Insights into Li and Li isotope cycling and sub-arc metasomatism from veined mantle xenoliths, Kamchatka

Harzburgitic xenoliths cut by pyroxenite veins from Avachinsky volcano, Kamchatka, are derived from the sub-arc mantle and record element transfer from the slab to the arc. Olivine and orthopyroxene in the harzburgites have Li isotopic compositions (δ7Li = +2.8 to +5.6) comparable to estimates of the upper mantle (δ7Li ~ +4 ± 2). The pyroxenite veins, which represent modal metasomatism and may therefore provide information about the metasomatic agent, have mantle-normalized trace element characteristics that suggest overprinting of their mantle source by an aqueous, slab-derived fluid. These include relative enrichments of Pb over Ce, U over Th and Sr over Nd. Li is enriched relative to the HREE, and ortho- and clinopyroxene from the veins are in Li elemental and isotopic equilibrium with each other and the surrounding harzburgite. Vein samples (δ7Li = +3.0 to +5.0) do not record a significant slab-derived δ7Li signature. These observations can be reconciled if slab Li diffusively re-equilibrates in the mantle wedge. Modeling demonstrates that Li equilibration of small (1–2 cm width) veins or melt conduits is achieved at mantle wedge temperatures within 101–105 years. We conclude that strongly fractionated Li isotopic signatures cannot be sustained for long periods in the sub-arc mantle, at least at shallow (<70 km) depths

Predicting survival from colorectal cancer histology slides using deep learning: A retrospective multicenter study

BACKGROUND: For virtually every patient with colorectal cancer (CRC), hematoxylin-eosin (HE)-stained tissue slides are available. These images contain quantitative information, which is not routinely used to objectively extract prognostic biomarkers. In the present study, we investigated whether deep convolutional neural networks (CNNs) can extract prognosticators directly from these widely available images. METHODS AND FINDINGS: We hand-delineated single-tissue regions in 86 CRC tissue slides, yielding more than 100,000 HE image patches, and used these to train a CNN by transfer learning, reaching a nine-class accuracy of >94% in an independent data set of 7,180 images from 25 CRC patients. With this tool, we performed automated tissue decomposition of representative multitissue HE images from 862 HE slides in 500 stage I-IV CRC patients in the The Cancer Genome Atlas (TCGA) cohort, a large international multicenter collection of CRC tissue. Based on the output neuron activations in the CNN, we calculated a "deep stroma score," which was an independent prognostic factor for overall survival (OS) in a multivariable Cox proportional hazard model (hazard ratio [HR] with 95% confidence interval [CI]: 1.99 [1.27-3.12], p = 0.0028), while in the same cohort, manual quantification of stromal areas and a gene expression signature of cancer-associated fibroblasts (CAFs) were only prognostic in specific tumor stages. We validated these findings in an independent cohort of 409 stage I-IV CRC patients from the "Darmkrebs: Chancen der Verhütung durch Screening" (DACHS) study who were recruited between 2003 and 2007 in multiple institutions in Germany. Again, the score was an independent prognostic factor for OS (HR 1.63 [1.14-2.33], p = 0.008), CRC-specific OS (HR 2.29 [1.5-3.48], p = 0.0004), and relapse-free survival (RFS; HR 1.92 [1.34-2.76], p = 0.0004). A prospective validation is required before this biomarker can be implemented in clinical workflows. CONCLUSIONS: In our retrospective study, we show that a CNN can assess the human tumor microenvironment and predict prognosis directly from histopathological images

Metabolomics of dates (Phoenix dactylifera) reveals a highly dynamic ripening process accounting for major variation in fruit composition

