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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 145 records · Page 8
All sourcesNASA NTRSDOE OSTI
DOE OSTI2019

Jiangsu Nanjing – Lawrence Berkeley Life Sciences Center for Translational Medicine (CRADA AWD00000392)

Project 1: Our previous work demonstrated that the CES biomarker can be an approximate measure for the levels of chromosomal instability (CIN) in cancer, and that the CES (for Centromere and kinetochore gene Expression Score) biomarker effectively predicts which cancer patients benefit from adjuvant chemotherapies in lung and other cancer types. Such a utility can potentially reduce overtreatment that is common in lung cancer treatment. We determined performance of the multiplex Quantigene RNA assay platform for measuring mRNA levels of CES genes using clinical tumor samples. These experiments determined sensitivity, specificity and detection limit of 12 CES genes and 5 control genes using clinical tumor samples with paired normal tissue samples. We determined how sample concentration and storage conditions affect measurement sensitivity and specificity, and whether sample storage over time affects result reproducibility. Importantly, we confirmed that early stage lung cancer CES values are significantly higher than those of paired normal tissues in all cases. This result greatly extended our bioinformatic data mining by confirming that we can measure CES values directly from patient tumor tissue, and that tumors have higher CES values than normal tissues. Unfortunately, our CRADA partner in China did not finish measuring CES expression levels for a larger group of ~100 tumor samples, due to the long period time required for human subject review in China. This delay prevented us from generating enough additional data to generate a significant statistical model. We finished analyzing all the data acquired during the CRADA, and are trying to work collaboratively with the Shanghai University Lung Cancer Hospital to complete the analysis of more tumor samples. Although no publications have resulted from this research, the findings are crucial for ongoing efforts to obtain funding to develop the technology to address problems in deciding on appropriate treatment regimens for individual patients, in clinical settings. Project 2: The overarching milestones of CRADA Project 2 were to investigate the role of FAM83 family members in cancer progression. Two publications resulted from this work which are highlighted below. The first major goal of the CRADA was to broadly assess the role of FAM83 family oncogenes in human cancer using a multi-omic bioinformatic approach (Snijders et al 2017 Mol. Oncol 11). The second major goal was to specifically assess the role of FAM83D in a cancer progression and metastasis (Yin et al 2019 Cell Oncol; in revision). Role of FAM83 family oncogenes in human cancers Recent studies from our laboratory as well as other groups have demonstrated that FAM83 family members have oncogenic properties and have significantly elevated expression levels in multiple human tumor types, including breast cancers (BC). We performed an integrative multi-omics bio-informatic analysis of the role of FAM83 family oncogenes in human cancers. Our findings were published in the journal Molecular Oncology (Snijders et al; Mol Oncol. 2017 Feb;11(2):167-179). Highlights from this manuscript are: • Transcriptional levels of FAM83 family members are frequently and dramatically elevated across tumor types in human • DNA copy number increase appears to be a potential mechanism for increased expression of FAM83 genes • FAM83 family gene signature is associated with poor survival across human tumor types • FAM83 gene alterations are significantly correlated with TP53, PIK3CA and Ecadherin mutations. In conclusion, this analysis of FAM83 family members opened up a new horizon for further understanding the significance of FAM83 genes in cancer and clinical applications in diagnosis, prognosis and therapy. Role of FAM83D in human non-small cell lung cancer (NSCLC) metastasis and its impact on chemotherapy. Lung cancer is one of the most common malignant tumors in the world and non-small cell lung cancer (NSCLC) accounts for 80~85% of all diagnosed lung cancer cases, one of the deadliest cancers worldwide. FAM83D has been proposed as an oncoprotein in several types of human cancer, yet its role and molecular mechanism in human non-small cell lung cancer (NSCLC) metastasis and its impact on chemotherapy are poorly understood. We evaluated the expression of FAM83D in NSCLC cells and cancerous tissues and its prognostic significance, then investigated the effect of FAM83D on tumorigenic phenotypes such as cell proliferation, EMT and invasive capability, and finally assessed impact of FAM83D on NSCLC chemo-drug resistance. The results of this study are currently in revision at the journal Cellular Oncology. Highlights from this manuscript are: • FAM83D expression is elevated in NSCLC cells and tissues and associated with poor prognosis • FAM83D promotes NSCLC cell proliferation • FAM83D induces EMT in NSCLC cells • FAM83D promotes NSCLC cell migration and invasion • FAM83D promotes EMT and invasive capability of NSCLC cells by regulating AKT/mTOR pathway • FAM83D silencing increases cisplatin sensitivity of NSCLC cells In summary, this second study demonstrated for the first time that FAM83D promoted EMT and metastasis of NSCLC cells through AKT/mTOR signal pathway as well as increased the sensitivity of NSCLC to cisplatin. This study may provide potential targets for advanced NSCLC treatment and personalized therapy.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2003

