A study of the potential use of membrane perturbants in enhancing the hyperthermic treatment of cancer

Many tumour cells are more sensitive to hyperthermia than non-cancerous cells. The nature of this greater thermal sensitivity is not clear. The present study indicates that a likely cause for this increased thermal sensitivity is membrane-associated. Plasma membrane enriched fractions were obtained from two solid rat tumours: D23, a hepatoma, and Mc7, a sarcoma. Lipids from these membranes were extracted, characterized, and compared to equivalent fractions from control tissue (liver). In both cases the tumour membranes had lowered cholesterol: phospholipid ratios. There was little differenceln the phospholipid classes, but there was somecliSigfetice in the fatty acid composition of the individual phospholipids. Fluorescence polarization studies were carried out on whole membranes and indicated that the overall 'order' of the tumour membranes was decreased with respect to the controls. In addition a plasma membrane bound enzyme, the Mg2+ATPase, was found to be considerably more thermolabile in the tumour cells. The addition of the membrane pertubant tetracaine produced a greater degree of disorder in the tumour membranes compared to controls, and enhanced the thermolability of the Mg2+ATPase. These differences are further evidence that the plasma membrane is a likely site for the primary lesion in cell heat injury. Results from in vivo studies support the above mentioned in vitro work. D23 and Mc7 tumours, grown in the foot, were subject to hyperthermia and the simultaneous application of a membrane perturbant, tetracaine. The addition of the tetracaine significantly increased the efficacy of the treatment. When the D23 tumour was grown in ethanol-dependent rats there was no difference in the 'adaptive' response of the tumour, compared to the normal, plasma membranes. There was no difference in the heat sensitivity of foot tumours grown in ethanol-fed rats compared to tumours from pair fed controls

Evaluation of variable rate irrigation using a remote-sensing-based model

Improvements in soil water balance modeling can be beneficial for optimizing irrigation management to account for spatial variability in soil properties and evapotranspiration (ET). A remote-sensing-based ET and water balance model was tested for irrigation management in an experiment at two University of Nebraska-Lincoln research sites located near Mead and Brule, Nebraska. Both fields included a center pivot equipped with variable rate irrigation (VRI). The study included maize in 2015 and 2016 and soybean in 2016 at Mead, and maize in 2016 at Brule, for a total of 210 plot-years. Four irrigation treatments were applied at Mead, including: VRI based on a remote sensing model (VRI-RS); VRI based on neutron probe soil water content measurement (VRINP); uniform irrigation based on neutron probe measurement; and rainfed. Only the VRI-RS and uniform treatments were applied at Brule. Landsat 7 and 8 imagery were used for model input. In 2015, the remote sensing model included reflectance-based crop coefficients for ET estimation in the water balance. In 2016, a hybrid component of the model was activated, which included energy-balance-modeled ET as an input. Both 2015 and 2016 had above-average precipitation at Mead; subsequently, irrigation amounts were relatively low. Seasonal irrigation was greatest for the VRI-RS treatment in all cases because of drift in the water balance model. This was likely caused by excessive soil evaporation estimates. Irrigation application for the VRI-NP at Mead was about 0 mm, 6 mm, and –12 mm less in separate analyses than for the uniform treatment. Irrigation for the VRIRS was about 40 mm, 50 mm, and –98 mm greater in separate analyses than the uniform at Mead and about 18mm greater at Brule. For maize at Mead, treatment effects were primarily limited to hydrologic responses (e.g., ET), with differences in yield generally attributed to random error. Rainfed soybean yields were greater than VRI-RS yields, which may have been related to yield loss from lodging, perhaps due to over-irrigation. Regarding the magnitude of spatial variability in the fields, soil available water capacity generally ranked above ET, precipitation, and yield. Future research should include increased cloud-free imagery frequency, incorporation of soil water content measurements into the model, and improved wet soil evaporation and drainage estimates

Use of temperature to improve West Nile virus forecasts

Ecological and laboratory studies have demonstrated that temperature modulates West Nile virus (WNV) transmission dynamics and spillover infection to humans. Here we explore whether inclusion of temperature forcing in a model depicting WNV transmission improves WNV forecast accuracy relative to a baseline model depicting WNV transmission without temperature forcing. Both models are optimized using a data assimilation method and two observed data streams: mosquito infection rates and reported human WNV cases. Each coupled model-inference framework is then used to generate retrospective ensemble forecasts of WNV for 110 outbreak years from among 12 geographically diverse United States counties. The temperature-forced model improves forecast accuracy for much of the outbreak season. From the end of July until the beginning of October, a timespan during which 70% of human cases are reported, the temperature-forced model generated forecasts of the total number of human cases over the next 3 weeks, total number of human cases over the season, the week with the highest percentage of infectious mosquitoes, and the peak percentage of infectious mosquitoes that on average increased absolute forecast accuracy 5%, 10%, 12%, and 6%, respectively, over the non-temperature forced baseline model. These results indicate that use of temperature forcing improves WNV forecast accuracy and provide further evidence that temperature influences rates of WNV transmission. The findings provide a foundation for implementation of a statistically rigorous system for real-time forecast of seasonal WNV outbreaks and their use as a quantitative decision support tool for public health officials and mosquito control programs

