Interaction between the NS4B amphipathic helix, AH2, and charged lipid headgroups alters membrane morphology and AH2 oligomeric state — Implications for the Hepatitis C virus life cycle

AbstractThe non-structural protein 4B (NS4B) from Hepatitis C virus (HCV) plays a pivotal role in the remodelling of the host cell's membranes, required for the formation of the viral replication complex where genome synthesis occurs. NS4B is an integral membrane protein that possesses a number of domains vital for viral replication. Structural and biophysical studies have revealed that one of these, the second amphipathic N-terminal helix (AH2), plays a key role in these remodelling events. However, there is still limited understanding of the mechanism through which AH2 promotes these changes. Here we report on solid-state NMR and molecular dynamics studies that demonstrate that AH2 promotes the clustering of negatively charged lipids within the bilayer, a process that reduces the strain within the bilayer facilitating the remodelling of the lipid bilayer. Furthermore, the presence of negatively charged lipids within the bilayer appears to promote the disassociation of AH2 oligomers, highlighting a potential role for lipid recruitment in regulating NS protein interactions

A Pilot Study Investigating the Influence of Glucagon-Like Peptide-1 Receptor Single Nucleotide Polymorphisms on Gastric Emptying Rate in Caucasian Men

Gastric emptying rate in humans is subject to large individual variability, but previous research on the influence of genetics is scarce. Variation in the glucagon-like peptide-1 receptor (GLP1R) gene is a plausible candidate gene to partially explain the high variance. This study aimed to investigate the influence of genetic variation in the GLP1R gene on gastric emptying rate of a glucose solution in humans. Forty eight healthy Caucasian males took part in this investigation. Gastric emptying rate of a 6% glucose solution was assessed using the 13C breath test method and a venous blood sample was obtained from each participant. Participants were genotyped for 27 Tag single nucleotide polymorphisms (SNPs) in the GLP1R locus using Sequenom MassARRAY iPLEX GOLD analysis and MALDI-TOF mass spectrometry. The time at which maximal emptying rate occurred (Tlag) was faster in participants with the CC genotype than in TT and TC genotypes for SNP rs742764: [median (quartiles) CC, 35 (30–36) min vs. TT, 43 (39–46) min, and TC, 41 (39–45) min; P < 0.01]. Tlag was also slower in participants with the AA genotype compared to the TT and TA genotypes for SNP rs2254336: [AA, 43 (39–49) min vs. TT, 36 (34–41) min, and TA, 39 (35–42) min; P < 0.05]. Analysis by phenotype also showed differences in half-emptying time (T12) and Tlag for SNPs rs9283907, rs2268657, and rs2254336. Several neighboring Tag SNPs within the GLP1R gene were found to be associated with gastric emptying rate, and should be further investigated

Recommendations for the management of MPS IVA: systematic evidence- and consensus-based guidance.

IntroductionMucopolysaccharidosis (MPS) IVA or Morquio A syndrome is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme, which impairs lysosomal degradation of keratan sulphate and chondroitin-6-sulphate. The multiple clinical manifestations of MPS IVA present numerous challenges for management and necessitate the need for individualised treatment. Although treatment guidelines are available, the methodology used to develop this guidance has come under increased scrutiny. This programme was conducted to provide evidence-based, expert-agreed recommendations to optimise management of MPS IVA.MethodsTwenty six international healthcare professionals across multiple disciplines, with expertise in managing MPS IVA, and three patient advocates formed the Steering Committee (SC) and contributed to the development of this guidance. Representatives from six Patient Advocacy Groups (PAGs) were interviewed to gain insights on patient perspectives. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with experience managing patients with MPS IVA and the manuscript was evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers.ResultsA total of 87 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) disease-modifying interventions (enzyme replacement therapy [ERT] and haematopoietic stem cell transplantation [HSCT]); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions (including spinal, limb, ophthalmic, cardio-thoracic and ear-nose-throat [ENT] surgeries). Consensus was reached on all statements after two rounds of voting. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance).ConclusionThis manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS IVA and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps

Recommendations for the management of MPS VI: systematic evidence- and consensus-based guidance.

