semiaza-Bambusurils are anion-specific transmembrane transporters.

semiaza-Bambus[6]urils efficiently transport anions across lipid membranes. A systematic modification of their lipophilic side chains to include various alkyl groups and thioethers reveals that the most efficient chloride transporters are those that agree with Lipinski's rule-of-lipophilicity, exhibiting clog Po/w values close to 5. Furthermore, vesicle anion-transport assays show that the new anion-transporters are independent of the cation identity but exhibit high anion selectivity, NO3- > Br- > Cl- > SO42-, in agreement with the Hofmeister series. These findings will allow for the design of highly specific anion transporters for biomedical applications, particularly for managing anion channelopathies.

Induction of ß-cell replication by a synthetic HNF4α antagonist.

Increasing the number of ß cells is critical to a definitive therapy for diabetes. Previously, we discovered potent synthetic small molecule antagonists of the nuclear receptor transcription factor HNF4α. The natural ligands of HNF4α are thought to be fatty acids. Because obesity, in which there are high circulating levels of free fatty acids, is one of the few conditions leading to ß-cell hyperplasia, we tested the hypothesis that a potent HNF4α antagonist might stimulate ß-cell replication. A bioavailable HNF4α antagonist was injected into normal mice and rabbits and ß-cell ablated mice and the effect on ß-cell replication was measured. In normal mice and rabbits, the compound induced ß-cell replication and repressed the expression of multiple cyclin-dependent kinase inhibitors, including p16 that plays a critical role in suppressing ß-cell replication. Interestingly, in ß-cell ablated mice, the compound induced α- and δ-cell, in addition to ß-cell replication, and ß-cell number was substantially increased. Overall, the data presented here are consistent with a model in which the well-known effects of obesity and high fat diet on ß-cell replication occur by inhibition of HNF4α. The availability of a potent synthetic HNF4α antagonist raises the possibility that this effect might be a viable route to promote significant increases in ß-cell replication in diseases with reduced ß-cell mass, including type I and type II diabetes.

Pancreatic ß-cell neogenesis by direct conversion from mature α-cells.

Because type 1 and type 2 diabetes are characterized by loss of ß-cells, ß-cell regeneration has garnered great interest as an approach to diabetes therapy. Here, we developed a new model of ß-cell regeneration, combining pancreatic duct ligation (PDL) with elimination of pre-existing ß-cells with alloxan. In this model, in which virtually all ß-cells observed are neogenic, large numbers of ß-cells were generated within 2 weeks. Strikingly, the neogenic ß-cells arose primarily from α-cells. α-cell proliferation was prominent following PDL plus alloxan, providing a large pool of precursors, but we found that ß-cells could form from α-cells by direct conversion with or without intervening cell division. Thus, classical asymmetric division was not a required feature of the process of α- to ß-cell conversion. Intermediate cells coexpressing α-cell- and ß-cell-specific markers appeared within the first week following PDL plus alloxan, declining gradually in number by 2 weeks as ß-cells with a mature phenotype, as defined by lack of glucagon and expression of MafA, became predominant. In summary, these data revealed a novel function of α-cells as ß-cell progenitors. The high efficiency and rapidity of this process make it attractive for performing the studies required to gain the mechanistic understanding of the process of α- to ß-cell conversion that will be required for eventual clinical translation as a therapy for diabetes.

Parallel biomolecular computation on surfaces with advanced finite automata.

A biomolecular, programmable 3-symbol-3-state finite automaton is reported. This automaton computes autonomously with all of its components, including hardware, software, input, and output being biomolecules mixed together in solution. The hardware consisted of two enzymes: an endonuclease, BbvI, and T4 DNA ligase. The software (transition rules represented by transition molecules) and the input were double-stranded (ds) DNA oligomers. Computation was carried out by autonomous processing of the input molecules via repetitive cycles of restriction, hybridization, and ligation reactions to produce a final-state output in the form of a dsDNA molecule. The 3-symbol-3-state deterministic automaton is an extension of the 2-symbol-2-state automaton previously reported, and theoretically it can be further expanded to a 37-symbol-3-state automaton. The applicability of this design was further amplified by employing surface-anchored input molecules, using the surface plasmon resonance technology to monitor the computation steps in real time. Computation was performed by alternating the feed solutions between endonuclease and a solution containing the ligase, ATP, and appropriate transition molecules. The output detection involved final ligation with one of three soluble detection molecules. Parallel computation and stepwise detection were carried out automatically with a Biacore chip that was loaded with four different inputs.

Total synthesis of 34-hydroxyasimicin and its photoactive derivative for affinity labeling of the mitochondrial complex I.

The asymmetric total synthesis of the 34-hydroxyasimicin and its 3-(4-benzoylphenyl)propionate ester was achieved by means of a convergent synthetic strategy. This ester, which contains eight asymmetric centers, represents the first photoaffinity-labeling agent that is derived from an Annonaceous acetogenin. The key transformations in the synthesis include the Sharpless asymmetric dihydroxylation reaction, the Wittig olefination reaction, an oxidative cyclization reaction with rhenium(vii) oxide, the Williamson etherification reaction, and a palladium-catalyzed cross-coupling reaction. Use of the target molecule for photoaffinity-labeling studies of bovine mitochondrial NADH-ubiquinone oxidoreductase (Complex I) may shed light on the structure/function of this intricate enzyme and on the origin of the high antitumor activity exhibited by the Annonaceous acetogenins.