Some approaches to medical support for Martian expedition

Medical support in a Martian expedition will be within the scope of crew responsibilities and maximally autonomous. Requirements to the system of diagnostics in this mission include considerable use of means and methods of visualization of the main physiological parameters, telemedicine, broad usage of biochemical analyses (including "dry" chemistry), computerized collection, measurement, analysis and storage of medical information. The countermeasure system will be based on objective methods of crew fitness and working ability evaluation, individual selection of training regimens, and intensive use of computer controlled training. Implementation of the above principles implies modernization and refinement of the countermeasures currently used by space crews of long-term missions (LTM), and increases of the assortment of active and passive training devices, among them a short-arm centrifuge. The system of medical care with the functions of prevention, clinical diagnostics and timely treatment will be autonomous, too. The general requirements to medical care during the future mission are the following: availability of conditions and means for autonomous urgent and special medical aid and treatment of the most possible states and diseases, "a hospital", and assignment to the crew of one or two doctors. To ensure independence of medical support and medical care in an expedition to Mars an automated expert system needs to be designed and constructed to control the medical situation as a whole. c2003 Published by Elsevier Science Ltd.

Mars↗
DOE OSTI2024

Physiologically based modeling reveals different risk of respiratory depression after fentanyl overdose between adults and children

Despite a rapid increase in pediatric mortality rate from prescription and illicit opioids, there is limited research on the dose-dependent impact of opioids on respiratory depression in children, the leading cause of opioid-associated death. In this article, we extend a previously developed translational model to cover pediatric populations by incorporating age-dependent pharmacokinetic, pharmacodynamic, and physiological changes compared to adults. Our model reproduced previous perioperative clinical findings that adults and children have similar risk of respiratory depression at the same plasma fentanyl concentration when specific endpoints (minute ventilation, CO 2 tension in the blood) were used. However, our model points to a potential caveat that, in a perioperative setting, routine use of mechanical ventilation and supplemental oxygen maintained the blood and tissue oxygen partial pressures in patients and prevented the use of oxygen-related endpoints to evaluate the consequences of respiratory depression. In a community setting when such oxygenation procedures are not immediately available, our model suggests that the higher oxygen demand and reduced cerebrovascular reactivity could make children more susceptible to severe hypoxemia and brain hypoxia, even with the same plasma fentanyl concentration as adults. Our work indicates that when developing intervention strategies to protect children from opioid overdose in a community setting, these pediatric-specific factors may need to be considered.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2024

SupportU: Smart UAS Program for the Population by Offering Resources and Tools to the Unhoused

Global warming, challenging economic conditions, the opioid epidemic, and other widespread problems, have impacted people globally, particularly over the past several years. Preventable diseases like the common cold and the effects of heat stroke have become increasingly prevalent due to these issues. It is estimated that 150 million people of the world’s population are unhoused globally, with many dwelling in unsafe and unsanitary conditions while lacking access to basic hygienic items and other essentials. Unsanitary conditions coupled with this lack of access exacerbates and prolongs health problems and harms quality of life. Traditional methods of aid, such as homeless shelters and meal programs, face numerous challenges such as having limited reach and resources. To address these problems, the Smart UAS Program for the Population by Offering Resources and Tools to the Unhoused (SUPPORT U) utilizes Uncrewed Aircraft Systems (UAS) to deliver resources to the unhoused and those in need of basic aid, prior to and during extreme temperature conditions, and after natural disasters in rural, suburban, and urban areas. The UA is envisioned to be an autonomous aircraft capable of efficiently distributing essential supplies, including blankets, water, food, and medicine. The UAS fleet relies on advanced navigation and communication technologies to accurately identify unhoused people and efficiently and safely distribute materials to them. This will be done through a machine learning algorithm. By focusing on identified “homeless clusters”, places where unhoused individuals are concentrated, the UAS network increases access to critical resources, thereby helping to mitigate some of the external risks to the health of unhoused individuals. The UA can also be used during crises, such as by transporting supplies to medical tents that are stationed in difficult-to-reach areas suffering from natural disasters.

Samuel Beard↗
NASA NTRS1991

Is there a role for nonsedating antihistamines in motion sickness? Fallout from space research may soon benefit your patients

The rotating chair test, a novel research technique for simulating motion sickness, is used to study the effect of nonsedating oral antihistamines in preventing or forestalling motion sickness. After receiving terfenadine, astemizole, doxepin, or placebo, four groups of male volunteers were rotated at accelerating speed, and they made head movements out of the axis of rotation until they perceived that vomiting would occur if additional head movements were made. Those pretreated with doxepin or terfenadine experienced a statistically significant prophylactic effect, as measured by increased tolerance to Coriolis stimulation. This suggests that selective peripheral H1 antihistamine action may protect against motion sickness.

