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Abstract Background Mechanisms of development and progression of high-grade serous ovarian cancer (HGSOC) are poorly understood. EVI1 and PARP1, part of TGF-ß pathway, are upregulated in cancers with DNA repair deficiencies with DNA repair deficiencies and may influce disease progression and survival. Therefore we questioned the prognostic significance of protein expression of EVI1 alone and in combination with PARP1 and analyzed them in a cohort of patients with HGSOC. Methods For 562 HGSOC patients, we evaluated EVI1 and PARP1 expression by immunohistochemical staining on tissue microarrays with QuPath digital semi-automatic positive cell detection. Results High EVI1 expressing (> 30% positive tumor cells) HGSOC were associated with improved progression-free survival (PFS) (HR = 0.66, 95% CI: 0.504–0.852, p = 0.002) and overall survival (OS) (HR = 0.45, 95% CI: 0.352–0.563, p

Background: The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays a crucial role in regulating the immune system's response to tumors, but its exact role in cancer, especially in high-grade serous ovarian cancer (HGSOC), remains controversial. We aimed to investigate the prognostic impact of IDO1 expression and its correlation with tumor-infiltrating lymphocytes (TILs) in HGSOC. Methods: Immunohistochemical (IHC) staining and bioimage analysis using the QuPath software were employed to assess IDO1 protein expression in a well-characterized cohort of 507 patients with primary HGSOC. Statistical evaluation was performed using SPSS, and in silico validation considering IDO1 mRNA expression in bulk and single-cell gene expression datasets was conducted. Additionally, IDO1 expression in interferon-gamma (IFNG) stimulated HGSOC cell lines was analyzed. Results: Our findings revealed that IDO1 protein and mRNA expression serve as positive prognostic markers for overall survival (OS) and progression-free survival (PFS) in HGSOC. High IDO1 expression was associated with a significant improvement in OS by 21 months (p

The Mozambique Basin, which occurs onshore and offshore in the central and southern parts of Mozambique, contains a thick sequence of volcanic and sedimentary rocks that range in age from the Jurassic to Cenozoic. This basin, along with the Rovuma basin to the north, has been the main target for hydrocarbon exploration; however, published data on hydrocarbon occurrences do not exist. In this context, the present study aims to contribute to the understanding of the nature of the organic matter of a sedimentary sequence intercepted by the Nemo-1X exploration well located in the offshore area of the Mozambique Basin. The well reached a depth of 4127 m, and 33 samples were collected from a depth of 2219–3676 m ranging in age from early to Late Cretaceous. In this study, petrographic and geochemical analytical methods were applied to assess the level of vitrinite reflectance and the organic matter type as well as the total organic carbon, total sulfur, and CaCO 3 contents. The results show that the total organic carbon content ranges from 0.41 to 1.34 wt%, with the highest values determined in the samples from the Lower Domo Shale and Sena Formations, which may be related to the presence of the solid bitumens that occur in the carbonate fraction of those samples. The vitrinite random reflectances range from 0.65 to 0.86%Rrandom, suggesting that the organic matter in all of the samples is in the peak phase of the “oil generation window” (0.65–0.9%Rrandom). The organic matter is mainly composed of vitrinite and inertinite macerals, with a minor contribution of sporinite from the liptinite group, which is typical of kerogen type III. Although all of the samples have vitrinite reflectances corresponding to the oil window, the formation of liquid hydrocarbons is rather limited because the organic matter is dominated by gas-prone kerogen type III.

Sinorhizobium meliloti, the nitrogen-fixing bacterial symbiont of Medicago spp. and other legumes, secretes a considerable amount of riboflavin. This precursor of the cofactors flavin mononucleotide and flavin adenine dinucleotide is a bioactive molecule that has a beneficial effect on plant growth. The ribBA gene of S. meliloti codes for a putative bifunctional enzyme with dihydroxybutanone phosphate synthase and guanosine triphosphate (GTP) cyclohydrolase II activities, catalyzing the initial steps of the riboflavin biosynthesis pathway. We show here that an in-frame deletion of ribBA does not cause riboflavin auxotrophy or affect the ability of S. meliloti to establish an effective symbiosis with the host plant but does affect the ability of the bacteria to secrete flavins, colonize host-plant roots, and compete for nodulation. A strain missing the RibBA protein retains considerable GTP cyclohydrolase II activity. Based on these results, we hypothesize that S. meliloti has two partly interchangeable modules for biosynthesis of riboflavin, one fulfilling the internal need for flavins in bacterial metabolism and the other producing riboflavin for secretion. Our data also indicate that bacteria-derived flavins play a role in communication between rhizobia and the legume host and that the RibBA protein is important in this communication process even though it is not essential for riboflavin biosynthesis and symbiosis.

