Uncomputably complex renormalisation group flows.

Renormalisation group methods are among the most important techniques for analysing the physics of many-body systems: by iterating a renormalisation group map, which coarse-grains the description of a system and generates a flow in the parameter space, physical properties of interest can be extracted. However, recent work has shown that important physical features, such as the spectral gap and phase diagram, may be impossible to determine, even in principle. Following these insights, we construct a rigorous renormalisation group map for the original undecidable many-body system that appeared in the literature, which reveals a renormalisation group flow so complex that it cannot be predicted. We prove that each step of this map is computable, and that it converges to the correct fixed points, yet the resulting flow is uncomputable. This extreme form of unpredictability for renormalisation group flows had not been shown before and goes beyond the chaotic behaviour seen previously.

[Fp(CH4)]+, [η5-CpRu(CO)2(CH4)]+, and [η5-CpOs(CO)2(CH4)]+: A Complete Set of Group 8 Metal-Methane Complexes.

Here, we report the NMR spectroscopic analysis of the group 8 transition metal methane σ-complexes [η5-CpM(CO)2(CH4)][Al(OC(CF3)3)4] (M = Fe, Ru) at -90 °C in the weakly coordinating solvent 1,1,1,3,3,3-hexafluoropropane. The iron(II)-methane complex has a 1H resonance at δ -4.27, a 13C resonance at δ -53.0, and 1JC-H = 126 Hz for the bound methane fragment. The ruthenium(II)-methane complex has a 1H resonance at δ -2.10, a 13C resonance at δ -48.8, and a 1JC-H = 126 Hz for the bound methane fragment. DFT and ab initio calculations support these experimental observations and provide further detail on the structures of the [η5-CpM(CO)2(CH4)]+ (M = Fe, Ru) complexes of the Group 8 metals. Both the iron centered methane complex, [η5-CpFe(CO)2(CH4)][Al(OC(CF3)3)4], and the ruthenium centered methane complex, [η5-CpRu(CO)2(CH4)][Al(OC(CF3)3)4], are significantly less stable than the previously reported osmium-methane complex [η5-CpOs(CO)2(CH4)][Al(OC(CF3)3)4].

Binding methane to a metal centre.

The σ-alkane complexes of transition metals, which contain an essentially intact alkane molecule weakly bound to the metal, have been well established as crucial intermediates in the activation of the strong C-H σ-bonds found in alkanes. Methane, the simplest alkane, binds even more weakly than larger alkanes. Here we report an example of a long-lived methane complex formed by directly binding methane as an incoming ligand to a reactive organometallic complex. Photo-ejection of carbon monoxide from a cationic osmium-carbonyl complex dissolved in an inert hydrofluorocarbon solvent saturated with methane at -90 °C affords an osmium(II) complex, [η5-CpOs(CO)2(CH4)]+, containing methane bound to the metal centre. Nuclear magnetic resonance (NMR) spectroscopy confirms the identity of the σ-methane complex and shows that the four protons of the metal-bound methane are in rapid exchange with each other. The methane ligand has a characteristically shielded 1H NMR resonance (δ -2.16), and the highly shielded carbon resonance (δ -56.3) shows coupling to the four attached protons (1JC-H = 127 Hz). The methane complex has an effective half-life of about 13 hours at -90 °C.

Uncomputability of phase diagrams.

The phase diagram of a material is of central importance in describing the properties and behaviour of a condensed matter system. In this work, we prove that the task of determining the phase diagram of a many-body Hamiltonian is in general uncomputable, by explicitly constructing a continuous one-parameter family of Hamiltonians H(φ), where [Formula: see text], for which this is the case. The H(φ) are translationally-invariant, with nearest-neighbour couplings on a 2D spin lattice. As well as implying uncomputablity of phase diagrams, our result also proves that undecidability can hold for a set of positive measure of a Hamiltonian's parameter space, whereas previous results only implied undecidability on a zero measure set. This brings the spectral gap undecidability results a step closer to standard condensed matter problems, where one typically studies phase diagrams of many-body models as a function of one or more continuously varying real parameters, such as magnetic field strength or pressure.

