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At least 919 records · Page 51
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Quantitative Gadolinium-Free Cardiac Fibrosis Imaging in End Stage Renal Disease Patients Reveals A Longitudinal Correlation with Structural and Functional Decline

Patients with end stage renal disease (ESRD) suffer high mortality from arrhythmias linked to fibrosis, but are contraindicated to late gadolinium enhancement magnetic resonance imaging (MRI). We present a quantitative method for gadolinium-free cardiac fibrosis imaging using magnetization transfer (MT) weighted MRI, and probe correlations with widely used surrogate markers including cardiac structure and contractile function in patients with ESRD. In a sub-group of patients who returned for follow-up imaging after one year, we examine the correlation between changes in fibrosis and ventricular structure/function. Quantification of changes in MT revealed significantly greater fibrotic burden in patients with ESRD compared to a healthy age matched control cohort. Ventricular mechanics, including circumferential strain and diastolic strain rate were unchanged in patients with ESRD. No correlation was observed between fibrotic burden and concomitant measures of either circumferential or longitudinal strains or strain rates. However, among patients who returned for follow up examination a strong correlation existed between initial fibrotic burden and subsequent loss of contractile function. Gadolinium-free myocardial fibrosis imaging in patients with ESRD revealed a complex and longitudinal, not contemporary, association between fibrosis and ventricular contractile function.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Electrocardiographic changes predate Parkinson’s disease onset

Autonomic nervous system involvement precedes the motor features of Parkinson’s disease (PD). Our goal was to develop a proof-of-concept model for identifying subjects at high risk of developing PD by analysis of cardiac electrical activity. We used standard 10-s electrocardiogram (ECG) recordings of 60 subjects from the Honolulu Asia Aging Study including 10 with prevalent PD, 25 with prodromal PD, and 25 controls who never developed PD. Various methods were implemented to extract features from ECGs including simple heart rate variability (HRV) metrics, commonly used signal processing methods, and a Probabilistic Symbolic Pattern Recognition (PSPR) method. Extracted features were analyzed via stepwise logistic regression to distinguish between prodromal cases and controls. Stepwise logistic regression selected four features from PSPR as predictors of PD. The final regression model built on the entire dataset provided an area under receiver operating characteristics curve (AUC) with 95% confidence interval of 0.90 [0.80, 0.99]. The five-fold cross-validation process produced an average AUC of 0.835 [0.831, 0.839]. We conclude that cardiac electrical activity provides important information about the likelihood of future PD not captured by classical HRV metrics. Machine learning applied to ECGs may help identify subjects at high risk of having prodromal PD.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Effects of presenilin-1 familial Alzheimer’s disease mutations on γ-secretase activation for cleavage of amyloid precursor protein

Presenilin-1 (PS1) is the catalytic subunit of γ-secretase which cleaves within the transmembrane domain of over 150 peptide substrates. Dominant missense mutations in PS1 cause early-onset familial Alzheimer’s disease (FAD); however, the exact pathogenic mechanism remains unknown. Here we combined Gaussian accelerated molecular dynamics (GaMD) simulations and biochemical experiments to determine the effects of six representative PS1 FAD mutations (P117L, I143T, L166P, G384A, L435F, and L286V) on the enzyme-substrate interactions between γ-secretase and amyloid precursor protein (APP). Biochemical experiments showed that all six PS1 FAD mutations rendered γ-secretase less active for the endoproteolytic (ε) cleavage of APP. Distinct low-energy conformational states were identified from the free energy profiles of wildtype and PS1 FAD-mutant γ-secretase. The P117L and L286V FAD mutants could still sample the “Active” state for substrate cleavage, but with noticeably reduced conformational space compared with the wildtype. The other mutants hardly visited the “Active” state. The PS1 FAD mutants were found to reduce γ-secretase proteolytic activity by hindering APP residue L49 from proper orientation in the active site and/or disrupting the distance between the catalytic aspartates. Therefore, our findings provide mechanistic insights into how PS1 FAD mutations affect structural dynamics and enzyme-substrate interactions of γ-secretase and APP.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Continuum- and particle-based modeling of shapes and dynamics of red blood cells in health and disease

