Destination Areas (DAs)

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Destination Areas provide faculty and students with new tools to identify and solve complex, 21st-century problems in which Virginia Tech already has significant strengths and can take a global leadership role. The initiative represents the next step in the evolution of the land-grant university to meet economic and societal needs of the world.

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Aberrant early growth of individual trigeminal sensory and motor axons in a series of mouse genetic models of 22q11.2 deletion syndrome
Motahari, Zahra; Maynard, Thomas M.; Popratiloff, Anastas; Moody, Sally A.; LaMantia, Anthony-Samuel (2020-09-15)
We identified divergent modes of initial axon growth that prefigure disrupted differentiation of the trigeminal nerve (CN V), a cranial nerve essential for suckling, feeding and swallowing (S/F/S), a key innate behavior compromised in multiple genetic developmental disorders including DiGeorge/22q11.2 Deletion Syndrome (22q11.2 DS). We combined rapid in vivo labeling of single CN V axons in LgDel(+/-) mouse embryos, a genomically accurate 22q11.2DS model, and 3D imaging to identify and quantify phenotypes that could not be resolved using existing methods. We assessed these phenotypes in three 22q11.2-related genotypes to determine whether individual CN V motor and sensory axons wander, branch and sprout aberrantly in register with altered anterior-posterior hindbrain patterning and gross morphological disruption of CN V seen in LgDel(+/-). In the additional 22q11.2-related genotypes: Tbx1(+/-), Ranbp1(+/-), Ranbp1(+/-) and LgDel(+/-):Raldh2(+/-); axon phenotypes are seen when hindbrain patterning and CN V gross morphology is altered, but not when it is normal or restored toward WT. This disordered growth of CN V sensory and motor axons, whose appropriate targeting is critical for optimal S/F/S, may be an early, critical determinant of imprecise innervation leading to inefficient oropharyngeal function associated with 22q11.2 deletion from birth onward.
Assessment of Nutrient Limitation in Floodplain Forests with Two Different Techniques
Neatrour, Matthew A.; Jones, Robert H.; Golladay, Stephen W. (Hindawi, 2008-05-15)
We assessed nitrogen and phosphorus limitation in a floodplain forest in southern Georgia in USA using two commonly used methods: nitrogen to phosphorus (N:P) ratios in litterfall and fertilized ingrowth cores. We measured nitrogen (N) and phosphorus (P) concentrations in litterfall to determine N:P mass ratios. We also installed ingrowth cores within each site containing native soil amended with nitrogen (N), phosphorus (P), or nitrogen and phosphorus (N + P) fertilizers or without added fertilizer (C). Litter N:P ratios ranged from 16 to 22, suggesting P limitation. However, fertilized ingrowth cores indicated N limitation because fine-root length density was greater in cores fertilized with N or N + P than in those fertilized with P or without added fertilizer. We feel that these two methods of assessing nutrient limitation should be corroborated with fertilization trials prior to use on a wider basis.
Cross-scale Perspectives: Integrating Long-term and High-frequency Data into Our Understanding of Communities and Ecosystems
Carey, Cayelan C.; Cottingham, Kathryn L. (Ecological Society of America, 2016-01)
Ecologists are amassing extensive data sets that include both long-term records documenting trends and variability in natural systems on inter-annual to decadal time scales and sensor-based measurements on minute to subhourly scales for extended periods (Hampton et al. 2013). Together, these long- term and high- frequency data are contributing to our ecological understanding. Although there have been several previous ESA sessions that have explored the insights provided by either long-term data or high frequency data, to our knowledge this organized oral session provided one of the first opportunities to synthesize the lessons learned from leveraging both long-term data and high-frequency approaches.
