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"Smith, Jennifer J"
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Juno
Faced with an unplanned pregnancy, an offbeat young woman makes an unusual decision regarding her unborn child.
DVD
Structural basis for the modulation of voltage-gated sodium channels by animal toxins
In “excitable” cells, like neurons and muscle cells, a difference in electrical potential is used to transmit signals across the cell membrane. This difference is regulated by opening or closing ion channels in the cell membrane. For example, mutations in human voltage-gated sodium (Na v ) channels are associated with disorders such as chronic pain, epilepsy, and cardiac arrhythmia. Pan et al. report the high-resolution structure of a human Na v channel, and Shen et al. report the structures of an insect Na v channel bound to the toxins that cause pufferfish and shellfish poisoning in humans. Together, the structures give insight into the molecular basis of sodium ion permeation and provide a path toward structure-based drug discovery.
Science , this issue p. eaau2486 , p. eaau2596
Structures provide insight into how voltage-gated sodium channels function and how they can be inhibited.
Animal toxins that modulate the activity of voltage-gated sodium (Na v ) channels are broadly divided into two categories—pore blockers and gating modifiers. The pore blockers tetrodotoxin (TTX) and saxitoxin (STX) are responsible for puffer fish and shellfish poisoning in humans, respectively. Here, we present structures of the insect Na v channel Na v PaS bound to a gating modifier toxin Dc1a at 2.8 angstrom-resolution and in the presence of TTX or STX at 2.6-Å and 3.2-Å resolution, respectively. Dc1a inserts into the cleft between VSD II and the pore of Na v PaS, making key contacts with both domains. The structures with bound TTX or STX reveal the molecular details for the specific blockade of Na + access to the selectivity filter from the extracellular side by these guanidinium toxins. The structures shed light on structure-based development of Na v channel drugs.
Journal Article
The American Short Story Cycle
The American Short Story Cycle shows the roots of modernism and postmodernism winds through the short story cycle. Reviewers ranging from the The New York Times to Amazon do not know what to call books like Jennifer Egan’s A Visit from the Goon Squad or Jhumpa Lahiri’s Unaccustomed Earth. Why do such popular and acclaimed books spark debates about what they are and how they should be read? The American Short Story Cycle provides a history of this genre that has been hiding in plain sight. Dating back to the early nineteenth century and proliferating to the present, the short story cycle has been wildly popular both in the US and around the world. Stories in a cycle, which can be read singly but mean more together, reflect the individualism and pluralism that shape modern experience. This book gives a name and theory to the genre that has fostered the aesthetics of fragmentation and recurrence that characterize fiction today.
eBook
The insecticidal potential of venom peptides
Pest insect species are a burden to humans as they destroy crops and serve as vectors for a wide range of diseases including malaria and dengue. Chemical insecticides are currently the dominant approach for combating these pests. However, the de-registration of key classes of chemical insecticides due to their perceived ecological and human health risks in combination with the development of insecticide resistance in many pest insect populations has created an urgent need for improved methods of insect pest control. The venoms of arthropod predators such as spiders and scorpions are a promising source of novel insecticidal peptides that often have different modes of action to extant chemical insecticides. These peptides have been optimized via a prey–predator arms race spanning hundreds of millions of years to target specific types of insect ion channels and receptors. Here we review the current literature on insecticidal venom peptides, with a particular focus on their structural and pharmacological diversity, and discuss their potential for deployment as insecticides.
Journal Article
True Lies: Using Proteomics to Assess the Accuracy of Transcriptome-Based Venomics in Centipedes Uncovers False Positives and Reveals Startling Intraspecific Variation in Scolopendra subspinipes
Centipede venoms have emerged as a rich source of novel bioactive compounds. However, most centipede species are commonly considered too small for venom extraction and transcriptomics is likely to be an attractive way of probing the molecular diversity of these venoms. Examining the venom composition of Scolopendra subspinipes, we test the accuracy of this approach. We compared the proteomically determined venom profile with four common toxin transcriptomic toxin annotation approaches: BLAST search against toxins in UniProt, lineage-specific toxins, or species-specific toxins and comparative expression analyses of venom and non-venom producing tissues. This demonstrated that even toxin annotation based on lineage-specific homology searches is prone to substantial errors compared to a proteomic approach. However, combined comparative transcriptomics and phylogenetic analysis of putative toxin families substantially improves annotation accuracy. Furthermore, comparison of the venom composition of S. subspinipes with the closely related S. subspinipes mutilans revealed a surprising lack of overlap. This first insight into the intraspecific venom variability of centipedes contrasts the sequence conservation expected from previous findings that centipede toxins evolve under strong negative selection. Our results highlight the importance of proteomic data in studies of even comparably well-characterized venoms and warrants caution when sourcing venom from centipedes of unknown origin.
Journal Article
Evidence that auxin is required for normal seed size and starch synthesis in pea
In recent years the biosynthesis of auxin has been clarified with the aid of mutations in auxin biosynthesis genes. However, we know little about the effects of these mutations on the seed-filling stage of seed development.
Here we investigate a key auxin biosynthesis mutation of the garden pea, which results in auxin deficiency in developing seeds. We exploit the large seed size of this model species, which facilitates the measurement of compounds in individual seeds.
The mutation results in small seeds with reduced starch content and a wrinkled phenotype at the dry stage. The phenotypic effects of the mutation were fully reversed by introduction of the wild-type gene as a transgene, and partially reversed by auxin application.
The results indicate that auxin is required for normal seed size and starch accumulation in pea, an important grain legume crop.
