Binary regression: Total gain in positive and negative predictive values

Models that predict disease incidence or disease recurrence are attractive for clinicians as well as for patients. The usefulness of a risk prediction model is linked to the two questions whether the observed outcome is confirmed by the prediction and whether the risk prediction is accurate in predicting the future outcome, respectively. The first phrasing of the question is linked to considering sensitivity and specificity and the latter to the positive and negative predictive values. We present the measures of standardized total gain in positive and negative predictive values dealing with the performance or accuracy of the prediction model for a binary outcome. Both measures provide a useful tool for assessing the performance or accuracy of a set of predictor variables for the prediction of a binary outcome. This concept is a tool for evaluating the optimal prediction model in future research.     

Fine tuning of hepcidin expression by positive and negative regulators

Hepcidin, the systemic regulator of iron homeostasis is activated by proteins responsible for hereditary hemochromatosis, bone morphogenetic proteins (BMPs), and inflammatory cytokines. Three recent publications now identify a novel hepcidin suppressor, the transmembrane serine protease TMPRSS6 (also known as matriptase-2), which is required to sense iron deficiency.     

Multiple positive and negative regulators of signaling by the EGF-receptor

Signaling via the epidermal growth factor (EGF)-receptor family is subject to regulation and modulation by multiple ligands, effectors and negative regulators, as well as regulation by heterodimerization between family members and crosstalk between heterologous signaling pathways. Besides serving as a paradigm for receptor tyrosine kinases in general, this family is crucial for development and is often mutated or amplified in human tumors.     

Annotations and functional analyses of the rice WRKY gene superfamily reveal positive and negative regulators of abscisic acid signaling in aleurone cells

The WRKY proteins are a superfamily of regulators that control diverse developmental and physiological processes. This family was believed to be plant specific until the recent identification of WRKY genes in nonphotosynthetic eukaryotes. We have undertaken a comprehensive computational analysis of the rice (Oryza sativa) genomic sequences and predicted the structures of 81 OsWRKY genes, 48 of which are supported by full-length cDNA sequences. Eleven OsWRKY proteins contain two conserved WRKY domains, while the rest have only one. Phylogenetic analyses of the WRKY domain sequences provide support for the hypothesis that gene duplication of single- and two-domain WRKY genes, and loss of the WRKY domain, occurred in the evolutionary history of this gene family in rice. The phylogeny deduced from the WRKY domain peptide sequences is further supported by the position and phase of the intron in the regions encoding the WRKY domains. Analyses for chromosomal distributions reveal that 26% of the predicted OsWRKY genes are located on chromosome 1. Among the dozen genes tested, OsWRKY24, -51, -71, and -72 are induced by abscisic acid (ABA) in aleurone cells. Using a transient expression system, we have demonstrated that OsWRKY24 and -45 repress ABA induction of the HVA22 promoter-beta-glucuronidase construct, while OsWRKY72 and -77 synergistically interact with ABA to activate this reporter construct. This study provides a solid base for functional genomics studies of this important superfamily of regulatory genes in monocotyledonous plants and reveals a novel function for WRKY genes, i.e. mediating plant responses to ABA.     

In quiescence of fission yeast,autophagy and the proteasome collaborate for mitochondrial maintenance and longevity

Regulation of proliferation and quiescence in response to intra- or extracellular environmental signals are important for medicine and basic biology. Quiescence is relevant to tumorigenesis and tissue regeneration, and the maintenance of post-mitotic cells is important with regard to a number of senescence-related diseases such as neurodegeneration. We employ fission yeast, Schizosaccharomyces pombe, as a model to study quiescence and longevity as this lower eukaryote has a long chronological life span (over months) in quiescence that is induced by nitrogen starvation. We recently reported that autophagy and the proteasome cooperate in proper mitochondrial maintenance in the quiescent phase. Such cooperativity is not found in proliferating cells. In quiescence, the proteasome is required for normal mitochondrial functions; inactivation of the proteasome results in a large accumulation of reactive oxygen species (ROS), diminished mitochondrial function, and the elevation of proteins and compounds having anti-oxidant activities. Autophagy contributes to preventing the lethal accumulation of ROS by degrading mitochondria, the primary source of ROS. Our results indicate that the degradation of mitochondria by autophagy during proteasome dysfunction is a defense mechanism of quiescenct cells against the accumulation of ROS.     

Type IV collagens and Dpp positive and negative regulators of signaling

Decapentaplegic (Dpp) is an essential morphogen in the TGF-β/BMP superfamily which patterns fields of cells during multiple stages of Drosophila development, including the ovary and embryo. We have found that type IV collagens bind to Dpp and play essential roles in the regulation of its signaling during these two developmental stages. This article primarily focuses on type IV collagens and embryonic Dpp signaling to discuss aspects of the type IV collagen mutant phenotype in the context of additional data from the field. In addition, the restriction of Dpp signaling in the the ovary by type IV collagens is described, as the differences between the embryonic and ovarian Dpp sources result in distinct effects of collagen IV proteins in the two systems.     

