Favorite Model Research Articles

The role of basic helix-loop-helix genes in vertebrate retinogenesis

The developing eye is a favorite model for the study of pattern formation and cell fate determination. Retinal neuron development, in particular, is an approachable system to study molecular and cellular aspects of cell determination and differentiation. Basic helix-loop-helix (bHLH) transcription factors are important regulators of retinal neurogenesis. Proneural bHLH genes have highly defined expression in the developing retina that are influenced by pattern formation and cell specification pathways. Each retinal cell class has unique bHLH requirements, implying that these genes regulate neuronal identity and function. Therefore, proneural genes represent a molecular focal point through which epithelial cells are transformed into a precise neural network. In this review, we focus on the bHLH factor Ath5, an important regulator of retinal ganglion cell development, and discuss factors that regulate its expression in the retina and the target genes through which it may confer specific neuronal properties.

Genome engineering via homologous recombination in mouse embryonic stem (ES) cells: an amazingly versatile tool for the study of mammalian biology.

The ability to introduce genetic modifications in the germ line of complex organisms has been a long-standing goal of those who study developmental biology. In this regard, the mouse, a favorite model for the study of the mammals, is unique: indeed not only is it possible since the late seventies, to add genes to the mouse genome like in several other complex organisms but also to perform gene replacement and modification. This has been made possible via two technological breakthroughs: 1) the isolation and culture of embryonic stem cells (ES), which have the unique ability to colonize all the tissues of an host embryo including its germ line; 2) the development of methods allowing homologous recombination between an incoming DNA and its cognate chromosomal sequence (gene "targeting"). As a result, it has become possible to create mice bearing null mutations in any cloned gene (knock-out mice). Such a possibility has revolutionized the genetic approach of almost all aspects of the biology of the mouse. In recent years, the scope of gene targeting has been widened even more, due to the refinement of the knock-out technology: other types of genetic modifications may now be created, including subtle mutations (point mutations, micro deletions or insertions, etc.) and chromosomal rearrangements such as large deletions, duplications and translocations. Finally, methods have been devised which permit the creation of conditional mutations, allowing the study of gene function throughout the life of an animal, when gene inactivation entails embryonic lethality. In this paper, we present an overview of the methods and scenarios used for the programmed modification of mouse genome, and we underline their enormous interest for the study of mammalian biology.

Insect photoperiodism and circadian clocks: models and mechanisms.

Photoperiodic clocks allow organisms to predict the coming season. In insects, the seasonal adaptive response mainly takes the form of diapause. The extensively studied photoperiodic clock in insects was primarily characterized by a "black-box" approach, resulting in numerous cybernetic models. This is in contrast with the circadian clock, which has been dissected pragmatically at the molecular level, particularly in Drosophila. Unfortunately, Drosophila melanogaster, the favorite model organism for circadian studies, does not demonstrate a pronounced seasonal response, and consequently molecular analysis has not progressed in this area. In the current article, the authors explore different ways in which identified molecular components of the circadian pacemaker may play a role in photoperiodism. Future progress in understanding the Drosophila circadian pacemaker, particularly as further output components are identified, may provide a direct link between the clock and photoperiodism. In addition, with improved molecular tools, it is now possible to turn to other insects that have a more dramatic photoperiodic response.

Expressed sequence tags from a NaCl-treated Suaedasalsa cDNA library

Past efforts to improve plant tolerance to osmotic stress have had limited success owing to the genetic complexity of stress responses. The first step towards cataloging and categorizing genetically complex abotic stress responses is the rapid discovery of genes by the large-scale partial sequencing of randomly selected cDNA clones or expressed sequence tags (ESTs). Suaeda salsa, which can survive seawater-level salinity, is a favorite halophytic model for salt tolerant research. We constructed a NaCl-treated cDNA library of Suaeda salsa and sequenced 1048 randomly selected clones, out of which 1016 clones produced readable sequences (773 showed homology to previously identified genes, 227 matched unknown protein coding regions, 16 anomalous sequences or sequences of bacterial origin were excluded from further analysis). By sequence analysis we identified 492 unique clones: 315 showed homology to previously identified genes, 177 matched unknown protein coding regions (101 of which have been found before in other organisms and 76 are completely novel). All our EST data are available on the Internet. We believe that our dbEST and the associated DNA materials will be a useful source to scientists engaging in stress-tolerance study.

What is the most promising strategy for the treatment of metastasizing melanoma?

