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DOE OSTI2024

Electrochemical Amyloid β Immunosensor Based on Ti 3 C 2 T x MXene Nanosheets

Alzheimer’s disease (AD) is the most common neurodegenerative disease and a major health-care problem. More than 55 million people in the world, including 6.7 million Americans, are living with AD. As AD is characterized by production and deposition of β-amyloid peptide (Aβ) in the brain, Aβ is considered as a potential biomarker for diagnosing and monitoring the progression of AD. Nanomaterials-based electrochemical immunosensor is one of the most promising methods for early diagnosis and therapeutic of AD, due to its highly selective, sensitive, and label-free advantages. The graphene-like two-dimensional (2D) MXene nanosheets have shown large surface area, good conductivity, biocompatibility, high ion transport, and low diffusion barrier, attracting attention in recent years to use it as the nanomaterial substrate for biosensor fabrication. In this paper, we presented a Ti 3 C 2 T x MXene nanosheets-based electrochemical immunosensor to detect trace Aβ for early diagnosis of AD.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Increased Attack Rates and Decreased Incubation Periods in Raccoons with Chronic Wasting Disease Passaged through Meadow Voles

Chronic wasting disease (CWD) is a naturally-occurring neurodegenerative disease of cervids. Raccoons (Procyon lotor) and meadow voles (Microtus pennsylvanicus) have previously been shown to be susceptible to the CWD agent. To investigate the potential for transmission of the agent of CWD from white-tailed deer to voles and subsequently to raccoons, we intracranially inoculated raccoons with brain homogenate from a CWD-affected white-tailed deer (CWD Wtd ) or derivatives of this isolate after it had been passaged through voles 1 or 5 times. We found that passage of the CWDWtd isolate through voles led to a change in the biologic behavior of the CWD agent, including increased attack rates and decreased incubation periods in raccoons. A better understanding of the dynamics of cross-species transmission of CWD prions can provide insights into how these infectious proteins evolve in new hosts.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Specific iron binding to natural sphingomyelin membrane induced by non-specific co-solutes

Sphingomyelin (SPM), a crucial phospholipid in the myelin sheath, plays a vital role in insulating nerve fibers. We hypothesize that iron ions selectively bind to the phosphatidylcholine (PC) template within the SPM membrane under near-physiological conditions, resulting in disruptions to membrane organization. These interactions could potentially contribute to the degradation of the myelin sheath, thereby playing a role in the development of neurodegenerative diseases. We utilized synchrotron-based X-ray spectroscopy and diffraction techniques to study the interaction of iron ions with a bovine spinal-cord SPM monolayer (ML) at the liquid-vapor interface under physiological conditions. The SPM ML serves as a model system, representing localized patches of lipids within a more complex membrane structure. The experiments assessed iron binding to the SPM membrane both in the presence of salts and with additional evaluation of the effects of various ion species on membrane behavior. Grazing incidence X-ray diffraction was employed to analyze the impact of iron binding on the structural integrity of the SPM membrane. Furthermore, our results demonstrate that iron ions in dilute solution selectively bind to the PC template of the SPM membrane exclusively at near-physiological salt concentrations (e.g., NaCl, KCl, KI, or CaCl 2 ) and are pH-dependent. In-significant binding was detected in the absence of these salts or at near-neutral pH with salts. The surface adsorption of iron ions is correlated with salt concentration, reaching saturation at physiological levels. In contrast, multivalent ions such as La 3+ and Ca 2+ do not bind to SPM under similar conditions. Notably, iron binding to the SPM membrane disrupts its in-plane organization, suggesting that these interactions may compromise membrane integrity and contribute to myelin sheath damage associated with neurological disorders.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Large-scale survey of prion protein genetic variability in scrapie disease-free goats from the United States

