Results for “preventive medicine” — Page 3

DOE OSTI2023

Epidemiologic Factors Supporting Triage of Infected Dog Patients Admitted to a Veterinary Hospital Biological Isolation and Containment Unit

The teaching hospital of the Faculty of Veterinary Medicine at the University of Lisbon hosts a Biological Isolation and Containment Unit (BICU) for the hospitalization of both confirmed and suspected animals of an infectious disease. This study targets the BICU dog population to identify and characterize the most frequent infectious diseases recorded in a 7-year period. Several epidemiologic factors were analyzed for their significance to triage infected cases. During the study period, 534 dogs were admitted, of which 263 (49.3%) had a confirmed infectious disease diagnosis: parvovirosis (49.4%; n = 130); leptospirosis (21.7%; n = 57); multidrug-resistant (MDR) bacterial infection; (10.6%; n = 28), and canine distemper (9.9%; n = 26). Several potential risk factors for these diseases were identified: age under 2 years old (p < 0.001), incomplete vaccination for parvovirosis (p < 0.001), age ≥ 10 years old (p < 0.001), and the presence of concomitant disorders for MDR-infected cases (p = 0.03). Logistic regression models were constructed to classify cases and controls. The sensitivity and specificity estimates were very high (>0.83) for parvovirosis, MDR, and distemper infections. A lower sensitivity (0.77) was obtained for identifying cases with leptospirosis. In conclusion, infectious diseases are frequent, hence, it is essential to decrease their occurrence through effective preventive measures such as vaccination. The constructed logistic models can also help in triaging admitted dogs with a potential infectious disease.

Machado, Inês Cunha (ORCID:0000000238151125)↗

DOE OSTI2021

Diagnostic, Prognostic, and Therapeutic Use of Radiopharmaceuticals in the Context of SARS-CoV-2

The coronavirus disease 2019 (COVID-19) outbreak has devastated the healthcare systems and economies of over 200 countries in just a few months. The etiological agent of COVID-19, SARS-CoV-2, is a highly contagious virus that can be transmitted by asymptomatic and symptomatic carriers alike. While in vitro testing techniques have allowed for population-wide screening, prognostic tools are required to assess the disease severity and therapeutic response, contributing to improve the patient clinical outcomes. Moreover, no specific antiviral against COVID-19 exists at the time of publication, severely limiting treatment against the infection. Hence, there is an urgent clinical need for innovative therapeutic strategies that may contribute to manage the COVID-19 outbreak and prevent future pandemics. In this work, we critically examine recent diagnostic, prognostic, and therapeutic advancements for COVID-19 in the field of radiopharmaceuticals. First, we summarize the gold standard techniques used to diagnose COVID-19, including in vitro assays and imaging techniques, and then discuss how radionuclide-based nuclear imaging provides complementary information for prognosis and treatment management of infected patients. Second, we introduce new emerging types of radiotherapies that employ radioimmunoconjugates, which have shown selective cytotoxic response in oncological studies, and critically analyze how these compounds could be used as therapeutic agents against SARS-CoV-2. Finally, this Perspective further discusses the emerging applications of radionuclides to study the behavior of pulmonary SARS-CoV-2 aerosol particles.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2024

Pharmacologic or genetic interference with atrogene signaling protects against glucocorticoid-induced musculoskeletal and cardiac disease

Despite their beneficial actions as immunosuppressants, glucocorticoids (GC) have devastating effects on the musculoskeletal and cardiac systems, as long-term treated patients exhibit high incidence of falls, bone fractures, and cardiovascular events. Herein, we show that GC upregulate simultaneously in bone, skeletal muscle, and the heart the expression of E3 ubiquitin ligases (atrogenes), known to stimulate the proteasomal degradation of proteins. Activation of vitamin D receptor (VDR) signaling with the VDR ligands calcitriol or eldecalcitol prevented GC-induced atrogene upregulation in vivo and ex vivo in bone/muscle organ cultures and preserved tissue structure/mass and function of the 3 tissues in vivo. Direct pharmacologic inhibition of the proteasome with carfilzomib also conferred musculoskeletal protection. Genetic loss of the atrogene MuRF1-mediated protein ubiquitination in ΔRING mice afforded temporary or sustained protection from GC excess in bone or skeletal and heart muscle. We concluded that the atrogene pathway downstream of MuRF1 underlies GC action in bone, muscle, and the heart, and it can be pharmacologically or genetically targeted to confer protection against the damaging actions of GC simultaneously in the 3 tissues.