Dengue illness impacts daily human mobility patterns in Iquitos, Peru

Background Human mobility plays a central role in shaping pathogen transmission by generating spatial and/or individual variability in potential pathogen-transmitting contacts. Recent research has shown that symptomatic infection can influence human mobility and pathogen transmission dynamics. Better understanding the complex relationship between symptom severity, infectiousness, and human mobility requires quantification of movement patterns throughout infectiousness. For dengue virus (DENV), human infectiousness peaks 0–2 days after symptom onset, making it paramount to understand human movement patterns from the beginning of illness. Methodology and principal findings Through community-based febrile surveillance and RT-PCR assays, we identified a cohort of DENV+ residents of the city of Iquitos, Peru (n = 63). Using retrospective interviews, we measured the movements of these individuals when healthy and during each day of symptomatic illness. The most dramatic changes in mobility occurred during the first three days after symptom onset; individuals visited significantly fewer locations (Wilcoxon test, p = 0.017) and spent significantly more time at home (Wilcoxon test, p = 0.005), compared to when healthy. By 7–9 days after symptom onset, mobility measures had returned to healthy levels. Throughout an individual’s symptomatic period, the day of illness and their subjective sense of well-being were the most significant predictors for the number of locations and houses they visited. Conclusions/Significance Our study is one of the first to collect and analyze human mobility data at a daily scale during symptomatic infection. Accounting for the observed changes in human mobility throughout illness will improve understanding of the impact of disease on DENV transmission dynamics and the interpretation of public health-based surveillance data

Measuring Health Related Quality of Life for Dengue Patients in Iquitos, Peru

Previous studies measuring the health-related quality of life (HRQoL) of individuals with dengue focused on treatment seeking populations. However, the vast majority of global dengue cases are unlikely to be detected by health systems. Representative measurements of HRQoL should therefore include patients with disease not likely to trigger treatment-seeking behavior. This study based in Iquitos, Peru used the Quality of Wellbeing Scale-Self Administered, a survey that enquires about not only physical health, but also psychological health, self-care, mobility, and usual social activities, and rates HRQoL between 0 (death) and 1 (optimum function), to evaluate the impact of dengue on HRQoL. In order to enroll treatment and non treatment-seeking participants, three modalities of participant recruitment were used. In addition to clinic and community-based febrile surveillance, a contact-cluster methodology was also employed to identify infected individuals less likely to seek treatment. We measured changes in HRQoL and identified common areas of health impairment in 73 virologically confirmed dengue cases at 3 time points during the participant\u27s illness; the early-acute (days 0-6 post symptom onset), late-acute (days 7-20), and convalescent illness phases (days 21 +). Participants reported HRQoL related impairments at significantly higher frequency during the early-acute versus convalescent illness phase (Fisher\u27s exact: P\u3c0.01). There was substantial heterogeneity in scores during each illness phase with median scores in the early-acute, late-acute and convalescent phases of 0.56 (IQR: 0.41-0.64), 0.70 (IQR: 0.57-0.94), and 1 (IQR: 0.80-1.00), respectively. In all illness phases participants recruited in clinics had on average the lowest HRQoL scores where as those recruited in the contact clusters had the highest. Only 1 individual who was recruited in the contact-clusters had no reduction in HRQoL score during their illness. These data illustrate that dengue should be considered as a disease that may have significant implications for not only physical health but also psychological health and social functioning. The impact of dengue on the HRQoL of non-treatment-seeking individuals, although lower than the impact among treatment-seeking individuals, is not necessarily trivial

Urges to Move and Other Motivation States for Physical Activity in Clinical and Healthy Populations: A Scoping Review Protocol

