The major human AP endonuclease (Ape1) is involved in the nucleotide incision repair pathway

In nucleotide incision repair (NIR), an endonuclease nicks oxidatively damaged DNA in a DNA glycosylase-independent manner, providing the correct ends for DNA synthesis coupled to the repair of the remaining 5'-dangling modified nucleotide. This mechanistic feature is distinct from DNA glycosylase-mediated base excision repair. Here we report that Ape1, the major apurinic/apyrimidinic endonuclease in human cells, is the damage- specific endonuclease involved in NIR. We show that Ape1 incises DNA containing 5,6-dihydro-2'-deoxyuridine, 5,6-dihydrothymidine, 5-hydroxy-2'-deoxyuridine, alpha-2'-deoxyadenosine and alpha-thymidine adducts, generating 3'-hydroxyl and 5'-phosphate termini. The kinetic constants indicate that Ape1-catalysed NIR activity is highly efficient. The substrate specificity and protein conformation of Ape1 is modulated by MgCl2 concentrations, thus providing conditions under which NIR becomes a major activity in cell-free extracts. While the N-terminal region of Ape1 is not required for AP endonuclease function, we show that it regulates the NIR activity. The physiological relevance of the mammalian NIR pathway is discussed

Snowex 2017 Community Snow Depth Measurements: A Quality-Controlled, Georeferenced Product

Snow depth was one of the core ground measurements required to validate remotely-sensed data collected during SnowEx Year 1, which occurred in Colorado. The use of a single, common protocol was fundamental to produce a community reference dataset of high quality. Most of the nearly 100 Grand Mesa and Senator Beck Basin SnowEx ground crew participants contributed to this crucial dataset during 6-25 February 2017. Snow depths were measured along ~300 m transects, whose locations were determined according to a random-stratified approach using snowfall and tree-density gradients. Two-person teams used snowmobiles, skis, or snowshoes to travel to staked transect locations and to conduct measurements. Depths were measured with a 1-cm incremented probe every 3 meters along transects. In shallow areas of Grand Mesa, depth measurements were also collected with GPS snow-depth probes (a.k.a. MagnaProbes) at ~1-m intervals. During summer 2017, all reference stake positions were surveyed with <10 cm accuracy to improve overall snow depth location accuracy. During the campaign, 193 transects were measured over three weeks at Grand Mesa and 40 were collected over two weeks in Senator Beck Basin, representing more than 27,000 depth values. Each day of the campaign depth measurements were written in waterproof field books and photographed by National Snow and Ice Data Center (NSIDC) participants. The data were later transcribed and prepared for extensive quality assessment and control. Common issues such as protocol errors (e.g., survey in reverse direction), notebook image issues (e.g., halo in the center of digitized picture), and data-entry errors (sloppy writing and transcription errors) were identified and fixed on a point-by-point basis. In addition, we strove to produce a georeferenced product of fine quality, so we calculated and interpolated coordinates for every depth measurement based on surveyed stakes and the number of measurements made per transect. The product has been submitted to NSIDC in csv format. To educate data users, we present the study design and processing steps that have improved the quality and usability of this product. Also, we will address measurement and design uncertainties, which are different in open vs. forest areas

Tied factor analysis for face recognition across large pose differences

Face recognition algorithms perform very unreliably when the pose of the probe face is different from the gallery face: typical feature vectors vary more with pose than with identity. We propose a generative model that creates a one-to-many mapping from an idealized “identity” space to the observed data space. In identity space, the representation for each individual does not vary with pose. We model the measured feature vector as being generated by a pose-contingent linear transformation of the identity variable in the presence of Gaussian noise. We term this model “tied” factor analysis. The choice of linear transformation (factors) depends on the pose, but the loadings are constant (tied) for a given individual. We use the EM algorithm to estimate the linear transformations and the noise parameters from training data. We propose a probabilistic distance metric that allows a full posterior over possible matches to be established. We introduce a novel feature extraction process and investigate recognition performance by using the FERET, XM2VTS, and PIE databases. Recognition performance compares favorably with contemporary approaches

The Oldham Notebooks: an analysis of the development of IVF 1969-1978. I. Introduction, materials and methods.

In this introductory paper, we describe the primary source material studied in this Symposium, namely a set of 21 notebooks and 571 pages of loose sheets and scraps of paper, which, on cross-referencing, have allowed us to reconstruct the sequence, timing and numbers of the laparoscopic cycles planned, attempted and undertaken between 9 January 1969 and 1 August 1978 by Robert Edwards, Patrick Steptoe and Jean Purdy in Oldham, UK, as well as to identify most of the patients involved. In addition, we describe the background to the five papers that follow, and the secondary sources and recorded interviews, which have provided useful ancillary material.The research was supported by grants from the Wellcome Trust (088708 to Nick Hopwood, Martin Johnson et al. and 094985 to Allen Packwood and Martin Johnson), which otherwise had no involvement in the research or its publication.This is the final published version. It first appeared at http://www.sciencedirect.com/science/article/pii/S2405661815000027

The Oldham Notebooks: an analysis of the development of IVF 1969-1978. IV. Ethical aspects.

Six evidential sources are examined to investigate how Edwards and Steptoe applied ethical standards to their research leading to the birth of Louise Brown: (i) Their own contemporary writings from 1970 onwards. (ii) Archival evidence from the British Medical Association (BMA), the British Association for the Advancement of Science (BAAS), and correspondence between Edwards and the Ford Foundation. (iii) Minutes of Oldham General Hospital (OGH) Ethics Committee. (iv) Letters by Edwards to prospective patients. (v) oral evidence from interviews with a patient and colleagues. (vi) Evidence from their clinical case management of patients. Taken together these sources suggest that Edwards and Steptoe demonstrated a strong awareness of the ethical issues involved, and offer evidence of honesty to patients about the realistic prospects of success and ethical practice. Nonetheless, decisive evidence that ethical aspirations were put into practice is not available.The research was supported by grants from the Wellcome Trust (088708 and 094985), which otherwise had no involvement in the research or its publication.This is the final published version. It first appeared at http://www.sciencedirect.com/science/article/pii/S2405661815000039

The Oldham Notebooks: an analysis of the development of IVF 1969-1978. II. The treatment cycles and their outcomes.

This paper reports on the numbers of treatment cycles involved in the development of IVF (1969-1978) and their outcomes. We show that between 1969 and 1978: (i) a minimum of 282 women were involved in 495 cycles of potential laparoscopic oocyte retrieval (LOR); (ii) of these cycles, 457/495 proceeded to LOR to attempt egg collection; (iii) of which an outcome was recorded in 436/457; (iv) eggs were recovered in 388/436 of these; (v) inseminations were recorded in 331/388; (vi) embryos were recorded in at least 167; (vii) a total of 112 embryo transfers were attempted; and (viii) a maximum of 11 possible biochemical/preclinical pregnancies plus five clinical pregnancies were observed; (ix) from which two healthy live births resulted.The research was supported by grants from the Wellcome Trust (088708 and 094985), which otherwise had no involvement in the research or its publication.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.rbms.2015.04.00