein isoforms, the two largest of which are caused by the usage of conserved methionine translation start sites. The work described in this manuscript presents an initial characterization of the Caytaxin protein and its expression in wild type and several mutant mouse models. Utilizing these animal models of human Cayman Ataxia will now allow an in-depth analysis to elucidate Caytaxin's role in maintaining normal neuronal function.

Obesity-Linked Mouse Models of Liver Cancer | Center for Cancer Research

Science.gov (United States)

Jimmy Stauffer, Ph.D., and colleagues working with Robert  Wiltrout, Ph.D., in CCR’s Cancer and Inflammation Program, along with collaborators in the Laboratory of Human Carcinogenesis, have developed a novel mouse model that demonstrates how fat-producing phenotypes can influence the development of hepatic cancer.   The team recently reported their findings in Cancer Research.

Altered Gastrointestinal Function in the Neuroligin-3 Mouse Model of Autism

Science.gov (United States)

2013-10-01

the Neuroligin-3 Mouse Model of Autism PRINCIPAL INVESTIGATOR: Professor Joel Bornstein CONTRACTING ORGANIZATION: The University of...NUMBER The University of Melbourne PARKVILLE, AU 9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR...of the DDC GI forum at Texas Children’s Hospital in Houston, TX, May 2013 20 Conclusion The data obtained in this component of the project

Impact of co-pretreatment of calcium hydroxide and steam explosion on anaerobic digestion efficiency with corn stover.

Science.gov (United States)

Ji, Jinli; Zhang, Jiyu; Yang, Liutianyi; He, Yanfeng; Zhang, Ruihong; Liu, Guangqing; Chen, Chang

2017-06-01

Anaerobic digestion (AD) is an effective way to utilize the abundant resource of corn stover (CS). In this light, Ca(OH) 2 pretreatment alone, steam explosion (SE) pretreatment alone, and co-pretreatment of Ca(OH) 2 and SE were applied to improve the digestion efficiency of CS. Results showed that AD of co-pretreated CS with 1.0% Ca(OH) 2 and SE at 1.5 MPa achieved the highest cumulative methane yield of [Formula: see text], which was 61.54% significantly higher (p < .01) than untreated CS. The biodegradability value of CS after co-pretreatment enhanced from 43.03% to 69.52%. Methane yield could be well fitted by the first-order model and the modified Gompertz model. In addition, composition and structural changes of CS after pretreatment were analyzed by a fiber analyzer, scanning electron microscopy, Fourier transform infrared spectroscopy, and X-ray diffraction. The validated results indicated that co-pretreatment of Ca(OH) 2 and SE was efficient to improve the digestion performance of CS and might be a suitable method for agricultural waste pretreatment in the future AD industry.

Inner ear morphology is perturbed in two novel mouse models of recessive deafness.

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Kerry A Miller

Full Text Available Human MYO7A mutations can cause a variety of conditions involving the inner ear. These include dominant and recessive non-syndromic hearing loss and syndromic conditions such as Usher syndrome. Mouse models of deafness allow us to investigate functional pathways involved in normal and abnormal hearing processes. We present two novel mouse models with mutations in the Myo7a gene with distinct phenotypes. The mutation in Myo7a(I487N/I487N ewaso is located within the head motor domain of Myo7a. Mice exhibit a profound hearing loss and manifest behaviour associated with a vestibular defect. A mutation located in the linker region between the coiled-coil and the first MyTH4 domains of the protein is responsible in Myo7a(F947I/F947I dumbo. These mice show a less severe hearing loss than in Myo7a(I487N/I487N ewaso; their hearing loss threshold is elevated at 4 weeks old, and progressively worsens with age. These mice show no obvious signs of vestibular dysfunction, although scanning electron microscopy reveals a mild phenotype in vestibular stereocilia bundles. The Myo7a(F947I/F947I dumbo strain is therefore the first reported Myo7a mouse model without an overt vestibular phenotype; a possible model for human DFNB2 deafness. Understanding the molecular basis of these newly identified mutations will provide knowledge into the complex genetic pathways involved in the maintenance of hearing, and will provide insight into recessively inherited sensorineural hearing loss in humans.

Prevention of fetal demise and growth restriction in a mouse model of fetal alcohol syndrome.

Science.gov (United States)

Spong, C Y; Abebe, D T; Gozes, I; Brenneman, D E; Hill, J M

2001-05-01

Two peptides [NAPVSIPQ (NAP) and SALLRSIPA (ADNF-9)], that are associated with novel glial proteins regulated by vasoactive intestinal peptide, are shown now to provide protective intervention in a model of fetal alcohol syndrome. Fetal demise and growth restrictions were produced after intraperitoneal injection of ethanol to pregnant mice during midgestation (E8). Death and growth abnormalities elicited by alcohol treatment during development are believed to be associated, in part, with severe oxidative damage. NAP and ADNF-9 have been shown to exhibit antioxidative and antiapoptotic actions in vitro. Pretreatment with an equimolar combination of the peptides prevented the alcohol-induced fetal death and growth abnormalities. Pretreatment with NAP alone resulted in a significant decrease in alcohol-associated fetal death; whereas ADNF-9 alone had no detectable effect on fetal survival after alcohol exposure, indicating a pharmacological distinction between the peptides. Biochemical assessment of the fetuses indicated that the combination peptide treatment prevented the alcohol-induced decreases in reduced glutathione. Peptide efficacy was evident with either 30-min pretreatment or with 1-h post-alcohol administration. Bioavailability studies with [(3)H]NAPVSIPQ indicated that 39% of the total radioactivity comigrated with intact peptide in the fetus 60 min after administration. These studies demonstrate that fetal death and growth restriction associated with prenatal alcohol exposure were prevented by combinatorial peptide treatment and suggest that this therapeutic strategy be explored in other models/diseases associated with oxidative stress.

Hybrid liposomes showing enhanced accumulation in tumors as theranostic agents in the orthotopic graft model mouse of colorectal cancer.

Science.gov (United States)

Okumura, Masaki; Ichihara, Hideaki; Matsumoto, Yoko

2018-11-01

Hybrid liposomes (HLs) can be prepared by simply sonicating a mixture of vesicular and micellar molecules in a buffer solution. This study aimed to elucidate the therapeutic effects and ability of HLs to detect (diagnosis) cancer in an orthotopic graft mouse model of colorectal cancer with HCT116 cells for the use of HLs as theranostic agents. In the absence of a chemotherapeutic drug, HLs exhibited therapeutic effects by inhibiting the growth of HCT116 colorectal cancer cells in vitro, possibly through an increase in apoptosis. Intravenously administered HLs also caused a remarkable reduction in the relative cecum weight in an orthotopic graft mouse model of colorectal cancer. A decrease in tumor size in the cecal sections was confirmed by histological analysis using HE staining. TUNEL staining indicated an induction of apoptosis in HCT116 cells in the orthotopic graft mouse model of colorectal cancer. For the detection (diagnosis) of colorectal cancer by HLs, the accumulation of HLs encapsulating a fluorescent probe (ICG) was observed in HCT116 cells in the in vivo colorectal cancer model following intravenous administration. These data indicate that HLs can accumulate in tumor cells in the cecum of the orthotopic graft mouse model of colorectal cancer for a prolonged period of time, and inhibit the growth of HCT116 cells.

Damaging role of neutrophilic infiltration in a mouse model of progressive tuberculosis.

Science.gov (United States)

Marzo, Elena; Vilaplana, Cristina; Tapia, Gustavo; Diaz, Jorge; Garcia, Vanessa; Cardona, Pere-Joan

2014-01-01

Tuberculosis was studied using an experimental model based on the C3HeB/FeJ mouse strain, which mimics the liquefaction of caseous necrosis occurring during active disease in immunocompetent adults. Mice were intravenously infected with 2 × 10(4) Colony Forming Units of Mycobacterium tuberculosis and their histopathology, immune response, bacillary load, and survival were evaluated. The effects of the administration of drugs with anti-inflammatory activity were examined, and the C3H/HeN mouse strain was also included for comparative purposes. Massive intra-alveolar neutrophilic infiltration led to rapid granuloma growth and coalescence of lesions into superlesions. A central necrotic area appeared showing progressive cellular destruction, the alveoli cell walls being initially conserved (caseous necrosis) but finally destroyed (liquefactive necrosis). Increasing levels of pro-inflammatory mediators were detected in lungs. C3HeB/FeJ treated with anti-inflammatory drugs and C3H/HeN animals presented lower levels of pro-inflammatory mediators such as TNF-α, IL-17, IL-6 and CXCL5, a lower bacillary load, better histopathology, and increased survival compared with untreated C3HeB/FeJ. The observation of massive neutrophilic infiltration suggests that inflammation may be a key factor in progression towards active tuberculosis. On the basis of our findings, we consider that the C3HeB/FeJ mouse model would be useful for evaluating new therapeutic strategies against human tuberculosis. Copyright © 2013 Elsevier Ltd. All rights reserved.

Breeding a PKU-mouse model on Phe-free diet, is it possible?

DEFF Research Database (Denmark)

Dagnæs-Hansen, Frederik; Johansen, Karen Singers; Vorup-Jensen, Thomas

2014-01-01

The PKU-mouse model mutated in the PAH gene was developed in the 1990s in the laboratory of Dr. Alexandra Shedlovsky at the McArdle Laboratory for Cancer Research, University of Wisconsin. The mutation was generated by ENU (N-ethyl-N-nitrosourea) treatment of BTBR males. Several mutation was found...

Brain Transcriptome Profiles in Mouse Model Simulating Features of Post-traumatic Stress Disorder

Science.gov (United States)

2015-02-28

analyses of DEGs suggested pos- sible roles in anxiety-related behavioral responses, synaptic plasticity, neurogenesis, inflammation, obesity...Behavioral evaluation of mouse model We established [29] a rodent model manifesting PTSD- like behavioral features. We believe that, because the stres - sor...hippo- campus (HC), medial prefrontal cortex (MPFC) play primary roles in fear learning and memory, and thus, may contribute to the behavioral

Prevention of radiation-induced salivary gland dysfunction utilizing a CDK inhibitor in a mouse model.

Directory of Open Access Journals (Sweden)

Katie L Martin

Full Text Available Treatment of head and neck cancer with radiation often results in damage to surrounding normal tissues such as salivary glands. Permanent loss of function in the salivary glands often leads patients to discontinue treatment due to incapacitating side effects. It has previously been shown that IGF-1 suppresses radiation-induced apoptosis and enhances G2/M arrest leading to preservation of salivary gland function. In an effort to recapitulate the effects of IGF-1, as well as increase the likelihood of translating these findings to the clinic, the small molecule therapeutic Roscovitine, is being tested. Roscovitine is a cyclin-dependent kinase inhibitor that acts to transiently inhibit cell cycle progression and allow for DNA repair in damaged tissues.Treatment with Roscovitine prior to irradiation induced a significant increase in the percentage of cells in the G(2/M phase, as demonstrated by flow cytometry. In contrast, mice treated with radiation exhibit no differences in the percentage of cells in G(2/M when compared to unirradiated controls. Similar to previous studies utilizing IGF-1, pretreatment with Roscovitine leads to a significant up-regulation of p21 expression and a significant decrease in the number of PCNA positive cells. Radiation treatment leads to a significant increase in activated caspase-3 positive salivary acinar cells, which is suppressed by pretreatment with Roscovitine. Administration of Roscovitine prior to targeted head and neck irradiation preserves normal tissue function in mouse parotid salivary glands, both acutely and chronically, as measured by salivary output.These studies suggest that induction of transient G(2/M cell cycle arrest by Roscovitine allows for suppression of apoptosis, thus preserving normal salivary function following targeted head and neck irradiation. This could have an important clinical impact by preventing the negative side effects of radiation therapy in surrounding normal tissues.

Investigation of the neuroprotective effects of bee-venom acupuncture in a mouse model of Parkinson's disease by using immunohistochemistry and In-vivo 1H magnetic resonance spectroscopy at 9.4 T

Science.gov (United States)

Yoon, Moon-Hyun; Lee, Do-Wan; Kim, Hyun-Jin; Chung, Jin-Yeung; Doo, Ah-Reum; Park, Hi-Joon; Kim, Seung-Nam; Choe, Bo-Young

2013-01-01

Neuroprotective therapeutics slows down the degeneration process in animal models of Parkinson's disease (PD). The neuronal survival in PD animal models is often measured by using immunohistochemistry. However, dynamic changes in the pathology of the brain cannot be explored with this technique. Application of in-vivo 1H magnetic resonance spectroscopy (1H MRS) can cover this shortcoming, as these techniques are non-invasive and can be repeated over time in the same animal. Thus, the sensitivity of both techniques to measure changes in the PD pathology was explored in an experiment studying the neuroprotective effects of the vigilance enhancer bee-venom (BV) in a mouse model of PD. The mice were pre-treated with 0.02-ml BV administered to the acupuncture point GB34 (Yangneungcheon) once every 3 days for 2 weeks. Three groups were classified as control, MPTP-intoxicated PD model and BV-treated mice. Outer volume suppression combined with the ultra-short echo-time STEAM (TE = 2.2 ms, TM = 20 ms, TR = 5000 ms) was used for localized in-vivo 1H MRS. Based on the 1H MRS spectral analysis, substantial changes of the neurochemical profiles were evaluated in the three investigated groups. In particular, the glutamate complex (Glx)/creatine (Cr) ratio (7.72 ± 1.25) in the PD group was significantly increased compared to that in the control group (3.93 ± 2.21, P = 0.001). Compared to the baseline values, the Glx/Cr ratio of the BV-treated group was significantly decreased 2 weeks after MPTP intoxication (one-way ANOVA, p < 0.05). In conclusion, the present study demonstrated that neurochemical alterations occurred in the three groups and that the neuroprotective effects of the BV acupuncture in a mouse model of PD could be quantified by using immunohistochemistry and 1H MRS.

Mouse Genome Informatics (MGI) Is the International Resource for Information on the Laboratory Mouse.

Science.gov (United States)

Law, MeiYee; Shaw, David R

2018-01-01

Mouse Genome Informatics (MGI, http://www.informatics.jax.org/ ) web resources provide free access to meticulously curated information about the laboratory mouse. MGI's primary goal is to help researchers investigate the genetic foundations of human diseases by translating information from mouse phenotypes and disease models studies to human systems. MGI provides comprehensive phenotypes for over 50,000 mutant alleles in mice and provides experimental model descriptions for over 1500 human diseases. Curated data from scientific publications are integrated with those from high-throughput phenotyping and gene expression centers. Data are standardized using defined, hierarchical vocabularies such as the Mammalian Phenotype (MP) Ontology, Mouse Developmental Anatomy and the Gene Ontologies (GO). This chapter introduces you to Gene and Allele Detail pages and provides step-by-step instructions for simple searches and those that take advantage of the breadth of MGI data integration.

¹H MRS characterization of neurochemical profiles in orthotopic mouse models of human brain tumors.

Science.gov (United States)

Hulsey, Keith M; Mashimo, Tomoyuki; Banerjee, Abhishek; Soesbe, Todd C; Spence, Jeffrey S; Vemireddy, Vamsidhara; Maher, Elizabeth A; Bachoo, Robert M; Choi, Changho

2015-01-01

Glioblastoma (GBM), the most common primary brain tumor, is resistant to currently available treatments. The development of mouse models of human GBM has provided a tool for studying mechanisms involved in tumor initiation and growth as well as a platform for preclinical investigation of new drugs. In this study we used (1) H MR spectroscopy to study the neurochemical profile of a human orthotopic tumor (HOT) mouse model of human GBM. The goal of this study was to evaluate differences in metabolite concentrations in the GBM HOT mice when compared with normal mouse brain in order to determine if MRS could reliably differentiate tumor from normal brain. A TE =19 ms PRESS sequence at 9.4 T was used for measuring metabolite levels in 12 GBM mice and 8 healthy mice. Levels for 12 metabolites and for lipids/macromolecules at 0.9 ppm and at 1.3 ppm were reliably detected in all mouse spectra. The tumors had significantly lower concentrations of total creatine, GABA, glutamate, total N-acetylaspartate, aspartate, lipids/macromolecules at 0.9 ppm, and lipids/macromolecules at 1.3 ppm than did the brains of normal mice. The concentrations of glycine and lactate, however, were significantly higher in tumors than in normal brain. Copyright © 2014 John Wiley & Sons, Ltd.

