Compensatory Ability to Null Mutation in Metabolic Networks

Robustness is an inherent property of biological system. It is still a limited understanding of how it is accomplished at the cellular or molecular level. To this end, this article analyzes the impact degree of each reaction to others, which is defined as the number of cascading failures of following and/or forward reactions when an initial reaction is deleted. By analyzing more than 800 organism’s metabolic networks, it suggests that the reactions with larger impact degrees are likely essential and the universal reactions should also be essential. Alternative metabolic pathways compensate null mutations, which represents that average impact degrees for all organisms are small. Interestingly, average impact degrees of archaea organisms are smaller than other two categories of organisms, eukayote and bacteria, indicating that archaea organisms have strong robustness to resist the various perturbations during the evolution process. The results show that scale-free feature and reaction reversibility contribute to the robustness in metabolic networks. The optimal growth temperature of organism also relates the robust structure of metabolic network.

Altered fast- and slow-twitch muscle fibre characteristics in female mice with a (S248F) knock-in mutation of the brain neuronal nicotinic acetylcholine receptor

We generated a mouse line with a missense mutation (S248F) in the gene (CHRNA4) encoding the α4 subunit of neuronal nicotinic acetylcholine receptor (nAChR). Mutant mice demonstrate brief nicotine induced dystonia that resembles the clinical events seen in patients with the same mutation. Drug-induced dystonia is more pronounced in female mice, thus our aim was to determine if the S248F mutation changed the properties of fast- and slow-twitch muscle fibres from female mutant mice. Reverse transcriptase-PCR confirmed CHRNA4 gene expression in the brain but not skeletal muscles in normal and mutant mice. Ca²⁺ and Sr²⁺ force activation curves were obtained using skinned muscle fibres prepared from slow-twitch (soleus) and fast-twitch (EDL) muscles. Two significant results were found: (1) the (pCa₅₀ - pSr₅₀) value from EDL fibres was smaller in mutant mice than in wild type (1.01 vs. 1.30), (2) the percentage force produced at pSr 5.5 was larger in mutants than in wild type (5.76 vs. 0.24%). Both results indicate a shift to slow-twitch characteristics in the mutant. This conclusion is supported by the identification of the myosin heavy chain (MHC) isoforms. Mutant EDL fibres expressed MHC I (usually only found in slow-twitch fibres) as well as MHC IIa. Despite the lack of spontaneous dystonic events, our findings suggest that mutant mice may be having subclinical events or the mutation results in a chronic alteration to muscle neural input.

Age and exposure to arsenic alter base excision repair transcript levels in mice

Arsenic (As) induces DNA-damaging reactive oxygen species. Most oxidative DNA damage is countered by base excision repair (BER), the capacity for which may be reduced in older animals. We examined whether age and consumption of As in lactational milk or drinking water influences BER gene transcript levels in mice. Lactating mothers and 24-week-old mice were exposed (24 h or 2 weeks) to As (2 or 50 p.p.m.) in drinking water. Lung tissue was harvested from adults, neonates (initially 1 week old) feeding from lactating mothers and untreated animals 1– 26 weeks old. Transcripts encoding BER proteins were quantified. BER transcript levels decreased precipitously with age in untreated mice but increased in neonates whose mothers were exposed to 50 p.p.m. As for 24 h or 2 weeks. Treatment of 24-week-old mice with 2 or 50 p.p.m. As for 2 weeks decreased all transcript levels measured. Exposure to As attenuated the age-related transcript level decline for only one BER gene. We conclude that aging is associated with a rapid reduction of BER transcript levels in mice, which may contribute to decreased BER activity in older animals. Levels of As that can alter gene expression are transmitted to neonatal mice in lactational milk produced by mothers drinking water containing As, raising concerns about breastfeeding in countries having As-contaminated groundwater. Reduction of BER transcript levels in 24- week-old mice exposed to As for 2 weeks suggests As may potentiate sensitivity to itself in older animals.

Role of glutathione in schizophrenia? The effect of brain glutathione depletion on prepulse inhibition (PPI) in rats and mice