The treatment of patients with metastasizing melanoma, still one of the most deadly diseases in modern medicine, ranks among the greatest challenges that a clinician has to face. Metastatic melanoma also is one of the most profound sources of clinical frustration, since it provides far more ultimately defeating experiences than clinical victories. At the same time, the fascinating biology of melanoma has invited the study of this neuroectodermal tumor as a model system for dissecting many of the key problems of modern oncology, ranging from molecular oncogenesis via the controls of tumor proliferation, apoptosis, invasion, metastasis, and angiogenesis to tumor immunosurveillance and tumor drug resistance. Together with the dire need to develop more effective treatment modalities for improving both life expectancy and quality of life of affected patients, this has made metastatic melanoma a favorite model for the exploration of innovative strategies for tumor management. Encouragingly, many of these have already generated very promising results in animal models. However, this impressive level of research progress in conquering melanoma in the animal room contrasts rather pitifully with the actual progress made on the ward. This CONTROVERSIES feature, therefore, critically and soberly reviews the state of the art of treating metastatic melanoma today (distinguishing between nodal and distant metastases), and sharply defines unresolved or comparatively neglected key problems. In addition, this feature highlights several novel, provocative, hitherto underappreciated, yet potentially promising treatment approaches that deserve systematic exploration. Hopefully, this will offer further inspiration for the design and pursuit of innovative anti-melanoma strategies off-the-beaten-track.

Featured organism: Danio rerio, the zebrafish

The zebrafish has long been a favourite model for the study of vertebrate development. Here we provide an overview of the current state of knowledge and resources for the study of this fish, with comments on the future direction of zebrafish genomics from Professor Mark Fishman and Dr Stephen Wilson.

Model selection for a medical diagnostic decision support system: a breast cancer detection case

There are a number of different quantitative models that can be used in a medical diagnostic decision support system (MDSS) including parametric methods (linear discriminant analysis or logistic regression), non-parametric models ( K nearest neighbor, or kernel density) and several neural network models. The complexity of the diagnostic task is thought to be one of the prime determinants of model selection. Unfortunately, there is no theory available to guide model selection. Practitioners are left to either choose a favorite model or to test a small subset using cross validation methods. This paper illustrates the use of a self-organizing map (SOM) to guide model selection for a breast cancer MDSS. The topological ordering properties of the SOM are used to define targets for an ideal accuracy level similar to a Bayes optimal level. These targets can then be used in model selection, variable reduction, parameter determination, and to assess the adequacy of the clinical measurement system. These ideas are applied to a successful model selection for a real-world breast cancer database. Diagnostic accuracy results are reported for individual models, for ensembles of neural networks, and for stacked predictors.

Finite difference modelling of P-wave scattering in the upper mantle

Summary Scattering within the upper mantle is prominently documented in the so-called high-frequency teleseismic Pn phase, generated by velocity fluctuations in the upper mantle. This phase is seen in many data sets from active and passive seismology. Whenever the source-generated frequencies are high enough (5–10 Hz) to allow their observation at large distances (>2000 km), this phase appears in the recordings of the Russian PNE programme, in other long-range refraction experiments, and in numerous recordings of earthquakes. Using a 2-D finite difference scheme we calculate complete synthetic seismograms in order to relate the scales of the fluctuation of the elastic parameters to wavefield properties. We discuss the influence of critical parameters on the scattering properties of the upper mantle and on the propagation mechanism of the teleseismic Pn: variations in vertical and horizontal correlation lengths, rms velocity fluctuations, thickness of the heterogeneous layer, and cross-correlation of P- and S-wave velocities. A teleseismic Pn phase arises only if the velocity fluctuations are strong enough to cause multiple scattering and if the horizontal correlation length exceeds the vertical by an order of magnitude. Our favourite model for the Russian PNE profiles includes a 100–150-km-thick zone of scatterers below the Moho, containing heterogeneities with a horizontal correlation length of 20 km, a vertical correlation length of 0.5 km and an rms velocity perturbation of 2 per cent, while keeping the P- and S-wave velocities correlated. As the teleseismic Pn is often observed, this scale of velocity fluctuations seems to be characteristic of the uppermost mantle. Anisotropy is likely to contribute to the inferred velocity fluctuations.

Featured organism: Danio rerio, the zebrafish.

The zebrafish has long been a favourite model for the study of vertebrate development. Here we provide an overview of the current state of knowledge and resources for the study of this fish, with comments on the future direction of zebrafish genomics from Professor Mark Fishman and Dr Stephen Wilson.

Danio rerio, the Zebrafish

The zebrafish has long been a favourite model for the study of vertebrate development. Here we provide an overview of the current state of knowledge and resources for the study of this fish, with comments on the future direction of zebrafish genomics from Professor Mark Fishman and Dr Stephen Wilson.