BACKGROUND: Dates are tropical fruits with appreciable nutritional value. Previous attempts at global metabolic characterization of the date metabolome were constrained by small sample size and limited geographical sampling. In this study, two independent large cohorts of mature dates exhibiting substantial diversity in origin, varieties and fruit processing conditions were measured by metabolomics techniques in order to identify major determinants of the fruit metabolome. RESULTS: Multivariate analysis revealed a first principal component (PC1) significantly associated with the dates’ countries of production. The availability of a smaller dataset featuring immature dates from different development stages served to build a model of the ripening process in dates, which helped reveal a strong ripening signature in PC1. Analysis revealed enrichment in the dry type of dates amongst fruits with early ripening profiles at one end of PC1 as oppose to an overrepresentation of the soft type of dates with late ripening profiles at the other end of PC1. Dry dates are typical to the North African region whilst soft dates are more popular in the Gulf region, which partly explains the observed association between PC1 and geography. Analysis of the loading values, expressing metabolite correlation levels with PC1, revealed enrichment patterns of a comprehensive range of metabolite classes along PC1. Three distinct metabolic phases corresponding to known stages of date ripening were observed: An early phase enriched in regulatory hormones, amines and polyamines, energy production, tannins, sucrose and anti-oxidant activity, a second phase with on-going phenylpropanoid secondary metabolism, gene expression and phospholipid metabolism and a late phase with marked sugar dehydration activity and degradation reactions leading to increased volatile synthesis. CONCLUSIONS: These data indicate the importance of date ripening as a main driver of variation in the date metabolome responsible for their diverse nutritional and economical values. The biochemistry of the ripening process in dates is consistent with other fruits but natural dryness may prevent degenerative senescence in dates following ripening. Based on the finding that mature dates present varying extents of ripening, our survey of the date metabolome essentially revealed snapshots of interchanging metabolic states during ripening empowering an in-depth characterization of underlying biology. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12870-015-0672-5) contains supplementary material, which is available to authorized users

Mechanical and corrosion properties of aluminium alloy EN AW 6082 after severe plastic deformation (SPD)

The aim had been to study changes in the properties of aluminium alloy AlSiMgMn. Influence of SPD of the mechanical properties had increased (Rm by 86 MPa, Ro0,2 by 175 MPa, while A had decreased to 20 %). The corrosion potentials had been evaluated in the environment of H2O and in SARS. After SPD was observed in the environment of H2O, that resistance had increased by -218 mV and after exposure up to 1 000 min there was a slight deterioration of resistance in SARS. On the surface specimens after SPD were observed higher quantities of corrosion products. After SPD was observed fatigue characteristics in torsional stress in the oblique branches Wohler curves showed favourable characteristics of about 35 %

Personalized Drug Dosage – Closing the Loop

A brief account is given of various approaches to the individualization of drug dosage, including the use of pharmacodynamic markers, therapeutic monitoring of plasma drug concentrations, genotyping, computer-guided dosage using ‘dashboards’, and automatic closed-loop control of pharmacological action. The potential for linking the real patient to his or her ‘virtual twin’ through the application of physiologically-based pharmacokinetic modeling is also discussed

Electrochemical Estimations of the Gold Nanoparticle Size Effect on Cysteine-Gold Oxidation,

Gold nanoparticles are interesting for nanobiomedical applications, such as for drug delivery and as diagnostic imaging contrast agents. However, their stability and reactivity in-vivo are influenced by their surface properties and size. Here, we investigate the electrochemical oxidation of differently sized citrate-coated gold nanoparticles in the presence and absence of L-cysteine, a thiol-containing amino acid with high binding affinity to gold. We found that smaller sized (5, 10 nm) gold nanoparticles were significantly more susceptible to electrochemical L-cysteine interactions and/or L-cysteine-facilitated gold oxidation than larger (20, 50 nm) sized gold nanoparticles, both for the same mass and nominal surface area, under the conditions investigated (pH 7.4, room temperature, stagnant solutions, and scan rates of 0.5 to 450 mV s−1). The electrochemical measurements of drop-casted gold nanoparticle suspensions on paraffin-impregnated graphite electrodes were susceptible to the quality of the electrode. Increased cycling resulted in irreversible oxidation and detachment/oxidation of gold into solution. Our results suggest that L-cysteine-gold interactions are stronger for smaller nanoparticles

