Altered extracellular vesicle microrna expression in ischemic stroke and small vessel disease

Active transport of microRNAs (miRNA) in extracellular vesicles (EV) occurs in disease. Circulating EV-packaged miRNAs in the serum of stroke patients were compared to stroke mimics with matched cardio- and cerebrovascular risk factors, with corroboration of results in a pre-clinical model. An unbiased miRNA microarray was performed in stroke vs stroke mimic patients (n=39). Results were validated (n=173 patients) by real-time quantitative polymerase chain reaction. miRNA expression was quantified in total serum/EV (n=5-7) of naïve adult spontaneously hypertensive stroke-prone rats (SHRSP), their normotensive reference strain (Wistar Kyoto, WKY) and in circulating EV (n=3), peri-infarct brain (n=6) or EV derived from this region (n=3) in SHRSP following transient middle cerebral artery occlusion (tMCAO). Circulating EV concentration did not differ between stroke and stroke mimic patients. The microarray identified many altered EV-packaged miRNAs: levels of miRNA-17-5p, -20b-5p and -93-5p (miRNA-17 family members) and miRNA-27b-3p were significantly (p≤0.05) increased in stroke vs stroke mimic patients. Patients with small vessel disease (SVD) consistently had the highest miRNA levels. Circulating EV concentration was unaltered between naïve SHRSP and WKY but levels of miRNA-17-5p and -93-5p were significantly increased in SHRSP. tMCAO in SHRSP did not further alter circulating EV miRNA-17 family member expression and nor did it change total miRNA-17 family levels in peri-infarct brain tissue or in EV isolated from this region at 24hrs post-tMCAO. Changes in EV packaged miRNA expression was validated in patients with stroke, particularly those with SVD, and corroborated pre-clinically. Together, altered circulating EV levels of miRNA-17 family members may reflect the chronic sequelae underlying cerebrovascular SVD rather than the acute ischemic stroke itself

Trace element systematics and ore-forming processes in mafic VMS deposits: Evidence from the Troodos ophiolite, Cyprus

The volcanogenic massive sulfide (VMS) deposits in the Troodos ophiolite (Cyprus) are ancient analogues for modern day seafloor massive sulfide mineralisation formed in a supra-subduction zone environment. In this study we present the first detailed in situ study of trace elements in sulfides from twenty VMS deposits hosted in the Troodos ophiolite to better understand factors that influence the distribution, enrichment and incorporation of trace elements in different sulfide minerals. On a mineral scale, trace elements exhibit systematic variations between pyrite, chalcopyrite and sphalerite. Pyrite preferentially incorporates As, Sb, Au and Te, whilst chalcopyrite is enriched in Co and Se. Sphalerite is trace element poor with the exception of Ag and Cd. Selenium averages 278 ppm (n = 150) in chalcopyrite but only 42 ppm (n = 1322) in pyrite. Bismuth and Te in pyrite show a weak positive correlation (R2 = 0.35) in some VMS deposits possibly linked with the occurrence of Bi-telluride inclusions. Trace element concentrations also vary between colloform and euhedral pyrite, with an enrichment of Au, As, Sb, Cu and Zn in colloform compared to euhedral pyrite. Time resolved laser ablation profiles reveal that the trace element distribution on a mineral scale is not uniform and varies with crystallographic effects, fluctuating physicochemical fluid conditions such as temperature, pH, fS2, fO2 and ligand availability during sulfide precipitation. Incorporation mechanisms in sulfides differ between elements in pyrite, Ag, As, Se and Pb are hosted in solid solution or as nanoscale inclusions, whilst Au, Sb and Te may form micro-scale inclusions. On a regional scale (20 km) the distribution of trace elements exhibits systematic variations between three major structural domains; namely the Solea, Mitsero and Larnaca grabens. The VMS deposits of the magmatic-tectonic Solea graben are enriched in Se, Co, Te, Au and Cu relative to Mitsero, which is a purely extensional feature. Therefore, we hypothesise that a variable magmatic volatile influx related to a) ‘magma’ volume, b) migration of the magmatic-hydrothermal crack front and associated brine liberation or c) a variation in protolith metal concentration are responsible for regional scale variations in VMS geochemistry. This is suggested to be intrinsically linked to the spreading architecture of Troodos

Mineral-scale variation in the trace metal and sulfur isotope composition of pyrite: implications for metal and sulfur sources in mafic VMS deposits

