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Ross W Stephens,1 Gregory D Tredwell,1 Karen J Knox,1 Lee A Philip,1 David W King,1 Kelly M Debono,2 Jessica L Bell,1 Tim J Senden,1 Marcel R Tanudji,3 Jillean G Winter,3 Stephanie A Bickley,3 Michael J Tapner,3 Stephen K Jones3 1The Biomedical Radiochemistry Laboratory, Department of Applied Mathematics, Research School of Physics and Engineering, Australian National University, Canberra, ACT, Australia; 2Animal Services Division, Research School of Biology, Australian National University, Canberra, ACT, Australia; 3Research and Development, Sirtex Medical Limited, Sydney, NSW, Australia Purpose: Selective internal radiation therapy (SIRT) is an effective treatment option for liver tumors, using Y-90-loaded polymer microspheres that are delivered via catheterization of the hepatic artery. Since Y-90 is a beta emitter and not conveniently imaged by standard clinical instrumentation, dosimetry is currently evaluated in each patient using a surrogate particle, 99mTechnetium-labeled macroaggregated albumin (99mTc-MAA). We report a new composite consisting of 99mTc-labeled nanoparticles attached to the same polymer microspheres as used for SIRT, which can be imaged with standard SPECT.Methods: Carbon nanoparticles with an encapsulated core of 99mTc were coated with the polycation protamine sulfate to provide electrostatic attachment to anionic polystyrene sulfonate microspheres of different sizes (30, 12, and 8 µm). The in vivo stability of these composites was determined via intravenous injection and entrapment in the capillary network of normal rabbit lungs for up to 3 hours. Furthermore, we evaluated their biodistribution in normal rabbit livers, and livers implanted with VX2 tumors, following intrahepatic artery instillation. Results: We report distribution tests for three different sizes of radiolabeled microspheres and compare the results with those obtained using 99mTc-MAA. Lung retention of the radiolabeled microspheres ranged from 72.8% to 92.9%, with the smaller diameter microspheres showing the lowest retention. Liver retention of the microspheres was higher, with retention in normal livers ranging from 99.2% to 99.8%, and in livers with VX2 tumors from 98.2% to 99.2%. The radiolabeled microspheres clearly demonstrated preferential uptake at tumor sites due to the increased arterial perfusion produced by angiogenesis.Conclusion: We describe a novel use of radiolabeled carbon nanoparticles to generate an imageable microsphere that is stable in vivo under the shear stress conditions of arterial networks. Following intra-arterial instillation in the normal rabbit liver, they distribute in a distinct segmented pattern, with the smaller microspheres extending throughout the organ in finer detail, while still being well retained within the liver. Furthermore, in livers hosting an implanted VX2 tumor, they reveal the increased arterial perfusion of tumor tissue resulting from angiogenesis. These novel composites may have potential as a more representative mimic of the vascular distribution of therapeutic microspheres in patients undergoing SIRT. Keywords: liver cancer, SIRT, radiolabeled microspheres, medical imaging

TH Nguyen Pham,1 Nigel A Lengkeek,2 Ivan Greguric,2 Byung J Kim,1 Paul A Pellegrini,2 Stephanie A Bickley,3 Marcel R Tanudji,3 Stephen K Jones,3 Brian S Hawkett,1 Binh TT Pham1 1Key Centre for Polymers and Colloids, School of Chemistry, University of Sydney, 2Radioisotopes and Radiotracers, NSTLI, Australian Nuclear Science and Technology Organisation, Sydney, 3Sirtex Medical Limited, North Sydney, NSW, Australia Abstract: Physiologically stable multimodality imaging probes for positron emission tomography/single-photon emission computed tomography (PET/SPECT)-magnetic resonance imaging (MRI) were synthesized using the superparamagnetic maghemite iron oxide (γ-Fe2O3) nanoparticles (SPIONs). The SPIONs were sterically stabilized with a finely tuned mixture of diblock copolymers with either methoxypolyethylene glycol (MPEG) or primary amine NH2 end groups. The radioisotope for PET or SPECT imaging was incorporated with the SPIONs at high temperature. 57Co2+ ions with a long half-life of 270.9 days were used as a model for the radiotracer to study the kinetics of radiolabeling, characterization, and the stability of the radiolabeled SPIONs. Radioactive 67Ga3+ and Cu2+-labeled SPIONs were also produced successfully using the optimized conditions from the 57Co2+-labeling process. No free radioisotopes were detected in the aqueous phase for the radiolabeled SPIONs 1 week after dispersion in phosphate-buffered saline (PBS). All labeled SPIONs were not only well dispersed and stable under physiological conditions but also noncytotoxic in vitro. The ability to design and produce physiologically stable radiolabeled magnetic nanoparticles with a finely controlled number of functionalizable end groups on the SPIONs enables the generation of a desirable and biologically compatible multimodality PET/SPECT-MRI agent on a single T2 contrast MRI probe. Keywords: magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography, SPIONs, radiolabeling

