The reversible and dynamic nature of non-covalent interactions between the constituting building blocks renders many supramolecular polymers stimuli-responsive. This was previously exploited to ...create thermally and optically healable polymers, but it proved challenging to achieve high stiffness and good healability. Here we present a glass-forming supramolecular material that is based on a trifunctional low-molecular-weight monomer ((UPyU)3TMP). Carrying three ureido-4-pyrimidinone (UPy) groups, (UPyU)3TMP forms a dynamic supramolecular polymer network, whose properties are governed by its cross-linked architecture and the large content of the binding motif. This design promotes the formation of a disordered glass, which, in spite of the low molecular weight of the building block, displays typical polymeric behaviour. The material exhibits a high stiffness and offers excellent coating and adhesive properties. On account of reversible dissociation and the formation of a low-viscosity liquid upon irradiation with ultraviolet light, rapid optical healing as well as (de)bonding on demand is possible.
A tri‐federal initiative arising out of the Cancer Moonshot has resulted in the formation of a program to utilize advanced genomic and proteomic expression platforms on high‐quality human ...biospecimens in near‐real‐time in order to identify potentially actionable therapeutic molecular targets, study the relationship of molecular findings to cancer treatment outcomes, and accelerate novel clinical trials with biomarkers of prognostic and predictive value.
Sponges have long been known to be ecologically important members of the benthic fauna on coral reefs. Recently, it has been shown that sponges are also important contributors to the nitrogen ...biogeochemistry of coral reefs. The studies that have been done show that most sponges are net sources of dissolved inorganic nitrogen (DIN; NH4 (+) and NO3 (-)) and that nitrification, mediated by their symbiotic prokaryotes, is the primary process involved in supplying DIN to adjacent reefs.
A natural experiment was conducted with the Caribbean sponge Xestospongia muta from three different locations (Florida Keys, USA; Lee Stocking Island, Bahamas and Little Cayman, Cayman Islands). The DIN fluxes of sponges were studied using nutrient analysis, stable isotope ratios, and isotope tracer experiments. Results showed that the fluxes of DIN were variable between locations and that X. muta can be either a source or sink of DIN. Stable isotope values of sponge and symbiotic bacterial fractions indicate that the prokaryotic community is capable of taking up both NH4 (+) and NO3 (-) while the differences in δ (15)N between the sponge and bacterial fractions from the NH4 (+) tracer experiment suggest that there is translocation of labeled N from the symbiotic bacteria to the host.
Nitrogen cycling in X. muta appears to be more complex than previous studies have shown and our results suggest that anaerobic processes such as denitrification or anammox occur in these sponges in addition to aerobic nitrification. Furthermore, the metabolism of this sponge and its prokaryotic symbionts may have a significant impact on the nitrogen biogeochemistry on Caribbean coral reefs by releasing large amounts of DIN, including higher NH4 (+) concentrations that previously reported.
Nearly two decades after Westhof and Michel first proposed that RNA tetraloops may interact with distal helices, tetraloop–receptor interactions have been recognized as ubiquitous elements of RNA ...tertiary structure. The unique architecture of GNRA tetraloops (N=any nucleotide, R=purine) enables interaction with a variety of receptors, e.g., helical minor grooves and asymmetric internal loops. The most common example of the latter is the GAAA tetraloop–11 nt tetraloop receptor motif. Biophysical characterization of this motif provided evidence for the modularity of RNA structure, with applications spanning improved crystallization methods to RNA tectonics. In this review, we identify and compare types of GNRA tetraloop–receptor interactions. Then we explore the abundance of structural, kinetic, and thermodynamic information on the frequently occurring and most widely studied GAAA tetraloop–11 nt receptor motif. Studies of this interaction have revealed powerful paradigms for structural assembly of RNA, as well as providing new insights into the roles of cations, transition states and protein chaperones in RNA folding pathways. However, further research will clearly be necessary to characterize other tetraloop–receptor and long-range tertiary binding interactions in detail – an important milestone in the quantitative prediction of free energy landscapes for RNA folding.
Compared to our understanding of the taxonomic composition of the symbiotic microbes in marine sponges, the functional diversity of these symbionts is largely unknown. Furthermore, the application of ...genomic, transcriptomic, and proteomic techniques to functional questions on sponge host-symbiont interactions is in its infancy. In this study, we generated a transcriptome for the host and a metatranscriptome of its microbial symbionts for the giant barrel sponge, Xestospongia muta, from the Caribbean. In combination with a gene-specific approach, our goals were to (1) characterize genetic evidence for nitrogen cycling in X. muta, an important limiting nutrient on coral reefs (2) identify which prokaryotic symbiont lineages are metabolically active and, (3) characterize the metabolic potential of the prokaryotic community. Xestospongia muta expresses genes from multiple nitrogen transformation pathways that when combined with the abundance of this sponge, and previous data on dissolved inorganic nitrogen fluxes, shows that this sponge is an important contributor to nitrogen cycling biogeochemistry on coral reefs. Additionally, we observed significant differences in gene expression of the archaeal amoA gene, which is involved in ammonia oxidation, between coral reef locations consistent with differences in the fluxes of dissolved inorganic nitrogen previously reported. In regards to symbiont metabolic potential, the genes in the biosynthetic pathways of several amino acids were present in the prokaryotic metatranscriptome dataset but in the host-derived transcripts only the catabolic reactions for these amino acids were present. A similar pattern was observed for the B vitamins (riboflavin, biotin, thiamin, cobalamin). These results expand our understanding of biogeochemical cycling in sponges, and the metabolic interchange highlighted here advances the field of symbiont physiology by elucidating specific metabolic pathways where there is high potential for host-prokaryote interactions.
