Stringent Selection of Knobby Plasmodium falciparum-Infected Erythrocytes during Cytoadhesion at Febrile Temperature.

Changes in the erythrocyte membrane induced by Plasmodium falciparum invasion allow cytoadhesion of infected erythrocytes (IEs) to the host endothelium, which can lead to severe complications. Binding to endothelial cell receptors (ECRs) is mainly mediated by members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, encoded by var genes. Malaria infection causes several common symptoms, with fever being the most apparent. In this study, the effects of febrile conditions on cytoadhesion of predominately knobless erythrocytes infected with the laboratory isolate IT4 to chondroitin-4-sulfate A (CSA), intercellular adhesion molecule 1 (ICAM-1), and CD36 were investigated. IEs enriched for binding to CSA at 40 °C exhibited significantly increased binding capacity relative to parasites enriched at 37 °C. This interaction was due to increased var2csa expression and trafficking of the corresponding PfEMP1 to the IE surface as well as to a selection of knobby IEs. Furthermore, the enrichment of IEs to ICAM-1 at 40 °C also led to selection of knobby IEs over knobless IEs, whereas enrichment on CD36 did not lead to a selection. In summary, these findings demonstrate that knobs are crucial for parasitic survival in the host, especially during fever episodes, and thus, that selection pressure on the formation of knobs could be controlled by the host.

Retinoic acid and arsenic trioxide for acute promyelocytic leukemia.

BACKGROUND: All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity. METHODS: We conducted a phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell count, ≤10×10(9) per liter). Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5%. RESULTS: Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P=0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide). Overall survival was also better with ATRA-arsenic trioxide (P=0.02). As compared with ATRA-chemotherapy, ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity. CONCLUSIONS: ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833.).

The maize (Zea mays L.) RTCS gene encodes a LOB domain protein that is a key regulator of embryonic seminal and post-embryonic shoot-borne root initiation.

Maize has a complex root system composed of different root types formed during different stages of development. The rtcs (rootless concerning crown and seminal roots) mutant is impaired in the initiation of the embryonic seminal roots and the post-embryonic shoot-borne root system. The primary root of the mutant shows a reduced gravitropic response, while its elongation, lateral root density and reaction to exogenously applied auxin is not affected. We report here the map-based cloning of the RTCS gene which encodes a 25.5 kDa LOB domain protein located on chromosome 1S. The RTCS gene has been duplicated during evolution. The RTCS-LIKE (RTCL) gene displays 72% sequence identity on the protein level. Both genes are preferentially expressed in roots. Expression of RTCS in coleoptilar nodes is confined to emerging shoot-borne root primordia. Sequence analyses of the RTCS and RTCL upstream genomic regions identified auxin response elements. Reverse transcriptase-PCR revealed that both genes are auxin induced. Microsynteny analyses between maize and rice genomes revealed co-linearity of 14 genes in the RTCS region. We conclude from our data that RTCS and RTCL are auxin-responsive genes involved in the early events that lead to the initiation and maintenance of seminal and shoot-borne root primordia formation.

Proteomic dissection of plant development.

Plant development is controlled by complex endogenous genetic programs and responses to environmental cues. Proteome analyses have recently been introduced to plant biology to identify proteins instrumental in these developmental processes. To date most plant proteome studies have been employed to generate reference maps of the most abundant soluble proteins of plant organs at a defined developmental stage. However, proteomics is now also utilized for genetic studies comparing the proteomes of different plant genotypes, for physiological studies analyzing the influences of exogenous signals on a particular plant organ, and developmental studies investigating proteome changes during development. Technical advances are now beginning to allow a proteomic dissection of individual cell types, thus greatly increasing the information revealed by proteome analyses.

Proteomic analysis of shoot-borne root initiation in maize (Zea mays L.).

Postembryonically formed shoot-borne roots make up the major backbone of the adult maize root stock. In this study the abundant soluble proteins of the first node (coleoptilar node) of wild-type and mutant rtcs seedlings, which do not initiate crown roots, were compared at two early stages of crown root formation. In Coomassie Bluestained 2-D gels, representing soluble proteins of coleoptilar nodes 5 and 10 days after germination, 146 and 203 proteins were detected, respectively. Five differentially accumulated proteins (> two-fold change; t-test: 95% significance) were identified in 5-day-old and 14 differentially accumulated proteins in 10-day-old coleoptilar nodes of wild-type versus rtcs. All 19 differentially accumulated proteins were identified via ESI MS/MS mass spectrometry. Five differentially accumulated proteins, including a regulatory G-protein and a putative auxin-binding protein, were further analyzed at the RNA expression level. These experiments confirmed differential gene expression and revealed subtle developmental regulation of these genes during early coleoptilar node development. This study represents the first proteomic analysis of shoot-borne root initiation in cereals and will contribute to a better understanding of the molecular basis of this developmental process unique to cereals.

The roothairless1 gene of maize encodes a homolog of sec3, which is involved in polar exocytosis.

The roothairless1 (rth1) mutant is impaired in root hair elongation and exhibits other growth abnormalities. Unicellular root hairs elongate via localized tip growth, a process mediated by polar exocytosis of secretory vesicles. We report here the cloning of the rth1 gene that encodes a sec3 homolog. In yeast (Saccharomyces cerevisiae) and mammals, sec3 is a subunit of the exocyst complex, which tethers exocytotic vesicles prior to their fusion. The cloning of the rth1 gene associates the homologs of exocyst subunits to an exocytotic process in plant development and supports the hypothesis that exocyst-like proteins are involved in plant exocytosis. Proteomic analyses identified four proteins that accumulate to different levels in wild-type and rth1 primary roots. The preferential accumulation in the rth1 mutant proteome of a negative regulator of the cell cycle (a prohibitin) may at least partially explain the delayed development and flowering of the rth1 mutant.

Genetic dissection of root formation in maize (Zea mays) reveals root-type specific developmental programmes.

BACKGROUND: Maize (Zea mays) forms a complex root system comprising embryonic and post-embryonic roots. The embryonically formed root system is made up of the primary root and a variable number of seminal roots. Later in development the post-embryonic shoot-borne root system becomes dominant and is responsible together with its lateral roots for the major portion of water and nutrient uptake. Although the anatomical structure of the different root-types is very similar they are initiated from different tissues during embryonic and post-embryonic development. Recently, a number of mutants specifically affected in maize root development have been identified. These mutants indicate that various root-type specific developmental programmes are involved in the establishment of the maize root stock. SCOPE: This review summarizes these genetic data in the context of the maize root morphology and anatomy and gives an outlook on possible perspectives of the molecular analysis of maize root formation.

From weeds to crops: genetic analysis of root development in cereals.

Root development of Arabidopsis, Zea mays (maize) and Oryza sativa (rice) differs in both overall architecture and the anatomy of individual roots. In maize and rice, the post-embryonic shoot-borne root system becomes the major backbone of the root stock; in Arabidopsis, the embryonic root system formed by a simple primary root and its lateral roots remains dominant. Recently, several specific root mutants and root-specific genes have been identified and characterized in maize and rice. Interestingly, some of these mutants indicate that the formation of primary-, seminal-, crown- and lateral roots is regulated by alternative root-type-specific pathways. Further analyses of these unique pathways will contribute to the understanding of the complex molecular networks involved in cereal root formation.