Avian cryptochrome 4 binds superoxide

This is the final version. Available on open access from Elsevier via the DOI in this recordData availability: The data that support the findings of this study are available from the authors upon reasonable request.Flavin-binding cryptochromes are blue-light sensitive photoreceptors that have been implicated with magnetoreception in some species. The photocycle involves an intra-protein photo-reduction of the flavin cofactor, generating a magnetosensitive radical pair, and its subsequent re-oxidation. Superoxide (O2•−) is generated in the re-oxidation with molecular oxygen. The resulting O2•−-containing radical pairs have also been hypothesised to underpin various magnetosensitive traits, but due to fast spin relaxation when tumbling in solution would require immobilisation. We here describe our insights in the binding of superoxide to cryptochrome 4 from C. livia based on extensive all-atom molecular dynamics studies and density-functional theory calculations. The positively charged “crypt” region that leads to the flavin binding pocket transiently binds O2•− at 5 flexible binding sites centred on arginine residues. Typical binding times amounted to tens of nanoseconds, but exceptional binding events extended to several hundreds of nanoseconds and slowed the rotational diffusion, thereby realising rotational correlation times as large as 1 ns. The binding sites are particularly efficient in scavenging superoxide escaping from a putative generation site close to the flavin-cofactor, possibly implying a functional relevance. We discuss our findings in view of a potential magnetosensitivity of biological flavin semiquinone/superoxide radical pairs.UK Defence Science and Technology LaboratoryLeverhulme TrustEngineering and Physical Sciences Research Council (EPSRC

Nummular keratopathy in a patient with Hyper-IgD Syndrome

<p>Abstract</p> <p>Purpose</p> <p>To report a case of recurrent nummular keratitis in a pediatric patient with Hyperimmunoglobulinemia D syndrome.</p> <p>Methods</p> <p>A retrospective chart review.</p> <p>Results</p> <p>A 14-year-old boy with Hyperimmunoglobulinemia D syndrome (HIDS) presented with photophobia and ocular irritation concomitant with disease exacerbation. He was found on exam to have significant nummular keratitis, which responded to a short course of topical steroids. Despite acute response to local immunosuppression, the patient had several recurrent attacks and eventually developed a large corneal scar and decreased vision. After initiation of infliximab therapy his ocular sequelae improved dramatically and his vision returned to 20/20.</p> <p>Conclusion</p> <p>One possible form of end-organ damage associated with HIDS is vision threatening nummular keratopathy.</p

A potential new, stable state of the E-cadherin strand-swapped dimer in solution

E-cadherin is a transmembrane glycoprotein that facilitates inter-cellular adhesion in the epithelium. The ectodomain of the native structure is comprised of five repeated immunoglobulin-like domains. All E-cadherin crystal structures show the protein in one of three alternative conformations: a monomer, a strand-swapped trans homodimer and the so-called X-dimer, which is proposed to be a kinetic intermediate to forming the strand-swapped trans homodimer. However, previous studies have indicated that even once the trans strand-swapped dimer is formed, the complex is highly dynamic and the E-cadherin monomers may reorient relative to each other. Here, molecular dynamics simulations have been used to investigate the stability and conformational flexibility of the human E-cadherin trans strand-swapped dimer. In four independent, 100 ns simulations, the dimer moved away from the starting structure and converged to a previously unreported structure, which we call the Y-dimer. The Y-dimer was present for over 90% of the combined simulation time, suggesting that it represents a stable conformation of the E-cadherin dimer in solution. The Y-dimer conformation is stabilised by interactions present in both the trans strand-swapped dimer and X-dimer crystal structures, as well as additional interactions not found in any E-cadherin dimer crystal structures. The Y-dimer represents a previously unreported, stable conformation of the human E-cadherin trans strand-swapped dimer and suggests that the available crystal structures do not fully capture the conformations that the human E-cadherin trans homodimer adopts in solution

Partial distance correlation with methods for dissimilarities

Partial distance correlation measures association between two random vectors with respect to a third random vector, analogous to, but more general than (linear) partial correlation. Distance correlation characterizes independence of random vectors in arbitrary dimension. Motivation for the definition is discussed. We introduce a Hilbert space of U-centered distance matrices in which squared distance covariance is the inner product. Simple computation of the sample partial distance correlation and definitions of the population coefficients are presented. Power of the test for zero partial distance correlation is compared with power of the partial correlation test and the partial Mantel test. © Springer International Publishing Switzerland 2016

Impact of Preoperative Chemotherapy Features on Patient Outcomes after Hepatectomy for Initially Unresectable Colorectal Cancer Liver Metastases: A LiverMetSurvey Analysis

