Geometric isomerism in coordination cages based on tris-chelate vertices: a tool to control both assembly and host/guest chemistry.

This 'Perspective' article summarises recent work from the authors' research group on the exploitation of the simple fac/mer geometric isomerism of octahedral metal tris-chelates as a tool to control the chemistry of coordination cages based on bis(pyrazolyl-pyridine) ligands, in two different respects. Firstly this geometric isomerism plays a major role in controlling the guest binding properties of cages because a fac tris-chelate arrangement of pyrazolyl-pyridine chelates around a metal ion vertex results in formation of a convergent set of inwardly-directed C-H protons in a region of high positive electrostatic potential close to a metal cation. This collection of δ+ protons therefore provides a charge-assisted hydrogen-bond donor site, which interacts with the electron-rich regions of guest molecules that are of the correct size and shape to occupy the cage cavity, and the strength of this hydrogen-bonding interaction plays a major role in guest recognition in non-aqueous solvents. Secondly the ability to prepare mononuclear complexes with either a fac or mer arrangement of ligands provides an entry into the controlled, stepwise assembly of heterometallic cages based on a combination of kinetically inert and kinetically labile metal ions at different sites. This has allowed introduction of useful physical properties such as redox activity or luminescence, commonly associated with inert metal ions which are not amenable to participation in thermodynamic self-assembly processes, to be incorporated in a predictable way into the superstructures of coordination cages at specific sites

Coordination‐cage‐catalysed hydrolysis of organophosphates : cavity‐ or surface‐based?

The hydrophobic central cavity of a water‐soluble M8L12 cubic coordination cage can accommodate a range of phospho‐diester and phospho‐triester guests such as the insecticide “dichlorvos” (2,2‐dichlorovinyl dimethyl phosphate) and the chemical warfare agent analogue di(isopropyl) chlorophosphate. The accumulation of hydroxide ions around the cationic cage surface due to ion‐pairing in solution generates a high local pH around the cage, resulting in catalysed hydrolysis of the phospho‐triester guests. A series of control experiments unexpectedly demonstrates that—in marked contrast to previous cases—it is not necessary for the phospho‐triester substrates to be bound inside the cavity for catalysed hydrolysis to occur. This suggests that catalysis can occur on the exterior surface of the cage as well as the interior surface, with the exterior‐binding catalysis pathway dominating here because of the small binding constants for these phospho‐triester substrates in the cage cavity. These observations suggest that cationic but hydrophobic surfaces could act as quite general catalysts in water by bringing substrates into contact with the surface (via the hydrophobic effect) where there is also a high local concentration of anions (due to ion pairing/electrostatic effects)

Stepwise assembly of mixed-metal coordination cages containing both kinetically inert and kinetically labile metal ions: introduction of metal-centred redox and photophysical activity at specific sites

Stepwise preparation of the heterometallic octanuclear coordination cages [(Ma)4(Mb)4L12]16+ is reported, in which Ma = Ru or Os and Mb = Cd or Co (all in their +2 oxidation state). This requires initial preparation of the kinetically inert mononuclear complexes [(Ma)L3]2+ in which L is a ditopic ligand with two bidentate chelating pyrazolyl-pyridine units: in the complexes [(Ma)L3]2+ one terminus of each ligand is bound to the metal ion, such that the complex has three pendant bidentate sites at which cage assembly can propagate by coordination to additional labile ions Mb in a separate step. Thus, combination of four [(Ma)L3]2+ units and four [Mb]2+ ions results in assembly of the complete cages [(Ma)4(Mb)4L12]16+ in which a metal ion lies at each of the eight vertices, and a bridging ligand spans each of the twelve edges, of a cube. The different types of metal ion necessarily alternate around the periphery with each bridging ligand bound to one metal ion of each type. All four cages have been structurally characterised: in the Ru(II)/Cd(II) cage (reported in a recent communication) the Ru(II) and Cd(II) ions are crystallographically distinct; in the other three cages [Ru(II)/Co(II), Os(II)/Cd(II) and Os(II)/Co(II), reported here] the ions are disordered around the periphery such that every metal site refines as a 50 : 50 mixture of the two metal atom types. The incorporation of Os(II) units into the cages results in both redox activity [a reversible Os(II)/Os(III) couple for all four metal ions simultaneously, at a modest potential] and luminescence [the Os(II) units have luminescent 3MLCT excited states which will be good photo-electron donors] being incorporated into the cage superstructure

