The Pacific oyster Crassostrea gigas belongs to one of the most species-rich but genomically poorly explored phyla, the Mollusca. Here we report the sequencing and assembly of the oyster genome using short reads and a fosmid-pooling strategy, along with transcriptomes of development and stress response and the proteome of the shell. The oyster genome is highly polymorphic and rich in repetitive sequences, with some transposable elements still actively shaping variation. Transcriptome studies reveal an extensive set of genes responding to environmental stress. The expansion of genes coding for heat shock protein 70 and inhibitors of apoptosis is probably central to the oyster's adaptation to sessile life in the highly stressful intertidal zone. Our analyses also show that shell formation in molluscs is more complex than currently understood and involves extensive participation of cells and their exosomes. The oyster genome sequence fills a void in our understanding of the Lophotrochozoa.Oceans cover approximately 71% of the Earth's surface and harbour most of the phylum diversity of the animal kingdom. Understanding marine biodiversity and its evolution remains a major challenge. The Pacific oyster C. gigas (Thunberg, 1793) is a marine bivalve belonging to the phylum Mollusca, which contains the largest number of described marine animal species 1 . Molluscs have vital roles in the functioning of marine, freshwater and terrestrial ecosystems, and have had major effects on humans, primarily as food sources but also as sources of dyes, decorative pearls and shells, vectors of parasites, and biofouling or destructive agents. Many molluscs are important fishery and aquaculture species, as well as models for studying neurobiology, biomineralization, ocean acidification and adaptation to coastal environments under climate change 2,3 . As the most speciose member of the Lophotrochozoa, phylum Mollusca is central to our understanding of the biology and evolution of this superphylum of protostomes.As sessile marine animals living in estuarine and intertidal regions, oysters must cope with harsh and dynamically changing environments. Abiotic factors such as temperature and salinity fluctuate wildly, and toxic metals and desiccation also pose serious challenges. Filter-feeding oysters face tremendous exposure to microbial pathogens. Oysters do have a notable physical line of defence against predation and desiccation in the formation of thick calcified shells, a key evolutionary innovation making molluscs a successful group. However, acidification of the world's oceans by uptake of anthropogenic carbon dioxide poses a potentially serious threat to this ancient adaptation 4 . Understanding biomineralization and molluscan shell formation is, thus, a major area of interest 5 . Crassostrea gigas is also an interesting model for developmental biology owing to its mosaic development with typical molluscan stages, including trochophore and veliger larvae and metamorphosis.A complete genome sequence of C. gigas would enable a more th...

The genome of the mesopolyploid crop species Brassica rapaThe Brassica rapa Genome Sequencing Project Consortium 1 Abstract:The Brassicaceae family which includes Arabidopsis thaliana, is a natural priority for reaching beyond botanical models to more deeply sample angiosperm genomic and functional diversity. Here we report the draft genome sequence and its annoation of Brassica rapa, one of the two ancestral species of oilseed rape. We modeled 41,174 protein-coding genes in the B. rapa genome. B. rapa has experienced only the second genome triplication reported to date, with its close relationship to A. thaliana providing a useful outgroup for investigating many consequences of triplication for its structural and functional evolution. The extent of gene loss (fractionation) among triplicated genome segments varies, with one copy containing a greater proportion of genes expected to have been present in its ancestor (70%) than the remaining two (46% and 36%). Both a generally rapid evolutionary rate, and specific copy number amplifications of particular gene families, may contribute to the remarkable propensity of Brassica species for the development of new morphological variants. The B. rapa genome provides a new resource for comparative and evolutionary analysis of the Brassicaceae genomes and also a platform for genetic improvement of Brassica oil and vegetable crops.2

The objective of this study was to identify and characterize a self-renewing subpopulation of human ovarian tumor cells (ovarian cancer-initiating cells, OCICs) fully capable of serial propagation of their original tumor phenotype in animals.

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The draft genome of the pear (Pyrus bretschneideri) using a combination of BAC-by-BAC and next-generation sequencing is reported. A 512.0-Mb sequence corresponding to 97.1% of the estimated genome size of this highly heterozygous species is assembled with 1943 coverage. High-density genetic maps comprising 2005 SNP markers anchored 75.5% of the sequence to all 17 chromosomes. The pear genome encodes 42,812 protein-coding genes, and of these,~28.5% encode multiple isoforms. Repetitive sequences of 271.9 Mb in length, accounting for 53.1% of the pear genome, are identified. Simulation of eudicots to the ancestor of Rosaceae has reconstructed nine ancestral chromosomes. Pear and apple diverged from each other~5.4-21.5 million years ago, and a recent whole-genome duplication (WGD) event must have occurred 30-45 MYA prior to their divergence, but following divergence from strawberry. When compared with the apple genome sequence, size differences between the apple and pear genomes are confirmed mainly due to the presence of repetitive sequences predominantly contributed by transposable elements (TEs), while genic regions are similar in both species. Genes critical for self-incompatibility, lignified stone cells (a unique feature of pear fruit), sorbitol metabolism, and volatile compounds of fruit have also been identified. Multiple candidate SFB genes appear as tandem repeats in the S-locus region of pear; while lignin synthesis-related gene family expansion and highly expressed gene families of HCT, C39H, and CCOMT contribute to high accumulation of both G-lignin and S-lignin. Moreover, alpha-linolenic acid metabolism is a key pathway for aroma in pear fruit.