WE-AB-202-11: Radiobiological Modeling of Tumor Response During Radiotherapy Based On Pre-Treatment Dynamic PET Imaging Data

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Crispin-Ortuzar, M; Grkovski, M; Beattie, B; Lee, N; Riaz, N; Humm, J; Jeong, J; Fontanella, A; Deasy, J [Memorial Sloan Kettering Cancer Center, New York, NY (United States)

2016-06-15

Purpose: To evaluate the ability of a multiscale radiobiological model of tumor response to predict mid-treatment hypoxia images, based on pretreatment imaging of perfusion and hypoxia with [18-F]FMISO dynamic PET and glucose metabolism with [18-F]FDG PET. Methods: A mechanistic tumor control probability (TCP) radiobiological model describing the interplay between tumor cell proliferation and hypoxia (Jeong et al., PMB 2013) was extended to account for intra-tumor nutrient heterogeneity, dynamic cell migration due to nutrient gradients, and stromal cells. This extended model was tested on 10 head and neck cancer patients treated with chemoradiotherapy, randomly drawn from a larger MSKCC protocol involving baseline and mid-therapy dynamic PET scans. For each voxel, initial fractions of proliferative and hypoxic tumor cells were obtained by finding an approximate solution to a system of linear equations relating cell fractions to voxel-level FDG uptake, perfusion (FMISO K{sub 1}) and hypoxia (FMISO k{sub 3}). The TCP model then predicted their evolution over time up until the mid treatment scan. Finally, the linear model was reapplied to predict each lesion’s median hypoxia level (k{sub 3}[med,sim]) which in turn was compared to the FMISO k{sub 3}[med] measured at mid-therapy. Results: The average k3[med] of the tumors in pre-treatment scans was 0.0035 min{sup −1}, with an inter-tumor standard deviation of σ[pre]=0.0034 min{sup −1}. The initial simulated k{sub 3}[med,sim] of each tumor agreed with the corresponding measurements within 0.1σ[pre]. In 7 out of 10 lesions, the mid-treatment k{sub 3}[med,sim] prediction agreed with the data within 0.3σ[pre]. The remaining cases corresponded to the most extreme relative changes in k{sub 3}[med]. Conclusion: This work presents a method to personalize the prediction of a TCP model using pre-treatment kinetic imaging data, and validates the modeling of radiotherapy response by predicting changes in median hypoxia

Lrit3 deficient mouse (nob6): a novel model of complete congenital stationary night blindness (cCSNB).

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Neuillé, Marion; El Shamieh, Said; Orhan, Elise; Michiels, Christelle; Antonio, Aline; Lancelot, Marie-Elise; Condroyer, Christel; Bujakowska, Kinga; Poch, Olivier; Sahel, José-Alain; Audo, Isabelle; Zeitz, Christina

2014-01-01

Mutations in LRIT3, coding for a Leucine-Rich Repeat, immunoglobulin-like and transmembrane domains 3 protein lead to autosomal recessive complete congenital stationary night blindness (cCSNB). The role of the corresponding protein in the ON-bipolar cell signaling cascade remains to be elucidated. Here we genetically and functionally characterize a commercially available Lrit3 knock-out mouse, a model to study the function and the pathogenic mechanism of LRIT3. We confirm that the insertion of a Bgeo/Puro cassette in the knock-out allele introduces a premature stop codon, which presumably codes for a non-functional protein. The mouse line does not harbor other mutations present in common laboratory mouse strains or in other known cCSNB genes. Lrit3 mutant mice exhibit a so-called no b-wave (nob) phenotype with lacking or severely reduced b-wave amplitudes in the scotopic and photopic electroretinogram (ERG), respectively. Optomotor tests reveal strongly decreased optomotor responses in scotopic conditions. No obvious fundus auto-fluorescence or histological retinal structure abnormalities are observed. However, spectral domain optical coherence tomography (SD-OCT) reveals thinned inner nuclear layer and part of the retina containing inner plexiform layer, ganglion cell layer and nerve fiber layer in these mice. To our knowledge, this is the first time that SD-OCT technology is used to characterize an animal model for CSNB. This phenotype is noted at 6 weeks and at 6 months. The stationary nob phenotype of mice lacking Lrit3, which we named nob6, confirms the findings previously reported in patients carrying LRIT3 mutations and is similar to other cCSNB mouse models. This novel mouse model will be useful for investigating the pathogenic mechanism(s) associated with LRIT3 mutations and clarifying the role of LRIT3 in the ON-bipolar cell signaling cascade.

Lrit3 deficient mouse (nob6: a novel model of complete congenital stationary night blindness (cCSNB.

Directory of Open Access Journals (Sweden)

Marion Neuillé

Full Text Available Mutations in LRIT3, coding for a Leucine-Rich Repeat, immunoglobulin-like and transmembrane domains 3 protein lead to autosomal recessive complete congenital stationary night blindness (cCSNB. The role of the corresponding protein in the ON-bipolar cell signaling cascade remains to be elucidated. Here we genetically and functionally characterize a commercially available Lrit3 knock-out mouse, a model to study the function and the pathogenic mechanism of LRIT3. We confirm that the insertion of a Bgeo/Puro cassette in the knock-out allele introduces a premature stop codon, which presumably codes for a non-functional protein. The mouse line does not harbor other mutations present in common laboratory mouse strains or in other known cCSNB genes. Lrit3 mutant mice exhibit a so-called no b-wave (nob phenotype with lacking or severely reduced b-wave amplitudes in the scotopic and photopic electroretinogram (ERG, respectively. Optomotor tests reveal strongly decreased optomotor responses in scotopic conditions. No obvious fundus auto-fluorescence or histological retinal structure abnormalities are observed. However, spectral domain optical coherence tomography (SD-OCT reveals thinned inner nuclear layer and part of the retina containing inner plexiform layer, ganglion cell layer and nerve fiber layer in these mice. To our knowledge, this is the first time that SD-OCT technology is used to characterize an animal model for CSNB. This phenotype is noted at 6 weeks and at 6 months. The stationary nob phenotype of mice lacking Lrit3, which we named nob6, confirms the findings previously reported in patients carrying LRIT3 mutations and is similar to other cCSNB mouse models. This novel mouse model will be useful for investigating the pathogenic mechanism(s associated with LRIT3 mutations and clarifying the role of LRIT3 in the ON-bipolar cell signaling cascade.

Osthole pretreatment alleviates TNBS-induced colitis in mice via both cAMP/PKA-dependent and independent pathways.

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Sun, Wu; Cai, Yun; Zhang, Xin-Xin; Chen, Hao; Lin, Yan-Die; Li, Hao

2017-08-01

Osthole, a natural coumarin found in traditional Chinese medicinal plants, has shown multiple biological activities. In the present study, we investigated the preventive effects of osthole on inflammatory bowel disease (IBD). Colitis was induced in mice by infusing TNBS into the colonic lumen. Before TNBS treatment, the mice received osthole (100 mg·kg -1 ·d -1 , ip) for 3 d. Pretreatment with osthole significantly ameliorated the clinical scores, colon length shortening, colonic histopathological changes and the expression of inflammatory mediators in TNBS-induced colitis. Pretreatment with osthole elevated serum cAMP levels; but treatment with the PKA inhibitor H89 (10 mg·kg -1 ·d -1 , ip) did not abolish the beneficial effects of osthole on TNBS-induced colitis. In mouse peritoneal macrophages, pretreatment with osthole (50 μmol/L) significantly attenuated the LPS-induced elevation of cytokines at the mRNA level; inhibition of PKA completely reversed the inhibitory effects of osthole on IL-1β, IL-6, COX2, and MCP-1 but not on TNFα. In Raw264.7 cells, the p38 inhibitor SB203580 markedly suppressed LPS-induced upregulation of the cytokines, whereas the PKA inhibitors H89 or KT5720 did not abolish the inhibitory effects of SB203580. Moreover, in LPS-stimulated mouse peritoneal macrophages, SB203580 strongly inhibited the restored expression of IL-1β, IL-6, COX2, and MCP-1, which was achieved by abolishing the suppressive effects of osthole with the PKA inhibitors. Western blot analysis showed that osthole significantly suppressed the phosphorylation of p38, which was induced by TNBS in mice or by LPS in Raw264.7 cells. Inhibition of PKA partially reversed the suppressive effects of osthole on p38 phosphorylation in LPS-stimulated cells. Collectively, our results suggest that osthole is effective in the prevention of TNBS-induced colitis by reducing the expression of inflammatory mediators and attenuating p38 phosphorylation via both cAMP/PKA-dependent and

pH catalyzed pretreatment of corn bran for enhanced enzymatic arabinoxylan degradation

DEFF Research Database (Denmark)

Agger, Jane; Johansen, Katja Salomon; Meyer, Anne S.

2011-01-01

Corn bran is mainly made up of the pericarp of corn kernels and is a byproduct stream resulting from the wet milling step in corn starch processing. Through statistic modeling this study examined the optimization of pretreatment of corn bran for enzymatic hydrolysis. A low pH pretreatment (pH 2......, 150°C, 65min) boosted the enzymatic release of xylose and glucose and maximized biomass solubilization. With more acidic pretreatment followed by enzymatic hydrolysis the total xylose release was maximized (at pH 1.3) reaching ∼50% by weight of the original amount present in destarched corn bran......, but the enzyme catalyzed xylose release was maximal after pretreatment at approx. pH 2. The total glucose release peaked after pretreatment of approx. pH 1.5 with an enzymatic release of approx. 68% by weight of the original amounts present in destarched corn bran. For arabinose the enzymatic release...

A Transgenic Tri-Modality Reporter Mouse

OpenAIRE

Yan, Xinrui; Ray, Pritha; Paulmurugan, Ramasamy; Tong, Ricky; Gong, Yongquan; Sathirachinda, Ataya; Wu, Joseph C.; Gambhir, Sanjiv S.

2013-01-01

Transgenic mouse with a stably integrated reporter gene(s) can be a valuable resource for obtaining uniformly labeled stem cells, tissues, and organs for various applications. We have generated a transgenic mouse model that ubiquitously expresses a tri-fusion reporter gene (fluc2-tdTomato-ttk) driven by a constitutive chicken β-actin promoter. This "Tri-Modality Reporter Mouse" system allows one to isolate most cells from this donor mouse and image them for bioluminescent (fluc2), fluorescent...

Bridging gaps: On the performance of airborne LiDAR to model wood mouse-habitat structure relationships in pine forests.

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Jaime-González, Carlos; Acebes, Pablo; Mateos, Ana; Mezquida, Eduardo T

2017-01-01

LiDAR technology has firmly contributed to strengthen the knowledge of habitat structure-wildlife relationships, though there is an evident bias towards flying vertebrates. To bridge this gap, we investigated and compared the performance of LiDAR and field data to model habitat preferences of wood mouse (Apodemus sylvaticus) in a Mediterranean high mountain pine forest (Pinus sylvestris). We recorded nine field and 13 LiDAR variables that were summarized by means of Principal Component Analyses (PCA). We then analyzed wood mouse's habitat preferences using three different models based on: (i) field PCs predictors, (ii) LiDAR PCs predictors; and (iii) both set of predictors in a combined model, including a variance partitioning analysis. Elevation was also included as a predictor in the three models. Our results indicate that LiDAR derived variables were better predictors than field-based variables. The model combining both data sets slightly improved the predictive power of the model. Field derived variables indicated that wood mouse was positively influenced by the gradient of increasing shrub cover and negatively affected by elevation. Regarding LiDAR data, two LiDAR PCs, i.e. gradients in canopy openness and complexity in forest vertical structure positively influenced wood mouse, although elevation interacted negatively with the complexity in vertical structure, indicating wood mouse's preferences for plots with lower elevations but with complex forest vertical structure. The combined model was similar to the LiDAR-based model and included the gradient of shrub cover measured in the field. Variance partitioning showed that LiDAR-based variables, together with elevation, were the most important predictors and that part of the variation explained by shrub cover was shared. LiDAR derived variables were good surrogates of environmental characteristics explaining habitat preferences by the wood mouse. Our LiDAR metrics represented structural features of the forest

Late effects of irradiation in mouse jejunum

International Nuclear Information System (INIS)

Reynaud, A.; Travis, E.L.

1984-01-01

The response of mouse jejunum at intervals up to 1 year after single 'priming' doses of X-rays has been assessed by crypt survival after retreatment with single doses of X-rays and morphometric analysis of changes in the intestinal submucosa. The crypt dose-survival curves in mice re-irradiated at 2, 6, or 12 months after priming irradiation were displaced to higher doses in pre-treated than in non-pre-treated mice and were characterized by higher D 0 values. Misonidazole given before the test exposure reversed this effect so that the dose survival curve for crypts in pre-treated mice were superimposed on that for mice not previously irradiated, suggesting that the increase in isoeffect dose and the change in the D 0 in previously exposed mice was due to crypt hypoxia. Quantifications of the area of the submucosa showed that its area was increased at all three times after the priming doses and was a result of collagen deposition and oedema. Thus, the hypoxia in the crypts was probably secondary to these changes. Deaths began at 6-7 months after priming irradiation and were due to intestinal obstruction and stenosis. Thus, as in other tissues, two phases of injury can be assayed in the intestine of experimental animals. (author)

Utrophin Compensates dystrophin Loss during Mouse Spermatogenesis

OpenAIRE

Chen, Hung-Chih; Chin, Yu-Feng; Lundy, David J.; Liang, Chung-Tiang; Chi, Ya-Hui; Kuo, Paolin; Hsieh, Patrick C. H.

2017-01-01

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder resulting from mutations in the dystrophin gene. The mdx/utrn ?/? mouse, lacking in both dystrophin and its autosomal homologue utrophin, is commonly used to model the clinical symptoms of DMD. Interestingly, these mice are infertile but the mechanisms underlying this phenomenon remain unclear. Using dystrophin deficient mdx mouse and utrophin haplodeficient mdx/utrn +/? mouse models, we demonstrate the contribution of Dp427 (f...

Sodium homeostasis is preserved in a global 11β-hydroxysteroid dehydrogenase type 1 knockout mouse model

DEFF Research Database (Denmark)

Christensen, Thorbjørn H; Bailey, Matthew A; Kenyon, Christopher J

2015-01-01

hypothesized that loss of renal 11βHSD1 would result in salt wasting and tested this in a knockout mouse model in which 11βHSD1 was deleted in all body tissues. In balance studies, 11βHSD1 deletion had no effect on water, sodium or potassium metabolism; transition to a low-sodium diet did not reveal...... that global deletion of 11βHSD1 in the mouse would give rise to a salt-wasting renal phenotype. What is the main finding and its importance? We subjected a mouse model of global 11βHSD1 deletion to studies of water and electrolyte balance, renal clearance, urinary steroid excretion, renin-angiotensin system...... a natriuretic phenotype. Renal clearance studies demonstrated identical haemodynamic parameters (arterial blood pressure, renal blood flow and glomerular filtration rate) in knockout and wild-type mice, but revealed an augmented kaliuretic response to thiazides in 11βHSD1 knockout animals. There was no effect...

A Phenotype-Driven Approach to Generate Mouse Models with Pathogenic mtDNA Mutations Causing Mitochondrial Disease

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Johanna H.K. Kauppila

2016-09-01

Full Text Available Mutations of mtDNA are an important cause of human disease, but few animal models exist. Because mammalian mitochondria cannot be transfected, the development of mice with pathogenic mtDNA mutations has been challenging, and the main strategy has therefore been to introduce mutations found in cell lines into mouse embryos. Here, we describe a phenotype-driven strategy that is based on detecting clonal expansion of pathogenic mtDNA mutations in colonic crypts of founder mice derived from heterozygous mtDNA mutator mice. As proof of concept, we report the generation of a mouse line transmitting a heteroplasmic pathogenic mutation in the alanine tRNA gene of mtDNA displaying typical characteristics of classic mitochondrial disease. In summary, we describe a straightforward and technically simple strategy based on mouse breeding and histology to generate animal models of mtDNA-mutation disease, which will be of great importance for studies of disease pathophysiology and preclinical treatment trials.