The complex interplay between mosquito positive and negative regulators of Plasmodium development

The malaria parasite, Plasmodium, requires sexual development in the mosquito before it can be transmitted to the vertebrate host. Mosquito genes are able to substantially modulate this process, which can result in major decreases in parasite numbers. Even in susceptible mosquitoes, haemolymph proteins implicated in systemic immune reactions, together with local epithelial responses, cause lysis of more than 80% of the ookinetes that cross the mosquito midgut. In a refractory mosquito strain, immune responses lead to melanisation of virtually all parasites. Conversely, certain mosquito genes have an opposite effect: they are used by the parasite to evade defence reactions. Detailed understanding of the interplay between positive and negative regulators of parasite development could lead to the generation of novel approaches for malaria control through the vector.     

A perspective on mammalian caspases as positive and negative regulators of inflammation

Members of the caspase family of cysteine proteases coordinate the morphological and biochemical events that typify apoptosis. However, neutralization of caspase activity in mammals fails to block death in response to most proapoptotic stimuli. This is because many cell death triggers provoke mitochondrial dysfunction upstream of caspase activation as a consequence of BAX/BAK channel opening. Although genetic or pharmacological inactivation of caspases fails to block cell death in most instances, it does convert the phenotype from apoptosis to necrosis. This has important implications for how the immune system responds to such cells, as necrotic cells provoke inflammation whereas apoptotic cells typically do not. Here, we propose an alternative perspective on apoptosis-associated caspase function by suggesting that these proteases are activated, not to kill, but to extinguish the proinflammatory properties of dying cells. This perspective unifies the mammalian caspase family as either positive or negative regulators of inflammation.     

Immunomodulatory mast cells: negative, as well as positive, regulators of immunity

Mast cells can promote inflammation and other tissue changes in IgE-associated allergic disorders, as well as in certain innate and adaptive immune responses that are thought to be independent of IgE. However, mast cells can also have anti-inflammatory and immunosuppressive functions. Here, we review the evidence that mast cells can have negative, as well as positive, immunomodulatory roles in vivo, and we propose that mast cells can both enhance and later suppress certain features of an immune response.     

A modified yeast three-hybrid system enabling both positive and negative selections

Objective

To increase the reporter repertoire of the yeast three-hybrid system and introduce the option of negative selection.

Results

Two new versions of the yeast three-hybrid system were made by modifying the MS2 coat RNA-binding protein and fusing it to the Gal4 DNA-binding protein. This allows the use of Gal4 inducible reporters to measure RNA–protein interactions. We introduced two mutations, V29I and N55K into the tandem MS2 dimer and an 11 amino acid deletion to increase RNA–protein affinity and inhibit capsid formation. Introduction of these constructs into the yeast strains MaV204K and PJ69-2A (which contain more reporters than the conventional yeast three-hybrid strains L40-coat and YBZ-1) allows RNA–protein binding interactions with a wide range of affinities to be detected using histidine auxotrophy, and negative selection with 5-fluoroorotic acid.

Conclusion

This yeast three-hybrid system has advantages over previous versions as demonstrated by the increased dynamic range of detectable binding interactions using yeast survival assays and colony forming assays with multiple reporters using known RNA–protein interactions.

     

Interspecific interactions between feral pigs and native birds reveal both positive and negative effects

In tropical Australian rainforests, predators and scavengers aggregate beneath emergent trees that house large colonies of metallic starlings (Aplonis metallica), feeding in the nutrient‐rich open areas below. Analysis of camera‐trap records shows that the presence of feral pigs (Sus scrofa) is associated with an absence of birds (cockatoos and brush turkeys), presumably reflecting behavioural avoidance (pigs pose a direct danger to birds). However, bird numbers increase as soon as pigs depart, then fall if pigs are absent for long periods. Feral pigs thus displace native birds from these resource hotspots; but by turning over the soil and enhancing the birds' access to food, the pigs also have a positive impact on food availability for the avifauna. Thus, although invasive species have caused irreparable environmental damages worldwide, they may also provide positive benefits for certain species. The net benefit of such interspecific interactions will depend on the outcome of both positive and negative effects.     

Ski and SnoN: negative regulators of TGF-beta signaling

Ski and SnoN are unique proto-oncoproteins in that they can induce both oncogenic transformation and terminal muscle differentiation when expressed at high levels. Recent studies using in vitro and in vivo approaches have begun to unravel the complex roles of Ski and SnoN in tumorigenesis and embryonic development. The identification of Ski and SnoN as important negative regulators of signal transduction by the transforming growth factor-beta superfamily of cytokines provides a valuable molecular basis for the complex functions of Ski and SnoN.