GWAS is going to the dogs

Genome-wide association studies in canine models may help locate genomic susceptibility regions that are relevant to human disease. See related Research: http://genomebiology.com/2014/15/3/R25     

The FADD is going nuclear

Fas-associated death domain protein (FADD) is an adaptor molecule that bridges the interactions between membrane death receptors and initiator caspases. Thus, the site of its action has always been expected to be the cytoplasmic death-inducing signaling complex (DISC). Recent evidence indicates that FADD primarily resides in the nucleus and appears to shuttle between nucleus and cytoplasm. In addition to its well-established role in transduction of apoptotic signals, FADD may also play a role in regulating genome surveillance and perhaps in other as yet unidentified cellular processes.     

Endophyte research: going beyond isolation and metabolite documentation

Many fungi belonging to mostly Ascomycota inhabit living tissues of plants of all major lineages without causing any visible symptoms. Termed horizontally transmitted endophytes, they have been investigated mostly for their capacity to produce bioactive secondary metabolites. However, many questions regarding the interactions between endophytes and their plant hosts, phytophagous insects and other fungi remain unanswered. This review highlights some of these areas of endophyte biology about which very little or no knowledge exists. Information garnered' using modern methodologies' on these grey areas of ‘endophytism’ (endophytic mode of lifestyle) would help immensely in understanding the evolution of endophytes of aerial plant tissues and in exploiting endophytes in various fields of biotechnology.     

Repairing quite swimmingly: advances in regenerative medicine using zebrafish

Regenerative medicine has the promise to alleviate morbidity and mortality caused by organ dysfunction, longstanding injury and trauma. Although regenerative approaches for a few diseases have been highly successful, some organs either do not regenerate well or have no current treatment approach to harness their intrinsic regenerative potential. In this Review, we describe the modeling of human disease and tissue repair in zebrafish, through the discovery of disease-causing genes using classical forward-genetic screens and by modulating clinically relevant phenotypes through chemical genetic screening approaches. Furthermore, we present an overview of those organ systems that regenerate well in zebrafish in contrast to mammalian tissue, as well as those organs in which the regenerative potential is conserved from fish to mammals, enabling drug discovery in preclinical disease-relevant models. We provide two examples from our own work in which the clinical translation of zebrafish findings is either imminent or has already proven successful. The promising results in multiple organs suggest that further insight into regenerative mechanisms and novel clinically relevant therapeutic approaches will emerge from zebrafish research in the future.KEY WORDS: Regeneration, Zebrafish, Disease model, Gastrointestinal, Hematovascular     

Advances in vertebrate aging research 2007

Among this year's highlights in vertebrate aging research, we find a study in which, contrary to the oxidative stress hypothesis of aging, reduced expression of a major cellular antioxidant, glutathione peroxidase 4, led to a small increase in mouse lifespan. By contrast, a large comparative proteomic analysis discovered a remarkably robust and previous unsuspected inverse association between species lifespan and relative frequency of cysteine residues in mitochondrially encoded respiratory chain proteins only, which the authors attribute to cysteine's ease of oxidation. Another study evaluated more cleanly than any previous work the hypothesis that blood glucose concentration is a key mediator of aging, and concluded that it wasn't. Several new mouse longevity mutants were also reported this year, some ( PAPP-A, IRS-1 , and IRS-2 knockouts) supporting previous work on the importance of insulin/insulin-like growth factor-1 signaling and aging. However, there were inconsistencies between laboratories in some of the results, which merit further investigation. Also, somewhat inconsistent with these findings, over-expression of insulin-like growth factor-1 in heart only lengthened life. From a completely new direction, type 5 adenylyl cyclase knockout mice were observed to live more than 30% longer than controls. Finally, a new program for evaluating potential pharmaceutical interventions in aging and longevity made its appearance, and is notable at this point chiefly for the excellence of its experimental design. A similar program for the disinterested evaluation of reported longevity mutations in mice would be a service to the community of vertebrate aging researchers.     

Endoglin is expressed in the chicken vasculature and is involved in angiogenesis.

