Vertebrate DNA damage tolerance requires the C-terminus but not BRCT or transferase domains of REV1

REV1 is central to the DNA damage response of eukaryotes through an as yet poorly understood role in translesion synthesis. REV1 is a member of the Y-type DNA polymerase family and is capable of in vitro deoxycytidyl transferase activity opposite a range of damaged bases. However, non-catalytic roles for REV1 have been suggested by the Saccharomyces cerevisiae rev1-1 mutant, which carries a point mutation in the N-terminal BRCT domain, and the recently demonstrated ability of the mammalian protein to interact with each of the other translesion polymerases via its extreme C-terminus. Here, we show that a region adjacent to this polymerase interacting domain mediates an interaction with PCNA. These C-terminal domains of REV1 are necessary, although not sufficient, for effective tolerance of DNA damage in the avian cell line DT40, while the BRCT domain and transferase activity are not directly required. Together these data provide strong support for REV1 playing an important non-catalytic role in coordinating translesion synthesis. Further, unlike in budding yeast, rad18 is not epistatic to rev1 for DNA damage tolerance suggesting that REV1 and RAD18 play largely independent roles in the control of vertebrate translesion synthesis

Biventricular Assist Device Terminates Polymorphic Ventricular Tachycardia in Giant Cell Myocarditis

We present the case of a 55-year-old woman with giant cell myocarditis who experienced a rapid deterioration in her condition. As her heart failure progressed, she developed more ventricular ectopic beats, which culminated in a polymorphic ventricular tachycardia that did not improve despite immunosuppressive and antiarrhythmic therapy. Emergent biventricular assist device placement, however, did eliminate her arrhythmia

Measuring Redshift-Space Distortions using Photometric Surveys

We outline how redshift-space distortions (RSD) can be measured from the angular correlation function w({\theta}), of galaxies selected from photometric surveys. The natural degeneracy between RSD and galaxy bias can be minimized by comparing results from bins with top-hat galaxy selection in redshift, and bins based on the radial position of galaxy pair centres. This comparison can also be used to test the accuracy of the photometric redshifts. The presence of RSD will be clearly detectable with the next generation of photometric redshift surveys. We show that the Dark Energy Survey (DES) will be able to measure f(z){\sigma}_8(z) to a 1{\sigma} accuracy of (17 {\times} b)%, using galaxies drawn from a single narrow redshift slice centered at z = 1. Here b is the linear bias, and f is the logarithmic rate of change of the linear growth rate with respect to the scale factor. Extending to measurements of w({\theta}) for a series of bins of width 0.02(1 + z) over 0.5 < z < 1.4 will measure {\gamma} to a 1{\sigma} accuracy of 25%, given the model f = {\Omega}_m(z)^{\gamma}, and assuming a linear bias model that evolves such that b = 0.5 + z (and fixing other cosmological parameters). The accuracy of our analytic predictions is confirmed using mock catalogs drawn from simulations conducted by the MICE collaboration.Comment: Accepted by MNRAS, revisions include fixing of typos and clarification of the tex

Changes in the capacity of visual working memory in 5- to 10-year-olds

Using the Luck and Vogel change detection paradigm, we sought to investigate the capacity of visual working memory in 5-, 7-, and 10-year-olds. We found that performance on the task improved significantly with age and also obtained evidence that the capacity of visual working memory approximately doubles between 5 and 10 years of age, where it reaches adult levels of approximately three to four items

Structure and metallicity of phase V of hydrogen

A new phase V of hydrogen was recently claimed in experiments above 325 GPa and 300 K. Due to the extremely small sample size at such record pressures the measurements were limited to Raman spectroscopy. The experimental data on increase of pressure shows decreasing Raman activity and darkening of the sample, which suggests band-gap closure and impending molecular dissociation, but no definite conclusions could be reached. Furthermore, the available data is insufficient to determine the structure of phase V, which remains unknown. Introducing saddle-point ab initio random structure searching (sp-AIRSS), we find several new structural candidates of hydrogen which could describe the observed properties of phase V. We investigate hydrogen metallisation in the proposed candidate structures, and demonstrate that smaller band gaps are associated with longer bond lengths. We conclude that phase V is a stepping stone towards metallisation

Developing Novel Host-Based Therapies Targeting Microbicidal Responses in Macrophages and Neutrophils to Combat Bacterial Antimicrobial Resistance

Antimicrobial therapy has provided the main component of chemotherapy against bacterial pathogens. The effectiveness of this strategy has, however, been increasingly challenged by the emergence of antimicrobial resistance which now threatens the sustained utility of this approach. Humans and animals are constantly exposed to bacteria and have developed effective strategies to control pathogens involving innate and adaptive immune responses. Impaired pathogen handling by the innate immune system is a key determinant of susceptibility to bacterial infection. However, the essential components of this response, specifically those which are amenable to re-calibration to improve host defense, remain elusive despite extensive research. We provide a mini-review focusing on therapeutic targeting of microbicidal responses in macrophages and neutrophils to de-stress reliance on antimicrobial therapy. We highlight pre-clinical and clinical data pointing toward potential targets and therapies. We suggest that developing focused host-directed therapeutic strategies to enhance “pauci-inflammatory” microbial killing in myeloid phagocytes that maximizes pathogen clearance while minimizing the harmful consequences of the inflammatory response merits particular attention. We also suggest the importance of One Health approaches in developing host-based approaches through model development and comparative medicine in informing our understanding of how to deliver this strategy