The unprecedented performance of Deepmind’s Alphafold2 in predicting protein structure in CASP XIV and the creation of a database of structures for multiple proteomes and protein sequence ...repositories is reshaping structural biology. However, because this database returns a single structure, it brought into question Alphafold’s ability to capture the intrinsic conformational flexibility of proteins. Here we present a general approach to drive Alphafold2 to model alternate protein conformations through simple manipulation of the multiple sequence alignment via
in silico
mutagenesis. The approach is grounded in the hypothesis that the multiple sequence alignment must also encode for protein structural heterogeneity, thus its rational manipulation will enable Alphafold2 to sample alternate conformations. A systematic modeling pipeline is benchmarked against canonical examples of protein conformational flexibility and applied to interrogate the conformational landscape of membrane proteins. This work broadens the applicability of Alphafold2 by generating multiple protein conformations to be tested biologically, biochemically, biophysically, and for use in structure-based drug design.
This report highlights developments in the fields of microporous and mesoporous materials that were published mostly during the year 2002. Selected examples are provided to illustrate new zeolite ...structures, porous coordination materials, mesoporous solids with new compositions, controlled morphologies, and increased hydrothermal and thermal stabilities, as well as porous solids with tunable pore openings or other structural features that can be dynamically modified. A number of applications are discussed, including stabilization of reactive guests, separations, electronic materials, and sensors.
Recent progress in research into micro‐ and mesoporous materials is presented. Selected examples are provided to illustrate new zeolite structures, porous coordination materials, mesoporous solids with new compositions, controlled morphologies (see Figure), and increased hydrothermal and thermal stabilities, as well as porous solids with structural features that can be dynamically modified. A number of applications are also discussed.
Local resonance band gaps in acoustic metamaterials are widely known for their strong attenuation yet narrow frequency span. The latter limits the practical ability to implement subwavelength band ...gaps for broadband attenuation and has motivated novel metamaterial designs in recent years. In this paper, we investigate the behavior of acoustic metamaterials where unit cells house multiple resonating elements stacked in different configurations, aimed at instigating a wide array of wave propagation profiles that are otherwise unattainable. The dispersion mechanics of the multi-resonator metamaterials are developed using purely analytical expressions which depict and explain the underlying dynamics of such systems both at the unit cell level as well as the frequency response of their finite realizations. The framework reveals the mechanism behind the transition of the lower and upper band gap bounds in metamaterials with parallel resonators resulting in a significant band gap widening. The analysis also illustrates the ability of metamaterials with dual-periodic super cells to exhibit a range of dispersion transitions culminating in collapsing solutions of acoustic and optical bands, enabling a coalescence of local resonance band gaps, vanishing resonances, and a number of intriguing scenarios in between.
•Dispersion mechanics of multi-resonator metamaterials are analytically derived.•Band gap widening in parallel-resonator finite metamaterials achieved via shorter chains.•Band gap coupling and transition in dual-periodic super cells is fully explained.•Coalescence of local resonance band gaps with single and double attenuation peaks.
The Hybrid Single-Particle Lagrangian Integrated Trajectory model (HYSPLIT), developed by NOAA’s Air Resources Laboratory, is one of the most widely used models for atmospheric trajectory and ...dispersion calculations. We present the model’s historical evolution over the last 30 years from simple hand-drawn back trajectories to very sophisticated computations of transport, mixing, chemical transformation, and deposition of pollutants and hazardous materials. We highlight recent applications of the HYSPLIT modeling system, including the simulation of atmospheric tracer release experiments, radionuclides, smoke originated from wild fires, volcanic ash, mercury, and wind-blown dust.
Human neuroimaging studies suggest that neural cue reactivity is strongly associated with indices of drug use, including addiction severity and treatment success. However, little is known about ...factors that modulate cue reactivity. The goal of this review, in which we survey published fMRI and PET studies on drug cue reactivity in cocaine, alcohol, and tobacco cigarette users, is to highlight major factors that modulate brain reactivity to drug cues. First, we describe cue reactivity paradigms used in neuroimaging research and outline the brain circuits that underlie cue reactivity. We then discuss major factors that have been shown to modulate cue reactivity and review specific evidence as well as outstanding questions related to each factor. Building on previous model-building reviews on the topic, we then outline a simplified model that includes the key modulatory factors and a tentative ranking of their relative impact. We conclude with a discussion of outstanding challenges and future research directions, which can inform future neuroimaging studies as well as the design of treatment and prevention programs.
