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Lipophilic bisphosphonates reduced cyst burden and ameliorated hyperactivity of mice chronically infected with Toxoplasma gondii

ABSTRACT The current treatments for toxoplasmosis are only active against fast-growing tachyzoites, present in acute infections, with little effect on slow-growing bradyzoites within tissue cysts, present in latent chronic infections. The mitochondrion ofToxoplasma gondiiis essential for its survival, and one of the major anti-parasitic drugs, atovaquone, inhibits the mitochondrial electron transport chain at the coenzyme Q:cytochrome c oxidoreductase site. Coenzyme Q (also known as ubiquinone [UQ]) consists of a quinone head and a lipophilic, isoprenoid tail that anchors UQ to membranes. The synthesis of the isoprenoid unit is essential for cell growth and is inhibited by lipophilic bisphosphonates, which inhibit the parasite growth. In this work, we investigated the effect of lipophilic bisphosphonates on the chronic stages ofT. gondii. We discovered that three lipophilic bisphosphonates (BPH-1218, BPH-1236, and BPH-1238), effective for the acute infection, were also effective in controlling the development of chronic stages. We showed effectiveness by testing them againstin vitrocysts andin vivoderived tissue cysts and, most importantly, these compounds reduced the cyst burden in the brains of chronically infected mice. We monitored the activity of infected mice non-invasively and continuously with a novel device termed the CageDot. A decrease in activity accompanied the acute phase, but mice recovered to normal activity and showed signs of hyperactivity when the chronic infection was established. Moreover, treatment with atovaquone or BPH-1218 ameliorated the hyperactivity observed during the chronic infection. IMPORTANCE Treatment for toxoplasmosis is challenged by a lack of effective drugs to eradicate the chronic stages. Most of the drugs currently used are poorly distributed to the central nervous system, and they trigger allergic reactions in a large number of patients. There is a compelling need for safe and effective treatments for toxoplasmosis. Bisphosphonates (BPs) are analogs of inorganic pyrophosphate and are used for the treatment of bone disorders. BPs target the isoprenoid pathway and are effective against several experimental parasitic infections. Some lipophilic BPs can specifically inhibit the mitochondrial activity ofToxoplasma gondiiby interfering with the mechanism by which ubiquinone is inserted into the inner mitochondrial membrane. In this work, we present the effect of three lipophilic BPs againstT. gondiichronic stages. We also present a new strategy for the monitoring of animal activity during disease and treatment that is non-invasive and continuous.

Microbiology

Proteomic characterization of Mycobacterium tuberculosis subjected to carbon starvation

ABSTRACT Mycobacterium tuberculosis(Mtb) is the causative agent of tuberculosis (TB), the leading cause of infectious disease-related deaths worldwide. TB infections present on a spectrum from active to latent disease. In the human host,Mtbfaces hostile environments, such as nutrient deprivation, hypoxia, and low pH. Under these conditions,Mtbcan enter a dormant, but viable, state characterized by a lack of cell replication and increased resistance to antibiotics. DormantMtbposes a major challenge to curing infections and eradicating TB globally. We subjectedMtbmc 2 6020 (ΔlysAand ΔpanCD), a double auxotrophic strain, to carbon starvation (CS), a culture condition that induces growth stasis and mimics environmental conditions associated with dormancyin vivo. We provide a detailed analysis of the proteome in CS compared to replicating samples. We observed extensive proteomic reprogramming, with 36% of identified proteins significantly altered in CS. Many enzymes involved in oxidative phosphorylation and lipid metabolism were retained or more abundant in CS. The cell wall biosynthetic machinery was present in CS, although numerous changes in the abundance of peptidoglycan, arabinogalactan, and mycolic acid biosynthetic enzymes likely result in pronounced remodeling of the cell wall. Many clinically approved anti-TB drugs target cell wall biosynthesis, and we found that these enzymes were largely retained in CS. Lastly, we compared our results to those of other dormancy models and propose that CS produces a physiologically distinct state of stasis compared to hypoxia inMtb. IMPORTANCE Tuberculosis is a devastating human disease that kills over 1.2 million people a year. This disease is caused by the bacterial pathogenMycobacterium tuberculosis(Mtb).Mtbexcels at surviving in the human host by entering a non-replicating, dormant state. The current work investigated the proteomic changes thatMtbundergoes in response to carbon starvation, a culture condition that models dormancy. The authors found broad effects of carbon starvation on the proteome, with the relative abundance of 37% of proteins significantly altered. Protein changes related to cell wall biosynthesis, metabolism, and drug susceptibility are discussed. Proteins associated with a carbon starvation phenotype are identified, and results are compared to other dormancy models, including hypoxia.

Microbiology

Strategies for Flood Resilience and Grid Investment Among Iowa's Electric Distribution Utilities

Flooding poses a growing threat to Iowa's electric distribution system, yet utilities face significant data and modeling challenges in planning effective resilience investments. This report provides a foundational assessment of how distribution utilities in Iowa, investor-owned, municipal, and cooperative, approach resilience planning, with a focus on flood risk. It combines hazard characterization, review of state and utility practices, and application of NLR's Energy Resilience Analysis for Distribution Systems (ERAD) and Capacity Expansion Decision Support for Distribution Networks (CADET) tools. Using FEMA floodplains, Iowa Flood Center depth grids, and utility infrastructure data, the analysis quantifies asset exposure, simulates outage risks, and evaluates resilience strategies such as pole hardening, undergrounding, and substation protection. Results indicate that while feeder-level upgrades provide incremental benefits, the most significant reductions in outage risk are achieved through targeted substation interventions. The report highlights key data gaps, such as limited elevation data and fragility functions, and underscores the need for probability-weighted investment frameworks to address both frequent and catastrophic flood events. These insights aim to support utilities, state agencies, and federal partners in prioritizing resilience investments that safeguard Iowa's electric grid against future flooding.

24 POWER TRANSMISSION AND DISTRIBUTION

Multi-modal dynamic radiography using short-pulse laser-generated probe beams

Radiography is an important tool for the interrogation of dynamic experiments in the fields of dynamic properties of materials, and in condensed matter, high explosive, and high-energy-density physics. Multi-modal radiography advances the hypothesis that combining the information delivered by multiple radiographic modalities can lead to more constrained (improved) “reconstruction” of the scene than can be obtained from a single probe. We identify four modalities: multi-probe, time sequence, multi-view, and multi-messenger. Multi-probe radiography is a promising candidate for a next-generation dynamic radiographic facility. High-energy X-rays are the most frequently used probe for dynamic radiography, although recent developments show the utility of proton (pRad), electron (eRad), and neutron probe beams. Because each probing species interacts with material in the radiographic scene through quantitatively different mechanisms, each returns independent information about the scene, which can add extra constraints to the reconstruction process. How to conduct detailed, quantitative “co-analysis” of multiple data streams remains an area of active research. Multi-beam, short-pulse, laser-generated probes offer sufficient dose, an appropriate spectrum, and appropriate spatio-temporal resolution to produce high-quality dynamic radiographs. This paper reports on technology development to advance the state of the art of multi-modal/multi-probe radiography and the pursuit of both deterministic and inferential (AI/ML assisted) co-analysis methodologies to produce more constrained reconstructions from multi-modal data.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY

The Principle of Maximum Conformality Correctly Resolves the Renormalization-Scheme-Dependence Problem

In this paper, we clarify a serious misinterpretation and consequent misuse of the Principle of Maximum Conformality (PMC), which also can serve as a mini-review of PMC. In a recently published article, P. M. Stevenson has claimed that “the PMC is ineffective and does nothing to resolve the renormalization-scheme-dependence problem”, concluding incorrectly that the success of PMC predictions is due to the PMC being a “laborious, ad hoc, and back-door” version of the Principle of Minimal Sensitivity (PMS). We show that such conclusions are incorrect, deriving from a misinterpretation of the PMC and an overestimation of the applicability of the PMS. The purpose of the PMC is to achieve precise fixed-order pQCD predictions, free from conventional renormalization schemes and scale ambiguities. We demonstrate that the PMC predictions satisfy all the self-consistency conditions of the renormalization group and standard renormalization-group invariance; the PMC predictions are thus independent of any initial choice of renormalization scheme and scale. The scheme independence of the PMC is also ensured by commensurate scale relations, which relate different observables to each other. Moreover, in the Abelian limit, the PMC dovetails into the well-known Gell-Mann–Low framework, a method universally revered for its precision in QED calculations. Due to the elimination of factorially divergent renormalon terms, the PMC series not only attains a convergence behavior far superior to that of its conventional counterparts but also deftly curtails any residual scale dependence caused by the unknown higher-order terms. This refined convergence, coupled with its robust suppression of residual uncertainties, furnishes a sound and reliable foundation for estimating the contributions from unknown higher-order terms. Anchored in the bedrock of standard renormalization-group invariance, the PMC simultaneously eradicates the factorial divergences and eliminates superfluous systematic errors, which inversely provides a good foundation for achieving high-precision pQCD predictions. Consequently, owing to its rigorous theoretical underpinnings, the PMC is eminently applicable to virtually all high-energy hadronic processes.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC

EFFECT OF STERILIZATION IN SPACECRAFT DESIGN

Modern spacecraft design no longer involves only the Engineering Sciences. To get "the bugs" out of a system must now be taken literally to signify eradication of actual free-living microorganisms. A severe impact of a non-sterilized space vehicle could result in overt, reckless contamination, virtually eliminating a celestial body as a scientific base for the exobiological phases of space exploration. Recognizing the potentially damaging effects of septic launches, the National Aeronautics and Space Administration in December, 1960 authorized spacecraft sterilization and decontamination as National policy, thereby elevating the space effort onto a higher scientific plane. In the NASA directive, the basic reasons for sterilization were established, viz., "to preserve clues to the origin of life and of the universe, which may be hidden beneath the lunar strata or under the atmospheres of strange planets, to prevent inadvertent seeding of extraterrestrial surfaces by earth-life cultures, and to protect the earth from mutual contamination." In light of the foregoing, spacecraft sterilization should be regarded as the most significant single mission as well as design requirement of planetary space exploration --- especially if our objectives are primarily scientific.

Ranger project

Photochromism of 1,2-dihydroquinolines

Photochromism of dihydroquinoline compounds and absorption spectra of color forms, noting color development upon UV light irradiation and thermal eradication

Becker, R. S.

Lasers in biology and medicine

Laser applications in biology and medicine covering surgery, ophthalmology, microorganisms, viruses, tissue culture, tumor eradication, radiation hazards, etc

Fine, S.

Inventory of forest and rangeland and detection of forest stress

The author has identified the following significant results. At the Atlanta site (226B) it was found that bulk color composites for October 15, 1972, and April 13, 1973, can be interpreted together to disclose the location of the perennial Kudzu vine (Pyeraria lobata). Land managers concerned with Kudzu eradication could use ERTS-1 to inventory locations over 200 meters (660 feet) square. Microdensitometer data collected on ERTS-1 Bulk photographic products for the Manitou test site (226C) have shown that the 15-step gray-scale tablets are not of systematic equal values corresponding to 1/14 the maximum radiant energy incident on the MSS sensor. The gray-scale values present a third-order polynomial function rather than a direct linear relationship. Although data collected on step tablets for precision photographic products appear more discrete, the density variation within blocks in almost as great as variations between blocks. These system errors will cause problems when attempting to analyze radiometric variances among vegetation and land use classes.

Heller, R. C.

Selenium in soils of the Lower Wasatch Formation, Campbell County, Wyoming: Geochemistry, distribution, and environmental hazards

The author has identified the following significant results. Seleniferous Shingle series soils and sandstone outcrops of section 27, T 48 N, R 71 W, Wyoming are mapped on aerial photography by their association with Astragalus bisulcatus. Chemical leachate analyses and atomic absorption methods reveal all studied Samsil and Shingle soils to contain acid, base, and water soluble selenium compounds, and that water extractions showed varied concentration behavior due to soil pH. Acid-soluble selenium is found to be associated with smectite. Statistical analyses confirm that A. bisulcatus presence has a weak influence on soil-lens organic selenium concentration, and determine the importance of other geobotanical factors for convertor presence. Environmental procedures of high selenium lens burial, convertor plant eradication, and revegetated site monitoring are recommended. Usage of density analysis and photographic enlargement are used to successfully produce both a control area and a Campbell County, Wyoming regional map of A. bisulcatus supportive soils and outcrops using Skylab photography.

Kolm, K. E.

Estimation of daily mean air temperature from satellite derived radiometric data

The Screwworm Eradication Data System (SEDS) at JSC utilizes satellite derived estimates of daily mean air temperature (DMAT) to monitor the effect of temperature on screwworm populations. The performance of the SEDS screwworm growth potential predictions depends in large part upon the accuracy of the DMAT estimates.

Phinney, D.

