Mammary molecular portraits reveal lineage-specific features and progenitor cell vulnerabilities.

The mammary epithelium depends on specific lineages and their stem and progenitor function to accommodate hormone-triggered physiological demands in the adult female. Perturbations of these lineages underpin breast cancer risk, yet our understanding of normal mammary cell composition is incomplete. Here, we build a multimodal resource for the adult gland through comprehensive profiling of primary cell epigenomes, transcriptomes, and proteomes. We define systems-level relationships between chromatin-DNA-RNA-protein states, identify lineage-specific DNA methylation of transcription factor binding sites, and pinpoint proteins underlying progesterone responsiveness. Comparative proteomics of estrogen and progesterone receptor-positive and -negative cell populations, extensive target validation, and drug testing lead to discovery of stem and progenitor cell vulnerabilities. Top epigenetic drugs exert cytostatic effects; prevent adult mammary cell expansion, clonogenicity, and mammopoiesis; and deplete stem cell frequency. Select drugs also abrogate human breast progenitor cell activity in normal and high-risk patient samples. This integrative computational and functional study provides fundamental insight into mammary lineage and stem cell biology

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

The telomere length landscape of prostate cancer

Despite the known role of telomere length in cancer, its association with genomic features remains unclear. Here, the authors integrate telomere length, genomics, transcriptomics and proteomics in localized prostate cancer and reveal links between telomere maintenance, disease drivers and clinical outcomes

The telomere length landscape of prostate cancer.

Replicative immortality is a hallmark of cancer, and can be achieved through telomere lengthening and maintenance. Although the role of telomere length in cancer has been well studied, its association to genomic features is less well known. Here, we report the telomere lengths of 392 localized prostate cancer tumours and characterize their relationship to genomic, transcriptomic and proteomic features. Shorter tumour telomere lengths are associated with elevated genomic instability, including single-nucleotide variants, indels and structural variants. Genes involved in cell proliferation and signaling are correlated with tumour telomere length at all levels of the central dogma. Telomere length is also associated with multiple clinical features of a tumour. Longer telomere lengths in non-tumour samples are associated with a lower rate of biochemical relapse. In summary, we describe the multi-level integration of telomere length, genomics, transcriptomics and proteomics in localized prostate cancer

Precession phasing offset between Indian summer monsoon and Arabian Sea productivity linked to changes in Atlantic overturning circulation

Results from transient climate modeling experiments indicate an in-phase relationship between insolation forcing and Indian summer monsoonal precipitation. This is in contrast to high-resolution radioisotopically dated speleothem oxygen isotope (δ18O) records of China, which showed that East Asian Monsoon maxima lag Northern Hemisphere peak summer insolation by ∼2,700 years, while an approximately 8,000-year time lag was derived from late Pleistocene records of Arabian Sea sediments. Here, we evaluate the precession phase of the Arabian Sea signal by comparing a new high-resolution productivity and oxygen minimum zone (OMZ) intensity record from the Arabian Sea over the past 450,000 years with the results of a transient climate modeling experiment that includes glacial-bound ice volume variations. The well established tuning technique between radioisotopically dated North Atlantic cold events and the occurrence of deep-dwelling planktonic foraminifera in the Arabian Sea for the last glacial cycle was used to extend the Arabian Sea chronology, independent of orbital tuning. Cross-spectral analysis over the last 224,000 years reveals that Arabian Sea productivity maxima lag precession minima by ∼6,900 ± 200 years, i.e., in close agreement with previous reconstructions. Also our climate modeling simulations are in accord with previous studies indicating an in-phase relationship between precession minima and maximum summer monsoon intensity. We argue that the summer monsoon is most likely not the main driver of changes in Arabian Sea biological productivity and OMZ intensity at the precession frequency band, but that changes in the intensity of the Atlantic meridional overturning circulation (AMOC) have played the prominent role in controlling the nutrient delivery into the euphotic layer of the northern Indian Ocean, and hence the amount of primary productivity and intensity of the oxygen minimum zone in the Arabian Sea. Such a mechanism explains the large precession-related time lag between minimum precession and maximum productivity and OMZ conditions in the Arabian Sea, since intensified AMOC occurred during precession maxima

Leveraging European infrastructures to access 1 million human genomes by 2022

Human genomics is undergoing a step change from being a predominantly research-driven activity to one driven through health care as many countries in Europe now have nascent precision medicine programmes. To maximize the value of the genomic data generated, these data will need to be shared between institutions and across countries. In recognition of this challenge, 21 European countries recently signed a declaration to transnationally share data on at least 1 million human genomes by 2022. In this Roadmap, we identify the challenges of data sharing across borders and demonstrate that European research infrastructures are well-positioned to support the rapid implementation of widespread genomic data access.status: publishe

Leveraging European infrastructures to access 1 million human genomes by 2022 (vol 20, pg 693, 2019)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.status: publishe

Leveraging European European infrastructures to access 1 million human genomes by 2022

Human genomics is undergoing a step change from being a predominantly research-driven activity to one driven through health care as many countries in Europe now have nascent precision medicine programmes. To maximize the value of the genomic data generated, these data will need to be shared between institutions and across countries. In recognition of this challenge, 21 European countries recently signed a declaration to transnationally share data on at least 1 million human genomes by 2022. In this Roadmap, we identify the challenges of data sharing across borders and demonstrate that European research infrastructures are well-positioned to support the rapid implementation of widespread genomic data access