Gastrointestinal helminths of nine species of Cnemaspis (Squamata: Gekkonidae) from Peninsular Malaysia,one species from Cambodia and Thailand and two species from Vietnam

A total of 12 species of Cnemaspis (N = 104) from Southeast Asia were examined for gastrointestinal helminths. Samples consisted of nine species (n = 86) from Peninsular Malaysia: Cnemaspis affinis (n = 4); Cnemaspis baueri (n = 17); Cnemaspis biocellata (n = 12); Cnemaspis grismeri (n = 8); Cnemaspis kumpoli (n = 11); Cnemaspis limi (n = 9): Cnemaspis monachorum (n = 7); Cnemaspis pemanggilensis (n = 10); Cnemaspis peninsularis (n = 8); one species (n = 5) from Cambodia and Thailand, Cnemaspis chanthaburiensis (n = 5); and two species (n = 13) from Vietnam: Cnemaspis nuicamensis (n = 6) and Cnemaspis tucdupensis (n = 7). The aggregate helminth community consisted of one species of Cestoda, Cylindrotaenia malayi and nine species of Nematoda: Bakeria schadi, Meteterakis singaporensis, Parapharyngodon maplestoni, Maxvachonia sp., Physalopteroides sp., Physalopteridae gen. sp., Riticulariidae gen. sp., Seuratoidea gen. sp., Ascaridoidea gen. sp. Meteterakis singaporensis had the largest number of individuals (457) and greatest prevalence (24%). Twenty-eight new host records are reported.     

Common variants at 12q14 and 12q24 are associated with hippocampal volume

Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.     

Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer

Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer.     

Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease

Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease.     

Bayesian inference of ancient human demography from individual genome sequences

Whole-genome sequences provide a rich source of information about human evolution. Here we describe an effort to estimate key evolutionary parameters based on the whole-genome sequences of six individuals from diverse human populations. We used a Bayesian, coalescent-based approach to obtain information about ancestral population sizes, divergence times and migration rates from inferred genealogies at many neutrally evolving loci across the genome. We introduce new methods for accommodating gene flow between populations and integrating over possible phasings of diploid genotypes. We also describe a custom pipeline for genotype inference to mitigate biases from heterogeneous sequencing technologies and coverage levels. Our analysis indicates that the San population of southern Africa diverged from other human populations approximately 108-157 thousand years ago, that Eurasians diverged from an ancestral African population 38-64 thousand years ago, and that the effective population size of the ancestors of all modern humans was ～9,000.     

The extent of linkage disequilibrium in Arabidopsis thaliana.

Linkage disequilibrium (LD), the nonrandom occurrence of alleles in haplotypes, has long been of interest to population geneticists. Recently, the rapidly increasing availability of genomic polymorphism data has fueled interest in LD as a tool for fine-scale mapping, in particular for human disease loci. The chromosomal extent of LD is crucial in this context, because it determines how dense a map must be for associations to be detected and, conversely, limits how finely loci may be mapped. Arabidopsis thaliana is expected to harbor unusually extensive LD because of its high degree of selfing. Several polymorphism studies have found very strong LD within individual loci, but also evidence of some recombination. Here we investigate the pattern of LD on a genomic scale and show that in global samples, LD decays within approximately 1 cM, or 250 kb. We also show that LD in local populations may be much stronger than that of global populations, presumably as a result of founder events. The combination of a relatively high level of polymorphism and extensive haplotype structure bodes well for developing a genome-wide LD map in A. thaliana.     

Nitrification by plants that also fix nitrogen

Nitrification is a key stage in the nitrogen cycle; it enables the transformation of nitrogen into an oxidized, inorganic state. The availability of nitrates produced by this process often limits primary productivity and is an important determinant in plant community ecology and biodiversity. Chemoautotrophic prokaryotes are recognized as the main facilitators of this process, although heterotrophic nitrification by fungi may be significant under certain conditions. However, there has been neither biochemical nor ecological evidence to support nitrification by photoautotrophic plants. Here we show how certain legumes that accumulate the toxin, 3-nitropropionic acid, generate oxidized inorganic nitrogen in their shoots, which is returned to the soil in their litter. In nitrogen-fixing populations this 'new' nitrate and nitrite can be derived from the assimilation of nitrogen gas. Normally, the transformation of elemental nitrogen from the atmosphere into a fixed oxidized form (as nitrate) is represented in the nitrogen cycle as a multiphasic process involving several different organisms. We show how this can occur in a single photoautotrophic organism, representing a previously undescribed feature of this biogeochemical cycle.     

Immunogenicity of a highly attenuated MVA smallpox vaccine and protection against monkeypox

The potential use of smallpox as a biological weapon has led to the production and stockpiling of smallpox vaccine and the immunization of some healthcare workers. Another public health goal is the licensing of a safer vaccine that could benefit the millions of people advised not to take the current one because they or their contacts have increased susceptibility to severe vaccine side effects. As vaccines can no longer be tested for their ability to prevent smallpox, licensing will necessarily include comparative immunogenicity and protection studies in non-human primates. Here we compare the highly attenuated modified vaccinia virus Ankara (MVA) with the licensed Dryvax vaccine in a monkey model. After two doses of MVA or one dose of MVA followed by Dryvax, antibody binding and neutralizing titres and T-cell responses were equivalent or higher than those induced by Dryvax alone. After challenge with monkeypox virus, unimmunized animals developed more than 500 pustular skin lesions and became gravely ill or died, whereas vaccinated animals were healthy and asymptomatic, except for a small number of transient skin lesions in animals immunized only with MVA.