Bicuspid Aortic Valve Disease With Early Onset Complications: Characteristics And Aortic Outcomes.

Bicuspid aortic valve (BAV) is the most common congenital heart malformation in adults but can also cause childhood-onset complications. In multicenter study, we found that adults who experience significant complications of BAV disease before age 30 are distinguished from the majority of BAV cases that manifest after age 50 by a relatively severe clinical course, with higher rates of surgical interventions, more frequent second interventions, and a greater burden of congenital heart malformations. These observations highlight the need for prompt recognition, regular lifelong surveillance, and targeted interventions to address the significant health burdens of patients with early onset BAV complications.

Sediment microbial fuel cells as a barrier to sulfide accumulation and their potential for sediment remediation beneath aquaculture pens.

Sediment microbial fuel cells (SMFCs) generate electricity through the oxidation of reduced compounds, such as sulfide or organic carbon compounds, buried in anoxic sediments. The ability to remove sulfide suggests their use in the remediation of sediments impacted by point source organic matter loading, such as occurs beneath open pen aquaculture farms. However, for SMFCs to be a viable technology they must remove sulfide at a scale relevant to the environmental contamination and their impact on the sediment geochemistry as a whole must be evaluated. Here we address these issues through a laboratory microcosm experiment. Two SMFCs placed in high organic matter sediments were operated for 96 days and compared to open circuit and sediment only controls. The impact on sediment geochemistry was evaluated with microsensor profiling for oxygen, sulfide, and pH. The SMFCs had no discernable effect on oxygen profiles, however porewater sulfide was significantly lower in the sediment microcosms with functioning SMFCs than those without. Depth integrated sulfide inventories in the SMFCs were only 20% that of the controls. However, the SMFCs also lowered pH in the sediments and the consequences of this acidification on sediment geochemistry should be considered if developing SMFCs for remediation. The data presented here indicate that SMFCs have potential for the remediation of sulfidic sediments around aquaculture operations.

Abiraterone acetate plus Prednisone/Prednisolone compared with Enzalutamide in metastatic castration resistant prostate cancer before or after chemotherapy: A retrospective study of real-world data (ACES).

Background: Abiraterone acetate combined with Prednisone/Prednisolone (AA+P) and Enzalutamide (ENZ) have proven survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC) in chemotherapy-naïve and prior chemotherapy patients. There have been no studies directly comparing the effectiveness of ENZ to AA+P in mCRPC patients. Methods: A retrospective, survival analysis study of 143 real-world mCRPC patients (90 in AA+P and 53 in ENZ group) was conducted. Patients who started their treatment between February 2012 and May 2016 were included. The primary end point was biochemical progression-free survival (bPFS). Secondary end points were radiological progression-free survival (rPFS) and overall survival (OS). Toxicity data were also collected. Data were analyzed using Cox proportional hazards (PH) models, adjusting for covariates: prior radical treatment; Gleason score; prostate-specific antigen; age; and chemotherapy naïve or not. Results: After median follow-up of 15 months (interquartile range 7 to 23), 112 events of biochemical progression were observed (71 in AA+P and 41 in ENZ). About 41% in AA+P group and 30% patients in ENZ group received prior chemotherapy. The chance of biochemical progression was significantly lower among ENZ patients than AA+P patients, when adjusting for all covariates in the Cox PH model (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.35 to 0.82, P = .004). There was a trend implying the chance of rPFS could be higher among ENZ patients than AA+P patients (HR 1.24, 95% CI 0.76 to 2.02, P = .4). There is no difference in OS between ENZ and AA+P patients, when adjusting for all covariates in the Cox PH model (HR 0.91, 95% CI 0.59 to 1.41, P = .7). About 38% of ENZ patients reported fatigue compared to 16% of AA+P patients, while hypertension was reported slightly more in AA+P patients. Conclusions: This study showed a statistically significant difference in bPFS, favoring ENZ, but no significant difference in rPFS or OS.

Environmental evaluation and nano-mineralogical study of fresh and unsaturated weathered coal fly ashes.

