Crustal rejuvenation stabilised Earth’s first cratons

This work was funded by Australian Research Council grant FL160100168 and Australian Research Council grant DP180100580.The formation of stable, evolved (silica-rich) crust was essential in constructing Earth’s first cratons, the ancient nuclei of continents. Eoarchaean (4000–3600 million years ago, Ma) evolved crust occurs on most continents, yet evidence for older, Hadean evolved crust is mostly limited to rare Hadean zircons recycled into younger rocks. Resolving why the preserved volume of evolved crust increased in the Eoarchaean is key to understanding how the first cratons stabilised. Here we report new zircon uranium-lead and hafnium isotope data from the Yilgarn Craton, Australia, which provides an extensive record of Hadean–Eoarchaean evolved magmatism. These data reveal that the first stable, evolved rocks in the Yilgarn Craton formed during an influx of juvenile (recently extracted from the mantle) magmatic source material into the craton. The concurrent shift to juvenile sources and onset of crustal preservation links craton stabilisation to the accumulation of enduring rafts of buoyant, melt-depleted mantle.Publisher PDFPeer reviewe

Relationship Between Optimal Gain and Coherence Zone in Flight Simulation

In motion simulation the inertial information generated by the motion platform is most of the times different from the visual information in the simulator displays. This occurs due to the physical limits of the motion platform. However, for small motions that are within the physical limits of the motion platform, one-to-one motion, i.e. visual information equal to inertial information, is possible. It has been shown in previous studies that one-to-one motion is often judged as too strong, causing researchers to lower the inertial amplitude. When trying to measure the optimal inertial gain for a visual amplitude, we found a zone of optimal gains instead of a single value. Such result seems related with the coherence zones that have been measured in flight simulation studies. However, the optimal gain results were never directly related with the coherence zones. In this study we investigated whether the optimal gain measurements are the same as the coherence zone measurements. We also try to infer if the results obtained from the two measurements can be used to differentiate between simulators with different configurations. An experiment was conducted at the NASA Langley Research Center which used both the Cockpit Motion Facility and the Visual Motion Simulator. The results show that the inertial gains obtained with the optimal gain are different than the ones obtained with the coherence zone measurements. The optimal gain is within the coherence zone.The point of mean optimal gain was lower and further away from the one-to-one line than the point of mean coherence. The zone width obtained for the coherence zone measurements was dependent on the visual amplitude and frequency. For the optimal gain, the zone width remained constant when the visual amplitude and frequency were varied. We found no effect of the simulator configuration in both the coherence zone and optimal gain measurements

Erythrocytosis in the general population:clinical characteristics and association with clonal hematopoiesis

Erythrocytosis is a common reason for referral to hematology services and is usually secondary in origin. The aim of this study was to assess clinical characteristics and clonal hematopoiesis (CH) in individuals with erythrocytosis in the population-based Lifelines cohort (n 5 147 167). Erythrocytosis was defined using strict (World Health Organization [WHO] 2008/British Committee for Standards in Hematology) and wide (WHO 2016) criteria. Individuals with erythrocytosis (strict criteria) and concurrent leukocytosis and/or thrombocytosis were 1:2 matched with individuals with isolated erythrocytosis and analyzed for somatic mutations indicative of CH ($5% variant allele frequency). One hundred eighty five males (0.3%) and 223 females (0.3%) met the strict criteria, whereas 4868 males (7.6%) and 309 females (0.4%) met the wide criteria. Erythrocytosis, only when defined using strict criteria, was associated with cardiovascular morbidity (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2-2.6), cardiovascular mortality (hazard ratio [HR], 2.2; 95% CI, 1.0-4.6), and all-cause mortality (HR, 1.7; 95% CI, 1.2-2.6), independent of conventional risk factors. Mutations were detected in 51 of 133 (38%) evaluable individuals, with comparable frequencies between individuals with and without concurrent cytosis. The JAK2 V617F mutation was observed in 7 of 133 (5.3%) individuals, all having concurrent cytosis. The prevalence of mutations in BCOR/BCORL1 (16%) was high, suggesting aberrant epigenetic regulation. Erythrocytosis with CH was associated with cardiovascular morbidity (OR, 9.1; 95% CI, 1.2-68.4) in a multivariable model. Our data indicate that only when defined using strict criteria erythrocytosis is associated with cardiovascular morbidity (especially in the presence of CH), cardiovascular mortality, and all-cause mortality

Clonal hematopoiesis in patients with stem cell mobilization failure:a nested case-control study