Research & Experimental Medicine↗

DOE OSTI2025

Source function from two-particle correlation function through entropy-regularized Richardson-Lucy deblurring

Source functions are obtained from p – p and d – α correlation functions by applying the Richardson-Lucy (RL) deblurring to the Koonin-Pratt (KP) equation. To prevent fitting of noise in the correlation function, total-variation (TV) regularization is employed that has been effective in ordinary image restoration. TV alone cannot ensure normalization of the source functions. To ensure the latter, we propose a maximum-entropy regularized RL algorithm (MEM-RL). We outline the MEM-RL formalism and optimization strategy for the KP equation, demonstrating its effectiveness on both simulated and experimental data, including the p – p and d – α correlation functions.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2025

A combined designed CSP and Pfs48/45 infection and transmission blocking vaccine for malaria

Abstract The multiple stages of the malaria parasite life cycle hampers vaccine development. Combining a pre-erythrocytic antigen with a transmission-blocking antigen would target two independent stages of the life cycle for disease control, resulting in a multistage vaccine that can prevent infection and disease transmission simultaneously. Here, we generated a self-assembled ferritin nanoparticle vaccine that simultaneously presents designed immunogens CSPj5c and 17-4 from the infection-blocking circumsporozoite and the transmission-blocking Pfs48/45 antigens. These immunogens were designed, through structure-based approaches, to retain protective epitopes and confer protection upon vaccination. Immunization with CSPj5c-17-4-ferritin nanoparticles conferred protection against challenge with transgenic sporozoites expressingPlasmodium falciparumCSP in mice, and purified IgGs from immunized rabbits elicited potent transmission-reducing activity. Addition of the engineered 17-4 improved the immune responses to CSPj5c and protection from sporozoite challenge. CSPj5c-17-4-ferritin is therefore a promising multistage malaria vaccine with a potential role in malaria control.

Immunology↗

DOE OSTI2024

Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention

Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malaria through human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, and selective pyrazolebased Plasmodium DHODH inhibitors through a scaffold hop from a pyrrole-based series. Optimized pyrazole-based compounds were identified with low nM-to-pM Plasmodium falciparum cell potency and oral activity in a humanized SCID mouse malaria infection model. The lead compound DSM1465 is more potent and has improved absorption, distribution, metabolism and excretion/pharmacokinetic (ADME/PK) properties compared to DSM265 that support the potential for once-monthly chemoprevention at a low dose. This compound meets the objective of identifying compounds with potential to be used for monthly chemoprevention in Africa to support malaria elimination efforts.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2023

Natural and enriched Cr target development for production of Manganese-52

52 Mn is a promising PET radiometal with a half-life of 5.6 days and an average positron energy of 242 keV. Typically, chromium of natural isotope abundance is used as a target material to produce this isotope through the nat/52 Cr(p,n) 52 Mn reaction. While natural Cr is a suitable target material, higher purity 52 Mn could be produced by transitioning to enriched 52 Cr targets to prevent the co-production of long-lived 54 Mn (t 1/2 = 312 day). Unfortunately, 52 Cr targets are not cost-effective without recycling processes in place, therefore, this work aims to explore routes to prepare Cr targets that could be recycled. Natural Cr foils, metal powder pellets, enriched chromium-52 oxide and Cr(III) electroplated targets were investigated in this work. Each of these cyclotron targets were irradiated, and the produced 52 Mn was purified, when possible, using a semi-automated system. An improved purification by solid-phase anion exchange from ethanol-HCl mixtures resulted in recoveries of 94.5 ± 2.2% of 52 Mn. The most promising target configuration to produce a recyclable target was electroplated Cr(III). This work presents several pathways to optimize enriched Cr targets for the production of high purity 52 Mn.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2020

