Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).     

Identification of common variants associated with human hippocampal and intracranial volumes

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).     

Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA

The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.     

Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule

The mechanisms that govern homeostasis of complex systems have been elusive but can be illuminated by mutations that disrupt system behavior. Mutations in the gene encoding the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and hyperkalemia. We show that physiology in mice transgenic for genomic segments harboring wild-type (TgWnk4(WT)) or PHAII mutant (TgWnk4(PHAII)) Wnk4 is changed in opposite directions: TgWnk4(PHAII) mice have higher blood pressure, hyperkalemia, hypercalciuria and marked hyperplasia of the distal convoluted tubule (DCT), whereas the opposite is true in TgWnk4(WT) mice. Genetic deficiency for the Na-Cl cotransporter of the DCT (NCC) reverses phenotypes seen in TgWnk4(PHAII) mice, demonstrating that the effects of the PHAII mutation are due to altered NCC activity. These findings establish that Wnk4 is a molecular switch that regulates the balance between NaCl reabsorption and K+ secretion by altering the mass and function of the DCT through its effect on NCC.     

A global synthesis reveals biodiversity loss as a major driver of ecosystem change

Evidence is mounting that extinctions are altering key processes important to the productivity and sustainability of Earth's ecosystems. Further species loss will accelerate change in ecosystem processes, but it is unclear how these effects compare to the direct effects of other forms of environmental change that are both driving diversity loss and altering ecosystem function. Here we use a suite of meta-analyses of published data to show that the effects of species loss on productivity and decomposition--two processes important in all ecosystems--are of comparable magnitude to the effects of many other global environmental changes. In experiments, intermediate levels of species loss (21-40%) reduced plant production by 5-10%, comparable to previously documented effects of ultraviolet radiation and climate warming. Higher levels of extinction (41-60%) had effects rivalling those of ozone, acidification, elevated CO(2) and nutrient pollution. At intermediate levels, species loss generally had equal or greater effects on decomposition than did elevated CO(2) and nitrogen addition. The identity of species lost also had a large effect on changes in productivity and decomposition, generating a wide range of plausible outcomes for extinction. Despite the need for more studies on interactive effects of diversity loss and environmental changes, our analyses clearly show that the ecosystem consequences of local species loss are as quantitatively significant as the direct effects of several global change stressors that have mobilized major international concern and remediation efforts.     

中国煤炭的供给能力:基于供给方程的分析

中国煤炭供给能力一直是学术界讨论热点,但鲜有研究揭示出价格与供给间的基本规律,而这在煤炭运营全面市场化的背景下尤为重要.根据煤种、产地和硫分的差异,归纳出19个区域的51种供给曲线,并在不同煤种价格差异主要由产品类别决定这一假设基础上,借助计量经济学和校准技术,得到了19个区域原煤的供给回归方程和51个不同区域煤种的供给曲线方程.以2011年为基准年份的分析表明:中国煤炭市场均衡价格和数量分别为809元和34.01亿吨,在现有产能约束下,当各地煤炭价格上涨50元时,全国煤炭供给增量为1.19亿吨,其中无烟煤、烟煤、次烟煤和褐煤各为0.16、0.21、0.69和0.13亿吨,但各地的供给弹性和持续供给能力表现各异,此时全国低硫煤的供给增量为0.68亿吨.研究结果对当前的煤炭市场化改革、供给战略设计和清洁能源供给都有着重要的政策启示意义.     

Diet of the Mogollon vole as indicated by stable-isotope analysis (δ 13 C and δ 15 N)

There are no published studies on the diet of Mogollon voles ( Microtus mogollonensis ) although this species occurs throughout the Southwest in montane forestlands. Mogollon voles are believed to be herbivorous, selecting the vegetative portion of grass as their dominant food source. Herbivores frequently select more easily digested C 3 plants over C 4 plants; we thus expected Mogollon voles would feed primarily on C 3 plants. We collected hair samples from Mogollon voles captured in northern Arizona between 1967 and 2003 and plant samples from some capture sites. Then we compared stable carbon (δ 13 C) and nitrogen (δ 15 N) isotope ratios to investigate dietary preferences for C 3 or C 4 plants. Mean isotope ratios for C 3 plants we sampled were –26.84‰ ( s = 0.17) for δ 13 C and –0.02‰ ( s = 0.32) for δ 15 N. For C 4 plants, mean isotope ratios for δ 13 C and δ 15 N were –15.04 ‰ ( s = 0.38) and –0.74‰ ( s = 0.55), respectively. Mogollon voles were largely herbivorous based on δ 15 N (mean and standard error: 3.77 ± 0.17‰) and used C 3 plants more than C 4 based on δ 13 C (–24.21 ± 0.14‰). Activities that lead to changes in plant species composition or reduction in C 3 plants in montane grasslands and forests (e.g., excessive ungulate grazing) may reduce habitat quality for Mogollon voles.     

Avian use of desert wildlife water developments as determined by remote videography

In the desert Southwest, migrating birds have been documented using upland habitat and xeroriparian washes as well as riparian areas. Yet aside from the river corridors, natural water sources (e.g., natural rock tanks [tinajas], springs, and ephemeral washes) in upland areas are scarce. Because of this scarcity, state and federal resource managers augmented water sources throughout the Southwest by constructing permanent wildlife water developments with the intention of enhancing game populations. However, despite these increases in free-standing water, there is a paucity of information on the use of water by birds during migration. Our objectives were to document use of these wildlife water developments by resident and migratory songbirds and assess the effectiveness of monitoring these species using remote color videography. We placed color video cameras at 2 wildlife water developments in southwestern Arizona during the spring and fall of 2004. Although we observed more use by migrants during spring than fall, overall use by migratory birds was low. However, the wildlife water developments were frequently used by resident birds. Remote videography provided continuous information on daily and seasonal patterns of bird use at wildlife water catchments with negligible disturbance by observers, yet for passerines, we felt that the benefits of remote videography did not justify the high cost of equipment purchase, installation, maintenance, and data processing.     

“Pando” lives: molecular genetic evidence of a giant aspen clone in central Utah

While clones of trembling aspen ( Populus tremuloides, Michx.) in the Intermountain West of North America are expected to be large, one putative genet in central Utah, identified from morphological evidence, has garnered particular attention for its size, even gaining the nickname “Pando” (Latin for “I spread”). In order to determine if a single genetic individual coincides with the morphological boundary of “Pando,” we sampled 209 stems on a 50-m grid throughout the putative clone for analysis at 7 microsatellite loci. We have identified a single genetic entity concurrent with that described from morphological characteristics. Spatial analyses indicate that the clone covers approximately 43.6 ha. Surprisingly, an additional 40 genotypes were identified adjacent to the putative clone, indicating that genet diversity may be high in the stand as a whole. In confirming the existence of the “Pando” clone, we suggest that this organism will provide valuable opportunities to study important biological processes such as clonal growth, somatic mutation, and senescence.     

The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome

We determined the complete genome sequence of Clostridium difficile strain 630, a virulent and multidrug-resistant strain. Our analysis indicates that a large proportion (11%) of the genome consists of mobile genetic elements, mainly in the form of conjugative transposons. These mobile elements are putatively responsible for the acquisition by C. difficile of an extensive array of genes involved in antimicrobial resistance, virulence, host interaction and the production of surface structures. The metabolic capabilities encoded in the genome show multiple adaptations for survival and growth within the gut environment. The extreme genome variability was confirmed by whole-genome microarray analysis; it may reflect the organism's niche in the gut and should provide information on the evolution of virulence in this organism.