165 research outputs found
Pore Shape Modification of a Microporous Metal-Organic Framework Using High Pressure:Accessing a New Phase with Oversized Guest Molecules
The authors thank the Royal Society of Edinburgh and the Scottish Government for a fellowship to S.A.M. The authors thank EPSRC (EP/J02077X/1) and Leverhulme Trust for a research project grant (RPG-209) for financial support. They also thank the UK Carr Parinello consortium for allocation of computing time on the EPSRC high performance computing resource ARCHER (managed by the Edinburgh Parallel Computing Centre, the EaSTCHEM Research Computing Facility and the University of Edinburgh ECDF facility).Pressures up to 0.8 GPa have been used to squeeze a range of sterically "oversized" C5-C8 alkane guest molecules into the cavities of a small-pore Sc-based metal?organic framework. Guest inclusion causes a pronounced reorientation of the aromatic rings of one-third of the terephthalate linkers, which act as "torsion springs", resulting in a fully reversible change in the local pore structure. The study demonstrates how pressure-induced guest uptake can be used to investigate framework flexibility relevant to "breathing" behavior and to understand the uptake of guest molecules in MOFs relevant to hydrocarbon separation.PostprintPeer reviewe
Exploring the mechanism of tryptophan 2,3-dioxygenase
The haem proteins TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase) are specific and powerful oxidation catalysts that insert one molecule of dioxygen into L-tryptophan in the first and rate-limiting step in the kynurenine pathway. Recent crystallographic and biochemical analyses of TDO and IDO have greatly aided our understanding of the mechanisms employed by these enzymes in the binding and activation of dioxygen and tryptophan. In the present paper, we briefly discuss the function, structure and possible catalytic mechanism of these enzymes
Yield of colorectal cancer at colonoscopy according to faecal haemoglobin concentration in symptomatic patients referred from primary care
Background:
Lower gastrointestinal (GI) symptoms are poor predictors of colorectal cancer (CRC). This study examined the diagnostic yield of colonoscopy by faecal haemoglobin concentration (f‐Hb) in symptomatic patients assessed in primary care by faecal immunochemical testing (FIT).
Methods:
In three Scottish NHS Boards, FIT kits (HM‐JACKarc, Hitachi Chemical Diagnostics Systems Co., Ltd, Tokyo, Japan) were used by GPs to guide referrals for patients with lower GI symptoms (lab data studied for 12 months from December 2015 onward in Tayside, 18 months from June 2018 onward in Fife, and 5 months from September 2018 onward in Greater Glasgow and Clyde). CRC cases diagnosed at colonoscopy were ascertained from colonoscopy and pathology records.
Results:
4841 symptomatic patients who underwent colonoscopy after FIT submission were included. Of 2166 patients (44.7%) with f‐Hb <10 µg Hb/g faeces (µg/g), 14 (0.6%) were diagnosed with CRC, with a number needed to scope (NNS) of 155. Of 2675 patients (55.3%) with f‐Hb ≥10 µg/g, 252 were diagnosed with CRC (9.4%) with a NNS of 11. Of 705 patients with f‐Hb ≥400 µg/g, 158 (22.4%) were diagnosed with CRC with a NNS of 5. Over half of those diagnosed with CRC with f‐Hb <10 µg/g had co‐existing anaemia.
Conclusions:
Symptomatic patients with f‐Hb ≥10 µg/g should undergo further investigation for CRC, while higher f‐Hb could be used to triage its urgency during the COVID‐19 recovery phase. Patients with f‐Hb <10 µg/g, without anaemia, are very unlikely to be diagnosed with CRC and the majority need no further investigation
Molecular simulations studies of gas adsorption in metal–organic frameworks
Using computational tools ranging from molecular simulations – including
both Monte Carlo and molecular dynamics methods – to quantum
mechanical (QM) calculations (primarily at density functional theory (DFT)
level), this work focuses on addressing some of the challenges faced in
molecular simulations of gas adsorption in metal–organic frameworks
(MOFs). This work consists of two themes: one concerns gas adsorption in
MOFs with coordinatively unsaturated metal sites (cus’s), and the other one
deals with predicting and understanding the breathing behaviour of the
flexible MOF MIL-53(Sc).
It has been shown experimentally that incorporation of cus’s – also known as
“open” metal sites or unsaturated metal centres – into MOFs significantly
enhances the uptake of certain gases such as CO2 and CH4. As a result of the
considerably enhanced, localized guest-molecule interactions with the cus’s,
it, however, remains a challenge to predict correctly adsorption isotherms
and/or mechanisms in MOFs with cus’s using grand-canonical Monte Carlo
(GCMC) simulations based on generic classical force fields. To address this
problem, two multi-scale modelling approaches – which combine GCMC
simulations with QM calculations – have been proposed in this work. The
first approach is based on the direct implementation of a fluid–framework
potential energy surface, calculated by a hybrid DFT/ab initio method, in the
GCMC simulations. The second approach involves parameterization of ab
initio force fields for GCMC simulations of gas adsorption in MOFs with
cus’s. This approach focuses on the generation of accurate ab initio reference
data, selection of semiempirical model potentials, and force-field fitting
through a multi-objective genetic algorithm approach. The multi-scale
simulation strategy not only yields adsorption isotherms in very good
agreement with experimental data but also correctly captures adsorption
mechanisms, including the adsorption on the cus’s, observed experimentally
but absent from GCMC simulations based on generic force fields.
