Common and disparate clinical presentations and mechanisms in different eosinophilic gastrointestinal diseases.

Eosinophilic gastrointestinal diseases (EGIDs) are a group of diseases characterized by selective eosinophil infiltration of the gastrointestinal (GI) tract in the absence of other causes of eosinophilia. These diseases are generally driven by type 2 inflammation, often in response to food allergen exposure. Among all EGIDs, the clinical presentation often includes a history of atopic disease with a variety of GI symptoms. EGIDs are traditionally separated into eosinophilic esophagitis (EoE) and non-EoE EGIDs. EoE is relatively better understood and now associated with clinical guidelines and 2 US Food and Drug Administration-approved treatments, whereas non-EoE EGIDs are rarer and less well-understood diseases without US Food and Drug Administration-approved treatments. Non-EoE EGIDs are further subclassified by the area of the GI tract that is involved; they comprise eosinophilic gastritis, eosinophilic enteritis (including eosinophilic duodenitis), and eosinophilic colitis. As with other GI disorders, the disease presentations and mechanisms differ depending on the involved segment of the GI tract; however, the differences between EoE and non-EoE EGIDs extend beyond which GI tract segment is involved. The aim of this article is to summarize the commonalities and differences between the clinical presentations and disease mechanisms for EoE and non-EoE EGIDs.

Effects of inappropriate cause-of-death certification on mortality from cardiovascular disease and diabetes mellitus in Tonga.

BACKGROUND: Cardiovascular disease (CVD) and diabetes mellitus are major health issues in Tonga and other Pacific countries, although mortality levels and trends are unclear. We assess the impacts of cause-of-death certification on coding of CVD and diabetes as underlying causes of death (UCoD). METHODS: Tongan records containing cause-of-death data (2001-2018), including medical certificates of cause-of-death (MCCD), had UCoD assigned according to International Classification of Diseases 10th revision (ICD-10) coding rules. Deaths without recorded cause were included to ascertain total mortality. Diabetes and hypertension causes were reallocated from Part 1 of the MCCD (direct cause) to Part 2 (contributory cause) if potentially fatal complications were not recorded, and an alternative UCoD was assigned. Proportional mortality by cause based on the alternative UCoD were applied to total deaths then mortality rates calculated by age and sex using census/intercensal population estimates. CVD and diabetes mortality rates for unaltered and alternative UCoD were compared using Poisson regression. RESULTS: Over 2001-18, in ages 35-59 years, alternative CVD mortality was higher than unaltered CVD mortality in men (p = 0.043) and women (p = 0.15); for 2010-18, alternative versus unaltered measures in men were 3.3/103 (95%CI: 3.0-3.7/103) versus 2.9/103 (95%CI: 2.6-3.2/103), and in women were 1.1/103 (95%CI: 0.9-1.3/103) versus 0.9/103 (95%CI: 0.8-1.1/103). Conversely, alternative diabetes mortality rates were significantly lower than the unaltered rates over 2001-18 in men (p < 0.0001) and women (p = 0.013); for 2010-18, these measures in men were 1.3/103 (95%CI: 1.1-1.5/103) versus 1.9/103 (95%CI: 1.6-2.2/103), and in women were 1.4/103 (95%CI: 1.2-1.7/103) versus 1.7/103 (95%CI: 1.5-2.0/103). Diabetes mortality rates increased significantly over 2001-18 in men (unaltered: p < 0.0001; alternative: p = 0.0007) and increased overall in women (unaltered: p = 0.0015; alternative: p = 0.014). CONCLUSIONS: Diabetes reporting in Part 1 of the MCCD, without potentially fatal diabetes complications, has led to over-estimation of diabetes, and under-estimation of CVD, as UCoD in Tonga. This indicates the importance of controlling various modifiable risks for atherosclerotic CVD (including stroke) including hypertension, tobacco use, and saturated fat intake, besides obesity and diabetes. Accurate certification of diabetes as a direct cause of death (Part 1) or contributory factor (Part 2) is needed to ensure that valid UCoD are assigned. Examination of multiple cause-of-death data can improve understanding of the underlying causes of premature mortality to better inform health planning.