Development and implementation of a scalable and versatile test for COVID-19 diagnostics in rural communities
Ceci, Alessandro; Muñoz-Ballester, Carmen; Tegge, Allison N.; Brown, Katherine L.; Umans, Robyn A.; Michel, F. Marc; Patel, Dipankumar; Tewari, Bhanu P.; Martin, James E.; Alcoreza, Oscar Jr.; Maynard, Thomas M.; Martinez-Martinez, Daniel; Bordwine, Paige; Bissell, Noelle; Friedlander, Michael J.; Sontheimer, Harald; Finkielstein, Carla V. (Nature Publishing Group, 2021-07-20)
Rapid and widespread testing of severe acute respiratory coronavirus 2 (SARS-CoV-2) is essential for an effective public health response aimed at containing and mitigating the coronavirus disease 2019 (COVID-19) pandemic. Successful health policy implementation relies on early identification of infected individuals and extensive contact tracing. However, rural communities, where resources for testing are sparse or simply absent, face distinctive challenges to achieving this success. Accordingly, we report the development of an academic, public land grant University laboratory-based detection assay for the identification of SARS-CoV-2 in samples from various clinical specimens that can be readily deployed in areas where access to testing is limited. The test, which is a quantitative reverse transcription polymerase chain reaction (RT-qPCR)-based procedure, was validated on samples provided by the state laboratory and submitted for FDA Emergency Use Authorization. Our test exhibits comparable sensitivity and exceeds specificity and inclusivity values compared to other molecular assays. Additionally, this test can be re-configured to meet supply chain shortages, modified for scale up demands, and is amenable to several clinical specimens. Test development also involved 3D engineering critical supplies and formulating a stable collection media that allowed samples to be transported for hours over a dispersed rural region without the need for a cold-chain. These two elements that were critical when shortages impacted testing and when personnel needed to reach areas that were geographically isolated from the testing center. Overall, using a robust, easy-to-adapt methodology, we show that an academic laboratory can supplement COVID-19 testing needs and help local health departments assess and manage outbreaks. This additional testing capacity is particularly germane for smaller cities and rural regions that would otherwise be unable to meet the testing demand.
Divergent age-dependent peripheral immune transcriptomic profile following traumatic brain injury
Hazy, Amanda; Bochicchio, Lauren; Oliver, Andrea; Xie, Eric; Geng, Shuo; Brickler, Thomas; Xie, Hehuang David; Li, Liwu; Allen, Irving C.; Theus, Michelle H. (Springer Nature, 2019-06-12)
The peripheral immune system is a major regulator of the pathophysiology associated with traumatic brain injury (TBI). While age-at-injury influences recovery from TBI, the differential effects on the peripheral immune response remain unknown. Here, we investigated the effects of TBI on gene expression changes in murine whole blood using RNAseq analysis, gene ontology and network topology-based key driver analysis. Genome-wide comparison of CCI-injured peripheral whole blood showed a significant increase in genes involved in proteolysis and oxidative-reduction processes in juvenile compared to adult. Conversely, a greater number of genes, involved in migration, cytokine-mediated signaling and adhesion, were found reduced in CCI-injured juvenile compared to CCI-injured adult immune cells. Key driver analysis also identified G-protein coupled and novel pattern recognition receptor (PRR), P2RY10, as a central regulator of these genes. Lastly, we found Dectin-1, a c-type lectin PRR to be reduced at the protein level in both naive neutrophils and on infiltrating immune cells in the CCI-injured juvenile cortex. These findings demonstrate a distinct peripheral inflammatory profile in juvenile mice, which may impact the injury and repair response to brain trauma.
DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation
Navabpour, Shaghayegh; Rogers, Jessie; McFadden, Taylor; Jarome, Timothy J. (MDPI, 2020-11-26)
Numerous studies have shown that following retrieval, a previously consolidated memory requires increased transcriptional regulation in order to be reconsolidated. Previously, it was reported that histone H3 lysine-4 trimethylation (H3K4me3), a marker of active transcription, is increased in the hippocampus after the retrieval of contextual fear memory. However, it is currently unknown how this epigenetic mark is regulated during the reconsolidation process. Furthermore, though recent evidence suggests that neuronal activity triggers DNA double-strand breaks (DSBs) in some early-response genes, it is currently unknown if DSBs contribute to the reconsolidation of a memory following retrieval. Here, using chromatin immunoprecipitation (ChIP) analyses, we report a significant overlap between DSBs and H3K4me3 in area CA1 of the hippocampus during the reconsolidation process. We found an increase in phosphorylation of histone H2A.X at serine 139 (H2A.XpS139), a marker of DSB, in the Npas4, but not c-fos, promoter region 5 min after retrieval, which correlated with increased H3K4me3 levels, suggesting that the two epigenetic marks may work in concert during the reconsolidation process. Consistent with this, in vivo siRNA-mediated knockdown of topoisomerase II β, the enzyme responsible for DSB, prior to retrieval, reduced Npas4 promoter-specific H2A.XpS139 and H3K4me3 levels and impaired long-term memory, indicating an indispensable role of DSBs in the memory reconsolidation process. Collectively, our data propose a novel mechanism for memory reconsolidation through increases in epigenetic-mediated transcriptional control via DNA double-strand breaks.