Reductions in brain glutathione (GSH) levels have been reported in schizophrenia. We investigated the effects of brain GSH depletion on prepulse inhibition (PPI), a model of sensorimotor gating which is disrupted in individuals with schizophrenia. It was hypothesized that GSH depletion would lead to disruption of PPI similar to that seen in schizophrenia and enhance the effect of increased dopamine release by amphetamine. Sprague-Dawley rats and C57Bl/6 mice were treated with saline or 2-cyclohexene-1-one (CHX, 75 mg/kg and 120 mg/kg respectively) to deplete brain GSH. 225 minutes later the animals were injected with amphetamine (2.5 mg/kg in rats and 25 mg/kg in mice). Total brain GSH levels were measured using an enzymatic recycling assay. Surprisingly, in rats CHX treatment prevented the disruption of PPI by amphetamine. Thus, while there was the expected disruption of PPI caused by amphetamine on its own (average %PPI reduced from 58 ± 5 to 44 ± 4), in combination with CHX, amphetamine had no significant effect (67 ± 4 vs. 63 ± 3, respectively). In contrast to rats, in mice CHX had no effect on PPI. Thus, amphetamine similarly disrupted PPI after saline (41 ± 5 vs. 28 ± 5) and CHX pretreatment (45 ± 6 vs. 26 ± 5). There were significant 40-63% depletions of GSH in frontal cortex and striatum of CHX-treated rats and mice. These data show that GSH depletion in the brain by CHX treatment did not induce the expected decrease in PPI. Because the levels of GSH depletion in this study were similar to those found in schizophrenia, these results cast doubt on a direct interaction between brain GSH levels and PPI disruption in this illness. In rats, CHX treatment prevented the disruption of PPI caused by amphetamine. We have observed that resting levels of GSH are lower in rats than in mice. It is plausible that some oxidative damage may occur after amphetamine treatment alone, which induces marked release of the electroactive species, dopamine. In mice with their higher levels of GSH (either with or without CHX treatment) and in control rats, this does not cause functional effects. However, in CHX-treated rats GSH levels are reduced to a point where amphetamine-induced dopamine release may cause increased metabolism and lipid peroxidation inducing a decrease in postsynaptic dopamine receptor function and consequently leading to an apparent inhibition of the disruption of PPI. In conclusion, while individuals with schizophrenia show disruption of PPI and reduced brain GSH levels, in rats and mice brain GSH depletion alone does not impact on PPI. In combination with a hyperdopaminergic state, functional effects on PPI regulation were found. These effects warrant further investigation.

Angiotensin converting enzyme inhibition lowers body weight and improves glucose tolerance in C57BL/6J mice maintained on a high fat diet

The renin–angiotensin system (RAS) is functional within adipose tissue and angiotensin II, the active component of RAS, has been implicated in adipose tissue hypertrophy and insulin resistance. In this study, captopril, an angiotensin converting enzyme (ACE) inhibitor that prevents angiotensin II formation, was used to study the development of diet-induced obesity and insulin resistance in obesity prone C57BL/6J mice. The mice were fed a high fat diet (w/w 21% fat) and allowed access to either water or water with captopril added (0.2 mg/ml). Body weight was recorded weekly and water and food intake daily. Glucose tolerance was determined after 11–12 weeks. On completion of the study (after 16 weeks of treatment), the mice were killed and kidney, liver, epididymal fat and extensor digitorum longus muscle (EDL) were weighed. Blood samples were collected and plasma analysed for metabolites and hormones. Captopril treatment decreased body weight in the first 2 weeks of treatment. Food intake of captopril-treated mice was similar to control mice prior to weight loss and was decreased after weight loss. Glucose tolerance was improved in captopril-treated mice. Captopril-treated mice had less epididymal fat than control mice. Relative to body weight, captopril-treated mice had increased EDL weight. Relative to control mice, mice administered captopril had a higher plasma concentration of adiponectin and lower concentrations of leptin and non-esterified fatty acids (NEFA). The results indicate that captopril both induced weight loss and improved insulin sensitivity. Thus, captopril may eventually be used for the treatment of obesity and Type 2 diabetes.

Null referring expressions in a conversational context

Two contexts where null referring expressions seem to be the most appropriate form for tracking referents in Persian conversation are discussed in this paper. The null referring expression is the unmarked form of tracking referents in both contexts. One context is where a referent acts as the protagonist of the discourse and has a role of primary importance. The other context is where there is a general schema in the sense discussed by Fillmore (1975), Prince (1981) and Chafe (1987). In these contexts, however, where Persian speakers’ preference is for null referring expressions, English speakers’ preference is for a pronominal form.

A nonlinear approach to testing the unit root null hypothesis : an application to international health expenditures

In this article, we examine the unit root null hypothesis for per capita total Health Expenditures (HEs), per capita private HEs and per capita public HEs for 29 Organization for Economic Co-operation and Development (OECD) countries. The novelty of our work is that we use a new nonlinear unit root test that allows for one structural break in the data series. We find that for around 45% of the countries, we are able to reject the unit root hypothesis for each of the three HE series. Moreover, using Monte Carlo simulations, we show that our proposed unit root model has better size and power properties than the widely used Augmented Dickey–Fuller (ADF) and Lagrange Multiplier (LM) type tests.