Science 25 April 2008: Vol. 320. no. 5875, pp. 454 - 455
Education Forum LEARNING THEORY:
The Advantage of Abstract Examples in Learning Math
Undergraduate students may benefit more from learning mathematics through a single abstract, symbolic representation than from learning multiple concrete examples.

Science 25 April 2008: Vol. 320. no. 5875, pp. 520 - 523
Reports Efficient Inhibition of the Alzheimer's Disease β-Secretase by Membrane Targeting
β-Secretase plays a critical role in β-amyloid formation and thus provides a therapeutic target for Alzheimer's disease. Inhibitor design has usually focused on active-site binding, neglecting the subcellular localization of active enzyme. We have addressed this issue by synthesizing a membrane-anchored version of a β-secretase transition-state inhibitor by linking it to a sterol moiety. Thus, we targeted the inhibitor to active β-secretase found in endosomes and also reduced the dimensionality of the inhibitor, increasing its local membrane concentration. This inhibitor reduced enzyme activity much more efficiently than did the free inhibitor in cultured cells and in vivo. In addition to effectively targeting β-secretase, this strategy could also be used in designing potent drugs against other membrane protein targets.

Science 25 April 2008: Vol. 320. no. 5875, pp. 524 - 527
Reports Plastin 3 Is a Protective Modifier of Autosomal Recessive Spinal Muscular Atrophy
Homozygous deletion of the survival motor neuron 1 gene (SMN1) causes spinal muscular atrophy (SMA), the most frequent genetic cause of early childhood lethality. In rare instances, however, individuals are asymptomatic despite carrying the same SMN1 mutations as their affected siblings, thereby suggesting the influence of modifier genes. We discovered that unaffected SMN1-deleted females exhibit significantly higher expression of plastin 3 (PLS3) than their SMA-affected counterparts. We demonstrated that PLS3 is important for axonogenesis through increasing the F-actin level. Overexpression of PLS3 rescued the axon length and outgrowth defects associated with SMN down-regulation in motor neurons of SMA mouse embryos and in zebrafish. Our study suggests that defects in axonogenesis are the major cause of SMA, thereby opening new therapeutic options for SMA and similar neuromuscular diseases.

Science 25 April 2008: Vol. 320. no. 5875, pp. 539 - 543
Reports Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways
in Schizophrenia
Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.

Nature 452, 944 (24 April 2008)
Neuroscience: Current views on odour receptors
Insects possess refined olfactory systems that use specific receptors on their antennae. It emerges that these receptors not only detect odour molecules but, unexpectedly, can also act as ion channels.
All creatures sample their environment for chemicals that indicate the presence of food, mates, predators, dangers and attractions through mechanisms that were thought to be evolutionarily conserved from nematode worms to mammals. For example, in many organisms, odorant molecules bind to their receptors on the surface of neurons, initiating an intracellular signalling cascade.

Nature 452, 956-960 (24 April 2008)
Lateral presynaptic inhibition mediates gain control in an olfactory circuit
Olfactory signals are transduced by a large family of odorant receptor proteins, each of which corresponds to a unique glomerulus in the first olfactory relay of the brain. Crosstalk between glomeruli has been proposed to be important in olfactory processing, but it is not clear how these interactions shape the odour responses of second-order neurons. In the Drosophila antennal lobe (a region analogous to the vertebrate olfactory bulb), we selectively removed most interglomerular input to genetically identified second-order olfactory neurons. Here we show that this broadens the odour tuning of these neurons, implying that interglomerular inhibition dominates over interglomerular excitation. The strength of this inhibitory signal scales with total feedforward input to the entire antennal lobe, and has similar tuning in different glomeruli. A substantial portion of this interglomerular inhibition acts at a presynaptic locus, and our results imply that this is mediated by both ionotropic and metabotropic receptors on the same nerve terminal.

Nature 452, 997-1001 (24 April 2008)
Genetic variation in human NPY expression affects stress response and emotion
Understanding inter-individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y (NPY) is anxiolytic and its release is induced by stress. NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories. Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in post-mortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases.

Nature 452, 1002-1006 (24 April 2008)
Insect olfactory receptors are heteromeric ligand-gated ion channels
In insects, each olfactory sensory neuron expresses between one and three ligand-binding members of the olfactory receptor (OR) gene family, along with the highly conserved and broadly expressed Or83b co-receptor. The functional insect OR consists of a heteromeric complex of unknown stoichiometry but comprising at least one variable odorant-binding subunit and one constant Or83b family subunit. Insect ORs lack homology to G-protein-coupled chemosensory receptors in vertebrates and possess a distinct seven-transmembrane topology with the amino terminus located intracellularly. Here we provide evidence that heteromeric insect ORs comprise a new class of ligand-activated non-selective cation channels. Heterologous cells expressing silkmoth, fruitfly or mosquito heteromeric OR complexes showed extracellular Ca2+ influx and cation-non-selective ion conductance on stimulation with odorant. Odour-evoked OR currents are independent of known G-protein-coupled second messenger pathways. The fast response kinetics and OR-subunit-dependent K+ ion selectivity of the insect OR complex support the hypothesis that the complex between OR and Or83b itself confers channel activity. Direct evidence for odorant-gated channels was obtained by outside-out patch-clamp recording of Xenopus oocyte and HEK293T cell membranes expressing insect OR complexes. The ligand-gated ion channel formed by an insect OR complex seems to be the basis for a unique strategy that insects have acquired to respond to the olfactory environment.