Scrapie is a slowly progressive neurodegenerative disease of small ruminants caused by an accumulation of an abnormal isoform of prion protein in the central nervous system. Polymorphisms of the prion protein gene (PRNP) strongly modulate scrapie resistance and incubation period in goats. The aim of this study was to identify PRNP genetic variability in goats across the United States. Blood from a total of 6,029 apparent scrapie disease-free goats from 654 operations and 19 breeds were analyzed. Sequencing of PRNP revealed 26 genotypes with different rates based on eight codons. The GG127, RR154, and QQ222 genotypes were predominant and showed a remarkably high rate across all goats. The QK222 and NS146 genotypes, known to be protective against scrapie, were found in 0.6% [with 95% CI = (0.3, 1.2)] and 22.0% [95% CI = (19.1, 25.2)] of goats, respectively. The QK222 genotype was found in 23.1% of Oberhasli goats tested, with 95%CI = (3.9, 68.7)] and 22.0% of Toggenburg goats tested with 95%CI = (9.7, 42.5)], while NS146 was found in 65.5% of Savannah goats tested, with 95%CI = (30.8, 89.9), 36.7% of Boer goats tested, with 95%CI = (33.1, 40.4), 36.3% of Nubian goats tested, with 95%CI = (27.0, 46.7)], and 35.6% of LaMancha goats tested, with 95%CI = (22.8, 50.8%). The MM142 and IM142 genotypes were found more frequently in goats on dairy operations, while the HR143, NS146, and ND146 genotypes were found more frequently in goats on meat operations. Goats in the east region had a higher percentage of goats with RH154, RQ211, and QK222 genotypes than goats in the west region. The results of this study showed high genetic variability of PRNP among the U.S. goat population, with differences by location and breed, and may serve as a rationale for development of goat breeding programs at the national level to mitigate the risk of scrapie.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

A Double-Pronged Sword: XJB-5-131 Is a Suppressor of Somatic Instability and Toxicity in Huntington’s Disease

Due to large increases in the elderly populations across the world, age-related diseases are expected to expand dramatically in the coming years. Among these, neurodegenerative diseases will be among the most devastating in terms of their emotional and economic impact on patients, their families, and associated subsidized health costs. There is no currently available cure or rescue for dying brain cells. Viable therapeutics for any of these disorders would be a breakthrough and provide relief for the large number of affected patients and their families. Neurodegeneration is accompanied by elevated oxidative damage and inflammation. While natural antioxidants have largely failed in clinical trials, preclinical phenotyping of the unnatural, mitochondrial targeted nitroxide, XJB-5-131, bodes well for further translational development in advanced animal models or in humans. Here we consider the usefulness of synthetic antioxidants for the treatment of Huntington’s disease. The mitochondrial targeting properties of XJB-5-131 have great promise. It is both an electron scavenger and an antioxidant, reducing both somatic expansion and toxicity simultaneously through the same redox mechanism. By quenching reactive oxygen species, XJB-5-131 breaks the cycle between the rise in oxidative damage during disease progression and the somatic growth of the CAG repeat which depends on oxidation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Hofmeister Effect in RT-QuIC Seeding Activity of Chronic Wasting Disease Prions

Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) that causes a fatal neurodegenerative disease in cervids. Cases of CWD are rapidly increasing in North America among wild and farmed cervid populations, and potential for zoonotic transmission is not yet determined. Therefore, in order to manage the disease, it is imperative to devise a system that can detect CWD during its early phases to prevent spread to new captive herds through introduction of CWD-affected animals into otherwise CWD-free herds. Real-time quaking–induced conversion (RT-QuIC) assays have been applied to detect the presence of disease-associated prions from various samples in both animals and humans. In this study, we have tested the use of five Hofmeister anions that range from weakly hydrating to strongly hydrating: Na 3 citrate, Na 2 SO 4 , NaCl, NaI, and NaClO 4 in RT-QuIC reactions for CWD seeding activity using different recombinant prion proteins as substrates. This work shows how the ionic environment of the RT-QuIC reaction can enhance or diminish the seeding activity. The use of Na 2 SO 4 or NaI as the sodium salt for RT-QuIC using bank vole recombinant prion substrate for the detection of CWD using brain samples reduces the lag time to detect with reasonable specificity. For detection of the CWD in fecal samples, only NaI showed comparable reduction in lag time relative to NaCl but required reduced temperature to alleviate spontaneous fibril formation in negative control samples. Selection of the proper ion environment and recombinant prion protein substrate will make RT-QuIC a powerful diagnostic tool for early detection of CWD prions, further supporting CWD surveillance in wild and captive cervids.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Deep learning for Alzheimer's disease: Mapping large-scale histological tau protein for neuroimaging biomarker validation

