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Solar Orbiter is equipped with electrical antennas performing fast measurements of the surrounding electric field. The antennas register high-velocity dust impacts through the electrical signatures of impact ionization. Although the basic principle of the detection has been known for decades, the understanding of the underlying process is not complete, due to the unique mechanical and electrical design of each spacecraft and the variability of the process. We present a study of electrical signatures of dust impacts on Solar Orbiter's body, as measured with the Radio and Plasma Waves electrical suite. A large proportion of the signatures present double-peak electrical waveforms in addition to the fast pre-spike due to electron motion, which are systematically observed for the first time. We believe this is due to Solar Orbiter's unique antenna design and a high temporal resolution of the measurements. The double peaks are explained as being due to two distinct processes. Qualitative and quantitative features of both peaks are described. The process for producing the primary peak has been studied extensively before, and the process for producing the secondary peak has been proposed before (Pantellini et al., 2012a) for Solar Terrestrial Relations Observatory (STEREO), although the corresponding delay of 100–300 µs between the primary and the secondary peak has not been observed until now. Based on this study, we conclude that the primary peak's amplitude is the better measure of the impact-produced charge, for which we find a typical value of around 8 pC. Therefore, the primary peak should be used to derive the impact-generated charge rather than the maximum. The observed asymmetry between the primary peaks measured with individual antennas is quantitatively explained as electrostatic induction. A relationship between the amplitude of the primary and the secondary peak is found to be non-linear, and the relation is partially explained with a model for electrical interaction through the antennas' photoelectron sheath.

Introduction A variety of dimensions of psychopathology are observed in psychosis. However, the validation of clinical assessment scales, and their latent variable structure, is often derived from cross-sectional rather than longitudinal data, limiting our understanding of how variables interact and reinforce one another. Objectives Using experience sampling methodology (ESM) and analytic approaches optimised for longitudinal data, we assess potential latent variables of commonly-reported symptoms in psychosis, and explore the temporal relationship between them. Methods N=36 participants with a diagnosis of schizophrenia or schizoaffective disorder provided data for up to one year, as part of the Sleepsight study. Using a smartphone app, participants self-reported clinical symptoms once daily for a mean duration of 323 days (SD: 88), with a response rate of 69%. Symptoms were rated using seven-point Likert scale items. Items included symptoms traditionally implicated in psychosis (feeling “cheerful”, “anxious”, “relaxed”, “irritable”, “sad”, “in control”, “stressed”, “suspicious”, “trouble concentrating”, “preoccupied by thoughts”, “others dislike me”, “confused”, “others influence my thoughts” and “unusual sights and sounds”). We used a sparse PCA (SPCA) model to identify latent variables in the longitudinal data. SPCA has previously been applied to longitudinal ESM data, and was developed to achieve a compromise between the explained variance and the interpretability of the principal components. We then used a multistage exploratory and confirmatory differential time-varying effect model (DTVEM) to explore the temporal relationship between the latent variables. DTVEM generates a standardised β coefficient reflecting the strength of relationship between variables across multiple time lags. Only significant lags (p

The development and validation of hydroecological land-surface models to simulate agricultural areas require extensive data on weather, soil properties, agricultural management, and vegetation states and fluxes. However, these comprehensive data are rarely available since measurement, quality control, documentation, and compilation of the different data types are costly in terms of time and money. Here, we present a comprehensive dataset, which was collected at four agricultural sites within the Rur catchment in western Germany in the framework of the Transregional Collaborative Research Centre 32 (TR32) “Patterns in Soil–Vegetation–Atmosphere Systems: Monitoring, Modeling and Data Assimilation”. Vegetation-related data comprise fresh and dry biomass (green and brown, predominantly per organ), plant height, green and brown leaf area index, phenological development state, nitrogen and carbon content (overall > 17 000 entries), and masses of harvest residues and regrowth of vegetation after harvest or before planting of the main crop (> 250 entries). Vegetation data including LAI were collected in frequencies of 1 to 3 weeks in the years 2015 until 2017, mostly during overflights of the Sentinel 1 and Radarsat 2 satellites. In addition, fluxes of carbon, energy, and water (> 180 000 half-hourly records) measured using the eddy covariance technique are included. Three flux time series have simultaneous data from two different heights. Data on agricultural management include sowing and harvest dates as well as information on cultivation, fertilization, and agrochemicals (27 management periods). The dataset also includes gap-filled weather data (> 200 000 hourly records) and soil parameters (particle size distributions, carbon and nitrogen content; > 800 records). These data can also be useful for development and validation of remote-sensing products. The dataset is hosted at the TR32 database (https://www.tr32db.uni-koeln.de/data.php?dataID=1889, last access: 29 September 2020) and has the DOI https://doi.org/10.5880/TR32DB.39 (Reichenau et al., 2020).

