Structural variant analysis of a cancer reference cell line sample using multiple sequencing technologies.

BACKGROUND: The cancer genome is commonly altered with thousands of structural rearrangements including insertions, deletions, translocation, inversions, duplications, and copy number variations. Thus, structural variant (SV) characterization plays a paramount role in cancer target identification, oncology diagnostics, and personalized medicine. As part of the SEQC2 Consortium effort, the present study established and evaluated a consensus SV call set using a breast cancer reference cell line and matched normal control derived from the same donor, which were used in our companion benchmarking studies as reference samples. RESULTS: We systematically investigated somatic SVs in the reference cancer cell line by comparing to a matched normal cell line using multiple NGS platforms including Illumina short-read, 10X Genomics linked reads, PacBio long reads, Oxford Nanopore long reads, and high-throughput chromosome conformation capture (Hi-C). We established a consensus SV call set of a total of 1788 SVs including 717 deletions, 230 duplications, 551 insertions, 133 inversions, 146 translocations, and 11 breakends for the reference cancer cell line. To independently evaluate and cross-validate the accuracy of our consensus SV call set, we used orthogonal methods including PCR-based validation, Affymetrix arrays, Bionano optical mapping, and identification of fusion genes detected from RNA-seq. We evaluated the strengths and weaknesses of each NGS technology for SV determination, and our findings provide an actionable guide to improve cancer genome SV detection sensitivity and accuracy. CONCLUSIONS: A high-confidence consensus SV call set was established for the reference cancer cell line. A large subset of the variants identified was validated by multiple orthogonal methods.

Urca Cooling in Neutron Star Crusts and Oceans: Effects of Nuclear Excitations.

The excited-state structure of atomic nuclei can modify nuclear processes in stellar environments. In this Letter, we study the influence of nuclear excitations on Urca cooling (repeated back-and-forth ß decay and electron capture in a pair of nuclear isotopes) in the crust and ocean of neutron stars. We provide for the first time an expression for Urca process neutrino luminosity which accounts for a thermal Boltzmann distribution of excited states in both members of an Urca pair. We use our new formula with state-of-the-art nuclear structure inputs to compute neutrino luminosities of candidate Urca cooling pairs. Our nuclear inputs consist of the latest experimental data supplemented with calculations using the projected shell model. We show that, in contrast to previous results that only consider the ground states of both nuclei in the pair, our calculated neutrino luminosities for different Urca pairs vary sensitively with the environment temperature and can be radically different from those obtained in the one-transition approximation. We find that nuclear excitations can lead to an enhancement in total Urca neutrino luminosities in the accreted neutron star crust by about 5 times as compared with the previous Urca results, which is expected to cause significant observational effects.

Misannotated Multi-Nucleotide Variants in Public Cancer Genomics Datasets Lead to Inaccurate Mutation Calls with Significant Implications.

Although next-generation sequencing is widely used in cancer to profile tumors and detect variants, most somatic variant callers used in these pipelines identify variants at the lowest possible granularity, single-nucleotide variants (SNV). As a result, multiple adjacent SNVs are called individually instead of as a multi-nucleotide variants (MNV). With this approach, the amino acid change from the individual SNV within a codon could be different from the amino acid change based on the MNV that results from combining SNV, leading to incorrect conclusions about the downstream effects of the variants. Here, we analyzed 10,383 variant call files (VCF) from the Cancer Genome Atlas (TCGA) and found 12,141 incorrectly annotated MNVs. Analysis of seven commonly mutated genes from 178 studies in cBioPortal revealed that MNVs were consistently missed in 20 of these studies, whereas they were correctly annotated in 15 more recent studies. At the BRAF V600 locus, the most common example of MNV, several public datasets reported separate BRAF V600E and BRAF V600M variants instead of a single merged V600K variant. VCFs from the TCGA Mutect2 caller were used to develop a solution to merge SNV to MNV. Our custom script used the phasing information from the SNV VCF and determined whether SNVs were at the same codon and needed to be merged into MNV before variant annotation. This study shows that institutions performing NGS sequencing for cancer genomics should incorporate the step of merging MNV as a best practice in their pipelines. SIGNIFICANCE: Identification of incorrect mutation calls in TCGA, including clinically relevant BRAF V600 and KRAS G12, will influence research and potentially clinical decisions.

