Cell cycle-driven neuronal apoptosis specifically linked to amyloid peptide Abeta1-42 exposure is not exacerbated in a mouse model of presenilin-1 familial Alzheimer's disease

We have shown previously that β-catenin and cyclin D1 are up-regulated in cortical neurons from homozygous mice carrying the familial Alzheimer's disease (FAD) presenilin-1 M146V mutation in a knock-in model (PS1 KI^M146V mice), leading to cell cycle-associated apoptosis. Here, we have aimed to determine (i) whether this phenotype is present in heterozygous PS1 KI^M146V mice, which reflects more accurately the PS1 FAD condition in humans and (ii) whether Aβ_1–42, which is invariably present in the PS1 FAD brain and is thought to affect neuronal cell cycle kinetics, may contribute to the abnormal cell cycle/cell death phenotype seen in PS1 KI^M146V mice. We demonstrate that cell cycle-linked apoptosis occurs in heterozygous PS1 KI^M146V post-mitotic neurons. In addition, there is a significant Aβ-associated increase in cell cycle and cell death that is not further modified by the PS1 KI^M146V mutation. Our results are consistent with a cell cycle-associated neurodegeneration model in the PS1 FAD brain in which the loss of PS1-dependent β-catenin regulatory function is sufficient to commit susceptible neurons to an abortive cell cycle, and may act synergistically with the Aβ cytotoxic challenge present in the PS1 FAD brain to expand the neuronal population susceptible to cell cycle-driven apoptosis.     

Contributions of Yale neuroscience to Donald O. Hebb's organization of behavior

The neuropsychological concepts found in Donald Hebb’s The Organization of Behavior have greatly influenced many aspects of neuroscience research over the last half century. Hebb’s ideas arose from a rich tradition of research. An underappreciated contribution came from pioneering studies at Yale University. Here, we wish to reconsider these developments, placing particular emphasis on the roles of the neurophysiologists John Fulton, J.J. Dusser de Barenne, and Warren McCulloch and the psychologists Donald Marquis and Ernest Hilgard. These neuroscientists all contributed significantly to the intellectual climate that gave rise to Hebb’s remarkable synthesis.     

Isoprenylcysteine methylation and demethylation regulate abscisic acid signaling in Arabidopsis

Isoprenylated proteins bear an isoprenylcysteine methyl ester at the C terminus. Although isoprenylated proteins have been implicated in meristem development and negative regulation of abscisic acid (ABA) signaling, the functional role of the terminal methyl group has not been described. Here, we show that transgenic Arabidopsis thaliana plants overproducing isoprenylcysteine methyltransferase (ICMT) exhibit ABA insensitivity in stomatal closure and seed germination assays, establishing ICMT as a negative regulator of ABA signaling. By contrast, transgenic plants overproducing isoprenylcysteine methylesterase (ICME) exhibit ABA hypersensitivity in stomatal closure and seed germination assays. Thus, ICME is a positive regulator of ABA signaling. To test the hypothesis that ABA signaling is under feedback regulation at the level of isoprenylcysteine methylation, we examined the effect of ABA on ICMT and ICME gene expression. Interestingly, ABA induces ICME gene expression, establishing a positive feedback loop whereby ABA promotes ABA responsiveness of plant cells via induction of ICME expression, which presumably results in the demethylation and inactivation of isoprenylated negative regulators of ABA signaling. These results suggest strategies for metabolic engineering of crop species for drought tolerance by targeted alterations in isoprenylcysteine methylation.     