Simulating obstructive sleep apnea patients' oxygenation characteristics into a mouse model of cyclical intermittent hypoxia.

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Lim, Diane C; Brady, Daniel C; Po, Pengse; Chuang, Li Pang; Marcondes, Laise; Kim, Emily Y; Keenan, Brendan T; Guo, Xiaofeng; Maislin, Greg; Galante, Raymond J; Pack, Allan I

2015-03-01

Mouse models of cyclical intermittent hypoxia (CIH) are used to study the consequences of both hypoxia and oxidative stress in obstructive sleep apnea (OSA). Whether or not a mouse model of CIH that simulates OSA patients' oxygenation characteristics would translate into improved patient care remains unanswered. First we identified oxygenation characteristics using the desaturation and resaturation time in 47 OSA subjects from the Molecular Signatures of Obstructive Sleep Apnea Cohort (MSOSA). We observe that a cycle of intermittent hypoxia is not sinusoidal; specifically, desaturation time increases in an almost linear relationship to the degree of hypoxia (nadir), whereas resaturation time is somewhat constant (∼15 s), irrespective of the nadir. Second, we modified the Hycon mouse model of CIH to accommodate a 15-s resaturation time. Using this modified CIH model, we explored whether a short resaturation schedule (15 s), which includes the characteristics of OSA patients, had a different effect on levels of oxidative stress (i.e., urinary 8,12-iso-iPF2α-VI levels) compared with sham and a long resaturation schedule (90 s), a schedule that is not uncommon in rodent models of CIH. Results suggest that shorter resaturation time may result in a higher level of 8,12-iso-iPF2α-VI compared with long resaturation or sham conditions. Therefore, simulating the rodent model of CIH to reflect this and other OSA patients' oxygenation characteristics may be worthy of consideration to better understand the effects of hypoxia, oxidative stress, and their interactions. Copyright © 2015 the American Physiological Society.

Antibacterial effect of surface pretreatment techniques against ...

African Journals Online (AJOL)

Objective: The aim of this study was to evaluate the antibacterial surface pretreatment methods against Streptococcus mutans within the infected dentin surface using a tooth cavity model. Material and Methods: Seventy-two cavities were prepared on caries-free third molars (n = 8). After sterilization, teeth were inoculated ...

Cellular, molecular and functional characterisation of YAC transgenic mouse models of Friedreich ataxia.

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Sara Anjomani Virmouni

Full Text Available Friedreich ataxia (FRDA is an autosomal recessive neurodegenerative disorder, caused by a GAA repeat expansion mutation within intron 1 of the FXN gene. We have previously established and performed preliminary characterisation of several human FXN yeast artificial chromosome (YAC transgenic FRDA mouse models containing GAA repeat expansions, Y47R (9 GAA repeats, YG8R (90 and 190 GAA repeats and YG22R (190 GAA repeats.We now report extended cellular, molecular and functional characterisation of these FXN YAC transgenic mouse models. FXN transgene copy number analysis of the FRDA mice demonstrated that the YG22R and Y47R lines each have a single copy of the FXN transgene while the YG8R line has two copies. Single integration sites of all transgenes were confirmed by fluorescence in situ hybridisation (FISH analysis of metaphase and interphase chromosomes. We identified significant functional deficits, together with a degree of glucose intolerance and insulin hypersensitivity, in YG8R and YG22R FRDA mice compared to Y47R and wild-type control mice. We also confirmed increased somatic GAA repeat instability in the cerebellum and brain of YG22R and YG8R mice, together with significantly reduced levels of FXN mRNA and protein in the brain and liver of YG8R and YG22R compared to Y47R.Together these studies provide a detailed characterisation of our GAA repeat expansion-based YAC transgenic FRDA mouse models that will help investigations of FRDA disease mechanisms and therapy.

Skeletal muscle repair in a mouse model of nemaline myopathy

OpenAIRE

Sanoudou, Despina; Corbett, Mark A.; Han, Mei; Ghoddusi, Majid; Nguyen, Mai-Anh T.; Vlahovich, Nicole; Hardeman, Edna C.; Beggs, Alan H.

2006-01-01

Nemaline myopathy (NM), the most common non-dystrophic congenital myopathy, is a variably severe neuromuscular disorder for which no effective treatment is available. Although a number of genes have been identified in which mutations can cause NM, the pathogenetic mechanisms leading to the phenotypes are poorly understood. To address this question, we examined gene expression patterns in an NM mouse model carrying the human Met9Arg mutation of alpha-tropomyosin slow (Tpm3). We assessed five d...

Enhanced fear expression in a psychopathological mouse model of trait anxiety: pharmacological interventions.

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Simone B Sartori

Full Text Available The propensity to develop an anxiety disorder is thought to be determined by genetic and environmental factors. Here we investigated the relationship between a genetic predisposition to trait anxiety and experience-based learned fear in a psychopathological mouse model. Male CD-1 mice selectively bred for either high (HAB, or normal (NAB anxiety-related behaviour on the elevated plus maze were subjected to classical fear conditioning. During conditioning both mouse lines showed increased fear responses as assessed by freezing behaviour. However, 24 h later, HAB mice displayed more pronounced conditioned responses to both a contextual or cued stimulus when compared with NAB mice. Interestingly, 6 h and already 1 h after fear conditioning, freezing levels were high in HAB mice but not in NAB mice. These results suggest that trait anxiety determines stronger fear memory and/or a weaker ability to inhibit fear responses in the HAB line. The enhanced fear response of HAB mice was attenuated by treatment with either the α(2,3,5-subunit selective benzodiazepine partial agonist L-838,417, corticosterone or the selective neurokinin-1 receptor antagonist L-822,429. Overall, the HAB mouse line may represent an interesting model (i for identifying biological factors underlying misguided conditioned fear responses and (ii for studying novel anxiolytic pharmacotherapies for patients with fear-associated disorders, including post-traumatic stress disorder and phobias.

Intraocular Injection of ES Cell-Derived Neural Progenitors Improve Visual Function in Retinal Ganglion Cell-Depleted Mouse Models

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Mundackal S. Divya

2017-09-01

Full Text Available Retinal ganglion cell (RGC transplantation is a promising strategy to restore visual function resulting from irreversible RGC degeneration occurring in glaucoma or inherited optic neuropathies. We previously demonstrated FGF2 induced differentiation of mouse embryonic stem cells (ESC to RGC lineage, capable of retinal ganglion cell layer (GCL integration upon transplantation. Here, we evaluated possible improvement of visual function by transplantation of ES cell derived neural progenitors in RGC depleted glaucoma mice models. ESC derived neural progenitors (ES-NP were transplanted into N-Methyl-D-Aspartate (NMDA injected, RGC-ablated mouse models and a pre-clinical glaucoma mouse model (DBA/2J having sustained higher intra ocular pressure (IOP. Visual acuity and functional integration was evaluated by behavioral experiments and immunohistochemistry, respectively. GFP-expressing ES-NPs transplanted in NMDA-injected RGC-depleted mice differentiated into RGC lineage and possibly integrating into GCL. An improvement in visual acuity was observed after 2 months of transplantation, when compared to the pre-transplantation values. Expression of c-Fos in the transplanted cells, upon light induction, further suggests functional integration into the host retinal circuitry. However, the transplanted cells did not send axonal projections into optic nerve. Transplantation experiments in DBA/2J mouse showed no significant improvement in visual functions, possibly due to both host and transplanted retinal cell death which could be due to an inherent high IOP. We showed that, ES NPs transplanted into the retina of RGC-ablated mouse models could survive, differentiate to RGC lineage, and possibly integrate into GCL to improve visual function. However, for the survival of transplanted cells in glaucoma, strategies to control the IOP are warranted.

PKC theta ablation improves healing in a mouse model of muscular dystrophy.

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Luca Madaro

Full Text Available Inflammation is a key pathological characteristic of dystrophic muscle lesion formation, limiting muscle regeneration and resulting in fibrotic and fatty tissue replacement of muscle, which exacerbates the wasting process in dystrophic muscles. Limiting immune response is thus one of the therapeutic options to improve healing, as well as to improve the efficacy of gene- or cell-mediated strategies to restore dystrophin expression. Protein kinase C θ (PKCθ is a member of the PKCs family highly expressed in both immune cells and skeletal muscle; given its crucial role in adaptive, but also innate, immunity, it is being proposed as a valuable pharmacological target for immune disorders. In our study we asked whether targeting PKCθ could represent a valuable approach to efficiently prevent inflammatory response and disease progression in a mouse model of muscular dystrophy. We generated the bi-genetic mouse model mdx/θ(-/-, where PKCθ expression is lacking in mdx mice, the mouse model of Duchenne muscular dystrophy. We found that muscle wasting in mdx/θ(-/- mice was greatly prevented, while muscle regeneration, maintenance and performance was significantly improved, as compared to mdx mice. This phenotype was associated to reduction in inflammatory infiltrate, pro-inflammatory gene expression and pro-fibrotic markers activity, as compared to mdx mice. Moreover, BM transplantation experiments demonstrated that the phenotype observed was primarily dependent on lack of PKCθ expression in hematopoietic cells.These results demonstrate a hitherto unrecognized role of immune-cell intrinsic PKCθ activity in the development of DMD. Although the immune cell population(s involved remain unidentified, our findings reveal that PKCθ can be proposed as a new pharmacological target to counteract the disease, as well as to improve the efficacy of gene- or cell- therapy approaches.

Partial corrosion casting to assess cochlear vasculature in mouse models of presbycusis and CMV infection.

Science.gov (United States)

Carraro, Mattia; Park, Albert H; Harrison, Robert V

2016-02-01

Some forms of sensorineural hearing loss involve damage or degenerative changes to the stria vascularis and/or other vascular structures in the cochlea. In animal models, many methods for anatomical assessment of cochlear vasculature exist, each with advantages and limitations. One methodology, corrosion casting, has proved useful in some species, however in the mouse model this technique is difficult to achieve because digestion of non vascular tissue results in collapse of the delicate cast specimen. We have developed a partial corrosion cast method that allows visualization of vasculature along much of the cochlear length but maintains some structural integrity of the specimen. We provide a detailed step-by-step description of this novel technique. We give some illustrative examples of the use of the method in mouse models of presbycusis and cytomegalovirus (CMV) infection. Copyright © 2015 Elsevier B.V. All rights reserved.

Pretreatment techniques for biofuels and biorefineries

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Fang, Zhen (ed.) [Chinese Academy of Sciences, Kunming, YN (China). Xishuangbanna Tropical Botonical Garden

2013-02-01

The first book focused on pretreatment techniques for biofuels contributed by the world's leading experts. Extensively covers the different types of biomass, various pretreatment approaches and methods that show the subsequent production of biofuels and chemicals. In addition to traditional pretreatment methods, novel techniques are also introduced and discussed. An accessible reference work for students, researchers, academicians and industrialists in biorefineries. This book includes 19 chapters contributed by the world's leading experts on pretreatment methods for biomass. It extensively covers the different types of biomass (e.g. molasses, sugar beet pulp, cheese whey, sugarcane residues, palm waste, vegetable oil, straws, stalks and wood), various pretreatment approaches (e.g. physical, thermal, chemical, physicochemical and biological) and methods that show the subsequent production of biofuels and chemicals such as sugars, ethanol, extracellular polysaccharides, biodiesel, gas and oil. In addition to traditional methods such as steam, hot-water, hydrothermal, diluted-acid, organosolv, ozonolysis, sulfite, milling, fungal and bacterial, microwave, ultrasonic, plasma, torrefaction, pelletization, gasification (including biogas) and liquefaction pretreatments, it also introduces and discusses novel techniques such as nano and solid catalysts, organic electrolyte solutions and ionic liquids. This book offers a review of state-of-the-art research and provides guidance for the future paths of developing pretreatment techniques of biomass for biofuels, especially in the fields of biotechnology, microbiology, chemistry, materials science and engineering. It intends to provide a systematic introduction of pretreatment techniques. It is an accessible reference work for students, researchers, academicians and industrialists in biorefineries.

Humanized Mouse Models of Staphylococcus aureus Infection

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Dane Parker

2017-05-01

Full Text Available Staphylococcus aureus is a successful human pathogen that has adapted itself in response to selection pressure by the human immune system. A commensal of the human skin and nose, it is a leading cause of several conditions: skin and soft tissue infection, pneumonia, septicemia, peritonitis, bacteremia, and endocarditis. Mice have been used extensively in all these conditions to identify virulence factors and host components important for pathogenesis. Although significant effort has gone toward development of an anti-staphylococcal vaccine, antibodies have proven ineffective in preventing infection in humans after successful studies in mice. These results have raised questions as to the utility of mice to predict patient outcome and suggest that humanized mice might prove useful in modeling infection. The development of humanized mouse models of S. aureus infection will allow us to assess the contribution of several human-specific virulence factors, in addition to exploring components of the human immune system in protection against S. aureus infection. Their use is discussed in light of several recently reported studies.

Genetic mouse models relevant to schizophrenia: taking stock and looking forward.

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Harrison, Paul J; Pritchett, David; Stumpenhorst, Katharina; Betts, Jill F; Nissen, Wiebke; Schweimer, Judith; Lane, Tracy; Burnet, Philip W J; Lamsa, Karri P; Sharp, Trevor; Bannerman, David M; Tunbridge, Elizabeth M

2012-03-01

Genetic mouse models relevant to schizophrenia complement, and have to a large extent supplanted, pharmacological and lesion-based rat models. The main attraction is that they potentially have greater construct validity; however, they share the fundamental limitations of all animal models of psychiatric disorder, and must also be viewed in the context of the uncertain and complex genetic architecture of psychosis. Some of the key issues, including the choice of gene to target, the manner of its manipulation, gene-gene and gene-environment interactions, and phenotypic characterization, are briefly considered in this commentary, illustrated by the relevant papers reported in this special issue. Copyright © 2011 Elsevier Ltd. All rights reserved.

'Too much good news' - are Alzheimer mouse models trying to tell us how to prevent, not cure, Alzheimer's disease?

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Zahs, Kathleen R; Ashe, Karen H

2010-08-01

Scores of compounds ameliorate cognitive deficits or neuropathology in transgenic mouse models of Alzheimer's disease (AD), yet these triumphs in mice have not translated into successful therapies for people. Why have studies in mice failed to predict results of human trials? We argue that most transgenic mouse 'models of AD' actually simulate the asymptomatic phase of the disease, and the results of interventional studies in these mice should be considered in the context of disease prevention. In addition, recent advances in imaging technology and biomarker discovery should aid in comparisons of mouse and human neurological status and, importantly, might allow us to predict better the response of people to drugs tested in mice. Copyright 2010. Published by Elsevier Ltd.

Mild-temperature dilute acid pretreatment for integration of first and second generation ethanol processes.

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Nair, Ramkumar B; Kalif, Mahdi; Ferreira, Jorge A; Taherzadeh, Mohammad J; Lennartsson, Patrik R

2017-12-01

The use of hot-water (100°C) from the 1st generation ethanol plants for mild-temperature lignocellulose pretreatment can possibly cut down the operational (energy) cost of 2nd generation ethanol process, in an integrated model. Dilute-sulfuric and -phosphoric acid pretreatment at 100°C was carried out for wheat bran and whole-stillage fibers. Pretreatment time and acid type influenced the release of sugars from wheat bran, while acid-concentration was found significant for whole-stillage fibers. Pretreatment led up-to 300% improvement in the glucose yield compared to only-enzymatically treated substrates. The pretreated substrates were 191-344% and 115-300% richer in lignin and glucan, respectively. Fermentation using Neurospora intermedia, showed 81% and 91% ethanol yields from wheat bran and stillage-fibers, respectively. Sawdust proved to be a highly recalcitrant substrate for mild-temperature pretreatment with only 22% glucose yield. Both wheat bran and whole-stillage are potential substrates for pretreatment using waste heat from the 1st generation process for 2nd generation ethanol. Copyright © 2017 Elsevier Ltd. All rights reserved.

