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This Week in PNAS
BIOCHEMISTRY
Fucosylation and memory
Modification of brain proteins by certain sugars regulates neuron morphology, which may explain the ability to influence complex cognitive processes such as long-term memory formation, according to Heather Murrey et al. Behavioral and electrophysiological studies have suggested that fucosylation [modification of proteins by fucose-α(1-2)-galactose] is important in learning and memory, but the mechanism by which it regulates such complex processes has remained unclear. Murrey et al. analyzed the effects of fucosylation on cultured neurons and in the adult rat hippocampus. They found that the synaptic proteins synapsin Ia and Ib are the major fucose-α(1-2)-galactose glycoproteins in the adult rat brain. Fucosylation of these proteins protected them from degradation, and inhibition of fucosylation impaired neurite growth and delayed synapse formation. Because synapsins modulate a wide range of synaptic processes, including neurotransmitter release and axon outgrowth, their modification may influence the molecular processes that underlie learning and memory. In addition, the authors found several other proteins modified by fucose-α(1-2)-galactose, suggesting that fucosylation may serve an important and wide-ranging role in neural development and synaptic plasticity. — M.M.
Fucosylation inhibitor (2-dGal) impairs neurite outgrowth.
“Protein fucosylation regulates synapsin Ia/Ib expression and neuronal morphology in primary hippocampal neurons” by Heather E. Murrey, Cristal I. Gama, Stacey A. Kalovidouris, Wen.-I. Luo, Edward M. Driggers, Barbara Porton, and Linda C. Hsieh-Wilson (see pages 21–26)
CELL BIOLOGY
Hypoxia detection in mouse tissues
Michal Safran et al. have engineered a noninvasive system for detecting oxygenation and hypoxia in tissues in mice. Inadequate tissue oxygenation is a cause of or an early indication of diseases such as atherosclerosis and cancer. Previous research has shown that, under low-oxygen conditions, the transcription factor hypoxia-inducible factor (HIF) activates genes involved in cellular adaptation to hypoxia. In the presence of oxygen, prolyl hydroxylases act on HIFα subunits, marking them for ubiquitination and subsequent degradation. Safran et al. generated a chimeric HIFα protein fused to luciferase and transfected carcinoma cell lines with the fusion construct. These cells showed increased luciferase activity in low-oxygen conditions. Mice expressing the chimeric protein also demonstrated a nearly 10-fold increase in luciferase activity in a low-oxygen (8%) environment. Oral administration of a hydroxylase inhibitor to the mice resulted in a dose-dependent increase in light emission in the kidneys and liver. Levels of erythropoietin, which stimulates red blood cell production in response to renal hypoxia and is regulated by HIF, also increased in the inhibitor-treated mutant animals. — F.A.
Hypoxia imaging in HIF-luciferase mice.
“Mouse model for noninvasive imaging of HIF prolyl hydroxylase activity: Assessment of an oral agent that stimulates erythropoietin production” by Michal Safran, William Y. Kim, Fionnuala O'Connell, Lee Flippin, Volkmar Günzler, James W. Horner, Ronald A. DePinho, and William G. Kaelin, Jr. (see pages 105–110)
GENETICS, COMPUTER SCIENCES
SNP fingerprints of positive selection in human genes
Eric Wang et al. have developed a computational approach to detecting genetic architectures associated with recent positive selection. Designated the linkage disequilibrium decay (LDD) test, this probabilistic model, which does not require haplotype information, distinguishes large differences in linkage disequilibria surrounding a given pair of SNPs. Scanning a 1.6-million-SNP genotype data set, Wang et al. found that 1.6% of the SNPs exhibited a “fingerprint” of positive selection in the last 10,000– 50,000 years. These 25,386 SNPs corresponded to ≈1,800 genes, >80% of which clustered in the biological areas of reproduction, host–pathogen interaction, neuron function, cell division, and DNA and protein metabolism. The authors suggest that selection for alleles in these categories accompanied humankind's major population expansion and migration and/or the shift from hunter–gatherer to agrarian societies, because these events affected longevity, reproduction, dietary intake, and the spread of infectious diseases. Wang et al. noted that the genes identified, though high in number, did not represent a complete list of alleles but rather a preliminary set based on the available SNP data. — N.Z.
