The cerebellum contributes to generalized seizures by altering activity in the ventral posteromedial nucleus.

Thalamo-cortical networks are central to seizures, yet it is unclear how these circuits initiate seizures. We test whether a facial region of the thalamus, the ventral posteromedial nucleus (VPM), is a source of generalized, convulsive motor seizures and if convergent VPM input drives the behavior. To address this question, we devise an in vivo optogenetic mouse model to elicit convulsive motor seizures by driving these inputs and perform single-unit recordings during awake, convulsive seizures to define the local activity of thalamic neurons before, during, and after seizure onset. We find dynamic activity with biphasic properties, raising the possibility that heterogenous activity promotes seizures. Virus tracing identifies cerebellar and cerebral cortical afferents as robust contributors to the seizures. Of these inputs, only microinfusion of lidocaine into the cerebellar nuclei blocks seizure initiation. Our data reveal the VPM as a source of generalized convulsive seizures, with cerebellar input providing critical signals.

Detection of Aqueous Solvated Electrons Produced by Photoemission from Solids Using Transient Absorption Measurements.

Solvated electrons in water have long been of interest to chemists. While readily produced using intense multiphoton excitation of water and/or irradiation with high-energy particles, the possible role of solvated electrons in electrochemical and photoelectrochemical reactions at electrodes has been controversial. Recent studies showed that excitation of electrons to the conduction band of diamond leads to barrier-free emission of electrons into water. While these electrons can be inferred from the reactions they induce, direct detection by transient absorption measurements provides more direct evidence. Here, we present studies demonstrating direct detection of solvated electrons produced at diamond electrode surfaces and the influence of electrochemical potential and solution-phase electron scavengers. We further present a more detailed analysis of experimental conditions needed to detect solvated electrons emitted from diamond and other solid materials through transient optical absorption measurements.

High-Density Covalent Grafting of Spin-Active Molecular Moieties to Diamond Surfaces.

Functionalization of diamond surfaces with TEMPO and other surface paramagnetic species represents one approach to the implementation of novel chemical detection schemes that make use of shallow quantum color defects such as silicon-vacancy (SiV) and nitrogen-vacancy (NV) centers. Yet, prior approaches to quantum-based chemical sensing have been hampered by the absence of high-quality surface functionalization schemes for linking radicals to diamond surfaces. Here, we demonstrate a highly controlled approach to the functionalization of diamond surfaces with carboxylic acid groups via all-carbon tethers of different lengths, followed by covalent chemistry to yield high-quality, TEMPO-modified surfaces. Our studies yield estimated surface densities of 4-amino-TEMPO of approximately 1.4 molecules nm-2 on nanodiamond (varying with molecular linker length) and 3.3 molecules nm-2 on planar diamond. These values are higher than those reported previously using other functionalization methods. The ζ-potential of nanodiamonds was used to track reaction progress and elucidate the regioselectivity of the reaction between ethenyl and carboxylate groups and surface radicals.

Literature-based automated discovery of tumor suppressor p53 phosphorylation and inhibition by NEK2.

Scientific progress depends on formulating testable hypotheses informed by the literature. In many domains, however, this model is strained because the number of research papers exceeds human readability. Here, we developed computational assistance to analyze the biomedical literature by reading PubMed abstracts to suggest new hypotheses. The approach was tested experimentally on the tumor suppressor p53 by ranking its most likely kinases, based on all available abstracts. Many of the best-ranked kinases were found to bind and phosphorylate p53 (P value = 0.005), suggesting six likely p53 kinases so far. One of these, NEK2, was studied in detail. A known mitosis promoter, NEK2 was shown to phosphorylate p53 at Ser315 in vitro and in vivo and to functionally inhibit p53. These bona fide validations of text-based predictions of p53 phosphorylation, and the discovery of an inhibitory p53 kinase of pharmaceutical interest, suggest that automated reasoning using a large body of literature can generate valuable molecular hypotheses and has the potential to accelerate scientific discovery.

Impact of Electrocatalyst Activity and Ion Permeability on Water-Splitting Photoanodes.

Electrocatalyst (EC)-modified semiconductor (SC) photoelectrodes are key elements of solar water-splitting systems. The SC|EC interface affects the composite photoelectrode behavior but is poorly understood. We uncover the role of EC activity and SC|EC interface properties using a range of metal (Ni, Fe, Ni-Fe, Co, Ir) oxide or (oxy)hydroxide ECs deposited on model single-crystal n-TiO2 photoanodes. The impedance and photoelectrochemical response of the system was nearly independent of EC oxygen evolution activity if the catalyst was deposited electrochemically as an ion-permeable (oxy)hydroxide or hydrous oxide. When dense oxides (e.g., ion-impermeable) ECs were used, the response depended strongly on the EC. These data demonstrate that the EC and SC interface structures are more important than the EC activity in determining the composite photoanode response, confirming recent SC|EC interface simulations for ion-permeable ECs. These results thus inform the design of high-performance water-oxidizing photoanodes with direct SC|EC interfaces.

ETAscape: analyzing protein networks to predict enzymatic function and substrates in Cytoscape.

UNLABELLED: Most proteins lack experimentally validated functions. To address this problem, we implemented the Evolutionary Trace Annotation (ETA) method in the Cytoscape network visualization environment. The result is the ETAscape plugin, which builds a structural genomics network based on local structural and evolutionary similarities among proteins and then globally diffuses known annotations across the resulting network. The plugin displays these novel functional annotations, their confidence, the molecular basis for individual matches and the set of matches that lead to a prediction. AVAILABILITY: The ETA Network Plugin is available publicly for download at http://mammoth.bcm.tmc.edu/networks/.

The use of evolutionary patterns in protein annotation.

With genomic data skyrocketing, their biological interpretation remains a serious challenge. Diverse computational methods address this problem by pointing to the existence of recurrent patterns among sequence, structure, and function. These patterns emerge naturally from evolutionary variation, natural selection, and divergence--the defining features of biological systems--and they identify molecular events and shapes that underlie specificity of function and allosteric communication. Here we review these methods, and the patterns they identify in case studies and in proteome-wide applications, to infer and rationally redesign function.