Here, we review recent advances in multiscale modeling of the mechanics of healthy and diseased red blood cells (RBCs), and blood flow in the microcirculation. We cover the traditional continuum-based methods but also particle-based methods used to model both the RBCs and the blood plasma. We highlight examples of successful simulations of blood flow including malaria and sickle cell anemia.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Modular droplet injector for sample conservation providing new structural insight for the conformational heterogeneity in the disease-associated NQO1 enzyme

Droplet injection strategies are a promising tool to reduce the large amount of sample consumed in serial femtosecond crystallography (SFX) measurements at X-ray free electron lasers (XFELs) with continuous injection approaches. Here, we demonstrate a new modular microfluidic droplet injector (MDI) design that was successfully applied to deliver microcrystals of the human NAD(P)H:quinone oxidoreductase 1 (NQO1) and phycocyanin. We investigated droplet generation conditions through electrical stimulation for both protein samples and implemented hardware and software components for optimized crystal injection at the Macromolecular Femtosecond Crystallography (MFX) instrument at the Stanford Linac Coherent Light Source (LCLS). Under optimized droplet injection conditions, we demonstrate that up to 4-fold sample consumption savings can be achieved with the droplet injector. In addition, we collected a full data set with droplet injection for NQO1 protein crystals with a resolution up to 2.7 Å, leading to the first room-temperature structure of NQO1 at an XFEL. NQO1 is a flavoenzyme associated with cancer, Alzheimer's and Parkinson's disease, making it an attractive target for drug discovery. Further, our results reveal for the first time that residues Tyr128 and Phe232, which play key roles in the function of the protein, show an unexpected conformational heterogeneity at room temperature within the crystals. These results suggest that different substates exist in the conformational ensemble of NQO1 with functional and mechanistic implications for the enzyme's negative cooperativity through a conformational selection mechanism. Our study thus demonstrates that microfluidic droplet injection constitutes a robust sample-conserving injection method for SFX studies on protein crystals that are difficult to obtain in amounts necessary for continuous injection, including the large sample quantities required for time-resolved mix-and-inject studies.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

Gradient of γ rays and β particles irradiation’s energy produced by accelerator and its use in radiotherapy of cancer diseases

The Ionising irradiations used mostly in the treatment of tumoral diseases are: X, γ, β and e irradiations. The discussion will be about radiations, produced in accelerators, with photon energy 6 MV and 15 MV and electron energy from 5 MeV to 15 MeV. Due to the differences between γ and β radiations, their absorbtion in living tissues will be different. It is important to know, the absorption performance before and after the electronic equilibrium. For these purposes, we’ve use the function of dose gradient, for irradiations γ and β. It represents the velocity of dose change as a function of depth in tissue. From skin to maximum dose value, the increase of G-function is more accentuated for γ-rays than for β-particles, while after that the G-function decreasing is less sharp for γ-rays, while for β-particles, it is almost promptly. This fact allow us to use in radiotherapy, not only γ-rays but β-particles, too. The lasts, represents, a much more efficient tool, especially in terms of radiation protection, of health adjacent tissues and organs. Finally, we’ll to discus, about the advantages in terms of radiation protection of both, γ-rays and β-particles used in radiotherapy.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2021

Artificial intelligence velocimetry and microaneurysm-on-a-chip for three-dimensional analysis of blood flow in physiology and disease

Significance Microfluidics is an important in vitro platform to gain insights into mechanics of blood flow and mechanisms of pathophysiology of human diseases. Extraction of 3D fields in microfluidics with dense cell suspensions remains a formidable challenge. We present artificial-intelligence velocimetry (AIV) as a general platform to determine 3D flow fields and a microaneurysm-on-a-chip to simulate blood flow in microaneurysms in patients with diabetic retinopathy. AIV is built on physics-informed neural networks that integrate seamlessly 2D images from microfluidic experiments or in vivo observations with physical laws to estimate full 3D velocity and stress fields. AIV could be integrated into imaging technologies to automatically infer key hemodynamic metrics from in vivo and in vitro biomedical images.