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The bay is the most susceptible area in the marine to human interference. It is of significance for maintaining ecological security of the bay to build an assessment framework of losses of bay ecosystem services caused by the C9 leakage event and evaluate it quantitatively. This study used market value, alternative cost, carbon tax and emergy analysis methods to construct a monetary value evaluation model for the lossses of key ecosystem services (food production, gas regulation, climate regulation, waste treatment, human health, nutrient cycling, species diversity maintenance, and recreation entertainment) caused by C9 leakage accident, and analyzed the losses of x-Bay ecosystem services. The results showed that total value of the losses of ecosystem services caused by C9 spill was 1.93×108 yuan, and the monetary value of loss per unit area was 1.19×108 yuan·km-2, which was more than 2800 times of the general marine oil spill events. Among all the components, the loss of food production services accounted for 77.1% of the total, being much higher than the impact of the general marine oil spills on human production and life. Our results could provide references to the assessment of ecosystem services loss caused by toxic substances like C9, and to the government decision-making and national territory spatial planning.

Role of the antiferromagnetic bulk spin structure on exchange bias.

The cooling field dependence of the exchange bias field in ferromagnet/antiferromagnet (FM/AF) multilayers demonstrates that the bulk AF spin structure plays a crucial role on the origin of exchange bias. FM/AF/FM trilayers were designed to eliminate any interlayer exchange coupling between the FM slabs. By choosing the magnetic cooling field, the AF is ordered below its Néel temperature with the FM layers fully saturated either parallel or antiparallel to each other. The significant difference in the exchange bias field between these two cooling configurations confirms that exchange bias cannot be a purely interfacial effect and that the bulk AF moments play a significant role in pinning the uncompensated spins at the AF/FM interface. This experiment also demonstrates that the mechanism responsible for coercivity enhancement has a different origin and is independent of the process that gives rise to exchange bias.

Dynamic spin-polarized resonant tunneling in magnetic tunnel junctions.

Precisely engineered tunnel junctions exhibit a long sought effect that occurs when the energy of the electron is comparable to the potential energy of the tunneling barrier. The resistance of metal-insulator-metal tunnel junctions oscillates with an applied voltage when electrons that tunnel directly into the barrier's conduction band interfere upon reflection at the classical turning points: the insulator-metal interface and the dynamic point where the incident electron energy equals the potential barrier inside the insulator. A model of tunneling between free electron bands using the exact solution of the Schrödinger equation for a trapezoidal tunnel barrier qualitatively agrees with experiment.

Asymmetric reversal in inhomogeneous magnetic heterostructures.

Asymmetric magnetization reversal is an unusual phenomenon in antiferromagnet/ferromagnet (AF/FM) exchange biased bilayers. We investigated this phenomenon in a simple model system experimentally and by simulation assuming inhomogeneously distributed interfacial AF moments. The results suggest that the observed asymmetry originates from the intrinsic broken symmetry of the system, which results in local incomplete domain walls parallel to the interface in reversal to negative saturation of the FM. The magneto-optical Kerr effect unambiguously confirms such an asymmetric reversal and a depth-dependent FM domain wall in accord with the magnetometry and simulations.

Anomalous spontaneous reversal in magnetic heterostructures.

We observe a thermally induced spontaneous magnetization reversal of epitaxial ferromagnet/antiferromagnet heterostructures under a constant applied magnetic field. Unlike any other magnetic system, the magnetization spontaneously reverses, aligning antiparallel to an applied field with decreasing temperature. We show that this unusual phenomenon is caused by the interfacial antiferromagnetic coupling overcoming the Zeeman energy of the ferromagnet. A significant temperature hysteresis exists, whose height and width can be tuned by the field applied during thermal cycling. The hysteresis originates from the intrinsic magnetic anisotropy in the system. The observation of this phenomenon leads to open questions in the general understanding of magnetic heterostructures. Moreover, this shows that in general heterogeneous nanostructured materials may exhibit unexpected phenomena absent in the bulk.

Depth profile of uncompensated spins in an exchange bias system.

We have used the unique spatial sensitivity of polarized neutron and soft x-ray beams in reflection geometry to measure the depth dependence of magnetization across the interface between a ferromagnet and an antiferromagnet. The net uncompensated magnetization near the interface responds to applied field, while uncompensated spins in the antiferromagnet bulk are pinned, thus providing a means to establish exchange bias.

Exchange bias and asymmetric reversal in nanostructured dot arrays.

The size dependence of exchange bias field HE and coercivity Hc was studied by measuring exchange biased Fe-FeF2 dot arrays in comparison with an unstructured exchange biased Fe-FeF2 bilayer. The domain sizes in the ferromagnet (FM) and the antiferromagnet (AFM) play an important role for exchange bias (EB), and thus interesting phenomena may be expected when the size of an EB system becomes comparable to these sizes. We observe drastic changes of HE and Hc in nanostructured Fe-FeF2, which are unexpected because they appear even at a structure size which is too large for matching with AFM or FM domain size to play a role. We propose that under certain conditions the hysteresis loop is affected differently in the two branches of the reversal by shape anisotropy due to patterning. This is possible because the EB induces a reversal asymmetry already in the unpatterned bilayer system.