Deep avian evolutionary relationships have been difficult to resolve as a result of a putative explosive radiation. Our study examined ~32 kilobases of aligned nuclear DNA sequences from 19 ...independent loci for 169 species, representing all major extant groups, and recovered a robust phylogeny from a genome-wide signal supported by multiple analytical methods. We documented well-supported, previously unrecognized interordinal relationships (such as a sister relationship between passerines and parrots) and corroborated previously contentious groupings (such as flamingos and grebes). Our conclusions challenge current classifications and alter our understanding of trait evolution; for example, some diurnal birds evolved from nocturnal ancestors. Our results provide a valuable resource for phylogenetic and comparative studies in birds.
Ratites (ostriches, emus, rheas, cassowaries, and kiwis) are large, flightless birds that have long fascinated biologists. Their current distribution on isolated southern land masses is believed to ...reflect the breakup of the paleocontinent of Gondwana. The prevailing view is that ratites are monophyletic, with the flighted tinamous as their sister group, suggesting a single loss of flight in the common ancestry of ratites. However, phylogenetic analyses of 20 unlinked nuclear genes reveal a genome-wide signal that unequivocally places tinamous within ratites, making ratites polyphyletic and suggesting multiple losses of flight. Phenomena that can mislead phylogenetic analyses, including long branch attraction, base compositional bias, discordance between gene trees and species trees, and sequence alignment errors, have been eliminated as explanations for this result. The most plausible hypothesis requires at least three losses of flight and explains the many morphological and behavioral similarities among ratites by parallel or convergent evolution. Finally, this phylogeny demands fundamental reconsideration of proposals that relate ratite evolution to continental drift.
Uncontrolled hypertension remains a widely prevalent cardiovascular risk factor in the U.S. team-based care, established by adding new staff or changing the roles of existing staff such as nurses and ...pharmacists to work with a primary care provider and the patient. Team-based care has the potential to improve the quality of hypertension management. The goal of this Community Guide systematic review was to examine the effectiveness of team-based care in improving blood pressure (BP) outcomes.
An existing systematic review (search period, January 1980-July 2003) assessing team-based care for BP control was supplemented with a Community Guide update (January 2003-May 2012). For the Community Guide update, two reviewers independently abstracted data and assessed quality of eligible studies.
Twenty-eight studies in the prior review (1980-2003) and an additional 52 studies from the Community Guide update (2003-2012) qualified for inclusion. Results from both bodies of evidence suggest that team-based care is effective in improving BP outcomes. From the update, the proportion of patients with controlled BP improved (median increase=12 percentage points); systolic BP decreased (median reduction=5.4 mmHg); and diastolic BP also decreased (median reduction=1.8 mmHg).
Team-based care increased the proportion of people with controlled BP and reduced both systolic and diastolic BP, especially when pharmacists and nurses were part of the team. Findings are applicable to a range of U.S. settings and population groups. Implementation of this multidisciplinary approach will require health system-level organizational changes and could be an important element of the medical home.
Previous research in our group showed that tellurophenes with pinacolboronate (BPin) units at the 2- and/or 5-positions displayed efficient phosphorescence in the solid state, both in the presence of ...oxygen and water. In this current study, we show that luminescence from a tellurophene is possible when various aryl-based substituents are present, thus greatly expanding the family of known (and potentially accessible) Te-based phosphors. Moreover, for the green phosphorescent perborylated tellurium heterocycle, 2,3,4,5-TeC4BPin4 (4BTe), oxygen-mediated quenching of phosphorescence is an important contributor to the lack of emission in solution (when exposed to air); thus, this system displays aggregation-enhanced emission (AEE). These discoveries should facilitate the future design of color tunable tellurium-based luminogens.
A two-photon-activatable photoacid generator, based on a bis(diarylamino) styrylbenzene core with covalently attached sulfonium moieties, has been synthesized. The photoacid generator has both a ...large two-photon absorption cross section ( δ = 690 × 10-50centimeter4second per photon) and a high quantum yield for the photochemical generation of acid (φH
+= 0.5). Under near-infrared laser irradiation, the molecule produces acid after two-photon excitation and initiates the polymerization of epoxides at an incident intensity that is one to two orders of magnitude lower than that needed for conventional ultraviolet-sensitive initiators. This photoacid generator was used in conjunction with a positive-tone chemically amplified resist for the fabrication of a three-dimensional (3D) microchannel structure.