A mouse model of non-motor symptoms in Parkinson’s disease: focus on pharmacological interventions targeting affective dysfunctions

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Alessandra eBonito Oliva

2014-08-01

Full Text Available Non-motor symptoms, including psychiatric disorders, are increasingly recognized as a major challenge in the treatment of Parkinson’s disease (PD. These ailments, which often appear in the early stage of the disease, affect a large number of patients and are only partly resolved by conventional antiparkinsonian medications, such as L-DOPA. Here, we investigated non-motor symptoms of PD in a mouse model based on bilateral injection of the toxin 6-hydroxydopamine (6-OHDA in the dorsal striatum. This model presented only subtle gait modifications, which did not affect horizontal motor activity in the open-field test. Bilateral 6-OHDA lesion also impaired olfactory discrimination, in line with the anosmia typically observed in early stage parkinsonism. The effect of 6-OHDA was then examined for mood-related dysfunctions. Lesioned mice showed increased immobility in the forced swim test and tail suspension test, two behavioral paradigms of depression. Moreover, the lesion exerted anxiogenic effects, as shown by reduced time spent in the open arms, in the elevated plus maze test, and by increased thigmotaxis in the open-field test. L-DOPA did not modify depressive- and anxiety-like behaviors, which were instead counteracted by the dopamine D2/D3 receptor agonist, pramipexole. Reboxetine, a noradrenaline reuptake inhibitor, was also able to prevent the depressive and anxiogenic effects produced by the lesion with 6-OHDA. Interestingly, pre-treatment with desipramine prior to injection of 6-OHDA, which is commonly used to preserve noradrenaline neurons, did not modify the effect of the lesion on depressive- and anxiety-like behaviors. Thus, in the present model, mood-related conditions are independent of the reduction of noradrenaline caused by 6-OHDA. Based on these findings we propose that the anti-depressive and anxiolytic action of reboxetine is mediated by promoting dopamine transmission through blockade of dopamine uptake from residual

The Virtual Mouse Brain: A Computational Neuroinformatics Platform to Study Whole Mouse Brain Dynamics.

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Melozzi, Francesca; Woodman, Marmaduke M; Jirsa, Viktor K; Bernard, Christophe

2017-01-01

Connectome-based modeling of large-scale brain network dynamics enables causal in silico interrogation of the brain's structure-function relationship, necessitating the close integration of diverse neuroinformatics fields. Here we extend the open-source simulation software The Virtual Brain (TVB) to whole mouse brain network modeling based on individual diffusion magnetic resonance imaging (dMRI)-based or tracer-based detailed mouse connectomes. We provide practical examples on how to use The Virtual Mouse Brain (TVMB) to simulate brain activity, such as seizure propagation and the switching behavior of the resting state dynamics in health and disease. TVMB enables theoretically driven experimental planning and ways to test predictions in the numerous strains of mice available to study brain function in normal and pathological conditions.

Novel Vitamin K analogues suppress seizures in zebrafish and mouse models of epilepsy

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Rahn, Jennifer J.; Bestman, Jennifer E.; Josey, Benjamin J.; Inks, Elizabeth S.; Stackley, Krista D.; Rogers, Carolyn E.; Chou, C. James; Chan, Sherine S. L.

2014-01-01

Epilepsy is a debilitating disease affecting 1-2% of the world’s population. Despite this high prevalence, 30% of patients suffering from epilepsy are not successfully managed by current medication suggesting a critical need for new anti-epileptic drugs (AEDs). In an effort to discover new therapeutics for the management of epilepsy, we began our study by screening drugs that, like some currently used AEDs, inhibit HDACs using a well-established larval zebrafish model. In this model, 7-day post fertilization (dpf) larvae are treated with the widely used seizure-inducing compound pentylenetetrazol (PTZ) which stimulates a rapid increase in swimming behavior previously determined to be a measurable manifestation of seizures. In our first screen, we tested a number of different HDAC inhibitors and found that one, NQN1, significantly decreased swim activity to levels equal to that of VPA. We continued to screen structurally related compounds including Vitamin K3 (VK3) and a number of novel Vitamin K (VK) analogues. We found that VK3 was a robust inhibitor of the PTZ-induced swim activity, as were several of our novel compounds. Three of these compounds were subsequently tested on mouse seizure models at the National Institute of Neurological Disorders and Stroke (NINDS) Anticonvulsant Screening Program. Compound 2h reduced seizures particularly well in the minimal clonic seizure (6 Hz) and corneal kindled mouse models of epilepsy, with no observable toxicity. As VK3 affects mitochondrial function, we tested the effects of our compounds on mitochondrial respiration and ATP production in a mouse hippocampal cell line. We demonstrate that these compounds affect ATP metabolism and increase total cellular ATP. Our data indicate the potential utility of these and other VK analogues for prevention of seizures and suggest the potential mechanism for this protection may lie in the ability of these compounds to affect energy production. PMID:24291671

Effect of sclerostin antibody treatment in a mouse model of severe osteogenesis imperfecta.

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Roschger, Andreas; Roschger, Paul; Keplingter, Petra; Klaushofer, Klaus; Abdullah, Sami; Kneissel, Michaela; Rauch, Frank

2014-09-01

Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually caused by mutations affecting collagen type I production in osteoblasts. Stimulation of bone formation through sclerostin antibody treatment (Sost-ab) has shown promising results in mouse models of relatively mild OI. We assessed the effect of once-weekly intravenous Sost-ab injections for 4weeks in male Col1a1(Jrt)/+mice, a model of severe dominant OI, starting either at 4weeks (growing mice) or at 20weeks (adult mice) of age. Sost-ab had no effect on weight or femur length. In OI mice, no significant treatment-associated differences in serum markers of bone formation (alkaline phosphatase activity, procollagen type I N-propeptide) or resorption (C-telopeptide of collagen type I) were found. Micro-CT analyses at the femur showed that Sost-ab treatment was associated with higher trabecular bone volume and higher cortical thickness in wild type mice at both ages and in growing OI mice, but not in adult OI mice. Three-point bending tests of the femur showed that in wild type but not in OI mice, Sost-ab was associated with higher ultimate load and work to failure. Quantitative backscattered electron imaging of the femur did not show any effect of Sost-ab on CaPeak (the most frequently occurring calcium concentration in the bone mineral density distribution), regardless of genotype, age or measurement location. Thus, Sost-ab had a larger effect in wild type than in Col1a1(Jrt)/+mice. Previous studies had found marked improvements of Sost-ab on bone mass and strength in an OI mouse model with a milder phenotype. Our data therefore suggest that Sost-ab is less effective in a more severely affected OI mouse model. Copyright © 2014 Elsevier Inc. All rights reserved.

Maternal separation with early weaning: a novel mouse model of early life neglect

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Elwafi Hani M

2010-09-01

Full Text Available Abstract Background Childhood adversity is associated with increased risk for mood, anxiety, impulse control, and substance disorders. Although genetic and environmental factors contribute to the development of such disorders, the neurobiological mechanisms involved are poorly understood. A reliable mouse model of early life adversity leading to lasting behavioral changes would facilitate progress in elucidating the molecular mechanisms underlying these adverse effects. Maternal separation is a commonly used model of early life neglect, but has led to inconsistent results in the mouse. Results In an effort to develop a mouse model of early life neglect with long-lasting behavioral effects in C57BL/6 mice, we designed a new maternal separation paradigm that we call Maternal Separation with Early Weaning (MSEW. We tested the effects of MSEW on C57BL/6 mice as well as the genetically distinct DBA/2 strain and found significant MSEW effects on several behavioral tasks (i.e., the open field, elevated plus maze, and forced swim test when assessed more than two months following the MSEW procedure. Our findings are consistent with MSEW causing effects within multiple behavioral domains in both strains, and suggest increased anxiety, hyperactivity, and behavioral despair in the MSEW offspring. Analysis of pup weights and metabolic parameters showed no evidence for malnutrition in the MSEW pups. Additionally, strain differences in many of the behavioral tests suggest a role for genetic factors in the response to early life neglect. Conclusions These results suggest that MSEW may serve as a useful model to examine the complex behavioral abnormalities often apparent in individuals with histories of early life neglect, and may lead to greater understanding of these later life outcomes and offer insight into novel therapeutic strategies.

Long-term Exon Skipping Studies With 2′-O-Methyl Phosphorothioate Antisense Oligonucleotides in Dystrophic Mouse Models

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Christa L Tanganyika-de Winter

2012-01-01

Full Text Available Antisense-mediated exon skipping for Duchenne muscular dystrophy (DMD is currently tested in phase 3 clinical trials. The aim of this approach is to modulate splicing by skipping a specific exon to reframe disrupted dystrophin transcripts, allowing the synthesis of a partly functional dystrophin protein. Studies in animal models allow detailed analysis of the pharmacokinetic and pharmacodynamic profile of antisense oligonucleotides (AONs. Here, we tested the safety and efficacy of subcutaneously administered 2′-O-methyl phosphorothioate AON at 200 mg/kg/week for up to 6 months in mouse models with varying levels of disease severity: mdx mice (mild phenotype and mdx mice with one utrophin allele (mdx/utrn+/−; more severe phenotype. Long-term treatment was well tolerated and exon skipping and dystrophin restoration confirmed for all animals. Notably, in the more severely affected mdx/utrn+/− mice the therapeutic effect was larger: creatine kinase (CK levels were more decreased and rotarod running time was more increased. This suggests that the mdx/utrn+/− model may be a more suitable model to test potential therapies than the regular mdx mouse. Our results also indicate that long-term subcutaneous treatment in dystrophic mouse models with these AONs is safe and beneficial.

TRP channels in brown and white adipogenesis from human progenitors: new therapeutic targets and the caveats associated with the common antibiotic, streptomycin.

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Goralczyk, Anna; van Vijven, Marc; Koch, Mathilde; Badowski, Cedric; Yassin, M Shabeer; Toh, Sue-Anne; Shabbir, Asim; Franco-Obregón, Alfredo; Raghunath, Michael

2017-08-01

Transient receptor potential (TRP) channels are polymodal cell sensors responding to diverse stimuli and widely implicated in the developmental programs of numerous tissues. The evidence for an involvement of TRP family members in adipogenesis, however, is scant. We present the first comprehensive expression profile of all known 27 human TRP genes in mesenchymal progenitors cells during white or brown adipogenesis. Using positive trilineage differentiation as an exclusion criterion, TRP polycystic (P)3, and TPR melastatin (M)8 were found to be uniquely adipospecific. Knockdown of TRPP3 repressed the expression of the brown fat signature genes uncoupling protein (UCP)-1 and peroxisome proliferator-activated receptor γ coactivator (PGC)-1α as well as attenuated forskolin-stimulated uncoupled respiration. However, indices of generalized adipogenesis, such as lipid droplet morphology and fatty acid binding protein (FAPB)-4 expression, were not affected, indicating a principal mitochondrial role of TRPP3. Conversely, activating TRPM8 with menthol up-regulated UCP-1 expression and augmented uncoupled respiration predominantly in white adipocytes (browning), whereas streptomycin antagonized TRPM8-mediated calcium entry, downregulated UCP-1 expression, and mitigated uncoupled respiration; menthol was less capable of augmenting uncoupled respiration (thermogenesis) in brown adipocytes. TRPP3 and TRPM8 hence appear to be involved in the priming of mitochondria to perform uncoupled respiration downstream of adenylate cyclase. Our results also underscore the developmental caveats of using antibiotics in adipogenic studies.-Goralczyk, A., van Vijven, M., Koch, M., Badowski, C., Yassin, M. S., Toh, S.-A., Shabbir, A., Franco-Obregón, A., Raghunath, M. TRP channels in brown and white adipogenesis from human progenitors: new therapeutic targets and the caveats associated with the common antibiotic, streptomycin. © FASEB.

Serotonin Neuron Abnormalities in the BTBR Mouse Model of Autism

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Guo, Yue-Ping; Commons, Kathryn G.

2017-01-01

The inbred mouse strain BTBR T+ Itpr3tf/J (BTBR) i studied as a model of idiopathic autism because they are less social and more resistant to change than other strains. Forebrain serotonin receptors and the response to serotonin drugs are altered in BTBR mice, yet it remains unknown if serotonin neurons themselves are abnormal. In this study, we found that serotonin tissue content and the density of serotonin axons is reduced in the hippocampus of BTBR mice in comparison to C57BL/6J (C57) mice. This was accompanied by possible compensatory changes in serotonin neurons that were most pronounced in regions known to provide innervation to the hippocampus: the caudal dorsal raphe (B6) and the median raphe. These changes included increased numbers of serotonin neurons and hyperactivation of Fos expression. Metrics of serotonin neurons in the rostral 2/3 of the dorsal raphe and serotonin content of the prefrontal cortex were less impacted. Thus, serotonin neurons exhibit region-dependent abnormalities in the BTBR mouse that may contribute to their altered behavioral profile. PMID:27478061

A new dry eye mouse model produced by exorbital and intraorbital lacrimal gland excision.

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Shinomiya, Katsuhiko; Ueta, Mayumi; Kinoshita, Shigeru

2018-01-24

Chronic dry eye is an increasingly prevalent condition worldwide, with resulting loss of visual function and quality of life. Relevant, repeatable, and stable animal models of dry eye are still needed. We have developed an improved surgical mouse model for dry eye based on severe aqueous fluid deficiency, by excising both the exorbital and intraorbital lacrimal glands (ELG and ILG, respectively) of mice. After ELG plus ILG excision, dry eye symptoms were evaluated using fluorescein infiltration observation, tear production measurement, and histological evaluation of ocular surface. Tear production in the model mice was significantly decreased compared with the controls. The corneal fluorescein infiltration score of the model mice was also significantly increased compared with the controls. Histological examination revealed significant severe inflammatory changes in the cornea, conjunctiva or meibomian glands of the model mice after surgery. In the observation of LysM-eGFP (+/-) mice tissues, postsurgical infiltration of green fluorescent neutrophils was observed in the ocular surface tissues. We theorize that the inflammatory changes on the ocular surface of this model were induced secondarily by persistent severe tear reduction. The mouse model will be useful for investigations of both pathophysiology as well as new therapies for tear-volume-reduction type dry eye.

Glycomic analyses of mouse models of congenital muscular dystrophy.

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Stalnaker, Stephanie H; Aoki, Kazuhiro; Lim, Jae-Min; Porterfield, Mindy; Liu, Mian; Satz, Jakob S; Buskirk, Sean; Xiong, Yufang; Zhang, Peng; Campbell, Kevin P; Hu, Huaiyu; Live, David; Tiemeyer, Michael; Wells, Lance

2011-06-17

Dystroglycanopathies are a subset of congenital muscular dystrophies wherein α-dystroglycan (α-DG) is hypoglycosylated. α-DG is an extensively O-glycosylated extracellular matrix-binding protein and a key component of the dystrophin-glycoprotein complex. Previous studies have shown α-DG to be post-translationally modified by both O-GalNAc- and O-mannose-initiated glycan structures. Mutations in defined or putative glycosyltransferase genes involved in O-mannosylation are associated with a loss of ligand-binding activity of α-DG and are causal for various forms of congenital muscular dystrophy. In this study, we sought to perform glycomic analysis on brain O-linked glycan structures released from proteins of three different knock-out mouse models associated with O-mannosylation (POMGnT1, LARGE (Myd), and DAG1(-/-)). Using mass spectrometry approaches, we were able to identify nine O-mannose-initiated and 25 O-GalNAc-initiated glycan structures in wild-type littermate control mouse brains. Through our analysis, we were able to confirm that POMGnT1 is essential for the extension of all observed O-mannose glycan structures with β1,2-linked GlcNAc. Loss of LARGE expression in the Myd mouse had no observable effect on the O-mannose-initiated glycan structures characterized here. Interestingly, we also determined that similar amounts of O-mannose-initiated glycan structures are present on brain proteins from α-DG-lacking mice (DAG1) compared with wild-type mice, indicating that there must be additional proteins that are O-mannosylated in the mammalian brain. Our findings illustrate that classical β1,2-elongation and β1,6-GlcNAc branching of O-mannose glycan structures are dependent upon the POMGnT1 enzyme and that O-mannosylation is not limited solely to α-DG in the brain.

