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All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

Driving in the dark: Deciphering nighttime driver detection of free-ranging roadside wildlife

Wildlife-vehicle collisions are dangerous for motorists; however, few studies have addressed driver detection of roadside animals, and none have evaluated detection of free-ranging wildlife. Here, we used 24 volunteer drivers, infrared videography, a 75-km route, and free-ranging wildlife to quantify factors influencing (1) probability of wildlife detection, (2) detection distance, and (3) probability of dangerous encounters (i.e., detection distance < distance required for braking) for multiple species at night in South Carolina, USA. Detection probability of white-tailed deer (Odocoileus virginianus) was impacted by multiple driver, animal, and roadside factors. Deer detection distances increased by 20.99 m when drivers used high-beam headlights and 23.36 m when deer were moving but decreased by 0.71 m for every minute into a drive. Every encounter with wild pigs (Sus scrofa) and most encounters with small mammals were considered dangerous. Our findings suggest most drivers cannot safely detect deer, wild pigs, and small mammals at night.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2015

Small particle aerosol inoculation of cowpox Brighton Red in rhesus monkeys results in a severe respiratory disease

Cowpox virus (CPXV) inoculation of nonhuman primates (NHPs) has been suggested as an alternate model for smallpox (Kramski et al., 2010, PLoS One, 5, e10412). Previously, we have demonstrated that intrabronchial inoculation of CPXV-Brighton Red (CPXV-BR) into cynomolgus monkeys resulted in a disease that shared many similarities to smallpox; however, severe respiratory tract disease was observed (Smith et al., 2011, J. Gen. Virol.). Here we describe the course of disease after small particle aerosol exposure of rhesus monkeys using computed tomography (CT) to monitor respiratory disease progression. Subjects developed a severe respiratory disease that was uniformly lethal at 5.7 log{sub 10} PFU of CPXV-BR. CT indicated changes in lung architecture that correlated with changes in peripheral blood monocytes and peripheral oxygen saturation. While the small particle aerosol inoculation route does not accurately mimic human smallpox, the data suggest that CT can be used as a tool to monitor real-time disease progression for evaluation of animal models for human diseases. - Highlights: • Small particle aerosol exposure of rhesus results in a severe respiratory disease. • CT findings correlated with peripheral oxygen saturation and monocyte increases. • Virus dissemination was limited and mainly confined to the respiratory tract. • CT provides insight into pathogenesis to aid development of animal models of disease.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

An historical note on the cell theory

The development of the microscope was a precondition for the discovery of cells. This instrument magnifies objects too small to be seen by the naked eye. In 1673, the Dutch botanist, Anton van Leeuwenhoek, made a more advanced microscope and reported seeing a myriad of microscopic “animalcules” in water. He also made further studies of red blood cells and sperm cells. Most studies that followed were done on the easily studied plant tissues. Plant cells, rigidly encased in their cell walls, were ideal to study in situ. The cell theory proposes that nucleated cells are the basic structure of plants and animals. This concept was observed and published separately, first by the botanist, Matthias Schleiden, in 1838, and then by the zoologist, Theodor Schwann, in 1839. Their work demonstrated that cells form the basic unit of life of plants and animals. Rudolf Virchow concluded that all living organisms are the sum of single cellular units and that cells multiply.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Egr-1 mediated cardiac miR-99 family expression diverges physiological hypertrophy from pathological hypertrophy

The physiological cardiac hypertrophy is an adaptive condition without myocyte cell death, while pathological hypertrophy is a maladaptive condition associated with myocyte cell death. This study explores the miRNome of α-2M-induced physiologically hypertrophied cardiomyocytes and the role of miRNA-99 family during cardiac hypertrophy. Physiological and pathological cardiac hypertrophy was induced in H9c2 cardiomyoblast cell lines using α-2M and isoproterenol respectively. Total RNA isolation and small RNA sequencing were executed for physiological hypertrophy model. The differentially expressed miRNAs and its target mRNAs were validated in animal models. Transcription factor binding sites were predicted in the promoter of specific miRNAs and validated by ChIP-PCR. Subsequently, the selected miRNA was functionally characterized by overexpression and silencing. The effects of silencing of upstream regulator and downstream target gene were studied. Analysis of small RNA reads revealed the differential expression of a large set of miRNAs during hypertrophy, of which miR-99 family was highly downregulated upon α-2M treatment. However, this miR-99 family expression was upregulated during pathological hypertrophy and confirmed in animal models. ChIP-PCR confirms the binding of Egr-1 transcription factor to the miR-99 promoter. Further, silencing of Egr-1 decreased the expression of miR-99. The overexpression or silencing of miR-99 diverges the physiological hypertrophy to pathological hypertrophy and vice versa by regulating Akt-1 pathway. Silencing of Akt-1 replicates the effect of overexpression of miR-99.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

A Human Life-Stage Physiologically Based Pharmacokinetic and Pharmacodynamic Model for Chlorpyrifos: Development and Validation

Sensitivity to chemicals in animals and humans are known to vary with age. Age-related changes in sensitivity to chlorpyrifos have been reported in animal models. A life-stage physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed to computationally predict disposition of CPF and its metabolites, chlorpyrifos-oxon (the ultimate toxicant) and 3,5,6-trichloro-2-pyridinol (TCPy), as well as B-esterase inhibition by chlorpyrifos-oxon in humans. In this model, age-dependent body weight was calculated from a generalized Gompertz function, and compartments (liver, brain, fat, blood, diaphragm, rapid, and slow) were scaled based on body weight from polynomial functions on a fractional body weight basis. Blood flows among compartments were calculated as a constant flow per compartment volume. The life-stage PBPK/PD model was calibrated and tested against controlled adult human exposure studies. Model simulations suggest age-dependent pharmacokinetics and response may exist. At oral doses ≥ 0.55 mg/kg of chlorpyrifos (significantly higher than environmental exposure levels), 6 mo old children are predicted to have higher levels of chlorpyrifos-oxon in blood and higher levels of red blood cell cholinesterase inhibition compared to adults from equivalent oral doses of chlorpyrifos. At lower doses that are more relevant to environmental exposures, the model predicts that adults will have slightly higher levels of chlorpyrifos-oxon in blood and greater cholinesterase inhibition. This model provides a computational framework for age-comparative simulations that can be utilized to predict CPF disposition and biological response over various postnatal life-stages.

Smith, Jordan N.↗
DOE OSTI2015

Absorption and Phase Contrast X-Ray Imaging in Paleontology Using Laboratory and Synchrotron Sources

X-ray micro-computed tomography (CT) is commonly used for imaging of samples in biomedical or materials science research. Owing to the ability to visualize a sample in a nondestructive way, X-ray CT is perfectly suited to inspect fossilized specimens, which are mostly unique or rare. In certain regions of the world where important sedimentation events occurred in the Precambrian geological time, several fossilized animals are studied to understand questions related to their origin, environment, and life evolution. This article demonstrates the advantages of applying absorption and phase-contrast CT on the enigmatic fossil Corumbella werneri, one of the oldest known animals capable of building hard parts, originally discovered in Corumba (Brazil). Different tomographic setups were tested to visualize the fossilized inner structures: a commercial laboratory-based CT device, two synchrotron-based imaging setups using conventional absorption and propagation-based phase contrast, and a commercial X-ray microscope with a lens-coupled detector system, dedicated for radiography and tomography. Based on our results we discuss the strengths and weaknesses of the different imaging setups for paleontological studies.

Corumbella werneri↗
DOE OSTI2017

Bacillus anthracis Prolyl 4-Hydroxylase Interacts with and Modifies Elongation Factor Tu

Prolyl hydroxylation is a very common post-translational modification and plays many roles in eukaryotes such as collagen stabilization, hypoxia sensing, and controlling protein transcription and translation. There is a growing body of evidence that suggests that prokaryotes contain prolyl 4-hydroxylases (P4Hs) homologous to the hypoxia-inducible factor (HIF) prolyl hydroxylase domain (PHD) enzymes that act on elongation factor Tu (EFTu) and are likely involved in the regulation of bacterial translation. Recent biochemical and structural studies with a PHD from Pseudomonas putida (PPHD) determined that it forms a complex with EFTu and hydroxylates a prolyl residue of EFTu. Moreover, while animal, plant, and viral P4Hs act on peptidyl proline, most prokaryotic P4Hs have been known to target free l-proline; the exceptions include PPHD and a P4H from Bacillus anthracis (BaP4H) that modifies collagen-like proline-rich peptides. Here we use biophysical and mass spectrometric methods to demonstrate that BaP4H recognizes full-length BaEFTu and a BaEFTu 9-mer peptide for site-specific proline hydroxylation. Using size-exclusion chromatography coupled small-angle X-ray scattering (SEC–SAXS) and binding studies, we determined that BaP4H forms a 1:1 heterodimeric complex with BaEFTu. The SEC–SAXS studies reveal dissociation of BaP4H dimeric subunits upon interaction with BaEFTu. While BaP4H is unusual within bacteria in that it is structurally and functionally similar to the animal PHDs and collagen P4Hs, respectively, this work provides further evidence of its promiscuous substrate recognition. Lastly, it is possible that the enzyme might have evolved to hydroxylate a universally conserved protein in prokaryotes, similar to the PHDs, and implies a functional role in B. anthracis.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2016

Human Microdosing with Carcinogenic Polycyclic Aromatic Hydrocarbons: In Vivo Pharmacokinetics of Dibenzo[ def,p ]chrysene and Metabolites by UPLC Accelerator Mass Spectrometry

Metabolism is a key health risk factor following exposures to pro-carcinogenic polycyclic aromatic hydrocarbons (PAHs) such as dibenzo[def,p]chrysene (DBC), an IARC classified 2A probable human carcinogen. Human exposure to PAHs occurs primarily from the diet in non-smokers. However, little data is available on the metabolism and pharmacokinetics in humans of high molecular weight PAHs (≥4 aromatic rings), including DBC. We previously determined the pharmacokinetics of DBC in human volunteers orally administered a micro-dose (29 ng; 5 nCi) of [14C]-DBC by accelerator mass spectrometry (AMS) analysis of total [14C] in plasma and urine. In the current study, we utilized a novel “moving wire” interface between ultra-performance liquid chromatography (UPLC) and AMS to detect and quantify parent DBC and its major metabolites. The major [14C] product identified in plasma was unmetabolized [14C]-DBC itself, (Cmax= 18.5 ± 15.9 fg/mL, Tmax= 2.1 ± 1.0 h), whereas the major metabolite was identified as [14C]-(+/-)-DBC-11,12-diol (Cmax= 2.5 ± 1.3 fg/mL, Tmax= 1.8 h). Several minor species of [14C]-DBC metabolites were also detected for which no reference standards were available. Free and conjugated metabolites were detected in urine with [14C]-(+/-)-DBC-11,12,13,14-tetraol isomers identified as the major metabolites, 56.3% of which were conjugated (Cmax= 35.8 ± 23.0 pg/pool, Tmax= 6-12 h pool). [14C]-DBC-11,12-diol, of which 97.5% was conjugated, was also identified in urine (Cmax= 29.4 ± 11.6 pg/pool, Tmax= 6-12 h pool). Parent [14C]-DBC was not detected in urine. This is the first dataset to assess metabolite profiles and associated pharmacokinetics of a carcinogenic PAH in human volunteers at an environmentally relevant dose, providing the data necessary for translation of high dose animal models to humans for translation of environmental health risk assessment.

Madeen, Erin P.↗
DOE OSTI2025

Introduction: Neuromorphic Materials

The explosive growth in data collection and the need to process it efficiently, as well as the desire to automate increasingly complex tasks in transportation, medical care, manufacturing, security and many other fields have motivated a growing interest in neuromorphic computing. Unlike the binary, transistorbased ON/OFF logic gates and separate logic and memory functionalities employed in digital computing, neuromorphic computing is inspired by animal brains that use interconnected synapses and neurons to perform processing, storage and transmission of information at the same location, while only consuming ~20 W or less of power. Motivated by the brain’s efficiency, adaptability, self-learning and resiliency qualities, neuromorphic computing can be broadly defined as an approach to processing and storing information using hardware and algorithms inspired by models of biological neural systems. Present research in neuromorphic computing encompasses approaches that vary significantly in their degree of neuro-inspiration, from systems that only incorporate features such as asynchronous, event-driven operation or use crossbar arrays of non-volatile memory (NVM) elements to accelerate deep neural networks (DNNs), to designs that embrace the extreme parallelism, sparsity, reconfigurability, adaptability, complexity and stochasticity observed in nervous systems. The term ‘neuromorphic’ computing is often credited to Carver Mead, who in the 1980s investigated Si-based analog electronics to replicate functions of the animal retina. Earlier important advances in this field include the work of Frank Rosenblatt, who proposed the concept of the perceptron, Bernard Widrow, who used this concept to build one of the first analog neural networks, the Adaline and many other researchers (see ref. 6 for an historical perspective on neuromorphic computing). With the recent increase in the use of artificial intelligence and large language models, and rising concerns over the associated energy costs, interest in neuromorphic hardware has expanded rapidly. According to some estimates, driven largely by the drastic growth in the training use of artificial intelligence (AI) models using the current computing architectures, the energy cost of computing is projected to reach the energy supply worldwide by 2045. Furthermore, while this is not a realistic outcome, it means that, if more efficient computing technologies are not developed -- soon -- the world will soon become one where demand for energy and market constraints limit the continued increase of societal access to AI and cloud services from data centers. Data centers used for training and use of these models consume hundreds of terawatt hours of electricity, already past 4% of the US electricity demand.

Circuits↗
DOE OSTI2026

Investigating the Theranostic Potential of Elementally Matched [ 43 Sc]Sc-PSMA-617 and [ 47 Sc]Sc-PSMA-617

The theranostic approach, which employs diagnostic radiopharmaceuticals to select patients who would benefit from targeted radiotherapy agents, has become an invaluable strategy for effective medical care. Scandium radionuclides offer the advantage of forming elementally matched and chemically identical diagnostic and therapeutic compounds, making them ideal candidates for this strategy. PSMA-617 is an established prostate-specific membrane antigen targeting agent and can be used as a proof of concept to investigate 43 Sc, the diagnostic nuclide, and 47 Sc, the therapeutic nuclide, as a theranostic pair. Methods: Cellular uptake, competitive binding assays, and internalization studies were carried out using LNCaP or PC-3 cell lines. [ 43 Sc]Sc-PSMA-617 was used in PET imaging studies in LNCaP or PC-3 tumor models, with time points ranging from 1–9 h. LNCaP tumor-bearing mice injected with [ 47 Sc]Sc-PSMA-617 were imaged using SPECT up to 48 h. A longitudinal study was carried out using LNCaP tumor-bearing mice imaged with [ 43 Sc]Sc-PSMA-617 prior to receiving a therapeutic dose of [ 47 Sc]Sc-PSMA-617. Results: 43 Sc and 47 Sc were incorporated into PSMA-617 at radiochemical yields of >99%. Cellular uptake studies demonstrated high uptake and specificity to PSMA receptors for [ 47 Sc]Sc-PSMA-617. In vivo PET studies showed specificity of [ 43 Sc]Sc-PSMA-617 while SPECT studies demonstrated tumor retention of [ 47 Sc]Sc-PSMA-617 up to 48 h. [ 47 Sc]Sc-PSMA-617 demonstrated therapeutic efficacy by delaying tumor growth and increasing survival rates from a single administered dose in xenograft models. More importantly, the PET results from [ 43 Sc]Sc-PSMA-617 PET were highly correlated with the therapeutic response from [ 47 Sc]Sc-PSMA-617, showing that 43 Sc PET data can predict therapeutic outcomes in individual animals from 47 Sc agents, even in animals sharing a genetic background and implanted with tumors from the same cell line. Conclusions: Two chemically identical, PSMA-targeting radioscandium pharmaceuticals demonstrated in vivo stability, specificity and retention in PSMA+ tumor models. A theranostic study showed that a higher 43 Sc PET SUVmean was strongly correlated to therapeutic response from the 47 Sc agent, demonstrating that 43 Sc and 47 Sc can be used as an elementally matched theranostic pair.