A Total Cost Comparison of Alternative Tolerancing Formulae

An important part of many engineering design projects is to specify the amount of variability permitted in critical characteristics of materials, components, and assembly. Different formulae have been suggested for relating input and output specifications. This article reviews the four basic tolerancing formulae that have appeared in the literature and shows that each solves a slightly different problem. In particular, optimal tolerances are based on costs and the probability distributions of input characteristics. Examples of alternative cost-distribution models are provided that support the use of each of the four basic formulae as well as a solution not related to any of these formulae. This establishes that optimal tolerancing is influenced by issues not explicitly considered in the traditional debate over worst-case vs. statistical tolerancing. The approach here differs from previous optimal tolerancing studies in two respects. First, earlier work optimized the allocation of tolerances to components to achieve a given assembly tolerance, while we seek global optima. Second, earlier studies advocated an author’s favorite model, while we explore the relative domains of applicability of alternative formulae.

Inductive competence, its significance in retinal cell fate determination and a role for Delta–Notch signaling

The retina is a favorite model for studying determination and differentiation in the central nervous system because of its ready accessibility, diversity of cell types and regular organization. Many molecules which act as potential inducers of cell fate have been identified by exposing progenitors to them and assaying their differentiation. In addition, heterochronic transplants demonstrate that regulation of cellular competence (i.e. the ability of progenitors to respond to inducers) plays an important role in differentiation. The neurogenic genes Deltaand Notchacting as ligand and receptor, respectively, play a role in regulating cell competence by normally inhibiting progenitors from differentiating. Misexpression of an activated form of Notch `freezes' progenitors in an undifferentiated, neuroepithelial state. Conversely, progenitors failing to be inhibited, either by their own overexpression of Delta, or by a dominant-negative Delta construct which blocks signaling, adopt the earliest fates generated in the retina (i.e. cones and ganglion cells). We suggest that retinal progenitors use lateral inhibition mediated by Delta–Notch to regulate their competence to respond to inductive cues in a changing environment. Such signaling is essential for formation of the proper cell types in appropriate numbers at the right stage of development to make functional circuits.

Light-dependent production of ethylene in Tillandsia usneoides L.

Tillandsia usneoides L. is a favorite model plant for investigating ethylene biosynthesis because no soil is needed for cultivation (important for long-term measurements) and small plants and different clones are available. We investigated the endogenous production of ethylene in relation to temperature, light, daylength and CO2 concentration. Using a novel and most sensitive technique to measure ethylene, laser-driven photoacoustic spectroscopy, real-time online measurements were performed. Since T. usneoides is a crassulacean acid metabolism (CAM) plant and does not take up CO2 during the day we could show that ethylene production is strictly light dependent and does not follow any endogenous rhythm. In contrast to reports on other plants, CO2 concentration did not influence the production of ethylene by T. usneoides. However, high ethylene production was obtained after application of 1-aminoacyclopropane-1-carboxylic acid (ACC).

A molecular evolutionary framework for the phylum Nematoda.

Nematodes are important: parasitic nematodes threaten the health of plants, animals and humans on a global scale; interstitial nematodes pervade sediment and soil ecosystems in overwhelming numbers; and Caenorhabditis elegans is a favourite experimental model system. A lack of clearly homologous characters and the absence of an informative fossil record have prevented us from deriving a consistent evolutionary framework for the phylum. Here we present a phylogenetic analysis, using 53 small subunit ribosomal DNA sequences from a wide range of nematodes. With this analysis, we can compare animal-parasitic, plant-parasitic and free-living taxa using a common measurement. Our results indicate that convergent morphological evolution may be extensive and that present higher-level classification of the Nematoda will need revision. We identify five major clades within the phylum, all of which include parasitic species. We suggest that animal parasitism arose independently at least four times, and plant parasitism three times. We clarify the relationship of C. elegans to major parasitic groups; this will allow more effective exploitation of our genetic and biological knowledge of this model species.

Drosophila Immune Responses as Models for Human Immunity

Why do insects need immune defenses? They are so small and multiply so rapidly that it is understandable to think that, although infected individuals might die, the species could survive by sheer reproductive capacity. The fallacy of this reasoning is in the numbers. Under optimal conditions, bacteria double every 20 min or so, whereas even the rapidly maturing (and favorite model) insect, the fruit fly Drosophila melanogaster, requires close to 2 wk to reproduce. If insects were unable to fight off bacterial infections, they would never survive to reproductive maturity.