42 ENGINEERING↗
DOE OSTI2019

Climate change impacts the spread potential of wheat stem rust, a significant crop disease

Abstract Long range atmospheric transport is an important pathway for the spread of plant pathogens, such as rust fungi which can devastate cereal crop health and food security worldwide. In recent years, serious concern has been caused by the evolution of new virulent races of Puccinia graminis f. sp. tritici , a pathogen causing wheat stem rust that can result in close to 100% yield losses on susceptible wheat cultivars in favourable weather conditions. We applied an Earth system model to compare the suitability of the current climate and a business-as-usual climate scenario (RCP 8.5) for 2100 for wheat stem rust. Although there are large uncertainties in modelling changes in disease spread, we focus in this paper on the changes which are likely to be robust to model assumptions. We show that the warmer climate with lower relative humidity and enhanced turbulence will lead to ∼40% increase in the urediniospore emitting potential of an infected field as global average. The main predicted changes in the atmospheric long-range transport include reduced connections between Europe, Africa and South Asia, and increased frequency of spores crossing the mid-latitude oceans. Due to reduction in subfreezing conditions, the overwintering areas of the fungus will expand. On the other hand, projected drier conditions will reduce substantially the probability of an infection starting from deposited spores, except in irrigated fields.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2017

Improved annotation of the insect vector of citrus greening disease: biocuration by a diverse genomics community

The Asian citrus psyllid ( Diaphorina citri Kuwayama) is the insect vector of the bacterium Candidatus Liberibacter asiaticus (CLas), the pathogen associated with citrus Huanglongbing (HLB, citrus greening). HLB threatens citrus production worldwide. Suppression or reduction of the insect vector using chemical insecticides has been the primary method to inhibit the spread of citrus greening disease. Accurate structural and functional annotation of the Asian citrus psyllid genome, as well as a clear understanding of the interactions between the insect and CLas, are required for development of new molecular-based HLB control methods. A draft assembly of the D. citri genome has been generated and annotated with automated pipelines. However, knowledge transfer from well-curated reference genomes such as that of Drosophila melanogaster to newly sequenced ones is challenging due to the complexity and diversity of insect genomes. To identify and improve gene models as potential targets for pest control, we manually curated several gene families with a focus on genes that have key functional roles in D. citri biology and CLas interactions. This community effort produced 530 manually curated gene models across developmental, physiological, RNAi regulatory and immunity-related pathways. As previously shown in the pea aphid, RNAi machinery genes putatively involved in the microRNA pathway have been specifically duplicated. A comprehensive transcriptome enabled us to identify a number of gene families that are either missing or misassembled in the draft genome. In order to develop biocuration as a training experience, we included undergraduate and graduate students from multiple institutions, as well as experienced annotators from the insect genomics research community. The resulting gene set (OGS v1.0) combines both automatically predicted and manually curated gene models.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Structure analysis of the telomere resolvase from the Lyme disease spirochete Borrelia garinii reveals functional divergence of its C-terminal domain

Borrelia spirochetes are the causative agents of Lyme disease and relapsing fever, two of the most common tick-borne illnesses. A characteristic feature of these spirochetes is their highly segmented genomes which consists of a linear chromosome and a mixture of up to approximately 24 linear and circular extrachromosomal plasmids. The complexity of this genomic arrangement requires multiple strategies for efficient replication and partitioning during cell division, including the generation of hairpin ends found on linear replicons mediated by the essential enzyme ResT, a telomere resolvase. Using an integrative structural biology approach employing advanced modelling, circular dichroism, X-ray crystallography and small-angle X-ray scattering, we have generated high resolution structural data on ResT from B. garinii. Our data provides the first high-resolution structures of ResT from Borrelia spirochetes and revealed active site positioning in the catalytic domain. We also demonstrate that the C-terminal domain of ResT is required for both transesterification steps of telomere resolution, and is a requirement for DNA binding, distinguishing ResT from other telomere resolvases from phage and bacteria. These results advance our understanding of the molecular function of this essential enzyme involved in genome maintenance in Borrelia pathogens.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