Mito-oncology agent: fermented extract suppresses the Warburg effect, restores oxidative mitochondrial activity, and inhibits in vivo tumor growth.

Mitochondrial dysfunction and significant changes in metabolic pathways accompany cancer development and are responsible for maintaining the tumor microenvironment. Normal mitochondria can trigger intrinsic apoptosis by releasing cytochrome c into the cytosol. The survival of malignant cells highly depends on the suppression of this function. We validated that A250, a highly purified fraction of fermented wheat germ extract (FWGE), increases the carbon flux into the mitochondria, the expression of key elements of the Krebs cycle and oxidative phosphorylation (OXPHOS). The increased respiratory chain activity is related to the mitochondria's ability to release cytochrome c into the cytosol, which triggers the apoptotic cascade. The 68% tumor growth inhibitory effect observed in the murine melanoma study is related to this effect, as proteomic analysis validated similar changes in mitochondrial protein levels in the isolated tumor tissue samples. Blood count data indicated that this effect was not accompanied by general toxicity. This study is significant, as it shows that a highly concentrated form of FWGE is an effective agent that increases normal mitochondrial functionality. The lack of hepatotoxic and general toxic effects makes A250 an excellent candidate targeting mitochondria function in cancer therapy.

On the Basicity of Carboranylphosphines.

Three new carboranylphosphines, [1-(1'-closo-1',7'-C2B10H11)-7-PPh2-closo-1,7-C2B10H10], [1-(1'-7'-PPh2-closo-1',7'-C2B10H10)-7-PPh2-closo-1,7-C2B10H10], and [1-{PPh-(1'-closo-1',2'-C2B10H11)}-closo-1,2-C2B10H11], have been prepared, and from a combination of these and literature compounds, eight new carboranylphosphine selenides were subsequently synthesized. The relative basicities of the carboranylphosphines were established by (i) measurement of the 1JPSe NMR coupling constant of the selenide and (ii) calculation of the proton affinity of the phosphine, in an attempt to establish which of several factors are the most important in controlling the basicity. It is found that the basicity of the carboranylphosphines is significantly influenced by the nature of other substituents on the P atom, the nature of the carborane cage vertex (C or B) to which the P atom is attached, and the charge on the carboranylphosphine. In contrast, the basicity of the carboranylphosphines appears to be relatively insensitive to the nature of other substituents on the carborane cage, the isomeric form of the carborane, and whether the cage is closo or nido (insofar as that does not alter the charge on the cluster). Such information is likely to be of significant importance in optimizing future applications of carboranylphosphines, e.g., as components of frustrated Lewis pairs.

Bioactivation of Napabucasin Triggers Reactive Oxygen Species-Mediated Cancer Cell Death.

PURPOSE: Napabucasin (2-acetylfuro-1,4-naphthoquinone or BBI-608) is a small molecule currently being clinically evaluated in various cancer types. It has mostly been recognized for its ability to inhibit STAT3 signaling. However, based on its chemical structure, we hypothesized that napabucasin is a substrate for intracellular oxidoreductases and therefore may exert its anticancer effect through redox cycling, resulting in reactive oxygen species (ROS) production and cell death. EXPERIMENTAL DESIGN: Binding of napabucasin to NAD(P)H:quinone oxidoreductase-1 (NQO1), and other oxidoreductases, was measured. Pancreatic cancer cell lines were treated with napabucasin, and cell survival, ROS generation, DNA damage, transcriptomic changes, and alterations in STAT3 activation were assayed in vitro and in vivo. Genetic knockout or pharmacologic inhibition with dicoumarol was used to evaluate the dependency on NQO1. RESULTS: Napabucasin was found to bind with high affinity to NQO1 and to a lesser degree to cytochrome P450 oxidoreductase (POR). Treatment resulted in marked induction of ROS and DNA damage with an NQO1- and ROS-dependent decrease in STAT3 phosphorylation. Differential cytotoxic effects were observed, where NQO1-expressing cells generating cytotoxic levels of ROS at low napabucasin concentrations were more sensitive. Cells with low or no baseline NQO1 expression also produced ROS in response to napabucasin, albeit to a lesser extent, through the one-electron reductase POR. CONCLUSIONS: Napabucasin is bioactivated by NQO1, and to a lesser degree by POR, resulting in futile redox cycling and ROS generation. The increased ROS levels result in DNA damage and multiple intracellular changes, one of which is a reduction in STAT3 phosphorylation.