Background Disease of the pilonidal sinus is a common condition that affects mainly young adults. Options for management include excision of the sinus tracts, leaving the wound open to heal by secondary intention. The aim of this study was to compare wound healing with dialkylcarbamoyl chloride (DACC)‐coated dressings versus alginate dressings. Methods This multicentre trial randomized consecutive patients undergoing surgery for pilonidal disease to postoperative wound care with either DACC‐coated or alginate dressings. The primary outcome was the proportion of wounds healed after 75 days. Secondary outcomes were the local status of wounds during the healing process, the quality assessment of the dressings by the patient, and the time needed to return to usual activities. Results A total of 246 patients were included: 120 in the DACC‐coated group and 126 in the alginate group. In per‐protocol analysis, there were significantly more patients with completely healed wounds after 75 days in the DACC group than in the alginate group: 78 of 103 (75·7 per cent) versus 58 of 97 (60 per cent) respectively (odds ratio 2·55, 95 per cent c.i. 1·12 to 5·92; P = 0·023). During follow‐up, wounds with alginate dressings had more fibrin than those with DACC‐coated dressings, but the difference was not significant (P = 0·079). There was no difference between the two arms in patients' assessment of the dressings. Conclusion The number of wounds completely healed at 75 days was significantly higher for DACC‐coated compared with alginate dressings. However, the preplanned, clinically significant improvement in healing of 20 per cent was not reached. Registration number: NCT02011802 ( https://clinicaltrials.gov/).

The electric and magnetic field instrument suite FIELDS on board the NASA Parker Solar Probe and the radio and plasma waves instrument RPW on the ESA Solar Orbiter mission that explore the inner heliosphere are sensitive to signals generated by dust impacts. Dust impacts have been observed using electric field antennas on spacecraft since the 1980s and the method was recently used with a number of space missions to derive dust fluxes. Here, we consider the details of dust impacts, subsequent development of the impact generated plasma and how it produces the measured signals. We describe empirical approaches to characterise the signals and compare these in a qualitative discussion of laboratory simulations to predict signal shapes for spacecraft measurements in the inner solar system. While the amount of charge production from a dust impact will be higher near the Sun than observed in the interplanetary medium before, the amplitude of pulses is determined by the recovery behaviour that is different near the Sun since it varies with the plasma environment.

Background: Nivolumab and pembrolizumab, two PD1 inhibitors, trigger immune-related adverse events in approximately 50% of patients. Our objective was to determine whether these immune-related adverse events are associated with patient outcomes. Patients and Methods: Retrospective cohort study, realized at the Institut Universitaire du Cancer de Toulouse, of all the patients treated with nivolumab or pembrolizumab off clinical trials. We included patients (i) diagnosed with unresectable stage III or stage IV melanoma or with recurrent stage IIIB or stage IV non-small cell lung cancer (ii) on nivolumab 3mg/kg or pembrolizumab 2mg/kg every 2 or 3 weeks respectively. Results: Of the 311 patients included (of 641 eligible subjects), 120 (38.6%) had melanoma and 191 (61.4%) had non-small cell lung cancer; 241 (77.5%) were treated with nivolumab with a median follow-up of 24 months (20–29). We observed 166 immune-related adverse events in 116 (37.3%) patients, categorized as “early” (onset before 12 weeks in melanoma and before 8 weeks in lung cancer) in 63 (54.3%) patients. Early and late adverse events were significantly associated with an increase in overall survival: adjusted hazard ratio 0.58 [0.41–0.84] (p = .003) and 0.28 [0.16–0.50] (p

Abstract A search is made for charged Higgs bosons predicted by Two-Higgs-Doublet extensions of the Standard Model (2HDM) using electron-positron collision data collected by the OPAL experiment at $\sqrt{s}=189\mbox{--}209\ \mbox{GeV}$ , corresponding to an integrated luminosity of approximately 600 pb−1. Charged Higgs bosons are assumed to be pair-produced and to decay into $\mathrm{q} \bar{\mathrm{q}}$ , τν τ or AW±. No signal is observed. Model-independent limits on the charged Higgs-boson production cross section are derived by combining these results with previous searches at lower energies. Under the assumption $\mathrm{BR} (\mathrm{H}^{\pm} \to \tau\nu_{\tau}) + \mathrm{BR} (\mathrm{H}^{\pm} \to \mathrm{q} \bar{\mathrm{q}}) = 1$ , motivated by general 2HDM type II models, excluded areas on the $[m_{\mathrm{H}^{\pm}} , \mathrm{BR} (\mathrm {H}^{\pm} \to \tau\nu_{\tau})]$ plane are presented and charged Higgs bosons are excluded up to a mass of 76.3 GeV at 95 % confidence level, independent of the branching ratio BR(H±→τν τ). A scan of the 2HDM type I model parameter space is performed and limits on the Higgs-boson masses $m_{\mathrm{H}^{\pm}}$ and m A are presented for different choices of tanβ.