Hf–Zr anomalies in clinopyroxene from mantle xenoliths from France and Poland: implications for Lu–Hf dating of spinel peridotite lithospheric mantle

Clinopyroxenes in some fresh anhydrous spinel peridotite mantle xenoliths from the northern Massif Central (France) and Lower Silesia (Poland), analysed for a range of incompatible trace elements by laser ablation inductively coupled plasma mass spectrometry, show unusually strong negative anomalies in Hf and Zr relative to adjacent elements Sm and Nd, on primitive mantle-normalised diagrams. Similar Zr–Hf anomalies have only rarely been reported from clinopyroxene in spinel peridotite mantle xenoliths worldwide, and most are not as strong as the examples reported here. Low Hf contents give rise to a wide range of Lu/Hf ratios, which over geological time would result in highly radiogenic εHf values, decoupling them from εNd ratios. The high 176Lu/177Hf could in theory produce an isochronous relationship with 176Hf/177Hf over time; an errorchron is shown by clinopyroxene from mantle xenoliths from the northern Massif Central. However, in a review of the literature, we show that most mantle spinel peridotites do not show such high Lu/Hf ratios in their constituent clinopyroxenes, because they lack the distinctive Zr–Hf anomaly, and this limits the usefulness of the application of the Lu–Hf system of dating to garnet-free mantle rocks. Nevertheless, some mantle xenoliths from Poland or the Czech Republic may be amenable to Hf-isotope dating in the future

Th Inducing POZ-Kruppel Factor (ThPOK) Is a Key Regulator of the Immune Response since the Early Steps of Colorectal Carcinogenesis

We purposed to evaluate the role of Th inducing POZ-Kruppel Factor (ThPOK), a transcriptional regulator of T cell fate, in tumour-induced immune system plasticity in colorectal carcinogenesis. The amounts of CD4+, CD8+ and CD56+ and ThPOK+ cells infiltrate in normal colorectal mucosa (NM), in dysplastic aberrant crypt foci (microadenomas, MA), the earliest detectable lesions in colorectal carcinogenesis, and in colorectal carcinomas (CRC), were measured, and the colocalization of ThPOK with the above-mentioned markers of immune cells was evaluated using confocal microscopy. Interestingly, ThPOK showed a prominent increase since MA. A strong colocalization of ThPOK with CD4 both in NM and in MA was observed, weaker in carcinomas. Surprisingly, there was a peak in the colocalization levels of ThPOK with CD8 in MA, which was evident, although to a lesser extent, in carcinomas, too. In conclusion, according to the data of the present study, ThPOK may be considered a central regulator of the earliest events in the immune system during colorectal cancer development, decreasing the immune response against cancer cells

Familial clustering of Leiomyomatosis peritonealis disseminata: an unknown genetic syndrome?

BACKGROUND: Leiomyomatosis peritonealis disseminata (LPD) is defined as the occurrence of multiple tumorous intraabdominal lesions, which are myomatous nodules. LPD is a rare disease with only about 100 cases reported. The usual course of LPD is benign with the majority of the patients being premenopausal females. Only two cases involving men have been reported, no syndrome or familial occurrence of LPD has been described. CASE PRESENTATION: We describe a Caucasian-American family in which six members (three men) are diagnosed with Leiomyomatosis peritonealis disseminata (LPD) and three deceased family members most likely had LPD (based on the autopsy reports). Furthermore we describe the association of LPD with Raynaud's syndrome and Prurigo nodularis. CONCLUSION: Familial clustering of Leiomyomatosis peritonealis disseminata (LPD) has not been reported so far. The etiology of LPD is unknown and no mode of inheritance is known. We discuss possible modes of inheritance in the presented case, taking into account the possibility of a genetic syndrome. Given the similarity to other genetic syndromes with leiomyomatosis and skin alterations, we describe possible similar genetic pathomechanisms