Abnormal tau inclusions are hallmarks of Alzheimer's disease and predictors of clinical decline. Several tau PET tracers are available for neurodegenerative disease research, opening avenues for molecular diagnosis in vivo. However, few have been approved for clinical use. Understanding the neurobiological basis of PET signal validation remains problematic because it requires a large-scale, voxel-to-voxel correlation between PET and (immuno) histological signals. Large dimensionality of whole human brains, tissue deformation impacting co-registration, and computing requirements to process terabytes of information preclude proper validation. We developed a computational pipeline to identify and segment particles of interest in billion-pixel digital pathology images to generate quantitative, 3D density maps. The proposed convolutional neural network for immunohistochemistry samples, IHCNet, is at the pipeline's core. We have successfully processed and immunostained over 500 slides from two whole human brains with three phospho-tau antibodies (AT100, AT8, and MC1), spanning several terabytes of images. Our artificial neural network estimated tau inclusion from brain images, which performs with ROC AUC of 0.87, 0.85, and 0.91 for AT100, AT8, and MC1, respectively. Introspection studies further assessed the ability of our trained model to learn tau-related features. We present an end-to-end pipeline to create terabytes-large 3D tau inclusion density maps co-registered to MRI as a means to facilitate validation of PET tracers.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

MicroRNAs as disease progression biomarkers and therapeutic targets in experimental autoimmune encephalomyelitis model of multiple sclerosis

Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain, spinal cord and optic nerve leading to demyelination. Focal demyelination is associated with relapsing-remitting multiple sclerosis, while progressive forms of the disease show axonal degeneration and neuronal loss. The tests currently used in the clinical diagnosis and management of multiple sclerosis have limitations due to specificity and sensitivity. MicroRNAs (miRNAs) are dysregulated in many diseases and disorders including demyelinating and neuroinflammatory diseases. A review of recent studies with the experimental autoimmune encephalomyelitis animal model (mostly female mice 6–12 weeks of age) has confirmed miRNAs as biomarkers of experimental autoimmune encephalomyelitis disease and importantly at the pre-onset (asymptomatic) stage when assessed in blood plasma and urine exosomes, and spinal cord tissue. The expression of certain miRNAs was also dysregulated at the onset and peak of disease in blood plasma and urine exosomes, brain and spinal cord tissue, and at the post-peak (chronic) stage of experimental autoimmune encephalomyelitis disease in spinal cord tissue. Therapies using miRNA mimics or inhibitors were found to delay the induction and alleviate the severity of experimental autoimmune encephalomyelitis disease. Interestingly, experimental autoimmune encephalomyelitis disease severity was reduced by overexpression of miR-146a, miR-23b, miR-497, miR-26a, and miR-20b, or by suppression of miR-182, miR-181c, miR-223, miR-155, and miR873. Further studies are warranted on determining more fully miRNA profiles in blood plasma and urine exosomes of experimental autoimmune encephalomyelitis animals since they could serve as biomarkers of asymptomatic multiple sclerosis and disease course. Additionally, studies should be performed with male mice of a similar age, and with aged male and female mice.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Drosophila models to study causative genes for human rare intractable neurological diseases