Experimental Investigation of Nanosecond and Subnanosecond Pulsed DBD in Atmospheric Air: Fast Imaging and Spectroscopy

Dielectric barrier discharge (DBD), as an easy and simple way of generation of non-thermal plasma, has found a number of applications in variuos fields. However, development of a homogeneous, or uniform, DBD that would operate at atmospheric pressure conditions in atmospheric air, would open a number of new applications in various fields from thin film coatings to plasma medicine. Unfortunately, at atmospheric pressure, a uniform DBD can be easily transformed into a filamentary dielectric DBD; therefore some serious issues arise, such as gas heating due to strong discharges in the random microdischarge channel and non-uniform energy distribution, which adversely affect applications. These issues traditionally are solved by the use of an appropriate working gas composition, an alternating current driving frequency, lowering of gas pressure, etc. The transitions between discharge modes in the same experimental conditions have been thoroughly investigated in nitrogen, rare gases and their mixtures with air and other gases. In many cases (for example, in plasma medicine), these methods, especially those related to gas composition and pressure, may not be applied in a convenient manner. Recent advances in pulsed power technology permitted application of much faster voltage rise times (including the subnanosecond range) and short (few nanoseconds) pulses, and revealed that uniform DBD can, in fact, be generated in atmospheric air. Such discharges are in the great interest for many applications, however to date there still little understanding of the mechanisms of their operation and characteristics. Currently, there is no adequate model of the uniform dielectric barrier discharge development in atmospheric air. Although extensive studies have been performed on understanding of the nature of the pulsed DBD uniformity, until now there is still little understanding of the mechanism of the DBD transition from the filamentary mode to uniform mode. One of the reasons for this is that development of streamers, and later – filaments, occurs on the sub-nanosecond and nanosecond time scales, and therefore requires imaging and other diagnostic techniques with corresponding speed of registration. Recently developed technologies allow such studies. Here we demonstrate that DBD uniformity strongly depends on applied electric field in the discharge gap. More specifically, the discharge uniformity may be achieved in the case when two conditions are satisfied: (1) stong overvoltage in the discharge gap (provided by fast rise times), when anode-directed streamers are formed, and (2) short pulse duration that prevents discharge overheating due to rising conductivity (current) which leads to formation of filaments. We show that by controlling the applied (global) electric field in ns-pulsed DBD, it is possible to control the uniformity of the discharge. In addition, this offers better control of the discharge chemistry due to local changes of electric fields and therefore electron energy distribution function.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

DOE OSTI2025

Spatial metabolomics and lipidomics in kidney disease

Kidney disease is a global health issue that affects over 850 million people, and early detection is key to preventing severe disease and complications. Kidney diseases are associated with complex dysregulation of lipid metabolism. Spatial metabolomics through mass spectrometry imaging (MSI) enables spatial mapping of the lipids in tissue and includes a variety of techniques that can be used to image lipids. In the kidney MSI studies often seek to resolve individual functional tissue units such as glomeruli and proximal tubules. Several different MSI techniques such as matrix-assisted laser desorption/ionization and desorption electrospray ionization have been used to characterize lipids and small molecules in chronic kidney disease, acute kidney injury, genetic kidney disease, and cancer. In this review we provide several examples of how spatial metabolomics data can provide critical information concerning localization of changes in disease states. Additionally, when combined with pathology, measurements, transcriptomics, or proteomics, the metabolomic changes can illuminate underlying mechanisms and provide new clinical insights.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2025