Coal combustion and the disposal of combustion wastes emit enormous quantities of nano-sized particles that pose significant health concerns on exposure, particularly in unindustrialized countries. Samples of fresh and weathered class F fly ash were analysed through various techniques including X-ray fluorescence (XRF), X-ray diffraction (XRD), focused ion beam scanning electron microscopy (FIB-SEM), field-emission gun scanning electron microscopy (FE-SEM), high-resolution transmission electron microscopy (HR-TEM) coupled with energy dispersive x-ray spectroscopy (EDS), and Raman Spectroscopy. The imaging techniques showed that the fresh and weathered coal fly ash nanoparticles (CFA-NPs) are mostly spherical shaped. The crystalline phases detected were quartz, mullite, ettringite, calcite, maghemite, hematite, gypsum, magnetite, clay residues, and sulphides. The most abundant crystalline phases were quartz mixed with Al-Fe-Si-K-Ti-O-amorphous phases whereas mullite was detected in several amorphous phases of Al, Fe, Ca, Si, O, K, Mg, Mn, and P. The analyses revealed that CFA-NPs are 5-500 nm in diameter and encapsulate several potentially hazardous elements (PHEs). The carbon species were detected as 5-50 nm carbon nanoballs of graphitic layers and massive fullerenes. Lastly, the aspects of health risks related to exposure to some detected ambient nanoparticles are also discussed.

Corrigendum: Earliest signs of life on land preserved in ca. 3.5 Ga hot spring deposits.

This corrects the article DOI: 10.1038/ncomms15263.

Earliest signs of life on land preserved in ca. 3.5 Ga hot spring deposits.

The ca. 3.48 Ga Dresser Formation, Pilbara Craton, Western Australia, is well known for hosting some of Earth's earliest convincing evidence of life (stromatolites, fractionated sulfur/carbon isotopes, microfossils) within a dynamic, low-eruptive volcanic caldera affected by voluminous hydrothermal fluid circulation. However, missing from the caldera model were surface manifestations of the volcanic-hydrothermal system (hot springs, geysers) and their unequivocal link with life. Here we present new discoveries of hot spring deposits including geyserite, sinter terracettes and mineralized remnants of hot spring pools/vents, all of which preserve a suite of microbial biosignatures indicative of the earliest life on land. These include stromatolites, newly observed microbial palisade fabric and gas bubbles preserved in inferred mineralized, exopolymeric substance. These findings extend the known geological record of inhabited terrestrial hot springs on Earth by ∼3 billion years and offer an analogue in the search for potential fossil life in ancient Martian hot springs.

Is it time to retire the genus Rymovirus from the family Potyviridae?

In the most recent Report of the International Committee on Taxonomy of Viruses (9th Report, 2011) (King et al., Virus Taxonomy, Elsevier, New York, 2011) the family Potyviridae is described as comprising seven genera - Potyvirus, Ipomovirus, Macluravirus, Rymovirus, Tritimovirus, Brambyvirus and Bymovirus - despite previous suggestions questioning the validity of the taxonomic status of the genus Rymovirus. Since then the ICTV website records that an eighth genus Poacevirus has been approved for the Potyviridae family. The creation of the genus Rymovirus at the 1990 Potyvirus Taxonomy Workshop in Braunschweig, Germany was based on two things: (i) the incorrect assumption that the genomes of all mite-transmitted members of the Potyviridae would have strong sequence similarity to that of wheat streak mosaic virus, the only mite-transmitted member of this genus for which sequence data were available at that time, and (ii) that the genus should be named Rymovirus (based on a virus for which there was no sequence information) rather than a name based on wheat streak mosaic virus (e.g., "Whestremovirus") because ryegrass mosaic virus (RGMV) was the first mite-transmitted virus to be described and thus should take precedence. When sequence data for RGMV became available in 1995, these data showed that RGMV was very different from wheat streak mosaic virus (WSMV) and should not be assigned to the same genus. WSMV was subsequently re-assigned to a new genus, Tritimovirus, while the genus Rymovirus was retained. In this author's opinion, this retention is not justified, and the removal of Rymovirus as a distinct genus in the family Potyviridae is recommended. There may be merit when assigning it to the genus Potyvirus in sequestering these viruses in a rymovirus subgroup, as is done with other potyviruses, to reflect their different mode of transmission.

Insulin Mimetic Peptide Disrupts the Primary Binding Site of the Insulin Receptor.