Inadequate mobilization of peripheral blood progenitor cells (PBPCs) is a limiting factor to proceeding with autologous hematopoietic cell transplantation (auto-HCT). To assess the impact of clonal hematopoiesis (CH) on mobilization failure of PBPC for auto-HCT, we investigated the characteristics of poor mobilizers (with a total PBPC collection &lt;2 × 106 CD34+ cells per kg) in a consecutive single-center cohort of 776 patients. Targeted error-corrected next-generation sequencing of 28 genes was performed in a nested case-control cohort of 90 poor mobilizers and 89 matched controls. CH was detected in 48 out of 179 patients (27%), with most patients carrying a single mutation. The presence of CH (detected at variant allele frequency [VAF] ≥ 1%) did not associate with poor mobilization potential (31% vs 22% in controls, odds ratio, 1.55; 95% confidence interval, 0.76-3.23; P = .238). PPM1D mutations were detected more often in poor mobilizers (P = .005). In addition, TP53 mutations in this cohort were detected exclusively in patients with poor mobilization potential (P = .06). The incidence of therapy-related myeloid neoplasms (t-MN) was higher among patients with mobilization failure (P = .014). Although poor mobilizers experienced worse overall survival (P = .019), this was not affected by the presence of CH. We conclude that CH at low VAF (1%-10%) is common at the time of stem cell mobilization. TP53 mutations and PPM1D mutations are associated with poor mobilization potential and their role in subsequent development of t-MN in these individuals should be established.</p

Evaluating the Shinumo-Sespe drainage connection: Arguments against the “old” (70–17 Ma) Grand Canyon models for Colorado Plateau drainage evolution

The provocative hypothesis that the Shinumo Sandstone in the depths of Grand Canyon was the source for clasts of orthoquartzite in conglomerate of the Sespe Formation of coastal California, if verified, would indicate that a major river system flowed southwest from the Colorado Plateau to the Pacific Ocean prior to opening of the Gulf of California, and would imply that Grand Canyon had been carved to within a few hundred meters of its modern depth at the time of this drainage connection. The proposed Eocene Shinumo-Sespe connection, however, is not supported by detrital zircon nor paleomagnetic-inclination data and is refuted by thermochronology that shows that the Shinumo Sandstone of eastern Grand Canyon was \u3e60 °C (∼1.8 km deep) and hence not incised at this time. A proposed 20 Ma (Miocene) Shinumo-Sespe drainage connection based on clasts in the Sespe Formation is also refuted. We point out numerous caveats and non-unique interpretations of paleomagnetic data from clasts. Further, our detrital zircon analysis requires diverse sources for Sespe clasts, with better statistical matches for the four “most-Shinumo-like” Sespe clasts with quartzites of the Big Bear Group and Ontario Ridge metasedimentary succession of the Transverse Ranges, Horse Thief Springs Formation from Death Valley, and Troy Quartzite of central Arizona. Diverse thermochronologic and geologic data also refute a Miocene river pathway through western Grand Canyon and Grand Wash trough. Thus, Sespe clasts do not require a drainage connection from Grand Canyon or the Colorado Plateau and provide no constraints for the history of carving of Grand Canyon. Instead, abundant evidence refutes the “old” (70–17 Ma) Grand Canyon models and supports a \u3c6 Ma Grand Canyon

HIF1/2-exerted control over glycolytic gene expression is not functionally relevant for glycolysis in human leukemic stem/progenitor cells

Background Hypoxia-inducible factors (HIF)1 and 2 are transcription factors that regulate the homeostatic response to low oxygen conditions. Since data related to the importance of HIF1 and 2 in hematopoietic stem and progenitors is conflicting, we investigated the chromatin binding profiles of HIF1 and HIF2 and linked that to transcriptional networks and the cellular metabolic state. Methods Genome-wide ChIPseq and ChIP-PCR experiments were performed to identify HIF1 and HIF2 binding sites in human acute myeloid leukemia (AML) cells and healthy CD34(+) hematopoietic stem/progenitor cells. Transcriptome studies were performed to identify gene expression changes induced by hypoxia or by overexpression of oxygen-insensitive HIF1 and HIF2 mutants. Metabolism studies were performed by 1D-NMR, and glucose consumption and lactate production levels were determined by spectrophotometric enzyme assays. CRISPR-CAS9-mediated HIF1, HIF2, and ARNT(-/-) lines were generated to study the functional consequences upon loss of HIF signaling, in vitro and in vivo upon transplantation of knockout lines in xenograft mice. Results Genome-wide ChIP-seq and transcriptome studies revealed that overlapping HIF1- and HIF2-controlled loci were highly enriched for various processes including metabolism, particularly glucose metabolism, but also for chromatin organization, cellular response to stress and G protein-coupled receptor signaling. ChIP-qPCR validation studies confirmed that glycolysis-related genes but not genes related to the TCA cycle or glutaminolysis were controlled by both HIF1 and HIF2 in leukemic cell lines and primary AMLs, while in healthy human CD34(+) cells these loci were predominantly controlled by HIF1 and not HIF2. However, and in contrast to our initial hypotheses, CRISPR/Cas9-mediated knockout of HIF signaling did not affect growth, internal metabolite concentrations, glucose consumption or lactate production under hypoxia, not even in vivo upon transplantation of knockout cells into xenograft mice. Conclusion These data indicate that, while HIFs exert control over glycolysis but not OxPHOS gene expression in human leukemic cells, this is not critically important for their metabolic state. In contrast, inhibition of BCR-ABL did impact on glucose consumption and lactate production regardless of the presence of HIFs. These data indicate that oncogene-mediated control over glycolysis can occur independently of hypoxic signaling modules.</p