A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress

Fis1-mediated mitochondrial localization of Drp1 and excessive mitochondrial fission occur in human pathologies associated with oxidative stress. However, it is not known how Fis1 detects oxidative stress and what structural changes in Fis1 enable mitochondrial recruitment of Drp1. We find that conformational change involving α1 helix in Fis1 exposes its only cysteine, Cys41. In the presence of oxidative stress, the exposed Cys41 in activated Fis1 forms a disulfide bridge and the Fis1 covalent homodimers cause increased mitochondrial fission through increased Drp1 recruitment to mitochondria. Our discovery of a small molecule, SP11, that binds only to activated Fis1 by engaging Cys41, and data from genetically engineered cell lines lacking Cys41 strongly suggest a role of Fis1 homodimerization in Drp1 recruitment to mitochondria and excessive mitochondrial fission. The structure of activated Fis1-SP11 complex further confirms these insights related to Cys41 being the sensor for oxidative stress. Importantly, SP11 preserves mitochondrial integrity and function in cells during oxidative stress and thus may serve as a candidate molecule for the development of treatment for diseases with underlying Fis1-mediated mitochondrial fragmentation and dysfunction.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2026

EEPD1 evolved a unique DNA clamping dimer protecting reversed replication forks

Exonuclease/endonuclease/phosphatase (EEP)-fold hydrolases are canonically monomeric phosphodiesterases exemplified by APE1, DNase I, and TDP2 nucleases. While EEP family domain containing protein 1 (EEPD1) acts in DNA stress responses, its proposed nuclease activities are enigmatic. Here, we integrate hybrid structural methods, evolution, biochemistry, cancer genomics, plus molecular and cell biology to define EEPD1 structure, assembly, and function at stalled DNA replication forks. Results imply EEPD1 surprisingly requires both unique EEP domain dimer and distinctive tandem Helix-hairpin-Helix [(HhH) 2 ] domains to clamp double-stranded (ds) DNA at reversed DNA replication forks for fork protection. Small-angle X-ray Scattering (SAXS), crystal, and cryo-EM structures unveil an unprecedented tryptophan handshake dimer, conserved interface di-Trp-Pro pocket, and adjustable “wrist” enabling an open-closed conformational switch. EEPD1 dimer cooperatively binds complex dsDNA replication fork intermediates but alone lacks nuclease activity due to loss of key EEP catalytic residues during Metazoan evolution and atmospheric oxygen buildup. Instead, EEPD1 prevents nucleolytic degradation of reversed replication forks by MRE11. Furthermore, cancer bioinformatics support oxidative damage-dependent EEPD1 association as a significant modulator of overall patient survival. Collective findings uncover unexpected EEP dimer and fork protection function in clamping, not cleaving, reversed replication forks for metazoan oxidative stress responses controlling genome stability and cancer outcomes.

Shen, Runze [Univ. of Texas, Houston, TX (United S↗

DOE OSTI2026

Correlation of Surface Acoustic Wave (SAW) force myography sensor output with elbow joint torque

Accurate assessment of skeletal muscle forces and net joint torque is essential for preventing fatigue-related injuries, optimizing physical training, and monitoring disease progression in neuromuscular conditions. However, existing joint torque evaluation techniques are hindered by limited portability and high operational costs, confining their use to controlled laboratory or clinical settings. Despite substantial advances in wearable joint torque estimation systems, ongoing challenges such as power constraints, bulky wired setups, and susceptibility to environmental or motion artifacts underscore the urgent need for truly batteryless, wireless solutions deployable in real-world settings. This paper proposes a novel surface acoustic wave (SAW)-based force myography (FMG) system for noninvasive measurement of joint torque, validated against a gold-standard electromechanical dynamometer. The approach uses a single SAW sensor embedded in an armband to detect volumetric biceps brachii changes, with a second-order polynomial mapping sensor output and elbow angle to torque. Seven participants were tested in both isometric (15°–90°) and isokinetic (10°/s and 20°/s) supinated elbow flexion tasks. Under isometric conditions, subject-specific calibration achieved a normalized root-mean-square error (NRMSE) of 13.6% ± 6.0% and R 2 = 0.834 ± 0.180, while a group-level model yielded 14.4% ± 6.8% and 0.808 ± 0.208, respectively. For isokinetic trials, the group model produced an NRMSE of 24.1% ± 6.6% at 10°/s and 24.9% ± 08.9% at 20°/s, highlighting the feasibility of using a single-sensor SAW-FMG setup across different speeds. Because SAW devices support wireless, battery-free operation, the proposed system offers a pathway to portable, real-time monitoring for sports medicine, rehabilitation, and clinical diagnostics.