Sets of synthetic peptides that interact with the insulin receptor ectodomain have been discovered by phage display and reported in the literature. These peptides were grouped into three classes termed Site 1, Site 2, and Site 3 based on their mutual competition of binding to the receptor. Further refinement has yielded, in particular, a 36-residue Site 2-Site 1 fusion peptide, S519, that binds the insulin receptor with subnanomolar affinity and exhibits agonist activity in both lipogenesis and glucose uptake assays. Here, we report three-dimensional crystallographic detail of the interaction of the C-terminal, 16-residue Site 1 component (S519C16) of S519 with the first leucine-rich repeat domain (L1) of the insulin receptor. Our structure shows that S519C16 binds to the same site on the L1 surface as that occupied by a critical component of the primary binding site, namely the helical C-terminal segment of the insulin receptor α-chain (termed αCT). In particular, the two phenylalanine residues within the FYXWF motif of S519C16 are seen to engage the insulin receptor L1 domain surface in a fashion almost identical to the respective αCT residues Phe(701) and Phe(705) The structure provides a platform for the further development of peptidic and/or small molecule agents directed toward the insulin receptor and/or the type 1 insulin-like growth factor receptor.

Higher-Resolution Structure of the Human Insulin Receptor Ectodomain: Multi-Modal Inclusion of the Insert Domain.

Insulin receptor (IR) signaling is critical to controlling nutrient uptake and metabolism. However, only a low-resolution (3.8 Å) structure currently exists for the IR ectodomain, with some segments ill-defined or unmodeled due to disorder. Here, we revise this structure using new diffraction data to 3.3 Å resolution that allow improved modeling of the N-linked glycans, the first and third fibronectin type III domains, and the insert domain. A novel haptic interactive molecular dynamics strategy was used to aid fitting to low-resolution electron density maps. The resulting model provides a foundation for investigation of structural transitions in IR upon ligand binding.

Structural Congruency of Ligand Binding to the Insulin and Insulin/Type 1 Insulin-like Growth Factor Hybrid Receptors.

The homodimeric insulin and type 1 insulin-like growth factor receptors (IR and IGF-1R) share a common architecture and each can bind all three ligands within the family: insulin and insulin-like growth factors I and II (IGF-I and IFG-II). The receptor monomers also assemble as heterodimers, the primary ligand-binding sites of which each comprise the first leucine-rich repeat domain (L1) of one receptor type and an α-chain C-terminal segment (αCT) of the second receptor type. We present here crystal structures of IGF-I bound to such a hybrid primary binding site and of a ligand-free version of an IR αCT peptide bound to an IR L1 plus cysteine-rich domain construct (IR310.T). These structures, refined at 3.0-Å resolution, prove congruent to respective existing structures of insulin-complexed IR310.T and the intact apo-IR ectodomain. As such, they provide key missing links in the emerging, but sparse, repertoire of structures defining the receptor family.

Protective hinge in insulin opens to enable its receptor engagement.

Insulin provides a classical model of a globular protein, yet how the hormone changes conformation to engage its receptor has long been enigmatic. Interest has focused on the C-terminal B-chain segment, critical for protective self-assembly in ß cells and receptor binding at target tissues. Insight may be obtained from truncated "microreceptors" that reconstitute the primary hormone-binding site (α-subunit domains L1 and αCT). We demonstrate that, on microreceptor binding, this segment undergoes concerted hinge-like rotation at its B20-B23 ß-turn, coupling reorientation of Phe(B24) to a 60° rotation of the B25-B28 ß-strand away from the hormone core to lie antiparallel to the receptor's L1-ß2 sheet. Opening of this hinge enables conserved nonpolar side chains (Ile(A2), Val(A3), Val(B12), Phe(B24), and Phe(B25)) to engage the receptor. Restraining the hinge by nonstandard mutagenesis preserves native folding but blocks receptor binding, whereas its engineered opening maintains activity at the price of protein instability and nonnative aggregation. Our findings rationalize properties of clinical mutations in the insulin family and provide a previously unidentified foundation for designing therapeutic analogs. We envisage that a switch between free and receptor-bound conformations of insulin evolved as a solution to conflicting structural determinants of biosynthesis and function.

