Neuroanatomy: brain asymmetry and long-term memory

The asymmetrical positioning of neural structures on the left or right side of the brain in vertebrates and in invertebrates may be correlated with brain laterality, which is associated with cognitive skills. But until now this has not been illustrated experimentally. Here we describe an asymmetrically positioned brain structure in the fruitfly Drosophila and find that the small proportion of wild-type flies that have symmetrical brains with two such structures lack a normal long-term memory, although their short-term memory is intact. Our results indicate that brain asymmetry may be required for generating or retrieving long-term memory.     

Opioids block long-term potentiation of inhibitory synapses

Excitatory brain synapses are strengthened or weakened in response to specific patterns of synaptic activation, and these changes in synaptic strength are thought to underlie persistent pathologies such as drug addiction, as well as learning. In contrast, there are few examples of synaptic plasticity of inhibitory GABA (gamma-aminobutyric acid)-releasing synapses. Here we report long-term potentiation of GABA(A)-mediated synaptic transmission (LTP(GABA)) onto dopamine neurons of the rat brain ventral tegmental area, a region required for the development of drug addiction. This novel form of LTP is heterosynaptic, requiring postsynaptic NMDA (N-methyl-d-aspartate) receptor activation at glutamate synapses, but resulting from increased GABA release at neighbouring inhibitory nerve terminals. NMDA receptor activation produces nitric oxide, a retrograde signal released from the postsynaptic dopamine neuron. Nitric oxide initiates LTP(GABA) by activating guanylate cyclase in GABA-releasing nerve terminals. Exposure to morphine both in vitro and in vivo prevents LTP(GABA). Whereas brief treatment with morphine in vitro blocks LTP(GABA) by inhibiting presynaptic glutamate release, in vivo exposure to morphine persistently interrupts signalling from nitric oxide to guanylate cyclase. These neuroadaptations to opioid drugs might contribute to early stages of addiction, and may potentially be exploited therapeutically using drugs targeting GABA(A) receptors.     

WDR62 is associated with the spindle pole and is mutated in human microcephaly

Autosomal recessive primary microcephaly (MCPH) is a disorder of neurodevelopment resulting in a small brain. We identified WDR62 as the second most common cause of MCPH after finding homozygous missense and frame-shifting mutations in seven MCPH families. In human cell lines, we found that WDR62 is a spindle pole protein, as are ASPM and STIL, the MCPH7 and MCHP7 proteins. Mutant WDR62 proteins failed to localize to the mitotic spindle pole. In human and mouse embryonic brain, we found that WDR62 expression was restricted to neural precursors undergoing mitosis. These data lend support to the hypothesis that the exquisite control of the cleavage furrow orientation in mammalian neural precursor cell mitosis, controlled in great part by the centrosomes and spindle poles, is critical both in causing MCPH when perturbed and, when modulated, generating the evolutionarily enlarged human brain.     

Data,epistemic values,and multiple methods in case study research

Case Study research is characterized by the employment of multiple data gathering methods. In this paper, I examine the concurrent use of participant observation and qualitative interviews. The question I examine is: what is the rationale behind their combination in case study research? In the literature on case study research, the two most common reasons for using multiple methods appeal to comprehensiveness and convergent confirmation respectively. I argue that there is a third significant, yet overlooked, way to motivate the joint use of participant observation and qualitative interviews: the methods may generate complementary evidence and this puts the researcher in a better position to confirm that her data manifest central epistemic values and so are suitable as a basis for providing an adequate answer to her research question. I refer to this as the rationale of “blended epistemic value validation”.     

A ubiquitous thermoacidophilic archaeon from deep-sea hydrothermal vents

Deep-sea hydrothermal vents are important in global biogeochemical cycles, providing biological oases at the sea floor that are supported by the thermal and chemical flux from the Earth's interior. As hot, acidic and reduced hydrothermal fluids mix with cold, alkaline and oxygenated sea water, minerals precipitate to form porous sulphide-sulphate deposits. These structures provide microhabitats for a diversity of prokaryotes that exploit the geochemical and physical gradients in this dynamic ecosystem. It has been proposed that fluid pH in the actively venting sulphide structures is generally low (pH < 4.5), yet no extreme thermoacidophile has been isolated from vent deposits. Culture-independent surveys based on ribosomal RNA genes from deep-sea hydrothermal deposits have identified a widespread euryarchaeotal lineage, DHVE2 (deep-sea hydrothermal vent euryarchaeotic 2). Despite the ubiquity and apparent deep-sea endemism of DHVE2, cultivation of this group has been unsuccessful and thus its metabolism remains a mystery. Here we report the isolation and cultivation of a member of the DHVE2 group, which is an obligate thermoacidophilic sulphur- or iron-reducing heterotroph capable of growing from pH 3.3 to 5.8 and between 55 and 75 degrees C. In addition, we demonstrate that this isolate constitutes up to 15% of the archaeal population, providing evidence that thermoacidophiles may be key players in the sulphur and iron cycling at deep-sea vents.     