Pretransplantation MRD in Older Patients With AML After Treatment With Decitabine or Conventional Chemotherapy

The predictive value of measurable residual disease (MRD) for survival in acute myeloid leukemia (AML) has been firmly established in younger patients treated with intensive chemotherapy. The value of MRD after treatment with decitabine in older patients is unknown. This retrospective analysis included patients ≥60 years of age with AML who received an allogeneic hematopoietic cell transplantation (alloHCT) after treatment with decitabine or intensive chemotherapy. Of the 133 consecutively transplanted patients, 109 had available pretransplantation MRD analyses (by flowcytometry [threshold 0.1%]). Forty patients received decitabine treatment (10-day schedule), and 69 patients received intensive chemotherapy (7 + 3 regimen). Patients who received decitabine were older (median 67 versus 64 years) and more often had MRD (70% versus 38%). OS after alloHCT was comparable in both groups. In the chemotherapy group, MRD-positive patients had a significantly higher relapse probability (subdistribution hazard ratio [sHR] 4.81; P= .0031) and risk of death (HR 2.8; P= .02) compared to MRD-negative patients. In the decitabine group there was no significant association between the presence of MRD and relapse (sHR 0.85; P= .83) or death (HR 0.72; P= .60). Pretransplantation MRD in patients receiving decitabine treatment does not have similar predictive value for relapse or survival in older AML patients receiving an alloHCT, compared to patients receiving intensive chemotherapy

Structure of the Afferent Terminals in Terminal Ganglion of a Cricket and Persistent Homology

We use topological data analysis to investigate the three dimensional spatial structure of the locus of afferent neuron terminals in crickets Acheta domesticus. Each afferent neuron innervates a filiform hair positioned on a cercus: a protruding appendage at the rear of the animal. The hairs transduce air motion to the neuron signal that is used by a cricket to respond to the environment. We stratify the hairs (and the corresponding afferent terminals) into classes depending on hair length, along with position. Our analysis uncovers significant structure in the relative position of these terminal classes and suggests the functional relevance of this structure. Our method is very robust to the presence of significant experimental and developmental noise. It can be used to analyze a wide range of other point cloud data sets

WeaselBoard : zero-day exploit detection for programmable logic controllers.

Critical infrastructures, such as electrical power plants and oil refineries, rely on programmable logic controllers (PLCs) to control essential processes. State of the art security cannot detect attacks on PLCs at the hardware or firmware level. This renders critical infrastructure control systems vulnerable to costly and dangerous attacks. WeaselBoard is a PLC backplane analysis system that connects directly to the PLC backplane to capture backplane communications between modules. WeaselBoard forwards inter-module traffic to an external analysis system that detects changes to process control settings, sensor values, module configuration information, firmware updates, and process control program (logic) updates. WeaselBoard provides zero-day exploit detection for PLCs by detecting changes in the PLC and the process. This approach to PLC monitoring is protected under U.S. Patent Application 13/947,887

Solid phase extraction for removal of matrix effects in lipophilic marine toxin analysis by liquid chromatography-tandem mass spectrometry

The potential of solid phase extraction (SPE) clean-up has been assessed to reduce matrix effects (signal suppression or enhancement) in the liquid chromatography-tandem mass spectrometry (LC¿MS/MS) analysis of lipophilic marine toxins. A large array of ion-exchange, silica-based, and mixed-function SPE sorbents was tested. Polymeric sorbents were found to retain most of the toxins. Optimization experiments were carried out to maximize recoveries and the effectiveness of the clean-up. In LC¿MS/MS analysis, the observed matrix effects can depend on the chromatographic conditions used, therefore, two different HPLC methods were tested, using either an acidic or an alkaline mobile phase. The recovery of the optimized SPE protocol was around 90% for all toxins studied and no break-through was observed. The matrix effects were determined by comparing signal response from toxins spiked in crude and SPE-cleaned extracts with those derived from toxins prepared in methanol. In crude extracts, all toxins suffered from matrix effects, although in varying amounts. The most serious effects were observed for okadaic acid (OA) and pectenotoxin-2 (PTX2) in the positive electrospray ionization mode (ESI+). SPE clean-up on polymeric sorbents in combination with the alkaline LC method resulted in a substantial reduction of matrix effects to less than 15% (apparent recovery between 85 and 115%) for OA, yessotoxin (YTX) in ESI¿ and azaspiracid-1 (AZA1), PTX2, 13-desmethyl spirolides C (SPX1), and gymnodimine (GYM) in ESI+. In combination with the acidic LC method, the matrix effects after SPE were also reduced but nevertheless approximately 30% of the matrix effects remained for PTX2, SPX1, and GYM in ESI+. It was concluded that SPE of methanolic shellfish extracts can be very useful for reduction of matrix effects. However, the type of LC and MS methods used is also of great importance. SPE on polymeric sorbents in combination with LC under alkaline conditions was found the most effective method