The link between metal enrichment and the addition of a magmatic volatile phase in volcanogenic massive sulfide deposits and actively forming seafloor massive sulfide deposits remains poorly characterized. This is especially true when considering how metal, sulfur and fluid flux change with time. In this study, we combine in situ sulfur isotope (δ34S; n = 31) measurements with trace metal chemistry of pyrite (n = 143) from the Mala VMS deposit, Troodos, Cyprus. The aim of our study is to assess the links between volatile influx and metal enrichment and establish how, or indeed if, this is preserved at the scale of individual mineral grains. We classify pyrite based on texture into colloform, granular, disseminated and massive varieties. The trace metal content of different pyrite textures is highly variable and relates to fluid temperature and secondary reworking that are influenced by the location of the sample within the mound. The sulfur isotope composition of pyrite at Mala ranges from − 17.1 to 7.5‰ (n = 31), with a range of − 10.9 to 2.5‰ within a single pyrite crystal. This variation is attributed to changes in the relative proportion of sulfur sourced from (i) SO2 disproportionation, (ii) thermochemical sulfate reduction, (iii) the leaching of igneous sulfur/sulfide and (iv) bacterial sulfate reduction. Our data shows that there is no correlation between δ34S values and the concentration of volatile elements (Te, Se) and Au in pyrite at Mala indicating that remobilization of trace metals occurred within the mound

Effects of magmatic volatile influx in mafic VMS hydrothermal systems: Evidence from the Troodos ophiolite, Cyprus

The Troodos ophiolite, Cyprus is the principal on- land analogue for mafic-hosted volcanogenic massive sulfide (VMS) deposits. This study, for the first time, presents sulfur isotope (δ34S) data on a regional scale from VMS deposits and other mineralised zones across the Troodos ophiolite. In combination δ34S, Se/S ratios and trace element chemistry (e.g., Se, Cu and Au) of different hydrothermal sulfides are used to assess variations in magmatic volatile influx and the source of metals and sulfur in ancient hydrothermal systems. Sulfur isotope analyses (n = 180) across 19 mineral deposits indicate a variable source of sulfur in the Troodos VMS hydrothermal system, this in turn allows a variable source of metals to be inferred. Pyrite δ34S range from −5.5‰ to +13.2‰ with an average of +4.6‰ (n = 160) for all deposits investigated. These δ34S variations cannot only be explained by variable proportions of thermochemical seawater sulfate reduction (δ34S +18 to +19‰) and leaching of primary magmatic sulfur from igneous rocks (δ34S 0-1‰). Consequently, two processes are proposed, explaining the trace metal and δ34S variation across the Troodos ore-forming systems including, i) a variable source of metals in the sheeted dyke complex and ii) the addition of a magmatic volatile-rich phase to the VMS hydrothermal systems. Two distinct lava units exist in the Troodos stratigraphy, namely the upper and lower pillow lavas (UPL and LPL). The more primitive UPL are enriched in Au, Se and Cu relative to As, Sb and Zn that are concentrated in the LPL. Some VMS deposits pre-date the formation of the UPL (e.g., Agrokipia A) suggesting Se, Cu and Au depleted source rocks. Hence, the stratigraphic position of VMS deposits and the ratio of UPL:LPL affinity elements (e.g., As + Zn + Sb vs. Cu + Se + Au) imply a systematic relationship between trace element distribution and stratigraphic depth; this relates to the relative proportion of UPL and LPL affinity lavas within the metal source region. δ34S values <0‰ recorded in some VMS deposits that are less than the Troodos magmatic mean of 0- 1‰ may be related to anhydrite buffering during fluid ascent, microbial sulfate reduction or the direct contribution of magmatically derived sulfur, to the hydrothermal system from an underlying magma chamber via volatile exsolution. We propose that negative δ34S values combined with Se/S 106 ratios >500 in pyrite suggest the contribution of a magmatic volatile component (e.g., Apliki and Skouriotissa). We demonstrate that the source of metals and sulfur in the Troodos VMS hydrothermal system is affected by regional scale processes related to i) variable source lithologies and, ii) the contribution of a magmatic volatile phase to some Troodos VMS hydrothermal systems

Defining the Functional Domain of Programmed Cell Death 10 through Its Interactions with Phosphatidylinositol-3,4,5-Trisphosphate