The impact of digital technologies on knowledge networks in two engineering organisations.

The management and exploitation of knowledge can contribute to the competitive advantage of an organisation and hence can be a driver of its value. This paper examines knowledge management practices within two engineering organisations with an emphasis on barriers to its effectiveness and the influence of current and anticipated deployment of digital technologies. Two methods were used to gather research data across both organisations by combining a series of semi-structured interviews with a quantitative social network analysis. Examination of the acquired data provided insights into the relationship between the knowledge management culture in both organisations and their adoption of digital tools. Hudson's evolutionary model of safety culture has been modified to describe the culture of knowledge management in an organisation and the acquired data used to locate the two organisations on their knowledge management journey. It is proposed that social networks could be used as an indicator of the stage of evolution of knowledge management in engineering organisations more generally with low network densities and dispersed networks representing higher stages of evolution.

Eosinophil Involvement Outside the Esophagus in Eosinophilic Esophagitis.

Eosinophilic gastrointestinal diseases (EGIDs) are chronic, immune-mediated disorders, characterized clinically by gastrointestinal (GI) symptoms and histologically by eosinophil-predominant infiltration in ≥1 GI tract segment.1 A recent, international consensus by 91 experts proposed a new framework for EGID nomenclature to establish updated terms, designations, and conventions.2 Although this framework offers a standardized starting point for the field, debate is ongoing regarding the appropriate terminology for cases involving multiple areas, such as "non-eosinophilic esophagitis (EoE) EGID and EoE" or "non-EoE EGID with esophageal involvement (EI)." Notably, in a survey of these experts, 61% agreed with the later term "non-EoE EGID with EI," because EoE is isolated to the esophagus by current diagnostic criteria.3 However, limited molecular and pathogenic data exist to support the distinction. Furthermore, disease burden of symptoms and comorbidities generally is higher in non-EoE EGIDs than EoE.4 Presently, there is no screen to predict non-EoE EGID concomitance in EoE; therefore, decision-making to further explore other GI segment involvement is clinically challenging. We aimed to answer 2 fundamental questions in the field (Figure 1A): Is there a shared or distinct pathogenesis between patients with isolated EoE and non-EoE EGIDs with EI as assessed by patient characteristics and molecular profiles? Can we predict concomitant non-EoE EGIDs when EoE exists? Herein, we report a similar molecular signature between EoE and EI and a potential predictive model to identify concomitant non-EoE EGIDs in patients with EoE.

Small signal modulation of photonic crystal surface emitting lasers.

We report the small-signal characterization of a PCSEL device, extracting damping factors and modulation efficiencies, and demonstrating -3 dB modulation bandwidths of up to 4.26 GHz. Based on modelling we show that, by reducing the device width and improving the active region design for high-speed modulation, direct modulation frequencies in excess of 50 GHz are achievable.

A Phase 1/2A trial of idroxioleic acid: first-in-class sphingolipid regulator and glioma cell autophagy inducer with antitumor activity in refractory glioma.