Optimisation of dilute acid pre-treatment of artisan rice hulls for ethanol production

International Nuclear Information System (INIS)

Lopez, Yoney; Martin, Carlos; Gullon, Beatriz; Parajo, Juan Carlos

2011-01-01

Rice hulls are potential low-cost feedstocks for fuel ethanol production in many countries. In this work, the dilute-acid pre-treatment of artisan rice hulls was investigated using a central composite rotatable experimental design. The experimental variables were temperature (140-210 C), biomass load (5-20%) and sulphuric acid concentration (0.5-1.5 g per 100 g of reaction mixture). A total of 16 experimental runs, including a 23-plan, two replicates at the central point and six star points, were carried out. Low temperatures were found to be favourable for the hydrolysis of xylan and of the easily hydrolyzable glucan fraction. High glucose formation (up to 15.3 g/100 g), attributable to starch hydrolysis, was detected in the hydrolysates obtained under the least severe pre-treatment conditions. Using the experimental results, several models for predicting the effect of the operational conditions on the yield of pretreated solids, xylan and glucan conversion upon pre-treatment, and on enzymatic convertibility of cellulose were developed. Optimum results were predicted for the conversion of easily-hydrolyzable glucan in the material pretreated at 140.7 C, and for the enzymatic saccharification of cellulose in the material pretreated at 169 C. These results suggested the use of two-step acid hydrolysis as future pre-treatment strategy for artisan rice hulls. Key words: Dilute acid hydrolysis, enzymatic hydrolysis, pre-treatment, rice hulls. (author)

Optimization of Pre-Treatment Process Parameters to Generate Biodiesel from Microalga

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Chukwuma Onumaegbu

2018-03-01

Full Text Available Cell disruption is an integral part of microalga production process, which improves the release of intracellular products that are essential for biofuel production. In this work, pre-treatment parameters that will enhance the efficiency of lipid production using high-pressure homogenizer on microalgae biomass will be investigated. The high-pressure homogenizer that is considered is a GYB40-10S/GY60-6S; with a pre-treatment pressure of 1000 psi, 2000 psi, and 3000 psi, the number of passes; 1, 2, and 3, a reaction time of 3, 3.5, and 4 h. Pressure and cavitation increase the efficiency of the pre-treatment process of the homogenizer. In addition, homogenization shear force and pressure are the basic significant factors that enhance the efficiency of microalgae cell rupture. Also, the use of modelling to simulate pre-treatment processes (Response Surface Methodology (RSM, Box-Behnken Designs (BBD, and design of experiment (DOE for process optimization will be adopted in this study. The results clearly demonstrate that high-pressure homogenization pre-treatment can effectively disrupt microalga cell walls to enhance lipid recovery efficiency, with a relatively short extraction time, both that are essential for maintaining a good quality of lipids for biofuel production. A maximum of 18% lipid yields were obtained after 3 h of HPH pre-treatment at 3000 psi.

Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2.

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Loredana Leo

2011-06-01

Full Text Available Familial hemiplegic migraine type 2 (FHM2 is an autosomal dominant form of migraine with aura that is caused by mutations of the α2-subunit of the Na,K-ATPase, an isoform almost exclusively expressed in astrocytes in the adult brain. We generated the first FHM2 knock-in mouse model carrying the human W887R mutation in the Atp1a2 orthologous gene. Homozygous Atp1a2(R887/R887 mutants died just after birth, while heterozygous Atp1a2(+/R887 mice showed no apparent clinical phenotype. The mutant α2 Na,K-ATPase protein was barely detectable in the brain of homozygous mutants and strongly reduced in the brain of heterozygous mutants, likely as a consequence of endoplasmic reticulum retention and subsequent proteasomal degradation, as we demonstrate in transfected cells. In vivo analysis of cortical spreading depression (CSD, the phenomenon underlying migraine aura, revealed a decreased induction threshold and an increased velocity of propagation in the heterozygous FHM2 mouse. Since several lines of evidence involve a specific role of the glial α2 Na,K pump in active reuptake of glutamate from the synaptic cleft, we hypothesize that CSD facilitation in the FHM2 mouse model is sustained by inefficient glutamate clearance by astrocytes and consequent increased cortical excitatory neurotransmission. The demonstration that FHM2 and FHM1 mutations share the ability to facilitate induction and propagation of CSD in mouse models further support the role of CSD as a key migraine trigger.

Neurotropism In Vitro and Mouse Models of Severe and Mild Infection with Clinical Strains of Enterovirus 71

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Pin Yu

2017-11-01

Full Text Available Enterovirus 71 (EV71 is a common etiological agent of hand, foot, and mouth disease and fatal neurological diseases in children. The neuropathogenicity of severe EV71 infection has been documented, but studies comparing mouse models of severe and mild EV71 infection are lacking. The aim of the study was to investigate the neurovirulence of EV71 strains and the differences in serum cytokine and chemokine levels in mouse models of severe and mild EV71 infection. Nine EV71 isolates belonging to the C4 subgenogroup (proposed as genotype D displayed infectivity in human neuroblastoma SK-N-SH cells; moreover, ultrastructural observation confirmed viral particle replication. The survival rate of the severe model was 71.43% (5/7, and 60% (3/5 of the surviving severe model mice displayed sequelae of paralysis, whereas the only symptom in mild model mice was ruffled fur. Dynamic detection of serum cytokine and chemokine levels demonstrated that interleukin (IL-5, IL-13, IL-6, monocyte chemotactic protein 1 (MCP-1, and chemokine (C-C motif ligand 5 (also called Regulated upon Activation, Normal T-cell Expressed, and Secreted (CCL5/RANTES were significantly up-regulated at the early period of infection, indicating that these factors might herald a severe outcome. Our findings suggest that elevated cytokines and chemokines may have potential value as prognostic markers in mouse models.

A mouse model of alcoholic liver fibrosis-associated acute kidney injury identifies key molecular pathways

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Furuya, Shinji; Chappell, Grace A.; Iwata, Yasuhiro; Uehara, Takeki; Kato, Yuki; Kono, Hiroshi; Bataller, Ramon; Rusyn, Ivan

2016-01-01

Clinical data strongly indicate that acute kidney injury (AKI) is a critical complication in alcoholic hepatitis, an acute-on-chronic form of liver failure in patients with advanced alcoholic fibrosis. Development of targeted therapies for AKI in this setting is hampered by the lack of an animal model. To enable research into molecular drivers and novel therapies for fibrosis- and alcohol-associated AKI, we aimed to combine carbon tetrachloride (CCl 4 )-induced fibrosis with chronic intra-gastric alcohol feeding. Male C57BL/6J mice were administered a low dose of CCl 4 (0.2 ml/kg 2 × week/6 weeks) followed by alcohol intragastrically (up to 25 g/kg/day for 3 weeks) and with continued CCl 4 . We observed that combined treatment with CCl 4 and alcohol resulted in severe liver injury, more pronounced than using each treatment alone. Importantly, severe kidney injury was evident only in the combined treatment group. This mouse model reproduced distinct pathological features consistent with AKI in human alcoholic hepatitis. Transcriptomic analysis of kidneys revealed profound effects in the combined treatment group, with enrichment for damage-associated pathways, such as apoptosis, inflammation, immune-response and hypoxia. Interestingly, Havcr1 and Lcn2, biomarkers of AKI, were markedly up-regulated. Overall, this study established a novel mouse model of fibrosis- and alcohol-associated AKI and identified key mechanistic pathways. - Highlights: • Acute kidney injury (AKI) is a critical complication in alcoholic hepatitis • We developed a novel mouse model of fibrosis- and alcohol-associated AKI • This model reproduces key molecular and pathological features of human AKI • This animal model can help identify new targeted therapies for alcoholic hepatitis

Innovative pretreatment strategies for biogas production.

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Patinvoh, Regina J; Osadolor, Osagie A; Chandolias, Konstantinos; Sárvári Horváth, Ilona; Taherzadeh, Mohammad J

2017-01-01

Biogas or biomethane is traditionally produced via anaerobic digestion, or recently by thermochemical or a combination of thermochemical and biological processes via syngas (CO and H 2 ) fermentation. However, many of the feedstocks have recalcitrant structure and are difficult to digest (e.g., lignocelluloses or keratins), or they have toxic compounds (such as fruit flavors or high ammonia content), or not digestible at all (e.g., plastics). To overcome these challenges, innovative strategies for enhanced and economically favorable biogas production were proposed in this review. The strategies considered are commonly known physical pretreatment, rapid decompression, autohydrolysis, acid- or alkali pretreatments, solvents (e.g. for lignin or cellulose) pretreatments or leaching, supercritical, oxidative or biological pretreatments, as well as combined gasification and fermentation, integrated biogas production and pretreatment, innovative biogas digester design, co-digestion, and bio-augmentation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mouse infection models for space flight immunology

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Chapes, Stephen Keith; Ganta, Roman Reddy; Chapers, S. K. (Principal Investigator)

2005-01-01

Several immunological processes can be affected by space flight. However, there is little evidence to suggest that flight-induced immunological deficits lead to illness. Therefore, one of our goals has been to define models to examine host resistance during space flight. Our working hypothesis is that space flight crews will come from a heterogeneous population; the immune response gene make-up will be quite varied. It is unknown how much the immune response gene variation contributes to the potential threat from infectious organisms, allergic responses or other long term health problems (e.g. cancer). This article details recent efforts of the Kansas State University gravitational immunology group to assess how population heterogeneity impacts host health, either in laboratory experimental situations and/or using the skeletal unloading model of space-flight stress. This paper details our use of several mouse strains with several different genotypes. In particular, mice with varying MHCII allotypes and mice on the C57BL background with different genetic defects have been particularly useful tools with which to study infections by Staphylococcus aureus, Salmonella typhimurium, Pasteurella pneumotropica and Ehrlichia chaffeensis. We propose that some of these experimental challenge models will be useful to assess the effects of space flight on host resistance to infection.

Kinetic Modelling and Experimental Studies for the Effects of Fe2+ Ions on Xylan Hydrolysis with Dilute-Acid Pretreatment and Subsequent Enzymatic Hydrolysis

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Hui Wei

2018-01-01

Full Text Available High-temperature (150–170 °C pretreatment of lignocellulosic biomass with mineral acids is well established for xylan breakdown. Fe2+ is known to be a cocatalyst of this process although kinetics of its action remains unknown. The present work addresses the effect of ferrous ion concentration on sugar yield and degradation product formation from corn stover for the entire two-step treatment, including the subsequent enzymatic cellulose hydrolysis. The feedstock was impregnated with 0.5% acid and 0.75 mM iron cocatalyst, which was found to be optimal in preliminary experiments. The detailed kinetic data of acid pretreatment, with and without iron, was satisfactorily modelled with a four-step linear sequence of first-order irreversible reactions accounting for the formation of xylooligomers, xylose and furfural as intermediates to provide the values of Arrhenius activation energy. Based on this kinetic modelling, Fe2+ turned out to accelerate all four reactions, with a significant alteration of the last two steps, that is, xylose degradation. Consistent with this model, the greatest xylan conversion occurred at the highest severity tested under 170 °C/30 min with 0.75 mM Fe2+, with a total of 8% xylan remaining in the pretreated solids, whereas the operational conditions leading to the highest xylose monomer yield, 63%, were milder, 150 °C with 0.75 mM Fe2+ for 20 min. Furthermore, the subsequent enzymatic hydrolysis with the prior addition of 0.75 mM of iron(II increased the glucose production to 56.3% from 46.3% in the control (iron-free acid. The detailed analysis indicated that conducting the process at lower temperatures yet long residence times benefits the yield of sugars. The above kinetic modelling results of Fe2+ accelerating all four reactions are in line with our previous mechanistic research showing that the pretreatment likely targets multiple chemistries in plant cell wall polymer networks, including those represented by the C�

Honokiol inhibits pathological retinal neovascularization in oxygen-induced retinopathy mouse model

Energy Technology Data Exchange (ETDEWEB)

Vavilala, Divya Teja [Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, MO (United States); O’Bryhim, Bliss E. [Department of Ophthalmology, University of Kansas Medical Center, Kansas City, KS (United States); Ponnaluri, V.K. Chaithanya [Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, MO (United States); White, R. Sid; Radel, Jeff [Department of Ophthalmology, University of Kansas Medical Center, Kansas City, KS (United States); Symons, R.C. Andrew [Department of Ophthalmology, University of Kansas Medical Center, Kansas City, KS (United States); Ophthalmology Department, Royal Melbourne Hospital, University of Melbourne, Victoria (Australia); Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Victoria (Australia); Mukherji, Mridul, E-mail: mukherjim@umkc.edu [Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, MO (United States)

2013-09-06

Highlights: •Aberrant activation of HIF pathway is the underlying cause of ischemic neovascularization. •Honokiol has better therapeutic index as a HIF inhibitor than digoxin and doxorubicin. •Daily IP injection of honokiol in OIR mouse model reduced retinal neovascularization. •Honokiol also prevents vaso-obliteration, the characteristic feature of the OIR model. •Honokiol enhanced physiological revascularization of the retinal vascular plexuses. -- Abstract: Aberrant activation of the hypoxia inducible factor (HIF) pathway is the underlying cause of retinal neovascularization, one of the most common causes of blindness worldwide. The HIF pathway also plays critical roles during tumor angiogenesis and cancer stem cell transformation. We have recently shown that honokiol is a potent inhibitor of the HIF pathway in a number of cancer and retinal pigment epithelial cell lines. Here we evaluate the safety and efficacy of honokiol, digoxin, and doxorubicin, three recently identified HIF inhibitors from natural sources. Our studies show that honokiol has a better safety to efficacy profile as a HIF inhibitor than digoxin and doxorubicin. Further, we show for the first time that daily intraperitoneal injection of honokiol starting at postnatal day (P) 12 in an oxygen-induced retinopathy (OIR) mouse model significantly reduced retinal neovascularization at P17. Administration of honokiol also prevents the oxygen-induced central retinal vaso-obliteration, characteristic feature of the OIR model. Additionally, honokiol enhanced physiological revascularization of the retinal vascular plexuses. Since honokiol suppresses multiple pathways activated by HIF, in addition to the VEGF signaling, it may provide advantages over current treatments utilizing specific VEGF antagonists for ocular neovascular diseases and cancers.

Study on the protective effect of ethyl pyruvate on mouse models of sepsis-induced lung injury

International Nuclear Information System (INIS)

Ti Dongdong; Deng Zihui; Xue Hui; Wang Luhuan; Lin Ji; Yan Guangtao

2008-01-01

Objective: To investigate the protective role of ethyl pyruvate on mouse models of lung injury from sepsis. Methods: Mouse sepsis models were established by cecal ligation-perforation. Four enzyme parameters related to synthesis of free radicals in lung homogenized fluids namely malonaldehyde (MDA), pyruvate acid, lactic acid and total anti-oxidative capacity (TAOC) were determined with spectrophotometry, and serum leptin levels were detected with radioimmunoassay at 3, 6, 9, 12h after operation in these models. Half of the models were treated with intraperitoneal injection of ethyl pyruvate (EP) (75mg/kg). Results: In the models treated with ethyl pyruvate injection, the activity of malonaldehyde, pyruvate acid, lactic acid and total anti-oxidative capacity were affected to certain extent, at some time frames but the results were not unanimously inhibitive or promotive. Serum leptin levels in EP injection models at 6h and 12h after sepsis were significantly higher than those in non-treated models. Conclusion: Ethyl pyruvate perhaps exerted its protective effect on sepsis-induced lung injury through increase of leptin levels in the models. (authors)

Dry ice blasting as a substitution for the conventional electroplating pre-treatments

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Uhlmann Eckart

2016-01-01

Full Text Available For high quality electroplated products, surfaces must be thoroughly pre-treated. For this purpose electroplating currently needs a variety of chemical baths. The used chemicals are injurious to health and harmful to the environment. In addition, the conventional pre-treatment has a long process time which results in high costs. Dry ice blasting alone or in combination with other processes has the potential to completely substitute these conventional pre-treatment processes. Three process sequences as pre-treatment methods prior to electroplating were investigated on the aluminium alloys AlSi12 and AlMg3. The used processes are dry ice blasting, tempering during dry ice blasting and glass bead blasting followed by dry ice blasting. The influence of the parameters on the surface roughness, surface topography and surface tension of the workpieces was examined. A model to describe the correlation between the dry ice blasting parameters and surface parameters was developed. Finally, an adhesion test of electroplated specimen was conducted in order to determine the suitability of these alternative pre-treatment processes.

