Radiation effects, zero thermal expansion, and pressure-induced phase transition in CsMnCo(CN)6.

The Prussian blue analogue CsMnCo(CN)6 is studied using powder X-ray and neutron diffraction under variable temperature, pressure, and X-ray exposure. It retains cubic F4̄3m symmetry in the range 85-500 K with minimal thermal expansion, whereas a phase transition to P4̄n2 occurs at ∼2 GPa, driven by octahedral tilting. A small lattice contraction occurs upon increased X-ray dose. Comparisons with related systems indicate that the CsI ions decrease the thermal expansion and suppress the likelihood of phase transformations. The results improve the understanding of the stimuli-responsive behaviour of coordination polymers.

Variability in X-ray induced effects in [Rh(COD)Cl]2 with changing experimental parameters.

X-ray characterisation methods have undoubtedly enabled cutting-edge advances in all aspects of materials research. Despite the enormous breadth of information that can be extracted from these techniques, the challenge of radiation-induced sample change and damage remains prevalent. This is largely due to the emergence of modern, high-intensity X-ray source technologies and the growing potential to carry out more complex, longer duration in situ or in operando studies. The tunability of synchrotron beamlines enables the routine application of photon energy-dependent experiments. This work explores the structural stability of [Rh(COD)Cl]2, a widely used catalyst and precursor in the chemical industry, across a range of beamline parameters that target X-ray energies of 8 keV, 15 keV, 18 keV and 25 keV, on a powder X-ray diffraction synchrotron beamline at room temperature. Structural changes are discussed with respect to absorbed X-ray dose at each experimental setting associated with the respective photon energy. In addition, the X-ray radiation hardness of the catalyst is discussed, by utilising the diffraction data collected at the different energies to determine a dose limit, which is often considered in protein crystallography and typically overlooked in small molecule crystallography. This work not only gives fundamental insight into how damage manifests in this organometallic catalyst, but will encourage careful consideration of experimental X-ray parameters before conducting diffraction on similar radiation-sensitive organometallic materials.

Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.

Probing the Influence of Defects, Hydration, and Composition on Prussian Blue Analogues with Pressure.

The vast compositional space of Prussian blue analogues (PBAs), formula AxM[M'(CN)6]y·nH2O, allows for a diverse range of functionality. Yet, the interplay between composition and physical properties-e.g., flexibility and propensity for phase transitions-is still largely unknown, despite its fundamental and industrial relevance. Here we use variable-pressure X-ray and neutron diffraction to explore how key structural features, i.e., defects, hydration, and composition, influence the compressibility and phase behavior of PBAs. Defects enhance the flexibility, manifesting as a remarkably low bulk modulus (B0 ≈ 6 GPa) for defective PBAs. Interstitial water increases B0 and enables a pressure-induced phase transition in defective systems. Conversely, hydration does not alter the compressibility of stoichiometric MnPt(CN)6, but changes the high-pressure phase transitions, suggesting an interplay between low-energy distortions. AMnCo(CN)6 (AI = Rb, Cs) transition from F4̅3m to P4̅n2 upon compression due to octahedral tilting, and the critical pressure can be tuned by the A-site cation. At 1 GPa, the symmetry of Rb0.87Mn[Co(CN)6]0.91 is further lowered to the polar space group Pn by an improper ferroelectric mechanism. These fundamental insights aim to facilitate the rational design of PBAs for applications within a wide range of fields.

Structural and Electronic Effects of X-ray Irradiation on Prototypical [M(COD)Cl]2 Catalysts.

