Tryptophan metabolites kynurenine and serotonin regulate fibroblast activation and fibrosis

Fibrosis is a pathological form of aberrant tissue repair, the complications of which account for nearly half of all deaths in the industrialized world. All tissues are susceptible to fibrosis under particular pathological sets of conditions. Though each type of fibrosis has characteristics and hallmarks specific to that particular condition, there appear to be common factors underlying fibrotic diseases. One of these ubiquitous factors is the paradigm of the activated myofibroblast in the promotion of fibrotic phenotypes. Recent research has implicated metabolic byproducts of the amino acid tryptophan, namely serotonin and kynurenines, in the pathology or potential pharmacologic therapy of fibrosis, in part through their effects on development of myofibroblast phenotypes. Here, we review literature underlying what is known mechanistically about the effects of these compounds and their respective pathways on fibrosis. Pharmacologic administration of kynurenine improves scarring outcomes in vivo likely not only through its well-characterized immunosuppressive properties but also via its demonstrated antagonism of fibroblast activation and of collagen deposition. In contrast, serotonin directly promotes activation of fibroblasts via activation of canonical TGF-β signaling, and overstimulation with serotonin leads to fibrotic outcomes in vivo. Recently discovered feedback inhibition between serotonin and kynurenine pathways also reveals more information about the cellular physiology of tryptophan metabolism and may also underlie possible paradigms for anti-fibrotic therapy. Together, understanding of the effects of tryptophan metabolism on modulation of fibrosis may lead to the development of new therapeutic avenues for treatment through exploitation of these effects.     

Stabilizing feedbacks in glacier-bed erosion

Glaciers often erode, transport and deposit sediment much more rapidly than nonglacial environments, with implications for the evolution of glaciated mountain belts and their associated sedimentary basins. But modelling such glacial processes is difficult, partly because stabilizing feedbacks similar to those operating in rivers have not been identified for glacial landscapes. Here we combine new and existing data of glacier morphology and the processes governing glacier evolution from diverse settings to reveal such stabilizing feedbacks. We find that the long profiles of beds of highly erosive glaciers tend towards steady-state angles opposed to and slightly more than 50 per cent steeper than the overlying ice-air surface slopes, and that additional subglacial deepening must be enabled by non-glacial processes. Climatic or glaciological perturbations of the ice-air surface slope can have large transient effects on glaciofluvial sediment flux and apparent glacial erosion rate.     

Fluctuations in sarcomere length in the chick anterior and posterior latissimus dorsi muscles during isometric contraction

Zusammenfassung Es wird gezeigt, dass die Schwankung der Sarkomerenlänge bei Benützung der «laser beam» — Methode während der isometrischen Kontraktion der M. latissimi dorsi beim Hühnchen verschieden war. Der Schwankungsumfang war in den vorderen und hinteren Muskeln ungefähr gleich (900 Å), hingegen war die Frequenz in den hinteren phasischen Muskeln dreimal höher als in den vorderen tonischen Muskeln.     

Genetic variation increases during biological invasion by a Cuban lizard

A genetic paradox exists in invasion biology: how do introduced populations, whose genetic variation has probably been depleted by population bottlenecks, persist and adapt to new conditions? Lessons from conservation genetics show that reduced genetic variation due to genetic drift and founder effects limits the ability of a population to adapt, and small population size increases the risk of extinction. Nonetheless, many introduced species experiencing these same conditions during initial introductions persist, expand their ranges, evolve rapidly and become invasive. To address this issue, we studied the brown anole, a worldwide invasive lizard. Genetic analyses indicate that at least eight introductions have occurred in Florida from across this lizard's native range, blending genetic variation from different geographic source populations and producing populations that contain substantially more, not less, genetic variation than native populations. Moreover, recently introduced brown anole populations around the world originate from Florida, and some have maintained these elevated levels of genetic variation. Here we show that one key to invasion success may be the occurrence of multiple introductions that transform among-population variation in native ranges to within-population variation in introduced areas. Furthermore, these genetically variable populations may be particularly potent sources for introductions elsewhere. The growing problem of invasive species introductions brings considerable economic and biological costs. If these costs are to be mitigated, a greater understanding of the causes, progression and consequences of biological invasions is needed.     

A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization

Extremes of the electrocardiographic QT interval, a measure of cardiac repolarization, are associated with increased cardiovascular mortality. We identified a common genetic variant influencing this quantitative trait through a genome-wide association study on 200 subjects at the extremes of a population-based QT interval distribution of 3,966 subjects from the KORA cohort in Germany, with follow-up screening of selected markers in the remainder of the cohort. We validated statistically significant findings in two independent samples of 2,646 subjects from Germany and 1,805 subjects from the US Framingham Heart Study. This genome-wide study identified NOS1AP (CAPON), a regulator of neuronal nitric oxide synthase, as a new target that modulates cardiac repolarization. Approximately 60% of subjects of European ancestry carry at least one minor allele of the NOS1AP genetic variant, which explains up to 1.5% of QT interval variation.     

AID in antibody perfection

Expressed immunoglobulin (Ig) genes undergo alterations in sequence and genomic structure in order to optimize antibody function. A single B cell-specific factor, activation-induced deaminase (AID), initiates these changes by deamination of cytosine to uracil. Uracil in DNA is encountered commonly, and conserved pathways are responsible for its faithful repair. However, at the Ig loci of B cells, AID-initiated damage is processed to produce three distinct outcomes: somatic hypermutation, class switch recombination and gene conversion. This review focuses on the role of AID in Ig gene diversification, emphasizing how AID functions within the mechanism of the Ig gene diversification pathway; and highlights open questions for future research, particularly the most provocative current question: what makes a gene a target for AID-initiated mutagenesis?     

Sensory maps in the olfactory cortex defined by long-range viral tracing of single neurons

Sensory information may be represented in the brain by stereotyped mapping of axonal inputs or by patterning that varies between individuals. In olfaction, a stereotyped map is evident in the first sensory processing centre, the olfactory bulb (OB), where different odours elicit activity in unique combinatorial patterns of spatially invariant glomeruli. Activation of each glomerulus is relayed to higher cortical processing centres by a set of ～20-50 'homotypic' mitral and tufted (MT) neurons. In the cortex, target neurons integrate information from multiple glomeruli to detect distinct features of chemically diverse odours. How this is accomplished remains unclear, perhaps because the cortical mapping of glomerular information by individual MT neurons has not been described. Here we use new viral tracing and three-dimensional brain reconstruction methods to compare the cortical projections of defined sets of MT neurons. We show that the gross-scale organization of the OB is preserved in the patterns of axonal projections to one processing centre yet reordered in another, suggesting that distinct coding strategies may operate in different targets. However, at the level of individual neurons neither glomerular order nor stereotypy is preserved in either region. Rather, homotypic MT neurons from the same glomerulus innervate broad regions that differ between individuals. Strikingly, even in the same animal, MT neurons exhibit extensive diversity in wiring; axons of homotypic MT pairs diverge from each other, emit primary branches at distinct locations and 70-90% of branches of homotypic and heterotypic pairs are non-overlapping. This pronounced reorganization of sensory maps in the cortex offers an anatomic substrate for expanded combinatorial integration of information from spatially distinct glomeruli and predicts an unanticipated role for diversification of otherwise similar output neurons.