Structural Insight into KCNQ (Kv7) Channel Assembly and Channelopathy

SummaryKv7.x (KCNQ) voltage-gated potassium channels form the cardiac and auditory IKs current and the neuronal M-current. The five Kv7 subtypes have distinct assembly preferences encoded by a C-terminal cytoplasmic assembly domain, the A-domain Tail. Here, we present the high-resolution structure of the Kv7.4 A-domain Tail together with biochemical experiments that show that the domain is a self-assembling, parallel, four-stranded coiled coil. Structural analysis and biochemical studies indicate conservation of the coiled coil in all Kv7 subtypes and that a limited set of interactions encode assembly specificity determinants. Kv7 mutations have prominent roles in arrhythmias, deafness, and epilepsy. The structure together with biochemical data indicate that A-domain Tail arrhythmia mutations cluster on the solvent-accessible surface of the subunit interface at a likely site of action for modulatory proteins. Together, the data provide a framework for understanding Kv7 assembly specificity and the molecular basis of a distinct set of Kv7 channelopathies

Development and Implementation of a Community-Based Research Network

Introduction: People aging with long-term physical disabilities (PAwLTPD), meaning individuals with onset of disability from birth through midlife, often require long-term support services (LTSS) to remain independence. The LTSS system is fragmented into aging and disability organizations with little communication between them. In addition, there are currently no evidence-based LTSS-type programs listed on the Administration for Community Living website that have been demonstrated to be effective for PAwLTPD. Because of these gaps, we have developed a community-based research network (CBRN), drawing on the practice-based research network model (PBRN), to bring together aging and disability organizations to address the lack of evidence-based programs for PAwLTPD. Materials and methods: Community-based organizations serving PAwLTPD across the state of Missouri were recruited to join the CBRN. A formative process evaluation of the network was conducted after a year to evaluate the effectiveness of the network. Results: Nine community-based organizations across the state of Missouri joined the CBRN. CBRN members include three centers for independent living (CILs), three area agencies on aging (AAAs), one CIL/AAA hybrid, one non-CIL disability organization, and one non-AAA aging organization. To date, we have held seven meetings, provided educational opportunities for CBRN members, and launched an inaugural research study within the CBRN. Formative evaluation data indicate that CBRN members feel that participation in the CBRN is beneficial. Conclusion: The PBRN model appears to be a feasible framework for use with community-based organizations to facilitate communication between agencies and to support research aimed at addressing the needs of PAwLTPD.Funding for this research was supported by a grant from the National Institute on Disability, Independent Living and Rehabilitation Research (NIDILRR grant number 90DPCP0001) (SS, BM, MK, MD, MC, JD, SET). NIDILRR is a Center within the Administration for Community Living (ACL), Department of Health and Human Services (HHS). Research reported in this publication was also supported by the Washington University Institute of Clinical and Translational Sciences (grant UL1TR002345) (SS, BM) from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH)

Impact of Cigarette Smoke Exposure on Innate Immunity: A Caenorhabditis elegans Model

BACKGROUND: Cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD) and lung cancer. Respiratory bacterial infections have been shown to be involved in the development of COPD along with impaired airway innate immunity. METHODOLOGY/PRINCIPAL FINDINGS: To address the in vivo impact of cigarette smoke (CS) exclusively on host innate defense mechanisms, we took advantage of Caenorhabditis elegans (C. elegans), which has an innate immune system but lacks adaptive immune function. Pseudomonas aeruginosa (PA) clearance from intestines of C. elegans was dampened by CS. Microarray analysis identified 6 candidate genes with a 2-fold or greater reduction after CS exposure, that have a human orthologue, and that may participate in innate immunity. To confirm a role of CS-down-regulated genes in the innate immune response to PA, RNA interference (RNAi) by feeding was carried out in C. elegans to inhibit the gene of interest, followed by PA infection to determine if the gene affected innate immunity. Inhibition of lbp-7, which encodes a lipid binding protein, resulted in increased levels of intestinal PA. Primary human bronchial epithelial cells were shown to express mRNA of human Fatty Acid Binding Protein 5 (FABP-5), the human orthologue of lpb-7. Interestingly, FABP-5 mRNA levels from human smokers with COPD were significantly lower (p = 0.036) than those from smokers without COPD. Furthermore, FABP-5 mRNA levels were up-regulated (7-fold) after bacterial (i.e., Mycoplasma pneumoniae) infection in primary human bronchial epithelial cell culture (air-liquid interface culture). CONCLUSIONS: Our results suggest that the C. elegans model offers a novel in vivo approach to specifically study innate immune deficiencies resulting from exposure to cigarette smoke, and that results from the nematode may provide insight into human airway epithelial cell biology and cigarette smoke exposure

Temperature response surfaces for mortality risk of tree species with future drought