Diabetic mouse model of orthopaedic implant-related Staphylococcus aureus infection.

Science.gov (United States)

Lovati, Arianna B; Drago, Lorenzo; Monti, Lorenzo; De Vecchi, Elena; Previdi, Sara; Banfi, Giuseppe; Romanò, Carlo L

2013-01-01

Periprosthetic bacterial infections represent one of the most challenging orthopaedic complications that often require implant removal and surgical debridement and carry high social and economical costs. Diabetes is one of the most relevant risk factors of implant-related infection and its clinical occurrence is growing worldwide. The aim of the present study was to test a model of implant-related infection in the diabetic mouse, with a view to allow further investigation on the relative efficacy of prevention and treatment options in diabetic and non-diabetic individuals. A cohort of diabetic NOD/ShiLtJ mice was compared with non-diabetic CD1 mice as an in vivo model of S. aureus orthopaedic infection of bone and soft tissues after femur intramedullary pin implantation. We tested control and infected groups with 1×10(3) colony-forming units of S. aureus ATCC 25923 strain injected in the implant site. At 4 weeks post-inoculation, host response to infection, microbial biofilm formation, and bone damage were assessed by traditional diagnostic parameters (bacterial culture, C-reactive protein and white blood cell count), histological analysis and imaging techniques (micro computed tomography and scanning electron microscopy). Unlike the controls and the CD1 mice, all the diabetic mice challenged with a single inoculum of S. aureus displayed severe osteomyelitic changes around the implant. Our findings demonstrate for the first time that the diabetic mouse can be successfully used in a model of orthopaedic implant-related infection. Furthermore, the same bacteria inoculum induced periprosthetic infection in all the diabetic mice but not in the controls. This animal model of implant-related infection in diabetes may be a useful tool to test in vivo treatments in diabetic and non-diabetic individuals.

Diabetic mouse model of orthopaedic implant-related Staphylococcus aureus infection.

Directory of Open Access Journals (Sweden)

Arianna B Lovati

Full Text Available BACKGROUND: Periprosthetic bacterial infections represent one of the most challenging orthopaedic complications that often require implant removal and surgical debridement and carry high social and economical costs. Diabetes is one of the most relevant risk factors of implant-related infection and its clinical occurrence is growing worldwide. The aim of the present study was to test a model of implant-related infection in the diabetic mouse, with a view to allow further investigation on the relative efficacy of prevention and treatment options in diabetic and non-diabetic individuals. METHODOLOGY: A cohort of diabetic NOD/ShiLtJ mice was compared with non-diabetic CD1 mice as an in vivo model of S. aureus orthopaedic infection of bone and soft tissues after femur intramedullary pin implantation. We tested control and infected groups with 1×10(3 colony-forming units of S. aureus ATCC 25923 strain injected in the implant site. At 4 weeks post-inoculation, host response to infection, microbial biofilm formation, and bone damage were assessed by traditional diagnostic parameters (bacterial culture, C-reactive protein and white blood cell count, histological analysis and imaging techniques (micro computed tomography and scanning electron microscopy. RESULTS: Unlike the controls and the CD1 mice, all the diabetic mice challenged with a single inoculum of S. aureus displayed severe osteomyelitic changes around the implant. CONCLUSIONS: Our findings demonstrate for the first time that the diabetic mouse can be successfully used in a model of orthopaedic implant-related infection. Furthermore, the same bacteria inoculum induced periprosthetic infection in all the diabetic mice but not in the controls. This animal model of implant-related infection in diabetes may be a useful tool to test in vivo treatments in diabetic and non-diabetic individuals.

Dynamic changes in the distribution and time course of blood-brain barrier-permeative nitroxides in the mouse head with EPR imaging: visualization of blood flow in a mouse model of ischemia.

Science.gov (United States)

Emoto, Miho C; Sato-Akaba, Hideo; Hirata, Hiroshi; Fujii, Hirotada G

2014-09-01

Electron paramagnetic resonance (EPR) imaging using nitroxides as redox-sensitive probes is a powerful, noninvasive method that can be used under various physiological conditions to visualize changes in redox status that result from oxidative damage. Two blood-brain barrier-permeative nitroxides, 3-hydroxymethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (HMP) and 3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-yloxy (MCP), have been widely used as redox-sensitive probes in the brains of small animals, but their in vivo distribution and properties have not yet been analyzed in detail. In this study, a custom-made continuous-wave three-dimensional (3D) EPR imager was used to obtain 3D EPR images of mouse heads using MCP or HMP. This EPR imager made it possible to take 3D EPR images reconstructed from data from 181 projections acquired every 60s. Using this improved EPR imager and magnetic resonance imaging, the distribution and reduction time courses of HMP and MCP were examined in mouse heads. EPR images of living mice revealed that HMP and MCP have different distributions and different time courses for entering the brain. Based on the pharmacokinetics of the reduction reactions of HMP and MCP in the mouse head, the half-lives of HMP and MCP were clearly and accurately mapped pixel by pixel. An ischemic mouse model was prepared, and the half-life of MCP was mapped in the mouse head. Compared to the half-life in control mice, the half-life of MCP in the ischemic model mouse brain was significantly increased, suggesting a shift in the redox balance. This in vivo EPR imaging method using BBB-permeative MCP is a useful noninvasive method for assessing changes in the redox status in mouse brains under oxidative stress. Copyright © 2014 Elsevier Inc. All rights reserved.

Mouse Models for Pendrin-Associated Loss of Cochlear and Vestibular Function

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Philine Wangemann

2013-12-01

Full Text Available The human gene SLC26A4 and the mouse ortholog Slc26a4 code for the protein pendrin, which is an anion exchanger expressed in apical membranes of selected epithelia. In the inner ear, pendrin is expressed in the cochlea, the vestibular labyrinth and the endolymphatic sac. Loss-of-function and hypo-functional mutations cause an enlargement of the vestibular aqueduct (EVA and sensorineural hearing loss. The relatively high prevalence of SLC26A4 mutations provides a strong imperative to develop rational interventions that delay, ameliorate or prevent pendrin-associated loss of cochlear and vestibular function. This review summarizes recent studies in mouse models that have been developed to delineate the role of pendrin in the physiology of hearing and balance and that have brought forward the concept that a temporally and spatially limited therapy may be sufficient to secure a life-time of normal hearing in children bearing mutations of SLC26A4.

Cardiac remodeling in the mouse model of Marfan syndrome develops into two distinctive phenotypes.

Science.gov (United States)

Tae, Hyun-Jin; Petrashevskaya, Natalia; Marshall, Shannon; Krawczyk, Melissa; Talan, Mark

2016-01-15

Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by mutations in fibrillin-1. Cardiac dysfunction in MFS has not been characterized halting the development of therapies of cardiac complication in MFS. We aimed to study the age-dependent cardiac remodeling in the mouse model of MFS FbnC1039G+/- mouse [Marfan heterozygous (HT) mouse] and its association with valvular regurgitation. Marfan HT mice of 2-4 mo demonstrated a mild hypertrophic cardiac remodeling with predominant decline of diastolic function and increased transforming growth factor-β canonical (p-SMAD2/3) and noncanonical (p-ERK1/2 and p-p38 MAPK) signaling and upregulation of hypertrophic markers natriuretic peptides atrium natriuretic peptide and brain natriuretic peptide. Among older HT mice (6-14 mo), cardiac remodeling was associated with two distinct phenotypes, manifesting either dilated or constricted left ventricular chamber. Dilatation of left ventricular chamber was accompanied by biochemical evidence of greater mechanical stress, including elevated ERK1/2 and p38 MAPK phosphorylation and higher brain natriuretic peptide expression. The aortic valve regurgitation was registered in 20% of the constricted group and 60% of the dilated group, whereas mitral insufficiency was observed in 40% of the constricted group and 100% of the dilated group. Cardiac dysfunction was not associated with the increase of interstitial fibrosis and nonmyocyte proliferation. In the mouse model fibrillin-1, haploinsufficiency results in the early onset of nonfibrotic hypertrophic cardiac remodeling and dysfunction, independently from valvular abnormalities. MFS heart is vulnerable to stress-induced cardiac dilatation in the face of valvular regurgitation, and stress-activated MAPK signals represent a potential target for cardiac management in MFS.

Kinetic modeling of multi-feed simultaneous saccharification and co-fermentation of pretreated birch to ethanol.

Science.gov (United States)

Wang, Ruifei; Koppram, Rakesh; Olsson, Lisbeth; Franzén, Carl Johan

2014-11-01

Fed-batch simultaneous saccharification and fermentation (SSF) is a feasible option for bioethanol production from lignocellulosic raw materials at high substrate concentrations. In this work, a segregated kinetic model was developed for simulation of fed-batch simultaneous saccharification and co-fermentation (SSCF) of steam-pretreated birch, using substrate, enzymes and cell feeds. The model takes into account the dynamics of the cellulase-cellulose system and the cell population during SSCF, and the effects of pre-cultivation of yeast cells on fermentation performance. The model was cross-validated against experiments using different feed schemes. It could predict fermentation performance and explain observed differences between measured total yeast cells and dividing cells very well. The reproducibility of the experiments and the cell viability were significantly better in fed-batch than in batch SSCF at 15% and 20% total WIS contents. The model can be used for simulation of fed-batch SSCF and optimization of feed profiles. Copyright © 2014 Elsevier Ltd. All rights reserved.

Teratology studies in the mouse.

Science.gov (United States)

Marsden, Edward; Leroy, Mariline

2013-01-01

The rat is the routine species of choice as the rodent model for regulatory safety testing of xenobiotics such as medicinal products, food additives, and other chemicals. However, the rat is not always suitable for pharmacological, toxicological, immunogenic, pharmacokinetic, or even practical reasons. Under such circumstances, the mouse offers an alternative for finding a suitable rodent model acceptable to the regulatory authorities. Since all essential routes of administration are possible, the short reproductive cycle and large litter size of the mouse make it a species well adapted for use in teratology studies. Given that good quality animals, including virgin mated females, can be acquired relatively easily and inexpensively, the mouse has been used in reproductive toxicity studies for decades and study protocols are well established.

Using a Novel Transgenic Mouse Model to Study c-Myc Oncogenic Pathway in Castration Resistance and Chemoresistance of Prostate Cancer

Science.gov (United States)

2017-12-01

AWARD NUMBER: W81XWH-13-1-0162 TITLE: Using a Novel Transgenic Mouse Model to Study c -Myc Oncogenic Pathway in Castration Resistance and...DATES COVERED 15Sept2013 - 14Sept2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Using a Novel Transgenic Mouse Model to Study c -Myc Oncogenic...ABSTRACT We previously made a PB-Cre4/Ai-Myc model for Cre-induced and androgen-independent expression of c -Myc and Luc2 in prostate. This is designed

Thermogravimetric study and kinetic analysis of fungal pretreated corn stover using the distributed activation energy model.

Science.gov (United States)

Ma, Fuying; Zeng, Yelin; Wang, Jinjin; Yang, Yang; Yang, Xuewei; Zhang, Xiaoyu

2013-01-01

Non-isothermal thermogravimetry/derivative thermogravimetry (TG/DTG) measurements are used to determine pyrolytic characteristics and kinetics of lignocellulose. TG/DTG experiments at different heating rates with corn stover pretreated with monocultures of Irpex lacteus CD2 and Auricularia polytricha AP and their cocultures were conducted. Heating rates had little effect on the pyrolysis process, but the peak of weight loss rate in the DTG curves shifted towards higher temperature with heating rate. The maximum weight loss of biopretreated samples was 1.25-fold higher than that of the control at the three heating rates, and the maximum weight loss rate of the co-culture pretreated samples was intermediate between that of the two mono-cultures. The activation energies of the co-culture pretreated samples were 16-72 kJ mol(-1) lower than that of the mono-culture at the conversion rate range from 10% to 60%. This suggests that co-culture pretreatment can decrease activation energy and accelerate pyrolysis reaction thus reducing energy consumption. Copyright © 2012 Elsevier Ltd. All rights reserved.

Transient receptor potential ankyrin 1 activation enhances hapten sensitization in a T-helper type 2-driven fluorescein isothiocyanate-induced contact hypersensitivity mouse model

International Nuclear Information System (INIS)

Shiba, Takahiro; Tamai, Takuma; Sahara, Yurina; Kurohane, Kohta; Watanabe, Tatsuo; Imai, Yasuyuki

2012-01-01

Some chemicals contribute to the development of allergies by increasing the immunogenicity of other allergens. We have demonstrated that several phthalate esters, including dibutyl phthalate (DBP), enhance skin sensitization to fluorescein isothiocyanate (FITC) in a mouse contact hypersensitivity model, in which the T-helper type 2 (Th2) response is essential. On the other hand, some phthalate esters were found to activate transient receptor potential ankyrin 1 (TRPA1) cation channels on sensory neurons. We then found a positive correlation between the enhancing effects of several types of phthalate esters on skin sensitization to FITC and their ability to activate TRPA1. Here we examined the involvement of TRPA1 in sensitization to FITC by using TRPA1 agonists other than phthalate esters. During skin sensitization to FITC, the TRPA1 agonists (menthol, carvacrol, cinnamaldehyde and DBP) augmented the ear-swelling response as well as trafficking of FITC-presenting dendritic cells to draining lymph nodes. We confirmed that these TRPA1 agonists induced calcium influx into TRPA1-expressing Chinese hamster ovary (CHO) cells. We also found that TRPA1 antagonist HC-030031 inhibited DBP-induced calcium influx into TRPA1-expressing CHO cells. After pretreatment with this antagonist upon skin sensitization to FITC, the enhancing effect of DBP on sensitization was suppressed. These results suggest that TRPA1 activation will become a useful marker to find chemicals that facilitate sensitization in combination with other immunogenic haptens. -- Highlights: ► Role of TRPA1 activation was revealed in a mouse model of skin sensitization to FITC. ► TRPA1 agonists enhanced skin sensitization as well as dendritic cell trafficking. ► Dibutyl phthalate (DBP) has been shown to enhance skin sensitization to FITC. ► TRPA1 activation by DBP was inhibited by a selective antagonist, HC-030031. ► HC-030031 inhibited the enhancing effect of DBP on skin sensitization to FITC.