36 MATERIALS SCIENCE↗

DOE OSTI2024

A Self-Assembling Pfs230D1-Ferritin Nanoparticle Vaccine Has Potent and Durable Malaria Transmission-Reducing Activity

Malaria is caused by eukaryotic protozoan parasites of the genus Plasmodium. There are 249 million new cases and 608,000 deaths annually, and new interventions are desperately needed. Malaria vaccines can be divided into three categories: liver stage, blood stage, or transmission-blocking vaccines. Transmission-blocking vaccines prevent the transmission of disease by the mosquito vector from one human to another. Pfs230 is one of the leading transmission-blocking vaccine antigens for malaria. Here, we describe the development of a 24-copy self-assembling nanoparticle vaccine comprising domain 1 of Pfs230 genetically fused to H. pylori ferritin. The single-component Pfs230D1-ferritin construct forms a stable and homogenous 24-copy nanoparticle with good production yields. The nanoparticle is highly immunogenic, as two low-dose vaccinations of New Zealand White rabbits elicited a potent and durable antibody response with high transmission-reducing activity when formulated in two distinct adjuvants suitable for translation to human use. This single-component 24-copy Pfs230D1-ferritin nanoparticle vaccine has the potential to improve production pipelines and the cost of manufacturing a potent and durable transmission-blocking vaccine for malaria control.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2025

Multi-omics data compendium of pancreatic islet and β cell responses to pro-inflammatory cytokines

In type 1 diabetes (T1D), autoimmune response and inflammation cause the death of pancreatic ß cells, leading to the body’s inability to produce insulin and maintain glucose homeostasis. This process is at least in part mediated by pro-inflammatory cytokines, such as interferon (IFN)a, IFN?, interleukin (IL)-1ß, and tumor necrosis factor (TNF)a, which induce ß-cell dysfunction and apoptosis. A deep understanding of the ß-cell signaling and regulatory networks induced by these cytokines could lead to the identification of therapeutic targets to prevent T1D development. To study cytokine-mediated islets/ß-cell signaling and regulatory networks, a variety of omics experiments have been conducted, including transcriptomics, epigenomics (DNA methylation, UMI-4C, ATAC-seq & ChIP-seq), proteomics (bottom-up, top-down, post-translational modification analysis), lipidomics, and metabolomics. The combination of these datasets can be instrumental in identifying signaling components and regulatory factors involved in ß-cell stress/death. Here, we aggregated these multiple omics datasets into a centralized location, providing a quality-controlled and statistically rigorous resource for investigators seeking to holistically study ß-cell regulation by pro-inflammatory cytokines.

Sarkar, Soumyadeep [Pacific Northwest National Lab↗

DOE OSTI2025

Multi-omics data compendium: Data package 10 (Pck010)

In type 1 diabetes (T1D), autoimmune response and inflammation cause the death of pancreatic ß cells, leading to the body’s inability to produce insulin and maintain glucose homeostasis. This process is at least in part mediated by pro-inflammatory cytokines, such as interferon (IFN)a, IFN?, interleukin (IL)-1ß, and tumor necrosis factor (TNF)a, which induce ß-cell dysfunction and apoptosis. A deep understanding of the ß-cell signaling and regulatory networks induced by these cytokines could lead to the identification of therapeutic targets to prevent T1D development. To study cytokine-mediated islets/ß-cell signaling and regulatory networks, a variety of omics experiments have been conducted, including transcriptomics, epigenomics (DNA methylation, UMI-4C, ATAC-seq & ChIP-seq), proteomics (bottom-up, top-down, post-translational modification analysis), lipidomics, and metabolomics. The combination of these datasets can be instrumental in identifying signaling components and regulatory factors involved in ß-cell stress/death. Here, we aggregated these multiple omics datasets into a centralized location, providing a quality-controlled and statistically rigorous resource for investigators seeking to holistically study ß-cell regulation by pro-inflammatory cytokines.