Widespread, high levels of tree mortality, termed forest die-off, associated with drought and rising temperatures, are disrupting forests worldwide. Drought will likely become more frequent with climate change, but even without more frequent drought, higher temperatures can exacerbate tree water stress. The temperature sensitivity of drought-induced mortality of tree species has been evaluated experimentally for only single-step changes in temperature (ambient compared to ambient + increase) rather than as a response surface (multiple levels of temperature increase), which constrains our ability to relate changes in the driver with the biological response. Here we show that time-to-mortality during drought for seedlings of two western United States tree species, Pinus edulis (Engelm.) and Pinus ponderosa (Douglas ex C. Lawson), declined in continuous proportion with increasing temperature spanning a 7.7 °C increase. Although P. edulis outlived P. ponderosa at all temperatures, both species had similar relative declines in time-to-mortality as temperature increased (5.2% per °C for P. edulis; 5.8% per °C for P. ponderosa). When combined with the non-linear frequency distribution of drought duration—many more short droughts than long droughts—these findings point to a progressive increase in mortality events with global change due to warming alone and independent of additional changes in future drought frequency distributions. As such, dire future forest recruitment patterns are projected assuming the calculated 7–9 seedling mortality events per species by 2100 under business-as-usual warming occur, congruent with additional vulnerability predicted for adult trees from stressors like pathogens and pests. Our progressive projection for increased mortality events was driven primarily by the non-linear shape of the drought duration frequency distribution, a common climate feature of drought-affected regions. These results illustrate profound benefits for reducing emissions of carbon to the atmosphere from anthropogenic sources and slowing warming as rapidly as possible to maximize forest persistence.Peer reviewedPlant Biology, Ecology and Evolutio

Global urban environmental change drives adaptation in white clover

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale

Seed Removal Increased by Scramble Competition with an Invasive Species

<div><p>Competition for seeds has a major influence on the evolution of granivores and the plants on which they rely. The complexity of interactions and coevolutionary relationships vary across forest types. The introduction of non-native granivores has considerable potential to alter seed dispersal dynamics. Non-native species are a major cause of endangerment for native species, but the mechanisms are often unclear. As biological invasions continue to rise, it is important to understand mechanisms to build up strategies to mitigate the threat. Our field experiment quantified the impact of introduced Abert’s squirrels (<i>Sciurus aberti</i>) on rates of seed removal within the range of critically endangered Mount Graham red squirrels (<i>Tamiasciurus hudsonicus grahamensis</i>), which consumes similar foods. In the presence of invasive Abert’s squirrels, the time cones were removed was faster than when the invasive was excluded, accounting for a median removal time of cones available to red and Abert’s squirrels that is 32.8% less than that of cones available only to the rare native red squirrels. Moreover, in the presence of Abert’s squirrels, removal rates are higher at great distance from a territorial red squirrel larderhoard and in more open portions of the forest, which suggests differential patterns of seed dispersal. The impact on food availability as a result of cone removal by Abert’s squirrels suggests the potential of food competition as a mechanism of endangerment for the Mount Graham red squirrel. Furthermore, the magnitude and differential spatial patterns of seed removal suggest that non-native granivores may have impacts on forest regeneration and structure.</p></div

Exclusion experiment cone removal rates.

<p>Removal rates of cones available to both endangered Mount Graham red squirrels (<i>Tamiasciurus hudsonicus grahamensis</i>) and introduced Abert’s squirrels (<i>Sciurus aberti</i>) (control cone tube: solid line) and cones from which Abert’s squirrels are excluded (exclusion cone tube: dotted line) in the Pinaleño Mountains, Arizona.</p

Comparison between experimental plots and cone tubes.

<p>The removal rates of cones placed within a control cone tube (solid line) or on experimental plots not in a cone tube (no cone tube: dotted line) and available to both Mount Graham red squirrels (<i>Tamiasciurus hudsonicus grahamensis</i>) and Abert’s squirrels (<i>Sciurus aberti</i>) in the Pinaleño Mountains, Arizona during our field experiments.</p

Ecosystem carbon and water cycling from a sky island montane forest

Sky islands are characteristic of sequential mountain-valley terrain where mountains form an island archipelago rising from surrounding valleys of desert "sea". At high elevations in the Madrean sky islands of the southwestern United States (USA) and Mexico, mixed evergreen conifer forests occur near the latitudinal extent of their distribution. This setting provides a unique opportunity to explore the ecosystem response to warmer and drier conditions that are forecasted to become more common throughout the species range. Accordingly, this work used the eddy covariance method to quantify carbon and water cycling dynamics from a Madrean sky island forest ecosystem for nine years between 2009 and 2018. The forest functioned as net sink of carbon dioxide throughout the year, which resulted in more carbon sequestration than other monitored montane forests in the continental western USA. Sustained forest activity was made possible by the combination of mild winter temperatures and a bimodal precipitation regime that delivered moisture during both summer and winter. Seasonally, gross primary production (GPP) was temperature limited in winter and could become moisture limited during the dry early summer period depending on antecedent snowmelt moisture. Ecosystem respiration was more sensitive than GPP to moisture availability throughout the rest of the non-winter period. Forecasted warming could thus stimulate forest carbon gains during the winter and either increase or decrease respiratory carbon loss during summer as a function of moisture. Overall, a metric of snow aridity that included snow depth and potential evapotranspiration was the best predictor of the warm season carbon balance (R-2 = 0.86). The seasonally dissimilar impacts of warming and drying identified by this work inform current understanding of how climate change and/or variability may affect forest water and carbon cycling dynamics throughout the montane forest biome.24 month embargo; published online: 20 November 2019This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Engineering the Interface of Ceria and Silver Janus Nanoparticles for Enhanced Catalytic Performance in 4‑Nitrophenol Conversion

In this work, we present a modified simultaneous growth and self-aggregation method that produces ceria and silver Janus nanoparticles for the conversion of 4-nitrophenol, a chemical widely used in several industries. The nanoparticles had cerium-to-silver ratios ranging from 0 to 1.35 and well-defined heterodimer morphologies. By controlling the growth conditions, we have manipulated the interface between ceria and silver, maximizing its exposure to the chemical reactants and increasing the reaction rate constants between 2- and 4-fold. Taken together, these results can inform the design rules to achieve better performing hybrid nanocatalysts