Crystal structure of 1-hepta-fluoro-tolyl-closo-1,2-dicarbadodeca-borane.

The mol-ecular structure of the title compound 1-(2',3',5',6'-tetra-fluoro-4'-trifluoro-methyl-phen-yl)-closo-1,2-dicarbadodeca-borane, C9H11B10F7, features an intra-molecular ortho-F⋯H2 hydrogen bond [2.11 (2) Å], which is responsible for an orientation of the hepta-fluoro-tolyl substituent in which the plane of the aryl ring nearly eclipses the C1-C2 cage connectivity.

Tackling antibiotic resistance.

The development and spread of antibiotic resistance in bacteria is a universal threat to both humans and animals that is generally not preventable but can nevertheless be controlled, and it must be tackled in the most effective ways possible. To explore how the problem of antibiotic resistance might best be addressed, a group of 30 scientists from academia and industry gathered at the Banbury Conference Centre in Cold Spring Harbor, New York, USA, from 16 to 18 May 2011. From these discussions there emerged a priority list of steps that need to be taken to resolve this global crisis.

Curing "incurable" cancer.

Cancer cells are preferentially killed by anticancer agents because key signals for growth and cell division are "always on" as opposed to the alternative "on" and "off" signaling of normal cells. Too much of today's anticancer drug discovery effort may go toward reversing genetically promoted "always on" signals. More effective anticancer drug targets may be found through use of RNAi technologies that pinpoint the key gene regulatory and metabolic weakness of the "always on" cancer cells.

Potent subunit-specific effects on cell growth and drug sensitivity from optimised siRNA-mediated silencing of ribonucleotide reductase.

Ribonucleotide reductase (RR) has an essential role in DNA synthesis and repair and is a therapeutic target in a number of different cancers. Previous studies have shown that RNAi-mediated knockdown of either the RRM1 or RRM2 subunit sensitizes cells to the cytotoxic effects of the nucleoside analogs and more recently it has been shown that RRM2 knockdown itself has a growth inhibitory effect. Here we compare the effects of siRNA-mediated knockdown of both RRM1 and RRM2 subunits of RR in A549 and HCT-116 cells using an optimized transfection protocol. Growth of A549 cells was strongly inhibited by efficient siRNA-mediated silencing of either RRM1 or RRM2, and knockdown of each subunit led to long-term growth inhibition and cell-cycle arrest. Knockdown with sub growth inhibitory siRNA concentrations sensitized A549 and HCT-116 cells to gemcitabine when RRM1 was targeted, whereas RRM2 knockdown led to hydroxyurea sensitization. These results suggest that the inhibition of cell growth, rather than drug sensitization, is the major effect of RRM1 and RRM2 knockdown. In an A549 xenograft model, cells transfected with RRM1-specific siRNA failed to form tumors in 6 out of 8 CD1 nude mice, whereas those transfected with RRM2-specific siRNA grew but at a reduced rate. Taken together, these data demonstrate that siRNA-mediated knockdown of the RRM1 subunit is more effective than knockdown of RRM2 in inhibiting the growth of cancer cell lines and suggest that RRM1 is a potential target for nucleic acid-based cancer therapies, either alone or in combination with gemcitabine.

A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale.

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is critical, however, for both basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brainwide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brainwide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open-access data repository; compatibility with existing resources; and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.