BACKGROUND: The first-in-class brain-penetrating synthetic hydroxylated lipid idroxioleic acid (2-OHOA; sodium 2-hydroxyoleate), activates sphingomyelin synthase expression and regulates membrane-lipid composition and mitochondrial energy production, inducing cancer cell autophagy. We report the findings of a multicentric first-in-human Phase 1/2A trial (NCT01792310) of 2-OHOA, identifying the maximum tolerated dose (MTD) and assessing safety and preliminary efficacy. METHODS: We performed an open-label, non-randomised trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumour activity of daily oral treatment with 2-OHOA monotherapy (BID/TID) in 54 patients with glioma and other advanced solid tumours. A dose-escalation phase using a standard 3 + 3 design was performed to determine safety and tolerability. This was followed by two expansion cohorts at the MTD to determine the recommended Phase-2 dose (RP2D). RESULTS: In total, 32 recurrent patients were enrolled in the dose-escalation phase (500-16,000 mg/daily). 2-OHOA was rapidly absorbed with dose-proportional exposure. Treatment was well-tolerated overall, with reversible grade 1-2 nausea, vomiting, and diarrhoea as the most common treatment-related adverse events (AEs). Four patients had gastrointestinal dose-limiting toxicities (DLTs) of nausea, vomiting, diarrhoea (three patients at 16,000 mg and one patient at 12,000 mg), establishing an RP2D at 12,000 mg/daily. Potential activity was seen in patients with recurrent high-grade gliomas (HGG). Of the 21 patients with HGG treated across the dose escalation and expansion, 5 (24%) had the clinical benefit (RANO CR, PR and SD >6 cycles) with one exceptional response lasting >2.5 years. CONCLUSIONS: 2-OHOA demonstrated a good safety profile and encouraging activity in this difficult-to-treat malignant brain-tumour patient population, placing it as an ideal potential candidate for the treatment of glioma and other solid tumour malignancies. CLINICAL TRIAL REGISTRATION: EudraCT registration number: 2012-001527-13; Clinicaltrials.gov registration number: NCT01792310.

Modulation of IL-17 backbone dynamics reduces receptor affinity and reveals a new inhibitory mechanism.

Knowledge of protein dynamics is fundamental to the understanding of biological processes, with NMR and 2D-IR spectroscopy being two of the principal methods for studying protein dynamics. Here, we combine these two methods to gain a new understanding of the complex mechanism of a cytokine:receptor interaction. The dynamic nature of many cytokines is now being recognised as a key property in the signalling mechanism. Interleukin-17s (IL-17) are proinflammatory cytokines which, if unregulated, are associated with serious autoimmune diseases such as psoriasis, and although there are several therapeutics on the market for these conditions, small molecule therapeutics remain elusive. Previous studies, exploiting crystallographic methods alone, have been unable to explain the dramatic differences in affinity observed between IL-17 dimers and their receptors, suggesting there are factors that cannot be fully explained by the analysis of static structures alone. Here, we show that the IL-17 family of cytokines have varying degrees of flexibility which directly correlates to their receptor affinities. Small molecule inhibitors of the cytokine:receptor interaction are usually thought to function by either causing steric clashes or structural changes. However, our results, supported by other biophysical methods, provide evidence for an alternate mechanism of inhibition, in which the small molecule rigidifies the protein, causing a reduction in receptor affinity. The results presented here indicate an induced fit model of cytokine:receptor binding, with the more flexible cytokines having a higher affinity. Our approach could be applied to other systems where the inhibition of a protein-protein interaction has proved intractable, for example due to the flat, featureless nature of the interface. Targeting allosteric sites which modulate protein dynamics, opens up new avenues for novel therapeutic development.

High-resolution structural information of membrane-bound α-synuclein provides insight into the MoA of the anti-Parkinson drug UCB0599.

α-synuclein (αS) is an intrinsically disordered protein whose functional ambivalence and protein structural plasticity are iconic. Coordinated protein recruitment ensures proper vesicle dynamics at the synaptic cleft, while deregulated oligomerization on cellular membranes contributes to cell damage and Parkinson's disease (PD). Despite the protein's pathophysiological relevance, structural knowledge is limited. Here, we employ NMR spectroscopy and chemical cross-link mass spectrometry on 14N/15N-labeled αS mixtures to provide for the first time high-resolution structural information of the membrane-bound oligomeric state of αS and demonstrate that in this state, αS samples a surprisingly small conformational space. Interestingly, the study locates familial Parkinson's disease mutants at the interface between individual αS monomers and reveals different oligomerization processes depending on whether oligomerization occurs on the same membrane surface (cis) or between αS initially attached to different membrane particles (trans). The explanatory power of the obtained high-resolution structural model is used to help determine the mode-of-actionof UCB0599. Here, it is shown that the ligand changes the ensemble of membrane-bound structures, which helps to explain the success this compound, currently being tested in Parkinson's disease patients in a phase 2 trial, has had in animal models of PD.