Do not feed the wildlife: associations between garbage use, aggression, and disease in banded mongooses (Mungos Mungo)
Flint, Bonnie Fairbanks; Hawley, Dana M.; Alexander, Kathleen A. (Wiley, 2016-07-25)
Urbanization and other human modifications of the landscape may indirectly affect disease dynamics by altering host behavior in ways that influence pathogen transmission. Few opportunities arise to investigate behaviorally mediated effects of human habitat modification in natural host–pathogen systems, but we provide a potential example of this phenomenon in banded mongooses (Mungos mungo), a social mammal. Our banded mongoose study population in Botswana is endemically infected with a novel Mycobacterium tuberculosis complex pathogen, M. mungi, that primarily invades the mongoose host through the nasal planum and breaks in the skin. In this system, several study troops have access to human garbage sites and other modified landscapes for foraging. Banded mongooses in our study site (N = 4 troops, ~130 individuals) had significantly higher within-troop aggression levels when foraging in garbage compared to other foraging habitats. Second, monthly rates of aggression were a significant predictor of monthly number of injuries in troops. Finally, injured individuals had a 75% incidence of clinical tuberculosis (TB) compared to a 0% incidence in visibly uninjured mongooses during the study period. Our data suggest that mongoose troops that forage in garbage may be at greater risk of acquiring TB by incurring injuries that may allow for pathogen invasion. Our study suggests the need to consider the indirect effects of garbage on behavior and wildlife health when developing waste management approaches in human-modified areas.
Dynamic modeling of organic carbon fates in lake ecosystems
McCullough, Ian M.; Dugan, Hilary A.; Farrell, Kaitlin J.; Morales-Williams, Ana M.; Ouyang, Zutao; Roberts, Derek C.; Scordo, Facundo; Bartlett, Sarah L.; Burke, Samantha M.; Doubek, Jonathan P.; Krivak-Tetley, Flora E.; Skaff, Nicholas K.; Summers, Jamie C.; Weathers, Kathleen C.; Hanson, Paul C. (2018-10-24)
Lakes are active processors of organic carbon (OC) and play important roles in landscape and global carbon cycling. Allochthonous OC loads from the landscape, along with autochthonous OC loads from primary production, are mineralized in lakes, buried in lake sediments, and exported via surface or groundwater outflows. Although these processes provide a basis for a conceptual understanding of lake OC budgets, few studies have integrated these fluxes under a dynamic modeling framework to examine their interactions and relative magnitudes. We developed a simple, dynamic mass balance model for OC, and applied the model to a set of five lakes. We examined the relative magnitudes of OC fluxes and found that long-term (> 10 year) lake OC dynamics were predominantly driven by allochthonous loads in four of the five lakes, underscoring the importance of terrestrially-derived OC in northern lake ecosystems. Our model highlighted seasonal patterns in lake OC budgets, with increasing water temperatures and lake productivity throughout the growing season corresponding to a transition from burial- to respiration-dominated OC fates. Ratios of respiration to burial, however, were also mediated by the source (autochthonous vs. allochthonous) of total OC loads. Autochthonous OC is more readily respired and may therefore proportionally reduce burial under a warming climate, but allochthonous OC may increase burial due to changes in precipitation. The ratios of autochthonous to allochthonous inputs and respiration to burial demonstrate the importance of dynamic models for examining both the seasonal and inter-annual roles of lakes in landscape and global carbon cycling, particularly in a global change context. Finally, we highlighted critical data needs, which include surface water DOC observations in paired tributary and lake systems, measurements of OC burial rates, groundwater input volume and DOC, and budgets of particulate OC.
Eco-Ethics and Sustainability Ethics (part 1)
Cairns, John Jr. (Ethics in Science and Environmental Politics, 2003)
This book is part one of a collection of John Cairns, Jr's papers and articles highlighting the importance of eco-ethics and sustainability ethics in protecting the biospheric life support system.
EGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity
Sun, Zhixiong; Xu, Xiguang; He, Jianlin; Murray, Alexander; Sun, Ming-an; Wei, Xiaoran; Wang, Xia; McCoig, Emmarose; Xie, Evan; Jiang, Xi; Li, Liwu; Zhu, Jinsong; Chen, Jianjun; Morozov, Alexei; Pickrell, Alicia M.; Theus, Michelle H.; Xie, Hehuang David (2019-08-29)
Life experience can leave lasting marks, such as epigenetic changes, in the brain. How life experience is translated into storable epigenetic information remains largely unknown. With unbiased data-driven approaches, we predicted that Egr1, a transcription factor important for memory formation, plays an essential role in brain epigenetic programming. We performed EGR1 ChIP-seq and validated thousands of EGR1 binding sites with methylation patterns established during postnatal brain development. More specifically, these EGR1 binding sites become hypomethylated in mature neurons but remain heavily methylated in glia. We further demonstrated that EGR1 recruits a DNA demethylase TET1 to remove the methylation marks and activate downstream genes. The frontal cortices from the knockout mice lacking Egr1 or Tet1 share strikingly similar profiles in both gene expression and DNA methylation. In summary, our study reveals EGR1 programs the brain methylome together with TET1 providing new insight into how life experience may shape the brain methylome.
The evolution of self-control
MacLean, Evan L.; Hare, Brian; Nunn, Charles L.; Addessi, Elsa; Amici, Federica; Anderson, Rindy C.; Aureli, Filippo; Baker, Joseph M.; Bania, Amanda E.; Barnard, Allison M.; Boogert, Neeltje J.; Brannon, Elizabeth M.; Bray, Emily E.; Bray, Joel; Brent, Lauren J. N.; Burkart, Judith M.; Call, Josep; Cantlon, Jessica F.; Cheke, Lucy G.; Clayton, Nicola S.; Delgado, Mikel M.; DiVincenti, Louis J.; Fujita, Kazuo; Herrmann, Esther; Hiramatsu, Chihiro; Jacobs, Lucia F.; Jordan, Kerry E.; Laude, Jennifer R.; Leimgruber, Kristin L.; Messer, Emily J. E.; Moura, Antonio C. de A.; Ostojic, Ljerka; Picard, Alejandra; Platt, Michael L.; Plotnik, Joshua M.; Range, Friederike; Reader, Simon M.; Reddy, Rachna B.; Sandel, Aaron A.; Santos, Laurie R.; Schumann, Katrin; Seed, Amanda M.; Sewall, Kendra B.; Shaw, Rachael C.; Slocombe, Katie E.; Su, Yanjie; Takimoto, Ayaka; Tan, Jingzhi; Tao, Ruoting; van Schaik, Carel P.; Viranyi, Zsoia; Visalberghi, Elisabetta; Wade, Jordan C.; Watanabe, Arii; Widness, Jane; Young, Julie K.; Zentall, Thomas R.; Zhao, Yini (NAS, 2014-04-21)
Cognition presents evolutionary research with one of its greatest challenges. Cognitive evolution has been explained at the proximate level by shifts in absolute and relative brain volume and at the ultimate level by differences in social and dietary complexity. However, no study has integrated the experimental and phylogenetic approach at the scale required to rigorously test these explanations. Instead, previous research has largely relied on various measures of brain size as proxies for cognitive abilities. We experimentally evaluated these major evolutionary explanations by quantitatively comparing the cognitive performance of 567 individuals representing 36 species on two problem-solving tasks measuring self-control. Phylogenetic analysis revealed that absolute brain volume best predicted performance across species and accounted for considerably more variance than brain volume controlling for body mass. This result corroborates recent advances in evolutionary neurobiology and illustrates the cognitive consequences of cortical reorganization through increases in brain volume. Within primates, dietary breadth but not social group size was a strong predictor of species differences in self-control. Our results implicate robust evolutionary relationships between dietary breadth, absolute brain volume, and self-control. These findings provide a significant first step toward quantifying the primate cognitive phenome and explaining the process of cognitive evolution.