Many bacteria use quorum sensing (QS) as an intercellular signaling mechanism to regulate gene expression in local populations. Plant and algal hosts, in turn, secrete compounds that mimic bacterial QS signals, allowing these hosts to manipulate QS-regulated gene expression in bacteria. Lumichrome, a derivative of the vitamin riboflavin, was purified and chemically identified from culture filtrates of the alga Chlamydomonas as a QS signal-mimic compound capable of stimulating the Pseudomonas aeruginosa LasR QS receptor. LasR normally recognizes the N-acyl homoserine lactone (AHL) signal, N-3-oxo-dodecanoyl homoserine lactone. Authentic lumichrome and riboflavin stimulated the LasR receptor in bioassays and lumichrome activated LasR in gel shift experiments. Amino acid substitutions in LasR residues required for AHL binding altered responses to both AHLs and lumichrome or riboflavin. These results and docking studies indicate that the AHL binding pocket of LasR recognizes both AHLs and the structurally dissimilar lumichrome or riboflavin. Bacteria, plants, and algae commonly secrete riboflavin or lumichrome, raising the possibility that these compounds could serve as either QS signals or as interkingdom signal mimics capable of manipulating QS in bacteria with a LasR-like receptor.

Many behaviors in bacteria, including behaviors important to pathogenic and symbiotic interactions with eukaryotic hosts, are regulated by a mechanism called quorum sensing (QS). A “quorum-quenching” approach was used here to identify QS-regulated behaviors in the N-fixing bacterial symbiont Sinorhizobium meliloti. The AiiA lactonase from Bacillus produced in S. meliloti was shown to enzymatically inactivate S. meliloti's N-acyl homoserine lactone (AHL) QS signals, thereby disrupting normal QS regulation. Sixty proteins were differentially accumulated in the AiiA-producing strain versus the control in early log or early stationary phase cultures. Fifty-two of these QS-regulated proteins, with putative functions that include cell division, protein processing and translation, metabolite transport, oxidative stress, and amino acid metabolism, were identified by peptide mass fingerprinting. Transcription of representative genes was reduced significantly in the AiiA-producing strain, although the effects of AiiA on protein accumulation did not always correspond to effects on transcription. The QS signal-deficient strain was reduced significantly in nodule initiation during the first 12 h after inoculation onto Medicago truncatula host plants. The AiiA lactonase also was found to substantially inactivate two of the AHL mimic compounds secreted by M. truncatula. This suggests some structural similarity between bacterial AHLs and these mimic compounds. It also indicates that quorum quenching could be useful in identifying Sinorhizobium genes that are affected by such host QS mimics in planta.

Earlier work showed that higher plants produce unidentified compounds that specifically stimulate or inhibit quorum sensing (QS) regulated responses in bacteria. The ability of plants to produce substances that affect QS regulation may provide plants with important tools to manipulate gene expression and behavior in the bacteria they encounter. In order to examine the kinds of QS active substances produced by the model legume M. truncatula, young seedlings and seedling exudates were systematically extracted with various organic solvents, and the extracts were fractionated by reverse phase C18 high-performance liquid chromatography. M. truncatula appears to produce at least 15 to 20 separable substances capable of specifically stimulating or inhibiting responses in QS reporter bacteria, primarily substances that affect QS regulation dependent on N-acyl homoserine lactone (AHL) signals. The secretion of AHL QS mimic activities by germinating seeds and seedlings was found to change substantially with developmental age. The secretion of some mimic activities may be dependent upon prior exposure of the plants to bacteria.

Plant roots secrete a complex polysaccharide mucilage that may provide a significant source of carbon for microbes that colonize the rhizosphere. High molecular weight mucilage was separated by high-pressure liquid chromatography gel filtration from low molecular weight components of pea root exudate. Purified pea root mucilage generally was similar in sugar and glycosidic linkage composition to mucilage from cowpea, wheat, rice, and maize, but appeared to contain an unusually high amount of material that was similar to arabinogalactan protein. Purified pea mucilage was used as the sole carbon source for growth of several pea rhizosphere bacteria, including Rhizobium leguminosarum 8401 and 4292, Burkholderia cepacia AMMD, and Pseudomonas fluorescens PRA25. These species grew on mucilage to cell densities of three- to 25-fold higher than controls with no added carbon source, with cell densities of 1 to 15% of those obtained on an equal weight of glucose. Micromolar concentrations of nod gene-inducing flavonoids specifically stimulated mucilage-dependent growth of R. leguminosarum 8401 to levels almost equaling the glucose controls. R. leguminosarum 8401 was able to hydrolyze p-nitrophenyl glycosides of various sugars and partially utilize a number of purified plant polysaccharides as sole carbon sources, indicating that R. leguminosarum 8401 can make an unexpected variety of carbohydrases, in accordance with its ability to extensively utilize pea root mucilage.

In gram-negative bacteria, many important changes in gene expression and behavior are regulated in a popula tion density-dependent fashion by N-acyl homoserine lac tone (AHL) signal molecules. Exudates from pea (Pisum sativum) seedlings were found to contain several separable activities that mimicked AHL signals in well-characterized bacterial reporter strains, stimulating AHL-regulated be haviors in some strains while inhibiting such behaviors in others. The chemical nature of the active mimic com pounds is currently unknown, but all extracted differently into organic solvents than common bacterial AHLs. Various species of higher plants in addition to pea were found to secrete AHL mimic activities. The AHL signal-mimic compounds could prove to be important in determining the outcome of interactions between higher plants and a diver sity of pathogenic, symbiotic, and saprophytic bacteria.

