Inhibition of endogenous phosphodiesterase 7 promotes oligodendrocyte precursor differentiation and survival

During the development of the central nervous system (CNS), oligodendrocyte precursors (OPCs) are generated in specific sites within the neural tube and then migrate to colonize the entire CNS, where they differentiate into myelin-forming oligodendrocytes. Demyelinating diseases such as multiple sclerosis (MS) are characterized by the death of these cells. The CNS reacts to demyelination and by promoting spontaneous remyelination, an effect mediated by endogenous OPCs, cells that represent approximately 5–7 % of the cells in the adult brain. Numerous factors influence oligodendrogliogenesis and oligodendrocyte differentiation, including morphogens, growth factors, chemotropic molecules, extracellular matrix proteins, and intracellular cAMP levels. Here, we show that during development and in early adulthood, OPCs in the murine cerebral cortex contain phosphodiesterase-7 (PDE7) that metabolizes cAMP. We investigated the effects of different PDE7 inhibitors (the well-known BRL-50481 and two new ones, TC3.6 and VP1.15) on OPC proliferation, survival, and differentiation. While none of the PDE7 inhibitors analyzed altered OPC proliferation, TC3.6 and VP1.15 enhanced OPC survival and differentiation, processes in which ERK intracellular signaling played a key role. PDE7 expression was also observed in OPCs isolated from adult human brains and the differentiation of these OPCs into more mature oligodendroglial phenotypes was accelerated by treatment with both new PDE7 inhibitors. These findings reveal new roles for PDE7 in regulating OPC survival and differentiation during brain development and in adulthood, and they may further our understanding of myelination and facilitate the development of therapeutic remyelination strategies for the treatment of MS.     

Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation

While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor (GPCR) TGR5 and activate nuclear hormone receptors such as farnesoid X receptor alpha (FXR-alpha; NR1H4). FXR-alpha regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2) that inhibits the activity of other nuclear receptors. The FXR-alpha-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-alpha, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA-TGR5-cAMP-D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.     

Routing of anisotropic spatial solitons and modulational instability in liquid crystals

In certain materials, the spontaneous spreading of a laser beam (owing to diffraction) can be compensated for by the interplay of optical intensity and material nonlinearity. The resulting non-diffracting beams are called 'spatial solitons' (refs 1-3), and they have been observed in various bulk media. In nematic liquid crystals, solitons can be produced at milliwatt power levels and have been investigated for both practical applications and as a means of exploring fundamental aspects of light interactions with soft matter. Spatial solitons effectively operate as waveguides, and so can be considered as a means of channelling optical information along the self-sustaining filament. But actual steering of these solitons within the medium has proved more problematic, being limited to tilts of just a fraction of a degree. Here we report the results of an experimental and theoretical investigation of voltage-controlled 'walk-off' and steering of self-localized light in nematic liquid crystals. We find not only that the propagation direction of individual spatial solitons can be tuned by several degrees, but also that an array of direction-tunable solitons can be generated by modulation instability. Such control capabilities might find application in reconfigurable optical interconnects, optical tweezers and optical surgical techniques.     

Eight glacial cycles from an Antarctic ice core

The Antarctic Vostok ice core provided compelling evidence of the nature of climate, and of climate feedbacks, over the past 420,000 years. Marine records suggest that the amplitude of climate variability was smaller before that time, but such records are often poorly resolved. Moreover, it is not possible to infer the abundance of greenhouse gases in the atmosphere from marine records. Here we report the recovery of a deep ice core from Dome C, Antarctica, that provides a climate record for the past 740,000 years. For the four most recent glacial cycles, the data agree well with the record from Vostok. The earlier period, between 740,000 and 430,000 years ago, was characterized by less pronounced warmth in interglacial periods in Antarctica, but a higher proportion of each cycle was spent in the warm mode. The transition from glacial to interglacial conditions about 430,000 years ago (Termination V) resembles the transition into the present interglacial period in terms of the magnitude of change in temperatures and greenhouse gases, but there are significant differences in the patterns of change. The interglacial stage following Termination V was exceptionally long--28,000 years compared to, for example, the 12,000 years recorded so far in the present interglacial period. Given the similarities between this earlier warm period and today, our results may imply that without human intervention, a climate similar to the present one would extend well into the future.     

An autonomous molecular computer for logical control of gene expression

Early biomolecular computer research focused on laboratory-scale, human-operated computers for complex computational problems. Recently, simple molecular-scale autonomous programmable computers were demonstrated allowing both input and output information to be in molecular form. Such computers, using biological molecules as input data and biologically active molecules as outputs, could produce a system for 'logical' control of biological processes. Here we describe an autonomous biomolecular computer that, at least in vitro, logically analyses the levels of messenger RNA species, and in response produces a molecule capable of affecting levels of gene expression. The computer operates at a concentration of close to a trillion computers per microlitre and consists of three programmable modules: a computation module, that is, a stochastic molecular automaton; an input module, by which specific mRNA levels or point mutations regulate software molecule concentrations, and hence automaton transition probabilities; and an output module, capable of controlled release of a short single-stranded DNA molecule. This approach might be applied in vivo to biochemical sensing, genetic engineering and even medical diagnosis and treatment. As a proof of principle we programmed the computer to identify and analyse mRNA of disease-related genes associated with models of small-cell lung cancer and prostate cancer, and to produce a single-stranded DNA molecule modelled after an anticancer drug.     

Aldehyde suppression of copepod recruitment in blooms of a ubiquitous planktonic diatom

The growth cycle in nutrient-rich, aquatic environments starts with a diatom bloom that ends in mass sinking of ungrazed cells and phytodetritus. The low grazing pressure on these blooms has been attributed to the inability of overwintering copepod populations to track them temporally. We tested an alternative explanation: that dominant diatom species impair the reproductive success of their grazers. We compared larval development of a common overwintering copepod fed on a ubiquitous, early-blooming diatom species with its development when fed on a typical post-bloom dinoflagellate. Development was arrested in all larvae in which both mothers and their larvae were fed the diatom diet. Mortality remained high even if larvae were switched to the dinoflagellate diet. Aldehydes, cleaved from a fatty acid precursor by enzymes activated within seconds after crushing of the cell, elicit the teratogenic effect. This insidious mechanism, which does not deter the herbivore from feeding but impairs its recruitment, will restrain the cohort size of the next generation of early-rising overwinterers. Such a transgenerational plant-herbivore interaction could explain the recurringly inefficient use of a predictable, potentially valuable food resource--the spring diatom bloom--by marine zooplankton.