SNP fingerprinting categories.
“Global landscape of recent inferred Darwinian selection for Homo sapiens” by Eric T. Wang, Greg Kodama, Pierre Baldi, and Robert K. Moyzis (see pages 135–140)
MICROBIOLOGY
Genetic predisposition for malaria infection
Two polymorphisms within the toll-like receptor (TLR) genes appear to confer 1.5- and 2.6-fold risks of severe malaria, respectively, according to results from a case-control study by Frank Mockenhaupt et al. The authors examined 870 Ghanaian children to examine the influence of TLR-2, -4, and -9 polymorphisms in susceptibility to severe malaria. TLR-2 variants commonly found in Caucasian and Asian populations were absent in the study sample, but a rare mutation (Leu658Pro) that impairs signaling via TLR-2 was identified. No polymorphisms in the TLR-9/interleukin-1 receptor domain were found, and two frequent TLR-9 promoter polymorphisms failed to show an association with malaria severity. However, a TLR-4 variant (Asp299Gly) occurred at a rate of 17.6% in healthy controls versus 24.1% in severe malaria patients, constituting a 1.5-fold increased risk of severe malaria. Additionally, another TLR-4 variant (Thr399Ile) was seen in 2.4% of healthy children and 6.2% of diseased patients, constituting a 2.6-fold increased malaria risk. Both differences were statistically significant. These findings suggest that TLR-4-mediated responses to malaria in vivo and TLR-4 polymorphisms are associated with malaria manifestation. — T.D./R.N.
“Toll-like receptor (TLR) polymorphisms in African children: Common TLR-4 variants predispose to severe malaria” by Frank P. Mockenhaupt, Jakob P. Cramer, Lutz Hamann, Miriam S. Stegemann, Jana Eckert, Na-Ri Oh, Rowland N. Otchwemah, Ekkehart Dietz, Stephan Ehrhardt, Nicolas W. J. Schröder, Ulrich Bienzle, and Ralf R. Schumann (see pages 177–182)
PHYSIOLOGY
Androgen receptor deficiency in early ovary failure
Hiroko Shiina et al. demonstrate that androgen receptor deficiency may play a role in premature ovarian failure. Premature ovarian failure has been linked to X chromosome abnormalities, including various deletions and complete loss of one copy of the X chromosome, as seen in Turner syndrome. The specific X-linked genes responsible for premature ovarian failure have not been identified. Because the X chromosome encodes the androgen receptor, Shiina et al. generated androgen receptor-deficient mice and examined the effects on the female reproductive system. Although young female mice had apparently normal ovarian function, the animals showed a gradual decline in the number of ovarian follicles. By 40 weeks of age, female mice lacking the androgen receptor had no detectable follicles and became infertile. Also, altered expression of several genes involved in folliculogenesis was observed, suggesting that these genes are downstream targets of the androgen receptor. The findings suggest that androgen receptor-mediated signaling is important for the maintenance of follicles and that lack of male hormone signaling may be a cause of premature ovarian failure. — M.M.
Premature ovarian failure in mice lacking androgen receptor expression.
“Premature ovarian failure in androgen receptor-deficient mice” by Hiroko Shiina, Takahiro Matsumoto, Takashi Sato, Katsuhide Igarashi, Junko Miyamoto, Sayuri Takemasa, Matomo Sakari, Ichiro Takada, Takashi Nakamura, Daniel Metzger, Pierre Chambon, Jun Kanno, Hiroyuki Yoshikawa, and Shigeaki Kato (see pages 224–229)
