N-terminal lipid modification is required for the stable accumulation of CyanoQ in Synechocystis sp. PCC 6803

© 2016 Juneau et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The CyanoQ protein has been demonstrated to be a component of cyanobacterial Photosystem II (PS II), but there exist a number of outstanding questions concerning its physical association with the complex. CyanoQ is a lipoprotein; upon cleavage of its transit peptide by Signal Peptidase II, which targets delivery of the mature protein to the thylakoid lumenal space, the N-terminal cysteinyl residue is lipid-modified. This modification appears to tether this otherwise soluble component to the thylakoid membrane. To probe the functional significance of the lipid anchor, mutants of the CyanoQ protein have been generated in Synechocystis sp. PCC 6803 to eliminate the N-terminal cysteinyl residue, preventing lipid modification. Substitution of the N-terminal cysteinyl residue with serine (Q-C22S) resulted in a decrease in the amount of detectable CyanoQ protein to 17% that of the wild-type protein. Moreover, the physical properties of the accumulated Q-C22S protein were consistent with altered processing of the CyanoQ precursor. The Q-C22S protein was shifted to a higher apparent molecular mass and partitioned in the hydrophobic phase in TX-114 phase-partitioning experiments. These results suggest that the hydrophobic N-terminal 22 amino acids were not properly cleaved by a signal peptidase. Substitution of the entire CyanoQ transit peptide with the transit peptide of the soluble lumenal protein PsbO yielded the Q-SS mutant and resulted in no detectable accumulation of the modified CyanoQ protein. Finally, the CyanoQ protein was present at normal amounts in the PS II mutant strains ΔpsbB and ΔpsbO, indicating that an association with PS II was not a prerequisite for stable CyanoQ accumulation. Together these results indicate that CyanoQ accumulation in Synechocystis sp. PCC 6803 depends on the presence of the N-terminal lipid anchor, but not on the association of CyanoQ with the PS II complex

Acceptance and commitment therapy for symptom interference in metastatic breast cancer patients: a pilot randomized trial

PURPOSE: Breast cancer is the leading cause of cancer mortality in women worldwide. With medical advances, metastatic breast cancer (MBC) patients often live for years with many symptoms that interfere with activities. However, there is a paucity of efficacious interventions to address symptom-related suffering and functional interference. Thus, this study examined the feasibility and preliminary efficacy of telephone-based acceptance and commitment therapy (ACT) for symptom interference with functioning in MBC patients. METHODS: Symptomatic MBC patients (N = 47) were randomly assigned to six telephone sessions of ACT or six telephone sessions of education/support. Patients completed measures of symptom interference and measures assessing the severity of pain, fatigue, sleep disturbance, depressive symptoms, and anxiety. RESULTS: The eligibility screening rate (64%) and high retention (83% at 8 weeks post-baseline) demonstrated feasibility. When examining within-group change, ACT participants showed decreases in symptom interference (i.e., fatigue interference and sleep-related impairment; Cohen's d range = - 0.23 to - 0.31) at 8 and 12 weeks post-baseline, whereas education/support participants showed minimal change in these outcomes (d range = - 0.03 to 0.07). Additionally, at 12 weeks post-baseline, ACT participants showed moderate decreases in fatigue and sleep disturbance (both ds = - 0.43), whereas education/support participants showed small decreases in these outcomes (ds = - 0.24 and - 0.18 for fatigue and sleep disturbance, respectively). Both the ACT and education/support groups showed reductions in depressive symptoms (ds = - 0.27 and - 0.28) at 12 weeks post-baseline. Group differences in all outcomes were not statistically significant. CONCLUSIONS: ACT shows feasibility and promise in improving fatigue and sleep-related outcomes in MBC patients and warrants further investigation

