CD-1 mice Show Individual Differences in Nicotine Preference in a Modified Two-Bottle Oral Self-Administration Model

Although both animal and human studies reveal significant contributions of genetics to smoking addiction, many human studies were underpowered or biased by potential confounding variables, and animal genetic studies are challenged by limited genetic variations and lack of convincing phenotypes. To address these concerns, we used non-sibling outbred CD-1 mice to evaluate individual differences in nicotine preference with a modified two-bottle oral self-administration model. Animals were first given free access to two bottles, one filled with nicotine dissolved in 2% saccharin and the other with saccharin only. Under this regular two-bottle choice condition, the majority of animals avoided the nicotine solution with limited individual differences. However, when we modified the model by introducing 4 days of exposure to 5% saccharin in the drinking water, the animals significantly increased nicotine consumption in the two-bottle choice test, with about 30% animals showing a nicotine preference. Nicotine preference after 5% saccharin treatment remained elevated throughout the 28 days of the experiment. Further, we found there existed striking individual differences in nicotine consumption after exposure to 5% saccharin, with a range of 0–100% of total liquid consumption. The enhanced individual differences and the ratio of nicotine consumption were observed at different concentrations of nicotine (10–80 μg/ml) and in both adolescents and adults. Further examination on the induction mechanism showed that the long-lasting nicotine preference was not correlated with nicotine consumption before the induction, 5% saccharin consumption, or weight gain during the induction. Although liquid consumption during the 4 days of 5% saccharin exposure was decreased by about 30%, comparable liquid restriction alone for 4 days did not induce nicotine preference. Together, this study showed a strong and stable nicotine preference in CD-1 mice, which was induced by a short-term high concentration of saccharin in the drinking water. Considering the nature and heterogeneity of CD-1 mice, the striking individual differences imply that genetics plays an important role in nicotine preference observed in these animals

Amphetamine Administration into the Ventral Striatum Facilitates Behavioral Interaction with Unconditioned Visual Signals in Rats

Administration of psychomotor stimulants like amphetamine facilitates behavior in the presence of incentive distal stimuli, which have acquired the motivational properties of primary rewards through associative learning. This facilitation appears to be mediated by the mesolimbic dopamine system, which may also be involved in facilitating behavior in the presence of distal stimuli that have not been previously paired with primary rewards. However, it is unclear whether psychomotor stimulants facilitate behavioral interaction with unconditioned distal stimuli.We found that noncontingent administration of amphetamine into subregions of the rat ventral striatum, particularly in the vicinity of the medial olfactory tubercle, facilitates lever pressing followed by visual signals that had not been paired with primary rewards. Noncontingent administration of amphetamine failed to facilitate lever pressing when it was followed by either tones or delayed presentation or absence of visual signals, suggesting that visual signals are key for enhanced behavioral interaction. Systemic administration of amphetamine markedly increased locomotor activity, but did not necessarily increase lever pressing rewarded by visual signals, suggesting that lever pressing is not a byproduct of heightened locomotor activity. Lever pressing facilitated by amphetamine was reduced by co-administration of the dopamine receptor antagonists SCH 23390 (D1 selective) or sulpiride (D2 selective).Our results suggest that amphetamine administration into the ventral striatum, particularly in the vicinity of the medial olfactory tubercle, activates dopaminergic mechanisms that strongly enhance behavioral interaction with unconditioned visual stimuli

A dual role of BRCA1 in two distinct homologous recombination mediated repair in response to replication arrest

Homologous recombination (HR) is a major mechanism utilized to repair blockage of DNA replication forks. Here, we report that a sister chromatid exchange (SCE) generated by crossover-associated HR efficiently occurs in response to replication fork stalling before any measurable DNA double-strand breaks (DSBs). Interestingly, SCE produced by replication fork collapse following DNA DSBs creation is specifically suppressed by ATR, a central regulator of the replication checkpoint. BRCA1 depletion leads to decreased RPA2 phosphorylation (RPA2-P) following replication fork stalling but has no obvious effect on RPA2-P following replication fork collapse. Importantly, we found that BRCA1 promotes RAD51 recruitment and SCE induced by replication fork stalling independent of ATR. In contrast, BRCA1 depletion leads to a more profound defect in RAD51 recruitment and SCE induced by replication fork collapse when ATR is depleted. We concluded that BRCA1 plays a dual role in two distinct HR-mediated repair upon replication fork stalling and collapse. Our data established a molecular basis for the observation that defective BRCA1 leads to a high sensitivity to agents that cause replication blocks without being associated with DSBs, and also implicate a novel mechanism by which loss of cell cycle checkpoints promotes BRCA1-associated tumorigenesis via enhancing HR defect resulting from BRCA1 deficiency

BRCA1 loss activates cathepsin L–mediated degradation of 53BP1 in breast cancer cells