From concept to practice to policy: modeling coupled natural and human systems in lake catchments
Cobourn, Kelly M.; Carey, Cayelan C.; Boyle, Kevin J.; Duffy, Christopher J.; Dugan, Hilary A.; Farrell, Kaitlin J.; Fitchett, Leah Lynn; Hanson, Paul C.; Hart, Julia A.; Henson, Virginia Reilly; Hetherington, Amy L.; Kemanian, Armen R.; Rudstam, Lars G.; Shu, Lele; Soranno, Patricia A.; Sorice, Michael G.; Stachelek, Joseph; Ward, Nicole K.; Weathers, Kathleen C.; Weng, Weizhe; Zhang, Yu (Ecological Society of America, 2018-05-03)
Recent debate over the scope of the U.S. Clean Water Act underscores the need to develop a robust body of scientific work that defines the connectivity between freshwater systems and people. Coupled natural and human systems (CNHS) modeling is one tool that can be used to study the complex, reciprocal linkages between human actions and ecosystem processes. Well‐developed CNHS models exist at a conceptual level, but the mapping of these system representations in practice is limited in capturing these feedbacks. This article presents a paired conceptual–empirical methodology for functionally capturing feedbacks between human and natural systems in freshwater lake catchments, from human actions to the ecosystem and from the ecosystem back to human actions. We address extant challenges in CNHS modeling, which arise from differences in disciplinary approach, model structure, and spatiotemporal resolution, to connect a suite of models. In doing so, we create an integrated, multi‐disciplinary tool that captures diverse processes that operate at multiple scales, including land‐management decision‐making, hydrologic‐solute transport, aquatic nutrient cycling, and civic engagement. In this article, we build on this novel framework to advance cross‐disciplinary dialogue to move CNHS lake‐catchment modeling in a systematic direction and, ultimately, provide a foundation for smart decision‐making and policy.
A global parasite conservation plan
Carlson, Colin J.; Hopkins, Skylar R.; Bell, Kayce C.; Dona, Jorge; Godfrey, Stephanie S.; Kwak, Mackenzie L.; Lafferty, Kevin D.; Moir, Melinda L.; Speer, Kelly A.; Strona, Giovanni; Torchin, Mark; Wood, Chelsea L. (2020-10)
Found throughout the tree of life and in every ecosystem, parasites are some of the most diverse, ecologically important animals on Earth-but in almost all cases, the least protected by wildlife or ecosystem conservation efforts. For decades, ecologists have been calling for research to understand parasites' important ecological role, and increasingly, to protect as many species from extinction as possible. However, most conservationists still work within priority systems for funding and effort that exclude or ignore parasites, or treat parasites as an obstacle to be overcome. Our working group identified 12 goals for the next decade that could advance parasite biodiversity conservation through an ambitious mix of research, advocacy, and management.
Global synthesis of the temperature sensitivity of leaf litter breakdown in streams and rivers
Shah, Jennifer J. Follstad; Kominoski, John S.; Ardon, Marcelo; Dodds, Walter K.; Gessner, Mark O.; Griffiths, Natalie A.; Hawkins, Charles P.; Johnson, Sherri L.; Lecerf, Antoine; Leroy, Carri J.; Manning, David W. P.; Rosemond, Amy D.; Sinsabaugh, Robert L.; Swan, Christopher M.; Webster, Jackson R.; Zeglin, Lydia H. (2017-08)
Streams and rivers are important conduits of terrestrially derived carbon (C) to atmospheric and marine reservoirs. Leaf litter breakdown rates are expected to increase as water temperatures rise in response to climate change. The magnitude of increase in breakdown rates is uncertain, given differences in litter quality and microbial and detritivore community responses to temperature, factors that can influence the apparent temperature sensitivity of breakdown and the relative proportion of C lost to the atmosphere vs. stored or transported downstream. Here, we synthesized 1025 records of litter breakdown in streams and rivers to quantify its temperature sensitivity, as measured by the activation energy (E-a, in eV). Temperature sensitivity of litter breakdown varied among twelve plant genera for which E-a could be calculated. Higher values of E-a were correlated with lower-quality litter, but these correlations were influenced by a single, N-fixing genus (Alnus). E-a values converged when genera were classified into three breakdown rate categories, potentially due to continual water availability in streams and rivers modulating the influence of leaf chemistry on breakdown. Across all data representing 85 plant genera, the E-a was 0.34 +/- 0.04 eV, or approximately half the value (0.65 eV) predicted by metabolic theory. Our results indicate that average breakdown rates may increase by 5-21% with a 1-4 C rise in water temperature, rather than a 10-45% increase expected, according to metabolic theory. Differential warming of tropical and temperate biomes could result in a similar proportional increase in breakdown rates, despite variation in E-a values for these regions (0.75 +/- 0.13 eV and 0.27 +/- 0.05 eV, respectively). The relative proportions of gaseous C loss and organic matter transport downstream should not change with rising temperature given that E-a values for breakdown mediated by microbes alone and microbes plus detritivores were similar at the global scale.