Sarkar, Soumyadeep [Pacific Northwest National Lab↗

DOE OSTI2025

Multi-omics data compendium: Data package 11 (Pck011)

In type 1 diabetes (T1D), autoimmune response and inflammation cause the death of pancreatic ß cells, leading to the body’s inability to produce insulin and maintain glucose homeostasis. This process is at least in part mediated by pro-inflammatory cytokines, such as interferon (IFN)a, IFN?, interleukin (IL)-1ß, and tumor necrosis factor (TNF)a, which induce ß-cell dysfunction and apoptosis. A deep understanding of the ß-cell signaling and regulatory networks induced by these cytokines could lead to the identification of therapeutic targets to prevent T1D development. To study cytokine-mediated islets/ß-cell signaling and regulatory networks, a variety of omics experiments have been conducted, including transcriptomics, epigenomics (DNA methylation, UMI-4C, ATAC-seq & ChIP-seq), proteomics (bottom-up, top-down, post-translational modification analysis), lipidomics, and metabolomics. The combination of these datasets can be instrumental in identifying signaling components and regulatory factors involved in ß-cell stress/death. Here, we aggregated these multiple omics datasets into a centralized location, providing a quality-controlled and statistically rigorous resource for investigators seeking to holistically study ß-cell regulation by pro-inflammatory cytokines.

Sarkar, Soumyadeep [Pacific Northwest National Lab↗

DOE OSTI2025

Multi-omics data compendium: Data package 12 (Pck012)

In type 1 diabetes (T1D), autoimmune response and inflammation cause the death of pancreatic ß cells, leading to the body’s inability to produce insulin and maintain glucose homeostasis. This process is at least in part mediated by pro-inflammatory cytokines, such as interferon (IFN)a, IFN?, interleukin (IL)-1ß, and tumor necrosis factor (TNF)a, which induce ß-cell dysfunction and apoptosis. A deep understanding of the ß-cell signaling and regulatory networks induced by these cytokines could lead to the identification of therapeutic targets to prevent T1D development. To study cytokine-mediated islets/ß-cell signaling and regulatory networks, a variety of omics experiments have been conducted, including transcriptomics, epigenomics (DNA methylation, UMI-4C, ATAC-seq & ChIP-seq), proteomics (bottom-up, top-down, post-translational modification analysis), lipidomics, and metabolomics. The combination of these datasets can be instrumental in identifying signaling components and regulatory factors involved in ß-cell stress/death. Here, we aggregated these multiple omics datasets into a centralized location, providing a quality-controlled and statistically rigorous resource for investigators seeking to holistically study ß-cell regulation by pro-inflammatory cytokines.

Sarkar, Soumyadeep [Pacific Northwest National Lab↗

DOE OSTI2025

Multi-omics data compendium: Data package 13 (Pck013)

In type 1 diabetes (T1D), autoimmune response and inflammation cause the death of pancreatic ß cells, leading to the body’s inability to produce insulin and maintain glucose homeostasis. This process is at least in part mediated by pro-inflammatory cytokines, such as interferon (IFN)a, IFN?, interleukin (IL)-1ß, and tumor necrosis factor (TNF)a, which induce ß-cell dysfunction and apoptosis. A deep understanding of the ß-cell signaling and regulatory networks induced by these cytokines could lead to the identification of therapeutic targets to prevent T1D development. To study cytokine-mediated islets/ß-cell signaling and regulatory networks, a variety of omics experiments have been conducted, including transcriptomics, epigenomics (DNA methylation, UMI-4C, ATAC-seq & ChIP-seq), proteomics (bottom-up, top-down, post-translational modification analysis), lipidomics, and metabolomics. The combination of these datasets can be instrumental in identifying signaling components and regulatory factors involved in ß-cell stress/death. Here, we aggregated these multiple omics datasets into a centralized location, providing a quality-controlled and statistically rigorous resource for investigators seeking to holistically study ß-cell regulation by pro-inflammatory cytokines.

Sarkar, Soumyadeep [Pacific Northwest National Lab↗