Background: Prognostic factors have been extensively reported after resection of colorectal liver metastases (CLM); however, specific analyses of the impact of preoperative systemic anticancer therapy (PO-SACT) features on outcomes is lacking. Methods: For this real-world evidence study, we used prospectively collected data within the international surgical LiverMetSurvey database from all patients with initially-irresectable CLM. The main outcome was Overall Survival (OS) after surgery. Disease-free (DFS) and hepatic-specific relapse-free survival (HS-RFS) were secondary outcomes. PO-SACT features included duration (cumulative number of cycles), choice of the cytotoxic backbone (oxaliplatin- or irinotecan-based), fluoropyrimidine (infusional or oral) and addition or not of targeted monoclonal antibodies (anti-EGFR or anti-VEGF). Results: A total of 2793 patients in the database had received PO-SACT for initially irresectable diseases. Short (<7 or <13 cycles in 1st or 2nd line) PO-SACT duration was independently associated with longer OS (HR: 0.85 p = 0.046), DFS (HR: 0.81; p = 0.016) and HS-RFS (HR: 0.80; p = 0.05). All other PO-SACT features yielded basically comparable results. Conclusions: In this international cohort, provided that PO-SACT allowed conversion to resectability in initially irresectable CLM, surgery performed as soon as technically feasible resulted in the best outcomes. When resection was achieved, our findings indicate that the choice of PO-SACT regimen had a marginal if any, impact on outcomes.info:eu-repo/semantics/publishedVersio

Inflammasome and IL-1β-Mediated Disorders

The NLRP3 inflammasome is an intracellular complex that regulates the release of proinflammatory cytokines such as interleukin-1β in response to exogenous pathogens and endogenous danger signals. Evidence from studies involving human genetics, human ex vivo mononuclear cell responses, and in vivo and in vitro murine models confirms the importance of the inflammasome and interleukin-1β in the pathogenesis of several inherited and complex diseases. The availability of several effective interleukin-1β targeted therapies has allowed for successful proof-of-concept studies in several of these disorders. However, many other diseases are likely to be mediated by the inflammasome and interleukin-1β, providing additional targets in the future

Pediatr Nephrol

BACKGROUND: Distal renal tubular acidosis (dRTA), due to impaired acid secretion in the urine, can lead to severe long-term consequences. Standard of care (SoC) oral alkalizers, requiring several daily intakes, are currently used to restore normal plasma bicarbonate levels. A new prolonged-release formulation, ADV7103, has been developed to achieve a sustained effect with an improved dosing scheme. METHODS: In a multicenter, open-label, non-inferiority trial (n = 37), patients with dRTA were switched from SoC to ADV7103. Mean plasma bicarbonate values and proportion of responders during steady state therapy with both treatments were compared, as were other blood and urine parameters, as well as acceptability, tolerability, and safety. RESULTS: When switching from SoC to ADV7103, the number of daily intakes was reduced from a median of three to twice daily. Mean plasma bicarbonate was increased and non-inferiority of ADV7103 was demonstrated (p < 0.0001, per protocol), as was statistical superiority (p = 0.0008, intention to treat [ITT]), and the response rate increased from 43 to 90% with ADV7103 (p < 0.001, ITT). Urine calcium/citrate ratio was reduced below the threshold for risk of lithogenesis with ADV7103 in 56% of previously non-responders with SoC (p = 0.021, ITT). Palatability was improved (difference [95% CI] of 25 [10.7, 39.2] mm) and gastrointestinal discomfort was reduced (difference [95% CI] of - 14.2 [- 25.9, - 2.6] mm) with ADV7103. CONCLUSIONS: Plasma bicarbonate levels and response rate were significantly higher with ADV7103 than with SoC. Urine calcium/citrate ratio, palatability, and gastrointestinal safety were significantly improved, supporting the use of ADV7103 as first-line treatment for dRTA. TRIAL REGISTRATION: Registered as EudraCT 2013-002988-25 on the 1st July 2013 Graphical abstract

Nanofluidic transport governed by the liquid/vapour interface

Liquid/vapour interfaces govern the behaviour of a wide range of systems but remain poorly understood, leaving ample margin for the exploitation of intriguing functionalities for applications. Here, we systematically investigate the role of liquid/vapour interfaces in the transport of water across apposing liquid menisci in osmosis membranes comprising short hydrophobic nanopores that separate two fluid reservoirs. We show experimentally that mass transport is limited by molecular reflection from the liquid/vapour interface below a certain length scale, which depends on the transmission probability of water molecules across the nanopores and on the condensation probability of a water molecule incident on the liquid surface. This fundamental yet elusive condensation property of water is measured under near-equilibrium conditions and found to decrease from 0.36 ± 0.21 at 30 °C to 0.18 ± 0.09 at 60 °C. These findings define the regime in which liquid/vapour interfaces govern nanofluidic transport and have implications for understanding mass transport in nanofluidic devices, droplets and bubbles, biological components and porous media involving liquid/vapour interfaces.Center for Clean Water and Clean Energy at MIT and KFUPM (Project R10-CW-09