Excitotoxicity, the specific type of neurotoxicity mediated by glutamate, may be the missing link between ischemia and neuronal death, and intervening the mechanistic steps that lead to excitotoxicity can prevent stroke damage. Interest in excitotoxicity began fifty years ago when monosodium glutamate was found to be neurotoxic. Evidence soon demonstrated that glutamate is not only the primary excitatory neurotransmitter in the adult brain, but also a critical transmitter for signaling neurons to degenerate following stroke. The finding led to a number of clinical trials that tested inhibitors of excitotoxicity in stroke patients. Glutamate exerts its function in large by activating the calcium-permeable ionotropic NMDA receptor (NMDAR), and different subpopulations of the NMDAR may generate different functional outputs, depending on the signaling proteins directly bound or indirectly coupled to its large cytoplasmic tail. Synaptic activity activates the GluN2A subunit-containing NMDAR, leading to activation of the pro-survival signaling proteins Akt, ERK, and CREB. During a brief episode of ischemia, the extracellular glutamate concentration rises abruptly, and stimulation of the GluN2B-containing NMDAR in the extrasynaptic sites triggers excitotoxic neuronal death via PTEN, cdk5, and DAPK1, which are directly bound to the NMDAR, nNOS, which is indirectly coupled to the NMDAR via PSD95, and calpain, p25, STEP, p38, JNK, and SREBP1, which are further downstream. This review aims to provide a comprehensive summary of the literature on excitotoxicity and our perspectives on how the new generation of excitotoxicity inhibitors may succeed despite the failure of the previous generation of drugs.

In this historical comparison study, the transcatheter pacemaker met the prespecified safety and efficacy goals; it had a safety profile similar to that of a transvenous system while providing low and stable pacing thresholds. (Funded by Medtronic; Micra Transcatheter Pacing Study ClinicalTrials.gov number, NCT02004873.).

INTRODUCTION Parkinson’s disease (PD) is the second most common neurodegenerative disorder that leads to slowness of movement, tremor, rigidity and in the later stages of PD, cognitive impairment. Pathologically PD is characterized by the accumulation of α-synuclein in Lewy bodies and neurites. There is degeneration of neurons throughout the nervous system with the degeneration of dopamine neurons in the substantia nigra pars compacta leading to the major symptoms of PD. RATIONALE In the brains of PD patients, pathologic α-synuclein seems to spread from cell-to-cell via self-amplification, propagation, and transmission in a stereotypical and topographical pattern among neighboring cells and/or anatomically connected brain regions. The spread or transmission of pathologic α-synuclein is emerging as potentially important driver of PD pathogenesis. The underlying mechanisms and molecular entities responsible for the transmission of pathologic α-synuclein from cell-to-to cell are not known, but the entry of pathologic α-synuclein into neurons is thought to occur, in part through an active clathrin-dependent endocytic process. RESULTS Using recombinant α-synuclein pre-formed fibrils (PFF) as a model system to study the transmission of misfolded α-synuclein from neuron to neuron, we screened a library encoding transmembrane proteins for α-synuclein-biotin PFF binding candidates via detection by streptavidin-AP (alkaline phosphatase) staining. Three positive clones were identified that bind α-synuclein PFF and include lymphocyte-activation gene 3 (LAG3), neurexin 1β and amyloid beta precursor-like protein 1 (APLP1). Of these three transmembrane proteins, LAG3 demonstrated the highest ratio of selectivity for α-synuclein PFF over the α-synuclein monomer. α-Synuclein PFF binds to LAG3 in a saturable manner (Kd = 77 nM), while the α-synuclein monomer does not bind to LAG3. Co-immunoprecipitation also suggests that pathological α-synuclein PFF specifically binds to LAG3. Tau PFF, β-amyloid oligomer and β-amyloid PFF do not bind LAG3 indicating that LAG3 is specific for α-synuclein PFF. The internalization of α-synuclein PFF involves LAG3 since deletion of LAG3 reduces the endocytosis of α-synuclein PFF. LAG3 colocalizes with the endosomal GTPases, Rab5 and Rab7 and co-endocytoses with pathologic α-synuclein. Neuron-to-neuron transmission of pathologic α-synuclein and the accompanying pathology and neurotoxicity is substantially attenuated by deletion of LAG3 or by LAG3 antibodies. The lack of LAG3 also substantially delayed α-synuclein PFF induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo. CONCLUSION We discovered that pathologic α-synuclein transmission and toxicity is initiated by binding to LAG3 and that neuron-to-neuron transmission of pathological α-synuclein involves the endocytosis of exogenous α-synuclein PFF by the engagement of LAG3 on neurons. Depletion of LAG3 or antibodies to LAG3 substantially reduce the pathology set in motion by the transmission of pathologic α-...