The insulin receptor changes conformation in unforeseen ways on ligand binding: sharpening the picture of insulin receptor activation.

Unraveling the molecular detail of insulin receptor activation has proved challenging, but a major advance is the recent determination of crystallographic structures of insulin in complex with its primary binding site on the receptor. The current model for insulin receptor activation is that two distinct surfaces of insulin monomer engage sequentially with two distinct binding sites on the extracellular surface of the insulin receptor, which is itself a disulfide-linked (αß)2 homodimer. In the process, conformational changes occur both within the hormone and the receptor, the latter resulting in the disruption of the intracellular interactions that hold the kinase domains in their basal state and in the initiation of the phosphorylation events that drive insulin signaling. The purpose of this paper is to summarize the extant structural data relating to hormone binding and how it effects receptor activation, as well as to discuss the issues that remain unresolved.

How insulin engages its primary binding site on the insulin receptor.

Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer's disease; aberrant signalling occurs in diverse cancers, exacerbated by cross-talk with the homologous type 1 insulin-like growth factor receptor (IGF1R). Despite more than three decades of investigation, the three-dimensional structure of the insulin-insulin receptor complex has proved elusive, confounded by the complexity of producing the receptor protein. Here we present the first view, to our knowledge, of the interaction of insulin with its primary binding site on the insulin receptor, on the basis of four crystal structures of insulin bound to truncated insulin receptor constructs. The direct interaction of insulin with the first leucine-rich-repeat domain (L1) of insulin receptor is seen to be sparse, the hormone instead engaging the insulin receptor carboxy-terminal α-chain (αCT) segment, which is itself remodelled on the face of L1 upon insulin binding. Contact between insulin and L1 is restricted to insulin B-chain residues. The αCT segment displaces the B-chain C-terminal ß-strand away from the hormone core, revealing the mechanism of a long-proposed conformational switch in insulin upon receptor engagement. This mode of hormone-receptor recognition is novel within the broader family of receptor tyrosine kinases. We support these findings by photo-crosslinking data that place the suggested interactions into the context of the holoreceptor and by isothermal titration calorimetry data that dissect the hormone-insulin receptor interface. Together, our findings provide an explanation for a wealth of biochemical data from the insulin receptor and IGF1R systems relevant to the design of therapeutic insulin analogues.

A high-affinity ErbB4Fc fusion protein is a potent antagonist of heregulin-mediated receptor activation.

Ligand-mediated activation of ErbB3 and ErbB4 is implicated in the pathogenesis of several human malignancies including cancer of the ovary and melanoma. We have used the broad ErbB ligand specificity of ErbB4 to assemble and express an ErbB4 fusion protein comprising the first 497 amino acids of the mature ErbB4 ectodomain fused to the human IgG Fc constant region. The purified fusion protein, designated sErbB4.497.Fc, binds the ErbB receptor ligands betacellulin and heregulin-ß1 (HRG-ß1) with high affinity (K(D) = 130 pM), an increase in affinity of 10- to 20-fold, respectively, compared with sErbB4.615.Fc. sErbB4.497.Fc inhibited ligand-stimulated phosphorylation of epidermal growth factor receptor and ErbB2, and blocked HRG-ß1 activation of the IKB/MAP/JNK/AKT signalling pathways. sErbB4.497.Fc inhibited HRG-ß1-stimulated proliferation in MCF7 cells. In a mouse tumour xenograft model, sErbB4.497.Fc as a monotherapy modestly inhibited the growth of MDA-MB-231 breast cancer cells. sErbB4.497.Fc may be useful in an adjuvant setting in combination with conventional therapeutic agents.

Chemical composition and minerals in pyrite ash of an abandoned sulphuric acid production plant.

