Biology subjects

Garrett, K.

Publications and source records attributed to Garrett, K..

9 recordsLinked to original sources

bioRxiv2025

De novo protein design enables targeting of intractable oncogenic interfaces

Protein-protein interactions (PPIs) involving oncogenic drivers remain among the most intractable targets in cancer biology due to their dynamic conformations and limited accessibility to conventional small molecules. Although antibodies and indirect inhibitors have achieved clinical success against targets such as PD-1/PD-L1 and MYC, challenges persist related to tissue penetration, intracellular delivery, resistance, and incomplete blockade of key interface hotspots. Here, we present DesignForge, an integrated de novo protein design framework that combines deep-learning-based structure generation, sequence optimization, and energetic hotspot mapping to create compact miniprotein binders for PPIs. Using this approach, we engineered PD-1 mimetics predicted to disrupt the PD-1/PD-L1 immune checkpoint, designed scaffolds targeting the MYC/MAX dimerization interface, and generated KRAS binders in a manner predicted to occlude RAF interaction. The top designs showed high structural confidence by AlphaFold2, favorable stability metrics, and consistent hotspot engagement identified through MOE-based analyses. Collectively, these results establish DesignForge as a generalizable in silico platform for rational design of therapeutic protein binders that extend beyond antibody and small-molecule modalities to systematically target intractable oncogenic PPIs.

bioinformatics↗

bioRxiv2021

A two-year study on the phenology, host and habitat associations, and pathogens of Haemaphysalis longicornis in Virginia, U.S.A.

Understanding the abiotic and biotic variables affecting tick populations is essential for studying the biology and health risks associated with vector species. We conducted a study on the phenology of exotic Haemaphysalis longicornis (Asian longhorned tick) at a site in Albemarle County, Virginia. We assessed the importance of available wildlife hosts, habitats, and microclimate variables such as temperature, relative humidity, and wind speed on this exotic ticks presence and abundance. In addition, we determined the prevalence of selected tick-borne pathogens potentially transmitted by H. longicornis. We determined that the seasonal activity of H. longicornis was slightly different from previous studies in the northeastern United States. We observed nymphal ticks persist year-round but were most active in the spring, followed by a peak in adult activity in the summer and larval activity in the fall seasons. We also observed a lower probability of detecting H. longicornis in field habitats and the summer months. In addition, we detected H. longicornis on several wildlife hosts, including coyote (Canis latrans), eastern cottontail (Sylvilagus floridanus), raccoon (Procyon lotor), Virginia opossum (Didelphis virginiana), white-tailed deer (Odocoileus virginianus), woodchuck (Marmota monax), and a Peromyscus sp. This is the first detection of this tick on a rodent host important to the epidemiology of tick-borne pathogens of humans and animals. Finally, we continued to detect the exotic piroplasm parasite, Theileria orientalis Ikeda, in H. longicornis as well as other pathogens, including Rickettsia felis, Anaplasma phagocytophilum (AP-1), and a Hepatozoon sp. previously characterized in Amblyomma americanum. These represent some of the first detections of arthropod-borne pathogens native to the United States in host-seeking H. longicornis. These data increase our understanding of H. longicornis biology in the United States and provide valuable information into the future health risks associated with this tick and pathogens.

ecology↗

bioRxiv2019

Network analysis of the papaya orchard virome from two agroecological regions of Chiapas, Mexico

The study of complex ecological interactions - such as those among host, pathogen, and vector communities - can help to explain host ranges and the emergence of novel pathogens. The analysis of community structures using bipartite networks describe the associations between two trophic levels, for example plants and pollinators, or hosts and parasitoids. Bipartite networks represent interactions (links) occurring only between nodes in different levels - in our case, between viruses and hosts. We evaluated the viromes of papaya orchards (papaya, weeds, and insects) from intensive production of papaya in the Pacific Coastal Plain and the Central Depression of Chiapas, Mexico. Samples of papaya cultivar Maradol, which, like most cultivars, is susceptible to papaya ringspot virus (PRSV), were categorized by symptoms by local farmers (papaya ringspot symptoms, non-PRSV symptoms, or no symptoms). These analyses revealed the presence of 61 viruses, where only four species were shared among both physiographic regions. Nearly 52 complete viral genome sequences were recovered, of which 16 showed homology to known viruses, and 36 shared similarities with different genera including Potyvirus, Comovirus, and Tombusvirus (RNA viruses), and Begomovirus and Mastrevirus (DNA viruses). We analyzed the network of associations between viruses and host-location combinations, and described ecological properties of the network, such as asymmetry in interactions and nestedness compared to null models. Understanding the network structure informs management strategies, and advances understanding of interactions of hosts and viruses in the agroecological landscape.\n\nImportanceVirus-virus interactions in plants can modify host symptoms. As a result, disease management strategies may be unsuccessful if they are based solely on visual assessment and diagnostic assays for known individual viruses. Papaya ringspot virus is an important limiting factor for papaya production, and likely has interactions with other viruses that are not yet known. Using high-throughput sequencing, we recovered known and novel RNA and DNA viruses from papaya orchards in Chiapas, Mexico, categorized by host and, in the case of papaya, symptom type: asymptomatic papaya, papaya with ringspot virus symptoms, papaya with non-ringspot symptoms, weeds, and insects. Using network analysis, we demonstrated virus associations within and among host types, and described the ecological community patterns. Recovery of viruses from weeds and asymptomatic papaya suggests the need for additional management attention. These analyses contribute to the understanding of the community structure of viruses in the agroecological landscape.