Cerebral cavernous malformations (CCM) are vascular abnormalities of the central nervous system predisposing blood vessels to leakage, leading to hemorrhagic stroke. Three genes, Krit1 (CCM1), OSM (CCM2), and PDCD10 (CCM3) are involved in CCM development. PDCD10 binds specifically to PtdIns(3,4,5)P3 and OSM. Using threading analysis and multi-template modeling, we constructed a three-dimensional model of PDCD10. PDCD10 appears to be a six-helical-bundle protein formed by two heptad-repeat-hairpin structures (α1–3 and α4–6) sharing the closest 3D homology with the bacterial phosphate transporter, PhoU. We identified a stretch of five lysines forming an amphipathic helix, a potential PtdIns(3,4,5)P3 binding site, in the α5 helix. We generated a recombinant wild-type (WT) and three PDCD10 mutants that have two (Δ2KA), three (Δ3KA), and five (Δ5KA) K to A mutations. Δ2KA and Δ3KA mutants hypothetically lack binding residues to PtdIns(3,4,5)P3 at the beginning and the end of predicted helix, while Δ5KA completely lacks all predicted binding residues. The WT, Δ2KA, and Δ3KA mutants maintain their binding to PtdIns(3,4,5)P3. Only the Δ5KA abolishes binding to PtdIns(3,4,5)P3. Both Δ5KA and WT show similar secondary and tertiary structures; however, Δ5KA does not bind to OSM. When WT and Δ5KA are co-expressed with membrane-bound constitutively-active PI3 kinase (p110-CAAX), the majority of the WT is co-localized with p110-CAAX at the plasma membrane where PtdIns(3,4,5)P3 is presumably abundant. In contrast, the Δ5KA remains in the cytoplasm and is not present in the plasma membrane. Combining computational modeling and biological data, we propose that the CCM protein complex functions in the PI3K signaling pathway through the interaction between PDCD10 and PtdIns(3,4,5)P3

HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse

The psychological science accelerator’s COVID-19 rapid-response dataset

In response to the COVID-19 pandemic, the Psychological Science Accelerator coordinated three large-scale psychological studies to examine the effects of loss-gain framing, cognitive reappraisals, and autonomy framing manipulations on behavioral intentions and affective measures. The data collected (April to October 2020) included specific measures for each experimental study, a general questionnaire examining health prevention behaviors and COVID-19 experience, geographical and cultural context characterization, and demographic information for each participant. Each participant started the study with the same general questions and then was randomized to complete either one longer experiment or two shorter experiments. Data were provided by 73,223 participants with varying completion rates. Participants completed the survey from 111 geopolitical regions in 44 unique languages/dialects. The anonymized dataset described here is provided in both raw and processed formats to facilitate re-use and further analyses. The dataset offers secondary analytic opportunities to explore coping, framing, and self-determination across a diverse, global sample obtained at the onset of the COVID-19 pandemic, which can be merged with other time-sampled or geographic data

Registered replication report: a large multilab cross-cultural conceptual replication of Turri, Buckwalter, & Blouw (2015)

According to the Justified True Belief account of knowledge (JTB), a person can only truly know something if they have a belief that is both justified and true (i.e., knowledge is justified true belief). This account was challenged by Gettier (1963), who argued that JTB does not explain knowledge attributions in certain situations, later called Gettier-type cases, wherein a protagonist is justified in believing something to be true, but their belief was only correct due to luck. Lay people may not attribute knowledge to protagonists with justified but only luckily true beliefs. While some research has found evidence for these so-called Gettier intuitions (e.g., Machery et al., 2017a), Turri et al. (2015) found no evidence that participants attributed knowledge in a counterfeit-object Gettier-type case differently than in a matched case of justified true belief. In a large-scale, cross-cultural conceptual replication of Turri and colleagues’ (2015) Experiment 1 (N = 4,724) using a within-participants design and three vignettes across 19 geopolitical regions, we did find evidence for Gettier intuitions; participants were 1.86 times more likely to attribute knowledge to protagonists in standard cases of justified true belief than to protagonists in Gettier-type cases. These results suggest that Gettier intuitions may be detectable across different scenarios and cultural contexts. However, the size of the Gettier intuition effect did vary by vignette, and the Turri et al. (2015) vignette produced the smallest effect, which was similar in size to that observed in the original study. Differences across vignettes suggest epistemic intuitions may also depend on contextual factors unrelated to the criteria of knowledge, such as the characteristics of the protagonist being evaluated

The Psychological Science Accelerator’s COVID-19 rapid-response dataset

In response to the COVID-19 pandemic, the Psychological Science Accelerator coordinated three large-scale psychological studies to examine the effects of loss-gain framing, cognitive reappraisals, and autonomy framing manipulations on behavioral intentions and affective measures. The data collected (April to October 2020) included specific measures for each experimental study, a general questionnaire examining health prevention behaviors and COVID-19 experience, geographical and cultural context characterization, and demographic information for each participant. Each participant started the study with the same general questions and then was randomized to complete either one longer experiment or two shorter experiments. Data were provided by 73,223 participants with varying completion rates. Participants completed the survey from 111 geopolitical regions in 44 unique languages/dialects. The anonymized dataset described here is provided in both raw and processed formats to facilitate re-use and further analyses. The dataset offers secondary analytic opportunities to explore coping, framing, and self-determination across a diverse, global sample obtained at the onset of the COVID-19 pandemic, which can be merged with other time-sampled or geographic data