Structural insights into the design of nonpeptidic isothiazolidinone-containing inhibitors of protein-tyrosine phosphatase 1B

Structural analyses of the protein-tyrosine phosphatase 1B (PTP1B) active site and inhibitor complexes have aided in optimization of a peptide inhibitor containing the novel (S)-isothiazolidinone (IZD) phosphonate mimetic. Potency and permeability were simultaneously improved by replacing the polar peptidic backbone of the inhibitor with nonpeptidic moieties. The C-terminal primary amide was replaced with a benzimidazole ring, which hydrogen bonds to the carboxylate of Asp(48), and the N terminus of the peptide was replaced with an aryl sulfonamide, which hydrogen bonds to Asp(48) and the backbone NH of Arg(47) via a water molecule. Although both substituents retain the favorable hydrogen bonding network of the peptide scaffold, their aryl rings interact weakly with the protein. The aryl ring of benzimidazole is partially solvent exposed and only participates in van der Waals interactions with Phe(182) of the flap. The aryl ring of aryl sulfonamide adopts an unexpected conformation and only participates in intramolecular pi-stacking interactions with the benzimidazole ring. These results explain the flat SAR for substitutions on both rings and the reason why unsubstituted moieties were selected as candidates. Finally, substituents ortho to the IZD heterocycle on the aryl ring of the IZD-phenyl moiety bind in a small narrow site adjacent to the primary phosphate binding pocket. The crystal structure of an o-chloro derivative reveals that chlorine interacts extensively with residues in the small site. The structural insights that have led to the discovery of potent benzimidazole aryl sulfonamide o-substituted derivatives are discussed in detail.     

Impact of missing data,gene choice,and taxon sampling on phylogenetic reconstruction: the Caryophyllales (angiosperms)

Density of taxon sampling and number/kind of characters are central to achieving the ultimate goals in phylogenetic reconstruction: tree robustness and improved accuracy. In molecular phylogenetics, DNA sequence repositories such as GenBank are potential sources for expanding datasets in two dimensions, taxa and characters, to the level of “supermatrices.” However, the issue of missing characters/genomic regions is generally considered a major impediment to this endeavor. We used here the angiosperm order Caryophyllales to systematically address the impact of missing data when expanding taxon sampling and number of characters in phylogenetic reconstruction. Our analyses show that expansion of taxon sampling by ~13-fold resulted in improved phylogenetic assessment of the Caryophyllales despite up to 38% missing data. Expanding number of characters in the dataset by allowing for up to 100-fold increase in amount of missing data and inclusion of entries with about 40% missing genomic regions did not negatively impact tree structure or robustness, but to the contrary improved both. These results are timely regarding the ongoing efforts to achieve detailed assessment of the tree of life.     

Testing the distinctness of shoot ionomes of angiosperm families using the Rothamsted Park Grass Continuous Hay Experiment

? The ionome is the elemental composition of a tissue or organism. Phylogenetic variation in the ionomes of plant shoots has been widely reported based on controlled experiments, vegetation surveys and literature meta-analyses. However, environmental effects on phylogenetic variation in shoot ionomes have not been quantified. This study tests the hypothesis that phylogenetic variation in shoot ionomes is robust to environmental perturbation and that plant families can be distinguished by their shoot ionomes. ? Herbage was sampled from six subplots of the Rothamsted Park Grass Experiment. Subplots had received contrasting fertilizer treatments since 1856. Herbage was separated into its constituent species (n?=?21) and concentrations of eleven mineral elements were determined in dried shoot material. ? Shoot concentrations of calcium (Ca), zinc (Zn), manganese (Mn), magnesium (Mg) and sodium (Na) showed significant variation associated with plant species, and responded similarly to fertilizer treatments in diverse plant species. Species?×?treatment interactions were indicated for phosphorus (P), potassium (K), nickel (Ni), copper (Cu) and iron (Fe). Plant families could be distinguished by their shoot ionomes. The most informative elements for discriminant analysis were Ca?>?Mg?>?Ni?>?S?>?Na?>?Zn?>?K?>?Cu?>?Fe?>?Mn?>?P. ? Whilst shoot ionomes were sensitive to fertilizer treatment, phylogenetic variation in a subset of the shoot ionome (Ca, Zn, Mn, Mg) was robust to this environmental perturbation.     

Possible Impacts of the Invasive Plant Rubus niveus on the Native Vegetation of the Scalesia Forest in the Galapagos Islands

Originally from Asia, Rubus niveus has become one of the most widespread invasive plant species in the Galapagos Islands. It has invaded open vegetation, shrubland and forest alike. It forms dense thickets up to 4 m high, appearing to displace native vegetation, and threaten the integrity of several native communities. This study used correlation analysis between a R. niveus cover gradient and a number of biotic (vascular plant species richness, cover and vegetation structure) and abiotic (light and soil properties) parameters to help understand possible impacts in one of the last remaining fragments of the Scalesia forest in Santa Cruz Island, Galapagos. Higher cover of R. niveus was associated with significantly lower native species richness and cover, and a different forest structure. Results illustrated that 60% R. niveus cover could be considered a threshold for these impacts. We suggest that a maximum of 40% R. niveus cover could be a suitable management target.     

Unusual repertoire of vocalizations in the BTBR T+tf/J mouse model of autism

BTBR T+ tf/J (BTBR) is an inbred mouse strain that displays social abnormalities and repetitive behaviors analogous to the first and third diagnostic symptoms of autism. Here we investigate ultrasonic vocalizations in BTBR, to address the second diagnostic symptom of autism, communication deficits. As compared to the commonly used C57BL/6J (B6) strain, BTBR pups called more loudly and more frequently when separated from their mothers and siblings. Detailed analysis of ten categories of calls revealed an unusual pattern in BTBR as compared to B6. BTBR emitted high levels of harmonics, two-syllable, and composite calls, but minimal numbers of chevron-shaped syllables, upward, downward, and short calls. Because body weights were higher in BTBR than B6 pups, one possible explanation was that larger thoracic size was responsible for the louder calls and different distribution of syllable categories. To test this possibility, we recorded separation calls from FVB/NJ, a strain with body weights similar to BTBR, and 129X1/SvJ, a strain with body weights similar to B6. BTBR remained the outlier on number of calls, displaying low numbers of complex, upward, chevron, short, and frequency steps calls, along with high harmonics and composites. Further, developmental milestones and growth rates were accelerated in BTBR, indicating an unusual neurodevelopmental trajectory. Overall, our findings demonstrate strain-specific patterns of ultrasonic calls that may represent different lexicons, or innate variations in complex vocal repertoires, in genetically distinct strains of mice. Particularly intriguing is the unusual pattern of vocalizations and the more frequent, loud harmonics evident in the BTBR mouse model of autism that may resemble the atypical vocalizations seen in some autistic infants.