MLA Research Agenda: Appraising the Best Available Evidence

Offers guidelines for the formation and self-governance of autonomous teams as they conduct systematic reviews related to the MLA Research Agenda

Generic local distinguishability and completely entangled subspaces

A subspace of a multipartite Hilbert space is completely entangled if it contains no product states. Such subspaces can be large with a known maximum size, S, approaching the full dimension of the system, D. We show that almost all subspaces with dimension less than or equal to S are completely entangled, and then use this fact to prove that n random pure quantum states are unambiguously locally distinguishable if and only if n does not exceed D-S. This condition holds for almost all sets of states of all multipartite systems, and reveals something surprising. The criterion is identical for separable and for nonseparable states: entanglement makes no difference.Comment: 12 page

Hepatic lipids promote liver metastasis

Obesity predisposes to cancer and a virtual universality of nonalcoholic fatty liver disease (NAFLD). However, the impact of hepatic steatosis on liver metastasis is enigmatic. We find that while control mice were relatively resistant to hepatic metastasis, those which were lipodystrophic or obese, with NAFLD, had a dramatic increase in breast cancer and melanoma liver metastases. NAFLD promotes liver metastasis by reciprocal activation initiated by tumor-induced triglyceride lipolysis in juxtaposed hepatocytes. The lipolytic products are transferred to cancer cells via fatty acid transporter protein 1, where they are metabolized by mitochondrial oxidation to promote tumor growth. The histology of human liver metastasis indicated the same occurs in humans. Furthermore, comparison of isolates of normal and fatty liver established that steatotic lipids had enhanced tumor-stimulating capacity. Normalization of glucose metabolism by metformin did not reduce steatosis-induced metastasis, establishing the process is not mediated by the metabolic syndrome. Alternatively, eradication of NAFLD in lipodystrophic mice by adipose tissue transplantation reduced breast cancer metastasis to that of control mice, indicating the steatosis-induced predisposition is reversible

Effectiveness of earlier antenatal screening for sickle cell disease and thalassaemia in primary care: cluster randomised trial

Objective To evaluate the effectiveness of offering antenatal screening for sickle cell disease and thalassaemia in primary care as a way of facilitating earlier uptake of screening

Diffuse Stellar Light at 100 kpc Scales in M87

In a new survey of nearby galaxies from stacked photographic images, M87 shows a diffuse fan of stellar material which extends along the projected SE (major) axis out to about 100 kpc at a limiting (B) surface brightness of $28 \hbox{mag arcsec}^{-2}$. We suggest that disruption of a small spheroidal galaxy within a larger potential is the most likely explanation for the diffuse structure. Our simulations include a rigid primary potential with characteristics similar to those derived for M87 and a populated intruder. The orbit is required to pass close to the center of the potential to produce a fan which nearly aligns with the major axis and has a large opening angle, as seen in M87. The structure of the dark matter at large galactic radii is investigated by representing M87 with different potentials. The morphology and luminosity of the fan and the kinematics of debris in the center of the primary potential are analyzed and compared with substructure in M87. The short lifetimes (t_fan < 5 10^8 years) of the simulated diffuse fans indicate that several accretion events could be hidden in galaxies.Comment: 24 pages, Latex (aaspp4.sty), with 15 figures. Accepted for publication in Ap

Release of Histone H3K4-reading transcription factors from chromosomes in mitosis is independent of adjacent H3 phosphorylation

Histone modifications influence the recruitment of reader proteins to chromosomes to regulate events including transcription and cell division. The idea of a histone code, where combinations of modifications specify unique downstream functions, is widely accepted and can be demonstrated in vitro. For example, on synthetic peptides, phosphorylation of Histone H3 at threonine-3 (H3T3ph) prevents the binding of reader proteins that recognize trimethylation of the adjacent lysine-4 (H3K4me3), including the TAF3 component of TFIID. To study these combinatorial effects in cells, we analyzed the genome-wide distribution of H3T3ph and H3K4me2/3 during mitosis. We find that H3T3ph anti-correlates with adjacent H3K4me2/3 in cells, and that the PHD domain of TAF3 can bind H3K4me2/3 in isolated mitotic chromatin despite the presence of H3T3ph. Unlike in vitro, H3K4 readers are still displaced from chromosomes in mitosis in Haspin-depleted cells lacking H3T3ph. H3T3ph is therefore unlikely to be responsible for transcriptional downregulation during cell division.This study was funded by a Wellcome Trust Investigator Award (106951/Z/15/Z) and a Royal Society Wolfson Research Merit Award (WM130089) to J.M.G.H., an EPSRC DTP (Biological Informatics) PhD Studentship to M.H., a Barbour Foundation PhD Studentship to J.L.M., and by a J.G.W. Patterson Foundation grant to L.G.Peer reviewe

DNA cruciform arms nucleate through a correlated but non-synchronous cooperative mechanism

Inverted repeat (IR) sequences in DNA can form non-canonical cruciform structures to relieve torsional stress. We use Monte Carlo simulations of a recently developed coarse-grained model of DNA to demonstrate that the nucleation of a cruciform can proceed through a cooperative mechanism. Firstly, a twist-induced denaturation bubble must diffuse so that its midpoint is near the centre of symmetry of the IR sequence. Secondly, bubble fluctuations must be large enough to allow one of the arms to form a small number of hairpin bonds. Once the first arm is partially formed, the second arm can rapidly grow to a similar size. Because bubbles can twist back on themselves, they need considerably fewer bases to resolve torsional stress than the final cruciform state does. The initially stabilised cruciform therefore continues to grow, which typically proceeds synchronously, reminiscent of the S-type mechanism of cruciform formation. By using umbrella sampling techniques we calculate, for different temperatures and superhelical densities, the free energy as a function of the number of bonds in each cruciform along the correlated but non-synchronous nucleation pathways we observed in direct simulations.Comment: 12 pages main paper + 11 pages supplementary dat