Purpose: The purpose of this pilot study was to investigate the effect of different size pinholes on visual acuity (VA) at near (0.4 m) while various factors were altered. The alterations made involved accommodation and illumination. Method: Four subjects were selected and their ages ranged from 7 to 14 years. Subjective refractions were performed and then near visual acuities were measured at 0.4 m under two different lighting conditions (460 lux and 1 lux) by adding stigmatic (or spherical) lenses of positive and negative powers in front of pinholes of diameters 1.5 mm and 2 mm. Results: The results showed that there was an improvement in VA in most, however, the size of the pinhole played a minor role. Low illumination did have a drastic effect on our results not only by decreasing the amount of lenses used for near that gave more positive results, but also when the pinhole was placed in front of the subjects. According to Borish, the pinhole does improve VA by a straight forward process of elimination produced by spherical aberrations of the eye. However, this did not seem to be the case in this study under conditions of low illumination. Conclusion: The pinhole effect offers improvement in VA at near by reducing the amount of blupresented to the retina. This study showed that alsubjects had an improvement in VA of at least two lines in high illumination. Pinhole size did not alte the results sufficiently thus suggesting that a pinhole, no matter the size, should increase the VA. However this was not the case when illumination was decreased.

We report on an intercomparison of six different hygroscopicity tandem differential mobility analysers HTDMAs). These HTDMAs are used worldwide in laboratory experiments and field campaigns to measure the water uptake of aerosol particles and have never been intercompared. After an investigation of the different design of the instruments with their advantages and inconveniencies, the methods for calibration, validation and data analysis are presented. Measurements of nebulised ammonium sulphate as well as of secondary organic aerosol generated from a smog chamber were performed. Agreement and discrepancies between the instruments and to the theory are discussed, and final recommendations for a standard instrument are given, as a benchmark for laboratory or field experiments to ensure a high quality of HTDMA data.

Delayed and insufficient revascularization during islet transplantation deprives islets of oxygen and nutrients, resulting in graft failure. Vascular endothelial growth factor (VEGF) could play a critical role in islet revascularization. We aimed to develop pharmacological strategies for VEGF overexpression in pancreatic islets using the iron chelator deferoxamine (DFO), thus avoiding obstacles or safety risks associated with gene therapy. Rat pancreatic islets were infected in vivo using an adenovirus (ADE) encoding human VEGF gene (4.10 8 pfu/pancreas) or were incubated in the presence of DFO (10 μmol/L). In vitro viability, functionality, and the secretion of VEGF were evaluated in islets 1 and 3 days after treatment. Infected islets or islets incubated with DFO were transplanted into the liver of syngenic diabetic rats and the graft efficiency was estimated in vivo by measuring body weight, glycemia, C-peptide secretion, and animal survival over a period of 2 months. DFO induced transient VEGF overexpression over 3 days, whereas infection with ADE resulted in prolonged VEGF overexpression lasting 14 days; however, this was toxic and decreased islet viability and functionality. The in vivo study showed a decrease in rat deaths after the transplantation of islets treated with DFO or ADE compared with the sham and control group. ADE treatment improved body weight and C-peptide levels. Gene therapy and DFO improved metabolic control in diabetic rats after transplantation, but this effect was limited in the presence of DFO. The pharmacological approach is an interesting strategy for improving graft efficiency during transplantation, but this approach needs to be improved with drugs that are more specific.

Copyright of Polish Journal of Management Studies is the property of Czestochowa University of Technology, Faculty of Management and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Polish Journal of Management Studies is the property of Czestochowa University of Technology, Faculty of Management and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Polish Journal of Management Studies is the property of Czestochowa University of Technology, Faculty of Management and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Polish Journal of Management Studies is the property of Czestochowa University of Technology, Faculty of Management and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Polish Journal of Management Studies is the property of Czestochowa University of Technology, Faculty of Management and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Polish Journal of Management Studies is the property of Czestochowa University of Technology, Faculty of Management and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Polish Journal of Management Studies is the property of Czestochowa University of Technology, Faculty of Management and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Polish Journal of Management Studies is the property of Czestochowa University of Technology, Faculty of Management and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Polish Journal of Management Studies is the property of Czestochowa University of Technology, Faculty of Management and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Scanning electrochemical microscopy was used to probe the topography and electrochemical activity of CoCrMo alloys mechanically polished in the presence of bovine calf serum (BCS) in a hip simulator. These substrates are made of the same alloy used in metal-on-metal bearings for artificial hip joints. The BCS serves as an in vitro substitute for the synovial fluid which forms a lubricant in the actual orthopedic device. Chemical and mechanical processes result in the formation of a tribolayer which passivates the alloy surface. Our studies of the heterogeneous electron transfer between ferrocenemethanol and the alloy indicate that the tribolayer formed on both high- and low-carbon substrates is highly heterogeneous with regions of high electrochemical activity. Whereas pits in the samples polished in the absence of BCS show the regions of highest electrochemical activity, the tribolayer-coated samples have electrochemical hot spots in topographically smooth regions of the surface. The tribolayer provides some attenuation of the electrochemical activity of the alloy but does not prevent the possibility of corrosion from occurring. [ABSTRACT FROM AUTHOR]

Antiretroviral therapies based on nucleoside reverse transcriptase inhibitors (NRTIs), like zidovudine (3′‐azido‐3′‐deoxythymidine; AZT) and lamivudine ((‐)2′,3′‐dideoxy‐3′‐thiacytidine; 3TC), markedly reduce mother‐to‐child transmission of the human immunodeficiency virus (HIV). However, AZT induces damage in nuclear DNA of mice exposed in utero and postnatally, and mitochondrial DNA (mtDNA) damage has been observed in both human and mouse neonates following perinatal exposure to AZT and AZT/3TC in combination. To provide animal data modeling the NRTI‐induced heart damage reported in human infants, we treated pregnant CD‐1 mice throughout gestation and treated their pups by direct gavage from postnatal day (PND) 4 through PND 28 with daily doses of 150 mg/kg body weight (bw)/day AZT, 75 mg/kg bw/day 3TC, 125/62.5 mg/kg bw/day AZT/3TC, or the vehicle control. Half the pups were euthanized on PND 28; the remainder received no further dosing, and were euthanized at week 10. Heart tissue was collected, total DNA was extracted, and mtDNA copy number relative to nuclear DNA copy number, mtDNA damage, and mtDNA mutation assays were performed using PCR‐based methods. Analyses revealed increases in mtDNA lesions in 4‐week‐old males and females treated with AZT or 3TC, but not in 10‐week‐old mice, suggesting that the damage resolved after treatment ceased. Interestingly, 10‐week‐old females treated with AZT/3TC had significant increases in mtDNA damage. Point mutations were elevated in 10‐week‐old females treated with AZT or AZT/3TC, but not 3TC; no increases in mutations were seen in either gender at 4 weeks of age. Our data suggest that AZT/3TC combination treatment produces greater mtDNA damage than either agent individually, and that female mice are more sensitive than males to AZT/3TC‐induced mtDNA damage. Environ. Mol. Mutagen., 2006. Published 2006 Wiley‐Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract Poly(ADP-ribose) polymerases or PARPs are a family of NAD+-dependent enzymes that modify themselves and other substrate proteins with ADP-ribose polymers. The founding member PARP1 is localized predominantly in the nucleus and is activated by binding to DNA lesions. Excessive PARP1 activation following genotoxin treatment causes NAD+ depletion and cell death, whereas pharmacological PARP1 inhibition protects cells from genotoxicity. This study investigates whether cellular viability and NAD+ metabolism are regulated by tankyrase-1, a PARP member localized predominantly in the cytosol. Using a tetracycline-sensitive promoter to regulate tankyrase-1 expression in Madin–Darby canine kidney (MDCK) cells, we found that a 40-fold induction of tankyrase-1 (from 1500 to 60,000 copies per cell) lowers steady-state NAD+ levels but does not affect basal cellular viability. Moreover, the induction confers protection against the oxidative agent H2O2 and the alkylating agent MNNG, genotoxins that kill cells by activating PARP1. The cytoprotective effect of tankyrase-1 is not due to enhanced scavenging of oxidants or altered expression of Mcl-1, an anti-apoptotic molecule previously shown to be down-regulated by tankyrase-1 in CHO cells. Instead, tankyrase-1 appears to protect cells by preventing genotoxins from activating PARP1-mediated reactions such as PARP1 automodification and NAD+ consumption. Our findings therefore indicate a cytoprotective function of tankyrase-1 mediated through altered NAD+ homeostasis and inhibition of PARP1 function. [ABSTRACT FROM AUTHOR]

Abstract Background Sex differences in mitochondrial function have been reported in multiple tissue and cell types. Additionally, sex-variable responses to stressors including environmental pollutants and drugs that cause mitochondrial toxicity have been observed. The mechanisms that establish these differences are thought to include hormonal modulation, epigenetic regulation, double dosing of X-linked genes, and the maternal inheritance of mtDNA. Understanding the drivers of sex differences in mitochondrial function and being able to model them in vitro is important for identifying toxic compounds with sex-variable effects. Additionally, understanding how sex differences in mitochondrial function compare across species may permit insight into the drivers of these differences, which is important for basic biology research. This study explored whether Caenorhabditis elegans, a model organism commonly used to study stress biology and toxicology, exhibits sex differences in mitochondrial function and toxicant susceptibility. To assess sex differences in mitochondrial function, we utilized four male enriched populations (N2 wild-type male enriched, fog-2(q71), him-5(e1490), and him-8(e1498)). We performed whole worm respirometry and determined whole worm ATP levels and mtDNA copy number. To probe whether sex differences manifest only after stress and inform the growing use of C. elegans as a mitochondrial health and toxicologic model, we also assessed susceptibility to a classic mitochondrial toxicant, rotenone. Results We detected few to no large differences in mitochondrial function between C. elegans sexes. Though we saw no sex differences in vulnerability to rotenone, we did observe sex differences in the uptake of this lipophilic compound, which may be of interest to those utilizing C. elegans as a model organism for toxicologic studies. Additionally, we observed altered non-mitochondrial respiration in two him strains, which may be of interest to other researchers utilizing these strains. Conclusions Basal mitochondrial parameters in male and hermaphrodite C. elegans are similar, at least at the whole-organism level, as is toxicity associated with a mitochondrial Complex I inhibitor, rotenone. Our data highlights the limitation of using C. elegans as a model to study sex-variable mitochondrial function and toxicological responses.