Daniel B Moore,1 Rebecca F Neustein,2 Sarah K Jones,1 Alan L Robin,3 Kelly W Muir1,4 1Duke Eye Center, Duke University Medical Center, Durham, NC, 2Emory School of Medicine, Atlanta, GA, 3Department of Ophthalmology, Johns Hopkins School of Medicine and International Health, Bloomberg School of Public Health, Baltimore, MD, 4Health Services Research & Development, Durham VA Medical Center, Durham, NC, USA Abstract: As they grow older, most children with glaucoma must eventually face the transition to self-administering medications. We previously reported factors associated with better or worse medication adherence in children with glaucoma, using an objective, electronic monitor. Utilizing the same data set, the purpose of the current study was to determine whose report (the caregiver’s or the child’s) corresponded better with electronically monitored adherence. Of the 46 participants (22 girls), the mean age of children primarily responsible, and caregiver primarily responsible for medication administration was 15±2 and 10±2 years, respectively. For the children whose caregiver regularly administered the eyedrops, the caregiver’s assessment of drop adherence was associated with measured adherence (P=0.012), but the child’s was not (P=0.476). For the children who self-administered eyedrops, neither the child’s (P=0.218) nor the caregiver’s (P=0.395) assessment was associated with measured percent adherence. This study highlights potential errors when relying on self-reporting of compliance in patients and caregivers with pediatric glaucoma, particularly when the child is responsible for administering their own eyedrops. Frank discussions about the importance of medication adherence and how to improve compliance may help both the child and caregiver better communicate with the treating provider. Keywords: glaucoma, children, adherence

Binh TT Pham,1 Nirmesh Jain,1 Philip W Kuchel,2 Bogdan E Chapman,2,† Stephanie A Bickley,3 Stephen K Jones,3 Brian S Hawkett11School of Chemistry, University of Sydney, 2School of Molecular Bioscience, University of Sydney, 3Sirtex Medical Limited, Sydney, NSW, Australia†Bogdan E Chapman passed away on August 16, 2014Abstract: Sterically stabilized superparamagnetic iron oxide nanoparticles (SPIONs) were incubated with fresh human erythrocytes (red blood cells [RBCs]) to explore their potential application as magnetic resonance imaging contrast agents. The chemical shift and linewidth of 133Cs+ resonances from inside and outside the RBCs in 133Cs nuclear magnetic resonance spectra were monitored as a function of time. Thus, we investigated whether SPIONs of two different core sizes and with three different types of polymeric stabilizers entered metabolically active RBCs, consuming glucose at 37°C. The SPIONs broadened the extracellular 133Cs+ nuclear magnetic resonance, and brought about a small change in its chemical shift to a higher frequency; while the intracellular resonance remained unchanged in both amplitude and chemical shift. This situation pertained over incubation times of up to 90 minutes. If the SPIONs had entered the RBCs, the intracellular resonance would have become broader and possibly even shifted. Therefore, we concluded that our SPIONs did not enter the RBCs. In addition, the T2 relaxivity of the small and large particles was 368 and 953 mM-1 s-1, respectively (three and nine times that of the most effective commercially available samples). This suggests that these new SPIONs will provide a superior performance to any others reported thus far as magnetic resonance imaging contrast agents.Keywords: 133Cs NMR spectroscopy, bulk magnetic susceptibility, fresh human erythrocyte, particle stability, paramagnetic shift, superparamagnetic iron oxide nanoparticles, SPIONs

We propose a reciprocal, self-propelled model swimmer at intermediate Reynolds numbers (Re). Our swimmer consists of two unequal spheres that oscillate in antiphase, generating nonlinear steady streaming (SS) flows. We show computationally that the SS flows enable the swimmer to propel itself, and also switch direction as Re increases. We quantify the transition in the swimming direction by collapsing our data on a critical Re and show that the transition in swimming directions corresponds to the reversal of the SS flows. Based on our findings, we propose that SS can be an important physical mechanism for motility at intermediate Re.

Purpose: Prospective associations between preadolescent neurocognitive structure and onset of substance use in adolescence have not been examined. This study investigated associations between cognitive structure among youth aged 9 - 10 years and the likelihood of experimentation with tobacco and alcohol by ages 13-14 years., Methods: A principal component (PC) analysis of nine neurocognitive assessments was used to identify the cognitive structure of unrelated adolescent brain cognitive development study participants (n = 9,655). We modeled associations between neurocognitive PCs and odds of tobacco or alcohol use by ages 13-14 years using generalized linear mixed models with a logit link and random intercept for recruitment sites. Demographics, family conflict, neighborhood safety, and externalizing and internalizing behavior were considered covariates., Results: Four neurocognitive PCs were identified and labeled general ability, executive function, learning and memory, and mental rotation. Mental rotation [odds ratio [OR] = 0.88, p-value = .013] was associated with lower odds of youth tobacco use; the association was stronger among female youth. General ability [OR = 1.20, p-value < .0001] among both males and females, and learning and memory [OR = 1.11, p-value = .024] among females, were associated with increased odds of youth alcohol use., Discussion: Among youth, higher neurocognitive performance was protective for tobacco use but increased the likelihood of alcohol use. Potential sex differences were identified. The role of cognition in processing the social contexts surrounding tobacco and alcohol use in the United States may contribute to the formation of disparate youth expectancies for tobacco and alcohol use., (Copyright © 2024 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Cigarette smoking significantly contributes to preventable illness, death, and economic costs. Despite overall reduction in national smoking rates, disparities persist between demographic groups and geographic regions. While some studies have explored urban-rural differences in smoking prevalence, gaps exist in understanding localized patterns. This study focuses on examining smoking rates and related factors at the census tract level in McLennan County, Texas, a county that contains a mixture of urban, peri-urban, and rural areas. This study uses census tract level aggregate sociodemographic, smoking, and health-related data from the American Community Survey and the PLACES Project City Health Dashboard. Geospatial analyses mapped co-occurrence of high prevalence of smoking, mental and physical distress, and co-occurrence of lower routine medical check-ups, household income, and education. Multiple linear regression modeled associations between smoking and sociodemographic, and health-related factors. Geospatial analyses identified census tracts with co-occurring high prevalence of smoking, mental and physical distress, and co-occurrence of lower routine medical check-ups, household income, and education level in McLennan County. Regression analyses identified that smoking rates were positively correlated with frequent physical distress (p < 0.0001) and negatively correlated with the proportion of routine medical check-ups (p < 0.0001) and the proportion living in poverty (p = 0.0002). This study found significant variations in smoking rates, physical and mental distress, medical check-ups, and sociodemographic factors between neighboring census tracts which geospatial analyses examining larger geographic units may have overlooked. Future research should focus on obtaining individual-level and community-level data to develop more targeted interventions sensitive to specific community contexts., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Labile carbon (C) continuously delivered from the rhizosphere profoundly affects terrestrial nitrogen (N) cycling. However, nitrous oxide (N 2 O) and dinitrogen (N 2 ) production in agricultural soils in the presence of continuous root C exudation with applied N remains poorly understood. We conducted an incubation experiment using artificial roots to continuously deliver small-dose labile C combined with 15 N tracers to investigate N 2 O and N 2 emissions in agricultural soils with pH and organic C (SOC) gradients. A significantly negative exponential relationship existed between N 2 O and N 2 emissions under continuous C exudation. Increasing soil pH significantly promoted N 2 emissions while reducing N 2 O emissions. Higher SOC further promoted N 2 emissions in alkaline soils. Native soil-N (versus fertilizer-N) was the main source of N 2 O (average 67%) and N 2 (average 80%) emissions across all tested soils. Our study revealed the overlooked high N 2 emissions, mainly derived from native soil-N and strengthened by increasing soil pH, under relatively real-world conditions with continuous root C exudation. This highlights the important role of N 2 O and N 2 production from native soil-N in terrestrial N cycling when there is a continuous C supply (e.g., plant-root exudate) and helps mitigate emissions and constrain global budgets of the two concerned nitrogenous gases.

