Climate models show that ice-sheet melt will dominate sea-level rise over the coming centuries, but our understanding of ice-sheet variations before the last interglacial 125,000 years ago remains fragmentary. This is because terrestrial deposits of ancient glacial and interglacial periods are overrun and eroded by more recent glacial advances, and are therefore usually rare, isolated and poorly dated. In contrast, material shed almost continuously from continents is preserved as marine sediment that can be analysed to infer the time-varying state of major ice sheets. Here we show that the East Greenland Ice Sheet existed over the past 7.5 million years, as indicated by beryllium and aluminium isotopes (10Be and 26Al) in quartz sand removed by deep, ongoing glacial erosion on land and deposited offshore in the marine sedimentary record. During the early Pleistocene epoch, ice cover in East Greenland was dynamic; in contrast, East Greenland was mostly ice-covered during the mid-to-late Pleistocene. The isotope record we present is consistent with distinct signatures of changes in ice sheet behaviour coincident with major climate transitions. Although our data are continuous, they are from low-deposition-rate sites and sourced only from East Greenland. Consequently, the signal of extensive deglaciation during short, intense interglacials could be missed or blurred, and we cannot distinguish between a remnant ice sheet in the East Greenland highlands and a diminished continent-wide ice sheet. A clearer constraint on the behaviour of the ice sheet during past and, ultimately, future interglacial warmth could be produced by 10Be and 26Al records from a coring site with a higher deposition rate. Nonetheless, our analysis challenges the possibility of complete and extended deglaciation over the past several million years.

Changes in gamma oscillations (20-50 Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer's disease. Optogenetically driving fast-spiking parvalbumin-positive (FS-PV)-interneurons at gamma (40 Hz), but not other frequencies, reduces levels of amyloid-β (Aβ)1-40 and Aβ 1-42 isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia, and histological analysis confirmed increased microglia co-localization with Aβ. Subsequently, we designed a non-invasive 40 Hz light-flickering regime that reduced Aβ1-40 and Aβ1-42 levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate Alzheimer's-disease-associated pathology.

The concept of randomness plays an important part in many disciplines. On the one hand, the question of whether random processes exist is fundamental for our understanding of nature. On the other, randomness is a resource for cryptography, algorithms and simulations. Standard methods for generating randomness rely on assumptions about the devices that are often not valid in practice. However, quantum technologies enable new methods for generating certified randomness, based on the violation of Bell inequalities. These methods are referred to as device-independent because they do not rely on any modelling of the devices. Here we review efforts to design device-independent randomness generators and the associated challenges.

Refractoriness to induction chemotherapy and relapse after achievement of remission are the main obstacles to cure in acute myeloid leukaemia (AML). After standard induction chemotherapy, patients are assigned to different post-remission strategies on the basis of cytogenetic and molecular abnormalities that broadly define adverse, intermediate and favourable risk categories. However, some patients do not respond to induction therapy and another subset will eventually relapse despite the lack of adverse risk factors. There is an urgent need for better biomarkers to identify these high-risk patients before starting induction chemotherapy, to enable testing of alternative induction strategies in clinical trials. The high rate of relapse in AML has been attributed to the persistence of leukaemia stem cells (LSCs), which possess a number of stem cell properties, including quiescence, that are linked to therapy resistance. Here, to develop predictive and/or prognostic biomarkers related to stemness, we generated a list of genes that are differentially expressed between 138 LSC+ and 89 LSC- cell fractions from 78 AML patients validated by xenotransplantation. To extract the core transcriptional components of stemness relevant to clinical outcomes, we performed sparse regression analysis of LSC gene expression against survival in a large training cohort, generating a 17-gene LSC score (LSC17). The LSC17 score was highly prognostic in five independent cohorts comprising patients of diverse AML subtypes (n = 908) and contributed greatly to accurate prediction of initial therapy resistance. Patients with high LSC17 scores had poor outcomes with current treatments including allogeneic stem cell transplantation. The LSC17 score provides clinicians with a rapid and powerful tool to identify AML patients who do not benefit from standard therapy and who should be enrolled in trials evaluating novel upfront or post-remission strategies.

CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human class A G-protein-coupled receptors. CCR2 is expressed on monocytes, immature dendritic cells, and T-cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2 (ref. 1). CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer. These disease associations have motivated numerous preclinical studies and clinical trials (see http://www.clinicaltrials.gov) in search of therapies that target the CCR2-chemokine axis. To aid drug discovery efforts, here we solve a structure of CCR2 in a ternary complex with an orthosteric (BMS-681 (ref. 6)) and allosteric (CCR2-RA-[R]) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[R] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in class A G-protein-coupled receptors so far; this site spatially overlaps the G-protein-binding site in homologous receptors. CCR2-RA-[R] inhibits CCR2 non-competitively by blocking activation-associated conformational changes and formation of the G-protein-binding interface. The conformational signature of the conserved microswitch residues observed in double-antagonist-bound CCR2 resembles the most inactive G-protein-coupled receptor structures solved so far. Like other protein-protein interactions, receptor-chemokine complexes are considered challenging therapeutic targets for small molecules, and the present structure suggests diverse pocket epitopes that can be exploited to overcome obstacles in drug design.