The extrinsic proteins of Photosystem II

In this review we examine the structure and function of the extrinsic proteins of Photosystem II. These proteins include PsbO, present in all oxygenic organisms, the PsbP and PsbQ proteins, which are found in higher plants and eukaryotic algae, and the PsbU, PsbV, CyanoQ, and CyanoP proteins, which are found in the cyanobacteria. These proteins serve to optimize oxygen evolution at physiological calcium and chloride concentrations. They also shield the Mn 4CaO 5 cluster from exogenous reductants. Numerous biochemical, genetic and structural studies have been used to probe the structure and function of these proteins within the photosystem. We will discuss the most recent proposed functional roles for these components, their structures (as deduced from biochemical and X-ray crystallographic studies) and the locations of their proposed binding domains within the Photosystem II complex. This article is part of a Special Issue entitled: Photosystem II. © 2011 Elsevier B.V. All rights reserved

Therapeutic efficacy of favipiravir against Bourbon virus in mice

Bourbon virus (BRBV) is an emerging tick-borne RNA virus in the orthomyxoviridae family that was discovered in 2014. Although fatal human cases of BRBV have been described, little is known about its pathogenesis, and no antiviral therapies or vaccines exist. We obtained serum from a fatal case in 2017 and successfully recovered the second human infectious isolate of BRBV. Next-generation sequencing of the St. Louis isolate of BRBV (BRBV-STL) showed >99% nucleotide identity to the original reference isolate. Using BRBV-STL, we developed a small animal model to study BRBV-STL tropism in vivo and evaluated the prophylactic and therapeutic efficacy of the experimental antiviral drug favipiravir against BRBV-induced disease. Infection of Ifnar1-/- mice lacking the type I interferon receptor, but not congenic wild-type animals, resulted in uniformly fatal disease 6 to 10 days after infection. RNA in situ hybridization and viral yield assays demonstrated a broad tropism of BRBV-STL with highest levels detected in liver and spleen. In vitro replication and polymerase activity of BRBV-STL were inhibited by favipiravir. Moreover, administration of favipiravir as a prophylaxis or as post-exposure therapy three days after infection prevented BRBV-STL-induced mortality in immunocompromised Ifnar1-/- mice. These results suggest that favipiravir may be a candidate treatment for humans who become infected with BRBV

Race Differences in Initial Presentation, Early Treatment, and 1-year Outcomes of Pediatric Crohnʼs Disease: Results from the ImproveCareNow Network

BACKGROUND: Racially disparate care has been shown to contribute to suboptimal health care outcomes for minorities. Using the ImproveCareNow network, we investigated differences in management and outcomes of pediatric patients with Crohn's disease at diagnosis and 1-year postdiagnosis. METHODS: ImproveCareNow is a learning health network for pediatric inflammatory bowel disease. It contains prospective, longitudinal data from outpatient encounters. This retrospective study included all patients with Crohn's disease ≤21 years, September 2006 to October 2014, with the first recorded encounter ≤90 days from date of diagnosis and an encounter 1 year ±60 days. We examined the effect of race on remission rate and treatment at diagnosis and 1 year from diagnosis using t-tests, Wilcoxon rank-sum tests, χ statistic, and Fisher's exact tests, where appropriate, followed by univariate regression models. RESULTS: Nine hundred seventy-six patients (Black = 118 (12%), White = 858 (88%), mean age = 13 years, 63% male) from 39 sites were included. Black children had a higher percentage of Medicaid insurance (44% versus 11%, P < 0.001). At diagnosis, Black children had more active disease according to physician global assessment (P = 0.027), but not by short Pediatric Crohn's Disease Activity Index (P = 0.67). Race differences in treatment were not identified. Black children had lower hematocrit (34.8 versus 36.7, P < 0.001) and albumin levels (3.6 versus 3.9, P = 0.001). At 1 year, Black children had more active disease according to physician global assessment (P = 0.016), but not by short Pediatric Crohn's Disease Activity Index (P = 0.06). CONCLUSIONS: Black children with Crohn's disease may have more severe disease than White children based on physician global assessment. Neither disease phenotype differences at diagnosis nor treatment differences at 1-year follow-up were identified

Theoretical studies of the historical development of the accounting discipline: a review and evidence

