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Break-induced replication (BIR) proceeds via a migrating D-loop for hundreds of kilobases and is highly mutagenic. Previous studies identified long single-stranded (ss) nascent DNA that accumulates during leading strand synthesis to be a target for DNA damage and a primary source of BIR-induced mutagenesis. Here, we describe a new important source of mutagenic ssDNA formed during BIR: the ssDNA template for leading strand BIR synthesis formed during D-loop migration. Specifically, we demonstrate that this D-loop bottom template strand (D-BTS) is susceptible to APOBEC3A (A3A)-induced DNA lesions leading to mutations associated with BIR. Also, we demonstrate that BIR-associated ssDNA promotes an additional type of genetic instability: replication slippage between microhomologies stimulated by inverted DNA repeats. Based on our results we propose that these events are stimulated by both known sources of ssDNA formed during BIR, nascent DNA formed by leading strand synthesis, and the D-BTS that we describe here. Together we report a new source of mutagenesis during BIR that may also be shared by other homologous recombination pathways driven by D-loop repair synthesis.

Microhomology-mediated break-induced replication (MMBIR) is a DNA repair pathway initiated by polymerase template switching at microhomology, which can produce templated insertions that initiate chromosomal rearrangements leading to neurological and metabolic diseases, and promote complex genomic rearrangements (CGRs) found in cancer. Yet, how often templated insertions accumulate from processes like MMBIR in genomes is poorly understood due to difficulty in directly identifying these events by whole genome sequencing (WGS). Here, by using our newly developed MMBSearch software, we directly detect such templated insertions (MMB-TIs) in human genomes and report substantial differences in frequency and complexity of MMB-TI events between normal and cancer cells. Through analysis of 71 cancer genomes from The Cancer Genome Atlas (TCGA), we observed that MMB-TIs readily accumulate de novo across several cancer types, with particularly high accumulation in some breast and lung cancers. By contrast, MMB-TIs appear only as germline variants in normal human fibroblast cells, and do not accumulate as de novo somatic mutations. Finally, we performed WGS on a lung adenocarcinoma patient case and confirmed MMB-TI-initiated chromosome fusions that disrupted potential tumor suppressors and induced chromothripsis-like CGRs. Based on our findings we propose that MMB-TIs represent a trigger for widespread genomic instability and tumor evolution.

Microhomology-mediated break-induced replication (MMBIR) is a mechanism of polymerase template switching at microhomology, which can produce complex genomic rearrangements (CGRs), underlies neurological and metabolic diseases, and contributes to cancer development. Yet, the extent of MMBIR activity in genomes is poorly understood due to difficulty in directly identifying MMBIR events by whole genome sequencing (WGS). Here, by using our newly developed MMBSearch software, we directly detect MMBIR events in human genomes and report substantial differences in frequency and complexity of MMBIR events between normal and cancer cells. MMBIR events appear only as germline variants in normal human fibroblast cells but readily accumulate de novo across several cancer types. Detailed analysis of MMBIR mutations in lung adenocarcinomas revealed MMBIR-initiated chromosome fusions that disrupted potential tumor suppressor genes and induced CGRs. Our findings document MMBIR as a trigger for widespread genomic instability and highlight MMBIR as a potential driver of tumor evolution.

In this work, we present a local intrinsic rule that we developed, dubbed IP, inspired by the Infomax rule. Like Infomax, this rule works by controlling the gain and bias of a neuron to regulate its rate of fire. We discuss the biological plausibility of the IP rule and compare it to batch normalisation. We demonstrate that the IP rule improves learning in deep networks, and provides networks with considerable robustness to increases in synaptic learning rates. We also sample the error gradients during learning and show that the IP rule substantially increases the size of the gradients over the course of learning. This suggests that the IP rule solves the vanishing gradient problem. Supplementary analysis is provided to derive the equilibrium solutions that the neuronal gain and bias converge to using our IP rule. An analysis demonstrates that the IP rule results in neuronal information potential similar to that of Infomax, when tested on a fixed input distribution. We also show that batch normalisation also improves information potential, suggesting that this may be a cause for the efficacy of batch normalisation-an open problem at the time of this writing.

A man who's career began as a biochemist and ended as a botanist. A man who under the instruction of a Professor Butt realized what he wanted to do for the rest of his life. This was the story of Professor Jonathan Poulton, Emeritus Faculty at the University of Iowa. He comes from an English family with a religious background and ended up in the sciences when he decided to pursue biochemistry over a dinner with a family friend. He earned his PhD at Oxford University and traveled abroad to conduct research. Poulton eventually landed himself at the University of Iowa on a frigid day but this wasn't enough to deter him! Poulton became a professor of botany and conducted research on how plants stored and released cyanide from their leaves. Later in his career, his research focused on uncovering some of the genes in the Arabidopsis thaliana genome (a small flowering plant). His career was also comprised of several teaching experiences such as but not limited to Principles of Biology and Botany. If you would like to learn more about his outstanding career and unlikely story, read Professor Jonathan Poulton's profile story!

We examine the problem of finding the minimum number of Pauli measurements needed to uniquely determine an arbitrary $n$-qubit pure state among all quantum states. We show that only 11 Pauli measurements are needed to determine an arbitrary two-qubit pure state compared to the full quantum state tomography with 16 measurements, and only 31 Pauli measurements are needed to determine an arbitrary three-qubit pure state compared to the full quantum state tomography with 64 measurements. We demonstrate that our protocol is robust under depolarizing error with simulated random pure states. We experimentally test the protocol on two- and three-qubit systems with nuclear magnetic resonance techniques. We show that the pure-state tomography protocol saves us a number of measurements without considerable loss of fidelity. We compare our protocol with same-size sets of randomly selected Pauli operators and find that our selected set of Pauli measurements significantly outperforms those random sampling sets. As a direct application, our scheme can also be used to reduce the number of settings needed for pure-state tomography in quantum optical systems.

We discuss a method to construct quantum codes correcting amplitude damping errors via code concatenation. The inner codes are chosen as asymmetric Calderbank-Shor-Steane (CSS) codes. By concatenating with outer codes correcting symmetric errors, many new codes with good parameters are found, which are better than the amplitude damping codes obtained by any previously known construction., 5 pages

We discuss a method to adapt the codeword stabilized (CWS) quantum code framework to the problem of finding asymmetric quantum codes. We focus on the corresponding Pauli error models for amplitude damping noise and phase damping noise. In particular, we look at codes for Pauli error models that correct one or two amplitude damping errors. Applying local Clifford operations on graph states, we are able to exhaustively search for all possible codes up to length $9$. With a similar method, we also look at codes for the Pauli error model that detect a single amplitude error and detect multiple phase damping errors. Many new codes with good parameters are found, including nonadditive codes and degenerate codes., 5 pages