Objectives Pragmatic randomised controlled trials (pRCTs) are essential for determining the real-world safety and effectiveness of healthcare interventions. However, both laypeople and clinicians often demonstrate experiment aversion: preferring to implement either of two interventions for everyone rather than comparing them to determine which is best. We studied whether clinician and layperson views of pRCTs for COVID-19, as well as non-COVID-19, interventions became more positive during the pandemic, which increased both the urgency and public discussion of pRCTs.Design Randomised survey experiments.Setting Geisinger, a network of hospitals and clinics in central and northeastern Pennsylvania, USA; Amazon Mechanical Turk, a research participant platform used to recruit online participants residing across the USA. Data were collected between August 2020 and February 2021.Participants 2149 clinicians (the types of people who conduct or make decisions about conducting pRCTs) and 2909 laypeople (the types of people who are included in pRCTs as patients). The clinician sample was primarily female (81%), comprised doctors (15%), physician assistants (9%), registered nurses (54%) and other medical professionals, including other nurses, genetic counsellors and medical students (23%), and the majority of clinicians (62%) had more than 10 years of experience. The layperson sample ranges in age from 18 to 88 years old (mean=38, SD=13) and the majority were white (75%) and female (56%).Outcome measures Participants read vignettes in which a hypothetical decision-maker who sought to improve health could choose to implement intervention A for all, implement intervention B for all, or experimentally compare A and B and implement the superior intervention. Participants rated and ranked the appropriateness of each decision. Experiment aversion was defined as the degree to which a participant rated the experiment below their lowest-rated intervention.Results In a survey of laypeople administered during the pandemic, we found significant aversion to experiments involving catheterisation checklists and hypertension drugs unrelated to the treatment of COVID-19 (Cohen’s d=0.25–0.46, p

Aim of study: Chromosomal translocations involving neurotrophic receptor tyrosine kinases (NTRKs) have been identified in 20 % of soft tissue sarcomas. This work focuses on the EML4-NTRK3 translocation identified in cases of Infantile Fibrosarcoma, which contains the coiled-coil multimerization domain of Echinoderm Microtubule-like protein 4 (EML4) fused with the tyrosine kinase domain of Neurotrophic Receptor Tyrosine Kinase 3 (NTRK3). The aim of the study was to test the importance of tyrosine kinase activity and multimerization for the oncogenic activity of EML4-NTRK3. Methods: These studies examined EML4-NTRK3 proteins containing a kinase-dead or WT kinase domain, together with mutations in specific salt bridge residues within the coiled-coil domain. Biological activity was assayed using focus assays in NIH3T3 cells. The MAPK/ERK, JAK/STAT3 and PI3K/AKT pathways were analyzed for downstream activation of signaling pathways. Localization of EML4-NTRK3 proteins was examined by immunofluorescence microscopy, and the ability of the EML4 coiled-coil domain to drive protein multimerization was examined by biochemical assays. Results: Activation of EML4-NTRK3 relies on both the tyrosine kinase activity of NTRK3 and salt-bridge stabilization within the coiled-coil domain of EML4. The tyrosine kinase activity of NTRK3 is essential for the biological activation of EML4-NTRK3. Furthermore, EML4-NTRK3 activates downstream signaling pathways MAPK/ERK, JAK/STAT3 and PKC/PLCγ. The disruption of three specific salt bridge interactions within the EML4 coiled-coil domain of EML4-NTRK3 blocks downstream activation, biological activity, and the ability to hetero-multimerize with EML4. We also demonstrate that EML4-NTRK3 is localized in the cytoplasm and fails to associate with microtubules. Concluding statement: These data suggest potential therapeutic strategies for Infantile Fibrosarcoma cases bearing EML4-NTRK3 fusion through inhibition of salt bridge interactions and disruption of multimerization.

Summary: Alcohol use disorder (AUD) is a disorder of clinical and public health significance requiring novel and improved therapeutic solutions. Both environmental and genetic factors play a significant role in its pathophysiology. However, the underlying epigenetic molecular mechanisms that link the gene-environment interaction in AUD remain largely unknown. In this proof-of-concept study, we showed, for the first time, the neuroepigenetic biomarker capability of non-invasive imaging of class I histone deacetylase (HDAC) epigenetic enzymes in the in vivo brain for classifying AUD patients from healthy controls using a machine learning approach in the context of precision diagnosis. Eleven AUD patients and 16 age- and sex-matched healthy controls completed a simultaneous positron emission tomography-magnetic resonance (PET/MR) scan with the HDAC-binding radiotracer [11C]Martinostat. Our results showed lower HDAC expression in the anterior cingulate region in AUD. Furthermore, by applying a genetic algorithm feature selection, we identified five particular brain regions whose combined [11C]Martinostat relative standard uptake value (SUVR) features could reliably classify AUD vs. controls. We validate their promising classification reliability using a support vector machine classifier. These findings inform the potential of in vivo HDAC imaging biomarkers coupled with machine learning tools in the objective diagnosis and molecular translation of AUD that could complement the current diagnostic and statistical manual of mental disorders (DSM)-based intervention to propel precision medicine forward.