Goals and Conditions for a Sustainable World
Cairns, John Jr. (Ethics in Science and Environmental Politics, 2002)
This book is a collection of John Cairns, Jr.'s papers, articles, and commentaries focusing primarily on goals and conditions needed to achieve the sustainable use of the planet.
GRAPLEr: A Distributed Collaborative Environment for Lake Ecosystem Modeling that Integrates Overlay Networks, High-throughput Computing, and Web Services
Subratie, Kensworth C.; Aditya, Saumitra; Figueiredo, Renato J.; Carey, Cayelan C.; Hanson, Paul C. (2015-09-29)
The GLEON Research And PRAGMA Lake Expedition -- GRAPLE -- is a collaborative effort between computer science and lake ecology researchers. It aims to improve our understanding and predictive capacity of the threats to the water quality of our freshwater resources, including climate change. This paper presents GRAPLEr, a distributed computing system used to address the modeling needs of GRAPLE researchers. GRAPLEr integrates and applies overlay virtual network, high-throughput computing, and Web service technologies in a novel way. First, its user-level IP-over-P2P (IPOP) overlay network allows compute and storage resources distributed across independently-administered institutions (including private and public clouds) to be aggregated into a common virtual network, despite the presence of firewalls and network address translators. Second, resources aggregated by the IPOP virtual network run unmodified high-throughput computing middleware (HTCondor) to enable large numbers of model simulations to be executed concurrently across the distributed computing resources. Third, a Web service interface allows end users to submit job requests to the system using client libraries that integrate with the R statistical computing environment. The paper presents the GRAPLEr architecture, describes its implementation and reports on its performance for batches of General Lake Model (GLM) simulations across three cloud infrastructures (University of Florida, CloudLab, and Microsoft Azure).
Harnessing the Microbiome to Prevent Fungal Infections: Lessons from Amphibians
Walke, Jenifer B.; Belden, Lisa K. (PLOS, 2016-09-08)
All multicellular organisms are host to microbial symbionts that constitute the microbiome and can have significant impacts on the host, including altering development, behavior, and health [1]. In turn, aspects of the host and their environment can influence the microbiome [2]. Here, we briefly summarize current knowledge of the amphibian skin microbiome and its role in heath and disease. Given the increase in fungal diseases that now threaten amphibians and other wildlife—including bees, bats, snakes, and corals, as well as a variety of economically important crops [3]—we hope that lessons learned from amphibian host–microbe interactions can also ultimately be applied in other systems (Fig 1).
Heparin-based hydrogel scaffolding alters the transcriptomic profile and increases the chemoresistance of MDA-MB-231 triple-negative breast cancer cells
Menon, Nidhi; Dang, Ha X.; Datla, Udaya Sree; Moarefian, Maryam; Lawrence, Christopher B.; Maher, Christopher A.; Jones, Caroline N. (2020-05-21)
The tumor microenvironment plays a critical role in the proliferation and chemoresistance of cancer cells. Growth factors (GFs) are known to interact with the extracellular matrix (ECM) via heparin binding sites, and these associations influence cell behavior. In the present study, we demonstrate the ability to define signals presented by the scaffold by pre-mixing growth factors, such as epidermal growth factor, into the heparin-based (HP-B) hydrogel prior to gelation. In the 3D biomimetic microenvironment, breast cancer cells formed spheroids within 24 hours of initial seeding. Despite higher number of proliferating cells in 2D cultures, 3D spheroids exhibited a higher degree of chemoresistance after 72 hours. Further, our RNA sequencing results highlighted the phenotypic changes influenced by solid-phase GF presentation. Wnt/beta-catenin and TGF-beta signaling were upregulated in the cells grown in the hydrogel, while apoptosis, IL2-STAT5 and PI3K-AKT-mTOR signaling were downregulated. With emerging technologies for precision medicine in cancer, this nature of fine-tuning the microenvironment is paramount for cultivation and downstream characterization of primary cancer cells and rare circulating tumor cells (CTCs), and effective screening of chemotherapeutic agents.