Gamma Ray Bursts

When Mal so ended the first theory review on gamma-ray bursts (GRBs), I was on the other side of the world, practicing my fractions. But had he spoken these same words at the end of the fifth Huntsville GRB meeting in October 1999, his favorite model (though not his reasoning) would have been instantly recognized by all present as a very plausible and popular contender for GRBs. His dark horse is still easily identified with soft gamma repeaters — Plus ca change, plus que ca reste le meme. What happened roughly in between the two events is the topic of this tale. We shall see how the field emerged out of the mutual distrust of the Cold War adversaries in the 1960s, and was finally resolved by a determined effort of just about the entire membership of the United Nations in the late 1990s. Its progress, of course, was in fits and starts, interwoven with stagnation and frustration.

Towards a reconciliation of the introns early or late views: triosephosphate isomerase genes from insects

The gene encoding the glycolytic enzyme, triosephosphate isomerase (TPI; EC 5.3.1.1), is a favourite model for molecular evolutionists who either subscribe to the theory that introns co-evolved with the ancestral gene, the introns early view, or alternatively, that introns are more recent immigrants. The discovery of an intron in the TPI gene of Culex mosquitoes at a site which was predicted by proponents of the intron early school supported that theory. More recently, the discovery of additional intron sites in several eukaryotes was presented as evidence supporting the introns late school. We have found the ` Culex intron' in two closely related mosquitoes, but not in two more evolutionary primitive Dipterans, suggesting that, if it is an `ancient intron', loss may be more frequent than that supposed by the intron late school. In addition, we have found that three introns punctuating the TPI gene from the Lepidopteran, Heliothis, appear to be ancestrally related and may be the result of transposable element insertion, 50–90 million years ago. It is argued that both opposing schools in the intron debate be reconciled — some introns may have been early and certainly others have arrived subsequent to the appearance of the TPI gene.

Learner Attitudes and L2 Pronunciation in Austria

In the context of pronunciation teaching, the relevance of a standard native accent as teaching model and norm needs to be reconsidered in view of the learners’ attainment as well as their wishes and expectations. In order to test attitudes to native and non‐native varieties of English in Austria, a language attitude study was undertaken with 132 university students of English. In response to the modified matched‐guise test, the subjects evaluated three native accents RP (Received Pronunciation), near‐RP and GA (General American) and two Austrian non‐native accents of English. The results confirm the low status the non‐native accents have amongst their users and the overall preference for the three native accents. Generally, the respondents rate the accent best with which they have become familiar at school and/or during stays in English‐speaking countries. Reflecting historical and geopolitical circumstances, the majority of the subjects support RP as their favourite model of pronunciation. Furthermore, the study sheds light on the importance of personal exposure to English in its native environments. While the evaluations of the students with EFL experience reflect rather rigid stereotypes, those students who have spent some time in English‐speaking countries reveal more individualized, situation‐linked attitudes.

Harold Pfeiffer, 1908-1997

[Harold Pfieffer is best remembered for his bronze portraits of aboriginal peoples.] ... He had a special empathy with elderly Native people such as his favourite model, Satkatsiak of the Spence Bay region, with her weathered face, tattoos, and tales of the old days, good and bad. Harold rightly saw his bronze portraits as an indelible record of a vanishing way of life. Many of them can be seen in the Prince of Wales Northern Heritage Centre in Yellowknife and at the Glenbow Museum in Calgary. ... Harold went around the world several times as artist-in-residence aboard an educational cruise ship. He was a raconteur, a humorist, an unabashed name-dropper, a keen observer, and a good listener. His talents served him well in 1988, when he obtained access to Chukotka as a guest of the Soviet government, and completed his collection of portraits of indigenous people around the Northern Hemisphere. ...

Putnam's Brain-Teaser

1. Metaphysical Realists have traditionally relied upon the skeptic to give substance to the idea that truth is, in the words of Hilary Putnam, 'radically non-episternic,’ forever outstripping, in principle at least, the reach of justification. What better model of truth so conceived, after all, than the skeptic's contention that even our firmest convictions might be mistaken in that we might be the victims of demonic deception or the machinations of an evil scientist? But the availability of this favorite model of Realist truth, encapsulated in the claim that we might be ‘brains in avat,’has been called into question by Putnam in the opening chapter ofReason, Truth, and History.Putnam contends that, if we grant the Realist notion of truth, as referentially mediated correspondence to THE WORLD, then, given certain plausible constraints on reference, we can know that we arenotbrains in a vat (or, more accurately, ‘brains in avat'of a particular kind, as we shall see).