Journal Article
GluClR-mediated inhibitory postsynaptic currents reveal targets for ivermectin and potential mechanisms of ivermectin resistance
Glutamate-gated chloride channel receptors (GluClRs) mediate inhibitory neurotransmission at invertebrate synapses and are primary targets of parasites that impact drastically on agriculture and human health. Ivermectin (IVM) is a broad-spectrum pesticide that binds and potentiates GluClR activity. Resistance to IVM is a major economic and health concern, but the molecular and synaptic mechanisms of resistance are ill-defined. Here we focus on GluClRs of the agricultural endoparasite, Haemonchus contortus. We demonstrate that IVM potentiates inhibitory input by inducing a tonic current that plateaus over 15 minutes and by enhancing post-synaptic current peak amplitude and decay times. We further demonstrate that IVM greatly enhances the active durations of single receptors. These effects are greatly attenuated when endogenous IVM-insensitive subunits are incorporated into GluClRs, suggesting a mechanism of IVM resistance that does not affect glutamate sensitivity. We discovered functional groups of IVM that contribute to tuning its potency at different isoforms and show that the dominant mode of access of IVM is via the cell membrane to the receptor.
Journal Article
A bivalent remipede toxin promotes calcium release via ryanodine receptor activation
Multivalent ligands of ion channels have proven to be both very rare and highly valuable in yielding unique insights into channel structure and pharmacology. Here, we describe a bivalent peptide from the venom of
Xibalbanus tulumensis
, a troglobitic arthropod from the enigmatic class Remipedia, that causes persistent calcium release by activation of ion channels involved in muscle contraction. The high-resolution solution structure of φ-Xibalbin3-Xt3a reveals a tandem repeat arrangement of inhibitor-cysteine knot (ICK) domains previously only found in spider venoms. The individual repeats of Xt3a share sequence similarity with a family of scorpion toxins that target ryanodine receptors (RyR). Single-channel electrophysiology and quantification of released Ca
2+
stores within skinned muscle fibers confirm Xt3a as a bivalent RyR modulator. Our results reveal convergent evolution of RyR targeting toxins in remipede and scorpion venoms, while the tandem-ICK repeat architecture is an evolutionary innovation that is convergent with toxins from spider venoms.
Insect toxins with tandem repeats of neurotoxin domains have been found with enhanced receptor avidity. Here, the authors describe a bivalent toxin from remipede venom that targets ryanodine receptors, a rare target for animal venoms.
Journal Article
Combining inferred regulatory and reconstructed metabolic networks enhances phenotype prediction in yeast
Gene regulatory and metabolic network models have been used successfully in many organisms, but inherent differences between them make networks difficult to integrate. Probabilistic Regulation Of Metabolism (PROM) provides a partial solution, but it does not incorporate network inference and underperforms in eukaryotes. We present an Integrated Deduced And Metabolism (IDREAM) method that combines statistically inferred Environment and Gene Regulatory Influence Network (EGRIN) models with the PROM framework to create enhanced metabolic-regulatory network models. We used IDREAM to predict phenotypes and genetic interactions between transcription factors and genes encoding metabolic activities in the eukaryote, Saccharomyces cerevisiae. IDREAM models contain many fewer interactions than PROM and yet produce significantly more accurate growth predictions. IDREAM consistently outperformed PROM using any of three popular yeast metabolic models and across three experimental growth conditions. Importantly, IDREAM's enhanced accuracy makes it possible to identify subtle synthetic growth defects. With experimental validation, these novel genetic interactions involving the pyruvate dehydrogenase complex suggested a new role for fatty acid-responsive factor Oaf1 in regulating acetyl-CoA production in glucose grown cells.
Journal Article
Peroxisomes take shape
Key Points
Peroxisomes are dynamic and diverse organelles that are found in nearly all eukaryotic cells, and the disruption of their function is linked to peroxisome-related diseases. During biogenesis, peroxisomal membrane and matrix proteins are imported into peroxisomes, and this is mediated by the capacity of peroxisomes to import protein complexes.
Two mechanisms of peroxisome biogenesis,
de novo
generation and fission from pre-existing peroxisomes, have been characterized, and one possibility is that they are conditionally and coordinately regulated.
The regulation of peroxisome dynamics is mediated by multifunctional peroxins, which have potential roles in coordinating peroxisome proliferation (by
de novo
generation and fission) with inheritance and degradation to control peroxisome size and abundance. Exciting roles of peroxins in peroxisome differentiation, motility and inheritance are also emerging.
An important outstanding challenge is to elucidate how the processes that contribute to peroxisome dynamics are regulated and coordinated, and systems approaches such as mathematical modelling will be essential for tackling this.
The control of peroxisome biogenesis by different mechanisms, including
de novo
generation or growth and fisson of existing peroxisomes, may be coordinated to control peroxisome size and number. Dissecting this process should aid our understanding of how peroxisome dynamics are regulated, with implications for peroxisome-related diseases.
Peroxisomes carry out various oxidative reactions that are tightly regulated to adapt to the changing needs of the cell and varying external environments. Accordingly, they are remarkably fluid and can change dramatically in abundance, size, shape and content in response to numerous cues. These dynamics are controlled by multiple aspects of peroxisome biogenesis that are coordinately regulated with each other and with other cellular processes. Ongoing studies are deciphering the diverse molecular mechanisms that underlie biogenesis and how they cooperate to dynamically control peroxisome utility. These important challenges should lead to an understanding of peroxisome dynamics that can be capitalized upon for bioengineering and the development of therapies to improve human health.
Journal Article