Metabolic Changes Underlying Interactions Between Obesity and Non‐Alcoholic Fatty Liver Disease in South Asian Adults

Non‐alcoholic fatty liver disease (NAFLD) is often referred to as the hepatic manifestation of the metabolic syndrome, which is characterized by at least three of the following: hypertension, hyperglycemia, abdominal obesity, elevated plasma triglycerides and reduced plasma high‐density lipoproteins. While hepatic steatosis has been well studied in animal models, the relationship between body weight, hepatic steatosis and insulin resistance is not well characterized in humans. Moreover, not all human subjects with obesity develop metabolic complications. In addition, it is unclear why South Asian adults develop insulin resistance and diabetes even at lower levels of adiposity and body mass index compared to their Western counterparts. To address this question, we used a convenient sample of Sri Lankan adult females (n = 30) who underwent routine abdominal surgery at the Teaching Hospital of Peradeniya. Anthropometric data, adipose tissue specimens and fasted serum samples were collected for analyses of glucose, lipid and inflammatory markers. Histological sections of adipose tissue were obtained from omental fat (OF) and anterior abdominal wall fat (AF), and adipocyte cross‐sectional area was measured using the ImageJ software. Further, the presence of hepatic steatosis was assessed using ultrasound scanning by a radiologist. Participants with higher grade of fatty liver had a significantly higher body mass index (BMI), fasting blood glucose and aspartate aminotransferase levels. Additionally, participants with higher grade of fatty liver also had significantly higher serum levels of non‐HDL cholesterol and the pro‐inflammatory adipokine, resistin. Interestingly, there were no significant differences in serum adiponectin levels between the groups. Individuals with fatty liver also had a higher mean adipocyte area in both OF and AF, indicating a higher degree of adipocyte hypertrophy associated with fatty liver. Currently, the measurements of additional biomarkers of inflammation and insulin resistance are underway. These findings indicate distinct metabolic differences between South Asian adults with varying degrees of fatty liver, and may help in establishing effective treatment strategies for obesity‐associated NAFLD. Support or Funding Information Funded by an International Research/Development Seed grant from the Office of International Affairs and the Office of the Vice President for Research at Texas Tech university (TTU), and an International Research Seed Grant from The College of Human Sciences at TTU, and by the International Research Center, University of Peradeniya.

Albracht‐Schulte, Kembra↗
DOE OSTI2018

PIP4Kγ as a potential target for Huntington's disease

Phosphoinositide lipids provide spatial and temporal regulation of cell signaling and membrane traffic. The PI5P‐4‐kinase family is one of the less studied phosphoinositide lipid kinases. These enzymes catalyze the conversion of phosphatidylinositol 5‐phosphate to phosphatidylinositol 4,5‐bis phosphate. A recent study by Vicinanza et al., a suggested that depletion of the PI5P‐4‐kinase, PIP4Kγ promotes a non‐canonical autophagy pathway. Moreover, this depletion reduced the presence of huntingtin‐exon1‐polyglutamine aggregates. Expression of exon1 of huntingtin with an extended polyglutamine tract is a model for huntingtin protein aggregates. To further test the hypothesis that PIP4Kγ is a potential target to reduce huntingtin aggregates, we tested the depletion of PIP4Kγ in cell culture models that express full length mutant huntingtin (mHtt). We determined that depletion of PIP4Kγ, but not PIP4Kα or PIP4Kβ, lowers the levels of mHtt in patient fibroblasts and in immortalized Hdh Q111 mouse striatal neurons. We show that PIP4Kγ‐dependent depletion of mHtt requires lysosomal function because the depletion is blocked by the lysosomal inhibitor, bafilomycin A1. Moreover, we show that depletion of PIP4Kγ increases autophagic flux, as measured by an increase in LC3‐II levels by western blot analysis and an increase in LC3‐II puncta by microscopy. Our studies suggest that PIP4kγ should be further pursued as a target for Huntington's disease. Support or Funding Information This work was supported by AHA postdoctoral fellowship 14POST20480137 (Sai Srinivas Panapakkam Giridharan), NIH grants R01GM050403 and NS064015 (Lois S Weisman) and by HSS funding 1R03MH084839 (Juan Marugan)

