In silico APC/C substrate discovery reveals cell cycle-dependent degradation of UHRF1 and other chromatin regulators

The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase and critical regulator of cell cycle progression. Despite its vital role, it has remained challenging to globally map APC/C substrates. By combining orthogonal features of known substrates, we predicted APC/C substrates in silico. This analysis identified many known substrates and suggested numerous candidates. Unexpectedly, chromatin regulatory proteins are enriched among putative substrates, and we show experimentally that several chromatin proteins bind APC/C, oscillate during the cell cycle, and are degraded following APC/C activation, consistent with being direct APC/C substrates. Additional analysis revealed detailed mechanisms of ubiquitylation for UHRF1, a key chromatin regulator involved in histone ubiquitylation and DNA methylation maintenance. Disrupting UHRF1 degradation at mitotic exit accelerates G1-phase cell cycle progression and perturbs global DNA methylation patterning in the genome. We conclude that APC/C coordinates crosstalk between cell cycle and chromatin regulatory proteins. This has potential consequences in normal cell physiology, where the chromatin environment changes depending on proliferative state, as well as in disease. Copyright

Relationship between subjective fall risk assessment and falls and fall-related fractures in frail elderly people

<p>Abstract</p> <p>Background</p> <p>Objective measurements can be used to identify people with risks of falls, but many frail elderly adults cannot complete physical performance tests. The study examined the relationship between a subjective risk rating of specific tasks (SRRST) to screen for fall risks and falls and fall-related fractures in frail elderly people.</p> <p>Methods</p> <p>The SRRST was investigated in 5,062 individuals aged 65 years or older who were utilized day-care services. The SRRST comprised 7 dichotomous questions to screen for fall risks during movements and behaviours such as walking, transferring, and wandering. The history of falls and fall-related fractures during the previous year was reported by participants or determined from an interview with the participant's family and care staff.</p> <p>Results</p> <p>All SRRST items showed significant differences between the participants with and without falls and fall-related fractures. In multiple logistic regression analysis adjusted for age, sex, diseases, and behavioural variables, the SRRST score was independently associated with history of falls and fractures. Odds ratios for those in the high-risk SRRST group (≥ 5 points) compared with the no risk SRRST group (0 point) were 6.15 (p < 0.01) for a single fall, 15.04 (p < 0.01) for recurrent falls, and 5.05 (p < 0.01) for fall-related fractures. The results remained essentially unchanged in subgroup analysis accounting for locomotion status.</p> <p>Conclusion</p> <p>These results suggest that subjective ratings by care staff can be utilized to determine the risks of falls and fall-related fractures in the frail elderly, however, these preliminary results require confirmation in further prospective research.</p

Weber and church governance: religious practice and economic activity

The debate about the relationship between religion and economic activity in the wake of Weber has been cast largely in terms of belief and values. This article suggests an alternative focus on practice. It argues that taken for granted practices of church governance formed to-hand resources for the organization of economic activity. The argument is developed through an examination of the historical development of church governance practices in the Presbyterian Church of Scotland, with particular emphasis on the way in which theological belief gave rise to practices of accountability and record keeping. In turn such practices contributed to a ‘culture of organization’ which had implications for economic activity. A focus on governance practices can help to illuminate enduring patterns of difference in the organization of economic activity

Validity of the Falls Risk for Older People in the Community (FROP‑Com) tool to predict falls and fall injuries for older people presenting to the emergency department after falling

The aims of this study were to (1) externally validate the accuracy of the Falls Risk for Older People in the Community (FROP-Com) falls risk assessment tool in predicting falls and (2) undertake initial validation of the accuracy of the FROPCom to predict injurious falls (requiring medical attention) in people aged ≥ 60 years presenting to emergency departments (EDs) after falling. Two hundred and thirteen participants (mean age = 72.4 years; 59.2% women) were recruited (control group of a randomised controlled trial). A FROP-Com assessment was completed at a home visit within 2 weeks of ED discharge. Data on falls and injurious falls requiring medical attention were collected via monthly falls calendars for the next 12 months. Predictive accuracy was evaluated using sensitivity and specificity of a high-risk FROP-Com classification (score ≥ 19) in predicting a fall and injurious falls requiring medical attention. Fifty per cent of participants fell, with 60.4% of falls requiring medical attention. Thirty-two per cent were classified as high, 49% as moderate and 19% low falls risk. Low sensitivity was achieved for the FROP-Com high-risk classification for predicting falls (43.4%) and injurious falls (34.4%), although specificity was high (79.4% and 78.6%, respectively). Despite the FROP-Com’s low predictive accuracy, the high fall rate and high falls risk of the sample suggest that older people who fall, present to ED and are discharged home are at high risk of future falls. In high-falls-risk populations such as in this study, the FROP-Com is not a valid tool for classifying risk of falls or injurious falls. Its potential value may instead be in identifying risk factors for falling to direct tailoring of falls prevention interventions to reduce future falls

A Multi-cell, Multi-scale Model of Vertebrate Segmentation and Somite Formation

Somitogenesis, the formation of the body's primary segmental structure common to all vertebrate development, requires coordination between biological mechanisms at several scales. Explaining how these mechanisms interact across scales and how events are coordinated in space and time is necessary for a complete understanding of somitogenesis and its evolutionary flexibility. So far, mechanisms of somitogenesis have been studied independently. To test the consistency, integrability and combined explanatory power of current prevailing hypotheses, we built an integrated clock-and-wavefront model including submodels of the intracellular segmentation clock, intercellular segmentation-clock coupling via Delta/Notch signaling, an FGF8 determination front, delayed differentiation, clock-wavefront readout, and differential-cell-cell-adhesion-driven cell sorting. We identify inconsistencies between existing submodels and gaps in the current understanding of somitogenesis mechanisms, and propose novel submodels and extensions of existing submodels where necessary. For reasonable initial conditions, 2D simulations of our model robustly generate spatially and temporally regular somites, realistic dynamic morphologies and spontaneous emergence of anterior-traveling stripes of Lfng. We show that these traveling stripes are pseudo-waves rather than true propagating waves. Our model is flexible enough to generate interspecies-like variation in somite size in response to changes in the PSM growth rate and segmentation-clock period, and in the number and width of Lfng stripes in response to changes in the PSM growth rate, segmentation-clock period and PSM length

The FLUXNET2015 dataset and the ONEFlux processing pipeline for eddy covariance data.

The FLUXNET2015 dataset provides ecosystem-scale data on CO2, water, and energy exchange between the biosphere and the atmosphere, and other meteorological and biological measurements, from 212 sites around the globe (over 1500 site-years, up to and including year 2014). These sites, independently managed and operated, voluntarily contributed their data to create global datasets. Data were quality controlled and processed using uniform methods, to improve consistency and intercomparability across sites. The dataset is already being used in a number of applications, including ecophysiology studies, remote sensing studies, and development of ecosystem and Earth system models. FLUXNET2015 includes derived-data products, such as gap-filled time series, ecosystem respiration and photosynthetic uptake estimates, estimation of uncertainties, and metadata about the measurements, presented for the first time in this paper. In addition, 206 of these sites are for the first time distributed under a Creative Commons (CC-BY 4.0) license. This paper details this enhanced dataset and the processing methods, now made available as open-source codes, making the dataset more accessible, transparent, and reproducible