Clinical Trial↗
DOE OSTI2021

Dietary Methionine Supplementation Exacerbates Gastrointestinal Toxicity in a Mouse Model of Abdominal Irradiation

Identification of appropriate dietary strategies for prevention of weight and muscle loss in cancer patients is crucial for successful treatment and prolonged patient survival. High-protein oral nutritional supplements decrease mortality and improve indices of nutritional status in cancer patients; however, high-protein diets are often rich in methionine, and experimental evidence indicates that a methionine-supplemented diet (MSD) exacerbates gastrointestinal toxicity after total body irradiation. Here, we sought to investigate whether MSD can exacerbate gastrointestinal toxicity after local abdominal irradiation, an exposure regimen more relevant to clinical settings.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Fostering Radiation Oncology Physician Scientist Trainees Within a Diverse Workforce: The Radiation Oncology Research Scholar Track

There is a need to foster future generations of radiation oncology physician scientists, but the number of radiation oncologists with sufficient education, training, and funding to make transformative discoveries is relatively small. A large number of MD/PhD graduates have entered he field of radiation oncology over the past 2 decades, but this has not led to a significant cohort of externally funded physician scientists. Because radiation oncologists leading independent research labs have the potential to make transformative discoveries that advance our field and positively affect patients with cancer, we created the Duke Radiation Oncology Research Scholar (RORS) Program. In crafting this program, we sought to eliminate barriers preventing radiation oncology trainees from becoming independent physician scientists. The RORS program integrates the existing American Board of Radiology Holman Pathway with a 2-year post-graduate medical education instructor position with 80% research effort at the same institution. We use a separate match for RORS and traditional residency pathways, which we hope will increase the diversity of our residency program. Since the inception of the RORS program, we have matched 2 trainees into our program. We encourage other radiation oncology residency programs at peer institutions to consider this training pathway as a means to foster the development of independent physician scientists and a diverse workforce in radiation oncology.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
NASA NTRS2015

Pioneering a Biobased UAS

With the exponential growth of interest in unmanned aerial vehicles (UAVs) and their vast array of applications in both space exploration and terrestrial uses such as the delivery of medicine and monitoring the environment, the 2014 Stanford-Brown-Spelman iGEM team is pioneering the development of a fully biological UAV for scientific and humanitarian missions. The prospect of a biologically-produced UAV presents numerous advantages over the current manufacturing paradigm. First, a foundational architecture built by cells allows for construction or repair in locations where it would be difficult to bring traditional tools of production. Second, a major limitation of current research with UAVs is the size and high power consumption of analytical instruments, which require bulky electrical components and large fuselages to support their weight. By moving these functions into cells with biosensing capabilities - for example, a series of cells engineered to report GFP, green fluorescent protein, when conditions exceed a certain threshold concentration of a compound of interest, enabling their detection post-flight - these problems of scale can be avoided. To this end, we are working to engineer cells to synthesize cellulose acetate as a novel bioplastic, characterize biological methods of waterproofing the material, and program this material's systemic biodegradation. In addition, we aim to use an "amberless" system to prevent horizontal gene transfer from live cells on the material to microorganisms in the flight environment. So far, we have: successfully transformed Gluconacetobacter hansenii, a cellulose-producing bacterium, with a series of promoters to test transformation efficiency before adding the acetylation genes; isolated protein bands present in the wasp nest material; transformed the cellulose-degrading genes into Escherichia coli; and we have confirmed that the amberless construct prevents protein expression in wild-type cells. In addition, as part of our human outreach project, we have been in touch with leaders in the fields of UAVs, synthetic biology, and earth sciences, and it is clear that biodegradable UAVs could have a significant impact on the industry.

Escherichia↗
NASA NTRS2015

Pioneering a Biobased UAS

With the exponential growth of interest in unmanned aerial vehicles (UAVs) and their vast array of applications in both space exploration and terrestrial uses such as the delivery of medicine and monitoring the environment, the 2014 Stanford-Brown-Spelman iGEM team is pioneering the development of a fully biological UAV for scientific and humanitarian missions. The prospect of a biologically-produced UAV presents numerous advantages over the current manufacturing paradigm. First, a foundational architecture built by cells allows for construction or repair in locations where it would be difficult to bring traditional tools of production. Second, a major limitation of current research with UAVs is the size and high power consumption of analytical instruments, which require bulky electrical components and large fuselages to support their weight. By moving these functions into cells with biosensing capabilities – for example, a series of cells engineered to report GFP, green fluorescent protein, when conditions exceed a certain threshold concentration of a compound of interest, enabling their detection post-flight – these problems of scale can be avoided. To this end, we are working to engineer cells to synthesize cellulose acetate as a novel bioplastic, characterize biological methods of waterproofing the material, and program this material’s systemic biodegradation. In addition, we aim to use an “amberless” system to prevent horizontal gene transfer from live cells on the material to microorganisms in the flight environment. So far, we have: successfully transformed Gluconacetobacter hansenii, a cellulose-producing bacterium, with a series of promoters to test transformation efficiency before adding the acetylation genes; isolated protein bands present in the wasp nest material; transformed the cellulose-degrading genes into Escherichia coli; and we have confirmed that the amberless construct prevents protein expression in wild-type cells. In addition, as part of our human outreach project, we have been in touch with leaders in the fields of UAVs, synthetic biology, and earth sciences, and it is clear that biodegradable UAVs could have a significant impact on the industry.

