528 research outputs found

    Genomic aberrations in normal tissue adjacent to HER2-amplified breast cancers: field cancerization or contaminating tumor cells?

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    Field cancerization effects as well as isolated tumor cell foci extending well beyond the invasive tumor margin have been described previously to account for local recurrence rates following breast conserving surgery despite adequate surgical margins and breast radiotherapy. To look for evidence of possible tumor cell contamination or field cancerization by genetic effects, a pilot study (Study 1: 12 sample pairs) followed by a verification study (Study 2: 20 sample pairs) were performed on DNA extracted from HER2-positive breast tumors and matching normal adjacent mammary tissue samples excised 1-3 cm beyond the invasive tumor margin. High-resolution molecular inversion probe (MIP) arrays were used to compare genomic copy number variations, including increased HER2 gene copies, between the paired samples; as well, a detailed histologic and immunohistochemical (IHC) re-evaluation of all Study 2 samples was performed blinded to the genomic results to characterize the adjacent normal tissue composition bracketing the DNA-extracted samples. Overall, 14/32 (44 %) sample pairs from both studies produced genome-wide evidence of genetic aberrations including HER2 copy number gains within the adjacent normal tissue samples. The observed single-parental origin of monoallelic HER2 amplicon haplotypes shared by informative tumor-normal pairs, as well as commonly gained loci elsewhere on 17q, suggested the presence of contaminating tumor cells in the genomically aberrant normal samples. Histologic and IHC analyses identified occult 25-200 μm tumor cell clusters overexpressing HER2 scattered in more than half, but not all, of the genomically aberrant normal samples re-evaluated, but in none of the genomically normal samples. These genomic and microscopic findings support the conclusion that tumor cell contamination rather than genetic field cancerization represents the likeliest cause of local clinical recurrence rates following breast conserving surgery, and mandate caution in assuming the genomic normalcy of histologically benign appearing peritumor breast tissue

    Can we constrain interior structure of rocky exoplanets from mass and radius measurements?

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    We present an inversion method based on Bayesian analysis to constrain the interior structure of terrestrial exoplanets, in the form of chemical composition of the mantle and core size. Specifically, we identify what parts of the interior structure of terrestrial exoplanets can be determined from observations of mass, radius, and stellar elemental abundances. We perform a full probabilistic inverse analysis to formally account for observational and model uncertainties and obtain confidence regions of interior structure models. This enables us to characterize how model variability depends on data and associated uncertainties. We test our method on terrestrial solar system planets and find that our model predictions are consistent with independent estimates. Furthermore, we apply our method to synthetic exoplanets up to 10 Earth masses and up to 1.7 Earth radii as well as to exoplanet Kepler-36b. Importantly, the inversion strategy proposed here provides a framework for understanding the level of precision required to characterize the interior of exoplanets. Our main conclusions are: (1) observations of mass and radius are sufficient to constrain core size; (2) stellar elemental abundances (Fe, Si, Mg) are key constraints to reduce degeneracy in interior structure models and to constrain mantle composition; (3) the inherent degeneracy in determining interior structure from mass and radius observations does not only depend on measurement accuracies but also on the actual size and density of the exoplanet. We argue that precise observations of stellar elemental abundances are central in order to place constraints on planetary bulk composition and to reduce model degeneracy. [...]Comment: 19 pages, 18 figures, accepted in Astronomy & Astrophysics (no changes to previous version

    Near-Memory Parallel Indexing and Coalescing: Enabling Highly Efficient Indirect Access for SpMV

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    Sparse matrix vector multiplication (SpMV) is central to numerous data-intensive applications, but requires streaming indirect memory accesses that severely degrade both processing and memory throughput in state-of-the-art architectures. Near-memory hardware units, decoupling indirect streams from processing elements, partially alleviate the bottleneck, but rely on low DRAM access granularity, which is highly inefficient for modern DRAM standards like HBM and LPDDR. To fully address the end-to-end challenge, we propose a low-overhead data coalescer combined with a near-memory indirect streaming unit for AXI-Pack, an extension to the widespread AXI4 protocol packing narrow irregular stream elements onto wide memory buses. Our combined solution leverages the memory-level parallelism and coalescence of streaming indirect accesses in irregular applications like SpMV to maximize the performance and bandwidth efficiency attained on wide memory interfaces. Our solution delivers an average speedup of 8x in effective indirect access, often reaching the full memory bandwidth. As a result, we achieve an average end-to-end speedup on SpMV of 3x. Moreover, our approach demonstrates remarkable on-chip efficiency, requiring merely 27kB of on-chip storage and a very compact implementation area of 0.2-0.3mm^2 in a 12nm node.Comment: 6 pages, 6 figures. Submitted to DATE 202

    Propriété intellectuelle et ressources génétiques : la problématique des aliments de base dans une perspective de politique du développement

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    Les ressources génétiques des plantes agricoles cultivées englobent les variétés modernes, produits issus de programmes d’amélioration génétique publics ou privés, les variétés traditionnelles ou locales (races de pays), obtenues par des croisements et sélections naturels ou effectués par des paysans, ainsi que les espèces sauvages apparentées. Par ressources génétiques, il faut donc comprendre un matériel génétique de valeur actuelle ou future. Dans le cas du maïs, les ressources génétiques ..