The second challenge that this work aims to address concerns the “breathing”
phenomenon of MOFs, in which the framework structure adapts its pore
opening to accommodate guest molecules, for example. The breathing effect
gives rise to some exceptional properties of these MOFs and hence promising
applications. However, framework flexibility often poses a challenge for
computational studies of such MOFs, because suitable flexible force fields for
frameworks are lacking and the effort involved in developing a new one is
no less a challenge. Here, an alternative to the force-field-based approach is
adopted. Ab initio molecular dynamics (AIMD) simulations – which combine
classical molecular dynamics simulations with electronic-structure
calculations “on the fly” – have been deployed to study structural changes of
the breathing MOF MIL-53(Sc) in response to changes in temperature over
the range 100–623 K and adsorption of CO2 at 0–0.9 bar at 196 K. AIMD
simulations employing dispersion-corrected DFT accurately simulated the
experimentally observed closure of MIL-53(Sc) upon solvent removal and the
transition of the empty MOF from the closed-pore phase to the very-narrow-pore
phase with increasing temperature. AIMD simulations were also used to
mimic the CO2 adsorption of MIL-53(Sc) in silico by allowing the MIL-53(Sc)
framework to evolve freely in response to CO2 loadings corresponding to the
two steps in the experimental adsorption isotherm. The resulting structures
enabled the structure determination of the two CO2-containing intermediate
and large-pore phases observed by experimental synchrotron X-ray diffraction
studies with increasing CO2 pressure; this would not have been possible for
the intermediate structure via conventional methods because of diffraction
peak broadening. Furthermore, the strong and anisotropic peak broadening
observed for the intermediate structure could be explained in terms of
fluctuations of the framework predicted by the AIMD simulations.
Fundamental insights from the molecular-level interactions further revealed
the origin of the breathing of MIL-53(Sc) upon temperature variation and
CO2 adsorption.
Both the multi-scale simulation strategy for gas adsorption in MOFs with
cus’s and the AIMD study of the stimuli-responsive breathing behaviour of
MIL-53(Sc) illustrate the power and promise of combining molecular
simulations with quantum mechanical calculations for the prediction and
understanding of MOFs
Crystallization and preliminary crystallographic analysis of a novel cytochrome P450 from Mycobacterium tuberculosis
International audienceThe product of the Rv2276 gene of Mycobacterium tuberculosis is a cytochrome P450 (P450 MT2, CYP121) which has been shown to bind tightly to a range of azole-based antifungal drugs (e.g. miconazole, clotrimazole). These drugs are potent inhibitors of mycobacterial growth, suggesting that P450 MT2 (CYP121) may be a potential drug target. The enzyme has been overexpressed in Escherichia coli and crystallized by the hanging-drop method. Crystals of P450 MT2 (CYP121) belong to the hexagonal space group P6(1)22 or P6(5)22, with unit-cell parameters a = b = 78.3, c = 265.6 A. Native data have been collected to 1.6 A resolution and Hg-derivative data to 2.5 A resolution using a synchrotron-radiation source
Perfluorocarbon liquid under pressure:A medium for gas delivery
The authors thank the Royal Society of Edinburgh and the Scottish Government for a fellowship to Dr Stephen A. Moggach, and the Leverhulme Trust for financial support.A novel method for CO2 delivery to a porous material is reported, wherein a perfluorocarbon containing dissolved CO2 has been used as a pressure-transmitting liquid in a high-pressure single-crystal X-ray diffraction experiment. Pressure causes the gas to be squeezed out of the liquid into the host crystal, monitored via a single-crystal to single-crystal phase transition on uptake of CO2.PostprintPeer reviewe
Using Grizzly Bears to Assess Harvest-Ecosystem Tradeoffs in Salmon Fisheries
Using grizzly bears as surrogates for “salmon ecosystem” function, the authors develop a generalizable ecosystem-based management framework that enables decision-makers to quantify ecosystem-harvest tradeoffs between wild and human recipients of natural resources like fish
The Mechanism of Substrate Inhibition in Human Indoleamine 2,3-Dioxygenase
Indoleamine 2,3-dioxygenase catalyzes the O(2)-dependent oxidation of L-tryptophan (L-Trp) to N-formylkynurenine (NFK) as part of the kynurenine pathway. Inhibition of enzyme activity at high L-Trp concentrations was first noted more than 30 years ago, but the mechanism of inhibition has not been established. Using a combination of kinetic and reduction potential measurements, we present evidence showing that inhibition of enzyme activity in human indoleamine 2,3-dioxygenase (hIDO) and a number of site-directed variants during turnover with L-tryptophan (L-Trp) can be accounted for by the sequential, ordered binding of O(2) and L-Trp. Analysis of the data shows that at low concentrations of L-Trp, O(2) binds first followed by the binding of L-Trp; at higher concentrations of L-Trp, the order of binding is reversed. In addition, we show that the heme reduction potential (E(m)(0)) has a regulatory role in controlling the overall rate of catalysis (and hence the extent of inhibition) because there is a quantifiable correlation between E(m)(0) (that increases in the presence of L-Trp) and the rate constant for O(2) binding. This means that the initial formation of ferric superoxide (Fe(3+)-O(2)(•-)) from Fe(2+)-O(2) becomes thermodynamically less favorable as substrate binds, and we propose that it is the slowing down of this oxidation step at higher concentrations of substrate that is the origin of the inhibition. In contrast, we show that regeneration of the ferrous enzyme (and formation of NFK) in the final step of the mechanism, which formally requires reduction of the heme, is facilitated by the higher reduction potential in the substrate-bound enzyme and the two constants (k(cat) and E(m)(0)) are shown also to be correlated. Thus, the overall catalytic activity is balanced between the equal and opposite dependencies of the initial and final steps of the mechanism on the heme reduction potential. This tuning of the reduction potential provides a simple mechanism for regulation of the reactivity, which may be used more widely across this family of enzymes
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