What to do, or how to do it?

In this issue of Neuron, Ajemian et al. present a computational model of the activity of neurons in primary motor cortex (M1) during isometric movements in different postures. By modeling the output of M1 neurons in terms of their influence on muscles, they find each M1 neuron maps its output into a particular pattern of muscle actions.     

Spontaneous immune responses to sporadic tumors: tumor-promoting, tumor-protective or both?

Cancer cells cannot develop into invasive cancers without interactions with cells and soluble mediators present in the tumor microenvironment. Accumulating evidence indicates that the immune system is a critical determinant of malignant outgrowth; however, the tumor-modulating effects of spontaneous immune responses towards nascent malignancies are rather paradoxical. Both cancer-protective and cancer-promoting features of the immune system have been described. This review will discuss the role of the dynamic inflammatory tumor microenvironment during cancer development and progression, and will focus on the intriguing question: “Do malignancies develop in spite of—or because of—spontaneous immune responses?” Special emphasis will be put on recent progress in our understanding of the immune system’s double-edged sword function during de novo carcinogenesis.     

Tensile fatigue in bone: are cycles-, or time to failure, or both, important?

In life, bones are subjected to fatigue loading which has different frequency and amplitude components, as well as various kinds of loading modes like tension, compression, shear and combinations of them. Considerable variability is observed in fatigue results of bone, which may be caused by these experimental variables or by the bone itself. In past studies the effect of magnitude and mode of loading have been examined in standard fatigue strength (stress vs. cycles to failure) diagrams. The effect of frequency is not clear, but there is clear evidence (from Carter & co-workers) that, at least in human bone, tension "fatigue" failure was determined solely by time rather than by cycles. We sought to confirm these results in the same and a different species. We cycled human and bovine bone in tension at two frequencies: 0.5 and 5 Hz. There was no cycle number effect; the results from the tests at the two frequencies were different if plotted and analysed as a function of cycles to failure, but were not separable if plotted and analysed as a function of time to failure. In this respect bone differs from tendon, in which failure in tension is a function of both cycles and time.     

The human mandible: Lever,link, or both?

Hylander ('78) recently published important new data on bite force in humans, and showed that the human mandible cannot function purely as a link during incisal biting. He concluded instead that the mandible acts as a lever. Reexamination of Hylander's data suggests that the mandible cannot function purely as a lever either, and in fact it probably functions simultaneously as both lever and link during incisal biting.     

Conchodontus,Mitrellataxis and Fungulodus: Conodonts,fish or both?

Conchodontus, Mitrellataxis and Fungulodus are phosphatic microfossils from the Late Devonian of China and North America, alternatively interpreted as conodont elements or fish scales. The histology and microornament of these sclerites have been studied in an attempt to resolve their affinity, and to determine characters for distinguishing between conodont elements and the ichthyoliths of other lower vertebrates. The histology of all three genera is directly comparable to conodont elements, dispelling the notion that conodonts are histologically indistinguishable from the teeth and scales of other vertebrates. Microornament is found not to be useful in discriminating between high-level taxonomic groupings. White matter and thickness of prismless enamel are suggested as apomorphies of the Conodonta.     

Are species adapted to their regeneration niche, adult niche, or both?

Functional traits are important drivers of successional processes and the assembly of plant communities. It is generally assumed that functional traits are closely linked to the regeneration niche because of the high selection pressures in the seedling stage, but recent studies have challenged this view. In this study, I use cross species and phylogenetic correlation analysis between leaf traits and light environment to evaluate whether species are adapted to the regeneration niche, adult niche, or both. Leaf chemistry, morphology, physiology, and crown exposure were quantified for up to 58 Bolivian tropical moist forest tree species that differ in their regeneration and adult light niche. Multiple regression analysis shows that leaf traits of seedlings, saplings, and trees are most strongly related to the regeneration niche, and once this is taken into account, adult niche does not significantly explain any of the remaining variation in leaf traits. This suggests that, although the regeneration phase is short, it has a long-lasting effect on the form and shape of plant species.     

The susceptibility and resilience of corals to thermal stress: adaptation,acclimatization or both?

