Functional diversity governs ecosystem response to nutrient enrichment

The relationship between species diversity and ecosystem functioning is a central topic in ecology today. Classical approaches to studying ecosystem responses to nutrient enrichment have considered linear food chains. To what extent ecosystem structure, that is, the network of species interactions, affects such responses is currently unknown. This severely limits our ability to predict which species or functional groups will benefit or suffer from nutrient enrichment and to understand the underlying mechanisms. Here our approach takes ecosystem complexity into account by considering functional diversity at each trophic level. We conducted a mesocosm experiment to test the effects of nutrient enrichment in a lake ecosystem. We developed a model of intermediate complexity, which separates trophic levels into functional groups according to size and diet. This model successfully predicted the experimental results, whereas linear food-chain models did not. Our model shows the importance of functional diversity and indirect interactions in the response of ecosystems to perturbations, and indicates that new approaches are needed for the management of freshwater ecosystems subject to eutrophication.     

Low-dose radiation accelerates aging of the T-cell receptor repertoire in CBA/Ca mice

While the biological effects of high-dose-ionizing radiation on human health are well characterized, the consequences of low-dose radiation exposure remain poorly defined, even though they are of major importance for radiological protection. Lymphocytes are very radiosensitive, and radiation-induced health effects may result from immune cell loss and/or immune system impairment. To decipher the mechanisms of effects of low doses, we analyzed the modulation of the T-cell receptor gene repertoire in mice exposed to a single low (0.1 Gy) or high (1 Gy) dose of radiation. High-throughput T-cell receptor gene profiling was used to visualize T-lymphocyte dynamics over time in control and irradiated mice. Radiation exposure induces “aging-like” effects on the T-cell receptor gene repertoire, detectable as early as 1 month post-exposure and for at least 6 months. Surprisingly, these effects are more pronounced in animals exposed to 0.1 Gy than to 1 Gy, where partial correction occurs over time. Importantly, we found that low-dose radiation effects are partially due to the hematopoietic stem cell impairment. Collectively, our findings show that acute low-dose radiation exposure specifically results in long-term alterations of the T-lymphocyte repertoire.     

Functionalizing hydrogen-bonded surface networks with self-assembled monolayers

One of the central challenges in nanotechnology is the development of flexible and efficient methods for creating ordered structures with nanometre precision over an extended length scale. Supramolecular self-assembly on surfaces offers attractive features in this regard: it is a 'bottom-up' approach and thus allows the simple and rapid creation of surface assemblies, which are readily tuned through the choice of molecular building blocks used and stabilized by hydrogen bonding, van der Waals interactions, pi-pi bonding or metal coordination between the blocks. Assemblies in the form of two-dimensional open networks are of particular interest for possible applications because well-defined pores can be used for the precise localization and confinement of guest entities such as molecules or clusters, which can add functionality to the supramolecular network. Another widely used method for producing surface structures involves self-assembled monolayers (SAMs), which have introduced unprecedented flexibility in our ability to tailor interfaces and generate patterned surfaces. But SAMs are part of a top-down technology that is limited in terms of the spatial resolution that can be achieved. We therefore rationalized that a particularly powerful fabrication platform might be realized by combining non-covalent self-assembly of porous networks and SAMs, with the former providing nanometre-scale precision and the latter allowing versatile functionalization. Here we show that the two strategies can indeed be combined to create integrated network-SAM hybrid systems that are sufficiently robust for further processing. We show that the supramolecular network and the SAM can both be deposited from solution, which should enable the widespread and flexible use of this combined fabrication method.     

Substrate-targeting gamma-secretase modulators

Selective lowering of Abeta42 levels (the 42-residue isoform of the amyloid-beta peptide) with small-molecule gamma-secretase modulators (GSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer's disease. To identify the target of these agents we developed biotinylated photoactivatable GSMs. GSM photoprobes did not label the core proteins of the gamma-secretase complex, but instead labelled the beta-amyloid precursor protein (APP), APP carboxy-terminal fragments and amyloid-beta peptide in human neuroglioma H4 cells. Substrate labelling was competed by other GSMs, and labelling of an APP gamma-secretase substrate was more efficient than a Notch substrate. GSM interaction was localized to residues 28-36 of amyloid-beta, a region critical for aggregation. We also demonstrate that compounds known to interact with this region of amyloid-beta act as GSMs, and some GSMs alter the production of cell-derived amyloid-beta oligomers. Furthermore, mutation of the GSM binding site in the APP alters the sensitivity of the substrate to GSMs. These findings indicate that substrate targeting by GSMs mechanistically links two therapeutic actions: alteration in Abeta42 production and inhibition of amyloid-beta aggregation, which may synergistically reduce amyloid-beta deposition in Alzheimer's disease. These data also demonstrate the existence and feasibility of 'substrate targeting' by small-molecule effectors of proteolytic enzymes, which if generally applicable may significantly broaden the current notion of 'druggable' targets.     

The CRISPR/Cas bacterial immune system cleaves bacteriophage and plasmid DNA

Bacteria and Archaea have developed several defence strategies against foreign nucleic acids such as viral genomes and plasmids. Among them, clustered regularly interspaced short palindromic repeats (CRISPR) loci together with cas (CRISPR-associated) genes form the CRISPR/Cas immune system, which involves partially palindromic repeats separated by short stretches of DNA called spacers, acquired from extrachromosomal elements. It was recently demonstrated that these variable loci can incorporate spacers from infecting bacteriophages and then provide immunity against subsequent bacteriophage infections in a sequence-specific manner. Here we show that the Streptococcus thermophilus CRISPR1/Cas system can also naturally acquire spacers from a self-replicating plasmid containing an antibiotic-resistance gene, leading to plasmid loss. Acquired spacers that match antibiotic-resistance genes provide a novel means to naturally select bacteria that cannot uptake and disseminate such genes. We also provide in vivo evidence that the CRISPR1/Cas system specifically cleaves plasmid and bacteriophage double-stranded DNA within the proto-spacer, at specific sites. Our data show that the CRISPR/Cas immune system is remarkably adapted to cleave invading DNA rapidly and has the potential for exploitation to generate safer microbial strains.