High-Throughput Screen for Inhibitors of the Type IV Pilus Assembly ATPase PilB
Dye, Keane J.; Vogelaar, Nancy J.; Sobrado, Pablo; Yang, Zhaomin (2021-03)
The bacterial type IV pilus (T4P) is a prominent virulence factor in many significant human pathogens, some of which have become increasingly antibiotic resistant. Antivirulence chemotherapeutics are considered a promising alternative to antibiotics because they target the disease process instead of bacterial viability. However, a roadblock to the discovery of anti-T4P compounds is the lack of a high-throughput screen (HTS) that can be implemented relatively easily and economically. Here, we describe the first HTS for the identification of inhibitors specifically against the T4P assembly ATPase PilB in vitro. Chloracidobacterium thermophilum PilB (CtPilB) had been demonstrated to have robust ATPase activity and the ability to bind its expected ligands in vitro. We utilized CtPilB and MANT-ATP, a fluorescent ATP analog, to develop a binding assay and adapted it for an HTS. As a proof of principle, we performed a pilot screen with a small compound library of kinase inhibitors and identified quercetin as a PilB inhibitor in vitro. Using Myxococcus xanthus as a model bacterium, we found quercetin to reduce its T4P-dependent motility and T4P assembly in vivo. These results validated our HTS as effective in identifying PilB inhibitors. This assay may prove valuable in seeking leads for the development of antivirulence chemotherapeutics against PilB, an essential and universal component of all bacterial T4P systems. IMPORTANCE Many bacterial pathogens use their type IV pili (T4P) to facilitate and maintain infection of a human host. Small chemical compounds that inhibit the production or assembly of T4P hold promise in the treatment and prevention of infections, especially in the era of increasing threats from antibiotic-resistant bacteria. However, few chemicals are known to have inhibitory or anti-T4P activity. Their identification has not been easy due to the lack of a method for the screening of compound collections or libraries on a large scale. Here, we report the development of an assay that can be scaled up to screen compound libraries for inhibitors of a critical T4P assembly protein. We further demonstrate that it is feasible to use whole cells to examine potential inhibitors for their activity against T4P assembly in a bacterium.
Impact of censusing and research on wildlife populations
Kilpatrick, A. Marm; Hoyt, Joseph R.; King, R. Andrew; Kaarakka, Heather M.; Redell, Jennifer A.; White, J. Paul; Langwig, Kate E. (2020-11)
Population monitoring and research are essential for conserving wildlife, but these activities may directly impact the populations under study. These activities are often restricted to minimize disturbance, and impacts must be weighed against knowledge gained. However, few studies have quantified the effects of research or census-related visitation frequency on populations, and low visitation rates have been hypothesized to have little effect. Hibernating bats have been hypothesized to be especially sensitive to visitation because they have limited energetic stores to survive winter, and disturbance may partly deplete these stores. We examined the effect of site visitation frequency on population growth rates of three species of hibernating bats, little brown bats (Myotis lucifugus), Indiana bats (Myotis sodalis) and tri-colored bats (Perimyotis subflavus), both before and after detection of the disease white-nose syndrome. We found no evidence that more frequent visits decreased population growth rates for any of these species. Estimated coefficients were either the opposite sign as hypothesized (population growth rates increased with visitation frequency) or were very small (difference in population growth rates 0.067% [SE 2.5%]-1.8% [SE 9.8%]) relative to spatial and temporal variation (5.9-32%). In contrast, white-nose syndrome impacts on population growth rates were easily detected and well-characterized statistically (effect sizes 4.4-8.0; severe population declines occurred in the second and third years after pathogen detection) indicating that we had sufficient power to detect effects. These results indicate that visitation frequency (forM. sodalis:annual vs. semi-annual counts; forM. lucifugusandP. subflavus:1-3 three research visits per year) had undetectable impacts on bat population growth rates both with and without the additional stress of an emerging infectious disease. Knowledge gained from censuses and research may outweigh disturbance due to human visitation if it can be used to understand and conserve the species.

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