Gene or protein expression data are usually represented by metric or at least ordinal variables. In order to translate a continuous variable into a clinical decision, it is necessary to determine a cutoff point and to stratify patients into two groups each requiring a different kind of treatment. Currently, there is no standard method or standard software for biomarker cutoff determination. Therefore, we developed Cutoff Finder, a bundle of optimization and visualization methods for cutoff determination that is accessible online. While one of the methods for cutoff optimization is based solely on the distribution of the marker under investigation, other methods optimize the correlation of the dichotomization with respect to an outcome or survival variable. We illustrate the functionality of Cutoff Finder by the analysis of the gene expression of estrogen receptor (ER) and progesterone receptor (PgR) in breast cancer tissues. This distribution of these important markers is analyzed and correlated with immunohistologically determined ER status and distant metastasis free survival. Cutoff Finder is expected to fill a relevant gap in the available biometric software repertoire and will enable faster optimization of new diagnostic biomarkers. The tool can be accessed at http://molpath.charite.de/cutoff.

By examining the minor and trace element contents of chromites from three intrusions--the Bushveld Complex (South Africa), the Stillwater Complex (USA), and the Great Dyke (Zimbabwe)--and comparing these chromite compositions with those of magmas from which they could have formed (komatiites and picrites) we conclude that (i) the variations in Ti, V, Sc, and Ga contents across stratigraphy and across individual layers do not support the model of magma mixing leading to chromite-only crystallization, (ii) the chromites from the lowest levels of the intrusions could have crystallized from komatiite liquids that were contaminated with continental crust, (iii) the Great Dyke chromites have the highest Cr# and lowest incompatible element contents and formed from a liquid closest to komatiite, (iv) all of the chromites, except those of the Dunite Succession of the Great Dyke have equilibrated with a liquid that also had crystallized pyroxene, (v) the Great Dyke and Stillwater chromites show a narrower range in composition than the Bushveld chromites, and (vi) Chromites from the western limb of the Bushveld Complex contain much higher V contents than all the other chromites. This requires either, that the oxygen fugacity (f[O.sub.2])was lower in the western Bushveld or that the chromites equilibrated with a V-rich magma. We favor a model where chromite and silicate minerals crystallized in cotectic proportions (~2:98). The chromite, silicates, and transporting liquid are emplaced into the magma chamber. During emplacement the chromite and silicate separated due to viscous particle flow to form a massive chromite layer overlain by silicates. Key words: chromite, trace elements, komatiite, picrite, Stillwater, Bushveld, Introduction The composition of chromite is of interest for both petrogenetic and economic reasons. On the petrogenetic side, chromite is one of first minerals to crystallize from primary magmas and [...]

The accretion of volatile-rich material from the outer Solar System represents a crucial prerequisite for Earth to develop oceans and become a habitable planet.sup.1-4. However, the timing of this accretion remains controversial.sup.5-8. It has been proposed that volatile elements were added to Earth by the late accretion of a late veneer consisting of carbonaceous-chondrite-like material after core formation had ceased.sup.6,9,10. This view could not be reconciled with the ruthenium (Ru) isotope composition of carbonaceous chondrites.sup.5,11, which is distinct from that of the modern mantle.sup.12, or of any known meteorite group.sup.5. As a possible solution, Earth's pre-late-veneer mantle could already have contained a fraction of Ru that was not fully extracted by core formation.sup.13. The presence of such pre-late-veneer Ru can only be established if its isotope composition is distinct from that of the modern mantle. Here we report the first high-precision, mass-independent Ru isotope compositions for Eoarchaean ultramafic rocks from southwest Greenland, which display a relative .sup.100Ru excess of 22 parts per million compared with the modern mantle value. This .sup.100Ru excess indicates that the source of the Eoarchaean rocks already contained a substantial fraction of Ru before the accretion of the late veneer. By 3.7 billion years ago, the mantle beneath southwest Greenland had not yet fully equilibrated with late accreted material. Otherwise, no Ru isotopic difference relative to the modern mantle would be observed. If constraints from other highly siderophile elements besides Ru are also considered.sup.14, the composition of the modern mantle can only be reconciled if the late veneer contained substantial amounts of carbonaceous-chondrite-like materials with their characteristic .sup.100Ru deficits. These data therefore relax previous constraints on the late veneer and are consistent with volatile-rich material from the outer Solar System being delivered to Earth during late accretion. Ruthenium isotope compositions of the oldest preserved mantle rocks from Greenland imply that volatile-rich outer Solar System material was not delivered to Earth until very late in the planet's formation., Author(s): Mario Fischer-Gödde [sup.1] , Bo-Magnus Elfers [sup.1] , Carsten Münker [sup.1] , Kristoffer Szilas [sup.2] , Wolfgang D. Maier [sup.3] , Nils Messling [sup.1] , Tomoaki Morishita [sup.4] [sup.5] [...]