Effects of Chromium Picolinate on Micronucleus Frequency and Morphology of Lymphocytes in Calves

We report the effects of chromium picolinate (CrPic) on micronucleus frequency, morphology of lymphocytes, and lipid peroxidation in calves. Twenty-four Holstein calves were selected for the study. They were kept in a farm and were fed a commercially available calf diet and alfalfa, ad libitum. The animals were divided into three groups of eight subjects each and were treated as follows: The first group was supplemented with a daily dose of 200 μg Cr as chromium picolinate; a second group received 400 μg Cr per day and a third group that served as control received no supplemental chromium. After 12-week supplementation, blood samples were collected to determine the micronucleus frequency, the apoptotic cell percentage, and the malondialdehyde (MDA) and blood chromium levels. In both supplemented groups, the cells had irregularly shaped and segmented nuclei. Supplementation also increased the percentage of apoptotic cells (p < 0.001) and serum MDA (p < 0.01) and slightly increased the chromium levels. The animals supplemented with 400 μg showed a significant increase of micronucleus frequency (p < 0.01). The results of this study suggest that supplementation with 200 and 400 μg chromium as chromium picolinate may lead to cytotoxicity. The higher level of supplementation may also have genotoxic effects. However, further studies investigating the mechanism of the action of CrPic are required.     

C3G regulates cortical neuron migration, preplate splitting and radial glial cell attachment

Neuronal migration is integral to the development of the cerebral cortex and higher brain function. Cortical neuron migration defects lead to mental disorders such as lissencephaly and epilepsy. Interaction of neurons with their extracellular environment regulates cortical neuron migration through cell surface receptors. However, it is unclear how the signals from extracellular matrix proteins are transduced intracellularly. We report here that mouse embryos lacking the Ras family guanine nucleotide exchange factor, C3G (Rapgef1, Grf2), exhibit a cortical neuron migration defect resulting in a failure to split the preplate into marginal zone and subplate and a failure to form a cortical plate. C3G-deficient cortical neurons fail to migrate. Instead, they arrest in a multipolar state and accumulate below the preplate. The basement membrane is disrupted and radial glial processes are disorganised and lack attachment in C3G-deficient brains. C3G is activated in response to reelin in cortical neurons, which, in turn, leads to activation of the small GTPase Rap1. In C3G-deficient cells, Rap1 GTP loading in response to reelin stimulation is reduced. In conclusion, the Ras family regulator C3G is essential for two aspects of cortex development, namely radial glial attachment and neuronal migration.     

Particle-tethered NADH for production of methanol from CO(2) catalyzed by coimmobilized enzymes

Efficient cofactor regeneration and reuse are highly desired for many important biotransformation applications. Here we show for the first time that cofactor NAD(H) covalently attached to micro particles, which can be easily recovered and reused, effectively mediated multistep reactions catalyzed by enzymes that were also immobilized with the micro particles. Such an immobilized enzyme-cofactor catalytic system was examined for the production of methanol from CO(2) with in situ cofactor regeneration. Four enzymes including formate, formaldehyde, alcohol, and glutamate dehydrogenases were coimmobilized using the same particles as that used for cofactor immobilization (enzymes and cofactor were immobilized separately). Reactions were performed by bubbling CO(2) in a suspension solution of the particle-attached enzymes and cofactor. It appeared that the collision among the particles afforded sufficient interactions between the cofactor and enzymes, and thus enabled the sequential transformation of CO(2) to methanol along with cofactor regeneration. For a 30-min batch reaction, a productivity of 0.02 micromol methanol/h/g-enzyme was achieved. That was lower than but comparable to the 0.04 micromol methanol/h/g-enzyme observed for free enzymes and cofactor at the same reaction conditions. The immobilized system showed fairly good stabilities in reusing. Over 80% of their original productivity was retained after 11 reusing cycles, with a cumulative methanol yield based on the amount of cofactor reached 127%. That was a promising enhancement in cofactor utilization as compared to the single-batch yield of 12% observed with free enzymes and free cofactor.     

First Report of bla CTX-M-15-Type ESBL-Producing Klebsiella pneumoniae in Wild Migratory Birds in Pakistan

EcoHealth - We investigated wild migratory birds faecal swabs for extended-spectrum β-lactamases-producing Klebsiella pneumoniae (ESBL-K. pneumoniae) from wetland habitats in Pakistan. ESBL-K....     

Differential protein input in the maternal diet alters the skeletal muscle transcriptome in fetal sheep

Mammalian Genome - Maternal nutrition during pregnancy is one of the major intrauterine environmental factors that influence fetal development by significantly altering the expression of genes that...