Disruption of PCNA-lamins A/C interactions by prelamin A induces DNA replication fork stalling

The accumulation of prelamin A is linked to disruption of cellular homeostasis, tissue degeneration and aging. Its expression is implicated in compromised genome stability and increased levels of DNA damage, but to date there is no complete explanation for how prelamin A exerts its toxic effects. As the nuclear lamina is important for DNA replication we wanted to investigate the relationship between prelamin A expression and DNA replication fork stability. In this study we report that the expression of prelamin A in U2OS cells induced both mono-ubiquitination of proliferating cell nuclear antigen (PCNA) and subsequent induction of Pol η, two hallmarks of DNA replication fork stalling. Immunofluorescence microscopy revealed that cells expressing prelamin A presented with high levels of colocalisation between PCNA and γH2AX, indicating collapse of stalled DNA replication forks into DNA double-strand breaks. Subsequent protein-protein interaction assays showed prelamin A interacted with PCNA and that its presence mitigated interactions between PCNA and the mature nuclear lamina. Thus, we propose that the cytotoxicity of prelamin A arises in part, from it actively competing against mature lamin A to bind PCNA and that this destabilises DNA replication to induce fork stalling which in turn contributes to genomic instability

Prelamin A impairs 53BP1 nuclear entry by mislocalizing NUP153 and disrupting the Ran gradient.

The nuclear lamina is essential for the proper structure and organization of the nucleus. Deregulation of A-type lamins can compromise genomic stability, alter chromatin organization and cause premature vascular aging. Here, we show that accumulation of the lamin A precursor, prelamin A, inhibits 53BP1 recruitment to sites of DNA damage and increases basal levels of DNA damage in aged vascular smooth muscle cells. We identify that this genome instability arises through defective nuclear import of 53BP1 as a consequence of abnormal topological arrangement of nucleoporin NUP153. We show for the first time that this nucleoporin is important for the nuclear localization of Ran and that the deregulated Ran gradient is likely to be compromising the nuclear import of 53BP1. Importantly, many of the defects associated with prelamin A expression were significantly reduced upon treatment with Remodelin, a small molecule recently reported to reverse deficiencies associated with abnormal nuclear lamina.British Heart Foundation (Grant ID: RG/11/14/29056), Medical Research Council (Grant ID: MR/L019116/1), Cancer Research UK (Grant IDs: C6/A11224, C6946/A14492), European Research Council, European Community Seventh Framework Programme (Grant ID: HEALTH-F2-2010-259893) , Wellcome Trust (Grant ID: WT092096), University of CambridgeThis is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1111/acel.1250

Factors affecting follower responses to movement calls in cooperatively breeding dwarf mongooses

In social species, individuals maximize the benefits of group living by remaining cohesive and coordinating their actions. Communication is key to collective action, including ensuring that group members move together; individuals often produce signals when attempting to lead a group to a new area. However, the function of these signals, and how responses to them are affected by intrinsic characteristics of the caller and extrinsic factors, has rarely been experimentally tested. We conducted a series of field-based playback experiments with habituated wild dwarf mongooses, Helogale parvula, a cooperatively breeding and territorial species, to investigate follower responses to movement calls. In our first experiment, we found that focal individuals were more likely to respond to playback of ‘movement calls’ than control ‘close calls’, indicating movement calls function as recruitment signals. In a second experiment, we found that focal individuals responded similarly to the movement calls of dominant and subordinate groupmates, suggesting that dominance status (an intrinsic factor) does not influence receiver responses. In a final experiment, we found that individuals responded to the simulated presence of a rival group, but that this outgroup conflict (an extrinsic factor) did not affect responses to movement calls compared to a control situation. This may be because attention is instead focused on the potential presence of an imminent threat. By using playbacks to isolate the acoustic signal from physical movement cues, our results provide experimental evidence of how movement calls help leaders to attract followers and thus adds to our understanding of recruitment signals more generally

Varied Response of Western Pacific Hydrology to Climate Forcings over the Last Glacial Period

Atmospheric deep convection in the west Pacific plays a key role in the global heat and moisture budgets, yet its response to orbital and abrupt climate change events is poorly resolved. Here, we present four absolutely dated, overlapping stalagmite oxygen isotopic records from northern Borneo that span most of the last glacial cycle. The records suggest that northern Borneo’s hydroclimate shifted in phase with precessional forcing but was only weakly affected by glacial-interglacial changes in global climate boundary conditions. Regional convection likely decreased during Heinrich events, but other Northern Hemisphere abrupt climate change events are notably absent. The new records suggest that the deep tropical Pacific hydroclimate variability may have played an important role in shaping the global response to the largest abrupt climate change events

