One drawback of conventional quantum state tomography is that it does not readily provide access to single density matrix elements since it requires a global reconstruction. Here, we experimentally ...demonstrate a scheme that can be used to directly measure individual density matrix elements of general quantum states. The scheme relies on measuring a sequence of three observables, each complementary to the last. The first two measurements are made weak to minimize the disturbance they cause to the state, while the final measurement is strong. We perform this joint measurement on polarized photons in pure and mixed states to directly measure their density matrix. The weak measurements are achieved using two walk-off crystals, each inducing a polarization-dependent spatial shift that couples the spatial and polarization degrees of freedom of the photons. This direct measurement method provides an operational meaning to the density matrix and promises to be especially useful for large dimensional states.
Growing evidence links abnormal epigenetic control to the development of hematological malignancies. Accordingly, inhibition of epigenetic regulators is emerging as a promising therapeutic strategy. ...The acetylation status of lysine residues in histone tails is one of a number of epigenetic post-translational modifications that alter DNA-templated processes, such as transcription, to facilitate malignant transformation. Although histone deacetylases are already being clinically targeted, the role of histone lysine acetyltransferases (KAT) in malignancy is less well characterized. We chose to study this question in the context of acute myeloid leukemia (AML), where, using in vitro and in vivo genetic ablation and knockdown experiments in murine models, we demonstrate a role for the epigenetic regulators CBP and p300 in the induction and maintenance of AML. Furthermore, using selective small molecule inhibitors of their lysine acetyltransferase activity, we validate CBP/p300 as therapeutic targets in vitro across a wide range of human AML subtypes. We proceed to show that growth retardation occurs through the induction of transcriptional changes that induce apoptosis and cell-cycle arrest in leukemia cells and finally demonstrate the efficacy of the KAT inhibitors in decreasing clonogenic growth of primary AML patient samples. Taken together, these data suggest that CBP/p300 are promising therapeutic targets across multiple subtypes in AML.
The quantum mechanical bespoke (QUBE) force-field approach has been developed to facilitate the automated derivation of potential energy function parameters for modeling protein–ligand binding. To ...date, the approach has been validated in the context of Monte Carlo simulations of protein–ligand complexes. We describe here the implementation of the QUBE force field in the alchemical free-energy calculation molecular dynamics simulation package SOMD. The implementation is validated by demonstrating the reproducibility of absolute hydration free energies computed with the QUBE force field across the SOMD and GROMACS software packages. We further demonstrate, by way of a case study involving two series of non-nucleoside inhibitors of HIV-1 reverse transcriptase, that the availability of QUBE in a modern simulation package that makes efficient use of graphics processing unit acceleration will facilitate high-throughput alchemical free-energy calculations.
Recent evidence suggests that inhibition of bromodomain and extra-terminal (BET) epigenetic readers may have clinical utility against acute myeloid leukemia (AML). Here we validate this hypothesis, ...demonstrating the efficacy of the BET inhibitor I-BET151 across a variety of AML subtypes driven by disparate mutations. We demonstrate that a common 'core' transcriptional program, which is HOX gene independent, is downregulated in AML and underlies sensitivity to I-BET treatment. This program is enriched for genes that contain 'super-enhancers', recently described regulatory elements postulated to control key oncogenic driver genes. Moreover, our program can independently classify AML patients into distinct cytogenetic and molecular subgroups, suggesting that it contains biomarkers of sensitivity and response. We focus AML with mutations of the Nucleophosmin gene (NPM1) and show evidence to suggest that wild-type NPM1 has an inhibitory influence on BRD4 that is relieved upon NPM1c mutation and cytosplasmic dislocation. This leads to the upregulation of the core transcriptional program facilitating leukemia development. This program is abrogated by I-BET therapy and by nuclear restoration of NPM1. Finally, we demonstrate the efficacy of I-BET151 in a unique murine model and in primary patient samples of NPM1c AML. Taken together, our data support the use of BET inhibitors in clinical trials in AML.
East-Southeast Asia is currently one of the fastest urbanizing regions in the world, with countries such as China climbing from 20 to 50% urbanized in just a few decades. By 2050, these countries are ...projected to add 1 billion people, with 90% of that growth occurring in cities. This population shift parallels an equally astounding amount of built-up land expansion. However, spatially-and temporally-detailed information on regional-scale changes in urban land or population distribution do not exist; previous efforts have been either sample-based, focused on one country, or drawn conclusions from datasets with substantial temporal spatial mismatch and variability in urban definitions. Using consistent methodology, satellite imagery and census data for >1000 agglomerations in the East-Southeast Asian region, we show that urban land increased >22% between 2000 and 2010 (from 155 000 to 189 000 km2), an amount equivalent to the area of Taiwan, while urban populations climbed >31% (from 738 to 969 million). Although urban land expanded at unprecedented rates, urban populations grew more rapidly, resulting in increasing densities for the majority of urban agglomerations, including those in both more developed (Japan, South Korea) and industrializing nations (China, Vietnam, Indonesia). This result contrasts previous sample-based studies, which conclude that cities are universally declining in density. The patterns and rates of change uncovered by these datasets provide a unique record of the massive urban transition currently underway in East-Southeast Asia that is impacting local-regional climate, pollution levels, water quality availability, arable land, as well as the livelihoods and vulnerability of populations in the region.