X-ray characterization techniques are invaluable for probing material characteristics and properties, and have been instrumental in discoveries across materials research. However, there is a current lack of understanding of how X-ray-induced effects manifest in small molecular crystals. This is of particular concern as new X-ray sources with ever-increasing brilliance are developed. In this paper, systematic studies of X-ray-matter interactions are reported on two industrially important catalysts, [Ir(COD)Cl]2 and [Rh(COD)Cl]2, exposed to radiation in X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) experiments. From these complementary techniques, changes to structure, chemical environments, and electronic structure are observed as a function of X-ray exposure, allowing comparisons of stability to be made between the two catalysts. Radiation dose is estimated using recent developments to the RADDOSE-3D software for small molecules and applied to powder XRD and XPS experiments. Further insights into the electronic structure of the catalysts and changes occurring as a result of the irradiation are drawn from density functional theory (DFT). The techniques combined here offer much needed insight into the X-ray-induced effects in transition-metal catalysts and, consequently, their intrinsic stabilities. There is enormous potential to extend the application of these methods to other small molecular systems of scientific or industrial relevance.

Viral mimetic priming enhances α-synuclein-induced degeneration: Implications for Parkinson's disease.

Evidence is accumulating to suggest that viral infections and consequent viral-mediated neuroinflammation may contribute to the etiology of idiopathic Parkinson's disease. Moreover, viruses have been shown to influence α-synuclein oligomerization as well as the autophagic clearance of abnormal intra-cellular proteins aggregations, both of which are key neuropathological events in Parkinson's disease pathogenesis. To further investigate the interaction between viral-mediated neuroinflammation and α-synuclein aggregation in the context of Parkinson's disease, this study sought to determine the impact of viral neuroinflammatory priming on α-synuclein aggregate-induced neuroinflammation and neurotoxicity in the rat nigrostriatal pathway. To do so, male Sprague-Dawley rats were intra-nigrally injected with a synthetic mimetic of viral dsRNA (poly I:C) followed two weeks later by a peptidomimetic small molecule which accelerates α-synuclein fibril formation (FN075). The impact of the viral priming on α-synuclein aggregation-induced neuroinflammation, neurodegeneration and motor dysfunction was assessed. We found that prior administration of the viral mimetic poly I:C significantly exacerbated or precipitated the α-synuclein aggregate induced neuropathological and behavioral effects. Specifically, sequential exposure to the two challenges caused a significant increase in nigral microgliosis (p < 0.001) and astrocytosis (p < 0.01); precipitated a significant degeneration of the nigrostriatal cell bodies (p < 0.05); and precipitated a significant impairment in forelimb kinesis (p < 0.01) and sensorimotor integration (p < 0.01). The enhanced sensitivity of the nigrostriatal neurons to pathological α-synuclein aggregation after viral neuroinflammatory priming further suggests that viral infections may contribute to the etiology and pathogenesis of Parkinson's disease.

Pyridine-Fused 2-Pyridones via Povarov and A3 Reactions: Rapid Generation of Highly Functionalized Tricyclic Heterocycles Capable of Amyloid Fibril Binding.

We here describe the use of three-component reactions to synthesize tricyclic pyridine ring-fused 2-pyridones. The developed protocols have a wide substrate scope and allow for the installation of diverse chemical functionalities on the tricyclic central fragment. Several of these pyridine-fused rigid polyheterocycles are shown to bind to Aß and α-synuclein fibrils, which are associated with neurodegenerative diseases.

Intrinsic Flexibility of the EMT Zeolite Framework under Pressure.

The roles of organic additives in the assembly and crystallisation of zeolites are still not fully understood. This is important when attempting to prepare novel frameworks to produce new zeolites. We consider 18-crown-6 ether (18C6) as an additive, which has previously been shown to differentiate between the zeolite EMC-2 (EMT) and faujasite (FAU) frameworks. However, it is unclear whether this distinction is dictated by influences on the metastable free-energy landscape or geometric templating. Using high-pressure synchrotron X-ray diffraction, we have observed that the presence of 18C6 does not impact the EMT framework flexibility-agreeing with our previous geometric simulations and suggesting that 18C6 does not behave as a geometric template. This was further studied by computational modelling using solid-state density-functional theory and lattice dynamics calculations. It is shown that the lattice energy of FAU is lower than EMT, but is strongly impacted by the presence of solvent/guest molecules in the framework. Furthermore, the EMT topology possesses a greater vibrational entropy and is stabilised by free energy at a finite temperature. Overall, these findings demonstrate that the role of the 18C6 additive is to influence the free energy of crystallisation to assemble the EMT framework as opposed to FAU.

