Folding of the SAM-I riboswitch: A tale with a twist

Riboswitches are ligand-dependent RNA genetic regulators that control gene expression by altering their structures. The elucidation of riboswitch conformational changes before and after ligand recognition is crucial to understand how riboswitches can achieve high ligand binding affinity and discrimination against cellular analogs. The detailed characterization of riboswitch folding pathways suggest that they may use their intrinsic conformational dynamics to sample a large array of structures, some of which being nearly identical to ligand-bound molecules. Some of these structural conformers can be "captured" upon ligand binding, which is crucial for the outcome of gene regulation. Recent studies about the SAM-I riboswitch have revealed unexpected and previously unknown RNA folding mechanisms. For instance, the observed helical twist of the P1 stem upon ligand binding to the SAM-I aptamer adds a new element in the repertoire of RNA strategies for recognition of small metabolites. From an RNA folding perspective, these findings also strongly indicate that the SAM-I riboswitch could achieve ligand recognition by using an optimized combination of conformational capture and induced-fit approaches, a feature that may be shared by other RNA regulatory sequences.     

Cultivation of recalcitrant microbes: cells are alive,well and revealing their secrets in the 21st century laboratory

Any talk of the demise of in vitro cultivation as a useful mechanism for revealing many of nature's past and present secrets appears to be unfounded and premature. The first years of this century have been as productive in the cultivation of physiologically novel, environmentally abundant and phylogenetically distinct microbes as were the first years of the 20th century. The diversity of organic and inorganic electron donors and acceptors known to be used during microbial energy metabolisms continues to grow, expanding our appreciation for the niches that may be, or historically may have been, filled by microbes in the biosphere. Either guided and instigated by, or independent of, the results of gene inventories representing diverse environmental settings, significant advances are constantly being made in the isolation of bacteria and archaea, demonstrating either strikingly rich phylogenetic diversity or significant activity and abundance in their respective environments. The potential synergisms between molecular ecological analyses and innovative in vitro growth studies are real and should be embraced, rather than treated as dueling agents in some zero-sum game.     

A tale in molecular recognition: the hammerhead ribozyme

A new crystal structure of the hammerhead ribozyme demonstrates the influence of peripheral tertiary contacts on the local conformations around the active site. This structure resolves many conflicting results obtained on reduced systems.     

Removing all obstacles: A critical role for p53 in promoting tissue renewal

Defects in DNA repair pathways or exposure to high levels of DNA damaging agents limit the renewal potential of adult tissues and accelerate the development of age-related degenerative pathologies.^1-3 Many studies suggest these tissue homeostatic defects can result from the accumulation of DNA damage in tissue-specific stem cells.^{4, 5} Although maintenance of genome integrity in progenitor cells is required for the renewal of adult tissues, recent studies have highlighted the importance of additional mechanisms that facilitate and direct the process of tissue regeneration. These reports indicate that the p53 tumor suppressor gene maintains adult tissue homeostasis and promotes tissue renewal by suppressing the accumulation of DNA-damaged cells.^6-8 Without p53, tissue deterioration caused by the elimination of genome maintenance regulators (ATR, Hus1 or Terc) is exacerbated and, in some cases, leads to synthetic lethality at the organismal level. Importantly, the accumulation of highly damaged cells in multiple tissues appears to severely impede regeneration from undamaged progenitors, suggesting that p53-mediated removal of damaged cells is a prerequisite for efficient progenitor driven renewal. These findings argue that tissue homeostasis is governed not only by the intrinsic repopulating potential of competent progenitors, but also by mechanisms that limit the accumulation of defective cells and, thereby, promote compensatory regeneration. As discussed in this review, these findings advance our understanding of mechanisms that counter the effects of DNA damage at the tissue level and have important implications for the development of therapeutic approaches to combating age-related pathologies and p53-deficient malignancies.     

Hyperelastic modeling of the combined effects of tissue swelling and deformation-related collagen renewal in fibrous soft tissue

A continuum mechanics constitutive model is presented for the interaction between swelling and collagen remodeling in biological soft tissue. The model is inherently two-way: swelling stretches the collagen fibers which affects their rate of degradation—the remodeled fibrous microarchitecture provides selective directional stiffening that causes the swollen tissue to expand more in the unreinforced directions. The constitutive model specifically treats stretch-stabilization wherein the rate of enzymatic-induced degradation of collagen is a decreasing function of fiber stretch. New collagen replacement takes place in a generally swollen environment, and this synthesis is tracked as a function of time by means of a time integration scheme that accounts for the historical sequence of collagen recreation. The model allows for the specification of the collagen pre-stretch at the time of first synthesis, thus allowing for the consideration of either initially limp replacement fiber or initially pre-tensioned replacement fiber. Loading and swelling that occurs on time scales that are commensurate with the natural time scales for fiber degradation and replacement lead to the consideration of time-integral constitutive equations. Loading and swelling that take place on time scales that are very different from that of the remodeling time scales provide a simplified treatment in which there are definite notions of a short-time instantaneous response and also a large-time approach to a steady-state condition of homeostasis.