Extended Cave Drip Water Time Series Captures the 2015–2016 El Niño in Northern Borneo

Time series of cave drip water oxygen isotopes (δ18O) provide site‐specific assessments of the contributions of climate and karst processes to stalagmite δ18O records employed for hydroclimate reconstructions. We present ~12‐year‐long time series of biweekly cave drip water δ18O variations from three sites as well as a daily resolved local rainfall δ18O record from Gunung Mulu National Park in northern Borneo. Drip water δ18O variations closely match rainfall δ18O variations averaged over the preceding 3–18 months. We observe coherent interannual drip water δ18O variability of ~3‰ to 5‰ related to the El Niño–Southern Oscillation (ENSO), with sustained positive rainfall and drip water δ18O anomalies observed during the 2015/2016 El Niño. Evidence of nonlinear behavior at one of three drip water monitoring sites implies a time‐varying contribution from a longer‐term reservoir. Our results suggest that well‐replicated, high‐resolution stalagmite δ18O reconstructions from Mulu could characterize past ENSO‐related variability in regional hydroclimate.Plain Language SummaryCave stalagmites allow for the reconstruction of past regional rainfall variability over the last hundreds of thousands of years with robust age control. Such reconstructions rely on the fact that differences in the isotopic composition of rainwater set by regional rainfall patterns is preserved as the rainwater travels through cave bedrock to feed the cave drip waters forming stalagmites. Long‐term monitoring of rainwater and cave drip water isotopes ground truth the climate to stalagmite relationship across modern‐day changes in regional rainfall. Twelve years of monitoring data presented in this study identify individual El Niño–Southern Oscillation events in rainfall and cave drip water isotopic composition, providing a strong foundation for stalagmite‐based climate reconstructions from this site.Key PointsThree 12‐year‐long cave drip water δ18O time series capture El Niño and La Niña events in northern BorneoEstimates of karst residence times range from 3 to 18 months, with a secondary contribution from a longer‐term reservoir at one drip siteDrip water nonstationarity implies multiple stalagmites are required to reconstruct El Niño–Southern Oscillation variability over timePeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154266/1/grl60264-sup-0002-2019GL086363-SI.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154266/2/grl60264_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154266/3/grl60264.pd

Northern Borneo stalagmite records reveal West Pacific hydroclimate across MIS 5 and 6

Over the past decades, tropical stalagmite δ^(18)O records have provided valuable insight on glacial and interglacial hydrological variability and its relationship to a variety of natural climate forcings. The transition out of the penultimate glaciation (MIS 6) represents an important target for tropical hydroclimate reconstructions, yet relatively few such reconstructions resolve this transition. Particularly, comparisons between Termination 1 and 2 provide critical insight on the extent and influence of proposed climate mechanisms determined from paleorecords and model experiments spanning the recent deglaciation. Here we present a new compilation of western tropical Pacific hydrology spanning 0–160 ky BP, constructed from eleven different U/Th-dated stalagmite δ^(18)O records from Gunung Mulu National Park in northern Borneo. The reconstruction exhibits significant precessional power in phase with boreal fall insolation strength over the 0–160 ky BP period, identifying precessional insolation forcing as the dominant driver of hydroclimate variability in northern Borneo on orbital timescales. A comparison with a network of paleoclimate records from the circum-Pacific suggests the insolation sensitivity may arise from changes in the Walker circulation system. Distinct millennial-scale increases in stalagmite δ^(18)O, indicative of reduced regional convection, occur within glacial terminations and may reflect a response to shifts in inter-hemispheric temperature gradients. Our results imply that hydroclimate in this region is sensitive to external forcing, with a response dominated by large-scale temperature gradients

Trace metal and carbon isotopic variations in cave dripwater and stalagmite geochemistry from northern Borneo