Given conceptual frameworks of addiction as a disease of intercommunicating brain networks, examinations of network interactions may provide a holistic characterization of addiction‐related ...dysfunction. One such methodological approach is the examination of resting‐state functional connectivity, which quantifies correlations in low‐frequency fluctuations of the blood oxygen level–dependent magnetic resonance imaging signal between disparate brain regions in the absence of task performance. Here, evidence of differentiated effects of chronic nicotine exposure, which reduces the efficiency of network communication across the brain, and acute nicotine exposure, which increases connectivity within specific limbic circuits, is discussed. Several large‐scale resting networks, including the salience, default, and executive control networks, have also been implicated in nicotine addiction. The dynamics of connectivity changes among and between these large‐scale networks during nicotine withdrawal and satiety provide a heuristic framework with which to characterize the neurobiological mechanism of addiction. The ability to simultaneously quantify effects of both chronic (trait) and acute (state) nicotine exposure provides a platform to develop a neuroimaging‐based addiction biomarker. While such development remains in its early stages, evidence of coherent modulations in resting‐state functional connectivity at various stages of nicotine addiction suggests potential network interactions on which to focus future addiction biomarker development.
N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated, calcium-permeable ion channels that mediate synaptic transmission and underpin learning and memory. NMDAR dysfunction is directly ...implicated in diseases ranging from seizure to ischemia. Despite its fundamental importance, little is known about how the NMDAR transitions between inactive and active states and how small molecules inhibit or activate ion channel gating. Here, we report electron cryo-microscopy structures of the GluN1-GluN2B NMDA receptor in an ensemble of competitive antagonist-bound states, an agonist-bound form, and a state bound with agonists and the allosteric inhibitor Ro25-6981. Together with double electron-electron resonance experiments, we show how competitive antagonists rupture the ligand binding domain (LBD) gating “ring,” how agonists retain the ring in a dimer-of-dimers configuration, and how allosteric inhibitors, acting within the amino terminal domain, further stabilize the LBD layer. These studies illuminate how the LBD gating ring is fundamental to signal transduction and gating in NMDARs.
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•LBD gating ring ruptures upon antagonist binding•Allosteric inhibitors promote closure of GluN2B ATD “clamshell”•Broad spectrum of ATD and LBD conformations in antagonist-bound states•Antagonists and allosteric inhibitors utilize different mechanisms of inhibition
NMDA receptors are glutamate-coupled ion channels that underpin learning and memory and are promising targets of rapid acting antidepressants. Electron cryo-microscopy structures now reveal how small molecules affect ion channel opening and elucidate the transition between inactive and active states.
Homoploid hybrid speciation is thought to require unusual circumstances to yield reproductive isolation from the parental species, and few examples are known from nature. Here, we present genetic ...evidence for this mode of speciation in birds. Using Bayesian assignment analyses of 751 individuals genotyped for 14 unlinked, nuclear microsatellite loci, we show that the phenotypically intermediate Italian sparrow (Passer italiae) does not form a cluster of its own, but instead exhibits clear admixture (over its entire breeding range) between its putative parental species, the house sparrow (P. domesticus) and the Spanish sparrow (P. hispaniolensis). Further, the Italian sparrow possesses mitochondrial (mt) DNA haplotypes identical to both putative parental species (although mostly of house sparrow type), indicating a recent hybrid origin. Today, the Italian sparrow has a largely allopatric distribution on the Italian peninsula and some Mediterranean islands separated from its suggested parental species by the Alps and the Mediterranean Sea, but co‐occurs with the Spanish sparrow on the Gargano peninsula in southeast Italy. No evidence of interbreeding was found in this sympatric population. However, the Italian sparrow hybridizes with the house sparrow in a sparsely populated contact zone in the Alps. Yet, the contact zone is characterized by steep clines in species‐specific male plumage traits, suggesting that partial reproductive isolation may also have developed between these two taxa. Thus, geographic and reproductive barriers restrict gene flow into the nascent hybrid species. We propose that an origin of hybrid species where the hybrid lineage gets geographically isolated from its parental species, as seems to have happened in this system, might be more common in nature than previously assumed.
Microscale thermophoresis (MST) is a versatile technique to measure binding affinities of binder–ligand systems, based on the directional movement of molecules in a temperature gradient. We extended ...MST to measure binding kinetics as well as binding affinity in a single experiment by increasing the thermal dissipation of the sample. The kinetic relaxation fingerprints were derived from the fluorescence changes during thermodynamic re‐equilibration of the sample after local heating. Using this method, we measured DNA hybridization on‐rates and off‐rates in the range 104–106 m−1 s−1 and 10−4–10−1 s−1, respectively. We observed the expected exponential dependence of the DNA hybridization off‐rates on salt concentration, strand length and inverse temperature. The measured on‐rates showed a linear dependence on salt concentration and weak dependence on strand length and temperature. For biomolecular interactions with large enthalpic contributions, the kinetic MST technique offers a robust, cost‐effective and immobilization‐free determination of kinetic rates and binding affinity simultaneously, even in crowded solutions.
The extension of microscale thermophoresis (MST) to perform temperature jumps by increasing the heat dissipation of the sample allows for quantification of binding affinities together with the kinetic rates. Relaxation kinetics for DNA hybridization were measured with high fidelity at different temperatures and various experimental conditions. The results shed light on the hybridization mechanism of DNA and confirmed determinants of DNA binding.
Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor ...of mutant IDH1.
We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up.
Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval CI, 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment.
In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).
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