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Synchronous millennial-scale productivity change in the Arabian Sea Glacial-interglacial productivity change Productivity in the Arabian Sea is one of the highest in the world. It is controlled by seasonally reversing monsoonal wind-driven upwelling of nutrient-rich deeper waters which fuel phytoplankton growth. The detailed history of upwelling-induced productivity in the eastern Arabian Sea is unknown. Here we present paleoproductivity records from a composite sediment core at the millennial scale during the last 80 kyr B.P. These records are based on relative abundance counts of planktonic foraminifera and organic carbon contents, which are shown to mainly vary in concert. The eastern Arabian Sea upwelling-induced productivity was higher in the glacial period than in the Holocene, but it fell repeatedly on millennial timescales. These productivity declines occurred during cold events in the North Atlantic region, with the most pronounced changes prevailing during the Heinrich events. Hence, seasonal monsoon winds that drive upwelling-induced productivity in the east were weak when the North Atlantic was cold. These weak winds resulted in stratification of the water column, comparable to today's Arabian Sea stratification in the intermonsoonal period. Combining the new eastern with published western Arabian Sea results shows that the entire biological factory was severely diminished during the North Atlantic Heinrich events, and the seasonal productivity change in the Arabian Sea monsoon system was reduced with year-round low productivity.

The early Pliocene shoaling of the Central American Seaway (CAS), ~4.7–4.2 million years ago (mega annum-Ma), is thought to have strengthened Atlantic Meridional Overturning Circulation (AMOC). The associated increase in northward flux of heat and moisture may have significantly influenced the evolution of Pliocene climate. While some evidence for the predicted increase in North Atlantic Deep Water (NADW) formation exists in the Caribbean and Western Atlantic, similar evidence is missing in the wider Atlantic. Here, we present stable carbon (δ 13 C) and oxygen (δ 18 O) isotope records from the Southeast Atlantic-a key region for monitoring the southern extent of NADW. Using these data, together with other δ 13 C and δ 18 O records from the Atlantic, we assess the impact of the early Pliocene CAS shoaling phase on deep-water circulation. We find that NADW formation was vigorous prior to 4.7 Ma and showed limited subsequent change. Hence, the overall structure of the deep Atlantic was largely unaffected by the early Pliocene CAS shoaling, corroborating other evidence that indicates larger changes in NADW resulted from earlier and deeper shoaling phases. This finding implies that the early Pliocene shoaling of the CAS had no profound impact on the evolution of climate.

The oxygen isotopic composition of planktonic foraminifera tests is one of the widest used geochemical tools to reconstruct past changes of physical parameters of the upper ocean. It is common practice to analyze multiple individuals from a mono-specific population and assume that the outcome reflects a mean value of the environmental conditions during calcification of the analyzed individuals. Here we present the oxygen isotope composition of individual specimens of the surface-dwelling species Globigerinoides ruber and Globigerina bulloides from sediment cores in the Western Arabian Sea off Somalia, inferred as indicators of past seasonal ranges in temperature. Combining the δ18O measurements of individual specimens to obtain temperature ranges with Mg/Ca based mean calcification temperatures allows us to reconstruct temperature extrema. Our results indicate that over the past 20 kyr the seasonal temperature range has fluctuated from its present value of 16 °C to mean values of 13 °C and 11 °C for the Holocene and LGM, respectively. The data for the LGM suggest that the maximum temperature was lower, whilst minimum temperature remained approximately constant. The rather minor variability in lowest summer temperatures during the LGM suggests roughly constant summer monsoon intensity, while upwelling-induced productivity was lowered.

Indian-Asian monsoon has oscillated between warm/wet interglacial periods and cool/dry glacial periods with periodicities closely linked to variations in Earth’s orbital parameters. However, processes that control wet versus dry, i.e. aridity cyclical periods on the orbital time-scale in the low latitudes of the Indian-Asian continent remain poorly understood because records over millions of years are scarce. The sedimentary record from International Ocean Discovery Program (IODP) Expedition 359 provides a well-preserved, high-resolution, continuous archive of lithogenic input from the Maldives reflecting on low-latitude aridity cycles. Variability within the lithogenic component of sedimentary deposits of the Maldives results from changes in monsoon-controlled sedimentary sources. Here, we present X-ray fluorescence (XRF) core-scanning results from IODP Site U1467 for the past two million years, allowing full investigation of orbital periodicities. We specifically use the Fe/K as a terrestrial climate proxy reflecting on wet versus dry conditions in the source areas of the Indian-Asian landmass, or from further afield. The Fe/K record shows orbitally forced cycles reflecting on changes in the relative importance of aeolian (stronger winter monsoon) during glacial periods versus fluvial supply (stronger summer monsoon) during interglacial periods. For our chronology, we tuned the Fe/K cycles to precessional insolation changes, linking Fe/K maxima/minima to insolation minima/maxima with zero phase lag. Wavelet and spectral analyses of the Fe/K record show increased dominance of the 100 kyr cycles after the Mid Pleistocene Transition (MPT) at 1.25 Ma in tandem with the global ice volume benthic δ18O data (LR04 record). In contrast to the LR04 record, the Fe/K profile resolves 100-kyr-like cycles around the 130 kyr frequency band in the interval from 1.25 to 2 million years. These 100-kyr-like cycles likely form by bundling of two or three obliquity cycles, indicating that low-latitude Indian-Asian climate variability reflects on increased tilt sensitivity to regional eccentricity insolation changes (pacing tilt cycles) prior to the MPT. The implication of appearance of the 100 kyr cycles in the LR04 and the Fe/K records since the MPT suggests strengthening of a climate link between the low and high latitudes during this period of climate transition.

