Nicotinamide Inhibits Alkylating Agent-Induced Apoptotic Neurodegeneration in the Developing Rat Brain

BACKGROUND: Exposure to the chemotherapeutic alkylating agent thiotepa during brain development leads to neurological complications arising from neurodegeneration and irreversible damage to the developing central nerve system (CNS). Administration of single dose of thiotepa in 7-d postnatal (P7) rat triggers activation of apoptotic cascade and widespread neuronal death. The present study was aimed to elucidate whether nicotinamide may prevent thiotepa-induced neurodegeneration in the developing rat brain. METHODOLOGY/PRINCIPAL FINDINGS: Neuronal cell death induced by thiotepa was associated with the induction of Bax, release of cytochrome-c from mitochondria into the cytosol, activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP-1). Post-treatment of developing rats with nicotinamide suppressed thiotepa-induced upregulation of Bax, reduced cytochrome-c release into the cytosol and reduced expression of activated caspase-3 and cleavage of PARP-1. Cresyl violet staining showed numerous dead cells in the cortex hippocampus and thalamus; post-treatment with nicotinamide reduced the number of dead cells in these brain regions. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) and immunohistochemical analysis of caspase-3 show that thiotepa-induced cell death is apoptotic and that it is inhibited by nicotinamide treatment. CONCLUSION: Nicotinamide (Nic) treatment with thiotepa significantly improved neuronal survival and alleviated neuronal cell death in the developing rat. These data demonstrate that nicotinamide shows promise as a therapeutic and neuroprotective agent for the treatment of neurodegenerative disorders in newborns and infants

The 5-Choice Continuous Performance Test: Evidence for a Translational Test of Vigilance for Mice

Attentional dysfunction is related to functional disability in patients with neuropsychiatric disorders such as schizophrenia, bipolar disorder, and Alzheimer's disease. Indeed, sustained attention/vigilance is among the leading targets for new medications designed to improve cognition in schizophrenia. Although vigilance is assessed frequently using the continuous performance test (CPT) in humans, few tests specifically assess vigilance in rodents.We describe the 5-choice CPT (5C-CPT), an elaboration of the 5-choice serial reaction (5CSR) task that includes non-signal trials, thus mimicking task parameters of human CPTs that use signal and non-signal events to assess vigilance. The performances of C57BL/6J and DBA/2J mice were assessed in the 5C-CPT to determine whether this task could differentiate between strains. C57BL/6J mice were also trained in the 5CSR task and a simple reaction-time (RT) task involving only one choice (1CRT task). We hypothesized that: 1) C57BL/6J performance would be superior to DBA/2J mice in the 5C-CPT as measured by the sensitivity index measure from signal detection theory; 2) a vigilance decrement would be observed in both strains; and 3) RTs would increase across tasks with increased attentional load (1CRT task<5CSR task<5C-CPT).C57BL/6J mice exhibited superior SI levels compared to DBA/2J mice, but with no difference in accuracy. A vigilance decrement was observed in both strains, which was more pronounced in DBA/2J mice and unaffected by response bias. Finally, we observed increased RTs with increased attentional load, such that 1CRT task<5CSR task<5C-CPT, consistent with human performance in simple RT, choice RT, and CPT tasks. Thus we have demonstrated construct validity for the 5C-CPT as a measure of vigilance that is analogous to human CPT studies

Comparative Functional Genomics of Salt Stress in Related Model and Cultivated Plants Identifies and Overcomes Limitations to Translational Genomics

One of the objectives of plant translational genomics is to use knowledge and genes discovered in model species to improve crops. However, the value of translational genomics to plant breeding, especially for complex traits like abiotic stress tolerance, remains uncertain. Using comparative genomics (ionomics, transcriptomics and metabolomics) we analyzed the responses to salinity of three model and three cultivated species of the legume genus Lotus. At physiological and ionomic levels, models responded to salinity in a similar way to crop species, and changes in the concentration of shoot Cl− correlated well with tolerance. Metabolic changes were partially conserved, but divergence was observed amongst the genotypes. Transcriptome analysis showed that about 60% of expressed genes were responsive to salt treatment in one or more species, but less than 1% was responsive in all. Therefore, genotype-specific transcriptional and metabolic changes overshadowed conserved responses to salinity and represent an impediment to simple translational genomics. However, ‘triangulation’ from multiple genotypes enabled the identification of conserved and tolerant-specific responses that may provide durable tolerance across species

α7-Nicotinic Acetylcholine Receptor: Role in Early Odor Learning Preference in Mice

Recently, we have shown that mice with decreased expression of α7-nicotinic acetylcholine receptors (α7) in the olfactory bulb were associated with a deficit in odor discrimination compared to wild-type mice. However, it is unknown if mice with decreased α7-receptor expression also show a deficit in early odor learning preference (ELP), an enhanced behavioral response to odors with attractive value observed in rats. In this study, we modified ELP methods performed in rats and implemented similar conditions in mice. From post-natal days 5–18, wild-type mice were stroked simultaneously with an odor presentation (conditioned odor) for 90 s daily. Control mice were only stroked, exposed to odor, or neither. On the day of testing (P21), mice that were stroked in concert with a conditioned odor significantly investigated the conditioned odor compared to a novel odor, as observed similarly in rats. However, mice with a decrease in α7-receptor expression that were stroked during a conditioned odor did not show a behavioral response to that odorant. These results suggest that decreased α7-receptor expression has a role in associative learning, olfactory preference, and/or sensory processing deficits

Homeobox Transcription Factors Are Required for Conidiation and Appressorium Development in the Rice Blast Fungus Magnaporthe oryzae

The appropriate development of conidia and appressoria is critical in the disease cycle of many fungal pathogens, including Magnaporthe oryzae. A total of eight genes (MoHOX1 to MoHOX8) encoding putative homeobox transcription factors (TFs) were identified from the M. oryzae genome. Knockout mutants for each MoHOX gene were obtained via homology-dependent gene replacement. Two mutants, ΔMohox3 and ΔMohox5, exhibited no difference to wild-type in growth, conidiation, conidium size, conidial germination, appressorium formation, and pathogenicity. However, the ΔMohox1 showed a dramatic reduction in hyphal growth and increase in melanin pigmentation, compared to those in wild-type. ΔMohox4 and ΔMohox6 showed significantly reduced conidium size and hyphal growth, respectively. ΔMohox8 formed normal appressoria, but failed in pathogenicity, probably due to defects in the development of penetration peg and invasive growth. It is most notable that asexual reproduction was completely abolished in ΔMohox2, in which no conidia formed. ΔMohox2 was still pathogenic through hypha-driven appressoria in a manner similar to that of the wild-type. However, ΔMohox7 was unable to form appressoria either on conidial germ tubes, or at hyphal tips, being non-pathogenic. These factors indicate that M. oryzae is able to cause foliar disease via hyphal appressorium-mediated penetration, and MoHOX7 is mutually required to drive appressorium formation from hyphae and germ tubes. Transcriptional analyses suggest that the functioning of M. oryzae homeobox TFs is mediated through the regulation of gene expression and is affected by cAMP and Ca2+ signaling and/or MAPK pathways. The divergent roles of this gene set may help reveal how the genome and regulatory pathways evolved within the rice blast pathogen and close relatives

Evolution of the Reactor Antineutrino Flux and Spectrum at Daya Bay

published_or_final_versio

Improved measurement of the reactor antineutrino flux and spectrum at Daya Bay

published_or_final_versio

Measurement of electron antineutrino oscillation based on 1230 days of operation of the Daya Bay experiment

published_or_final_versio