Biodistribution↗
DOE OSTI2023

Evaluation of Copper Chelation Therapy in a Transgenic Rat Model of Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of the amyloid β (Aβ) protein in blood vessels and leads to hemorrhages, strokes, and dementia in elderly individuals. Recent reports have shown elevated copper levels colocalized with vascular amyloid in human CAA and Alzheimer’s disease patients, which have been suggested to contribute to cytotoxicity through the formation of reactive oxygen species. Here, we treated a transgenic rat model of CAA (rTg-DI) with the copper-specific chelator, tetrathiomolybdate (TTM), via intraperitoneal (IP) administration for 6 months to determine if it could lower copper content in vascular amyloid deposits and modify CAA pathology. In this work, results showed that TTM treatment led to elevated Aβ load in the hippocampus of the rTg-DI rats and increased microbleeds in the wild type (WT) animals. X-ray fluorescence microscopy was performed to image the distribution of copper and revealed a surprising increase in copper colocalized with Aβ aggregates in TTM-treated rTg-DI rats. Unexpectedly, we also found an increase in the copper content in unaffected vessels of both rTg-DI and WT animals. These results show that IP administration of TTM was ineffective in removing copper from vascular Aβ aggregates in vivo and increased the development of disease pathology in CAA.

36 MATERIALS SCIENCE↗
DOE OSTI2025

Subventricular Accumulation of Cu in the Aging Mouse Brain Does Not Associate with Anticipated Increases in Markers of Oxidative Stress

Natural aging is associated with mild memory loss and cognitive decline, and age is the greatest risk factor for neurodegenerative diseases, such as Alzheimer’s disease. There is substantial evidence that oxidative stress is a major contributor to both natural aging and neurodegenerative disease, and coincidently, levels of redox active metals such as Fe and Cu are known to be elevated later in life. Recently, a pronounced age-related increase in Cu content has been reported to occur in mice and rats around a vital regulatory brain region, the subventricular zone of lateral ventricles. In our study herein, we have characterized lateral ventricle Cu content in a unique murine model of accelerated aging, senescence accelerated mouse-prone 8 (SAMP8) mice. Our results confirm an age-related increase in ventricle Cu content, consistent with the studies by others in wild-type mice and rats. Specifically, we observed Cu content to increase over the time frame 1 to 5 months and 5 to 9 months, but interestingly, no significant increase occurred between 9 and 12 months (although brain Cu content at 12 months was significantly elevated relative to 1 and 5 month-old animals). Despite the magnitude of Cu increase observed within the cells that comprise the subventricular zone of lateral ventricles (average 3 mM Cu, with isolated subcellular concentrations of 17 mM), we did not detect spectroscopic markers of thiol oxidation, protein aggregation, or lipid oxidation. The lack of evidence for oxidative stress in ex vivo animal tissue is in contrast to in vitro studies demonstrating that thiol, protein, and lipid oxidation is pronounced at these Cu concentrations. We suggest that our findings most likely indicate that the Cu ions in this brain region are sequestered in an unreactive form, possibly extended chains of Cu-thiolate complexes, which do not readily redox cycle in the aqueous cytosol. In conclusion, these results also appear to partially challenge the long-held view that age-related increases in brain metal content drive oxidative stress as we did not observe a concomitant association between age-related Cu increase and markers of oxidative stress, nor did we observe a net increase in Cu content between mice aged 9 and 12 months.