Nature 452, 1007-1011 (24 April 2008)
Drosophila odorant receptors are both ligand-gated and cyclic-nucleotide-activated cation channels
From worm to man, many odorant signals are perceived by the binding of volatile ligands to odorant receptors1 that belong to the G-protein-coupled receptor (GPCR) family2. They couple to heterotrimeric G-proteins, most of which induce cAMP production3. This second messenger then activates cyclic-nucleotide-gated ion channels to depolarize the olfactory receptor neuron, thus providing a signal for further neuronal processing. Recent findings, however, have challenged this concept of odorant signal transduction in insects, because their odorant receptors, which lack any sequence similarity to other GPCRs4, are composed of conventional odorant receptors (for example, Or22a), dimerized with a ubiquitously expressed chaperone protein5, such as Or83b in Drosophila6. Or83b has a structure akin to GPCRs, but has an inverted orientation in the plasma membrane4, 7. However, G proteins are expressed in insect olfactory receptor neurons8, and olfactory perception is modified by mutations affecting the cAMP transduction pathway9. Here we show that application of odorants to mammalian cells co-expressing Or22a and Or83b results in non-selective cation currents activated by means of an ionotropic and a metabotropic pathway, and a subsequent increase in the intracellular Ca2+ concentration. Expression of Or83b alone leads to functional ion channels not directly responding to odorants, but being directly activated by intracellular cAMP or cGMP. Insect odorant receptors thus form ligand-gated channels as well as complexes of odorant-sensing units and cyclic-nucleotide-activated non-selective cation channels. Thereby, they provide rapid and transient as well as sensitive and prolonged odorant signalling.

Nature 452, 1012-1016 (24 April 2008)
Upper intestinal lipids trigger a gut–brain–liver axis to regulate glucose production
Energy and glucose homeostasis are regulated by food intake and liver glucose production, respectively. The upper intestine has a critical role in nutrient digestion and absorption. However, studies indicate that upper intestinal lipids inhibit food intake as well in rodents and humans by the activation of an intestine–brain axis. In parallel, a brain–liver axis has recently been proposed to detect blood lipids to inhibit glucose production in rodents5. Thus, we tested the hypothesis that upper intestinal lipids activate an intestine–brain–liver neural axis to regulate glucose homeostasis. Here we demonstrate that direct administration of lipids into the upper intestine increased upper intestinal long-chain fatty acyl-coenzyme A (LCFA-CoA) levels and suppressed glucose production. Co-infusion of the acyl-CoA synthase inhibitor triacsin C or the anaesthetic tetracaine with duodenal lipids abolished the inhibition of glucose production, indicating that upper intestinal LCFA-CoAs regulate glucose production in the preabsorptive state. Subdiaphragmatic vagotomy or gut vagal deafferentation interrupts the neural connection between the gut and the brain, and blocks the ability of upper intestinal lipids to inhibit glucose production. Direct administration of the N-methyl-d-aspartate ion channel blocker MK-801 into the fourth ventricle or the nucleus of the solitary tract where gut sensory fibres terminate abolished the upper-intestinal-lipid-induced inhibition of glucose production. Finally, hepatic vagotomy negated the inhibitory effects of upper intestinal lipids on glucose production. These findings indicate that upper intestinal lipids activate an intestine–brain–liver neural axis to inhibit glucose production, and thereby reveal a previously unappreciated pathway that regulates glucose homeostasis.

BMJ  2008;336:864-867 (19 April)
Analysis Development of palliative care and legalisation of euthanasia: antagonism or synergy?
Debates about euthanasia often polarise opinion, but Jan Bernheim and colleagues describe how in Belgium the two camps grew up side by side to mutual benefit
Although palliative care and legalised euthanasia are both based on the medical and ethical values of patient autonomy and caregiver beneficence and non-maleficence,1 they are often viewed as antagonistic causes. A popular perception, for instance, is that palliative care is the province of religiously motivated people and the advocacy of euthanasia that of agnostics or atheists.2 3 The European Association for Palliative Care has voiced concerns that legalising euthanasia would be the start of a slippery slope resulting in harm to vulnerable patients such as elderly and disabled people and that it would impede the development of palliative care by appearing as an alternative.4 Data from the Netherlands and Belgium, where euthanasia is legal, do not provide any evidence of a slippery slope.5 6 Here, we focus on the effect of the process of legalisation of euthanasia on palliative care and vice versa by reviewing the published historical, regulatory, and epidemiological evidence in Belgium.

NEJM Volume 358:1868-1869  April 24, 2008  Number 17
Major Depressive Disorder
In their review article, Belmaker and Agam (Jan. 3 issue) examine several mechanisms involved in depressive disorders, but they do not mention evidence that androgen-deprivation therapy, which is frequently used in the management of prostate cancer, can cause major depression. The mechanisms underlying this association may include loss of sexual potency, fatigue, cognitive impairment, and changes in body composition, which lead to deterioration of a patient's perception of his body. A direct effect of testosterone, however, cannot be ruled out.

NEJM Volume 358:1869-1870  April 24, 2008  Number 17
Case 40-2007: A Man with Weakness in the Hands
To the Editor: In the Case Record involving a 38-year-old man with multifocal motor neuropathy, discussed by Triggs and Cros (Dec. 27 issue), Triggs emphasizes that it is important to distinguish multifocal motor neuropathy from amyotrophic lateral sclerosis or other motor neuron diseases because it responds favorably to immunotherapy. He mentions that plasma exchange, cyclophosphamide, and intravenous immune globulin are all beneficial. However, only treatment with intravenous immune globulins has been shown to be beneficial in randomized, controlled trials.