microbiology↗

bioRxiv2018

Management performance mapping: the value of information for regional prioritization of project interventions

Policymakers and donors often need to identify the locations and settings where technologies are most likely to have important effects, to increase the benefits from agricultural development or extension efforts. Higher quality information may help to target the high-payoff locations. The value of information (VOI) in this context is formalized by evaluating the results of decision making guided by a set of information compared to the results of acting without taking the information into account. We present a framework for management performance mapping that includes evaluating the VOI for decision making about geographic priorities in regional intervention strategies, in case studies of Andean and Kenyan potato seed systems. We illustrate use of Bayesian network models and recursive partitioning to characterize the relationship between seed health and yield responses and environmental and management predictors used in studies of seed degeneration. These analyses address the expected performance of an intervention based on geographic predictor variables. In the Andean example, positive selection of seed from asymptomatic plants was more effective at high altitudes in Ecuador. In the Kenyan example, there was the potential to target locations with higher technology adoption rates and with higher potato cropland connectivity, i.e., a likely more important role in regional epidemics. Targeting training to high performance areas would often provide more benefits than would random selection of target areas. We illustrate how assessing the VOI can help inform targeted development programs and support a culture of continuous improvement for interventions.

ecology↗

bioRxiv2018

Rootstocks shape the rhizobiome: Rhizosphere and endosphere bacterial communities in the grafted tomato system

Root-associated microbes are critical to plant health and performance, although understanding of the factors that structure these microbial communities and theory to predict microbial assemblages are still limited. Here we use a grafted tomato system to study the effects of rootstock genotypes and grafting in endosphere and rhizosphere microbiomes that were evaluated by sequencing 16S rRNA. We compared the microbiomes of nongrafted tomato cultivar BHN589, selfgrafted BHN589, and BHN589 grafted to Maxifort or RST-04-106 hybrid rootstocks. OTU-based bacterial diversity was greater in Maxifort compared to nongraft controls, whereas bacterial diversity in the controls (selfgraft and nongraft) and the other rootstock (RST-04-106) was similar. Grafting itself did not affect bacterial diversity; diversity in the selfgraft was similar to the nongraft. Bacterial diversity was higher in the rhizosphere than in the endosphere for all treatments. However, despite the lower overall diversity, there was a greater number of differentially abundant OTUs (DAOTUs) in the endosphere, with the greatest number of DAOTUs associated with Maxifort. In a PERMANOVA analysis, there was evidence for an effect of rootstock genotype on bacterial communities. The endosphere-rhizosphere compartment and study site explained a high percentage of the differences among bacterial communities. Further analyses identified OTUs responsive to rootstock genotypes in both the endosphere and the rhizosphere. Our findings highlight the effects of rootstocks on bacterial diversity and composition. The influence of rootstock and plant compartment on microbial communities indicates opportunities for the development of designer communities and microbiome-based breeding to improve future crop production.\n\nImportanceUnderstanding factors that control microbial communities is essential for designing and supporting microbiome-based agriculture. In this study, we used a grafted tomato system to study the effect of rootstock genotypes and grafting on bacterial communities colonizing the endosphere and the rhizosphere. Comparing the bacterial communities in control treatments (nongraft and selfgraft plants) with the hybrid rootstocks used by farmers, we evaluated the effect of rootstocks on overall bacterial diversity and composition. These findings indicate the potential for using plant genotype to indirectly select bacterial taxa. In addition, we identify taxa responsive to each rootstock treatments, which may represent candidate taxa useful for biocontrol and in biofertilizers.

