On the organic carbon maximum on the continental slope of the eastern Arabian Sea

The sedimentary organic carbon maximum on the continental slope off western India is widely believed to be due to the preferential preservation of deposited organic matter at water depths where the intense oxygen minimum intersects the sea floor. This region is considered to constitute one of the modern analogues for the environment of formation of organic-rich sedimentary facies that are common in the geological record. We critically examine the hypothesis that the oxygen minimum in the eastern Arabian Sea is the site of enhanced organic matter accumulation and preservation using analyses of suites of samples with wide geographical coverage along this margin. Organic carbon and nitrogen reach maximum concentrations between 200 and 1600 m depth, whereas the lowest dissolved oxygen contents in the oxygen minimum lie between 200 and 800 m depth. The Corganic/N ratios and the δ13Corganic values show that the organic matter is overwhelmingly marine, and Rock-Eval pyrolysis data demonstrate that the hydrogen indices of the sediments are similar in the sediments accumulating within and outside the oxygen minimum. Thus, the organic carbon maximum extends over a larger depth range than the oxygen minimum (as is also evident on some other slopes), and there is no evidence for preferential preservation of the organic matter within the oxygen minimum. The distribution of organic matter on the western Indian continental margin is controlled by (1) variations in supply (decreasing westward away from the centers of coastal upwelling and also decreasing with increasing water depth), (2) dilution by other sedimentary components, and (3) the texture of the sediments (coarser-grained sediments having lower carbon contents), which is controlled in turn by sediment supply and reworking. The evidence available suggests that the organic carbon maximum on this slope is not related to the position of the oxygen minimum and, consequently, that oxygen minima cannot be used to explain the distribution of organic carbon at intermediate palaeodepths in the geological record

Geologische Untersuchungen an Sedimenten des indisch-pakistanischen Kontinentalrandes (Arabischs Meer)

From the R./V. "Meteor" and the Pakistan F./V. "Machhera" sediments from the Indian-Pakistan continental margin habe been investigated in order to delineate the facies distribution of the recent deposits. One of the several objectives of this study was to find out how far the suspended matter of the Indus River is being transported into the Arabian Sea. A close genetic relationship was recognised between the oceanographic conditions of the water masses (chemistry and currents) and the characteristics of the sediments. The activity of the monsoons is reflected by the rhythmic lamination of the sediments of the upper continental slope. The suspended matter from the Indus River can be traced far into the Arabian Sea. The clay minerals show the following tendenciey from litoral to abyssal regions and from the top ot the cores downward: detrital clay minerals (chlorite, muscovite, illite) - degraded clay minerals (montmorillonite, mixed-layer minerals) - "re-formational" minerals (illite). The biostratigraphic investigations of the sedimentds combined with several C14-dates results in sedimentation rates from >50 cm/1000 years at the upper continental slope decreasing to about 1 cm/1000 years inhe faunal composition proves the existende of a climatic optimum during part of the Holocene. The geochemical investigation of the recent pore fluids demonstrates that their composition very soon assumes the characteristics of fossil inerstitial waters (cf. V. Marchig, in this vol.). The results will be published in Meteor-Forschungsergebnisse, Reihe C

KRAS and CREBBP mutations: a relapse-linked malicious liaison in childhood high hyperdiploid acute lymphoblastic leukemia

High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18-30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL-AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information and achieved a 5-month remission. Thus, drug profiling captures disease-relevant features and unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs.Peer reviewe

The Transcriptional Response to DNA-Double-Strand Breaks in Physcomitrella patens

The model bryophyte Physcomitrella patens is unique among plants in supporting the generation of mutant alleles by facile homologous recombination-mediated gene targeting (GT). Reasoning that targeted transgene integration occurs through the capture of transforming DNA by the homology-dependent pathway for DNA double-strand break (DNA-DSB) repair, we analysed the genome-wide transcriptomic response to bleomycin-induced DNA damage and generated mutants in candidate DNA repair genes. Massively parallel (Illumina) cDNA sequencing identified potential participants in gene targeting. Transcripts encoding DNA repair proteins active in multiple repair pathways were significantly up-regulated. These included Rad51, CtIP, DNA ligase 1, Replication protein A and ATR in homology-dependent repair, Xrcc4, DNA ligase 4, Ku70 and Ku80 in non-homologous end-joining and Rad1, Tebichi/polymerase theta, PARP in microhomology-mediated end-joining. Differentially regulated cell-cycle components included up-regulated Rad9 and Hus1 DNA-damage-related checkpoint proteins and down-regulated D-type cyclins and B-type CDKs, commensurate with the imposition of a checkpoint at G2 of the cell cycle characteristic of homology-dependent DNA-DSB repair. Candidate genes, including ATP-dependent chromatin remodelling helicases associated with repair and recombination, were knocked out and analysed for growth defects, hypersensitivity to DNA damage and reduced GT efficiency. Targeted knockout of PpCtIP, a cell-cycle activated mediator of homology-dependent DSB resection, resulted in bleomycin-hypersensitivity and greatly reduced GT efficiency

A Metaheuristic Framework for Bi-level Programming Problems with Multi-disciplinary Applications

Bi-level programming problems arise in situations when the decision maker has to take into account the responses of the users to his decisions. Several problems arising in engineering and economics can be cast within the bi-level programming framework. The bi-level programming model is also known as a Stackleberg or leader-follower game in which the leader chooses his variables so as to optimise his objective function, taking into account the response of the follower(s) who separately optimise their own objectives, treating the leader’s decisions as exogenous. In this chapter, we present a unified framework fully consistent with the Stackleberg paradigm of bi-level programming that allows for the integration of meta-heuristic algorithms with traditional gradient based optimisation algorithms for the solution of bi-level programming problems. In particular we employ Differential Evolution as the main meta-heuristic in our proposal.We subsequently apply the proposed method (DEBLP) to a range of problems from many fields such as transportation systems management, parameter estimation and game theory. It is demonstrated that DEBLP is a robust and powerful search heuristic for this class of problems characterised by non smoothness and non convexity