From the Cover: Accumulation and enhanced cycling of polyphosphate by Sargasso Sea plankton in response to low phosphorus

Phytoplankton alter their biochemical composition according to nutrient availability, such that their bulk elemental composition varies across oceanic provinces. However, the links between plankton biochemical composition and variation in biogeochemical cycling of nutrients remain largely unknown. In a survey of phytoplankton phosphorus stress in the western North Atlantic, we found that phytoplankton in the phosphorus-depleted subtropical Sargasso Sea were enriched in the biochemical polyphosphate (polyP) compared with nutrient-rich temperate waters, contradicting the canonical oceanographic view of polyP as a luxury phosphorus storage molecule. The enrichment in polyP coincided with enhanced alkaline phosphatase activity and substitution of sulfolipids for phospholipids, which are both indicators of phosphorus stress. Further, polyP appeared to be liberated preferentially over bulk phosphorus from sinking particles in the Sargasso Sea, thereby retaining phosphorus in shallow waters. Thus, polyP cycling may form a feedback loop that attenuates the export of phosphorus when it becomes scarce, contributes bioavailable P for primary production, and supports the export of carbon and nitrogen via sinking particles.Phosphorus (P) is an essential element for all living organisms. However, P can be extremely scarce in open-ocean surface waters such as in the subtropical western North Atlantic (the Sargasso Sea), where soluble reactive P (SRP) concentrations are routinely <10 nmol⋅L⁻¹ and turnover rates are on the order of hours (1). Despite this scarcity, primary production by phytoplankton in the Sargasso Sea does not appear to be limited primarily by P (2, 3), reflecting the intensity of P recycling by the microbial community (4, 5) and the exquisite adaptations of marine phytoplankton to low P conditions, which remain to be fully characterized.Phytoplankton respond to low P by producing enzymes such as alkaline phosphatase to hydrolyze extracellular dissolved organic P molecules (4, 6, 7), increasing the affinity and rate of P uptake (8, 9) and reducing their inventory of P-containing biochemicals (1, 10). In contrast, when P is abundant, phytoplankton take up excess P and store it as a luxury reserve that is generally thought to be composed of polyphosphate (polyP) (10–12). This modulation of P-containing biochemicals results in basin-scale relationships between P availability and biomass carbon-to-phosphorus (C:P) ratios (13). Presently, the only class of molecules known to consistently contribute to these gradients in cellular P are lipids because P stress in phytoplankton triggers substitution of non–P-membrane lipids for phospholipids, such as the sulfolipid sulfoquinovosyldiacylglycerol (SQDG) for the phospholipid phosphatidylglycerol (PG) (1, 14). However, lipid substitution alone probably cannot account for the full range of C:P observed in the ocean, and yet an understanding of other biochemical drivers of the C:P gradient remains elusive. Further, it is unknown how changes in plankton biochemical composition influence the recycling of nutrients.Polyphosphate (polyP), a ubiquitous inorganic P polymer of three to hundreds of residues, has diverse physiological roles and complex dynamics in microbes. It is critical for surviving nutritional stress and stationary phase (15–17) but is also important for P homeostasis: microbes produce polyP when P is more abundant than required for growth, so-called luxury uptake, and break down this polyP store upon P stress (18). Moreover, if P-stressed cells experience a spike in P availability, they overproduce polyP in excess of luxury uptake levels, the so-called “overplus” response (19). Given these complex dynamics, it has been hypothesized that polyP might be either virtually absent, or particularly abundant, in oligotrophic marine systems (20).     