The extraction of sulphur produces a hematite-rich waste, known as roasted pyrite ash, which contains significant amounts of environmentally sensitive elements in variable concentrations and modes of occurrence. Whilst the mineralogy of roasted pyrite ash associated with iron or copper mining has been studied, as this is the main source of sulphur worldwide, the mineralogy, and more importantly, the characterization of submicron, ultrafine and nanoparticles, in coal-derived roasted pyrite ash remain to be resolved. In this work we provide essential data on the chemical composition and nanomineralogical assemblage of roasted pyrite ash. XRD, HR-TEM and FE-SEM were used to identify a large variety of minerals of anthropogenic origin. These phases result from highly complex chemical reactions occurring during the processing of coal pyrite of southern Brazil for sulphur extraction and further manufacture of sulphuric acid. Iron-rich submicron, ultrafine and nanoparticles within the ash may contain high proportions of toxic elements such as As, Se, U, among others. A number of elements, such as As, Cr, Cu, Co, La, Mn, Ni, Pb, Sb, Se, Sr, Ti, Zn, and Zr, were found to be present in individual nanoparticles and submicron, ultrafine and nanominerals (e.g. oxides, sulphates, clays) in concentrations of up to 5%. The study of nanominerals in roasted pyrite ash from coal rejects is important to develop an understanding on the nature of this by-product, and to assess the interaction between emitted nanominerals, ultra-fine particles, and atmospheric gases, rain or body fluids, and thus to evaluate the environmental and health impacts of pyrite ash materials.

Similar but different: ligand-induced activation of the insulin and epidermal growth factor receptor families.

The insulin and epidermal growth factor receptor families are among the most intensively studied proteins in biology. They are closely related members of the receptor tyrosine kinase superfamily and deregulated signaling by members of either receptor family has been implicated in the progression of a variety of cancers. These receptors have thus emerged as validated therapeutic targets for the development of anti-tumour agents. Recent studies have revealed detail of the ligand-binding sites in the insulin receptor family, as well as detail of conformational change upon ligand binding in the epidermal growth factor receptor family. Taken together, these findings and further data relating to kinase activation highlight the fact that while the receptor families share common structural elements, the structural detail of their functioning is remarkably different.

Landmarks in insulin research.

Ever since the discovery of insulin and its role in the regulation of glucose uptake and utilization, there has been great interest in insulin, its structure and the way in which it interacts with its receptor and effects signal transduction. As the 90th anniversary of the discovery of insulin approaches, it is timely to provide an overview of the landmark discoveries relating to the structure and function of this remarkable molecule and its receptor.

Identification of nanominerals and nanoparticles in burning coal waste piles from Portugal.

A range of carbon nanoparticles, agglomerates and mineral phases have been identified in burning coal waste pile materials from the Douro Coalfield of Portugal, as a basis for identifying their potential environmental and human health impacts. The fragile nature and fine particle size of these materials required novel characterization methods, including energy-dispersive X-ray spectrometry (EDS), field-emission scanning electron microscope (FE-SEM), and high-resolution transmission electron microscopy (HR-TEM) techniques. The chemical composition and possible correlations with morphology of the nanominerals and associated ultra-fine particles have been evaluated in the context of human health exposure, as well as in relation to management of such components in coal-fire environments.

Structural resolution of a tandem hormone-binding element in the insulin receptor and its implications for design of peptide agonists.

The C-terminal segment of the human insulin receptor alpha-chain (designated alphaCT) is critical to insulin binding as has been previously demonstrated by alanine scanning mutagenesis and photo-cross-linking. To date no information regarding the structure of this segment within the receptor has been available. We employ here the technique of thermal-factor sharpening to enhance the interpretability of the electron-density maps associated with the earlier crystal structure of the human insulin receptor ectodomain. The alphaCT segment is now resolved as being engaged with the central beta-sheet of the first leucine-rich repeat (L1) domain of the receptor. The segment is alpha-helical in conformation and extends 11 residues N-terminal of the classical alphaCT segment boundary originally defined by peptide mapping. This tandem structural element (alphaCT-L1) thus defines the intact primary insulin-binding surface of the apo-receptor. The structure, together with isothermal titration calorimetry data of mutant alphaCT peptides binding to an insulin minireceptor, leads to the conclusion that putative "insulin-mimetic" peptides in the literature act at least in part as mimics of the alphaCT segment as well as of insulin. Photo-cross-linking by novel bifunctional insulin derivatives demonstrates that the interaction of insulin with the alphaCT segment and the L1 domain occurs in trans, i.e., these components of the primary binding site are contributed by alternate alpha-chains within the insulin receptor homodimer. The tandem structural element defines a new target for the design of insulin agonists for the treatment of diabetes mellitus.