A decision support system and rule-based algorithm to augment the human interpretation of the 12-lead electrocardiogram.

BACKGROUND: The 12-lead Electrocardiogram (ECG) has been used to detect cardiac abnormalities in the same format for more than 70years. However, due to the complex nature of 12-lead ECG interpretation, there is a significant cognitive workload required from the interpreter. This complexity in ECG interpretation often leads to errors in diagnosis and subsequent treatment. We have previously reported on the development of an ECG interpretation support system designed to augment the human interpretation process. This computerised decision support system has been named 'Interactive Progressive based Interpretation' (IPI). In this study, a decision support algorithm was built into the IPI system to suggest potential diagnoses based on the interpreter's annotations of the 12-lead ECG. We hypothesise semi-automatic interpretation using a digital assistant can be an optimal man-machine model for ECG interpretation. OBJECTIVES: To improve interpretation accuracy and reduce missed co-abnormalities. METHODS: The Differential Diagnoses Algorithm (DDA) was developed using web technologies where diagnostic ECG criteria are defined in an open storage format, Javascript Object Notation (JSON), which is queried using a rule-based reasoning algorithm to suggest diagnoses. To test our hypothesis, a counterbalanced trial was designed where subjects interpreted ECGs using the conventional approach and using the IPI+DDA approach. RESULTS: A total of 375 interpretations were collected. The IPI+DDA approach was shown to improve diagnostic accuracy by 8.7% (although not statistically significant, p-value=0.1852), the IPI+DDA suggested the correct interpretation more often than the human interpreter in 7/10 cases (varying statistical significance). Human interpretation accuracy increased to 70% when seven suggestions were generated. CONCLUSION: Although results were not found to be statistically significant, we found; 1) our decision support tool increased the number of correct interpretations, 2) the DDA algorithm suggested the correct interpretation more often than humans, and 3) as many as 7 computerised diagnostic suggestions augmented human decision making in ECG interpretation. Statistical significance may be achieved by expanding sample size.

PDF-ECG in clinical practice: A model for long-term preservation of digital 12-lead ECG data.

BACKGROUND: In clinical practice, data archiving of resting 12-lead electrocardiograms (ECGs) is mainly achieved by storing a PDF report in the hospital electronic health record (EHR). When available, digital ECG source data (raw samples) are only retained within the ECG management system. OBJECTIVE: The widespread availability of the ECG source data would undoubtedly permit successive analysis and facilitate longitudinal studies, with both scientific and diagnostic benefits. METHODS & RESULTS: PDF-ECG is a hybrid archival format which allows to store in the same file both the standard graphical report of an ECG together with its source ECG data (waveforms). Using PDF-ECG as a model to address the challenge of ECG data portability, long-term archiving and documentation, a real-world proof-of-concept test was conducted in a northern Italy hospital. A set of volunteers undertook a basic ECG using routine hospital equipment and the source data captured. Using dedicated web services, PDF-ECG documents were then generated and seamlessly uploaded in the hospital EHR, replacing the standard PDF reports automatically generated at the time of acquisition. Finally, the PDF-ECG files could be successfully retrieved and re-analyzed. CONCLUSION: Adding PDF-ECG to an existing EHR had a minimal impact on the hospital's workflow, while preserving the ECG digital data.

Interlayer Bond Formation in Black Phosphorus at High Pressure.

