How to reach the right size?

Very little is known about how the size of an organism, or a specific tissue in an organism, is regulated. Coordinating and regulating the size of tissues is necessary for proper development, wound healing, and regeneration. Defects in a tissue-size regulation mechanism could lead to birth defects or cancer. In addition, there is a strong psychological aspect to some areas of tissue size regulation, as many cosmetic surgery procedures involve enlarging or reducing the size of some body parts. This review addresses the little bit that we know about size regulation. A key concept is that the size of a tissue is the size of the component cells multiplied by the number of those cells. This breaks the size regulation problem down to two parts. The size of cells can be regulated by nutrient sensing and secreted factors, and may have an upper limit due to an upper limit of a genome's ability to produce mRNA's and thus proteins. To regulate the number of cells in a tissue, there are several simple theoretical models involving secreted factors. In one case, the cells can secrete a characteristic factor and the concentration of the factor will increase with the number of cells secreting it, allowing the tissue to sense its own size. In another scenario, a specific cell secretes a limited amount of a factor necessary for the survival of a target population, and this then limits the size of the target population. There are currently several examples of secreted factors that regulate tissue size, including myostatin, which regulates the amount of muscles, leptin, which regulates adipose tissue, and growth hormone and insulin-like growth factors which regulate total mass. In addition, there are factors such as the found in Dictyostelium that regulate the breakup of a tissue into sub-groups. A better understanding of how these factors regulate size will hopefully allow us to develop new therapeutic procedures to treat birth defects or diseases that affect tissue size.     

The right time,the right place: will targeting human cancer-associated mutations to the mouse provide the perfect preclinical model?

Over the past 10 years the realisation that genetic mouse models of cancer may play a key role in preclinical drug development has gained strong momentum. Moreover sequencing studies of human tumours have provided key insights into the mutational complexity of epithelial cancer, unleashing important clues for researchers to generate accurate genetically engineered mouse (GEM) models of cancer. Thus by targeting multiple cancer associated human mutations to the appropriate murine epithelia, mice develop tumours that more closely recapitulate the human disease. As a number of excellent models now exist, the next 5-10 years will ascertain whether these models will predict response of human cancer to intervention. If so they might become the 'gold standard' where all drugs are required to be tested in mouse models of disease before proceeding into the patient. However, although this principle is very attractive, it is relatively untested and here, using examples of prevalent human cancers, we will review the latest data on preclinical GEM studies and comment on what challenges are left to overcome.     

Choosing the right path: does DNA-PK help make the decision?

DNA double-strand breaks are extremely harmful lesions that can lead to genomic instability and cell death if not properly repaired. There are at least three pathways that are responsible for repairing DNA double-strand breaks in mammalian cells: non-homologous end joining, homologous recombination and alternative non-homologous end joining. Here we review each of these three pathways with an emphasis on the role of the DNA-dependent protein kinase, a critical component of the non-homologous end joining pathway, in influencing which pathway is ultimately utilized for repair.     

Looking for food in all the right places?

Examining a potential functional role for growth hormone secretagogue receptors in the hippocampus, Diano and colleagues (Diano et al., 2006), demonstrate novel actions of the orexigenic peptide ghrelin in hippocampal synaptic architecture, LTP, and learning and memory. These data suggest functional links between metabolic signaling and higher neural function.     

Principle or pathology? Adjudicating the right to conscience in the Israeli military

The Israeli military's Conscience Committee evaluates and exempts pacifists from obligatory military service, based explicitly on concern for liberal tolerance. However, I found that liberal pacifist applicants’ principled objections to violence challenged the state, and as such, applicants who articulated their refusal in such terms are rejected by the military review board. By contrast, pacifist conscientious objection based in embodied visceral revulsion to violence did not challenge the state and moral order, and such cases were granted exemption. Objections based in understanding pacifism as a physical incapacity depoliticizes it by making it incommensurable with public moral debate concerning military service. The pathologization of pacifism demonstrates a contradiction between liberalism's ideology and its practices, revealing that the limits of liberalism are not only exterior, in nonliberal alterity, but also on liberalism's own interior frontiers.     

Clockwise or anticlockwise? Turning the centriole triplets in the right direction!

Centrosomes are small cytoplasmic macromolecular assemblies composed from two major components, centrioles and pericentriolar material, each with its own complex architecture. This organelle is of interest because it plays a role in a number of fundamental cellular processes and defects in these processes have recently been correlated with variety of human disease. Increasingly, what is known about the structure of this organelle has been overshadowed by the increasing wealth of information on its biochemistry. In this short review, we highlight some of the common centriole structural errors found in the literature and define a set of rules that define centriole structure.     

Where is the right path heading from the centromere to spindle microtubules?

The kinetochore is a large protein complex that ensures accurate chromosome segregation during mitosis by connecting the centromere and spindle microtubules. One of the kinetochore sub-complexes, the constitutive centromere-associated network (CCAN), associates with the centromere and recruits another sub-complex, the KMN (KNL1, Mis12, and Ndc80 complexes) network (KMN), which binds to spindle microtubules. The CCAN-KMN interaction is mediated by two parallel pathways (CENP-C- and CENP-T-pathways) in the kinetochore, which bridge the centromere and microtubules. Here, we discuss dynamic protein-interaction changes in the two pathways that couple the centromere with spindle microtubules during mitotic progression.     

Recruitment of marine species: Is the bandwagon rolling in the right direction?

A highly variable rate of recruitment from pelagic larval to demersal or sessile juvenile and adult stage is characteristic of marine organisms. At present it is a major subject of attention by ecologists interested in population or community processes. Several factors conspire to ensure this variability, but in studying them it will be important to focus on the behavioral capabilities of marine larvae, and on the very small proportion of (perhaps lucky) larvae destined to be successful.     

Golgi positioning: are we looking at the right MAP?

One of the characteristics of the mammalian Golgi is its position adjacent to the nucleus. This characteristic is maintained through the action of the microtubule (MT) minus end-directed motor dynein and MT-associated proteins (MAPs). Recent findings suggest that GMAP-210, a member of the golgin family of proteins, may help to link Golgi membranes and vesicles with the MT cytoskeleton. However, there are good grounds to doubt that either GMAP-210 or its yeast homologue Rud3p is a MAP. Instead, they appear to function in vesicle trafficking events at the Golgi together with the GTPase ARF1 and a small membrane protein, Erv14. As such, the interesting question of how the Golgi interacts with MTs may well remain open to further investigation.