Ir(III) and Ir(III)/Re(I) complexes of a new bis(pyrazolyl-pyridine) bridging ligand containing a naphthalene-2,7-diyl spacer: Structural and photophysical properties

A new bridging ligand has been prepared in which two chelating bidentate pyrazolyl-pyridine termini are connected to a central naphthalene-2,7-diyl core via methylene spacer units. This ligand has been used to prepared mononuclear and dinuclear Ir(III) complexes in which {Ir(F2ppy)2} [F2ppy = cyclometallating anion of 2-(3,5-difluorophenyl)-pyridine] complex fragments are coordinated to one or both of the pyrazolyl-pyridine termini; in addition a heterodinuclear complex has been prepared containing one {Ir(F2ppy)2} unit and one {Re(CO)3Cl} unit in the two binding sites. X-ray crystallographic studies show that the bridging naphthyl group lies stacked with a coordinated F2ppy ligand from a terminal {Ir(F2ppy)2} unit in every case. Luminescence measurements show that the usual strong Ir(III)-centred blue luminescence is substantially quenched by the presence of a low-lying triplet state on the naphthyl group; in the Ir(III)/Re(I) dyad we observe both weak Ir(III)-based emission as well as lower-energy Re(I)-based emission which overlap; Ir(III) → Re(I) energy-transfer occurs on a timescale of <1 ns as no rise-time for sensitised Re(I)-based emission could be detected, in contrast to other Ir(III)/Re(I) dyads in which the Ir(III) → Re(I) energy-transfer is slower (10–100 ns timescale). We ascribe this to the spatial and energetic intermediacy of the naphthyl group whose triplet energy lies between that of the Ir(III) and Re(I) termini, providing an effective conduit for energy-transfer to occur

Catalysis in a Cationic Coordination Cage Using a Cavity-Bound Guest and Surface-Bound Anions: Inhibition, Activation, and Autocatalysis

The Kemp elimination (reaction of benzisoxazole with base to give 2-cyanophenolate) is catalyzed in the cavity of a cubic M8L12coordination cage because of a combination of (i) benzisoxazole binding in the cage cavity driven by the hydrophobic effect, and (ii) accumulation of hydroxide ions around the 16+ cage surface driven by ion-pairing. Here we show how reaction of the cavity-bound guest is modified by the presence of other anions which can also accumulate around the cage surface and displace hydroxide, inhibiting catalysis of the cage-based reaction. Addition of chloride or fluoride inhibits the reaction with hydroxide to the extent that a new autocatalytic pathway becomes apparent, resulting in a sigmoidal reaction profile. In this pathway the product 2-cyanophenolate itself accumulates around the cationic cage surface, acting as the base for the next reaction cycle. The affinity of different anions for the cage surface is therefore 2-cyanophenolate (generating autocatalysis) > chloride > fluoride (which both inhibit the reaction with hydroxide but cannot deprotonate the benzisoxazole guest) > hydroxide (default reaction pathway). The presence of this autocatalytic pathway demonstrates that a reaction of a cavity-bound guest can be induced with different anions around the cage surface in a controllable way; this was confirmed by adding different phenolates to the reaction, which accelerate the Kemp elimination to different extents depending on their basicity. This represents a significant step toward the goal of using the cage as a catalyst for bimolecular reactions between a cavity-bound guest and anions accumulated around the surface

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Not everything that counts can be counted: ants use multiple metrics for a single nest trait

There are claims in the literature that certain insects can count. We question the generality of these claims and suggest that summation rather than counting (sensu stricto) is a more likely explanation. We show that Temnothorax albipennis ant colonies can discriminate between potential nest sites with different numbers of entrances. However, our experiments suggest that the ants use ambient light levels within the nest cavity to assess the abundance of nest entrances rather than counting per se. Intriguingly, Weber's Law cannot explain the ants' inaccuracy. The ants also use a second metric, independent of light, to assess and discriminate against wide entrances. Thus, these ants use at least two metrics to evaluate one nest trait: the configuration of the portals to their potential homes

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease