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At least 127 records · Page 7

A PCR Based Microbial Monitoring Alternative Method of Detection and Identification of Microbes Aboard ISS

Previous research has shown that microorganisms and potential human pathogens have been detected on the International Space Station (ISS) with additional introduction of new microflora occurring with every exchange of crew or addition of equipment and supplies. These microbes are readily transferred between crew and subsystems (i.e. ECLSS, environmental control and life support systems). As this can be detrimental to astronaut health and optimal performance of ISS systems, monitoring of systems such as ECLSS to include identification of microbial contaminants could prevent adverse effects on human health and life support systems. Current monitoring on ISS is laborious and utilizes culture based methods followed by sample return to Earth for complete analysis. Future, long-distance spaceflight missions will require real-time monitoring capabilities that enable efficient and rapid assessments of the microbial environment allowing for expedited decisions and more targeted response to cope with anomalies. Polymerase chain reaction (PCR), a molecular microbial monitoring method was chosen and numerous PCR instruments investigated for their potential to perform in microgravity conditions. Using ISS as a test bed for PCR verification in microgravity will enable NASA to assess whether molecular based microbiological sensors may be components of reliable, closed-loop life support and habitation systems in spacecraft, enhancing infrastructure capabilities through increased efficiency, reliability, and time savings by enabling sample analysis on orbit. NASA selected the Water Monitoring Suite as one of the rapid spaceflight hardware demonstration activities utilizing a streamlined process to minimize the time required to fly experimental flight hardware. The RAZOR EX (BioFire Defense, Salt Lake City, UT) system was part of the water monitoring suite and is a commercial off-the-shelf (COTS) real-time PCR instrument designed for field work. The RAZOR EX was originally designed for Department of Defense (DoD) under a small business innovative research (SBIR) grant and is ruggedized, compact and provides a rapid, sample to answer in less than an hour. PCR assays using a fluorescent probe were optimized and spiked with known concentrations of DNA (Pseudomonas aeruginosa) ranging from 0.002 to 20 ng. PCR reagents were lyophilized and configured in customized pouches and tested for flight readiness. Three types of water were used to rehydrate the reagents and demonstrate the fidelity of the PCR reaction in microgravity. Molecular grade deionized water served as a control while filtered and unfiltered ISS potable water served to test for chemical or biological inhibitors. All three types were compared to parallel ground test results. Nine tests were run on ISS (3 of each water type) and the critical threshold cycle (Ct) was compared to parallel ground tests completed at Kennedy Space Center, FL and Johnson Space Center, TX. All concentrations of Pseudomonas aeruginosa DNA were detected. A comparison of the Ct produced in real time PCR indicated similarity between flight and ground samples. There appeared to be no significant difference between flight or ground PCR reactions or between any of the three water types. This testing demonstrated the ability to perform molecular testing during spaceflight operations with similar sensitivity. It will allow for future ground development of molecular protocols and minimize the need for spaceflight testing. Future testing will include development of additional targets including environmental and health related organisms.

Christina Khodadad↗

Microbial Monitoring from the Frontlines to Space: Department of Defense Small Business Innovation Research Technology Aboard the International Space Station

The RAZOR (trademark) EX, a quantitative Polymerase Chain Reaction (qPCR) instrument, is a portable, ruggedized unit that was designed for the Department of Defense (DoD) with its reagent chemistries traceable to a Small Business Innovation Research (SBIR) contract beginning in 2002. The PCR instrument's primary function post 9/11 was to enable frontline soldiers and first responders to detect biological threat agents and bioterrorism activities in remote locations to include field environments. With its success for DoD, the instrument has also been employed by other governmental agencies including Department of Homeland Security (DHS). The RAZOR (Trademark) EX underwent stringent testing by the vendor, as well as through the DoD, and was certified in 2005. In addition, the RAZOR (trademark) EX passed DHS security sponsored Stakeholder Panel on Agent Detection Assays (SPADA) rigorous evaluation in 2011. The identification and quantitation of microbial pathogens is necessary both on the ground as well as during spaceflight to maintain the health of astronauts and to prevent biofouling of equipment. Currently, culture-based monitoring technology has been adequate for short-term spaceflight missions but may not be robust enough to meet the requirements for long-duration missions. During a NASA-sponsored workshop in 2011, it was determined that the more traditional culture-based method should be replaced or supplemented with more robust technologies. NASA scientists began investigating innovative molecular technologies for future space exploration and as a result, PCR was recommended. Shortly after, NASA sponsored market research in 2012 to identify and review current, commercial, cutting edge PCR technologies for potential applicability to spaceflight operations. Scientists identified and extensively evaluated three candidate technologies with the potential to function in microgravity. After a thorough voice-of-the-customer trade study and extensive functional and safety evaluations, the RAZOR (trademark) EX PCR instrument(Bio-Fire Defense, Salt Lake City, UT) was selected as the most promising current technology for spaceflight monitoring applications.

Cherie M Oubre↗

Expansion of Microbial Monitoring Capabilities on the International Space Station (ISS)

Microbial monitoring is one of the tools that the National Aeronautics and Space Administration (NASA) uses on the International Space Station (ISS) to help maintain crew health and safety. In combination with regular housekeeping and disinfection when needed, microbial monitoring provides important information to the crew about the quality of the environment. Rotation of astronauts, equipment, and cargo on the ISS can affect the microbial load in the air, surfaces, and water. The current ISS microbial monitoring methods are focused on culture-based enumeration during flight and require a significant amount of crew time as well as long incubation periods of up to 5 days there by proliferating potential pathogens. In addition, the samples require return to Earth for complete identification of the microorganisms cultivated. Although the current approach assess the quality of the ISS environment, molecular technology offers faster turn-around of information particularly beneficial in an off-nominal situation. In 2011, subject matter experts from industry and academia recommended implementation of molecular-based technologies such as quantitative real-time polymerase chain reaction (qPCR) for evaluation to replace current, culture-based technologies. The RAZOR EX (BioFire Defense, Inc, Salt Lake City, UT) a ruggedized, compact, COTS (commercial off the shelf) qPCR instrument was tested, evaluated and selected in the 2 X 2015 JSC rapid flight hardware demonstration initiative as part of the Water Monitoring Suite. RAZOR EX was launched to ISS on SpaceX-9 in July 2016 to evaluate the precision and accuracy of the hardware by testing various concentrations of DNA in microgravity compared to ground controls. Flight testing was completed between September 2016 and March 2017. Data presented will detail the hardware performance of flight testing results compared to ground controls. Future goals include additional operational ground-based testing and assay development to determine if this technology can meet spaceflight microbial monitoring requirements.

Khodadad, Christina L.↗

Dose- and Ion-Dependent Effects in the Oxidative Stress Response to Space-Like Radiation Exposure in the Skeletal System

Exposure to space radiation may pose a risk to skeletal health during subsequent aging. Irradiation acutely stimulates bone remodeling in mice, although the long-term influence of space radiation on bone-forming potential (osteoblastogenesis) and possible adaptive mechanisms are not well understood. We hypothesized exposure to ionizing radiation impairs osteoblastogenesis in an ion-type specific manner, with low doses capable of modulating expression of redox-related genes. 16-week old, male, C57BL6/J mice were exposed to low linear-energy-transfer (LET) protons (150 mega electron volts per nucleon) or high-LET (sup 56) Fe ions (600 mega electron volts per nucleon) using either low (5 or 10 centigrays) or high (50 or 200 centigrays) doses at NASAs Space Radiation Lab at Brookhaven National Lab (NSRL/BNL). Tissues were harvested 5 weeks or 1 year after irradiation and bones were analyzed by microcomputed tomography for cancellous microarchitecture and cortical geometry. Marrow-derived, adherent cells were grown under osteoblastogenic culture conditions. Cell lysates were analyzed for select groups by RT-PCR (Reverse Transcription-Polymerase Chain Reaction) during the proliferative phase or the mineralizing phase, and differentiation was analyzed by imaging mineralized nodules (percentage surface area). Representative genes were selected for expression analyses, including cell proliferation (PCNA, Cdk2, p21, p53), differentiation (Runx2, Alpl, Bglap), oxidative metabolism (Catalase, GPX, MnSOD, CuZnSOD, iNos, Foxo1), DNA-damage repair (Gadd45), or apoptosis (Caspase 3). As expected, a high dose (200 centigrays), but not low doses, of either (sup 56) Fe or protons caused a loss of cancellous bone volume per total volume. Marrow cells produced mineralized nodules ex vivo regardless of radiation type or dose; (sup 56) Fe (200 centigrays) inhibited median nodule area by more than 90 percent at 5 weeks and 1 year post-irradiation, compared to controls. At 5 weeks post exposure, irradiation with protons or (sup 56) Fe caused few changes in gene expression levels during osteoblastogenesis, although a high dose of (sup 56) Fe (200 centigrays) increased levels of Catalase and Gadd45. In addition, supplementing cell culture media with SOD protected marrow-derived osteoprogenitors from the damaging effects of exposure to low-LET ((sup 137) Cs gamma) if irradiated in vitro, but had limited protective effects on high-LET (sup 56) Fe-exposed cells. In sum, exposure of mice to either protons or (sup 56) Fe at a relatively high dose (200 cGy) caused persistent bone loss, whereas only high-LET (sup 56) Fe increased expression of redox-related genes and inhibited osteoblastogenesis, albeit to a limited extent. We conclude that high-LET irradiation impaired osteoblastogenesis and regulated steady-state gene expression of select redox-related genes during osteoblastogenesis, which may contribute to persistent bone loss.

ionizing radiation↗

Development of Solid-State Nanopore Technology for Life Detection

Biomarkers for life on Earth are an important starting point to guide the search for life elsewhere. However, the search for life beyond Earth should incorporate technologies capable of recognizing an array of potential biomarkers beyond what we see on Earth, in order to minimize the risk of false negatives from life detection missions. With this in mind, charged linear polymers may be a universal signature for life, due to their ability to store information while also inherently reducing the tendency of complex tertiary structure formation that significantly inhibit replication. Thus, these molecules are attractive targets for biosignature detection as potential "self-sustaining chemical signatures." Examples of charged linear polymers, or polyelectrolytes, include deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) as well as synthetic polyelectrolytes that could potentially support life, including threose nucleic acid (TNA) and other xenonucleic acids (XNAs). Nanopore analysis is a novel technology that has been developed for singlemolecule sequencing with exquisite single nucleotide resolution which is also well-suited for analysis of polyelectrolyte molecules. Nanopore analysis has the ability to detect repeating sequences of electrical charges in organic linear polymers, and it is not molecule- specific (i.e. it is not restricted to only DNA or RNA). In this sense, it is a better life detection technique than approaches that are based on specific molecules, such as the polymerase chain reaction (PCR), which requires that the molecule being detected be composed of DNA.

Bywaters, K. B.↗

Ionizing Radiation Affects Gene Expression in Mouse Skin and Bone

Future long-duration space exploration beyond low earth orbit will increase human exposure to space radiation and microgravity conditions as well as associated risks to skeletal health. In animal studies, radiation exposure (greater than 1 Gy) is associated with pathological changes in bone structure, enhanced bone resorption, reduced bone formation and decreased bone mineral density, which can lead to skeletal fragility. Definitive measurements and detection of bone loss typically require large and specialized equipment which can make their application to long duration space missions logistically challenging. Towards the goal of developing non-invasive and less complicated monitoring methods to predict astronauts' health during spaceflight, we examined whether radiation induced gene expression changes in skin may be predictive of the responses of skeletal tissue to radiation exposure. We examined oxidative stress and growth arrest pathways in mouse skin and long bones by measuring gene expression levels via quantitative polymerase chain reaction (qPCR) after exposure to total body irradiation (IR). To investigate the effects of irradiation on gene expression, we used skin and femora (cortical shaft) from the following treatment groups: control (normally loaded, sham-irradiated), and IR (0.5 Gy 56Fe 600 MeV/n and 0.5 Gy 1H 150 MeV/n), euthanized at one and 11 days post-irradiation (IR). To determine the extent of bone loss, tibiae were harvested and cancellous microarchitecture in the proximal tibia quantified ex vivo using microcomputed tomography (microCT). Statistical analysis was performed using Student's t-test. At one day post-IR, expression of FGF18 in skin was significantly greater (3.8X) than sham-irradiated controls, but did not differ at 11 days post IR. Expression levels of other genes associated with antioxidant response (Nfe2l2, FoxO3 and Sod1) and the cell cycle (Trp53, Cdkn1a, Gadd45g) did not significantly differ between the control and IR groups at either time point. Radiation exposure resulted in a 27.0% increase in FGF18-positive hair follicles at one day post-IR and returned to basal levels at 11 days post-IR. A similar trend was observed from FGF18 gene expression analysis of skin. In bone (femora), there was an increase in the expression of the pro-osteoclastogenic cytokine, MCP-1, one day after IR compared to non-irradiated controls. FGF18 expression in skin and MCP- 1 expression in bone were found to be positively correlated (P less than 0.002, r=0.8779). Further, microcomputed tomography analysis of tibia from these animals showed reduced cancellous bone volume (-9.9%) at 11 days post- IR. These results suggest that measurements of early radiation induced changes in FGF18 gene expression in skin may have value for predicting subsequent loss of cancellous bone mass. Further research may lead to the development of a relatively simple diagnostic tool for bone loss, with the advantage that hair follicles and skin are relatively easy to acquire from human subjects.

space radiation↗

A Ratio of Spore to Viable Organisms: A Case Study of the JPL-SAF Cleanroom

Spacecraft surfaces that are destined to land on potential life-harboring celestial bodies are required to be rigorously cleaned and continuously monitored for spore bioburden as a proxy for spacecraft cleanliness. The NASA standard assay (NSA), used for spacecraft bioburden estimates, specifically measures spores that are cultivable, aerobic, resistant to heat shock, and grow at 30 C in a nutrient-rich medium. Since the vast majority of microorganisms cannot be cultivated using the NSA, it is necessary to utilize state-of-the art molecular techniques to better understand the presence of all viable microorganisms, not just those measured with the NSA. In this study, the nutrient-deprived low biomass cleanrooms, where spacecraft are assembled, were used as a surrogate for spacecraft surfaces to measure the ratio of NSA spores in relation to the total viable microorganism population in order to make comparisons with the 2006 Space Studies Board (SSB) estimate of 1 spore per approximately 50,000 viable organisms. Ninety-eight surface wipe samples were collected from the Spacecraft Assembly Facility (SAF) cleanroom at the Jet Propulsion Laboratory (JPL) over a 6-month period. The samples were processed and analyzed using classical microbiology along with molecular methodology. Traditional microbiology plating methods were used to determine the cultivable bacterial, fungal, and spore populations. Molecular assays were used to determine the total organisms (TO, dead and live) and the viable organisms (VO, live). The TO was measured using adenosine triphosphate (ATP) and quantitative polymerase chain reaction (qPCR) assays. The VO was measured using internal ATP, propidium monoazide (PMA)-qPCR, and flow cytometry (after staining for viable microorganisms) assays. Based on the results, it was possible to establish a ratio between spore counts and VO for each viability assay. The ATP-based spore to VO ratio ranged from 149-746, and the bacterial PMA-qPCR assay-based ratio ranged from 314-1,491 VO, per spore. The most conservative estimate came from fluorescent-assisted cell sorting (FACS), which estimated the ratio to be 12,091 VO per 1 NSA spore. Since archaeal (less than 1%) and fungal (approximately 2%) populations were negligible, the spore to VO ratios were based on bacterial population estimates. The most conservative ratio from this study can be used as a replacement for the SSB estimate on nutrient-deprived (oligotrophic) desiccated spacecraft surfaces, to estimate the VO from NSA measurements without utilizing state-of-the art molecular methods that are costly and require more biomass than is typically found on spacecraft surfaces.

Hendrickson, Ryan↗

Innate Immune Responses of Drosophila Melanogaster are Altered by Spaceflight

Alterations and impairment of immune responses in humans present a health risk for space exploration missions. The molecular mechanisms under pinning innate immune defense can be confounded by the complexity of the acquired immune system of humans. Drosophila (fruit fly) innate immunity is simpler, and shares many similarities with human innate immunity at the level of molecular and genetic pathways. The goals of this study were to elucidate fundamental immune processes in Drosophila affected by spaceflight and to measure host-pathogen responses post-flight. Five containers, each containing ten female and five male fruit flies, were housed and bred on the space shuttle (average orbit altitude of330.35 km) for 12 days and 18.5 hours. A new generation of flies was reared in microgravity. In larvae, the immune system was examined by analyzing plasmatocyte number and activity in culture. In adults, the induced immune responses were analyzed by bacterial clearance and quantitative real-time polymerase chain reaction (qPCR) of selected genes following infection with E. coli. The RNA levels of relevant immune pathway genes were determined in both larvae and adults by microarray analysis. The ability of larval plasmatocytes to phagocytose E. coli in culture was attenuated following spaceflight, and in parallel, the expression of genes involved in cell maturation was down regulated. In addition, the level of constitutive expression of pattern recognition receptors and opsonins that specifically recognize bacteria, and of lysozymes, antimicrobial peptide (AMP) pathway and immune stress genes, hallmarks of humoral immunity, were also reduced in larvae. In adults, the efficiency of bacterial clearance measured in vivo following a systemic infection with E. coli post-flight, remained robust. We show that spaceflight altered both cellular and humoral immune responses in Drosophila and that the disruption occurs at multiple interacting pathways.

Marcu, Oana↗

Effects of Hindlimb Unloading and Ionizing Radiation on Murine Gene Expression in Skin and Bone

Long duration spaceflight causes a negative calcium balance and reduces bone density in astronauts. The underlying mechanisms of spaceflight-induced bone loss and the possible influences of both microgravity and radiation are not fully understood although emerging evidence suggests that these two factors may interact to result in increased bone loss. Previously, gene expression analysis of hair follicles from astronauts, as well as skin from space-flown mice, revealed changes in the expression of genes related to DNA damage and oxidative stress responses. These results resemble the responses of bone to spaceflight-like radiation and simulated weightlessness by hindlimb unloading (HU). Hence in this study, we initiated studies to determine whether skin can be used to predict the responses of bone to simulated microgravity and radiation. We examined oxidative stress and growth arrest pathways in mouse skin and long bones by measuring gene expression levels via quantitative polymerase chain reaction (qPCR). To investigate the effects of irradiation andor HU on gene expression, we used skin and femora (cortical shaft) from the following treatment groups: control (normally loaded, sham-irradiated) (CT), hindlimb unloading (HU), 56Fe radiation (IR) and both HU+IR. Animals were euthanized 11 days post-IR, and results were analyzed by 1-way ANOVA. In skin samples, Cdkn1a was decreased to the same extent in HU and HU+IR (47 of CT). In addition, HU reduced FoxO3 expression (46 of CT) and IR increased Gadd45g expression 135 compared CT in skin. But in bone, HU increased FoxO3 expression 31 compared the level of CT. These results suggest that radiation and simulated weightlessness regulated simliar oxidative stress and cell cycle arrest genes in both skin and bone, although the time course and direction of changes may differ. This research may lead to the development of a relatively simple diagnostic tool for bone loss with the advantage that hair follicles and skin are relatively easy to acquire from subjects.

Terada, Masahiro↗

Does Seed Sanitization Affect the Plant Rhizosphere Microbiome and Its Ability to Compete with the Human Associated Pathogen, E. coli on Salad Crops?

Cultivation of crops in controlled environmental agricultural systems may limit microbial colonization and reduce diversity of the microbial communities. Practices like seed and growth medium sanitization may further impact microbial communities in the mature plant and the plant’s capacity to limit the growth of pathogens through competition. As humans expand their travels to space, understanding plant growth, health, and development in closed environments will be critical to the success of producing a safe, supplemental food source for astronauts. To determine the persistence of a potential human pathogen in plant growth and development, sanitized and unsanitized seeds from, mizuna (Brassica rapa var japonica) and red romaine lettuce (Lactuca sativa cultivar ‘Outredgeous’), were inoculated with Escherichia coli, ATCC 21445, germinated under simulated International Space Station (ISS) environmental conditions and harvested every 7 days until maturity. The persistence of E. coli in the rhizosphere was determined by plating on selective media, real time PCR (Polymerase Chain Reaction) and community sequencing of the rhizosphere communities. E. coli was detected in the crops’ roots and leaves for several weeks post germination. At day 28, plants from sanitized seeds had significantly higher counts of E. coli on the roots than those from unsanitized seeds. E. coli was also detected on a few uninoculated plants indicating airborne cross contamination among plants in the same growth chamber and suggesting an influence of the natural microbiome on human pathogen survival and persistence in leafy greens. Sequencing analysis revealed variations in composition and diversity between the communities. Understanding the microbial community of the rhizospheric microbiome is only the first step in determining the relationships between plants. Additional studies to include genotypic and phenotypic variations in the plants should be considered to determine if the natural microbes in the rhizosphere may contribute to the health and therefore, safety of the edible plants.

Khodadad, Christina L. M.↗

Comprehensive Measurement of Microbial Burden in Nutrient-Deprived Cleanrooms

Spacecraft surfaces that are destined to land on potential life-harboring celestial bodies are required to be rigorously cleaned and continuously monitored for spore bioburden as a proxy for spacecraft cleanliness. The NASA standard spore assay (NSA), used for spacecraft bioburden estimates, specifically measures spores that are cultivable, aerobic, resistant to heat shock, and grow at 30˚C in a nutrient-rich medium. Since the vast majority of microorganisms cannot be cultivated using the NSA assay, it is necessary to utilize state-of-the art molecular techniques to better understand the presence of all viable microorganisms, not just those measured with the NSA. In this study, the nutrient-deprived low biomass cleanrooms, where spacecraft are assembled, were used as a surrogate to spacecraft surfaces to measure the ratio of NSA spores in relation to the total viable microorganism population to compare with a 2006 space studies report that estimates that for every 1 spore there is approximately 50,000 viable organisms. Ninety-eight surface wipe samples were collected from the spacecraft assembly facility (SAF) cleanroom at the Jet Propulsion Laboratory (JPL) over a 6-month period. The samples were processed and analyzed using classical microbiology along with molecular assays. Traditional microbiology plating methods were used to determine the cultivable bacterial, fungal, and spore populations. Molecular assays were used to determine the total organisms (TO, dead and live) and the viable organisms (VO, live). The TO was measured using adenine triphosphate (ATP) and quantitative polymerase chain reaction (qPCR) assays. The VO was measured using internal ATP, propidium monoazide (PMA)-qPCR, and flow cytometry (after staining for viable microorganisms) assays. Based on the results, it was possible to establish a ratio between spore counts and VO for each viability assay. The ATP based spore to VO ratio ranged from 149 – 746 and the bacterial PMA-qPCR assay based ratio ranged from 314 – 1491 VO. The most conservative estimate came from FACS, which estimated the ratio to be 12,091 VO per 1 NSA spore. Since archaeal (<1%) and fungal (~2%) populations were negligible, the spore to VO ratios were based on bacterial population estimates. The most conservative ratio from this study can be used as a replacement for the SSB estimate on nutrient-deprived (oligotrophic) desiccated spacecraft surfaces, to estimate the VO from NSA measurements without utilizing state-of-the art molecular methods that are costly and require more biomass than is typically found of spacecraft surfaces.

Venkateswaran, Kasthuri↗

Rapid Nucleic Acid Isolation Method and Fluid Handling Devices Overview

Sample preparation is a common bottleneck in genetic analysis. Tools that reduce time and effort are of value in a laboratory setting. There is a need for a genetic analysis/detection system that is not only mobile, ruggedized, easy-to-use but also provides an enclosed fluid handling that diminishes the risks of Ribonucleic acid (RNA) contamination and degradation during processing. NASA has developed a novel assay methodology and suite of devices to isolate nucleic acids and prepare samples for real-time (quantitative) polymerase chain reaction (PCR) analysis that solves the problem of contamination and degradation because of the advanced microfluidics which provides better fluid handling. The assay employs an aqueous-based non-alcohol method that yields robust RNA quality. The suite of ready-to-use devices provide pre-loaded reagents in liquid and lyophilized formats to enable rapid, cost effective, and portable manual operation in the laboratory or remote field environments.

Travis Boone↗

Impact of Recent Climate Extremes on Mosquito-borne Disease Transmission in Kenya

Climate change and variability influence temperature and rainfall, which impact vector abundance and the dynamics of vector-borne disease transmission. Climate change is projected to increase the frequency and intensity of extreme climate events. Mosquito-borne diseases, such as dengue fever, are primarily transmitted by Aedes aegypti mosquitoes. Freshwater availability and temperature affect dengue vector populations via a variety of biological processes and thus influence the ability of mosquitoes to effectively transmit disease. However, the effect of droughts, floods, heat waves, and cold waves is not well understood. Using vector, climate, and dengue disease data collected between 2013 and 2019 in Kenya, this retrospective cohort study aims to elucidate the impact of extreme rainfall and temperature on mosquito abundance and the risk of arboviral infections. To define extreme periods of rainfall and land surface temperature (LST), we calculated monthly anomalies as deviations from long-term means (1983–2019 for rainfall, 2000–2019 for LST) across four study locations in Kenya. We classified extreme climate events as the upper and lower 10% of these calculated LST or rainfall deviations. Monthly Ae. aegypti abundance was recorded in Kenya using four trapping methods. Blood samples were also collected from children with febrile illness presenting to four field sites and tested for dengue virus using an IgG enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR). We found that mosquito eggs and adults were significantly more abundant one month following an abnormally wet month. The relationship between mosquito abundance and dengue risk follows a non-linear association. Our findings suggest that early warnings and targeted interventions during periods of abnormal rainfall and temperature, especially flooding, can potentially contribute to reductions in risk of viral transmission

Aedes aegypti mosquitoes↗

Rational Design of Nanoplasmonic Array Geometries for Biosensing

Background: Molecular diagnostics provide early and accurate diagnosis, which is essential for the prevention and treatment of infectious as well as chronic diseases. These tests are designed to detect disease-specific bioanalytes such as nucleic acid (DNA or RNA) or protein (antigens, antibodies) biomarkers. In the context of infectious disease diagnosis, nucleic acid-based detection methods are known to provide more specific and sensitive results. Here, the presence of a unique sequence belonging to the pathogenic genomic material is targeted to identify species, organism, genera and/or antimicrobial resistant gene markers. The majority of the common nucleic acid based diagnostic techniques require amplification (polymerase chain reaction, isothermal amplification etc.) of the pathogenic genetic material prior to detection impacting diagnostic speed, complexity, and cost thereby limiting ease of use. Thus, the development of simplified nucleic acid-based diagnostics that can be even used in resource-poor settings may hugely benefit patients across the globe. Nanopath is a molecular diagnostics company utilizing a solid-state nanosensor to enable sequence-specific detection of target nucleic acids without the need of amplification. These nanostructures enable ultra-sensitive biomarker detection using geometric, feature-dependent properties highly dependent on the local dielectric environment, allowing them to be sensitive to low concentration binding events. This paper describes an application of this approach to provide highly relevant clinical information within a single doctor’s office visit. Intro: The Nanopath team is in collaboration with NASA (National Aeronautics and Space Administration) and NIST (National Institute of Standards and Technology) to push the bounds of the fundamental physics associated with their biosensing platform. The ability of metals to support electromagnetic surface waves gives rise to surface plasmons when optically illuminated. This property, and its strong sensitivity to changes in the local refractive index, allows for the use of metal nanoparticles as ultra-sensitive transducers. In prior work by members of this team, ensembles of randomly oriented nanoparticles (i.e., colloidal nanorods dispersed on chip) were employed for sequence-specific nucleic acid sensing (1-3). While these particle sensors have the advantage of rapid fabrication, they suffer from low sensitivity and quality factor due to the random particle dispersity. In contrast, in this study we employ ordered array nanoparticle ensembles which can be used to improve sensor sensitivity and figure-of-merit. Study Methods Overview: In this talk, we detail the results of sensing experiments and computational simulations to outline a rational design of the structure of these plasmonic nanoparticle arrays for biomolecular sensing. Through simulation and experiment, we iteratively tailor nanostructure dimension to provide high quality signal and large resonance shifts upon modeled nucleic acid binding. In particular, full-wave electromagnetic simulations were conducted using Lumerical photonic simulation software in which periodic boundary conditions were applied in the x- and y- dimensions for each of the nanoplasmonic sensor geometries. To simulate the resonance response to changes in the bulk solution in contact with the sensor surface, the refractive index of the surrounding media was changed appropriately. Nucleic acid hybridization events were modeled using either using spherical structures approximating the relevant radius of genomic material as estimated by polymer models, or as conformal layers with the known refractive indices for nucleic acids. On the basis of initial simulations, nanosensors were fabricated using traditional electron-beam lithography protocols at NIST. To evaluate consensus between simulations and experiments, bulk sensing experiments were carried out in which the resonance peaks were obtained by submerging the sensors in refractive index standards. Key nanosensor characteristics including resonance peak locations, resonance peak shifts as a function of refractive index, and figure of merit (FOM) of extinction curves were examined between the experimental and simulation results prior to proceeding with simulations on additional geometries and more complex solution conditions, and further device fabrication. This iterative process is repeated toward a rational design of nanoplasmonic array geometries for biosensing optimizing response for targeted disease detection. In summary, this study puts forth a methodology for rational design and characterization of regularly spaced nanoparticle arrays for optics-based biosensing. The results of this study will allow for more informed design of nanostructure geometries towards sequence-specific nucleic acid detection. These improved designs have the potential to improve clinical sensitivity and limit-of-detection across disease indication.

sensor↗

In vitro evolution of nucleic acids

The author reviews recent published reports of in vitro selection and evolution of nucleic acids. These nucleic acids will bind to a target ligand or catalyze a specific chemical reaction. The terms aptamers and systematic evolution of ligands by exponential enrichment (SELEX) are explained. The review focuses on protein binders, small molecule binders, and ribozymes obtained by directed evolution. The reference list identifies articles of special or outstanding interest.

Review↗

Pooled PPIseq: Screening the SARS-CoV-2 and human interface with a scalable multiplexed protein-protein interaction assay platform

Protein-Protein Interactions (PPIs) are a key interface between virus and host, and these interactions are important to both viral reprogramming of the host and to host restriction of viral infection. In particular, viral-host PPI networks can be used to further our understanding of the molecular mechanisms of tissue specificity, host range, and virulence. At higher scales, viral-host PPI screening could also be used to screen for small-molecule antivirals that interfere with essential viral-host interactions, or to explore how the PPI networks between interacting viral and host genomes co-evolve. Current high-throughput PPI assays have screened entire viral-host PPI networks. However, these studies are time consuming, often require specialized equipment, and are difficult to further scale. Here, we develop methods that make larger-scale viral-host PPI screening more accessible. This approach combines the mDHFR split-tag reporter with the iSeq2 interaction-barcoding system to permit massively-multiplexed PPI quantification by simple pooled engineering of barcoded constructs, integration of these constructs into budding yeast, and fitness measurements by pooled cell competitions and barcode-sequencing. We applied this method to screen for PPIs between SARS-CoV-2 proteins and human proteins, screening in triplicate >180,000 ORF-ORF combinations represented by >1,000,000 barcoded lineages. Our results complement previous screens by identifying 74 putative PPIs, including interactions between ORF7A with the taste receptors TAS2R41 and TAS2R7, and between NSP4 with the transmembrane KDELR2 and KDELR3. We show that this PPI screening method is highly scalable, enabling larger studies aimed at generating a broad understanding of how viral effector proteins converge on cellular targets to effect replication.

60 APPLIED LIFE SCIENCES↗

Influenza A viral burst size from thousands of infected single cells using droplet quantitative PCR (dqPCR)

An important aspect of how viruses spread and infect is the viral burst size, or the number of new viruses produced by each infected cell. Surprisingly, this value remains poorly characterized for influenza A virus (IAV), commonly known as the flu. In this study, we screened tens of thousands of cells using a microfluidic method called droplet quantitative PCR (dqPCR). The high-throughput capability of dqPCR enabled the measurement of a large population of infected cells producing progeny virus. By measuring the fully assembled and successfully released viruses from these infected cells, we discover that the viral burst sizes for both the seasonal H3N2 and the 2009 pandemic H1N1 strains vary significantly, with H3N2 ranging from 10 1 to 10 4 viruses per cell, and H1N1 ranging from 10 1 to 10 3 viruses per cell. Some infected cells produce average numbers of new viruses, while others generate extensive number of viruses. In fact, we find that only 10% of the single-cell infections are responsible for creating a significant portion of all the viruses. This small fraction produced approximately 60% of new viruses for H3N2 and 40% for H1N1. On average, each infected cell of the H3N2 flu strain produced 709 new viruses, whereas for H1N1, each infected cell produced 358 viruses. This novel method reveals insights into the flu virus and can lead to improved strategies for managing and preventing the spread of viruses.

60 APPLIED LIFE SCIENCES↗

Developmental gene regulatory network architecture across 500 million years of echinoderm evolution

Evolutionary change in morphological features must depend on architectural reorganization of developmental gene regulatory networks (GRNs), just as true conservation of morphological features must imply retention of ancestral developmental GRN features. Key elements of the provisional GRN for embryonic endomesoderm development in the sea urchin are here compared with those operating in embryos of a distantly related echinoderm, a starfish. These animals diverged from their common ancestor 520-480 million years ago. Their endomesodermal fate maps are similar, except that sea urchins generate a skeletogenic cell lineage that produces a prominent skeleton lacking entirely in starfish larvae. A relevant set of regulatory genes was isolated from the starfish Asterina miniata, their expression patterns determined, and effects on the other genes of perturbing the expression of each were demonstrated. A three-gene feedback loop that is a fundamental feature of the sea urchin GRN for endoderm specification is found in almost identical form in the starfish: a detailed element of GRN architecture has been retained since the Cambrian Period in both echinoderm lineages. The significance of this retention is highlighted by the observation of numerous specific differences in the GRN connections as well. A regulatory gene used to drive skeletogenesis in the sea urchin is used entirely differently in the starfish, where it responds to endomesodermal inputs that do not affect it in the sea urchin embryo. Evolutionary changes in the GRNs since divergence are limited sharply to certain cis-regulatory elements, whereas others have persisted unaltered.

NASA Program Fundamental Space Biology↗