Transient receptor potential ankyrin 1 activation enhances hapten sensitization in a T-helper type 2-driven fluorescein isothiocyanate-induced contact hypersensitivity mouse model

Energy Technology Data Exchange (ETDEWEB)

Shiba, Takahiro; Tamai, Takuma; Sahara, Yurina; Kurohane, Kohta [Laboratory of Microbiology and Immunology, School of Pharmaceutical Sciences, University of Shizuoka, 52‐1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422‐8526 (Japan); Watanabe, Tatsuo [Laboratory of Food Chemistry, School of Food and Nutritional Sciences, University of Shizuoka, 52‐1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422‐8526 (Japan); Imai, Yasuyuki, E-mail: imai@u-shizuoka-ken.ac.jp [Laboratory of Microbiology and Immunology, School of Pharmaceutical Sciences, University of Shizuoka, 52‐1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422‐8526 (Japan)

2012-11-01

Some chemicals contribute to the development of allergies by increasing the immunogenicity of other allergens. We have demonstrated that several phthalate esters, including dibutyl phthalate (DBP), enhance skin sensitization to fluorescein isothiocyanate (FITC) in a mouse contact hypersensitivity model, in which the T-helper type 2 (Th2) response is essential. On the other hand, some phthalate esters were found to activate transient receptor potential ankyrin 1 (TRPA1) cation channels on sensory neurons. We then found a positive correlation between the enhancing effects of several types of phthalate esters on skin sensitization to FITC and their ability to activate TRPA1. Here we examined the involvement of TRPA1 in sensitization to FITC by using TRPA1 agonists other than phthalate esters. During skin sensitization to FITC, the TRPA1 agonists (menthol, carvacrol, cinnamaldehyde and DBP) augmented the ear-swelling response as well as trafficking of FITC-presenting dendritic cells to draining lymph nodes. We confirmed that these TRPA1 agonists induced calcium influx into TRPA1-expressing Chinese hamster ovary (CHO) cells. We also found that TRPA1 antagonist HC-030031 inhibited DBP-induced calcium influx into TRPA1-expressing CHO cells. After pretreatment with this antagonist upon skin sensitization to FITC, the enhancing effect of DBP on sensitization was suppressed. These results suggest that TRPA1 activation will become a useful marker to find chemicals that facilitate sensitization in combination with other immunogenic haptens. -- Highlights: ► Role of TRPA1 activation was revealed in a mouse model of skin sensitization to FITC. ► TRPA1 agonists enhanced skin sensitization as well as dendritic cell trafficking. ► Dibutyl phthalate (DBP) has been shown to enhance skin sensitization to FITC. ► TRPA1 activation by DBP was inhibited by a selective antagonist, HC-030031. ► HC-030031 inhibited the enhancing effect of DBP on skin sensitization to FITC.

Drug Partitioning in Micellar Media and Its Implications in Rational Drug Design: Insights with Streptomycin.

Science.gov (United States)

Judy, Eva; Pagariya, Darshna; Kishore, Nand

2018-03-20

Oral bioavailability of a drug molecule requires its effective delivery to the target site. In general, majority of synthetically developed molecular entities have high hydrophobic nature as well as low bioavailability, therefore the need for suitable delivery vehicles arises. Self-assembled structures such as micelles, niosomes, and liposomes have been used as effective delivery vehicles and studied extensively. However, the information available in literature is mostly qualitative in nature. We have quantitatively investigated the partitioning of antibiotic drug streptomycin into cationic, nonionic, and a mixture of cationic and nonionic surfactant micelles and its interaction with the transport protein serum albumin upon subsequent delivery. A combination of calorimetry and spectroscopy has been used to obtain the thermodynamic signatures associated with partitioning and interaction with the protein and the resulting conformational changes in the latter. The results have been correlated with other class of drugs of different nature to understand the role of molecular features in the partitioning process. These studies are oriented toward understanding the physical chemistry of partitioning of a variety of drug molecules into suitable delivery vehicles and hence establishing structure-property-energetics relationships. Such studies provide general guidelines toward a broader goal of rational drug design.

Novel mouse model of chronic Pseudomonas aeruginosa lung infection mimicking cystic fibrosis

DEFF Research Database (Denmark)

Hoffmann, Nadine; Rasmussen, Thomas Bovbjerg; Jensen, Peter Østrup

2005-01-01

(NH57388C) from the mucoid isolate (NH57388A) and a nonmucoid isolate (NH57388B) deficient in AHL were almost cleared from the lungs of the mice. This model, in which P. aeruginosa is protected against the defense system of the lung by alginate, is similar to the clinical situation. Therefore...... pulmonary mouse model without artificial embedding. The model is based on a stable mucoid CF sputum isolate (NH57388A) with hyperproduction of alginate due to a deletion in mucA and functional N-acylhomoserine lactone (AHL)-based quorum-sensing systems. Chronic lung infection could be established in both CF...

Development of a metastatic fluorescent Lewis Lung carcinoma mouse model

DEFF Research Database (Denmark)

Rask, Lene; Fregil, Marianne; Høgdall, Estrid

2013-01-01

Cancer metastasis is the foremost cause of death in cancer patients. A series of observable pathological changes takes place during progression and metastasis of cancer, but the underlying genetic changes remain unclear. Therefore, new approaches are required, including insights from cancer mouse...... and the model is well suited for the identification of novel microRNAs and mRNAs involved in malignant progression. Our results suggest that increases in metalloproteinase expression and impairment of microRNA processing are involved in the acquirement of metastatic ability....

Mouse genetic model for clinical and immunological heterogeneity of leishmaniasis

Czech Academy of Sciences Publication Activity Database

Lipoldová, Marie; Svobodová, M.; Havelková, Helena; Krulová, Magdalena; Badalová, Jana; Nohýnková, E.; Hart, A. A. M.; Schlegel, David; Volf, P.; Demant, P.

2002-01-01

Roč. 54, č. 3 (2002), s. 174-183 ISSN 0093-7711 R&D Projects: GA MZd NM28; GA ČR GA310/00/0760; GA MŠk OK 394 Grant - others:Howard Hughes Medical Institute(US) HHMI55000323; WHO(XX) TDR I.D. 970772; EC(XE) ERBI-C15-CT98-0317; EC(XE) BIO-4-CT98-0445 Institutional research plan: CEZ:AV0Z5052915 Keywords : Leishmaniasis * mouse model * complex disease Subject RIV: EC - Immunology Impact factor: 2.475, year: 2002

Transgenic Mouse Models Transferred into the Test Tube: New Perspectives for Developmental Toxicity Testing In Vitro?

Science.gov (United States)

Kugler, Josephine; Luch, Andreas; Oelgeschläger, Michael

2016-10-01

Despite our increasing understanding of molecular mechanisms controlling embryogenesis, the identification and characterization of teratogenic substances still heavily relies on animal testing. Embryonic development depends on cell-autonomous and non-autonomous processes including spatiotemporally regulated extracellular signaling activities. These have been elucidated in transgenic mouse models harboring easily detectable reporter genes under the control of evolutionarily conserved signaling cascades. We propose combining these transgenic mouse models and cells derived thereof with existing alternative toxicological testing strategies. This would enable the plausibility of in vitro data to be verified in light of in vivo data and, ultimately, facilitate regulatory acceptance of in vitro test methods. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Contribution of microbiologists of Kirov City to development of penicillin and streptomycin production processes (70 years since development of technology for submerged production of first domestic antibiotics)].

Science.gov (United States)

Bakulin, M K; Tumanov, A S; Bakulin, V M; Kalininskiĭ, V B

2014-01-01

The publication is concerned with development of the technological processes for submered production of the first domestic antibiotics 70 years age. The literature data on the contribution of the microbiologists of the Kirov City and mainly the workers of the Red Army Research Institute of Epidemiology and Hygiene (nowadays Central Research Institute No. 48 of the Ministry of Defense of the Russian Federation, Kirov), to development of the manufacture processes for production of penicillin and streptomycin are reviewed.

The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease.

Science.gov (United States)

Beaumont, Vahri; Mrzljak, Ladislav; Dijkman, Ulrike; Freije, Robert; Heins, Mariette; Rassoulpour, Arash; Tombaugh, Geoffrey; Gelman, Simon; Bradaia, Amyaouch; Steidl, Esther; Gleyzes, Melanie; Heikkinen, Taneli; Lehtimäki, Kimmo; Puoliväli, Jukka; Kontkanen, Outi; Javier, Robyn M; Neagoe, Ioana; Deisemann, Heike; Winkler, Dirk; Ebneth, Andreas; Khetarpal, Vinod; Toledo-Sherman, Leticia; Dominguez, Celia; Park, Larry C; Munoz-Sanjuan, Ignacio

2016-08-01

Dysregulation of the kynurenine (Kyn) pathway has been associated with the progression of Huntington's disease (HD). In particular, elevated levels of the kynurenine metabolites 3-hydroxy kynurenine (3-OH-Kyn) and quinolinic acid (Quin), have been reported in the brains of HD patients as well as in rodent models of HD. The production of these metabolites is controlled by the activity of kynurenine mono-oxygenase (KMO), an enzyme which catalyzes the synthesis of 3-OH-Kyn from Kyn. In order to determine the role of KMO in the phenotype of mouse models of HD, we have developed a potent and selective KMO inhibitor termed CHDI-340246. We show that this compound, when administered orally to transgenic mouse models of HD, potently and dose-dependently modulates the Kyn pathway in peripheral tissues and in the central nervous system. The administration of CHDI-340246 leads to an inhibition of the formation of 3-OH-Kyn and Quin, and to an elevation of Kyn and Kynurenic acid (KynA) levels in brain tissues. We show that administration of CHDI-340246 or of Kyn and of KynA can restore several electrophysiological alterations in mouse models of HD, both acutely and after chronic administration. However, using a comprehensive panel of behavioral tests, we demonstrate that the chronic dosing of a selective KMO inhibitor does not significantly modify behavioral phenotypes or natural progression in mouse models of HD. Copyright © 2016. Published by Elsevier Inc.

Protective effects of resveratrol on ethanol-induced apoptosis in embryonic stem cells and disruption of embryonic development in mouse blastocysts

International Nuclear Information System (INIS)

Huang, L.-H.; Shiao, N.-H.; Hsuuw, Y.-D.; Chan, W.-H.

2007-01-01

Previous studies have established that ethanol induces apoptosis, but the precise molecular mechanisms are currently unclear. Here, we show that 0.3-1.0% (w/v) ethanol induces apoptosis in mouse blastocysts and that resveratrol, a grape-derived phytoalexin with known antioxidant and anti-inflammatory properties, prevents ethanol-induced apoptosis and inhibition of cell proliferation. Moreover, ethanol-treated blastocysts show normal levels of implantation on culture dishes in vitro but a reduced ability to reach the later stages of embryonic development. Pretreatment with resveratrol prevented ethanol-induced disruption of embryonic development in vitro and in vivo. In an in vitro cell-based assay, we further found that ethanol increases the production of reactive oxygen species in ESC-B5 embryonic stem cells, leading to an increase in the intracellular concentrations of cytoplasmic free Ca 2+ and NO, loss of mitochondrial membrane potential, mitochondrial release of cytochrome c, activation of caspase-9 and -3, and apoptosis. These changes were blocked by pretreatment with resveratrol. Based on these results, we propose a model for the protective effect of resveratrol on ethanol-induced cell injury in blastocysts and ESC-B5 cells

Reducing biomass recalcitrance via mild sodium carbonate pretreatment.

Science.gov (United States)

Mirmohamadsadeghi, Safoora; Chen, Zhu; Wan, Caixia

2016-06-01

This study examined the effects of mild sodium carbonate (Na2CO3) pretreatment on enzymatic hydrolysis of different feedstocks (i.e., corn stover, Miscanthus, and switchgrass). The results showed that sodium carbonate pretreatment markedly enhanced the sugar yields of the tested biomass feedstocks. The pretreated corn stover, Miscanthus, and switchgrass gave the glucose yields of 95.1%, 62.3%, and 81.3%, respectively, after enzymatic hydrolysis. The above glucose yields of pretreated feedstocks were 2-4 times that of untreated ones. The pretreatment also enhanced the xylose yields, 4 times for corn stover and 20 times for both Miscanthus and switchgrass. Sodium carbonate pretreatment removed 40-59% lignin from the tested feedstocks while preserving most of cellulose (sodium carbonate pretreatment was effective for reducing biomass recalcitrance and subsequently improving the digestibility of lignocellulosic biomass. Copyright © 2016 Elsevier Ltd. All rights reserved.

mouseTube – a database to collaboratively unravel mouse ultrasonic communication [version 1; referees: 2 approved

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Nicolas Torquet

2016-09-01

Full Text Available Ultrasonic vocalisation is a broadly used proxy to evaluate social communication in mouse models of neuropsychiatric disorders. The efficacy and robustness of testing these models suffer from limited knowledge of the structure and functions of these vocalisations as well as of the way to analyse the data. We created mouseTube, an open database with a web interface, to facilitate sharing and comparison of ultrasonic vocalisations data and metadata attached to a recording file. Metadata describe 1 the acquisition procedure, e.g., hardware, software, sampling frequency, bit depth; 2 the biological protocol used to elicit ultrasonic vocalisations; 3 the characteristics of the individual emitting ultrasonic vocalisations (e.g., strain, sex, age. To promote open science and enable reproducibility, data are made freely available. The website provides searching functions to facilitate the retrieval of recording files of interest. It is designed to enable comparisons of ultrasonic vocalisation emission between strains, protocols or laboratories, as well as to test different analysis algorithms and to search for protocols established to elicit mouse ultrasonic vocalisations. Over the long term, users will be able to download and compare different analysis results for each data file. Such application will boost the knowledge on mouse ultrasonic communication and stimulate sharing and comparison of automatic analysis methods to refine phenotyping techniques in mouse models of neuropsychiatric disorders.

The landscape of chromosomal aberrations in breast cancer mouse models reveals driver-specific routes to tumorigenesis

NARCIS (Netherlands)

Ben-David, Uri; Ha, Gavin; Khadka, Prasidda; Jin, Xin; Wong, Bang; Franke, Lude; Golub, Todd R.

Aneuploidy and copy-number alterations (CNAs) are a hallmark of human cancer. Although genetically engineered mouse models (GEMMs) are commonly used to model human cancer, their chromosomal landscapes remain underexplored. Here we use gene expression profiles to infer CNAs in 3,108 samples from 45

Mathematical modeling of drying of pretreated and untreated pumpkin

OpenAIRE

Tunde-Akintunde, T. Y.; Ogunlakin, G. O.

2011-01-01

In this study, drying characteristics of pretreated and untreated pumpkin were examined in a hot-air dryer at air temperatures within a range of 40–80 °C and a constant air velocity of 1.5 m/s. The drying was observed to be in the falling-rate drying period and thus liquid diffusion is the main mechanism of moisture movement from the internal regions to the product surface. The experimental drying data for the pumpkin fruits were used to fit Exponential, General exponential, Logarithmic, Page...

Genotypic and phenotypic characterization of the Sdccag8Tn(sb-Tyr2161B.CA1C2Ove mouse model.

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Katie Weihbrecht

Full Text Available Nephronophthisis-related ciliopathies (NPHP-RC are a group of disorders that present with end-stage renal failure in childhood/adolescence, kidney cysts, retinal degeneration, and cerebellar hypoplasia. One disorder that shares clinical features with NPHP-RC is Bardet-Biedl Syndrome (BBS. Serologically defined colon cancer antigen 8 (SDCCAG8; also known as NPHP10 and BBS16 is an NPHP gene that is also associated with BBS. To better understand the patho-mechanisms of NPHP and BBS caused by loss of SDCCAG8 function, we characterized an SDCCAG8 mouse model (Sdccag8Tn(sb-Tyr2161B.CA1C2Ove generated by Sleeping Beauty Transposon (SBT-mediated insertion mutagenesis. Consistent with the previously reported, independent SDCCAG8 mouse models, our mutant mice display pre-axial polydactyly in their hind limbs. In addition, we report patterning defects in the secondary palate, brain abnormalities, as well as neonatal lethality associated with developmental defects in the lung in our mouse model. The neonatal lethality phenotype is genetic background dependent and rescued by introducing 129S6/SvEvTac background. Genetic modifier(s responsible for this effect were mapped to a region between SNPs rs3714172 and rs3141832 on chromosome 11. While determining the precise genetic lesion in our mouse model, we found that SBT insertion resulted in a deletion of multiple exons from both Sdccag8 and its neighboring gene Akt3. We ascribe the patterning defects in the limb and the secondary palate as well as lung abnormalities to loss of SDCCAG8, while the developmental defects in the brain are likely due to the loss of AKT3. This mouse model may be useful to study features not observed in other SDCCAG8 models but cautions are needed in interpreting data.

Abnormal nuclear envelope in the cerebellar Purkinje cells and impaired motor learning in DYT11 myoclonus-dystonia mouse models

OpenAIRE

Yokoi, Fumiaki; Dang, Mai T.; Yang, Guang; Li, JinDong; Doroodchi, Atbin; Zhou, Tong; Li, Yuqing

2011-01-01

Myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonia. DYT11 M-D is caused by mutations in SGCE which codes for ε-sarcoglycan. SGCE is maternally imprinted and paternally expressed. Abnormal nuclear envelope has been reported in mouse models of DYT1 generalized torsion dystonia. However, it is not known whether similar alterations occur in DYT11 M-D. We developed a mouse model of DYT11 M-D using paternally-inherited Sgce heterozygous knockout (Sgce KO)...