Many existing studies of the development of accounting thought have either been atheoretical or have adopted Kuhn's model of scientific growth. The limitations of this 35-year-old model are discussed. Four different general neo-Kuhnian models of scholarly knowledge development are reviewed and compared with reference to an analytical matrix. The models are found to be mutually consistent, with each focusing on a different aspect of development. A composite model is proposed. Based on a hand-crafted database, author co-citation analysis is used to map empirically the entire literature structure of the accounting discipline during two consecutive time periods, 1972–81 and 1982–90. The changing structure of the accounting literature is interpreted using the proposed composite model of scholarly knowledge development

A dose-dependent requirement for the proline motif of CD28 in cellular and humoral immunity revealed by a targeted knockin mutant

Activation of naive T cells requires the integration of signals through the antigen receptor and CD28. Although there is agreement on the importance of CD28, there remains controversy on the mechanism by which CD28 regulates T cell function. We have generated a gene-targeted knockin mouse expressing a mutation in the C-terminal proline-rich region of the cytoplasmic tail of CD28. Our analysis conclusively showed that this motif is essential for CD28-dependent regulation of interleukin 2 secretion and proliferation. In vivo analysis revealed that mutation of this motif-dissociated CD28-dependent regulation of cellular and humoral responses in an allergic airway inflammation model. Furthermore, we find an important gene dosage effect on the phenotype of the mutation and provide a mechanistic explanation for the conflicting data on the significance of this motif in CD28 function

One-step isolation and biochemical characterization of a highlyactive plant PSII monomeric core

We describe a one-step detergent solubilization protocol for isolating a highly active form of Photosystem II (PSII) from Pisum sativum L. Detailed characterization of the preparation showed that the complex was a monomer having no light harvesting proteins attached. This core reaction centre complex had, however, a range of low molecular mass intrinsic proteins as well as the chlorophyll binding proteins CP43 and CP47 and the reaction centre proteins D1 and D2. Of particular note was the presence of a stoichiometric level of PsbW, a low molecular weight protein not present in PSII of cyanobacteria. Despite the high oxygen evolution rate, the core complex did not retain the PsbQ extrinsic protein although there was close to a full complement of PsbO and PsbR and partial level of PsbP. However, reconstitution of PsbP and PsbPQ was possible. The presence of PsbP in absence of LHCII and other chlorophyll a/b binding proteins confirms that LHCII proteins are not a strict requirement for the assembly of this extrinsic polypeptide to the PSII core in contrast with the conclusion of Caffarri et al. (2009)

Ontological dependence in a spacetime-world

Priority Monism (hereafter, ‘Monism’), as defined by Jonathan Schaffer (Philos Rev 119:131–176, 2010), has a number of components. It is the view that: the cosmos exists; the cosmos is a maximal actual concrete object, of which all actual concrete objects are parts; the cosmos is basic—there is no object upon which the cosmos depends, ontologically; ontological dependence is a primitive and unanalysable relation. In a recent attack, Lowe (Spinoza on monism. Palgave Macmillan, London, pp 92–122, 2012) has offered a series of arguments to show that Monism fails. He offers up four tranches of argument, with different focuses. These focal points are: (1) being a concrete object; (2) aggregation and dependence; (3) analyses of ontological dependence; (4) Schaffer’s no-overlap principle. These are all technical notions, but each figures at the heart of a cluster of arguments that Lowe puts forward. To respond, I work through each tranche of argument in turn. Before that, in the first section, I offer a cursory statement of Monism, as Schaffer presents it in his 2010 paper, Monism: The Priority of the Whole. I then respond to each of Lowe’s criticisms in turn, deploying material from Schaffer’s 2009 paper Spacetime: the One Substance, as well as various pieces of conceptual machinery from Lowe’s own works (The possibility of metaphysics. Clarendon, Oxford, 1998, 2010) to deflect Lowe’s (Spinoza on monism. Palgave Macmillan, London, pp 92–122, 2012) attacks. In the process of defending Monism from Lowe (Spinoza on monism. Palgave Macmillan, London, pp 92–122, 2012), I end up offering some subtle refinements to Schaffer’s (Philos Rev 119:131–176, 2010) view and explain how the resulting ‘hybrid’ view fares in the wider dialectic