Escherichia↗
DOE OSTI2019

Design of the Universal Neutron Irradiator

SHINE medical isotopes is developing a novel method to produce the medical isotope Mo-99, which is the parent of Tc-99m, the most widely used diagnostic compound in nuclear medicine. This method utilizes U-235 fission in a subcritical liquid target solution, driven by an accelerator-based neutron source that is based on a deuterium-tritium reaction in a gaseous target. In this approach, the neutron-generating target is surrounded by uranyl sulfate (low-enriched uranium); fission in the uranium salt solution efficiently produces the desired Mo-99, as well as other fission products. After irradiation, Mo-99 is separated and the uranyl sulfate solution can be irradiated again to produce Mo-99. This allows the solution to be recycled for a very long time and significantly reduces the amount of associated nuclear waste. SHINE has received U.S. Nuclear Regulatory Commission (NRC) approval to construct an Mo-99 production facility based on this method. In order to produce Mo-99 efficiently, the solution should be as close as possible to criticality. Because the solution is over moderated, any precipitation could push the solution to become critical and thereby hard to control. One of the possible precipitation scenarios is the formation of uranyl peroxide. Under irradiation, water decomposes into the products of radiolysis, some of which will form peroxide. To prevent precipitation, one has to develop a way to decompose the peroxide before it can react with uranium and form hard-to-dissolve precipitates. To study peroxide formation and develop methods to prevent precipitation, we are developing an experiment capable of mimicking radiation conditions in the SHINE system. This report describes the irradiation setup we designed to irradiate a small volume of uranyl sulfate solution for the duration of one SHINE irradiation (~6 days) at the relevant fission power (~0.5 W/cc)

38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEA↗
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↗
NASA NTRS2025

Potential Health Impacts, Treatments, and Countermeasures of Martian Dust on Future Human Space Exploration

The challenges of human space exploration produce some of humanity’s greatest technological and scientific advances, not excluding innovations in medicine. The microgravity environment causes a whole host of physiological changes, and exposure to dust on the Moon caused considerable pulmonary distress to astronauts during the Apollo missions. As the National Aeronautics and Space Administration (NASA)and other space organizations prepare for long duration exploration missions to Mars, the hazards and consequences of the Martian surface need to be accounted for. This review investigates how substances analogous to the hazardous components of Martian dust have caused disease in people on Earth. Because of the small grain size of Martian dust, dust on Mars is more likely to cause lung irritation, absorb into the bloodstream, and lead to diseases in astronauts. Toxic components of Martian dust to astronaut health include perchlorates, silica, nanophase iron oxides, and gypsum in addition to trace amounts of toxic metals whose abundances are debated: chromium, beryllium, arsenic, and cadmium. Predicted effects of dust exposure ranges from asymptomatic to life threatening, with many substances being carcinogenic and most damage impacting the pulmonary system. The longer transit time for astronauts to return home makes the operations of performing emergency medical treatment more difficult and increases both the likelihood and consequences of developing chronic disease. Exposure mitigation needs to be prioritized; however, supplements may be taken to prevent disease from breakthrough exposures and treatment regimens could lessen morbidity and mortality. Treatments and equipment need to be carefully thought out and transported with the astronauts to be prepared for all possible scenarios.

Justin L Wang↗
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↗
NASA NTRS2005

Human behavioral research in space: quandaries for research subjects and researchers

With the advent of long-duration spaceflight on board the International Space Station (ISS) and possible future missions beyond low Earth orbit (LEO) such as Mars, it is critical that those at NASA have a realistic assessment of the challenges that will face individuals on long-duration missions so that they can develop preventive and real-time countermeasures to behavioral health issues. While space travellers are very interested in having countermeasures to the deleterious effects of space missions, they have a powerful disincentive to participate in this research if they feel it could in any way negatively affect their flight status. The behavioral issues of isolation and confinement for extended-duration space missions are reviewed. Areas of basic and clinical behavioral research are listed. And the classical clinical model for research is not considered appropriate for the current configuration of the space program. The use of analogue environments and advanced statistical analysis are suggested as ways to address the limited spaceflight research opportunities. The challenge of research subject or patient confidentiality vs. mission safety and issues of personal flight status are addressed.

Review, Tutorial↗
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↗