Giridharan, Sai Srinivas Panapakkam↗
DOE OSTI2019

Effect of foot-and-mouth disease virus 3C protease B 2 β-strand proline mutagenesis on expression and processing of the P1 polypeptide using a plasmid expression vector

The production of experimental molecular vaccines against foot-and-mouth disease virus utilizes the viral encoded 3C protease for processing of the P1 polyprotein. Expression of wild type 3C protease is detrimental to host cells. The molecular vaccine constructs containing the 3C protease L127P mutant significantly reduce adverse effects associated with protease expression while retaining the ability to process and assemble virus-like particles. In published 3C protease crystal structures, the L127 residue is contained within the B 2 β-strand as part of the A 2 –B 2 β-sheet. To provide insight into the mechanism by which the L127P mutant alters the properties of the 3C protease, we performed scanning proline mutagenesis of residues 123–128 of the B 2 β-strand and monitored expression and P1 processing. Simultaneously, we utilized random mutagenesis of the full 3C sequence to identify additional mutations presenting a phenotype similar to the L127P mutation. Six of the tested mutants enhanced expression over wild type, and the I22P, T100P and V124P mutations surpassed the L127P mutation in certain cell lines. These data are interpreted in conjunction with published 3C protease crystal structures to provide insight into the mechanism by which these mutations enhance expression.

3C↗
DOE OSTI2019

Development of a mnemonic discrimination task using naturalistic stimuli with applications to aging and preclinical Alzheimer's disease

Most tasks test memory within the same day, however, most forgetting occurs after 24 h. Further, testing memory for simple words or objects does not mimic real-world memory experiences. We designed a memory task showing participants video clips of everyday kinds of experiences, including positive, negative, and neutral stimuli, and tested memory immediately and 24 h later. During the memory test, we included repeated and similar stimuli to tax both target recognition and lure discrimination ability. Participants’ memory was worse after 24 h, especially the ability to discriminate similar stimuli. Emotional videos were better remembered when tested immediately, however, after 24 h we find gist versus detail trade-offs in emotional forgetting. We also applied this paradigm to a sample of cognitively normal older adults that also underwent amyloid and tau PET imaging. We found that older adults performed worse on the task compared to young adults. While both young and older adults showed similar patterns of forgetting of repeated emotional and neutral clips, older adults showed preserved neutral compared to emotional discrimination after 24 h. Further, lure discrimination performance correlated with medial temporal lobe tau in older adults with preclinical Alzheimer’s disease. These results suggest factors such as time between encoding and retrieval, emotion, and similarity influence memory performance and should be considered when examining memory performance for an accurate picture of memory function and dysfunction.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2015

Structures of three polycystic kidney disease-like domains from Clostridium histolyticum collagenases ColG and ColH