Highlights: • Drosophila models targeting some ALS-causing genes are described. • Drosophila models targeting some CMT-causing genes are described. • Drosophila models targeting some Sotos syndrome-causing genes are described. • Genes and pathways that commonly interact with ALS- and/or CMT-causing genes are described. Drosophila is emerging as a convenient model for investigating human diseases. Functional homologues of almost 75% of human disease-related genes are found in Drosophila. Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that causes defects in motoneurons. Charcot-Marie-Tooth disease (CMT) is one of the most commonly found inherited neuropathies affecting both motor and sensory neurons. No effective therapy has been established for either of these diseases. In this review, after overviewing ALS, Drosophila models targeting several ALS-causing genes, including TDP-43, FUS and Ubiquilin2, are described with their genetic interactants. Then, after overviewing CMT, examples of Drosophila models targeting several CMT-causing genes, including mitochondria-related genes and FIG 4, are also described with their genetic interactants. In addition, we introduce Sotos syndrome caused by mutations in the epigenetic regulator gene NSD1. Lastly, several genes and pathways that commonly interact with ALS- and/or CMT-causing genes are described. In the case of ALS and CMT that have many causative genes, it may be not practical to perform gene therapy for each of the many disease-causing genes. The possible uses of the common genes and pathways as novel diagnosis markers and effective therapeutic targets are discussed.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

Adverse Neurological Effects of Wildfire Smoke

The respiratory and cardiovascular effects of smoke exposure are well documented from cigarette smoking and particulate matter (PM) associated with air-pollution studies, but epidemiological data also suggests exposure to high levels of woodsmoke correlate with central-nervous-system (CNS) dysfunction, including elevated rates of Alzheimer’s disease (AD) and dementia. Neuro-inflammation is believed to initiate the majority of Alzheimer’s and other neurodegenerative diseases attributed to environmental factors. We investigated whether inhaled PM and specific classes of compounds in wildfire smoke condensate extract (WSE) reach the brain and cause neuro-inflammation that can lead to progressive neurological degeneration, using isotope tracing of labeled particulate matter and major compound classes, biomarkers of blood-brain barrier (BBB) integrity, and biomarkers of neuro-inflammation. This project showed that inhalation exposure to PM and major compound classes present in WSE reached the brain through absorption in the nasal cavity and systemic circulation across the BBB. Twenty-four exposures of WSE to brain endothelial cells that form the main physical barrier of the BBB produced dose-dependent increases in biomarkers of inflammation and decreases in tight junction markers between cells. Intranasal exposure to WSE caused inflammatory disfunction in lung and brain. Biomarkers of inflammation increased and an enzyme inhibiting inflammation decreased. Similar patterns of chemical-induced changes in the lung and brain suggest either: (1) chemicals may act through shared molecular pathways upon entering lung and brain, or (2) that mediators originating in the lung circulate systemically to the brain and drive neuroinflammation. These findings warrant further mechanistic studies to delineate the temporal sequence of events to establish the lung-brain axis.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2022

Disentangling Alzheimer’s disease neurodegeneration from typical brain ageing using machine learning

Abstract Neuroimaging biomarkers that distinguish between changes due to typical brain ageing and Alzheimer’s disease are valuable for determining how much each contributes to cognitive decline. Supervised machine learning models can derive multivariate patterns of brain change related to the two processes, including the Spatial Patterns of Atrophy for Recognition of Alzheimer’s Disease (SPARE-AD) and of Brain Aging (SPARE-BA) scores investigated herein. However, the substantial overlap between brain regions affected in the two processes confounds measuring them independently. We present a methodology, and associated results, towards disentangling the two. T1-weighted MRI scans of 4054 participants (48–95 years) with Alzheimer’s disease, mild cognitive impairment (MCI), or cognitively normal (CN) diagnoses from the Imaging-based coordinate SysTem for AGIng and NeurodeGenerative diseases (iSTAGING) consortium were analysed. Multiple sets of SPARE scores were investigated, in order to probe imaging signatures of certain clinically or molecularly defined sub-cohorts. First, a subset of clinical Alzheimer’s disease patients (n = 718) and age- and sex-matched CN adults (n = 718) were selected based purely on clinical diagnoses to train SPARE-BA1 (regression of age using CN individuals) and SPARE-AD1 (classification of CN versus Alzheimer’s disease) models. Second, analogous groups were selected based on clinical and molecular markers to train SPARE-BA2 and SPARE-AD2 models: amyloid-positive Alzheimer’s disease continuum group (n = 718; consisting of amyloid-positive Alzheimer’s disease, amyloid-positive MCI, amyloid- and tau-positive CN individuals) and amyloid-negative CN group (n = 718). Finally, the combined group of the Alzheimer’s disease continuum and amyloid-negative CN individuals was used to train SPARE-BA3 model, with the intention to estimate brain age regardless of Alzheimer’s disease-related brain changes. The disentangled SPARE models, SPARE-AD2 and SPARE-BA3, derived brain patterns that were more specific to the two types of brain changes. The correlation between the SPARE-BA Gap (SPARE-BA minus chronological age) and SPARE-AD was significantly reduced after the decoupling (r = 0.56–0.06). The correlation of disentangled SPARE-AD was non-inferior to amyloid- and tau-related measurements and to the number of APOE ε4 alleles but was lower to Alzheimer’s disease-related psychometric test scores, suggesting the contribution of advanced brain ageing to the latter. The disentangled SPARE-BA was consistently less correlated with Alzheimer’s disease-related clinical, molecular and genetic variables. By employing conservative molecular diagnoses and introducing Alzheimer’s disease continuum cases to the SPARE-BA model training, we achieved more dissociable neuroanatomical biomarkers of typical brain ageing and Alzheimer’s disease.