Abstract
Mutation—whilst stochastic—is frequently biased toward certain loci. When combined with selection, this results in highly repeatable and predictable evolutionary outcomes. Immotile variants ...of the bacterium Pseudomonas fluorescens (SBW25) possess a “mutational hotspot” that facilitates repeated occurrences of an identical de novo single nucleotide polymorphism when re-evolving motility, where ≥95% independent lines fix the mutation ntrB A289C. Identifying hotspots of similar potency in other genes and genomic backgrounds would prove valuable for predictive evolutionary models but to do so we must understand the genomic features that enable such a hotspot to form. Here, we reveal that genomic location, local nucleotide sequence, gene strandedness, and presence of mismatch repair proteins operate in combination to facilitate the formation of this mutational hotspot. Our study therefore provides a framework for utilizing genomic features to predict and identify hotspot positions capable of enforcing near-deterministic evolution.
A long-standing and profound problem in astronomy is the difficulty in obtaining deep near-infrared observations due to the extreme brightness and variability of the night sky at these wavelengths. A ...solution to this problem is crucial if we are to obtain the deepest possible observations of the early Universe, as redshifted starlight from distant galaxies appears at these wavelengths. The atmospheric emission between 1,000 and 1,800 nm arises almost entirely from a forest of extremely bright, very narrow hydroxyl emission lines that varies on timescales of minutes. The astronomical community has long envisaged the prospect of selectively removing these lines, while retaining high throughput between them. Here we demonstrate such a filter for the first time, presenting results from the first on-sky tests. Its use on current 8 m telescopes and future 30 m telescopes will open up many new research avenues in the years to come.
Aims/hypothesis We sought to determine the effect of an aerobic exercise intervention on clustered metabolic risk and related outcomes in healthy older adults in a single-centre, explanatory ...randomised controlled trial. Methods Participants from the Hertfordshire Cohort Study (born 1931-1939) were randomly assigned to 36 supervised 1 h sessions on a cycle ergometer over 12 weeks or to a non-intervention control group. Randomisation and group allocation were conducted by the study co-ordinator, using a software programme. Those with prevalent diabetes, unstable ischaemic heart disease or poor mobility were excluded. All data were collected at our clinical research facility in Cambridge. Components of the metabolic syndrome were used to derive a standardised composite metabolic risk score (zMS) as the primary outcome. Trial status: closed to follow-up. Results We randomised 100 participants (50 to the intervention, 50 to the control group). Mean age was 71.4 (range 67.4-76.3) years. Overall, 96% of participants attended for follow-up measures. There were no serious adverse events. Using an intention-to-treat analysis, we saw a non-significant reduction in zMS in the exercise group compared with controls (0.07 95% CI −0.03, 0.17, p = 0.19). However, the exercise group had significantly decreased weight, waist circumference and intrahepatic lipid, with increased aerobic fitness and a 68% reduction in prevalence of abnormal glucose metabolism (OR 0.32 95% CI 0.11-0.92, p = 0.035) compared with controls. Results were similar in per-protocol analyses. Conclusions/interpretation Enrolment in a supervised aerobic exercise intervention led to weight loss, increased fitness and improvements in some but not all metabolic outcomes. In appropriately screened older individuals, such interventions appear to be safe. Trial registration: Controlled-trials.com ISRCTN60986572 Funding: Medical Research Council
The MLL-AF9 fusion gene is associated with aggressive leukemias of both the myeloid and lymphoid lineage in infants, whereas in adults, this translocation is mainly associated with acute myeloid ...leukemia. These observations suggest that differences exist between fetal and adult tissues in terms of the 'cell of origin' from which the leukemia develops. Here we show that depending on extrinsic cues, human neonatal CD34(+) cells are readily immortalized along either the myeloid or lymphoid lineage upon MLL-AF9 expression and give rise to mainly lymphoid leukemia in immunocompromised mice. In contrast, immortalization of adult bone marrow CD34(+) cells is more difficult to achieve and is myeloid-biased, even when MLL-AF9 is expressed in purified hematopoietic stem cells (HSCs). Transcriptome analysis identified enrichment of HSC but not progenitor gene signatures in MLL-AF9-expressing cells. Although not observed in adult cells, neonatal cells expressing MLL-AF9 were enriched for gene signatures associated with poor prognosis, resistance to chemotherapeutic agents and MYC signaling. These results indicate that neonatal cells are inherently more prone to MLL-AF9-mediated immortalization than adult cells and suggest that intrinsic properties of the cell of origin, in addition to extrinsic cues, dictate lineage of the immortalized cell.
At present, there are few technologies which enable the detection, identification and viability analysis of protozoan pathogens including Cryptosporidium and/or Giardia at the single (oo)cyst level. ...We report the use of Microfluidic Impedance Cytometry (MIC) to characterise the AC electrical (impedance) properties of single parasites and demonstrate rapid discrimination based on viability and species. Specifically, MIC was used to identify live and inactive C. parvum oocysts with over 90% certainty, whilst also detecting damaged and/or excysted oocysts. Furthermore, discrimination of Cryptosporidium parvum, Cryptosporidium muris and Giardia lamblia, with over 92% certainty was achieved. Enumeration and identification of (oo)cysts can be achieved in a few minutes, which offers a reduction in identification time and labour demands when compared to existing detection methods.
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