microbiology↗

bioRxiv2017

Global cropland connectivity: A risk factor for invasion and saturation by emerging pathogens and pests

The geographic pattern of cropland is an important risk factor for invasion and saturation by crop-specific pathogens and arthropods. Understanding cropland networks supports smart pest sampling and mitigation strategies. We evaluate global networks of cropland connectivity for key vegetatively-propagated crops (banana and plantain, cassava, potato, sweetpotato, and yam) important for food security in the tropics. For each crop, potential movement between geographic location pairs was evaluated using a gravity model, with associated uncertainty quantification. The highly-linked hub and bridge locations in cropland connectivity risk maps are likely priorities for surveillance and management, and for tracing intra-region movement of pathogens and pests. Important locations are identified beyond those locations that simply have high crop density. Cropland connectivity risk maps provide a new risk component for integration with other factors - such as climatic suitability, genetic resistance, and trade routes - to inform Pest Risk Assessment and mitigation.

ecology↗

bioRxiv2017

Analyzing Key Nodes and Epidemic Risk in Seed Networks: Sweetpotato in Northern Uganda

Seed systems are critical for deployment of improved varieties, but also serve as major conduits for the spread of seed-borne pathogens. We evaluated the structure of an informal sweetpotato seed system for its vulnerability to the spread of epidemics, and its utility for disseminating improved varieties. During the 2014 growing season, vine sellers were surveyed weekly in the Gulu Region of Northern Uganda. Our analysis draws on tools from network theory to evaluate the potential for epidemic spread in this region. Using empirical seed transaction data and estimated spatial spread, we constructed a network of seed and pathogen movement. We modeled the introduction of a pathogen, and evaluated the influence of both epidemic starting point and quarantine treatments on epidemic progress. Quarantine of 30 out of 99 villages reduced epidemic progress by up to 66%, when compared to the control (no quarantine), over 20 time steps. The starting position in the network was critical for epidemic progress and final epidemic outcomes, and influenced the percent control conferred by quarantine treatments. Considering equal likelihood of any node being an introduction point for a new epidemic, villages of particular utility for disease monitoring were identified. Sensitivity analysis identified important parameters and priorities for future data collection. The efficacy of node degree, closeness, and eigenvector centrality was similar for selecting quarantine locations, while betweenness had more limited utility. This analysis framework can be applied to provide recommendations for a wide variety of seed systems.

ecology↗

bioRxiv2017

Pathogen mitigation in an Ecuadorian potato seed system: Insights from network analysis

Seed systems have an important role in the distribution of high quality seed and improved varieties. The structure of seed networks also helps to determine the epidemiological risk for seedborne disease. We present a new method for evaluating the epidemiological role of nodes in seed networks, and apply it to a regional potato farmer consortium (CONPAPA) in Ecuador. We surveyed farmers to estimate the structure of networks of farmer seed tuber and ware potato transactions, and farmer information sources about pest and disease management. Then we simulated pathogen spread through seed transaction networks to identify priority nodes for disease detection. The likelihood of pathogen establishment was weighted based on the quality and/or quantity of information sources about disease management. CONPAPA staff and facilities, a market, and certain farms are priorities for disease management interventions, such as training, monitoring and variety dissemination. Advice from agrochemical store staff was common but assessed as significantly less reliable. Farmer access to information (reported number and quality of sources) was similar for both genders. Women had a smaller amount of the market share for seed-tubers and ware potato, however. Understanding seed system networks provides input for scenario analyses to evaluate potential system improvements.

ecology↗

bioRxiv2017

Resistance genes in global crop breeding networks

Resistance genes are a major tool for managing crop diseases. The crop breeder networks that exchange resistance genes and deploy them in elite varieties help to determine the global landscape of resistance and epidemics, and comprise an important system for maintaining food security. These networks function as complex adaptive systems, with associated strengths and vulnerabilities, and implications for policies to support resistance gene deployment strategies. Extensions of epidemic network analysis can be used to evaluate the multilayer agricultural networks that support and influence crop breeding networks. We evaluate the general structure of crop breeding networks for cassava, potato, rice, and wheat, which illustrate a range of public and private configurations. These systems must adapt to global change in climate and land use, the emergence of new diseases, and disruptive breeding technologies. Principles for maintaining system resilience can be applied to global resistance gene deployment. For example, both diversity and redundancy in the roles played by individual crop breeding groups (public versus private, global versus local) may support societal goals for crop production. Another principle is management of connectivity, where enhanced connectivity among crop breeders may benefit global resistance gene deployment, but increase risks to the durability of resistance genes without effective policies regarding deployment.

genetics↗