Hwang, Gyujoon↗
DOE OSTI2023

New cyclophilin D inhibitor rescues mitochondrial and cognitive function in Alzheimer’s disease

Abstract Mitochondrial dysfunction is an early pathological feature of Alzheimer disease and plays a crucial role in the development and progression of Alzheimer’s disease. Strategies to rescue mitochondrial function and cognition remain to be explored. Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key component in opening the mitochondrial membrane permeability transition pore, leading to mitochondrial dysfunction and cell death. Blocking membrane permeability transition pore opening by inhibiting CypD activity is a promising therapeutic approach for Alzheimer’s disease. However, there is currently no effective CypD inhibitor for Alzheimer’s disease, with previous candidates demonstrating high toxicity, poor ability to cross the blood–brain barrier, compromised biocompatibility and low selectivity. Here, we report a new class of non-toxic and biocompatible CypD inhibitor, ebselen, using a conventional PPIase assay to screen a library of ∼2000 FDA-approved drugs with crystallographic analysis of the CypD-ebselen crystal structure (PDB code: 8EJX). More importantly, we assessed the effects of genetic and pharmacological blockade of CypD on Alzheimer’s disease mitochondrial and glycolytic bioenergetics in Alzheimer’s disease-derived mitochondrial cybrid cells, an ex vivo human sporadic Alzheimer’s disease mitochondrial model, and on synaptic function, inflammatory response and learning and memory in Alzheimer’s disease mouse models. Inhibition of CypD by ebselen protects against sporadic Alzheimer’s disease- and amyloid-β-induced mitochondrial and glycolytic perturbation, synaptic and cognitive dysfunction, together with suppressing neuroinflammation in the brain of Alzheimer’s disease mouse models, which is linked to CypD-related membrane permeability transition pore formation. Thus, CypD inhibitors have the potential to slow the progression of neurodegenerative diseases, including Alzheimer’s disease, by boosting mitochondrial bioenergetics and improving synaptic and cognitive function.

Neurosciences & Neurology↗
DOE OSTI2025

Enhanced polymorph metastability drives glycine nucleation in aqueous salt solutions