We investigate stalagmite trace metal ratios and carbon isotopic composition (δ^(13)C) as potential paleoclimate proxies by comparing cave dripwaters, stalagmites, and bedrock composition from Gunung Mulu and Gunung Buda National Parks in northern Borneo, a tropical rainforest karst site. Three year long, biweekly time series of dripwater Mg/Ca, Sr/Ca, and δ^(13)C from several drips at our site are not correlated with rainfall variability, indicative of a relatively weak relationship between hydroclimate and dripwater geochemistry at our site. However, combining all of the dripwater geochemical data gathered over four field trips to our site (N > 300 samples), we find that drips with highly variable Mg[Sr]/Ca have relatively invariable δ^(18)O values close to the mean. We hypothesize that increased residence times translate into reduced variance in dripwater δ^(18)O through mixing in the epikarst as well as increased Mg[Sr]/Ca values through increased calcite precipitation in the epikarst. Mg/Ca, Sr/Ca, and δ^(13)C time series from three overlapping stalagmites that grew over the last 27 kyrs are characterized by strong centennial-scale variations, and bear little resemblance to previously published, well-reproduced δ^(18)O time series from the same stalagmites. The only shared signal among the three stalagmites' geochemical time series is a relative decrease of 1‰ in δ^(13)C from the Last Glacial Maximum to the Holocene, consistent with a transition from savannah (C4) to rainforest (C3) conditions documented in nearby records. Taken together, our study indicates that stalagmite Mg[Sr]/Ca ratios are poor indicators of hydroclimate conditions at our site, while stalagmite δ^(13)C exhibits some reproducible signals on glacial-interglacial timescales

Transformation of ENSO-related rainwater to dripwater δ^(18)O variability by vadose water mixing

Speleothem oxygen isotopes (δ^(18)O) are often used to reconstruct past rainfall δ^(18)O variability, and thereby hydroclimate changes, in many regions of the world. However, poor constraints on the karst hydrological processes that transform rainfall signals into cave dripwater add significant uncertainty to interpretations of speleothem-based reconstructions. Here we present several 6.5 year, biweekly dripwater δ^(18)O time series from northern Borneo and compare them to local rainfall δ^(18)O variability. We demonstrate that vadose water mixing is the primary rainfall-to-dripwater transformation process at our site, where dripwater δ^(18)O reflects amount-weighted rainfall δ^(18)O integrated over the previous 3–10 months. We document large interannual dripwater δ^(18)O variability related to the El Niño–Southern Oscillation (ENSO), with amplitudes inversely correlated to dripwater residence times. According to a simple stalagmite forward model, asymmetrical ENSO extremes produce significant offsets in stalagmite δ^(18)O time series given different dripwater residence times. Our study highlights the utility of generating multiyear, paired time series of rainfall and dripwater δ^(18)O to aid interpretations of stalagmite δ^(18)O reconstructions

The impact of changing cigarette smoking habits and smoke-free legislation on orofacial cleft incidence in the United Kingdom: Evidence from two time-series studies

BACKGROUND: Both active and passive cigarette smoking have previously been associated with orofacial cleft aetiology. We aimed to analyse the impact of declining active smoking prevalence and the implementation of smoke-free legislation on the incidence of children born with a cleft lip and/or palate within the United Kingdom. METHODS AND FINDINGS: We conducted regression analysis using national administrative data in the United Kingdom between 2000–2018. The main outcome measure was orofacial cleft incidence, reported annually for England, Wales and Northern Ireland and separately for Scotland. First, we conducted an ecological study with longitudinal time-series analysis using smoking prevalence data for females over 16 years of age. Second, we used a natural experiment design with interrupted time-series analysis to assess the impact of smoke-free legislation. Over the study period, the annual incidence of orofacial cleft per 10,000 live births ranged from 14.2–16.2 in England, Wales and Northern Ireland and 13.4–18.8 in Scotland. The proportion of active smokers amongst females in the United Kingdom declined by 37% during the study period. Adjusted regression analysis did not show a correlation between the proportion of active smokers and orofacial cleft incidence in either dataset, although we were unable to exclude a modest effect of the magnitude seen in individual-level observational studies. The data in England, Wales and Northern Ireland suggested an 8% reduction in orofacial cleft incidence (RR 0.92, 95%CI 0.85 to 0.99; P = 0.024) following the implementation of smoke-free legislation. In Scotland, there was weak evidence for an increase in orofacial cleft incidence following smoke-free legislation (RR 1.16, 95%CI 0.94 to 1.44; P = 0.173). CONCLUSIONS: These two ecological studies offer a novel insight into the influence of smoking in orofacial cleft aetiology, adding to the evidence base from individual-level studies. Our results suggest that smoke-free legislation may have reduced orofacial cleft incidence in England, Wales and Northern Ireland