In the original version of this article (Kunkelova et al. 2018), published on 18 December 2018, there was 1 error in the author name of Dr. Yu.

The ability to design functional sequences and predict effects of variation is central to protein engineering and biotherapeutics. State-of-art computational methods rely on models that leverage evolutionary information but are inadequate for important applications where multiple sequence alignments are not robust. Such applications include the prediction of variant effects of indels, disordered proteins, and the design of proteins such as antibodies due to the highly variable complementarity determining regions. We introduce a deep generative model adapted from natural language processing for prediction and design of diverse functional sequences without the need for alignments. The model performs state-of-art prediction of missense and indel effects and we successfully design and test a diverse 10 5 -nanobody library that shows better expression than a 1000-fold larger synthetic library. Our results demonstrate the power of the alignment-free autoregressive model in generalizing to regions of sequence space traditionally considered beyond the reach of prediction and design. The ability to design functional sequences is central to protein engineering and biotherapeutics. Here the authors introduce a deep generative alignment-free model for sequence design applied to highly variable regions and design and test a diverse nanobody library with improved properties for selection experiments.

Cellular differentiation involves profound remodelling of chromatic landscapes, yet the mechanisms by which somatic cell identity is subsequently maintained remain incompletely understood. To further elucidate regulatory pathways that safeguard the somatic state, we performed two comprehensive RNA interference (RNAi) screens targeting chromatin factors during transcription-factor-mediated reprogramming of mouse fibroblasts to induced pluripotent stem cells (iPS cells). Subunits of the chromatin assembly factor-1 (CAF-1) complex, including Chaf1a and Chaf1b, emerged as the most prominent hits from both screens, followed by modulators of lysine sumoylation and heterochromatin maintenance. Optimal modulation of both CAF-1 and transcription factor levels increased reprogramming efficiency by several orders of magnitude and facilitated iPS cell formation in as little as 4 days. Mechanistically, CAF-1 suppression led to a more accessible chromatin structure at enhancer elements early during reprogramming. These changes were accompanied by a decrease in somatic heterochromatin domains, increased binding of Sox2 to pluripotency-specific targets and activation of associated genes. Notably, suppression of CAF-1 also enhanced the direct conversion of B cells into macrophages and fibroblasts into neurons. Together, our findings reveal the histone chaperone CAF-1 to be a novel regulator of somatic cell identity during transcription-factor-induced cell-fate transitions and provide a potential strategy to modulate cellular plasticity in a regenerative setting. RNA interference screens were used to identify chromatin-associated factors that impede reprogramming of somatic cells into iPS cells; suppression of the chromatin assembly factor CAF-1 enhances the generation of iPS cells by rendering chromatin more accessible to pluripotency transcription factors. CAF-1 is a barrier to cell fate change Lineage fate determination in development, and reprogramming to a different fate in the laboratory, depend on gene expression programs that are regulated by factors influencing the chromatin landscape. Konrad Hochedlinger and colleagues have performed two RNA-interference-based screens to search for chromatin-associated factors that impede reprogramming. They identify the chromatin assembly factor-1 (CAF-1) complex as an important regulator of this process, acting by rendering the chromatin inaccessible to transcription factors. Suppression of CAF-1 function thus facilitates chromatin access to reprogramming factors, both during reprogramming to pluripotency and in direct fate conversion.