Insertion/deletion (indel) mutations, which are represented by gaps in multiple sequence alignments, have been used to examine phylogenetic hypotheses for some time. However, most analyses combine ...gap data with the nucleotide sequences in which they are embedded, probably because most phylogenetic datasets include few gap characters. Here, we report analyses of 12,030 gap characters from an alignment of avian nuclear genes using maximum parsimony (MP) and a simple maximum likelihood (ML) framework. Both trees were similar, and they exhibited almost all of the strongly supported relationships in the nucleotide tree, although neither gap tree supported many relationships that have proven difficult to recover in previous studies. Moreover, independent lines of evidence typically corroborated the nucleotide topology instead of the gap topology when they disagreed, although the number of conflicting nodes with high bootstrap support was limited. Filtering to remove short indels did not substantially reduce homoplasy or reduce conflict. Combined analyses of nucleotides and gaps resulted in the nucleotide topology, but with increased support, suggesting that gap data may prove most useful when analyzed in combination with nucleotide substitutions.
1H,15N-Heteronuclear Single Quantum Coherence (HSQC) NMR is a powerful technique that has been employed to characterize small-molecule interactions with intrinsically disordered monomeric α-Synuclein ...(aSyn). We report how solution pH can impact the interpretation of aSyn HSQC NMR spectra and demonstrate that small-molecule formulations (e.g., complexation with acidic salts) can lower sample pH and confound interpretation of drug binding and concomitant protein structural changes. Through stringent pH control, we confirm that several previously identified compounds (EGCG, Baicalin, and Dopamine (DOPA)) as well as a series of potent small-molecule inhibitors of aSyn pathology (Demeclocycline, Ro90-7501, and (±)-Bay K 8644) are capable of direct target engagement of aSyn. Previously, DOPA–aSyn interactions have been shown to elicit a dramatic chemical shift perturbation (CSP) localized to aSyn’s H50 at low DOPA concentrations then expanding to aSyn’s acidic C-terminal residues at increasing DOPA levels. Interestingly, this CSP profile mirrors our pH titration, where a small reduction in pH affects H50 CSP, and large pH changes induce robust C-terminal CSP. In contrast, under tightly controlled pH 5.0, DOPA induces significant CSPs observed at both ionizable and nonionizable residues. These results suggest that previous interpretations of DOPA–aSyn interactions were conflated with pH-induced CSP, highlighting the need for stringent pH control to minimize potential false-positive interpretations of ligand interactions in HSQC NMR experiments. Furthermore, DOPA’s preferential interaction with aSyn under acidic pH represents a novel understanding of DOPA–aSyn interactions that may provide insight into the potential gain of toxic function of aSyn misfolding in α-synucleinopathies.
We have developed a high-throughput drug discovery platform, measuring fluorescence resonance energy transfer (FRET) with fluorescent alpha-synuclein (αSN) biosensors, to detect spontaneous ...pre-fibrillar oligomers in living cells. Our two αSN FRET biosensors provide complementary insight into αSN oligomerization and conformation in order to improve the success of drug discovery campaigns for the treatment of Parkinson's disease. We measure FRET by fluorescence lifetime, rather than traditional fluorescence intensity, providing a structural readout with greater resolution and precision. This facilitates identification of compounds that cause subtle but significant conformational changes in the ensemble of oligomeric states that are easily missed using intensity-based FRET. We screened a 1280-compound small-molecule library and identified 21 compounds that changed the lifetime by >5 SD. Two of these compounds have nanomolar potency in protecting SH-SY5Y cells from αSN-induced death, providing a nearly tenfold improvement over known inhibitors. We tested the efficacy of several compounds in a primary mouse neuron assay of αSN pathology (phosphorylation of mouse αSN pre-formed fibrils) and show rescue of pathology for two of them. These hits were further characterized with biophysical and biochemical assays to explore potential mechanisms of action. In vitro αSN oligomerization, single-molecule FRET, and protein-observed fluorine NMR experiments demonstrate that these compounds modulate αSN oligomers but not monomers. Subsequent aggregation assays further show that these compounds also deter or block αSN fibril assembly.
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