Interplay of Mre11 Nuclease with Dna2 plus Sgs1 in Rad51-Dependent Recombinational Repair

The Mre11/Rad50/Xrs2 complex initiates IR repair by binding to the end of a double-strand break, resulting in 5′ to 3′ exonuclease degradation creating a single-stranded 3′ overhang competent for strand invasion into the unbroken chromosome. The nuclease(s) involved are not well understood. Mre11 encodes a nuclease, but it has 3′ to 5′, rather than 5′ to 3′ activity. Furthermore, mutations that inactivate only the nuclease activity of Mre11 but not its other repair functions, mre11-D56N and mre11-H125N, are resistant to IR. This suggests that another nuclease can catalyze 5′ to 3′ degradation. One candidate nuclease that has not been tested to date because it is encoded by an essential gene is the Dna2 helicase/nuclease. We recently reported the ability to suppress the lethality of a dna2Δ with a pif1Δ. The dna2Δ pif1Δ mutant is IR-resistant. We have determined that dna2Δ pif1Δ mre11-D56N and dna2Δ pif1Δ mre11-H125N strains are equally as sensitive to IR as mre11Δ strains, suggesting that in the absence of Dna2, Mre11 nuclease carries out repair. The dna2Δ pif1Δ mre11-D56N triple mutant is complemented by plasmids expressing Mre11, Dna2 or dna2K1080E, a mutant with defective helicase and functional nuclease, demonstrating that the nuclease of Dna2 compensates for the absence of Mre11 nuclease in IR repair, presumably in 5′ to 3′ degradation at DSB ends. We further show that sgs1Δ mre11-H125N, but not sgs1Δ, is very sensitive to IR, implicating the Sgs1 helicase in the Dna2-mediated pathway

The synthesis, chain-packing simulation and long-term gas permeability of highly selective spirobifluorene-based polymers of intrinsic microporosity

Membranes composed of Polymers of Intrinsic Microporosity (SBF-PIMs) have potential for commercial gas separation. Here we report a combined simulation and experimental study to investigate the effect on polymer microporosity and gas permeability by placing simple substituents such as methyl, t-butyl and fused benzo groups onto PIMs derived from spirobifluorene (PIM-SBFs). It is shown that methyl or t-butyl substituents both cause a large increase in gas permeabilities with four methyl groups enhancing the concentration of ultramicropores (1.0 nm). Long-term ageing studies (>3.5 years) demonstrate the potential of PIM-SBFs as high-performance membrane materials for gas separations. In particular, the data for the PIM derived from tetramethyl substituted SBF reaches the proposed 2015 Robeson upper bound for O2/N2 and, hence, hold promise for the oxygen or nitrogen enrichment of air. Mixed gas permeation measurements for CO2/CH4 of the aged PIM-SBFs also demonstrate their potential for natural gas or biogas upgrading

Durable Near-Complete Response to Anti-PD-1 Checkpoint Immunotherapy in a Refractory Malignant Solitary Fibrous Tumor of the Pleura

Solitary fibrous tumor of the pleura is a rare and usually benign primary neoplasm arising from mesenchymal cells of the submesothelial tissue. We present here the case of a patient diagnosed with CD34-positive advanced malignant solitary fibrous tumor of the pleura whose disease failed to respond to combination cytotoxic chemotherapy agents, but demonstrated a prompt near-complete response to checkpoint blockade treatment using the anti-programmed death (PD)-1 monoclonal antibody pembrolizumab, based on tumor molecular profiling revealing tumoral expression positivity for both programmed death-ligand 1 (PD-L1) and PD-1. The patient experienced minimal adverse effects from the treatment with durable favorable response lasting up to cycle 26

Binaural specialisation in human auditory cortex: an fMRI investigation of interaural correlation sensitivity

A listener's sensitivity to the interaural correlation (IAC) of sound plays an important role in several phenomena in binaural hearing. Although IAC has been examined extensively in neurophysiological studies in animals and in psychophysical studies in humans, little is known about the neural basis of sensitivity to IAC in humans. The present study employed functional magnetic resonance imaging to measure blood oxygen level-dependent (BOLD) activity in auditory brainstem and cortical structures in human listeners during presentation of band-pass noise stimuli between which IAC was varied systematically. The stimuli evoked significant bilateral activation in the inferior colliculus, medial geniculate body, and auditory cortex. There was a significant positive relationship between BOLD activity and IAC which was confined to a distinct subregion of primary auditory cortex located bilaterally at the lateral extent of Heschl's gyrus. Comparison with published anatomical data indicated that this area may also be cytoarchitecturally distinct. Larger differences in activation were found between levels of IAC near unity than between levels near zero. This response pattern is qualitatively compatible with previous measures of psychophysical and neurophysiological sensitivity to IAC

Mutation Testing as a Safety Net for Test Code Refactoring

Refactoring is an activity that improves the internal structure of the code without altering its external behavior. When performed on the production code, the tests can be used to verify that the external behavior of the production code is preserved. However, when the refactoring is performed on test code, there is no safety net that assures that the external behavior of the test code is preserved. In this paper, we propose to adopt mutation testing as a means to verify if the behavior of the test code is preserved after refactoring. Moreover, we also show how this approach can be used to identify the part of the test code which is improperly refactored

Assessment of C++ object-oriented mutation operators: A selective mutation approach

Mutation testing is an effective but costly testing technique. Several studies have observed that some mutants can be redundant and therefore removed without affecting its effectiveness. Similarly, some mutants may be more effective than others in guiding the tester on the creation of high‐quality test cases. On the basis of these findings, we present an assessment of C++ class mutation operators by classifying them into 2 rankings: the first ranking sorts the operators on the basis of their degree of redundancy and the second regarding the quality of the tests they help to design. Both rankings are used in a selective mutation study analysing the trade‐off between the reduction achieved and the effectiveness when using a subset of mutants. Experimental results consistently show that leveraging the operators at the top of the 2 rankings, which are different, lead to a significant reduction in the number of mutants with a minimum loss of effectiveness