Untangling the intracellular signalling network in cancer--a strategy for data integration in acute myeloid leukaemia

Protein and gene networks centred on the regulatory tumour suppressor proteins may be of crucial importance both in carcinogenesis and in the response to chemotherapy. Tumour suppressor protein p53 integrates intracellular data in stress responses, receiving signals and translating these into differential gene expression. Interpretation of the data integrated on p53 may therefore reveal the response to therapy in cancer. Proteomics offers more specific data - closer to "the real action" - than the hitherto more frequently used gene expression profiling. Integrated data analysis may reveal pathways disrupted at several regulatory levels. Ultimately, integrated data analysis may also contribute to finding key underlying cancer genes. We here proposes a Partial Least Squares Regression (PLSR)-based data integration strategy, which allows simultaneous analysis of proteomic data, gene expression data and classical clinical parameters. PLSR collapses multidimensional data into fewer relevant dimensions for data interpretation. PLSR can also aid identification of functionally important modules by also performing comparison to databases on known biological interactions. Further, PLSR allows meaningful visualization of complex datasets, aiding interpretation of the underlying biology. Extracting the true biological causal mechanisms from heterogeneous patient populations is the key to discovery of new therapeutic options in cancer.     

A drop of intracellular pH stimulates citric acid accumulation by some strains of Aspergillus niger

By comparing kinetic parameters of plasma membrane proton pumps from two Aspergillus niger strains, significant differences in specific activities were observed. In low citric acid producing A158 strain the H+ -ATPase activity was about four-fold higher than in a high yielding A60 strain. Previously pH homeostasis was reported in A158 strain while in A60 strain spontaneous drop of intracellular pH was observed. During the growth in the medium with ammonium ions more rapid drop of extracellular pH was recorded with A158 strain and not so fast proton accumulation in the medium with A60 strain, indicating that proton pumps from later strain perhaps can not extrude all the protons that are released in the cytosol after the assimilation of ammonium ions. Vanadium ions were found to be potent inhibitors of both H+ -ATPases. By adding sodium vanadate in millimolar concentrations to the chemically defined medium that induces citric acid accumulation by A. niger, reduced pHi and increased rate of acid production was observed in A158 strain while in A60 strain intracellular pH decreased below 6.5 and concomitantly citric acid overflow was suppressed. The presented results suggest that one of the mechanisms stimulating citric acid accumulation by A. niger could be also a slight cytoplasmic acidification.     

Artificial vision with wirelessly powered subretinal electronic implant alpha-IMS

This study aims at substituting the essential functions of photoreceptors in patients who are blind owing to untreatable forms of hereditary retinal degenerations. A microelectronic neuroprosthetic device, powered via transdermal inductive transmission, carrying 1500 independent microphotodiode-amplifier-electrode elements on a 9 mm² chip, was subretinally implanted in nine blind patients. Light perception (8/9), light localization (7/9), motion detection (5/9, angular speed up to 35 deg s⁻¹), grating acuity measurement (6/9, up to 3.3 cycles per degree) and visual acuity measurement with Landolt C-rings (2/9) up to Snellen visual acuity of 20/546 (corresponding to decimal 0.037 or corresponding to 1.43 logMAR (minimum angle of resolution)) were restored via the subretinal implant. Additionally, the identification, localization and discrimination of objects improved significantly (n = 8; p < 0.05 for each subtest) in repeated tests over a nine-month period. Three subjects were able to read letters spontaneously and one subject was able to read letters after training in an alternative-force choice test. Five subjects reported implant-mediated visual perceptions in daily life within a field of 15° of visual angle. Control tests were performed each time with the implant''s power source switched off. These data show that subretinal implants can restore visual functions that are useful for daily life.     

Interaction of angio-associated migratory cell protein with the TPα and TPβ isoforms of the human thromboxane A₂ receptor

In humans, thromboxane (TX) A₂ signals through the TPα and TPβ isoforms of its G-protein coupled TXA₂ receptor (TP) to mediate a host of (patho)physiologic responses. Herein, angio-associated migratory cell protein (AAMP) was identified as a novel interacting partner of both TPα and TPβ through an interaction dependent on common (residues 312-328) and unique (residues 366-392 of TPβ) sequences within their carboxyl-terminal (C)-tail domains. While the interaction was constitutive in mammalian cells, agonist-stimulation of TPα/TPβ led to a transient dissociation of AAMP from immune complexes which coincided with a transient redistribution of AAMP from its localization in an intracellular fibrous network. Although the GTPase RhoA is a downstream effector of both AAMP and the TPs, AAMP did not influence TP-mediated RhoA or vice versa. Small interfering RNA (siRNA)-mediated disruption of AAMP expression decreased migration of primary human coronary artery smooth muscle cells (1° hCoASMCs). Moreover, siRNA-disruption of AAMP significantly impaired 1° hCoASMC migration in the presence of the TXA₂ mimetic U46619 but did not affect VEGF-mediated cell migration. Given their roles within the vasculature, the identification of a specific interaction between TPα/TPβ and AAMP is likely to have substantial functional implications for vascular pathologies in which they are both implicated.     

Role of rhizosphere mechanisms in Cd uptake by various wheat cultivars

In each wheat type, cultivars have different propensities to accumulate Cd in their grains, likely depending on Cd uptake by roots and/or Cd distribution in the plant. This study investigates the processes in the root–soil interface and their role in high or low grain Cd accumulation. Twenty-four cultivars of spring bread, winter bread, durum, and spelt wheat with different grain Cd accumulation levels were investigated regarding removal of Cd from soil, pH, Cd and organic acids in root exudates, and cation-exchange capacity of roots (rootCEC). In addition, we investigated ¹⁰⁹Cd uptake from a nutrient solution resembling soil solution. The removal of Cd from the rhizosphere soil increased, likely due to increased rootCEC with increased grain Cd accumulation propensity, except in spring bread wheat. The ¹⁰⁹Cd uptake from solution did not differ between high and low grain Cd accumulators. If the soil Cd concentration was elevated, rootCEC increased, as did pH, and succinic acid levels in the exudates, while lactic and citric acid levels in root exudates decreased. This work indicates that high grain Cd accumulators take up more Cd from soil than do low accumulators. But not by a different capacity to take up Cd from soil solution. The higher rootCEC in high accumulating cultivars may influence the release of Cd from the soil particles.