X-ray fluorescence↗
DOE OSTI2020

Nutrient Capture from Aqueous Waste and Photocontrolled Fertilizer Delivery to Tomato Plants Using Fe(III)–Polysaccharide Hydrogels

Inexpensive and sustainable methods are needed to reclaim nutrients from agricultural waste solutions for use as a fertilizer while decreasing nutrient runoff. Fe(III)–polysaccharide hydrogels are able to flocculate solids and absorb nutrients in liquid animal waste from Confined Animal Feeding Operations (CAFOs). Fe(III)–alginate beads absorbed 0.05 mg g –1 NH 4 + and NO 3 - from 100 ppm solutions at pH = 7, with > 80% phosphate uptake and ~30% uptake of ammonium and nitrate. Ammonium uptake from a raw manure solution (1420 ppm NH 4 + ) showed a significant 0.7 mg g –1 uptake. Tomato plant trials carried out with Fe(III)–alginate hydrogel beads in greenhouse conditions showed controlled nutrient delivery for the plants compared to fertilizer solution with the same nutrient content. Plants showed an uptake of Fe from the gel beads, and Fe(III)–alginate hydrogel beads promoted root growth of the plants. The plants treated with nutrient-loaded Fe(III)–alginate hydrogels yielded comparable tomato harvest to plants treated with the conventional fertilizer solution.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2018

Reorientation of the Methyl Group in MAs(III) is the Rate-Limiting Step in the ArsM As(III) S -Adenosylmethionine Methyltransferase Reaction

The most common biotransformation of trivalent inorganic arsenic (As(III)) is methylation to mono-, di-, and trimethylated species. Methylation is catalyzed by As(III) S-adenosylmethionine (SAM) methyltransferase (termed ArsM in microbes and AS3MT in animals). Methylarsenite (MAs(III)) is both the product of the first methylation step and the substrate of the second methylation step. When the rate of the overall methylation reaction was determined with As(III) as the substrate, the first methylation step was rapid, whereas the second methylation step was slow. In contrast, when MAs(III) was used as the substrate, the rate of methylation was as fast as the first methylation step when As(III) was used as the substrate. These results indicate that there is a slow conformational change between the first and second methylation steps. The structure of CmArsM from the thermophilic alga Cyanidioschyzon merolae sp. 5508 was determined with bound MAs(III) at 2.27 Å resolution. The methyl group is facing the solvent, as would be expected when MAs(III) is bound as the substrate rather than facing the SAM-binding site, as would be expected for MAs(III) as a product. We propose that the rate-limiting step in arsenic methylation is slow reorientation of the methyl group from the SAM-binding site to the solvent, which is linked to the conformation of the side chain of a conserved residue Tyr70.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2014

Novel Oral Detoxification of Mercury, Cadmium, And Lead with Thiol-Modified Nanoporous Silica

We have developed a thiol-modified nanoporous silica material (SHSAMMS) as an oral therapy for the prevention and treatment of heavy metal poisoning. SH-SAMMS has been reported to be highly efficient at capturing heavy metals in biological fluids and water. Herein, SH-SAMMS was examined for efficacy and safety in both in vitro and in vivo animal models for the oral detoxification of heavy metals. In simulated gastrointestinal fluids, SH-SAMMS had a very high affinity (Kd) for methyl mercury (MeHg(I)), inorganic mercury (Hg(II)), lead (Pb(II)), and cadmium (Cd(II)) and was superior to other SAMMS with carboxylic acid or phosphonic acid ligands or commercially available metal chelating sorbents. SH-SAMMS also effectively removed Hg from biologically digested fish tissue with no effect on most nutritional minerals found in fish. SH-SAMMS could hold Hg(II) and MeHg(I) tightly inside the nanosize pores, thus preventing bacteria from converting them to more absorbable forms. Rats fed a diet containing MeHg(I), Cd(II), and Pb(II) and SH-SAMMS for 2 weeks had blood Hg levels significantly lower than rats fed the metal-rich diet only. Upon cessation of the metal-rich diet, continued administration of SH-SAMMS for 2 weeks facilitated faster and more extensive clearance of Hg than in animals not continued on oral SH-SAMMS. Rats receiving SH-SAMMS also suffered less weight loss as a result of the metal exposure. Retention of Hg and Cd in major organs was lowest in rats fed with SH-SAMMS throughout the entire four weeks. The reduction of blood Pb by SH-SAMMS was significant. SHSAMMS was safe to intestinal epithelium model (Caco-2) and common intestinal bacteria (Escherichia coli). Altogether, it has great potential as a new oral drug for the treatment of heavy metal poisoning. This new application is enabled by the installation of tailored interfacial chemistry upon nontoxic nanoporous materials.

cadmium, chelation therapy, detoxification, mercur↗
DOE OSTI2013

Impaired Transcriptional Response of the Murine Heart to Cigarette Smoke in the Setting of High Fat Diet and Obesity

Smoking and obesity are each well-established risk factors for cardiovascular heart disease, which together impose earlier onset and greater severity of disease. To identify early signaling events in the response of the heart to cigarette smoke exposure within the setting of obesity, we exposed normal weight and high fat diet-induced obese (DIO) C57BL/6 mice to repeated inhaled doses of mainstream (MS) or sidestream (SS) cigarette smoke administered over a two week period, monitoring effects on both cardiac and pulmonary transcriptomes. MS smoke (250 μg wet total particulate matter (WTPM)/L, 5 h/day) exposures elicited robust cellular and molecular inflammatory responses in the lung with 1466 differentially expressed pulmonary genes (p < 0.01) in normal weight animals and a much-attenuated response (463 genes) in the hearts of the same animals. In contrast, exposures to SS smoke (85 μg WTPM/L) with a CO concentration equivalent to that of MS smoke (250 CO ppm) induced a weak pulmonary response (328 genes) but an extensive cardiac response (1590 genes). SS smoke and to a lesser extent MS smoke preferentially elicited hypoxia- and stress-responsive genes as well as genes predicting early changes of vascular smooth muscle and endothelium, precursors of cardiovascular disease. The most sensitive smoke-induced cardiac transcriptional changes of normal weight mice were largely absent in DIO mice after smoke exposure, while genes involved in fatty acid utilization were unaffected. At the same time, smoke exposure suppressed multiple proteome maintenance genes induced in the hearts of DIO mice. Together, these results underscore the sensitivity of the heart to SS smoke and reveal adaptive responses in healthy individuals that are absent in the setting of high fat diet and obesity.

heart transcriptome↗
DOE OSTI2015

Structure of a eukaryotic SWEET transporter in a homotrimeric complex

Eukaryotes rely on efficient distribution of energy and carbon skeletons between organs in the form of sugars. Glucose in animals and sucrose in plants serve as the dominant distribution forms. Cellular sugar uptake and release require vesicular and/or plasma membrane transport proteins. Humans and plants use proteins from three superfamilies for sugar translocation: the major facilitator superfamily (MFS), the sodium solute symporter family (SSF; only in the animal kingdom), and SWEETs. SWEETs carry mono- and disaccharides across vacuolar or plasma membranes. Plant SWEETs play key roles in sugar translocation between compartments, cells, and organs, notably in nectar secretion, phloem loading for long distance translocation, pollen nutrition, and seed filling. Plant SWEETs cause pathogen susceptibility possibly by sugar leakage from infected cells. The vacuolar Arabidopsis thaliana AtSWEET2 sequesters sugars in root vacuoles; loss-of-function mutants show increased susceptibility to Pythium infection. In this paper, we show that its orthologue, the vacuolar glucose transporter OsSWEET2b from rice (Oryza sativa), consists of an asymmetrical pair of triple-helix bundles, connected by an inversion linker transmembrane helix (TM4) to create the translocation pathway. Structural and biochemical analyses show OsSWEET2b in an apparent inward (cytosolic) open state forming homomeric trimers. TM4 tightly interacts with the first triple-helix bundle within a protomer and mediates key contacts among protomers. Structure-guided mutagenesis of the close paralogue SWEET1 from Arabidopsis identified key residues in substrate translocation and protomer crosstalk. Finally, insights into the structure–function relationship of SWEETs are valuable for understanding the transport mechanism of eukaryotic SWEETs and may be useful for engineering sugar flux.

59 BASIC BIOLOGICAL SCIENCES↗