Loss of Residues 119–136, Including the First β-strand of Human Prion Protein,Generates an Aggregation-competent Partially “Open” Form

In prion replication, the cellular form of prion protein (PrP^C) must undergo a full conformational transition to its disease-associated fibrillar form. Transmembrane forms of PrP have been implicated in this structural conversion. The cooperative unfolding of a structural core in PrP^C presents a substantial energy barrier to prion formation, with membrane insertion and detachment of parts of PrP presenting a plausible route to its reduction. Here, we examined the removal of residues 119–136 of PrP, a region which includes the first β-strand and a substantial portion of the conserved hydrophobic region of PrP, a region which associates with the ER membrane, on the structure, stability and self-association of the folded domain of PrP^C. We see an “open” native-like conformer with increased solvent exposure which fibrilises more readily than the native state. These data suggest a stepwise folding transition, which is initiated by the conformational switch to this “open” form of PrP^C.     

Vicariant events in the montane hummingbird genera Augastes and Schistes in South America

We assessed the evolutionary histories of two hummingbirds, Augastes scutatus and Augastes lumachella, endemic to the highlands of the Espinhaço Range in Brazil. These hummingbirds are considered relictual taxa with phylogenetic affinities to members of the genus Schistes from the Andean region. We reconstructed phylogenetic relationships of Augastes through the use of mitochondrial DNA and nuclear sequences within the Polytminae hummingbird clade, and found that the inferred phylogenetic reconstructions placed A. scutatus as the sister species of A. lumachella and Augastes as sister to Schistes geoffroyi from the northern Andes, as previously suggested by similarities found in plumage and morphology. Our results are consistent with an initial divergence of Augastes and Schistes lineages in the Late Miocene, associated with geological and climatic changes across the South American landscape. A Late Pliocene vicariant event between A. scutatus and A. lumachella may be associated with climatically distinct environmental conditions influencing the local differentiation and adaptation of ancestral Augastes populations. Our findings represent additional important evidence of vicariant events between east and west in southern South America, and between north and south within the Espinhaço Range of Brazil.     

The Caune de l’Arago stone industries in their stratigraphical context

The Middle Stratigraphical Complex of the Caune de l’Arago cave site (Eastern Pyrenées, France) is dated to between 690,000 and 400,000 years old. The site contains successive, spatially distinct archaeological levels. At the base of the sequence, Unit I (OIS 14), where the P levels are among the earliest Mode 2 assemblages presently known in western Europe, contains finely shaped handaxes and a cleaver. Situated above this ensemble, Unit II (OIS 13) has revealed a series of artefact levels lacking handaxes and cleavers. Coiffing the sequence, Unit III (OIS12) has provided numerically rich faunal and lithic assemblages in association with Homo heidelbergensis remains. This paper analyses the stone industries from each artefact level taking into account raw material variability and highlights subtle technological and typological differences. This intrasite study uses a multidisciplinary approach to examine common elements and differences between levels, taking into consideration how external impact factors might have influenced global assemblage features. The Caune de l’Arago's long stratigraphical sequence provides an exceptional opportunity to observe both change and stability in Mode 2 stone-tool manufacture over a period spanning nearly 300,000 years, within the context of contrasting paleoenvironmental conditions.     

Resveratrol is an inhibitor of sodium-dependent inorganic phosphate transport in triple-negative MDA-MB-231 breast cancer cells

Metastasis is a major cause of death in patients with breast cancer. A growing body of evidence has demonstrated the antitumour effects of resveratrol, a non-flavonoid polyphenol. Resveratrol inhibits metastatic processes, such as the migration and invasion of cancer cells. In several cancer types, the importance of inorganic phosphate (Pi) for tumor progression has been demonstrated. The metastatic process in breast cancer is associated with Na⁺-dependent Pi transporters. In this study, we demonstrate, for the first time, that resveratrol inhibits the Na⁺-dependent Pi transporter. Results from kinetic analysis shows that resveratrol inhibits Na⁺-dependent Pi transport non-competitively. Resveratrol also inhibits adhesion/migration in MDA-MB-231 cells, likely related to inhibition of the Na⁺-dependent Pi transporter.     

Reductive carboxylation and 2-hydroxyglutarate formation by wild-type IDH2 in breast carcinoma cells

Mitochondrial NADPH-dependent isocitrate dehydrogenase, IDH2, and cytosolic IDH1, catalyze reductive carboxylation of 2-oxoglutarate. Both idh2 and idh1 monoallelic mutations are harbored in grade 2/3 gliomas, secondary glioblastomas and acute myeloid leukemia. Mutant IDH1/IDH2 enzymes were reported to form an oncometabolite r-2-hydroxyglutarate (2HG), further strengthening malignancy. We quantified CO₂-dependent reductive carboxylation glutaminolysis (RCG) and CO₂-independent 2HG production in HTB-126 and MDA-MB-231 breast carcinoma cells by measuring ¹³C incorporation from 1-¹³C-glutamine into citrate, malate, and 2HG. For HTB-126 cells, ¹³C-citrate, ¹³C-malate, and ¹³C-2-hydroxyglutarate were enriched by 2-, 5-, and 15-fold at 5 mM glucose (2-, 2.5-, and 13-fold at 25 mM glucose), respectively, after 6 h. Such enrichment decreased by 6% with IDH1 silencing, but by 30–50% upon IDH2 silencing while cell respiration and ATP levels rose up to 150%. Unlike 2HG production RCG declined at decreasing CO₂. At hypoxia (5% O₂), IDH2-related and unrelated ¹³C-accumulation into citrate and malate increased 1.5–2.5-fold with unchanged IDH2 expression; whereas hypoxic 2HG formation did not. ¹³C–2HG originated by ∼50% from other than IDH2 or IDH1 reactions, substantiating remaining activity in IDH1&2-silenced cells. Relatively high basal ¹²C–2HG levels existed (5-fold higher vs. non-tumor HTB-125 cells) and ¹³C–2HG was formed despite the absence of any idh2 and idh1 mutations in HTB-126 cells. Since RCG is enhanced at hypoxia (frequent in solid tumors) and 2HG can be formed without idh1/2 mutations, we suggest 2HG as an analytic marker (in serum, urine, or biopsies) predicting malignancy of breast cancer in all patients.     

Public health risk analysis for ambient polycyclic aromatic hydrocarbon exposure surrounding a petrochemical complex in Curaçao

Abstract

Antiquated petroleum refining methods may exacerbate polycyclic aromatic hydrocarbons (PAHs) in ambient air. There is currently an aging, yet active refinery on the island of Curaçao that has been the subject of public health concern. The objective of this study was to determine if ambient PAHs surrounding this refinery exceeded public health guidelines and investigate potential public health risks by calculating risk probability estimates. A number of recommended guidelines for the protection of public health from ambient PAHs were exceeded in Curaçao. Cumulative lifetime risk estimates for carcinogenic effects exceeded the upper bound level of acceptable risk at sites located both upwind and downwind of the petrochemical complex in 2011 and decreased to within the range considered acceptable in 2014. Risk probability estimates were highest for children and either exceeded or were approaching the upper bound advisory levels in 2011. Results indicate inhalation risks are higher at sites located downwind from the petrochemical complex compared to those upwind. This emphasizes the potential for higher risk probability estimates for residents that may have higher susceptibility, warranting the need for further health assessments in these populations and underscores the importance for continued monitoring of PAH sources and levels in Curaçao.