[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].

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.

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.

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.

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.

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.

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.

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.

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.

Towards fully automated structure-based function prediction in structural genomics: a case study.

As the global Structural Genomics projects have picked up pace, the number of structures annotated in the Protein Data Bank as hypothetical protein or unknown function has grown significantly. A major challenge now involves the development of computational methods to assign functions to these proteins accurately and automatically. As part of the Midwest Center for Structural Genomics (MCSG) we have developed a fully automated functional analysis server, ProFunc, which performs a battery of analyses on a submitted structure. The analyses combine a number of sequence-based and structure-based methods to identify functional clues. After the first stage of the Protein Structure Initiative (PSI), we review the success of the pipeline and the importance of structure-based function prediction. As a dataset, we have chosen all structures solved by the MCSG during the 5 years of the first PSI. Our analysis suggests that two of the structure-based methods are particularly successful and provide examples of local similarity that is difficult to identify using current sequence-based methods. No one method is successful in all cases, so, through the use of a number of complementary sequence and structural approaches, the ProFunc server increases the chances that at least one method will find a significant hit that can help elucidate function. Manual assessment of the results is a time-consuming process and subject to individual interpretation and human error. We present a method based on the Gene Ontology (GO) schema using GO-slims that can allow the automated assessment of hits with a success rate approaching that of expert manual assessment.

Predicting protein function from sequence and structural data.

When a protein's function cannot be experimentally determined, it can often be inferred from sequence similarity. Should this process fail, analysis of the protein structure can provide functional clues or confirm tentative functional assignments inferred from the sequence. Many structure-based approaches exist (e.g. fold similarity, three-dimensional templates), but as no single method can be expected to be successful in all cases, a more prudent approach involves combining multiple methods. Several automated servers that integrate evidence from multiple sources have been released this year and particular improvements have been seen with methods utilizing the Gene Ontology functional annotation schema.

Amyloid formation may involve alpha- to beta sheet interconversion via peptide plane flipping.

The toxic component of amyloid is not the mature fiber but a soluble prefibrillar intermediate. It has been proposed, from molecular dynamics simulations, that the precursor is composed of alpha sheet, which converts into the beta sheet of mature amyloid via peptide plane flipping. alpha sheet, not seen in proteins, occurs as isolated stretches of polypeptide. We show that the alpha- to beta sheet transition can occur by the flipping of alternate peptide planes. The flip can be described as alphaRalphaL<-->betabeta. A search conducted within sets of closely related protein crystal structures revealed that these flips are common, occurring in 8.5% of protein families. The average "alphaL" conformation found is in an adjacent and less populated region of the Ramachandran plot, as expected if the flanking peptide planes, being hydrogen bonded, are restricted in their movements. This work provides evidence for flips allowing direct alpha- to beta sheet interconversion.

ProFunc: a server for predicting protein function from 3D structure.

ProFunc (http://www.ebi.ac.uk/thornton-srv/databases/ProFunc) is a web server for predicting the likely function of proteins whose 3D structure is known but whose function is not. Users submit the coordinates of their structure to the server in PDB format. ProFunc makes use of both existing and novel methods to analyse the protein's sequence and structure identifying functional motifs or close relationships to functionally characterized proteins. A summary of the analyses provides an at-a-glance view of what each of the different methods has found. More detailed results are available on separate pages. Often where one method has failed to find anything useful another may be more forthcoming. The server is likely to be of most use in structural genomics where a large proportion of the proteins whose structures are solved are of hypothetical proteins of unknown function. However, it may also find use in a comparative analysis of members of large protein families. It provides a convenient compendium of sequence and structural information that often hold vital functional clues to be followed up experimentally.

Protein function prediction using local 3D templates.

The prediction of a protein's function from its 3D structure is becoming more and more important as the worldwide structural genomics initiatives gather pace and continue to solve 3D structures, many of which are of proteins of unknown function. Here, we present a methodology for predicting function from structure that shows great promise. It is based on 3D templates that are defined as specific 3D conformations of small numbers of residues. We use four types of template, covering enzyme active sites, ligand-binding residues, DNA-binding residues and reverse templates. The latter are templates generated from the target structure itself and scanned against a representative subset of all known protein structures. Together, the templates provide a fairly thorough coverage of the known structures and ensure that if there is a match to a known structure it is unlikely to be missed. A new scoring scheme provides a highly sensitive means of discriminating between true positive and false positive template matches. In all, the methodology provides a powerful new tool for function prediction to complement those already in use.

A novel main-chain anion-binding site in proteins: the nest. A particular combination of phi,psi values in successive residues gives rise to anion-binding sites that occur commonly and are found often at functionally important regions.

Main-chain conformations where one amino acid residue can be described as gamma(R) (or alpha(R)) and an adjacent one as gamma(L) (or alpha(L)) mostly result in the three main-chain NH groups (of the two residues and the one following) forming a depression that can accommodate an atom with a whole or partial negative charge. We propose the name nest for this feature. The negatively charged atom, when present, is also stabilized by hydrogen-bonding with the NH groups. In an average protein, 8 % of residues are involved in a nest. The anion, or partially negatively charged atom, that often occupies the nest may be a main-chain carbonyl oxygen atom as in the paperclip, also called the Schellman loop, and the oxyanion hole of serine proteases. It can be a phosphate group, as in the P-loop superfamily that binds ATP and GTP. Overlapping, compound, nests are observed often, as in the P-loop, which has five successive NH groups that bind the beta phosphate group of nucleotide triphosphate. The longest compound nests are found surrounding cysteine-bound [2Fe2S] and [4Fe4S] iron-sulfur centers, which are also anionic; nests may encourage binding of the more reduced forms. The nest is a novel feature in the sense of not having been described as a unique motif with anion-binding potential before, although some of the situations where it occurs are familiar.

The conformations of polypeptide chains where the main-chain parts of successive residues are enantiomeric. Their occurrence in cation and anion-binding regions of proteins.

We have investigated the shapes of polypeptides where successive residues have main-chain phi,psi conformations of opposite hand. A graph not unlike a Ramachandran plot is presented illustrating the various possible conformations. All are ring-shaped or extended. Some of these conformations occur in native proteins, the commonest approximating to a feature we propose calling a nest, described in the accompanying paper, where the main-chain NH groups point inwards relative to the ring and give rise to an anion-binding site. Another conformation is related but more extended and is found uniquely in the four stretches of polypeptide that line the tetrameric K(+) channel; their CO groups bind the K ions in the channel. In a different ring-shaped conformation that we propose calling a catgrip, the main-chain CO groups point into the ring; this is employed for specific Ca ion binding in the annexin, phospholipase A2 and subtilisin loops, and the regularly arranged beta-roll loops of the serralysin protease family.

The shape of things to come?

This fourth paper in the Future of Dentistry series examines the future of dental practice, particularly in terms of the National Health Service. David Watson-James' vision is, he explains, intrinsically linked to past and present developments in dentistry and as the last 50 years has seen dental practice largely influenced by the creation of the NHS, he looks at its importance and relevance in years to come.