Contrasting patterns of early twenty-first-century glacier mass change in the Himalayas

Glaciers are among the best indicators of terrestrial climate variability, contribute importantly to water resources in many mountainous regions and are a major contributor to global sea level rise. In the Hindu Kush-Karakoram-Himalaya region (HKKH), a paucity of appropriate glacier data has prevented a comprehensive assessment of current regional mass balance. There is, however, indirect evidence of a complex pattern of glacial responses in reaction to heterogeneous climate change signals. Here we use satellite laser altimetry and a global elevation model to show widespread glacier wastage in the eastern, central and south-western parts of the HKKH during 2003-08. Maximal regional thinning rates were 0.66?±?0.09 metres per year in the Jammu-Kashmir region. Conversely, in the Karakoram, glaciers thinned only slightly by a few centimetres per year. Contrary to expectations, regionally averaged thinning rates under debris-mantled ice were similar to those of clean ice despite insulation by debris covers. The 2003-08 specific mass balance for our entire HKKH study region was -0.21?±?0.05?m?yr(-1) water equivalent, significantly less negative than the estimated global average for glaciers and ice caps. This difference is mainly an effect of the balanced glacier mass budget in the Karakoram. The HKKH sea level contribution amounts to one per cent of the present-day sea level rise. Our 2003-08 mass budget of -12.8?±?3.5 gigatonnes (Gt) per year is more negative than recent satellite-gravimetry-based estimates of -5?±?3?Gt?yr(-1) over 2003-10 (ref. 12). For the mountain catchments of the Indus and Ganges basins, the glacier imbalance contributed about 3.5% and about 2.0%, respectively, to the annual average river discharge, and up to 10% for the Upper Indus basin.     

The Drosophila melanogaster Genetic Reference Panel

A major challenge of biology is understanding the relationship between molecular genetic variation and variation in quantitative traits, including fitness. This relationship determines our ability to predict phenotypes from genotypes and to understand how evolutionary forces shape variation within and between species. Previous efforts to dissect the genotype-phenotype map were based on incomplete genotypic information. Here, we describe the Drosophila melanogaster Genetic Reference Panel (DGRP), a community resource for analysis of population genomics and quantitative traits. The DGRP consists of fully sequenced inbred lines derived from a natural population. Population genomic analyses reveal reduced polymorphism in centromeric autosomal regions and the X chromosome, evidence for positive and negative selection, and rapid evolution of the X chromosome. Many variants in novel genes, most at low frequency, are associated with quantitative traits and explain a large fraction of the phenotypic variance. The DGRP facilitates genotype-phenotype mapping using the power of Drosophila genetics.     

A tumour suppressor network relying on the polyamine-hypusine axis

Tumour suppressor genes encode a broad class of molecules whose mutational attenuation contributes to malignant progression. In the canonical situation, the tumour suppressor is completely inactivated through a two-hit process involving a point mutation in one allele and chromosomal deletion of the other. Here, to identify tumour suppressor genes in lymphoma, we screen a short hairpin RNA library targeting genes deleted in human lymphomas. We functionally identify those genes whose suppression promotes tumorigenesis in a mouse lymphoma model. Of the nine tumour suppressors we identified, eight correspond to genes occurring in three physically linked 'clusters', suggesting that the common occurrence of large chromosomal deletions in human tumours reflects selective pressure to attenuate multiple genes. Among the new tumour suppressors are adenosylmethionine decarboxylase 1 (AMD1) and eukaryotic translation initiation factor 5A (eIF5A), two genes associated with hypusine, a unique amino acid produced as a product of polyamine metabolism through a highly conserved pathway. Through a secondary screen surveying the impact of all polyamine enzymes on tumorigenesis, we establish the polyamine-hypusine axis as a new tumour suppressor network regulating apoptosis. Unexpectedly, heterozygous deletions encompassing AMD1 and eIF5A often occur together in human lymphomas and co-suppression of both genes promotes lymphomagenesis in mice. Thus, some tumour suppressor functions can be disabled through a two-step process targeting different genes acting in the same pathway.