Lead (Pb) is a well-known neurotoxin with established adverse effects on the neurological functions of children and younger adults, including motor, learning, and memory abilities. However, its potential impact on older adults has received less attention. Using the zebrafish model, our study aims to characterize the dose–response relationship between environmentally relevant Pb exposure levels and their effects on changes in behavior and transcriptomics during the geriatric periods. We exposed two-year-old zebrafish to waterborne lead acetate (1, 10, 100, 1000, or 10,000 µg/L) or a vehicle (DMSO) for 5 days. While lower concentrations (1–100 µg/L) reflect environmentally relevant Pb levels, higher concentrations (1000–10,000 µg/L) were included to assess acute toxicity under extreme exposure scenarios. We conducted adult behavior assessment to evaluate the locomotor activity following exposure. The same individual fish were subsequently sacrificed for brain dissection after a day of recovery in the aquatic system. RNA extraction and sequencing were then performed to evaluate the Pb-induced transcriptomic changes. Higher (1000–10,000 ug/L) Pb levels induced hyperactive locomotor patterns in aged zebrafish, while lower (10–100 ug/L) Pb levels resulted in the lowest locomotor activity compared to the control group. Exposure to 100 µg/L led to the highest number of differentially expressed genes (DEGs), while 10,000 µg/L induced larger fold changes in both directions. The neurological pathways impacted by Pb exposure include functions related to neurotransmission, such as cytoskeletal regulation and synaptogenesis, and oxidative stress response, such as mitochondrial dysfunction and downregulation of heat shock protein genes. These findings emphasize a U-shape dose–response relationship with Pb concentrations in locomotor activity and transcriptomic changes in the aging brain.

IntroductionAttentional bias to reward-associated stimuli can occur even when it interferes with goal-driven behavior. One theory posits that dopaminergic signaling in the striatum during reward conditioning leads to changes in visual cortical and parietal representations of the stimulus used, and this, in turn, sustains attentional bias even when reward is discontinued. However, only a few studies have examined neural activity during both rewarded and unrewarded task phases.MethodsIn the current study, participants first completed a reward-conditioning phase, during which responses to certain stimuli were associated with monetary reward. These stimuli were then included as non-predictive cues in a spatial cueing task. Participants underwent functional brain imaging during both task phases.ResultsThe results show that striatal activity during the learning phase predicted increased visual cortical and parietal activity and decreased ventro-medial prefrontal cortex activity in response to conditioned stimuli during the test. Striatal activity was also associated with anterior cingulate cortex activation when the reward-conditioned stimulus directed attention away from the target.DiscussionOur findings suggest that striatal activity during reward conditioning predicts the degree to which reward history biases attention through learning-induced changes in visual and parietal activities.

Abstract Background Diets high in saturated fat and sugar, termed “Western diets,” have been associated with several negative health outcomes, including increased risk for neurodegenerative disease. Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease and is characterized by the progressive death of dopaminergic neurons in the brain. We build upon previous work characterizing the impact of high-sugar diets in Caenorhabditis elegans to mechanistically evaluate the relationship between high-sugar diets and dopaminergic neurodegeneration. Results Adult high-glucose and high-fructose diets, or exposure from day 1 to 5 of adulthood, led to increased lipid content, shorter lifespan, and decreased reproduction. However, in contrast to previous reports, we found that adult chronic high-glucose and high-fructose diets did not induce dopaminergic neurodegeneration alone and were protective from 6-hydroxydopamine (6-OHDA) induced degeneration. Neither sugar altered baseline electron transport chain function and both increased vulnerability to organism-wide ATP depletion when the electron transport chain was inhibited, arguing against energetic rescue as a basis for neuroprotection. The induction of oxidative stress by 6-OHDA is hypothesized to contribute to its pathology, and high-sugar diets prevented this increase in the soma of the dopaminergic neurons. However, we did not find increased expression of antioxidant enzymes or glutathione levels. Instead, we found evidence suggesting downregulation of the dopamine reuptake transporter dat-1 that could result in decreased 6-OHDA uptake. Conclusions Our work uncovers a neuroprotective role for high-sugar diets, despite concomitant decreases in lifespan and reproduction. Our results support the broader finding that ATP depletion alone is insufficient to induce dopaminergic neurodegeneration, whereas increased neuronal oxidative stress may drive degeneration. Finally, our work highlights the importance of evaluating lifestyle by toxicant interactions.