Black phosphorus was compressed at room temperature across the A17, A7 and simple-cubic phases up to 30 GPa, using a diamond anvil cell and He as pressure transmitting medium. Synchrotron X-ray diffraction showed the persistence of two previously unreported peaks related to the A7 structure in the pressure range of the simple-cubic phase. The Rietveld refinement of the data demonstrates the occurrence of a two-step mechanism for the A7 to simple-cubic phase transition, indicating the existence of an intermediate pseudo simple-cubic structure. From a chemical point of view this study represents a deep insight on the mechanism of interlayer bond formation during the transformation from the layered A7 to the non-layered simple-cubic phase of phosphorus, opening new perspectives for the design, synthesis and stabilization of phosphorene-based systems. As superconductivity is concerned, a new experimental evidence to explain the anomalous pressure behavior of Tc in phosphorus below 30 GPa is provided.

A computer-human interaction model to improve the diagnostic accuracy and clinical decision-making during 12-lead electrocardiogram interpretation.

INTRODUCTION: The 12-lead Electrocardiogram (ECG) presents a plethora of information and demands extensive knowledge and a high cognitive workload to interpret. Whilst the ECG is an important clinical tool, it is frequently incorrectly interpreted. Even expert clinicians are known to impulsively provide a diagnosis based on their first impression and often miss co-abnormalities. Given it is widely reported that there is a lack of competency in ECG interpretation, it is imperative to optimise the interpretation process. Predominantly the ECG interpretation process remains a paper based approach and whilst computer algorithms are used to assist interpreters by providing printed computerised diagnoses, there are a lack of interactive human-computer interfaces to guide and assist the interpreter. METHODS: An interactive computing system was developed to guide the decision making process of a clinician when interpreting the ECG. The system decomposes the interpretation process into a series of interactive sub-tasks and encourages the clinician to systematically interpret the ECG. We have named this model 'Interactive Progressive based Interpretation' (IPI) as the user cannot 'progress' unless they complete each sub-task. Using this model, the ECG is segmented into five parts and presented over five user interfaces (1: Rhythm interpretation, 2: Interpretation of the P-wave morphology, 3: Limb lead interpretation, 4: QRS morphology interpretation with chest lead and rhythm strip presentation and 5: Final review of 12-lead ECG). The IPI model was implemented using emerging web technologies (i.e. HTML5, CSS3, AJAX, PHP and MySQL). It was hypothesised that this system would reduce the number of interpretation errors and increase diagnostic accuracy in ECG interpreters. To test this, we compared the diagnostic accuracy of clinicians when they used the standard approach (control cohort) with clinicians who interpreted the same ECGs using the IPI approach (IPI cohort). RESULTS: For the control cohort, the (mean; standard deviation; confidence interval) of the ECG interpretation accuracy was (45.45%; SD=18.1%; CI=42.07, 48.83). The mean ECG interpretation accuracy rate for the IPI cohort was 58.85% (SD=42.4%; CI=49.12, 68.58), which indicates a positive mean difference of 13.4%. (CI=4.45, 22.35) An N-1 Chi-square test of independence indicated a 92% chance that the IPI cohort will have a higher accuracy rate. Interpreter self-rated confidence also increased between cohorts from a mean of 4.9/10 in the control cohort to 6.8/10 in the IPI cohort (p=0.06). Whilst the IPI cohort had greater diagnostic accuracy, the duration of ECG interpretation was six times longer when compared to the control cohort. CONCLUSIONS: We have developed a system that segments and presents the ECG across five graphical user interfaces. Results indicate that this approach improves diagnostic accuracy but with the expense of time, which is a valuable resource in medical practice.

Human factors analysis of the CardioQuick Patch®: A novel engineering solution to the problem of electrode misplacement during 12-lead electrocardiogram acquisition.