Clostridium histolyticum collagenases ColG and ColH are segmental enzymes that are thought to be activated by Ca 2+ -triggered domain reorientation to cause extensive tissue destruction. The collagenases consist of a collagenase module (s1), a variable number of polycystic kidney disease-like (PKD-like) domains (s2a and s2b in ColH and s2 in ColG) and a variable number of collagen-binding domains (s3 in ColH and s3a and s3b in ColG). The X-ray crystal structures of Ca 2+ -bound holo s2b (1.4 Å resolution, R = 15.0%, R free = 19.1%) and holo s2a (1.9 Å resolution, R = 16.3%, R free = 20.7%), as well as of Ca 2+ -free apo s2a (1.8 Å resolution, R = 20.7%, R free = 27.2%) and two new forms of N-terminally truncated apo s2 (1.4 Å resolution, R = 16.9%, R free = 21.2%; 1.6 Å resolution, R = 16.2%, R free = 19.2%), are reported. The structurally similar PKD-like domains resemble the V-set Ig fold. In addition to a conserved β-bulge, the PKD-like domains feature a second bulge that also changes the allegiance of the subsequent β-strand. This β-bulge and the genesis of a Ca 2+ pocket in the archaeal PKD-like domain suggest a close kinship between bacterial and archaeal PKD-like domains. Different surface properties and indications of different dynamics suggest unique roles for the PKD-like domains in ColG and in ColH. Surface aromatic residues found on ColH s2a-s2b, but not on ColG s2, may provide the weak interaction in the biphasic collagen-binding mode previously found in s2b-s3. B -factor analyses suggest that in the presence of Ca 2+ the midsection of s2 becomes more flexible but the midsections of s2a and s2b stay rigid. The different surface properties and dynamics of the domains suggest that the PKD-like domains of M9B bacterial collagenase can be grouped into either a ColG subset or a ColH subset. The conserved properties of PKD-like domains in ColG and in ColH include Ca 2+ binding. Conserved residues not only interact with Ca 2+ , but also position the Ca 2+ -interacting water molecule. Ca 2+ aligns the N-terminal linker approximately parallel to the major axis of the domain. Ca 2+ binding also increases stability against heat and guanidine hydrochloride, and may improve the longevity in the extracellular matrix. The results of this study will further assist in developing collagen-targeting vehicles for various signal molecules.

Bauer, Ryan↗
DOE OSTI2020

Converting Clinical Pathways to BPM+ Standards: A Case Study in Stable Ischemic Heart Disease

Clinical pathways (CPs) are structured healthcare plans designed to implement evidence-based clinical guidelines, medical algorithms, and protocols. In recent years, a community called BPM+ Health has worked to establish a shareable and computer-consumable representation of CP, leveraging standard notations. These notations, collectively referred to as BPM+, include the Business Process Management and Notation (BPMN), Case Management Model and Notation (CMMN), and Decision Model and Notation (DMN), which aim to support clinical management and standardized communication between different stakeholders. However, the adaptation of these notations for the existing guidelines has largely been left unexplored. This paper introduces procedural steps and criteria considerations to apply components of BPM+ notations to reconstruct a guideline for Stable Ischemic Heart Disease. This paper describes how each of the three different notations is mapped to a medical guideline and discusses the advantages and limitations of representing CPs with BPM+ as compared with paper-based medical guidelines.

Chae, Junghoon↗
DOE OSTI2021

Combining glomerular basement membrane and tubular basement membrane assessment improves the prediction of diabetic end‐stage renal disease

Abstract Background To address the prognostic value of combining tubular basement membrane (TBM) and glomerular basement membrane (GBM) thickness in diabetic nephropathy (DN). Methods This retrospective study enrolled 110 patients with type 2 diabetes and biopsy‐proven DN from 2011 to 2018. The pathological findings were confirmed according to the Renal Pathology Society classifications. GBM and TBM thicknesses were determined using the Haas' direct measurement/arithmetic mean method and orthogonal intercept method, respectively. Cox proportional hazard models were used to investigate the hazard ratios (HRs) for the influence of combined GBM and TBM thickness for predicting end‐stage renal disease (ESRD). Results Patients were assigned to three groups according to the median GBM and TBM thickness: GBM lo TBM lo (GBM < 681 nm and TBM < 1200 nm), GBM hi TBM lo /GBM lo TBM hi (GBM ≥ 681 nm and TBM < 1200 nm, or GBM < 681 nm and TBM ≥ 1200 nm), and GBM hi TBM hi (GBM ≥ 681 nm and TBM ≥ 1200 nm). The GBM hi TBM lo /GBM lo TBM hi and GBM hi TBM hi groups displayed poorer renal function, a more severe glomerular classification and interstitial inflammation, and poorer renal survival rates than the GBM lo TBM lo group The GBM hi TBM lo /GBM lo TBM hi and GBM hi TBM hi groups had adjusted HRs of 1.49 (95% confidence interval [CI], 1.21‐9.75) and 3.07 (95% CI, 2.87‐12.78), respectively, compared with the GBM lo TBM lo group. Conclusions TBM thickness enhanced GBM thickness for renal prognosis in patients with type 2 diabetes.

Zhao, Lijun↗