IntroductionExercise is recommended as an adjunct therapy in cancer, but its effectiveness varies. Our hypothesis is that the benefit depends on the exercise intensity.MethodsWe subjected mice to low intensity (Li), moderate intensity (Mi) or high intensity (Hi) exercise, or untrained control (Co) groups based on their individual maximal running capacity.ResultsWe found that exercise intensity played a critical role in tumor control. Only Mi exercise delayed tumor growth and reduced tumor burden, whereas Li or Hi exercise failed to exert similar antitumor effects. While both Li and Mi exercise normalized the tumor vasculature, only Mi exercise increased tumor infiltrated CD8+ T cells, that also displayed enhanced effector function (higher proliferation and expression of CD69, INFγ, GzmB). Moreover, exercise induced an intensity-dependent mobilization of CD8+ T cells into the bloodstream.ConclusionThese findings shed light on the intricate relationship between exercise intensity and cancer, with implications for personalized and optimal exercise prescriptions for tumor control.

Mitochondrial bioenergetic processes are fundamental to development, stress responses, and health. Caenorhabditis elegans is widely used to study developmental biology, mitochondrial disease, and mitochondrial toxicity. Oxidative phosphorylation generally increases during development in many species, and genetic and environmental factors may alter this normal trajectory. Altered mitochondrial function during development can lead to both drastic, short-term responses including arrested development and death, and subtle consequences that may persist throughout life and into subsequent generations. Understanding normal and altered developmental mitochondrial biology in C. elegans is currently constrained by incomplete and conflicting reports on how mitochondrial bioenergetic parameters change during development in this species. We used a Seahorse XFe24 Extracellular Flux (XF) Analyzer to carry out a comprehensive analysis of mitochondrial and non-mitochondrial oxygen consumption rates (OCR) throughout larval development in C. elegans. We optimized and describe conditions for analysis of basal OCR, basal mitochondrial OCR, ATP-linked OCR, spare and maximal respiratory capacity, proton leak, and non-mitochondrial OCR. A key consideration is normalization, and we present and discuss results as normalized per individual worm, protein content, worm volume, mitochondrial DNA (mtDNA) count, nuclear DNA (ncDNA) count, and mtDNA:ncDNA ratio. Which normalization process is best depends on the question being asked, and differences in normalization explain some of the discrepancies in previously reported developmental changes in OCR in C. elegans. Broadly, when normalized to worm number, our results agree with previous reports in showing dramatic increases in OCR throughout development. However, when normalized to total protein, worm volume, or ncDNA or mtDNA count, after a significant 2-3-fold increase from L1 to L2 stages, we found small or no changes in most OCR parameters from the L2 to the L4 stage, other than a marginal increase at L3 in spare and maximal respiratory capacity. Overall, our results indicate an earlier cellular shift to oxidative metabolism than suggested in most previous literature.

Neurotrophic receptor tyrosine kinases (NTRKs) belong to the receptor tyrosine kinase (RTK) family. NTRKs are responsible for the activation of multiple downstream signaling pathways that regulate cell growth, proliferation, differentiation, and apoptosis. NTRK-associated mutations often result in oncogenesis and lead to aberrant activation of downstream signaling pathways including MAPK, JAK/STAT, and PLCγ1. This study characterizes the NACC2-NTRK2 oncogenic fusion protein that leads to pilocytic astrocytoma and pediatric glioblastoma. This fusion joins the BTB domain (Broad-complex, Tramtrack, and Bric-a-brac) domain of NACC2 (Nucleus Accumbens-associated protein 2) with the transmembrane helix and tyrosine kinase domain of NTRK2. We focus on identifying critical domains for the biological activity of the fusion protein. Mutations were introduced in the charged pocket of the BTB domain or in the monomer core, based on a structural comparison of the NACC2 BTB domain with that of PLZF, another BTB-containing protein. Mutations were also introduced into the NTRK2-derived portion to allow comparison of two different breakpoints that have been clinically reported. We show that activation of the NTRK2 kinase domain relies on multimerization of the BTB domain in NACC2-NTRK2. Mutations which disrupt BTB-mediated multimerization significantly reduce kinase activity and downstream signaling. The ability of these mutations to abrogate biological activity suggests that BTB domain inhibition could be a potential treatment for NACC2-NTRK2-induced cancers. Removal of the transmembrane helix leads to enhanced stability of the fusion protein and increased activity of the NACC2-NTRK2 fusion, suggesting a mechanism for the oncogenicity of a distinct NACC2-NTRK2 isoform observed in pediatric glioblastoma.