Direct age constraints on the magnetism of Jack Hills zircon.

A potential record of Earth's magnetic field going back 4.2 billion years (Ga) ago is carried by magnetite inclusions in zircon grains from the Jack Hills. This magnetite may be secondary in nature, however, meaning that the magnetic record is much younger than the zircon crystallization age. Here, we use atom probe tomography to show that Pb-bearing nanoclusters in magnetite-bearing Jack Hills zircons formed during two discrete events at 3.4 and <2 Ga. The older population of clusters contains no detectable Fe, whereas roughly half of the younger population of clusters is Fe bearing. This result shows that the Fe required to form secondary magnetite entered the zircon sometime after 3.4 Ga and that remobilization of Pb and Fe during an annealing event occurred more than 1 Ga after deposition of the Jack Hills sediment at 3 Ga. The ability to date Fe mobility linked to secondary magnetite formation provides new possibilities to improve our knowledge of the Archean geodynamo.

Indole-ynones as Privileged Substrates for Radical Dearomatizing Spirocyclization Cascades.

Indole-ynones have been established as general substrates for radical dearomatizing spirocyclization cascade reactions. Five distinct and varied synthetic protocols have been developed─cyanomethylation, sulfonylation, trifluoromethylation, stannylation and borylation─using a variety of radical generation modes, ranging from photoredox catalysis to traditional AIBN methods. The simple and easily prepared indole-ynones can be used to rapidly generate diverse, densely functionalized spirocycles and have the potential to become routinely used to explore radical reactivity. Experimental and computational investigations support the proposed radical cascade mechanism and suggest that other new methods are now primed for development.

The structural basis for high affinity binding of α1-acid glycoprotein to the potent antitumor compound UCN-01.

The α1-acid glycoprotein (AGP) is an abundant blood plasma protein with important immunomodulatory functions coupled to endogenous and exogenous ligand-binding properties. Its affinity for many drug-like structures, however, means AGP can have a significant effect on the pharmokinetics and pharmacodynamics of numerous small molecule therapeutics. Staurosporine, and its hydroxylated forms UCN-01 and UCN-02, are kinase inhibitors that have been investigated at length as antitumour compounds. Despite their potency, these compounds display poor pharmokinetics due to binding to both AGP variants, AGP1 and AGP2. The recent renewed interest in UCN-01 as a cytostatic protective agent prompted us to solve the structure of the AGP2-UCN-01 complex by X-ray crystallography, revealing for the first time the precise binding mode of UCN-01. The solution NMR suggests AGP2 undergoes a significant conformational change upon ligand binding, but also that it uses a common set of sidechains with which it captures key groups of UCN-01 and other small molecule ligands. We anticipate that this structure and the supporting NMR data will facilitate rational redesign of small molecules that could evade AGP and therefore improve tissue distribution.

Membrane Interactions of α-Synuclein Revealed by Multiscale Molecular Dynamics Simulations, Markov State Models, and NMR.

α-Synuclein (αS) is a presynaptic protein that binds to cell membranes and is linked to Parkinson's disease (PD). Binding of αS to membranes is a likely first step in the molecular pathophysiology of PD. The αS molecule can adopt multiple conformations, being largely disordered in water, adopting a ß-sheet conformation when present in amyloid fibrils, and forming a dynamic multiplicity of α-helical conformations when bound to lipid bilayers and related membrane-mimetic surfaces. Multiscale molecular dynamics simulations in conjunction with nuclear magnetic resonance (NMR) and cross-linking mass spectrometry (XLMS) measurements are used to explore the interactions of αS with an anionic lipid bilayer. The simulations and NMR measurements together reveal a break in the helical structure of the central non-amyloid-ß component (NAC) region of αS in the vicinity of residues 65-70, which may facilitate subsequent oligomer formation. Coarse-grained simulations of αS starting from the structure of αS when bound to a detergent micelle reveal the overall pattern of protein contacts to anionic lipid bilayers, while subsequent all-atom simulations provide details of conformational changes upon membrane binding. In particular, simulations and NMR data for liposome-bound αS indicate incipient ß-strand formation in the NAC region, which is supported by intramolecular contacts seen via XLMS and simulations. Markov state models based on the all-atom simulations suggest a mechanism of conformational change of membrane-bound αS via a dynamic helix break in the region of residue 65 in the NAC region. The emergent dynamic model of membrane-interacting αS advances our understanding of the mechanism of PD, potentially aiding the design of novel therapeutic approaches.

