The essential Mcm7 protein PROLIFERA is localized to the nucleus of dividing cells during the G(1) phase and is required maternally for early Arabidopsis development

PROLIFERA (PRL) encodes a homologue of the DNA replication licensing factor Mcm7, a highly conserved protein found in all eukaryotes. Insertions in the PROLIFERA gene are lethal, resulting in decreased transmission through the female gametophyte, and homozygous embryonic lethality. We show here that PROLIFERA is specifically expressed in populations of dividing cells in sporophytic tissues of the plant body, such as the palisade layer of the leaf and founder cells of initiating flower primordia, Gene fusions with the green fluorescent protein (GFP) reveal that the PROLIFERA protein accumulates during the G(1) phase of the cell cycle, and is transiently localized to the nucleus. During mitosis, the fusion protein rapidly disappears, returning to daughter nuclei during G(1), PROLIFERA::GUS fusions are strongly expressed in the central cell nucleus of mature megagametophytes, which have a variety of arrest points reflecting a leaky lethality. Expression is also observed in the endosperm of mutant prl embryo sacs that arrest following fertilization. Crosses with wild-type pollen result in occasional embryonic lethals that also stain for GUS activity, In contrast, embryos resulting from crosses of wild-type carpels with PRL::GUS pollen do not stain and are phenotypically normal. In situ hybridization of GUS fusion RNA indicates transcription is equivalent from maternally and paternally derived alleles, so that accumulation of maternally derived gametophytic protein is likely to be responsible for the 'maternal' effect

A pattern-recognition theory of search in expert problem solving

Understanding how look-ahead search and pattern recognition interact is one of the important research questions in the study of expert problem-solving. This paper examines the implications of the template theory (Gobet & Simon, 1996a), a recent theory of expert memory, on the theory of problem solving in chess. Templates are "chunks" (Chase & Simon, 1973) that have evolved into more complex data structures and that possess slots allowing values to be encoded rapidly. Templates may facilitate search in three ways: (a) by allowing information to be stored into LTM rapidly; (b) by allowing a search in the template space in addition to a search in the move space; and (c) by compensating loss in the "mind's eye" due to interference and decay. A computer model implementing the main ideas of the theory is presented, and simulations of its search behaviour are discussed. The template theory accounts for the slight skill difference in average depth of search found in chess players, as well as for other empirical data

Expert chess memory: Revisiting the chunking hypothesis

After reviewing the relevant theory on chess expertise, this paper re-examines experimentally the finding of Chase and Simon (1973a) that the differences in ability of chess players at different skill levels to copy and to recall positions are attributable to the experts' storage of thousands of chunks (patterned clusters of pieces) in long-term memory. Despite important differences in the experimental apparatus, the data of the present experiments regarding latencies and chess relations between successively placed pieces are highly correlated with those of Chase and Simon. We conclude that the 2-second inter-chunk interval used to define chunk boundaries is robust, and that chunks have psychological reality. We discuss the possible reasons why Masters in our new study used substantially larger chunks than the Master of the 1973 study, and extend the chunking theory to take account of the evidence for large retrieval structures (templates) in long-term memory

Health‐related outcomes in patients enrolled on surgical and non‐surgical routes in a weight management service

Background and Aims This study evaluates a specialist weight management service and compares outcomes in participants referred to the service undergoing either surgery or non-surgical routes to support weight loss. Methods Four hundred and forty eight participants were assessed on various weight-related outcomes (body mass index [BMI], psychological distress, quality of life, nutrition, weight-related symptoms, physical activity) on referral to the service and on discharge. The effect of group (surgery or non-surgery) and time in the service were facilitated by doubly multivariate analyses of variance models. Results Between referral and discharge, participants improved significantly on a combination of outcomes (P < .001) and on each outcome assessed individually. The magnitude of overall improvement was moderate (partial-η2 = 0.141). Individual improvement components varied; including a moderate reduction of 3.2% in the BMI outcome measure and a substantive gain of 64.6% in quality of life. Participants on non-surgical routes performed significantly better than participants on surgical routes on a linear combination of outcomes (P < .001) and on all outcomes except nutrition; with an effect of route small-to-moderate in magnitude (partial-η2 = 0.090). Conclusions Weight management services are successful in achieving weight management-related outcomes in the short- and long-term, with large overall improvements between referral and discharge averaged over all participants observed. Non-surgical routes appear to confer benefits between referral and discharge compared to surgical routes