The characteristic changes of betung bamboo (Dendrocalamus asper pretreated by fungal pretreatment

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Widya Fatriasari

2014-05-01

Full Text Available Normal 0 false false false IN X-NONE X-NONE MicrosoftInternetExplorer4 The fungal pretreatment effect on chemical structural and morphological changes of Betung Bamboo was evaluated based on its biomass components after being cultivated by white rot fungi, Trametes versicolor. Betung bamboo powder (15 g was exposed to liquid inoculum of white rot fungi and incubated at 270C for 15, 30 and 45 days. The treated samples were then characterized by FT-IR spectroscopy, X-Ray diffraction and SEM-EDS analyses. Cultivation for 30 days with 5 and 10% loadings retained greater selectivity compared to that of the other treatments. FTIR spectra demonstrated that the fungus affected the decreasing of functional group quantities without changing the functional groups. The decrease in intensity at wave number of 1246 cm-1 (guaiacyl of lignin was greater than that at wave number of 1328 cm-1 (deformation combination of syringyl and xylan after fungal treatment. X-ray analysis showed the pretreated samples had a higher crystallinity than the untreated ones which might be due to the cleavage of amorphous fractions of cellulose. The pretreated samples have more fragile than the untreated ones confirmed by SEM. Crystalline allomorph calculated by XRD analysis showed that fungus pretreatment for 30 days has transformed triclinic structure of cellulose to monoclinic structure.

Enhancement of cell-cell contact by a nonmitogenic lectin increases blastogenic response and IL-2 release by mitogen-stimulated mouse thymocytes.

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Favero, J; Marti, J; Dornand, J; Bonnafous, J C; Mani, J C

1986-03-01

We have examined the influence of peanut agglutinin (PNA), a lectin which agglutinates but does not stimulate mouse thymocytes, on the responsiveness of these cells to concanavalin A (Con A) or galactose oxidase stimulation. Binding low amounts of PNA on unseparated mouse thymocytes pretreated with neuraminidase highly enhances the mitogenic response and the level of interleukin 2 release in the culture medium upon Con A stimulation. We have shown that PNA present on the cell surface acts as a crosslinking agent which favors intercellular binding between accessory cells (macrophages) and thymocytes, leading through this enhanced cooperation by cell-cell contact to an enhanced blastogenic response.

A genetically engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high-grade serous carcinoma development.

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Sherman-Baust, Cheryl A; Kuhn, Elisabetta; Valle, Blanca L; Shih, Ie-Ming; Kurman, Robert J; Wang, Tian-Li; Amano, Tomokazu; Ko, Minoru S H; Miyoshi, Ichiro; Araki, Yoshihiko; Lehrmann, Elin; Zhang, Yongqing; Becker, Kevin G; Morin, Patrice J

2014-07-01

Recent evidence suggests that ovarian high-grade serous carcinoma (HGSC) originates from the epithelium of the fallopian tube. However, most mouse models are based on the previous prevailing view that ovarian cancer develops from the transformation of the ovarian surface epithelium. Here, we report the extensive histological and molecular characterization of the mogp-TAg transgenic mouse, which expresses the SV40 large T-antigen (TAg) under the control of the mouse müllerian-specific Ovgp-1 promoter. Histological analysis of the fallopian tubes of mogp-TAg mice identified a variety of neoplastic lesions analogous to those described as precursors to ovarian HGSC. We identified areas of normal-appearing p53-positive epithelium that are similar to 'p53 signatures' in the human fallopian tube. More advanced proliferative lesions with nuclear atypia and epithelial stratification were also identified that were morphologically and immunohistochemically reminiscent of human serous tubal intraepithelial carcinoma (STIC), a potential precursor of ovarian HGSC. Beside these non-invasive precursor lesions, we also identified invasive adenocarcinoma in the ovaries of 56% of the mice. Microarray analysis revealed several genes differentially expressed between the fallopian tube of mogp-TAg and wild-type (WT) C57BL/6. One of these genes, Top2a, which encodes topoisomerase IIα, was shown by immunohistochemistry to be concurrently expressed with elevated p53 and was specifically elevated in mouse STICs but not in the surrounding tissues. TOP2A protein was also found elevated in human STICs, low-grade and high-grade serous carcinoma. The mouse model reported here displays a progression from normal tubal epithelium to invasive HGSC in the ovary, and therefore closely simulates the current emerging model of human ovarian HGSC pathogenesis. This mouse therefore has the potential to be a very useful new model for elucidating the mechanisms of serous ovarian tumourigenesis, as well as

αVβ6 integrin expression is induced in the POET and Ptenpc-/- mouse models of prostatic inflammation and prostatic adenocarcinoma

Science.gov (United States)

Garlick, David S; Li, Jing; Sansoucy, Brian; Wang, Tao; Griffith, Leeanne; FitzGerald, TJ; Butterfield, Julie; Charbonneau, Bridget; Violette, Shelia M; Weinreb, Paul H; Ratliff, Timothy L; Liao, Chun-Peng; Roy-Burman, Pradip; Vietri, Michele; Lian, Jane B; Stein, Gary S; Altieri, Dario C; Languino, Lucia R

2012-01-01

Chronic inflammation is proposed to prime the development of prostate cancer. However, the mechanisms of prostate cancer initiation and development are not completely understood. The αvβ6 integrin has been shown to play a role in epithelial development, wound healing and some epithelial cancers [1, 2]. Here, we investigate the expression of αvβ6 in mouse models of prostatic inflammation and prostate cancer to establish a possible relationship between inflammation of the prostate, αvβ6 expression and the progression of prostate cancer. Using immunohistochemical techniques, we show expression of αvβ6 in two in vivo mouse models; the Ptenpc-/- model containing a prostate- specific Pten tumor suppressor deletion that causes cancer, and the prostate ovalbumin-expressing transgenic (POET) inflammation mouse model. We show that the αvβ6 integrin is induced in prostate cancer and inflammation in vivo in these two mouse models. αvβ6 is expressed in all the mice with cancer in the Ptenpc-/- model but not in age-matched wild-type mice. In the POET inflammation model, αvβ6 is expressed in mice injected with activated T-cells, but in none of the control mice. In the POET model, we also used real time PCR to assess the expression of Transforming Growth Factor Beta 1 (TGFβ1), a factor in inflammation that is activated by αvβ6. In conclusion, through in vivo evidence, we conclude that αvβ6 integrin may be a crucial link between prostatic inflammation and prostatic adenocarcinoma. PMID:22611469

A mouse model of cytogenetic analysis to evaluate caesium137 radiation dose exposure and contamination level in lymphocytes

Energy Technology Data Exchange (ETDEWEB)

Roch-Lefevre, Sandrine; Martin-Bodiot, Cecile; Gregoire, Eric; Roy, Laurence [Institut de Radioprotection et de Surete Nucleaire (IRSN), Laboratoire de Dosimetrie Biologique (PRP-HOM/SRBE/LDB), Fontenay aux Roses Cedex (France); Desbree, Aurelie [Institut de Radioprotection et de Surete Nucleaire (IRSN), PRP-HOM/SDI, Laboratoire d' Evaluation de la Dose Interne, Fontenay aux Roses Cedex (France); Barquinero, Joan Francesc [Institut de Radioprotection et de Surete Nucleaire (IRSN), Laboratoire de Dosimetrie Biologique (PRP-HOM/SRBE/LDB), Fontenay aux Roses Cedex (France); Universitat Autonoma de Barcelona, Unitat d' Antropologia Biologica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Bellaterra (Spain)

2016-03-15

In case of external overexposure to ionizing radiation, an estimation of its genotoxic effects on exposed individuals can be made retrospectively by the measurement of radiation-induced chromosome aberrations on circulating lymphocytes. Compared with external irradiation, intakes of radionuclides may, however, lead to specific features influencing dose distribution at the scale of body, of tissue or even of cell. Therefore, in case of internal contamination by radionuclides, experimental studies, particularly using animal models, are required to better understand mechanisms of their genotoxic effects and to better estimate the absorbed dose. The present study was designed to evaluate a cytogenetic method in mouse peripheral blood lymphocytes that would allow determination of yields and complexities of chromosome aberrations after low-dose rate exposure to {sup 137}Cs delivered in vitro either by irradiation or by contamination. By using M-FISH analysis, we compared the low-dose rate responses observed in mouse to the high-dose rate responses observed both in mouse and in human. Promising similarities between the two species in the relative biological effect evaluation show that our cytogenetic model established in mouse might be useful to evaluate various radiation exposures, particularly relevant in case of intakes of radionuclides. (orig.)

Natural and molecular history of prolactinoma: insights from a Prlr-/- mouse model.

Science.gov (United States)

Bernard, Valérie; Villa, Chiara; Auguste, Aurélie; Lamothe, Sophie; Guillou, Anne; Martin, Agnès; Caburet, Sandrine; Young, Jacques; Veitia, Reiner A; Binart, Nadine

2018-01-19

Lactotroph adenoma, also called prolactinoma, is the most common pituitary tumor but little is known about its pathogenesis. Mouse models of prolactinoma can be useful to better understand molecular mechanisms involved in abnormal lactotroph cell proliferation and secretion. We have previously developed a prolactin receptor deficient ( Prlr -/- ) mouse, which develops prolactinoma. The present study aims to explore the natural history of prolactinoma formation in Prlr -/- mice, using hormonal, radiological, histological and molecular analyses to uncover mechanisms involved in lactotroph adenoma development. Prlr -/- females develop large secreting prolactinomas from 12 months of age, with a penetrance of 100%, mimicking human aggressive densely granulated macroprolactinoma, which is a highly secreting subtype. Mean blood PRL measurements reach 14 902 ng/mL at 24 months in Prlr -/- females while PRL levels were below 15 ng/mL in control mice ( p model in ACI rats, we pinpointed 218 concordantly differentially expressed (DE) genes involved in cell cycle, mitosis, cell adhesion molecules, dopaminergic synapse and estrogen signaling. Pathway/gene-set enrichment analyses suggest that the transcriptomic dysregulation in both models of prolactinoma might be mediated by a limited set of transcription factors (i.e., STAT5, STAT3, AhR, ESR1, BRD4, CEBPD, YAP, FOXO1) and kinases (i.e., JAK2, AKT1, BRAF, BMPR1A, CDK8, HUNK, ALK, FGFR1, ILK). Our experimental results and their bioinformatic analysis provide insights into early genomic changes in murine models of the most frequent human pituitary tumor.

A mouse model of alcoholic liver fibrosis-associated acute kidney injury identifies key molecular pathways

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Furuya, Shinji; Chappell, Grace A.; Iwata, Yasuhiro [Department of Veterinary Integrative Biosciences, Texas A& M University, College Station, TX (United States); Uehara, Takeki; Kato, Yuki [Laboratory of Veterinary Pathology, Osaka Prefecture University, Osaka (Japan); Kono, Hiroshi [First Department of Surgery, University of Yamanashi, Yamanashi (Japan); Bataller, Ramon [Division of Gastroenterology & Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, NC (United States); Rusyn, Ivan, E-mail: irusyn@tamu.edu [Department of Veterinary Integrative Biosciences, Texas A& M University, College Station, TX (United States)

2016-11-01

Clinical data strongly indicate that acute kidney injury (AKI) is a critical complication in alcoholic hepatitis, an acute-on-chronic form of liver failure in patients with advanced alcoholic fibrosis. Development of targeted therapies for AKI in this setting is hampered by the lack of an animal model. To enable research into molecular drivers and novel therapies for fibrosis- and alcohol-associated AKI, we aimed to combine carbon tetrachloride (CCl{sub 4})-induced fibrosis with chronic intra-gastric alcohol feeding. Male C57BL/6J mice were administered a low dose of CCl{sub 4} (0.2 ml/kg 2 × week/6 weeks) followed by alcohol intragastrically (up to 25 g/kg/day for 3 weeks) and with continued CCl{sub 4}. We observed that combined treatment with CCl{sub 4} and alcohol resulted in severe liver injury, more pronounced than using each treatment alone. Importantly, severe kidney injury was evident only in the combined treatment group. This mouse model reproduced distinct pathological features consistent with AKI in human alcoholic hepatitis. Transcriptomic analysis of kidneys revealed profound effects in the combined treatment group, with enrichment for damage-associated pathways, such as apoptosis, inflammation, immune-response and hypoxia. Interestingly, Havcr1 and Lcn2, biomarkers of AKI, were markedly up-regulated. Overall, this study established a novel mouse model of fibrosis- and alcohol-associated AKI and identified key mechanistic pathways. - Highlights: • Acute kidney injury (AKI) is a critical complication in alcoholic hepatitis • We developed a novel mouse model of fibrosis- and alcohol-associated AKI • This model reproduces key molecular and pathological features of human AKI • This animal model can help identify new targeted therapies for alcoholic hepatitis.

Glucosylceramide Administration as a Vaccination Strategy in Mouse Models of Cryptococcosis.

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Visesato Mor

Full Text Available Cryptococcus neoformans is an opportunistic fungal pathogen and the causative agent of the disease cryptococcosis. Cryptococcosis is initiated as a pulmonary infection and in conditions of immune deficiency disseminates to the blood stream and central nervous system, resulting in life-threatening meningoencephalitis. A number of studies have focused on the development of a vaccine against Cryptococcus, primarily utilizing protein-conjugated components of the Cryptococcus polysaccharide capsule as antigen. However, there is currently no vaccine against Cryptococcus in the clinic. Previous studies have shown that the glycosphingolipid, glucosylceramide (GlcCer, is a virulence factor in C. neoformans and antibodies against this lipid inhibit fungal growth and cell division. In the present study, we have investigated the possibility of using GlcCer as a therapeutic agent against C. neoformans infections in mouse models of cryptococcosis. GlcCer purified from a non-pathogenic fungus, Candida utilis, was administered intraperitoneally, prior to infecting mice with a lethal dose of C. neoformans. GlcCer administration prevented the dissemination of C. neoformans from the lungs to the brain and led to 60% mouse survival. GlcCer administration did not cause hepatic injury and elicited an anti-GlcCer antibody response, which was observed independent of the route of administration and the strains of mouse. Taken together, our results suggest that fungal GlcCer can protect mice against lethal doses of C. neoformans infection and can provide a viable vaccination strategy against Cryptococcus.

Glucosylceramide Administration as a Vaccination Strategy in Mouse Models of Cryptococcosis.

Science.gov (United States)

Mor, Visesato; Farnoud, Amir M; Singh, Ashutosh; Rella, Antonella; Tanno, Hiromasa; Ishii, Keiko; Kawakami, Kazuyoshi; Sato, Toshiya; Del Poeta, Maurizio

2016-01-01

Cryptococcus neoformans is an opportunistic fungal pathogen and the causative agent of the disease cryptococcosis. Cryptococcosis is initiated as a pulmonary infection and in conditions of immune deficiency disseminates to the blood stream and central nervous system, resulting in life-threatening meningoencephalitis. A number of studies have focused on the development of a vaccine against Cryptococcus, primarily utilizing protein-conjugated components of the Cryptococcus polysaccharide capsule as antigen. However, there is currently no vaccine against Cryptococcus in the clinic. Previous studies have shown that the glycosphingolipid, glucosylceramide (GlcCer), is a virulence factor in C. neoformans and antibodies against this lipid inhibit fungal growth and cell division. In the present study, we have investigated the possibility of using GlcCer as a therapeutic agent against C. neoformans infections in mouse models of cryptococcosis. GlcCer purified from a non-pathogenic fungus, Candida utilis, was administered intraperitoneally, prior to infecting mice with a lethal dose of C. neoformans. GlcCer administration prevented the dissemination of C. neoformans from the lungs to the brain and led to 60% mouse survival. GlcCer administration did not cause hepatic injury and elicited an anti-GlcCer antibody response, which was observed independent of the route of administration and the strains of mouse. Taken together, our results suggest that fungal GlcCer can protect mice against lethal doses of C. neoformans infection and can provide a viable vaccination strategy against Cryptococcus.