A Thiol-Mediated Three-Step Ring Expansion Cascade for the Conversion of Indoles into Functionalized Quinolines.

An operationally simple, high yielding three-step cascade process is described for the direct conversion of indole-tethered ynones into functionalized quinolines. A single "multitasking" thiol reagent is used to promote a three-step dearomatizing spirocyclization, nucleophilic substitution, and one-atom ring expansion reaction cascade under remarkably mild conditions. In addition, a novel route to thio-oxindoles is described, which was discovered by serendipity.

Conformational dynamics in interleukin 17A and 17F functional complexes is a key determinant of receptor A affinity and specificity.

The proinflammatory cytokines IL-17A and IL-17F have been identified as key drivers of a range of human inflammatory diseases, such as psoriasis, which has led to several therapeutic antibodies targeted at IL-17A. The two cytokines have been shown to tightly associate as functional homo and hetero dimers, which induce signalling via the formation of a cell surface signalling complex with a single copy of both IL-17RA and IL-17RC. Striking differences in affinity have been observed for IL-17RA binding to IL-17AA, IL-17AF and IL-17FF, however, the functional significance and molecular basis for this has remained unclear. We have obtained comprehensive backbone NMR assignments for full length IL-17AA (79%), IL-17AF (93%) and IL-17FF (89%), which show that the dimers adopt almost identical backbone topologies in solution to those observed in reported crystal structures. Analysis of the line widths and intensities of assigned backbone amide NMR signals has revealed striking differences in the conformational plasticity and dynamics of IL-17AA compared to both IL-17AF and IL-17FF. Our NMR data indicate that a number of regions of IL-17AA are interconverting between at least two distinct conformations on a relatively slow timescale. Such conformational heterogeneity has previously been shown to play an important role in the formation of many high affinity protein-protein complexes. The locations of the affected IL-17AA residues essentially coincides with the regions of both IL-17A and IL-17F previously shown to undergo significant structural changes on binding to IL-17RA. Substantially less conformational exchange was revealed by the NMR data for IL-17FF and IL-17AF. We propose that the markedly different conformational dynamic properties of the distinct functional IL-17 dimers plays a key role in determining their affinities for IL-17RA, with the more dynamic and plastic nature of IL-17AA contributing to the significantly tighter affinity observed for binding to IL-17RA. In contrast, the dynamic properties are expected to have little influence on the affinity of IL-17 dimers for IL-17RC, which has recently been shown to induce only small structural changes in IL-17FF upon binding.

Helium ion microscope - secondary ion mass spectrometry for geological materials.

The helium ion microscope (HIM) is a focussed ion beam instrument with unprecedented spatial resolution for secondary electron imaging but has traditionally lacked microanalytical capabilities. With the addition of the secondary ion mass spectrometry (SIMS) attachment, the capabilities of the instrument have expanded to microanalysis of isotopes from Li up to hundreds of atomic mass units, effectively opening up the analysis of all natural and geological systems. However, the instrument has thus far been underutilised by the geosciences community, due in no small part to a lack of a thorough understanding of the quantitative capabilities of the instrument. Li represents an ideal element for an exploration of the instrument as a tool for geological samples, due to its importance for economic geology and a green economy, and the difficult nature of observing Li with traditional microanalytical techniques. Also Li represents a "best-case" scenario for isotopic measurements. Here we present details of sample preparation, instrument sensitivity, theoretical, and measured detection limits for both elemental and isotopic analysis as well as practicalities for geological sample analyses of Li alongside a discussion of potential geological use cases of the HIM-SIMS instrument.