[EN] Motivation for bodily movement, physical activity and exercise varies from moment to moment. These motivation states may be “affectively-charged,” ranging from instances of lower tension (e.g., desires, wants) to higher tension (e.g., cravings and urges). Currently, it is not known how often these states have been investigated in clinical populations (e.g., eating disorders, exercise dependence/addiction, Restless Legs Syndrome, diabetes, obesity) vs. healthy populations (e.g., in studies of motor control; groove in music psychology). The objective of this scoping review protocol is to quantify the literature on motivation states, to determine what topical areas are represented in investigations of clinical and healthy populations, and to discover pertinent details, such as instrumentation, terminology, theories, and conceptual models, correlates and mechanisms of action. Iterative searches of scholarly databases will take place to determine which combination of search terms (e.g., “motivation states” and “physical activity”; “desire to be physically active,” etc.) captures the greatest number of relevant results. Studies will be included if motivation states for movement (e.g., desires, urges) are specifically measured or addressed. Studies will be excluded if referring to motivation as a trait. A charting data form was developed to scan all relevant documents for later data extraction. The primary outcome is simply the extent of the literature on the topic. Results will be stratified by population/condition. This scoping review will unify a diverse literature, which may result in the creation of unique models or paradigms that can be utilized to better understand motivation for bodily movement and exercise.GA was supported by a fellowship from the Office of Academic Affiliations at the United States Veterans Health Administration, a Robert E. Leet and Clara Guthrie Patterson Trust Mentored Research Award, Bank of America, N.A., Trustee, and American Heart Association Grant #852679 (GA, 2021–2024).We would like to thank Melissa Eden, Ph.D. (Hanover College, IN) for her valuable assistance in refining aspects of the search strategy. Khristdman Cavalcanti helped with technical aspects of the study. Sunao Akashi Slayton, PharmD BCOP (Smilow Cancer Hospital, Yale – New Haven Hospital, CT) evaluated clinical information and provided nomenclatur

A multiorganism pipeline for antiseizure drug discovery:Identification of chlorothymol as a novel γ-aminobutyric acidergic anticonvulsant

OBJECTIVE:Current medicines are ineffective in approximately one-third of people with epilepsy. Therefore, new antiseizure drugs are urgently needed to address this problem of pharmacoresistance. However, traditional rodent seizure and epilepsy models are poorly suited to high-throughput compound screening. Furthermore, testing in a single species increases the chance that therapeutic compounds act on molecular targets that may not be conserved in humans. To address these issues, we developed a pipeline approach using four different organisms. METHODS:We sequentially employed compound library screening in the zebrafish, Danio rerio, chemical genetics in the worm, Caenorhabditis elegans, electrophysiological analysis in mouse and human brain slices, and preclinical validation in mouse seizure models to identify novel antiseizure drugs and their molecular mechanism of action. RESULTS:Initially, a library of 1690 compounds was screened in an acute pentylenetetrazol seizure model using D rerio. From this screen, the compound chlorothymol was identified as an effective anticonvulsant not only in fish, but also in worms. A subsequent genetic screen in C elegans revealed the molecular target of chlorothymol to be LGC-37, a worm γ-aminobutyric acid type A (GABAA ) receptor subunit. This GABAergic effect was confirmed using in vitro brain slice preparations from both mice and humans, as chlorothymol was shown to enhance tonic and phasic inhibition and this action was reversed by the GABAA receptor antagonist, bicuculline. Finally, chlorothymol exhibited in vivo anticonvulsant efficacy in several mouse seizure assays, including the 6-Hz 44-mA model of pharmacoresistant seizures. SIGNIFICANCE:These findings establish a multiorganism approach that can identify compounds with evolutionarily conserved molecular targets and translational potential, and so may be useful in drug discovery for epilepsy and possibly other conditions

The combination of abundance and infection rates of Culicoides sonorensis estimates risk of subsequent bluetongue virus infection of sentinel cattle on California dairy farms

Bluetongue (BT) is an important viral disease of ruminants that is transmitted by hematophagous Culicoides midges. We examined the seasonal patterns of abundance and infection of Culicoides sonorensis at four dairy farms in the northern Central Valley of California to develop estimates of risk for bluetongue virus (BTV) transmission to cattle at each farm. These four farms were selected because of their similar meteorological conditions but varying levels of vector abundance and BTV infection of cattle. C. sonorensis midges were collected weekly at each farm during the seasonal transmission period, using three different trapping methods: traps baited with either carbon dioxide (CO2) alone or traps with CO2 and UV light, and by direct aspiration of midges from sentinel cattle. Analysis of BTV-infected midges using group and serotype-specific quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR) assays confirmed that BTV serotypes 10, 11, 13 and 17 are all present in the region, but that midge infection rates and the number of BTV serotypes circulating differed markedly among the individual farms. Furthermore, more serotypes of BTV were present in midges than in sentinel cattle at individual farms where BTV circulated, and the virus was detected at each farm in midges prior to detection in cattle. BTV infection rates were remarkably lower among female C. sonorensis midges collected by CO2 traps with UV light than among midges collected by either animal-baited aspirations or in CO2 traps without light. A subsample of female midges examined from each collection method showed no overall differences in the proportion of female midges that had previously fed on a host. Findings from this study confirm the importance of using sensitive surveillance methods for both midge collection and virus detection in epidemiological studies of BTV infection, which is especially critical if the data are to be used for development of mathematical models to predict the occurrence of BTV infection of livestock.The Center for Food Animal Health at the University of California-Davis, the U.S. Department of Agriculture and the Bernice Barbour Foundation.http://www.elsevier.com/locate/vetpa