One aspect of Caenorhabditis elegans that makes it a highly valuable model organism is the ease of use of in vivo genetic reporters, facilitated by its transparent cuticle and highly tractable genetics. Despite the rapid advancement of these technologies, worms must be paralyzed for most imaging applications, and few investigations have characterized the impacts of common chemical anesthetic methods on the parameters measured, in particular biochemical measurements such as cellular energetics and redox tone. Using two dynamic reporters, QUEEN-2m for relative ATP levels and reduction-oxidation sensitive GFP (roGFP) for redox tone, we assess the impact of commonly used chemical paralytics. We report that no chemical anesthetic is entirely effective at doses required for full paralysis without altering redox tone or ATP levels, and that anesthetic use alters the detected outcome of rotenone exposure on relative ATP levels and redox tone. We also assess the use of cold shock, commonly used in combination with physical restraint methods, and find that cold shock does not alter either ATP levels or redox tone. In addition to informing which paralytics are most appropriate for research in these topics, we highlight the need for tailoring the use of anesthetics to different endpoints and experimental questions. Further, we reinforce the need for developing less disruptive paralytic methods for optimal imaging of dynamic in vivo reporters.

[This corrects the article DOI: 10.1371/journal.pone.0287412.].

The field of environmental epigenetics is uniquely suited to investigate biologic mechanisms that have the potential to link stressors to health disparities. However, it is common practice in basic epigenetic research to treat race as a covariable in large data analyses in a way that can perpetuate harmful biases without providing any biologic insight. In this article, we i) propose that epigenetic researchers open a dialogue about how and why race is employed in study designs and think critically about how this might perpetuate harmful biases; ii) call for interdisciplinary conversation and collaboration between epigeneticists and social scientists to promote the collection of more detailed social metrics, particularly institutional and structural metrics such as levels of discrimination that could improve our understanding of individual health outcomes; iii) encourage the development of standards and practices that promote full transparency about data collection methods, particularly with regard to race; and iv) encourage the field of epigenetics to continue to investigate how social structures contribute to biological health disparities, with a particular focus on the influence that structural racism may have in driving these health disparities.

The mass distribution of small bodies in the solar system extends over more than 35 orders of magnitude, from asteroids to nanodust, which bridge the gap between molecules and macroscopic submicron grains. The small size of nanograins compared to the relevant basic scales gives them peculiar properties. Some of these properties affect their electric charging and their large charge-to-mass ratio drives their acceleration to very high speeds in moving magnetised plasmas, as the solar wind and rotating planetary magnetospheres. The electric charge and/or high speed of nanograins have enabled them to be detected serendipitously in various parts of the solar system by several instruments designed to study larger dust, plasma particles, or waves, on a number of spacecraft. These discoveries have opened an emerging field of research, in which many open questions remain, in particular concerning the lower size limit of the particles. [ABSTRACT FROM AUTHOR]

IntroductionSpinal muscular atrophy (SMA) is a rare neuromuscular disease requiring various clinical specialists and therapists to provide care. Due to the disease's dynamic nature and the long distances between specialized centers and local providers, integrating care between disciplines can be challenging. Care that is inadequately integrated can compromise the quality of care and become a burden for patients and families. This trial aimed to improve the care of patients through a case management (CM) intervention.MethodsWe conducted an exploratory, controlled, two-arm trial with pre-, post-, and follow-up measures (process and outcome evaluation). Proof of efficacy based on statistical significance was not our primary study objective since we were investigating a rare disease. Primary outcomes were caregivers' HRQoL and caregiver-rated quality of care integration. Our secondary outcome was the children's HRQoL.ResultsQuestionnaires and semi-structured interviews yielded heterogeneous results depending on caregivers' level of experience and desire (or possibility) to delegate care tasks.DiscussionDespite differing perceptions, all participants supported the establishment of a care coordination model. We recommend CM immediately after diagnosis to provide the greatest benefit to families. We hope that our trial will support the further development of CM interventions that can be customized for specific diseases.

The precise control of organic thin film processing by organic vapor phase deposition (OVPD®) is presented and analyzed on device level. OVPD®offers accurate and individual control of deposition layer properties like mixing of several materials (co-deposition) and the control of various morphologies by a wide process parameter space given by, e.g. substrate temperature, deposition rate and pressure. The benefit of precise co-deposition is demonstrated by an OLED with a sensitive twofold-doped emissive layer and revealed a doping level of 0.26% for the red dopant with a std. dev. of 0.38%. The effect of the various morphologies is investigated by optimizing the efficiency of molecular organic solar cells consisting of copper phthalocyanine (CuPc) and C60. With defined process parameters efficiencies of up to 3.0% were demonstrated. [ABSTRACT FROM AUTHOR]

The nematode Caenorhabditis elegans has emerged as an important animal model in various fields including neurobiology, developmental biology, and genetics. Characteristics of this animal model that have contributed to its success include its genetic manipulability, invariant and fully described developmental program, well-characterized genome, ease of maintenance, short and prolific life cycle, and small body size. These same features have led to an increasing use of C. elegans in toxicology, both for mechanistic studies and high-throughput screening approaches. We describe some of the research that has been carried out in the areas of neurotoxicology, genetic toxicology, and environmental toxicology, as well as high-throughput experiments with C. elegans including genome-wide screening for molecular targets of toxicity and rapid toxicity assessment for new chemicals. We argue for an increased role for C. elegans in complementing other model systems in toxicological research. [ABSTRACT FROM AUTHOR]