Crystal nucleation from aqueous solutions influences countless geological, biochemical, astrophysical, environmental, and materials science–related phenomena, including ice formation, the manufacturing of active pharmaceutical ingredients, development of diseases such as Alzheimer’s and the origin of life itself. Understanding and controlling nucleation is essential for designing materials with specific properties, developing strategies to inhibit or promote crystallization in various contexts and preventing pathological aggregation in neurodegenerative diseases. Similar to the protein structure prediction problem—where a single amino acid sequence can in theory adopt one most stable conformation but in practice may sample multiple competing conformations—crystal nucleation faces a parallel challenge: the same chemical species can form diverse polymorphs under different environmental conditions (e.g., temperature, pressure, solvent). Each polymorph presents its own set of physical and chemical properties, highlighting the importance of understanding and controlling polymorph selection in fields ranging from pharmaceuticals to materials design. Despite advances in experimental and computational methods for studying phase transitions and polymorph stability, nucleation remains challenging due to its nanoscale nature. Furthermore, in practical settings, salts and impurities can further influence crystal nucleation in diverse contexts, from scaling in pipelines and desalination plants to the durability of concrete and the efficiency of battery materials. This can lead to the formation of polymorphs that may differ from the most stable phase in pure solutions. Or, even though the final structure might appear same irrespective of whether the environment contained impurities or not, the mechanism through which it was formed might be completely different and not intuitive.

Wang, Ruiyu [University of Maryland, College Park,↗
DOE OSTI2021

Immobilization of transgenic plant cells towards bioprinting for production of a recombinant biodefense agent

Abstract Transgenic rice cells ( Oryza sativa ) producing recombinant butyrylcholinesterase (BChE) as a prophylactic/therapeutic against organophosphate nerve agent poisoning, cocaine toxicity, and neurodegenerative diseases like Alzheimer's were immobilized in a polyethylene glycol‐based hydrogel. The cells were sustained for 14 days in the semi‐solid matrix, undergoing a growth phase from days 0–6, a BChE production phase in sugar‐free medium from days 6–12, and a growth/recovery phase from days 12–14. Throughout this period, the cells maintained similar viability to those in suspension cultures and displayed analogous sugar consumption trends. The rice cells in the hydrogel also produced a significant amount of active BChE, comparable to the levels produced in liquid cultures. A considerable fraction of this BChE was secreted into the media, allowing for easier product separation. To the best of our knowledge, this proof‐of‐concept is the first report of immobilization of recombinant plant cells for continuous production of high‐value heterologous proteins. This work serves as a foundation for further investigation towards plant cell bioprinting and the development of a simple, efficient, robust, modular, and potentially field‐deployable bioreactor system for the manufacture of biologics.

Varma, Anika↗
DOE OSTI2020

Lipids status and copper in a single astrocyte of the rat model for amyotrophic lateral sclerosis: Correlative synchrotron-based X-ray and infrared imaging

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, causing death of motor neurons controlling voluntary muscles. The pathological mechanisms of the disease are only partially understood. The hSOD1-G93A ALS rat model is characterized by an overexpression of human mutated SOD1, causing increased vulnerability by forming intracellular protein aggregates, inducing excitotoxicity, affecting oxidative balance and disturbing axonal transport. In this study we followed the bio-macromolecular organic composition and compartmentalization together with trace metal distribution in situ in single astrocytes from the ALS rat model and compared them to the control astrocytes from nontransgenic littermates by simultaneous use of two synchrotron radiation-based methods: Fourier transform infrared microspectroscopy (SRFTIR) and hard X-ray fluorescence microscopy (XRF). Here we show that ALS cells contained more Cu, which colocalized with total lipids, increased carbonyl groups and oxidized lipids, thus implying direct involvement of Cu in oxidative stress of lipidic components without direct connection to protein aggregation in situ.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Detection of non‐native species formed during fibrillization of the myocilin olfactomedin domain