Phosphoranyl Radical Fragmentation Reactions Driven by Photoredox Catalysis.

Photocatalytic generation of phosphoranyl radicals is fast emerging as an essential method for the generation of diverse and valuable radicals, typically via deoxygenation or desulfurization processes. This Perspective is a comprehensive evaluation of all studies using phosphoranyl radicals as tunable mediators in photoredox catalysis, highlighting how two distinct methods for phosphoranyl radical formation (radical addition and nucleophilic addition) can be used to generate versatile radical intermediates with diverse reactivity profiles.

Photocatalytic Deoxygenation of Sulfoxides Using Visible Light: Mechanistic Investigations and Synthetic Applications.

The photocatalytic deoxygenation of sulfoxides to generate sulfides facilitated by either Ir[(dF(CF3)ppy)2(dtbbpy)]PF6 or fac-Ir(ppy)3 is reported. Mechanistic studies indicate that a radical chain mechanism operates, which proceeds via a phosphoranyl radical generated from a radical/polar crossover process. Initiation of the radical chain was found to proceed via two opposing photocatalytic quenching mechanisms, offering complementary reactivity. The mild nature of the radical deoxygenation process enables the reduction of a wide range of functionalized sulfoxides, including those containing acid-sensitive groups, in typically high isolated yields.

Reliability and Validity of Integrated External and Internal Load Ratios as Measures of Fitness in Academy Rugby Union Players.

Taylor, RJ, Sanders, D, Myers, T, and Akubat, I. Reliability and validity of integrated external and internal load ratios as measures of fitness in academy rugby union players. J Strength Cond Res 34(6): 1723-1730, 2020-This study aimed to assess the relationships between integrated ratios of external and internal load measures and aerobic fitness in 3 different training exercise protocols. Twelve academy rugby union players (aged; 17.6 ± 0.44 years, height; 179.4 ± 6.3 cm, body mass 83.3 ± 9.7 kg) performed a lactate threshold/V[Combining Dot Above]O2max test (LT/V[Combining Dot Above]O2max) followed by 3 exercise protocols; 760 m continuous shuttle running (20 m shuttle run at 9 km·h), sprint interval training (SIT: 6 × 6 seconds sprint with 54 seconds recovery), and a small-sided game (SSG: 6 vs. 6, 10 minutes on a 39 × 51 m pitch) on 2 occasions. A LT/V[Combining Dot Above]O2max test was used to determine velocity at lactate threshold (vLT) and at the onset of blood lactate accumulation (vOBLA), maximal oxygen uptake (V[Combining Dot Above]O2max) and the heart rate-blood lactate profile for the calculation of internal load (individualized training impulse or iTRIMP). The total distance (TD), PlayerLoad, metabolic power (MP), high-speed distance >15 km·h (HSD), very high-speed distance >18 km·h (VHSD) and individualized high-speed distance based on each player's vOBLA (iHSD) for the 3 exercise protocols were measured using Micro Electro Mechanical Systems/Global Positioning System technology. Bayesian analysis was used to assess the ratios validity and reliability. Ratios demonstrated large-to-very large associations with vOBLA (Rho = 0.64-0.76), vLT (Rho = 0.63-0.71). Reliability of the ratios ranged from 7.06 to 36.28% (coefficient of variation [CV]%). The results suggest that integrated load ratios from the SIT and SSG protocols provide a measure which is reliable with large-to-very large associations to submaximal aerobic fitness in rugby union.

Reevaluating the evidence for a Hadean-Eoarchean dynamo.

The time of origin of the geodynamo has important implications for the thermal evolution of the planetary interior and the habitability of early Earth. It has been proposed that detrital zircon grains from Jack Hills, Western Australia, provide evidence for an active geodynamo as early as 4.2 billion years (Ga) ago. However, our combined paleomagnetic, geochemical, and mineralogical studies on Jack Hills zircons indicate that most have poor magnetic recording properties and secondary magnetization carriers that postdate the formation of the zircons. Therefore, the existence of the geodynamo before 3.5 Ga ago remains unknown.