Effect of a Low-Intensity PSA-Based Screening Intervention on Prostate Cancer Mortality: The CAP Randomized Clinical Trial

IMPORTANCE Prostate cancer screening remains controversial because potential mortality or quality-of-life benefits may be outweighed by harms from overdetection and overtreatment. OBJECTIVE To evaluate the effect of a single prostate-specific antigen (PSA) screening intervention and standardized diagnostic pathway on prostate cancer-specific mortality. DESIGN, SETTING, AND PARTICIPANTS The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) included 419 582 men aged 50 to 69 years and was conducted at 573 primary care practices across the United Kingdom. Randomization and recruitment of the practices occurred between 2001 and 2009; patient follow-up ended on March 31, 2016. INTERVENTION An invitation to attend a PSA testing clinic and receive a single PSA test vs standard (unscreened) practice. MAIN OUTCOMES AND MEASURES Primary outcome: prostate cancer-specific mortality at a median follow-up of 10 years. Prespecified secondary outcomes: diagnostic cancer stage and Gleason grade (range, 2-10; higher scores indicate a poorer prognosis) of prostate cancers identified, all-cause mortality, and an instrumental variable analysis estimating the causal effect of attending the PSA screening clinic. RESULTS Among 415 357 randomizedmen(mean [SD] age, 59.0[5.6] years), 189 386 in the intervention group and 219 439 in the control groupwere included in the analysis (n = 408 825; 98%). In the intervention group, 75 707 (40%)attended the PSAtesting clinic and 67 313 (36%) underwent PSAtesting. Of 64 436 with a valid PSAtest result, 6857 (11%) had a PSA level between 3 ng/mLand 19.9 ng/mL, ofwhom5850 (85%) had a prostate biopsy. After a median follow-up of 10 years, 549 (0.30 per 1000 person-years) died of prostate cancer in the intervention group vs 647 (0.31 per 1000 person-years) in the control group (rate difference, -0.013 per 1000 person-years [95%CI, -0.047 to0.022]; rate ratio [RR] ,0.96 [95%CI,0.85 to 1.08]; P = .50). The number diagnosed with prostate cancerwas higher in the intervention group (n = 8054; 4.3%) than in the control group (n = 7853; 3.6%) (RR, 1.19 [95%CI, 1.14 to 1.25] ; P < .001). More prostate cancer tumors with a Gleason grade of 6 or lowerwere identified in the intervention group (n = 3263/189 386 [1.7%]) than in the control group (n = 2440/219 439 [1.1%] ) (difference per 1000 men, 6.11 [95%CI, 5.38 to 6.84]; P < .001). In the analysis of all-cause mortality, therewere 25 459 deaths in the intervention group vs 28 306 deaths in the control group (RR,0.99 [95%CI,0.94 to 1.03]; P = .49). In the instrumental variable analysis for prostate cancer mortality, the adherence-adjusted causal RRwas0.93 (95%CI,0.67 to 1.29; P = .66). CONCLUSIONS AND RELEVANCE Among practices randomized to a single PSA screening intervention vs standard practice without screening, there was no significant difference in prostate cancer mortality after a median follow-up of 10 years but the detection of low-risk prostate cancer cases increased. Although longer-term follow-up is under way, the findings do not support single PSA testing for population-based screening. TRIAL REGISTRATION ISRCTN Identifier: ISRCTN92187251

False discovery rate estimation and heterobifunctional cross-linkers

<div><p>False discovery rate (FDR) estimation is a cornerstone of proteomics that has recently been adapted to cross-linking/mass spectrometry. Here we demonstrate that heterobifunctional cross-linkers, while theoretically different from homobifunctional cross-linkers, need not be considered separately in practice. We develop and then evaluate the impact of applying a correct FDR formula for use of heterobifunctional cross-linkers and conclude that there are minimal practical advantages. Hence a single formula can be applied to data generated from the many different non-cleavable cross-linkers.</p></div