Latinx young adults' experiences of discrimination are associated with high levels of depressive symptoms and examining protective factors that buffer the negative consequences of discrimination is important. In a sample of 195 Latina college students, predominately of Mexican origin, we examined associations between perceived discrimination and depressive symptoms, and how sisters' dyadic coping behaviors and familism values moderated this association. We conducted hierarchical regression analyses to test our study hypotheses. We found that Latina college students who were older sisters reported more conflictual and antagonistic sibling relationships, or who perceived higher levels of discrimination also reported the most depressive symptoms, which supports prior research. Importantly, Latina college students who strongly endorsed supportive, obligatory, and referent familism values reported fewer depressive symptoms. Supportive familism values weakened the association between perceived discrimination and Latina college students' depressive symptoms but strengthened associations between sisters' negative dyadic coping behaviors and depressive symptoms. Furthermore, sisters' negative dyadic coping behaviors strengthened the positive association between perceived discrimination and depressive symptoms. Our findings highlight the importance of familism values for Latinx young adults' well-being, as well as the harmful effects of perceived discrimination, particularly in the context of sisters' negative dyadic coping behaviors., (© 2022 Family Process Institute.)

Environmental exposures produce heritable traits that can linger in the population for one or two generations. Millions of individuals consume substances such as artificial sweeteners daily that are declared safe by regulatory agencies without evaluation of their potential heritable effects. We show that consumption of aspartame, an FDA-approved artificial sweetener, daily for up to 16-weeks at doses equivalent to only 7-15% of the FDA recommended maximum daily intake value (equivalent to 2-4 small, 8 oz diet soda drinks per day) produces significant spatial learning and memory deficits in mice. Moreover, the cognitive deficits are transmitted to male and female descendants along the paternal lineage suggesting that aspartame's adverse cognitive effects are heritable, and that they are more pervasive than current estimates, which consider effects in the directly exposed individuals only. Traditionally, deleterious environmental exposures of pregnant and nursing women are viewed as risk factors for the health of future generations. Environmental exposures of men are not considered to pose similar risks. Our findings suggest that environmental exposures of men can produce adverse impact on cognitive function in future generations and demonstrate the need for considering heritable effects via the paternal lineage as part of the regulatory evaluations of artificial sweeteners., (© 2023. Springer Nature Limited.)

Nitration reactions are crucial for many industrial syntheses; however, current protocols lack site specificity and employ hazardous chemicals. The noncanonical cytochrome P450 enzymes RufO and TxtE catalyze the only known direct aromatic nitration reactions in nature, making them attractive model systems for the development of analogous biocatalytic and/or biomimetic reactions that proceed under mild conditions. While the associated mechanism has been well-characterized in TxtE, much less is known about RufO. Herein we present the first structure of RufO alongside a series of computational and biochemical studies investigating its unusual reactivity. We demonstrate that free l-tyrosine is not readily accepted as a substrate despite previous reports to the contrary. Instead, we propose that RufO natively modifies l-tyrosine tethered to the peptidyl carrier protein of a nonribosomal peptide synthetase encoded by the same biosynthetic gene cluster and present both docking and molecular dynamics simulations consistent with this hypothesis. Our results expand the scope of direct enzymatic nitration reactions and provide the first evidence for such a modification of a peptide synthetase-bound substrate. Both of these insights may aid in the downstream development of biocatalytic approaches to synthesize rufomycin analogues and related drug candidates.

Protein-DNA interactions are fundamental to many biological processes. Proteins must find their target site on a DNA molecule to perform their function, and mechanisms for target search differ across proteins. Especially challenging phenomena to monitor and understand are transient binding events that occur across two DNA target sites, whether occurring in cis or trans. Type IIS restriction endonucleases rely on such interactions. They play a crucial role in safeguarding bacteria against foreign DNA, including viral genetic material. BfiI, a type IIS restriction endonuclease, acts upon a specific asymmetric sequence, 5-ACTGGG-3, and precisely cuts both upper and lower DNA strands at fixed locations downstream of this sequence. Here, we present two single-molecule Förster resonance energy-transfer-based assays to study such interactions in a BfiI-DNA system. The first assay focuses on DNA looping, detecting both "Phi"- and "U"-shaped DNA looping events. The second assay only allows in trans BfiI-target DNA interactions, improving the specificity and reducing the limits on observation time. With total internal reflection fluorescence microscopy, we directly observe on- and off-target binding events and characterize BfiI binding events. Our results show that BfiI binds longer to target sites and that BfiI rarely changes conformations during binding. This newly developed assay could be employed for other DNA-interacting proteins that bind two targets and for the dsDNA substrate BfiI-PAINT, a useful strategy for DNA stretch assays and other super-resolution fluorescence microscopy studies.