    Geistiges Eigentum und genetische Ressourcen : die Problematik bei Grundnahrungsmitteln aus einer Entwicklungspolitischen Perspektive

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    Zu den genetischen Ressourcen landwirtschaftlicher Kulturpflanzen gehören die modernen Sorten als Produkte öffentlicher oder privater Züchtungsprogramme, die traditionellen Sorten oder Landsorten, entstanden durch natürliche oder von Bauern gemachte Kreuzungen und Auslese, sowie die verwandten Wildarten. Unter genetische Ressourcen verstehen wir also Genmaterial von gegenwärtigem oder künftigem Wert. Beim Mais umfassen die genetischen Ressourcen die modernen Hochleistungssorten, hergestellt u..

    Geistiges Eigentum und genetische Ressourcen : die Problematik bei Grundnahrungsmitteln aus einer Entwicklungspolitischen Perspektive

    Get PDF
    Zu den genetischen Ressourcen landwirtschaftlicher Kulturpflanzen gehören die modernen Sorten als Produkte öffentlicher oder privater Züchtungsprogramme, die traditionellen Sorten oder Landsorten, entstanden durch natürliche oder von Bauern gemachte Kreuzungen und Auslese, sowie die verwandten Wildarten. Unter genetische Ressourcen verstehen wir also Genmaterial von gegenwärtigem oder künftigem Wert. Beim Mais umfassen die genetischen Ressourcen die modernen Hochleistungssorten, hergestellt u..

    Insights from Basilisk: Are Open-Source EDA Tools Ready for a Multi-Million-Gate, Linux-Booting RV64 SoC Design?

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    Designing complex, multi-million-gate application-specific integrated circuits requires robust and mature electronic design automation (EDA) tools. We describe our efforts in enhancing the open-source Yosys+Openroad EDA flow to implement Basilisk, a fully open-source, Linux-booting RV64GC system-on-chip (SoC) design. We analyze the quality-of-results impact of our enhancements to synthesis tools, interfaces between EDA tools, logic optimization scripts, and a newly open-sourced library of optimized arithmetic macro-operators. We also introduce a streamlined physical design flow with an improved power grid and cell placement integration. Our Basilisk SoC design was taped out in IHP's open 130 nm technology. It achieves an operating frequency of 77 MHz (51 logic levels) under typical conditions, a 2.3x improvement compared to the baseline open-source EDA flow, while also reducing logic area by 1.6x. Furthermore, tool runtime was reduced by 2.5x, and peak RAM usage decreased by 2.9x. Through collaboration with EDA tool developers and domain experts, Basilisk establishes solid "proof of existence" for a fully open-source EDA flow used in designing a competitive multi-million-gate digital SoC.Comment: 8 pages, 6 figures, submitted at IWLS 202

    Positive allosteric modulation as a potential therapeutic strategy in anti-NMDA receptor encephalitis

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    N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors important for synaptic plasticity, memory, and neuropsychiatric health. NMDAR hypofunction contributes to multiple disorders, including anti-NMDAR encephalitis (NMDARE), an autoimmune disease of the CNS associated with GluN1 antibody-mediated NMDAR internalization. Here we characterize the functional/pharmacological consequences of exposure to CSF from female human NMDARE patients on NMDAR function, and we characterize the effects of intervention with recently described positive allosteric modulators (PAMs) of NMDARs. Incubation (48 h) of rat hippocampal neurons of both sexes in confirmed NMDARE patient CSF, but not control CSF, attenuated NMDA-induced current. Residual NMDAR function was characterized by lack of change in channel open probability, indiscriminate loss of synaptic and extrasynaptic NMDARs, and indiscriminate loss of GluN2B-containing and GluN2B-lacking NMDARs. NMDARs tagged with N-terminal pHluorin fluorescence demonstrated loss of surface receptors. Thus, function of residual NMDARs following CSF exposure was indistinguishable from baseline, and deficits appear wholly accounted for by receptor loss. Coapplication of CSF and PAMs of NMDARs (SGE-301 or SGE-550, oxysterol-mimetic) for 24 h restored NMDAR function following 24 h incubation in patient CSF. Curiously, restoration of NMDAR function was observed despite washout of PAMs before electrophysiological recordings. Subsequent experiments suggested that residual allosteric potentiation of NMDAR function explained the persistent rescue. Further studies of the pathogenesis of NMDARE and intervention with PAMs may inform new treatments for NMDARE and other disorders associated with NMDAR hypofunction.SIGNIFICANCE STATEMENTAnti-N-methyl-d-aspartate receptor encephalitis (NMDARE) is increasingly recognized as an important cause of sudden-onset psychosis and other neuropsychiatric symptoms. Current treatment leaves unmet medical need. Here we demonstrate cellular evidence that newly identified positive allosteric modulators of NMDAR function may be a viable therapeutic strategy.</jats:p
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