Abstract Glaucoma is a group of neurodegenerative diseases that together are the leading cause of irreversible blindness worldwide. Myocilin‐associated glaucoma is an inherited form of this disease, caused by intracellular aggregation of misfolded mutant myocilin. In vitro, the myocilin C‐terminal olfactomedin domain (OLF), the relevant domain for glaucoma pathogenesis, can be driven to form amyloid‐like fibrils under mild conditions. Here we characterize a species present during in vitro fibrillization. Purified OLF was subjected to fibrillization at concentrations required for downstream electron microscopy imaging and NMR spectroscopy. Additional biophysical techniques, including analytical ultracentrifugation and X‐ray crystallography, were employed to further characterize the multicomponent mixture. Negative stain transmission electron microscopy (TEM) shows a non‐native species reminiscent of known prefibrillar oligomers from other amyloid systems, NMR indicates a minor population of partially misfolded species is present in solution, and cryo‐EM imaging shows two‐dimensional protein arrays. The predominant soluble species remaining in solution after the fibril reaction is natively folded, as evidenced by X‐ray crystallography. In summary, after incubating OLF under fibrillization‐promoting conditions, there is a heterogeneous mixture consisting of soluble folded protein, mature amyloid‐like fibrils, and partially misfolded intermediate species that at present belie additional molecular detail. The characterization of OLF fibrillar species illustrates the challenges associated with developing a comprehensive understanding of the fibrillization process for large, non‐model amyloidogenic proteins.

Scelsi, Hailee F. [School of Chemistry and Biochem↗
DOE OSTI2025

A review on bacteria-derived antioxidant metabolites: their production, purification, characterization, potential applications, and limitations

Abstract Antioxidants are organic molecules that scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS), thereby maintaining cellular redox balance in living organisms. The human body synthesizes endogenous antioxidants, whereas humans obtain exogenous antioxidants from other organisms such as plants, animals, fungi, and bacteria. This review primarily focuses on the antioxidant potential of natural metabolites and extracts from five major bacterial phyla, including the well-studiedActinobacteriaandCyanobacteria, as well as less-studiedBacteroides,Firmicutes, andProteobacteria.The literature survey revealed that the metabolites and the extracts with antioxidant activity can be obtained from bacterial cells and their culture supernatants. The metabolites with antioxidant activity include pigments, phycobiliproteins, polysaccharides, mycosporins-like amino acids, peptides, phenolic compounds, and alkaloids. Both metabolites and extracts demonstrate in vitro antioxidant capacity through radical-scavenging, metal-reducing, and metal-chelating activity assays. In in vivo models, they can scavenge ROS and RNS directly and/or indirectly eliminate them by enhancing the activities of antioxidant enzymes, such as catalase, superoxide dismutase, and glutathione peroxidase. Due to their antioxidant activities, they may find applications in the cosmetic industry as anti-aging agents for the skin and in medicine as drugs or supplements for combating oxidative stress-related disorders, such as neurodegenerative diseases and diabetes. The literature survey also elucidated that some metabolites and extracts with antioxidant activity also exhibited strong antimicrobial properties. Therefore, we consider that they may have future applications in the treatment of infectious diseases, the preparation of pathogen-free healthy foods, and the extension of food shelf life.

Pharmacology & Pharmacy↗
DOE OSTI2021

Effects of pH on an IDP conformational ensemble explored by molecular dynamics simulation

The conformational ensemble of intrinsically disordered proteins, such as α-synuclein, are responsible for their function and malfunction. Misfolding of α-synuclein can lead to neurodegenerative diseases, and the ability to study their conformations and those of other intrinsically disordered proteins under varying physiological conditions can be crucial to understanding and preventing pathologies. In contrast to well-folded peptides, a consensus feature of IDPs is their low hydropathy and high charge, which makes their conformations sensitive to pH perturbation. We examine a prominent member of this subset of IDPs, α-synuclein, using a divide-and-conquer scheme that provides enhanced sampling of IDP structural ensembles. We constructed conformational ensembles of α-synuclein under neutral (pH ~ 7) and low (pH ~ 3) pH conditions and compared our results with available information obtained from smFRET, SAXS, and NMR studies. Specifically, α-synuclein has been found to in a more compact state at low pH conditions and the structural changes observed are consistent with those from experiments. We also characterize the conformational and dynamic differences between these ensembles and discussed the implication on promoting pathogenic fibril formation. We find that under low pH conditions, neutralization of negatively charged residues leads to compaction of the C-terminal portion of α-synuclein while internal reorganization allows α-synuclein to maintain its overall end-to-end distance. Here, we also observe different levels of intra-protein interaction between three regions of α-synuclein at varying pH and a shift towards more hydrophilic interactions with decreasing pH.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