INTRODUCTION: The CardioQuick Patch® (CQP) has been developed to assist operators in accurately positioning precordial electrodes during 12-lead electrocardiogram (ECG) acquisition. This study describes the CQP design and assesses the device in comparison to conventional electrode application. METHODS: Twenty ECG technicians were recruited and a total of 60 ECG acquisitions were performed on the same patient model over four phases: (1) all participants applied single electrodes to the patient; (2) all participants were then re-trained on electrode placement and on how to use the CQP; (3) participants were randomly divided into two groups, the standard group applied single electrodes and the CQP group used the CQP; (4) after a one day interval, the same participants returned to carry out the same procedure on the same patient (measuring intra-practitioner variability). Accuracy was measured with reference to pre-marked correct locations using ultra violet ink. NASA-TLK was used to measure cognitive workload and the Systematic Usability Scale (SUS) was used to quantify the usability of the CQP. RESULTS: There was a large difference between the minimum time taken to complete each approach (CQP=38.58s vs. 65.96s). The standard group exhibited significant levels of electrode placement error (V1=25.35mm±29.33, V2=18.1mm±24.49, V3=38.65mm±15.57, V4=37.73mm±12.14, V5=35.75mm±15.61, V6=44.15mm±14.32). The CQP group had statistically greater accuracy when placing five of the six electrodes (V1=6.68mm±8.53 [p<0.001], V2=8.8mm±9.64 [p=0.122], V3=6.83mm±8.99 [p<0.001], V4=14.90mm±11.76 [p<0.001], V5=8.63mm±10.70 [p<0.001], V6=18.13mm±14.37 [p<0.001]). There was less intra-practitioner variability when using the CQP on the same patient model. NASA TLX revealed that the CQP did increase the cognitive workload (CQP group=16.51%±8.11 vs. 12.22%±8.07 [p=0.251]). The CQP also achieved a high SUS score of 91±7.28. CONCLUSION: The CQP significantly improved the reproducibility and accuracy of placing precordial electrodes V1, V3-V6 with little additional cognitive effort, and with a high degree of usability.

Individuals with higher metabolic rates have lower levels of reactive oxygen species in vivo.

There is increasing interest in the effect of energy metabolism on oxidative stress, but much ambiguity over the relationship between the rate of oxygen consumption and the generation of reactive oxygen species (ROS). Production of ROS (such as hydrogen peroxide, H2O2) in the mitochondria is primarily inferred indirectly from measurements in vitro, which may not reflect actual ROS production in living animals. Here, we measured in vivo H2O2 content using the recently developed MitoB probe that becomes concentrated in the mitochondria of living organisms, where it is converted by H2O2 into an alternative form termed MitoP; the ratio of MitoP/MitoB indicates the level of mitochondrial H2O2 in vivo. Using the brown trout Salmo trutta, we tested whether this measurement of in vivo H2O2 content over a 24 h-period was related to interindividual variation in standard metabolic rate (SMR). We showed that the H2O2 content varied up to 26-fold among fish of the same age and under identical environmental conditions and nutritional states. Interindividual variation in H2O2 content was unrelated to mitochondrial density but was significantly associated with SMR: fish with a higher mass-independent SMR had a lower level of H2O2. The mechanism underlying this observed relationship between SMR and in vivo H2O2 content requires further investigation, but may implicate mitochondrial uncoupling which can simultaneously increase SMR but reduce ROS production. To our knowledge, this is the first study in living organisms to show that individuals with higher oxygen consumption rates can actually have lower levels of H2O2.

Negative linear compressibility.

While all materials reduce their intrinsic volume under hydrostatic (uniform) compression, a select few actually expand along one or more directions during this process of densification. As rare as it is counterintuitive, such "negative compressibility" behaviour has application in the design of pressure sensors, artificial muscles and actuators. The recent discovery of surprisingly strong and persistent negative compressibility effects in a variety of new families of materials has ignited the field. Here we review the phenomenology of negative compressibility in this context of materials diversity, placing particular emphasis on the common structural motifs that recur amongst known examples. Our goal is to present a mechanistic understanding of negative compressibility that will help inform a clear strategy for future materials design.

Synthesis of an azido-tagged low affinity ratiometric calcium sensor.