Metastasis suppressors comprise a growing class of genes whose downregulation triggers metastatic progression. In contrast to tumor suppressors, metastasis suppressors are rarely mutated or deleted, ...and little is known regarding the mechanisms by which their expression is downregulated. Here, we demonstrate that the metastasis suppressor, NM23-H1, is degraded by lysosomal cysteine cathepsins (L,B), which directly cleave NM23-H1. In addition, activation of c-Abl and Arg oncoproteins induces NM23-H1 degradation in invasive cancer cells by increasing cysteine cathepsin transcription and activation. Moreover, c-Abl activates cathepsins by promoting endosome maturation, which facilitates trafficking of NM23-H1 to the lysosome where it is degraded. Importantly, the invasion- and metastasis-promoting activity of c-Abl/Arg is dependent on their ability to induce NM23-H1 degradation, and the pathway is clinically relevant as c-Abl/Arg activity and NM23-H1 expression are inversely correlated in primary breast cancers and melanomas. Thus, we demonstrate a novel mechanism by which cathepsin expression is upregulated in cancer cells (via Abl kinases). We also identify a novel role for intracellular cathepsins in invasion and metastasis (degradation of a metastasis suppressor). Finally, we identify novel crosstalk between oncogenic and metastasis suppressor pathways, thereby providing mechanistic insight into the process of NM23-H1 loss, which may pave the way for new strategies to restore NM23-H1 expression and block metastatic progression.
Entropic origin of Mg2+-facilitated RNA folding Fiore, Julie L; Holmstrom, Erik D; Nesbitt, David J
Proceedings of the National Academy of Sciences - PNAS,
02/2012, Letnik:
109, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Mg2+ is essential for the proper folding and function of RNA, though the effect of Mg2+ concentration on the free energy, enthalpy, and entropy landscapes of RNA folding is unknown. This work ...exploits temperature-controlled single-molecule FRET methods to address the thermodynamics of RNA folding pathways by probing the intramolecular docking/undocking kinetics of the ubiquitous GAAA tetraloop–receptor tertiary interaction as a function of Mg2+. These measurements yield the barrier and standard state enthalpies, entropies, and free energies for an RNA tertiary transition, in particular, revealing the thermodynamic origin of Mg2+-facilitated folding. Surprisingly, these studies reveal that increasing Mg2+ promotes tetraloop–receptor interaction by reducing the entropic barrier (Formula ) and the overall entropic penalty (Formula ) for docking, with essentially negligible effects on both the activation enthalpy (Formula ) and overall exothermicity (Formula ). These observations contrast with the conventional notion that increasing Mg2+ facilitates folding by minimizing electrostatic repulsion of opposing RNA helices, which would incorrectly predict a decrease in Formula and Formula with Mg2+. Instead we propose that higher Mg2+ can aid RNA folding by decreasing the entropic penalty of counterion uptake and by reducing disorder of the unfolded conformational ensemble.
Despite 35 years of clinical trials, there is little improvement in 1-year survival rates for patients with metastatic melanoma, and the disease is essentially untreatable if not cured surgically. ...The paucity of chemotherapeutic agents that are effective for treating metastatic melanoma indicates a dire need to develop new therapies. Here, we found a previously unrecognized role for c-Abl and Arg in melanoma progression. We demonstrate that the kinase activities of c-Abl and Arg are elevated in primary melanomas (60%), in a subset of benign nevi (33%) and in some human melanoma cell lines. Using siRNA and pharmacological approaches, we show that c-Abl/Arg activation is functionally relevant because it is requiredfor melanoma cell proliferation, survival and invasion. Significantly, we identify the mechanism by which activated c-Abl promotes melanoma invasion by showing that it transcriptionally upregulates matrix metalloproteinase-1 (MMP-1), and using rescue approaches we demonstrate that c-Abl promotes invasion through a STAT3 → MMP-1 pathway. Additionally, we show that c-Abl and Arg are not merely redundant, as active Arg drives invasion in a STAT3-independent manner, and upregulates MMP-3 and MT1-MMP, in addition to MMP-1. Most importantly, c-Abl and Arg not only promote in vitro processes important for melanoma progression, but also promote metastasis in vivo, as inhibition of c-Abl/Arg kinase activity with the c-Abl/Arg inhibitor, nilotinib, dramatically inhibits metastasis in a mouse model. Taken together, these data identify c-Abl and Arg as critical, novel, drug targets in metastatic melanoma, and indicate that nilotinib may be useful in preventing metastasis in patients with melanomas harboring active c-Abl and Arg.
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