IntroductionMucopolysaccharidosis (MPS) VI or Maroteaux-Lamy syndrome (253200) is an autosomal recessive lysosomal storage disorder caused by deficiency in N-acetylgalactosamine-4-sulfatase (arylsulfatase B). The heterogeneity and progressive nature of MPS VI necessitates a multidisciplinary team approach and there is a need for robust guidance to achieve optimal management. This programme was convened to develop evidence-based, expert-agreed recommendations for the general principles of management, routine monitoring requirements and the use of medical and surgical interventions in patients with MPS VI.Methods26 international healthcare professionals from various disciplines, all with expertise in managing MPS VI, and three patient advocates formed the Steering Committee group (SC) and contributed to the development of this guidance. Members from six Patient Advocacy Groups (PAGs) acted as advisors and attended interviews to ensure representation of the patient perspective. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with expertise and experience managing patients with MPS VI and the manuscript has been evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers.ResultsA total of 93 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions. Consensus was reached on all statements after two rounds of voting. The greatest challenges faced by patients as relayed by consultation with PAGs were deficits in endurance, dexterity, hearing, vision and respiratory function. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance).ConclusionThis manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS VI and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis

‘Like being on death row’: Britain and the end of coal, c. 1970 to the present

ABSTRACT The introduction draws on the work of Raymond Williams to identify the ‘structures of feeling’ that surround the figure of the coal miner in contemporary British culture. As an analysis of the media coverage of the closure of the UK’s last deep-coal mine in December 2015 demonstrates, mine workers were cast as ‘residual proletarians’ whose modes of being and consciousness were portrayed as both admirable and pitifully out of date. The introduction goes on to demonstrate the dominance that selective memories of the miners’ strike of 1984/1985 exert over contemporary understandings of coal mining. Drawing on the work of Williams again, the introduction reflects on how certain images and tropes have reached hegemonic status while others have been marginalised. The introduction concludes by arguing that historical scholarship must extricate itself from the stranglehold of ‘1984/85’ and contends that the true significance of coal for contemporary British history lies in the extraordinary range of emotions, meanings and significations with which both the industry and the miners were invested by the contemporaries themselves

Treatment of anxiety in patients with coronary heart disease: Rationale and design of the UNderstanding the benefits of exercise and escitalopram in anxious patients WIth coroNary heart Disease (UNWIND) randomized clinical trial

Anxiety is highly prevalent among patients with coronary heart disease (CHD), and there is growing evidence that high levels of anxiety are associated with worse prognosis. However, few studies have evaluated the efficacy of treating anxiety in CHD patients for reducing symptoms and improving clinical outcomes. Exercise and selective serotonin reuptake inhibitors have been shown to be effective in treating patients with depression, but have not been studied in cardiac patients with high anxiety

Treatment of anxiety in patients with coronary heart disease: Rationale and design of the UNderstanding the benefits of exercise and escitalopram in anxious patients WIth coroNary heart Disease (UNWIND) randomized clinical trial

Anxiety is highly prevalent among patients with coronary heart disease (CHD), and there is growing evidence that high levels of anxiety are associated with worse prognosis. However, few studies have evaluated the efficacy of treating anxiety in CHD patients for reducing symptoms and improving clinical outcomes. Exercise and selective serotonin reuptake inhibitors have been shown to be effective in treating patients with depression, but have not been studied in cardiac patients with high anxiety

RosettaRemodel: A Generalized Framework for Flexible Backbone Protein Design

We describe RosettaRemodel, a generalized framework for flexible protein design that provides a versatile and convenient interface to the Rosetta modeling suite. RosettaRemodel employs a unified interface, called a blueprint, which allows detailed control over many aspects of flexible backbone protein design calculations. RosettaRemodel allows the construction and elaboration of customized protocols for a wide range of design problems ranging from loop insertion and deletion, disulfide engineering, domain assembly, loop remodeling, motif grafting, symmetrical units, to de novo structure modeling

Lifestyle modification for resistant hypertension: The TRIUMPH randomized clinical trial

Resistant hypertension (RH) is a growing health burden in this country affecting as many as one in five adults being treated for hypertension. RH is associated with increased risk of adverse cardiovascular disease (CVD) events and all-cause mortality. Strategies to reduce blood pressure in this high risk population are a national priority