Changes in high localised concentrations of Ca2+ ions are fundamental to cell signalling. The synthesis of a dual excitation, ratiometric calcium ion sensor with a Kd of 90 µM, is described. It is tagged with an azido group for bioconjugation, and absorbs in the blue/green and emits in the red region of the visible spectrum with a large Stokes shift. The binding modulating nitro group is introduced to the BAPTA core prior to construction of a benzofuran-2-yl carboxaldehyde by an allylation-oxidation-cyclisation sequence, which is followed by condensation with an azido-tagged thiohydantoin. The thiohydantoin unit has to be protected with an acetoxymethyl (AM) caging group to allow CuAAC click reaction and incorporation of the KDEL peptide endoplasmic reticulum (ER) retention sequence.

Flexibility transition and guest-driven reconstruction in a ferroelastic metal-organic framework†Electronic supplementary information (ESI) available: Atomic coordinates and lattice parameter data. CCDC 1016797. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ce01572jClick here for additional data file.

The metal-organic framework copper(i) tricyanomethanide, Cu(tcm), undergoes a ferroelastic transition on cooling below Tf = 240 K. Thermal expansion measurements reveal an order-of-magnitude variation in framework flexibility across Tf. The low-temperature phase α-Cu(tcm) exhibits colossal positive and negative thermal expansion that is the strongest ever reported for a framework material. On exposure to acetonitrile, Cu(tcm) undergoes a reconstructive solid-phase transition to acetonitrilocopper(i) tricyanomethanide. This transition can be reversed by heating under vacuum. Infrared spectroscopy measurements are sensitive to the phase change, suggesting that Cu(tcm) may find application in solid-phase acetonitrile sensing.

Zero-strain reductive intercalation in a molecular framework.

Reductive intercalation of potassium within the molecular framework Ag3[Fe(CN)6] gives rise to a volume strain that is an order of magnitude smaller than is typical for common ion-storage materials. We suggest that framework flexibility might be exploited as a general strategy for reducing cycling strain in battery and ion-storage materials.

Using computerised interactive response technology to assess electrocardiographers and for aggregating diagnoses.

The 12-lead electrocardiogram (ECG) is a crucial diagnostic tool. However, the ideal method to assess competency in ECG interpretation remains unclear. We sought to evaluate whether keypad response technology provides a rapid, interactive way to assess ECG knowledge. 75 participants were enrolled [32 (43%) Primary Care Physicians, 24 (32%) Hospital Medical Staff and 19 (25%) Nurse Practitioners]. Nineteen ECGs with 4 possible answers were interpreted. Out of 1425 possible decisions 1054 (73.9%) responses were made. Only 570/1425 (40%) of the responses were correct. Diagnostic accuracy varied (0% to 78%, mean 42%±21%) across the entire cohort. Participation was high, (median 83%, IQR 50%-100%). Hospital Medical Staff had significantly higher diagnostic accuracy than nurse practitioners (50±20% vs. 38±19%, p=0.04) and Primary Care Physicians (50±20% vs. 40±21%, p=0.07) although not significant. Interactive voting systems can be rapidly and successfully used to assess ECG interpretation. Further education is necessary to improve diagnostic accuracy.

Giant negative linear compressibility in zinc dicyanoaurate.

The counterintuitive phenomenon of negative linear compressibility (NLC) is a highly desirable but rare property exploitable in the development of artificial muscles, actuators and next-generation pressure sensors. In all cases, material performance is directly related to the magnitude of intrinsic NLC response. Here we show the molecular framework material zinc(II) dicyanoaurate(I), Zn[Au(CN)(2)](2), exhibits the most extreme and persistent NLC behaviour yet reported: under increasing hydrostatic pressure its crystal structure expands in one direction at a rate that is an order of magnitude greater than both the typical contraction observed for common engineering materials and also the anomalous expansion in established NLC candidates. This extreme behaviour arises from the honeycomb-like structure of Zn[Au(CN)(2)](2) coupling volume reduction to uniaxial expansion, and helical Au…Au 'aurophilic' interactions accommodating abnormally large linear strains by functioning as supramolecular springs.