Coral reefs are threatened with worldwide decline from multiple factors, chief among them climate change ( Hughes et al. 2003 ; Hoegh‐Guldberg et al. 2007 ). The foundation of coral reefs is an endosymbiosis between coral hosts and their resident photosynthetic dinoflagellates (genus Symbiodinium) and this partnership (or holobiont) is exquisitely sensitive to temperature stress. The primary response to hyperthermic stress is coral bleaching, which is the loss of symbionts from coral tissues—the collapse of the symbiosis ( Weis 2008 ). Bleaching can result in increased coral mortality which can ultimately lead to severely compromised reef health ( Hoegh‐Guldberg et al. 2007 ). Despite this grim picture of coral bleaching and reef degradation, coral susceptibility to stress and bleaching is highly variable ( Coles & Brown 2003 ). There is enormous interest in discovering the factors that determine susceptibility in order to help us predict if and how corals will survive a period of rapid global warming. In this issue, Barshis et al. (2010) examine the ecophysiological and genetic basis for differential responses to stress in Porites lobata in American Samoa. They combine a reciprocal transplant experimental design between two neighbouring, but very different reef environments with state‐of‐the‐art physiological biomarkers and molecular genetic markers for both partners to tease apart the contribution of environmental and fixed influences on stress susceptibility. Their results suggest the presence of a fixed, rather than environmental effect on expression of ubiquitin conjugates, one key marker for physiological stress response. In addition, the authors show genetic differentiation in host populations between the two sites suggesting strong selection for physiological adaptation to differing environments across small geographic distances. These conclusions point the study of coral resilience and susceptibility in a new direction.     

De novo DNA methyltransferases: oncogenes, tumor suppressors, or both?

Aberrant promoter DNA hypermethylation of tumor suppressor genes is a hallmark of cancer. This alteration is largely dependent on the action of de novo DNA methyltransferases (DNMTs) early during tumor progression, which supports the oncogenic role for these enzymes. However, recent research has identified several inactivating mutations of de novo DNMTs in various types of tumor. In addition, it has been shown that loss of de novo DNA methylation activity at advanced tumor stages leads to the promoter DNA demethylation-dependent expression of specific oncogenes. These new data support the notion that de novo DNMTs also have an important role in the maintenance of DNA methylation and suggest that, in addition to acting as oncogenes, they also behave as tumor suppressors. This potential dual role might have clinical implications, as DNMTs are currently considered bona fide targets in cancer therapy.     

Bridging consent: from toll bridges to lift bridges?

Background

One of the best and most accurate methods for identifying disease-causing genes is monitoring gene expression values in different samples using microarray technology. One of the shortcomings of microarray data is that they provide a small quantity of samples with respect to the number of genes. This problem reduces the classification accuracy of the methods, so gene selection is essential to improve the predictive accuracy and to identify potential marker genes for a disease. Among numerous existing methods for gene selection, support vector machine-based recursive feature elimination (SVMRFE) has become one of the leading methods, but its performance can be reduced because of the small sample size, noisy data and the fact that the method does not remove redundant genes.

Methods

We propose a novel framework for gene selection which uses the advantageous features of conventional methods and addresses their weaknesses. In fact, we have combined the Fisher method and SVMRFE to utilize the advantages of a filtering method as well as an embedded method. Furthermore, we have added a redundancy reduction stage to address the weakness of the Fisher method and SVMRFE. In addition to gene expression values, the proposed method uses Gene Ontology which is a reliable source of information on genes. The use of Gene Ontology can compensate, in part, for the limitations of microarrays, such as having a small number of samples and erroneous measurement results.

Results

The proposed method has been applied to colon, Diffuse Large B-Cell Lymphoma (DLBCL) and prostate cancer datasets. The empirical results show that our method has improved classification performance in terms of accuracy, sensitivity and specificity. In addition, the study of the molecular function of selected genes strengthened the hypothesis that these genes are involved in the process of cancer growth.

Conclusions

The proposed method addresses the weakness of conventional methods by adding a redundancy reduction stage and utilizing Gene Ontology information. It predicts marker genes for colon, DLBCL and prostate cancer with a high accuracy. The predictions made in this study can serve as a list of candidates for subsequent wet-lab verification and might help in the search for a cure for cancers.     

Death by chaperone: HSP90, HSP70 or both?

HSP70 family members are highly conserved proteins that function as molecular chaperones. Their principle role is to aid protein folding and promote the correct cellular localisations of their respective substrates. The function of HSP70 isoforms can be exhibited independently or with the HSP90 chaperone system in which HSP70 is important for substrate recruitment. In addition to their chaperone role, HSP70 isoforms promote cell survival by inhibiting apoptosis at multiple points within both the intrinsic and extrinsic cell death pathways. Consistent with this cytoprotective function, increased expression of HSP70 isoforms is commonly associated with the malignant phenotype. We recently reported that dual silencing of the major constitutive (HSC70) and inducible (HSP72) isoforms of HSP70 in cancer cells could phenocopy the effects of a pharmacologic HSP90 inhibitor to induce proteasome-dependent degradation of HSP90 client proteins CRAF, CDK4 and ERBB2. This was accompanied by a G1 cell cycle arrest and extensive apoptosis which was not seen in non-tumorigenic human cell lines. Here we discuss the possible implications of our research for the development of HSP70 family modulators which offer not only the possibility of inhibiting HSP70 activity but also the simultaneous inhibition of HSP90, resulting in extensive tumour-specific apoptosis.