Endoglin is a component of the transforming growth factor beta (TGF-beta) receptor complex, highly expressed by endothelial cells. Mutations in the endoglin gene are responsible for hereditary hemorrhagic telangiectasia type 1 (HHT1), an autosomal dominant vascular disorder caused by a haploinsufficiency mechanism. Vascular lesions (telangiectasia and arteriovenous malformations) in HHT1 are associated with loss of the capillary network, suggesting the involvement of endoglin in vascular repair processes. Using the chick chorioallantoic membrane (CAM) as an angiogenic model, we have analyzed the expression and function of chicken endoglin. A pan-specific polyclonal antibody (pAb) recognized chicken endoglin as demonstrated by immunostaining and Western blot analysis. In ovo treatment of chicken embryos with this pAb resulted in a significantly increased area of CAM. This effect was likely mediated by modulation of the ligand binding to endoglin as this pAb was able to inhibit TGF-beta1 binding. These results support the involvement of endoglin in the angiogenic process.     

Gene transfer to the vasculature: historical perspective and implication for future research objectives

Cardiovascular diseases are a major cause of fatality, disability, and economic burden in Western civilization. Although the pharmaceutical industry has delivered a plethora of drugs for treatment of diverse cardiovascular complaints, there remain many conditions for which pharmacological regimens are either nonexistent or largely ineffective. In contrast, remarkable progress has been made in the field of vascular gene transfer in the last decade. The vast majority of studies are preclinical, although a number of high profile vascular gene therapy clinical trials are in progress. In principle, vascular gene therapy represents an unprecedented opportunity to treat a host of cardiovascular diseases in humans although many scientific, clinical, and ethical obstacles remain. Here we discuss the rapid progress in preclinical vascular gene therapy, highlight the most appropriate gene delivery vectors, and discuss the advances toward the ultimate goal of an efficient and safe gene therapy for diverse cardiovascular diseases.     

Recent advances in vertebrate aging research 2009

Among the notable trends seen in this year’s highlights in mammalian aging research is an awakening of interest in the assessment of age‐related measures of mouse health in addition to the traditional focus on longevity. One finding of note is that overexpression of telomerase extended life and improved several indices of health in mice that had previously been genetically rendered cancer resistant. In another study, resveratrol supplementation led to amelioration of several degenerative conditions without affecting mouse lifespan. A primate dietary restriction (DR) study found that restriction led to major improvements in glucoregulatory status along with provocative but less striking effects on survival. Visceral fat removal in rats improved their survival, although not as dramatically as DR. An unexpected result showing the power of genetic background effects was that DR shortened the lifespan of long‐lived mice bearing Prop1^df, whereas a previous report in a different background had found DR to extend the lifespan of Prop1^df mice. Treatment with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, enhanced the survival of even elderly mice and improved their vaccine response. Genetic inhibition of a TOR target made female, but not male, mice live longer. This year saw the mTOR network firmly established as a major modulator of mammalian lifespan.     

Forty-five years of split-brain research and still going strong

Forty-five years ago, Roger Sperry, Joseph Bogen and I embarked on what are now known as the modern split-brain studies. These experiments opened up new frontiers in brain research and gave rise to much of what we know about hemispheric specialization and integration. The latest developments in split-brain research build on the groundwork laid by those early studies. Split-brain methodology, on its own and in conjunction with neuroimaging, has yielded insights into the remarkable regional specificity of the corpus callosum as well as into the integrative role of the callosum in the perception of causality and in our perception of an integrated sense of self.     

The vertebrate primary cilium is a sensory organelle

The primary cilium is a generally non-motile cilium that occurs singly on most cells in the vertebrate body. The function of this organelle, which has been the subject of much speculation but little experimentation, has been unknown. Recent findings reveal that the primary cilium is an antenna displaying specific receptors and relaying signals from these receptors to the cell body. For example, kidney primary cilia display polycystin-2, which forms part of a Ca2+ channel that initiates a signal that controls cell differentiation and proliferation. Kidney primary cilia also are mechanosensors that, when bent, initiate a Ca2+ signal that spreads throughout the cell and to neighboring cells. Primary cilia on other cell types specifically display different receptors, including those for somatostatin and serotonin.