FLUXNET comprises globally distributed eddy-covariance-based estimates of carbon fluxes between the biosphere and the atmosphere. Since eddy covariance flux towers have a relatively small footprint and are distributed unevenly across the world, upscaling the observations is necessary to obtain global-scale estimates of biosphere-atmosphere exchange. Based on cross-consistency checks with atmospheric inversions, sun-induced fluorescence (SIF) and dynamic global vegetation models (DGVMs), here we provide a systematic assessment of the latest upscaling efforts for gross primary production (GPP) and net ecosystem exchange (NEE) of the FLUXCOM initiative, where different machine learning methods, forcing data sets and sets of predictor variables were employed. Spatial patterns of mean GPP are consistent across FLUXCOM and DGVM ensembles ( at 1 spatial resolution) while the majority of DGVMs show, for 70 of the land surface, values outside the FLUXCOM range. Global mean GPP magnitudes for 2008-2010 from FLUXCOM members vary within 106 and 130 PgC class with the largest uncertainty in the tropics. Seasonal variations in independent SIF estimates agree better with FLUXCOM GPP (mean global pixel-wise) than with GPP from DGVMs (mean global pixel-wise). Seasonal variations in FLUXCOM NEE show good consistency with atmospheric inversion-based net land carbon fluxes, particularly for temperate and boreal regions. Interannual variability of global NEE in FLUXCOM is underestimated compared to inversions and DGVMs. The FLUXCOM version which also uses meteorological inputs shows a strong co-variation in interannual patterns with inversions (for 2001-2010). Mean regional NEE from FLUXCOM shows larger uptake than inversion and DGVM-based estimates, particularly in the tropics with discrepancies of up to several hundred grammes of carbon per square metre per year. These discrepancies can only partly be reconciled by carbon loss pathways that are implicit in inversions but not captured by the flux tower measurements such as carbon emissions from fires and water bodies. We hypothesize that a combination of systematic biases in the underlying eddy covariance data, in particular in tall tropical forests, and a lack of site history effects on NEE in FLUXCOM are likely responsible for the too strong tropical carbon sink estimated by FLUXCOM. Furthermore, as FLUXCOM does not account for fertilization effects, carbon flux trends are not realistic. Overall, current FLUXCOM estimates of mean annual and seasonal cycles of GPP as well as seasonal NEE variations provide useful constraints of global carbon cycling, while interannual variability patterns from FLUXCOM are valuable but require cautious interpretation. Exploring the diversity of Earth observation data and of machine learning concepts along with improved quality and quantity of flux tower measurements will facilitate further improvements of the FLUXCOM approach overall.

Splicing factors such as BUD31 are identified in a synthetic-lethal screen with cells overexpressing the transcription factor MYC; oncogenic MYC leads to an increase in pre-mRNA synthesis, and spliceosome inhibition impairs the growth and tumorigenicity of MYC-dependent breast cancers, suggesting that spliceosome components may be potential therapeutic targets for MYC-driven cancers. Tolerating overexpressed MYC The transcription factor MYC is frequently amplified or overexpressed in cancer and drives increased RNA and protein production. Here, Thomas Westbrook and colleagues identify the splicing factor BUD31 in a synthetic lethal screen with cells overexpressing MYC and show that other splicing factors are also required for cells to tolerate overexpressed MYC. Oncogenic MYC leads to an increase in pre-mRNA synthesis, and inhibition of the spliceosome impairs the growth and tumorigenicity of MYC-dependent breast cancer cells. Spliceosome components may therefore be potential therapeutic targets for MYC-driven cancers. MYC (also known as c-MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. MYC is a transcription factor, and many of its pro-tumorigenic functions have been attributed to its ability to regulate gene expression programs 1 , 2 , 3 . Notably, oncogenic MYC activation has also been shown to increase total RNA and protein production in many tissue and disease contexts 4 , 5 , 6 , 7 . While such increases in RNA and protein production may endow cancer cells with pro-tumour hallmarks, this increase in synthesis may also generate new or heightened burden on MYC-driven cancer cells to process these macromolecules properly 8 . Here we discover that the spliceosome is a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene in human mammary epithelial cells, and demonstrate that BUD31 is a component of the core spliceosome required for its assembly and catalytic activity. Core spliceosomal factors (such as SF3B1 and U2AF1) associated with BUD31 are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total precursor messenger RNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Notably, genetic or pharmacological inhibition of the spliceosome in vivo impairs survival, tumorigenicity and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing, and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers.

Cellular DNA damage caused by reactive oxygen species is repaired by the base excision repair (BER) pathway which includes the DNA glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, the mechanistic progression from germline MUTYH mutations to MUTYH-Associated Polyposis (MAP) is incompletely understood. Here, we sequence normal tissue DNAs from 10 individuals with MAP. Somatic base substitution mutation rates in intestinal epithelial cells were elevated 2 to 4-fold in all individuals, except for one showing a 31-fold increase, and were also increased in other tissues. The increased mutation burdens were of multiple mutational signatures characterised by C > A changes. Different mutation rates and signatures between individuals are likely due to different MUTYH mutations or additional inherited mutations in other BER pathway genes. The elevated base substitution rate in normal cells likely accounts for the predisposition to neoplasia in MAP. Despite ubiquitously elevated mutation rates, individuals with MAP do not display overt evidence of premature ageing. Thus, accumulation of somatic mutations may not be sufficient to cause the global organismal functional decline of ageing. Inherited mutations in MUTYH have been shown to predispose patients to colorectal cancers. Here, the authors show that MUTYH mutations lead to an increased somatic base substitution mutation rate in normal intestinal epithelial cells, which is the likely cause for the increased cancer risk.