Public health applications of remote sensing of vector borne and parasitic diseases

Results of an investigation of the potential application of remote sensing to various fields of public health are presented. Specific topics discussed include: detection of snail habitats in connection with the epidemiology of schistosomiasis; the detection of certain Anopheles breeding sites, and location of transient human populations, both in connection with malaria eradication programs; and detection of overwintering population sites for the primary screwworm (Cochliomyia americana). Emphasis was placed on the determination of ground truth data on the biological, chemical, and physical characteristics of ground waters which would or would not support the growth of significant populations of mosquitoes.

Source record

Remote sensing for control of tsetse flies

Remotely sensed information is discussed which has potential for aiding in the control or eradication of tsetse flies. Data are available from earth resources meteorological, and manned satellites, from airborne sensors, and possibly from data collection platforms. A new zone discrimination technique, based on data from meteorological satellites may also allow the identification of zones hospitable to one or another species of tsetse. For background, a review is presented of the vegetation of Tanzania and Zanzibar, and illustrations presented of automatic processing of data from these areas. In addition, a review is presented of the applicability of temperature data to tsetse areas.

Giddings, L. E.

The anomaly data base of screwworm information

Standard statistical processing of anomaly data in the screwworm eradication data system is possible from data compiled on magnetic tapes with the Univac 1108 computer. The format and organization of the data in the data base, which is also available on dedicated disc storage, are described.

Giddings, L. E.

Meteorological limits on the growth and development of screwworm populations

A program to evaluate the use of remotely sensed data as an additional tool in existing and projected efforts to eradicate the screwworm began in 1973. Estimating weather conditions by use of remotely sensed data was part of the study. Next, the effect of weather on screwworm populations was modeled. A significant portion of the variation in screwworm population growth and development has been traced to weather-related parameters. This report deals with the salient points of the weather and the screwworm population interaction.

Phinney, D. E.

Performance of a V/STOL tilt nacelle inlet with blowing boundary layer control

A scale model of a V/STOL tilt nacelle fitted to a 0.508 m single stage fan was tested in the NASA Lewis 9x15 ft low speed wind tunnel to determine the effect of diffuser blowing on the inlet aerodynamics and aeromechanical performance. The test was conducted over a range of freestream speeds (up to 120 knots) and angles of attack (up to 120 deg). Diffuser blowing had a beneficial affect on all performance parameters. The angle of attack range for separation free flow substantially increased, and the fan face distortion significantly reduced with a corresponding increase in total pressure recovery. Discrete narrow band blade stress peaks which were common to the nonblowing (baseline) configuration were eradicated with diffuser blowing.

Johns, A. L.

Static stability and thermal wind in an atmosphere of variable composition Applications to Mars

Radiometric measurements of the temperature of the south polar cap of Mars in winter have yielded values significantly below the expected 148 K. One proposed explanation for this result is a substantial reduction in the CO2 content of the atmosphere and a lowering of the mean molecule weight near the surface. The meteorological consequences of this explanation are explored by deriving a criterion for vertical static stability and a thermal wind law for an atmosphere of variable composition. The atmosphere proves to be statically unstable unless the anomaly in the CO2 mixing ratio extends to heights of tens of kilometers. The effect of varying molecular weight exceeds the effect of temperature gradient, producing shears with height of reversed sign. The shears are baroclinically unstable, and this instability would eradicate the latitudinal gradient of molecular weight. This inconsistency can be resolved by invoking a reasonable elevation of the central polar cap and by imposing an adequate zonal wind. It is concluded that if the explanation requiring a change in atmospheric composition is correct, it must be accompanied by other special circumstances to make it meteorologically consistent.

Hess, S. L.

Performance of a V/STOL tilt nacelle inlet with blowing boundary layer control

A scale model of a V/STOL tilt nacelle fitted to a 0.508 m single stage fan was tested in the NASA Lewis low speed wind tunnel to determine the effect of diffuser blowing on the inlet aerodynamics and aeromechanical performance. The test was conducted over a range of freestream speeds (up to 120 knots) and angles-of attack (up to 120 deg). In general, diffuser blowing had a beneficial affect on all performance parameters. The angle-of-attack range for a separation-free flow substantially increased, and the fan face distortion reduced with a corresponding increase in total pressure recovery. Discrete narrow band blade stress peaks which were common to the nonblowing (baseline) configuration were eradicated with diffuser blowing.

Johns, A. L.