The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity

The effect of the potent and selective poly(ADP-ribose) (PAR) polymerase-1 [and PAR polymerase-2] inhibitor CEP-8983 on the ability to sensitize chemoresistant glioblastoma (RG2), rhabdomyosarcoma (RH18), neuroblastoma (NB1691), and colon carcinoma (HT29) tumor cells to temozolomide- and camptothecin-induced cytotoxicity, DNA damage, and G(2)-M arrest and on the potentiation of chemotherapy-induced myelotoxicity was evaluated using in vitro assays. In addition, the effect of the prodrug CEP-9722 in combination with temozolomide and/or irinotecan on PAR accumulation and tumor growth was also determined using glioblastoma and/or colon carcinoma xenografts relative to chemotherapy alone. CEP-8983 sensitized carcinoma cells to the growth-inhibitory effects of temozolomide and/or SN38 increased the fraction of and/or lengthened duration of time tumor cells accumulated in chemotherapy-induced G(2)-M arrest and sensitized tumor cells to chemotherapy-induced DNA damage and apoptosis. A granulocyte-macrophage colony-forming unit colony formation assay showed that coincubation of CEP-8983 with temozolomide or topotecan did not potentiate chemotherapy-associated myelotoxicity. CEP-9722 (136 mg/kg) administered with temozolomide (68 mg/kg for 5 days) or irinotecan (10 mg/kg for 5 days) inhibited significantly the growth of RG2 tumors (60%) or HT29 tumors (80%) compared with temozolomide or irinotecan monotherapy, respectively. In addition, CEP-9722 showed "stand alone" antitumor efficacy in these preclinical xenografts. In vivo biochemical efficacy studies showed that CEP-9722 attenuated PAR accumulation in glioma xenografts in a dose- and time-related manner. These data indicate that CEP-8983 and its prodrug are effective chemosensitizing agents when administered in combination with select chemotherapeutic agents against chemoresistant tumors.     

Desferioxamine increases iron depletion and apoptosis induced by ara-C of human myeloid leukaemic cells

We investigated whether changes in iron metabolism and the transferrin receptor (TRF-R) expression were involved in the antileukaemic effects of arabinoside cytosine (ara-C). Treatment with 100 n M ara-C for 48 h reduced thymidine uptake and increased the surface expression of the TRF-R on leukaemic blasts derived from 13/16 (81%) patients and on the HL-60 and U-937 cell lines. Whereas intracellular non-haem iron was strongly depleted 24 h after ara-C addition, TRF-R up-regulation and recovery of intracellular non-haem iron concentration occurred together after a longer exposure of the cultured cells to the drug. Since iron is an essential regulator of cell proliferation we have evaluated the effects of the combination between ara-C and the iron chelator desferioxamine (DSF) on the growth of HL-60 and U-937 cells. We found that desferioxamine strongly potentiated the effects of ara-C on leukaemic cell growth inhibition and apoptosis. This is the first report of a positive interaction between ara-C and an iron chelator in terms of antileukaemic effects.     

Relations between catechol-O-methyltransferase Val158Met genotype and inhibitory control development in childhood

The Val158Met rs4680 single-nucleotide polymorphism (SNP) at the catechol-O-methyltransferase (COMT) gene, primarily involved in dopamine breakdown within prefrontal cortex, has shown relations with inhibitory control (IC) in both adults and children. However, little is known about how COMT genotype relates to developmental trajectories of IC throughout childhood. Here, our study explored the effects of the COMT genotype (Val/Val, Val/Met, and Met/Met) on IC trajectories between the ages of 5 and 10 years. Children (n = 222) completed a Go/Nogo task at ages 5, 7, and 10; IC was characterized using signal detection theory to examine IC performance (d′) and response strategy (RS) (criterion). COMT genotype was not related to initial levels of IC performance and RS at age 5 or change in RS from ages 5 to 10. In contrast, COMT genotype was related to change in IC performance between 5 and 10 years. While Val/Val children did not differ from Val/Met children in development of IC performance, children with the Met/Met genotype exhibited more rapid development of IC performance when compared with Val/Met peers. These results suggest that COMT genotype modulates the development of IC performance in middle childhood.     

Inflammatory Mediators as Biomarkers in Brain Disorders

Neurodegenerative diseases such as Alzheimer, Parkinson, amyotrophic lateral sclerosis, and Huntington are incurable and debilitating conditions that result in progressive death of the neurons. The definite diagnosis of a neurodegenerative disorder is disadvantaged by the difficulty in obtaining biopsies and thereby to validate the clinical diagnosis with pathological results. Biomarkers are valuable indicators for detecting different phases of a disease such as prevention, early onset, treatment, progression, and monitoring the effect of pharmacological responses to a therapeutic intervention. Inflammation occurs in neurodegenerative diseases, and identification and validation of molecules involved in this process could be a strategy for finding new biomarkers. The ideal inflammatory biomarker needs to be easily measurable, must be reproducible, not subject to wide variation in the population, and unaffected by external factors. Our review summarizes the most important inflammation biomarkers currently available, whose specificity could be utilized for identifying and monitoring distinctive phases of different neurodegenerative diseases.