Loss of 53BP1 rescues BRCA1 deficiency and is associated with BRCA1-deficient and triple-negative breast cancers (TNBC) and with resistance to genotoxic drugs. The mechanisms responsible for decreased 53BP1 transcript and protein levels in tumors remain unknown. Here, we demonstrate that BRCA1 loss activates cathepsin L (CTSL)–mediated degradation of 53BP1. Activation of this pathway rescued homologous recombination repair and allowed BRCA1-deficient cells to bypass growth arrest. Importantly, depletion or inhibition of CTSL with vitamin D or specific inhibitors stabilized 53BP1 and increased genomic instability in response to radiation and poly(adenosine diphosphate–ribose) polymerase inhibitors, compromising proliferation. Analysis of human breast tumors identified nuclear CTSL as a positive biomarker for TNBC, which correlated inversely with 53BP1. Importantly, nuclear levels of CTSL, vitamin D receptor, and 53BP1 emerged as a novel triple biomarker signature for stratification of patients with BRCA1-mutated tumors and TNBC, with potential predictive value for drug response. We identify here a novel pathway with prospective relevance for diagnosis and customization of breast cancer therapy

Recent Development of Nano-Materials Used in DNA Biosensors

As knowledge of the structure and function of nucleic acid molecules has increased, sequence-specific DNA detection has gained increased importance. DNA biosensors based on nucleic acid hybridization have been actively developed because of their specificity, speed, portability, and low cost. Recently, there has been considerable interest in using nano-materials for DNA biosensors. Because of their high surface-to-volume ratios and excellent biological compatibilities, nano-materials could be used to increase the amount of DNA immobilization; moreover, DNA bound to nano-materials can maintain its biological activity. Alternatively, signal amplification by labeling a targeted analyte with nano-materials has also been reported for DNA biosensors in many papers. This review summarizes the applications of various nano-materials for DNA biosensors during past five years. We found that nano-materials of small sizes were advantageous as substrates for DNA attachment or as labels for signal amplification; and use of two or more types of nano-materials in the biosensors could improve their overall quality and to overcome the deficiencies of the individual nano-components. Most current DNA biosensors require the use of polymerase chain reaction (PCR) in their protocols. However, further development of nano-materials with smaller size and/or with improved biological and chemical properties would substantially enhance the accuracy, selectivity and sensitivity of DNA biosensors. Thus, DNA biosensors without PCR amplification may become a reality in the foreseeable future

Social capital and healthy ageing in Indonesia

Abstract Background A large international literature has found a positive association between social capital and measures of physical and mental health. However, there is a paucity of research on the links between social capital and healthy ageing in a developing country environment, where universal social security coverage is absent and health infrastructure is poor. Method In this paper, we develop and empirically test a model of the linkages between social capital and the health outcomes for older adults in Indonesia, using data from the Indonesian Family Life Survey-East (IFLS-East), conducted in 2012. Using multivariate regression analysis, we examine whether social capital plays a role in mitigating poor health among older individuals aged 50 years and above in Indonesia’s most vulnerable provinces. We test the robustness of these social capital variables across different health measures (self-assessed health, Activities of Daily Living (ADL), measures of chronic illness and mental health measures), as well as across different demographic groups, after controlling for an array of socio-economic, demographic and geographic characteristics. Results Our findings show that access to better social capital (using measures of neighbourhood trust and community participation) is associated with a higher degree of physical mobility, independence, and mental well-being among older individuals but has no influence on chronic illnesses. These results are consistent when we estimate samples disaggregated by gender, rural/urban residence, and by age categories. Conclusion From a policy perspective these results point to the importance of social capital measures in moderating the influence of poor health, particularly in the Activities of Daily Living

Negentropy Spectrum Decomposition and Its Application in Compound Fault Diagnosis of Rolling Bearing

The rolling bearings often suffer from compound fault in practice. Compared with single fault, compound fault contains multiple fault features that are coupled together and make it difficult to detect and extract all fault features by traditional methods such as Hilbert envelope demodulation, wavelet transform and empirical node decomposition (EMD). In order to realize the compound fault diagnosis of rolling bearings and improve the diagnostic accuracy, we developed negentropy spectrum decomposition (NSD), which is based on fast empirical wavelet transform (FEWT) and spectral negentropy, with cyclic extraction as the extraction method. The infogram is constructed by FEWT combined with spectral negentropy to select the best band center and bandwidth for band-pass filtering. The filtered signal is used as a new measured signal, and the fast empirical wavelet transform combined with spectral negentropy is used to filter the new measured signal again. This operation is repeated to achieve cyclic extraction, until the signal no longer contains obvious fault features. After obtaining the envelope of all extracted components, compound fault diagnosis of rolling bearings can be realized. The analysis of the simulation signal and the experimental signal shows that the method can realize the compound fault diagnosis of rolling bearings, which verifies the feasibility and effectiveness of the method. The method proposed in this paper can detect and extract all the fault features of compound fault completely, and it is more reliable for the diagnosis of compound fault. Therefore, the method has practical significance in rolling bearing compound fault diagnosis