Objective: We investigated adult-onset epilepsy as a risk factor for the development of substance use disorder (SUD) by comparing the rate of SUD diagnosis among adults diagnosed with epilepsy with presumably healthy controls with lower extremity fractures (LEF). For additional comparison, we investigated the risk for adults with migraine only. Epilepsy and migraine are both episodic neurological disorders and migraine is frequently comorbid with epilepsy., Methods: We conducted a time-to-event analysis using a subset of surveillance data of hospital admissions, emergency department visits, and outpatient visits in South Carolina, USA from January 1, 2000, through December 31, 2011. Individuals aged 18 years or older were identified using the International Classification of Disease, 9thRevision Clinical Modification (ICD-9) with a diagnosis of epilepsy (n = 78,547; 52.7% female, mean age 51.3 years), migraine (n = 121,155; 81.5% female, mean age 40.0 years), or LEF (n = 73,911; 55.4% female, mean age 48.7 years). Individuals with SUD diagnosis following epilepsy, migraine, or LEF were identified with ICD-9 codes. We used Cox proportional hazards regression to model the time to SUD diagnosis comparing adults diagnosed with epilepsy, migraine, and LEF, adjusting for insurance payer, age, sex, race/ethnicity, and prior mental health comorbidities., Results: Compared to LEF controls, adults with epilepsy were diagnosed with SUD at 2.5 times the rate [HR 2.48 (2.37, 2.60)] and adults with migraine only were diagnosed with SUD at 1.12 times the rate [HR 1.12 (1.06, 1.18)]. We found an interaction between disease diagnosis and insurance payer, with hazard ratios comparing epilepsy to LEF of 4.59, 3.48, 1.97, and 1.44 within the commercial payer, uninsured, Medicaid, and Medicare strata, respectively., Significance: Compared to presumably healthy controls, adults with epilepsy had a substantially higher hazard of SUD, while adults with migraine only showed a small, but significant, increased hazard of SUD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Smoking cessation is more than 50% heritable. Genetic studies of smoking cessation have been limited by short-term follow-up or cross-sectional design., Aims and Methods: This study tests single nucleotide polymorphism (SNP) associations with cessation during long-term follow-up throughout adulthood in women. The secondary aim tests whether genetic associations differ by smoking intensity. Associations between 10 SNPs in CHRNA5, CHRNA3, CHRNB2, CHRNB4, DRD2, and COMT and the probability of smoking cessation over time were evaluated in two longitudinal cohort studies of female nurses, the Nurses' Health Study (NHS) (n = 10 017) and NHS-2 (n = 2793). Participant follow-up ranged from 2 to 38 years with data collected every 2 years., Results: Women with the minor allele of either CHRNA5 SNP rs16969968 or CHRNA3 SNP rs1051730 had lower odds of cessation throughout adulthood [OR = 0.93, p-value = .003]. Women had increased odds of cessation if they had the minor allele of CHRNA3 SNP rs578776 [OR = 1.17, p-value = .002]. The minor allele of DRD2 SNP rs1800497 was associated with lower odds of cessation in moderate-to-heavy smokers [OR = 0.92, p-value = .0183] but increased odds in light smokers [OR = 1.24, p-value = .096]., Conclusions: Some SNP associations with short-term smoking abstinence observed in prior studies were shown in the present study to persist throughout adulthood over decades of follow-up. Other SNP associations with short-term abstinence did not persist long-term. The secondary aim findings suggest genetic associations may differ by smoking intensity., Implications: The results of the present study expand on previous studies of SNP associations in relation to short-term smoking cessation to demonstrate some of these SNPs were associated with smoking cessation throughout decades of follow-up, whereas other SNP associations with short-term abstinence did not persist long-term. The rate of relapse to smoking remains high for several years after quitting smoking, and many smokers experience multiple quit attempts and relapse episodes throughout adulthood. Understanding genetic associations with long-term cessation has potential importance for precision medicine approaches to long-term cessation management., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Prevention Relevance: This study is the first to quantify genetic associations with smoking relapse among female smokers throughout adulthood. These findings could inform precision medicine approaches to improve long-term smoking relapse prevention to reduce smoking attributable cancer morbidity and mortality., (©2023 American Association for Cancer Research.)

Sediment export and retention are important ecosystem processes in any landscape causing soil erosion and sediment loading in waterways consequently affecting the health of aquatic habitats downstream. The present study quantifies sediment export and retention in four watersheds, viz., Hivra, Satrapur, Konta, and Jagdalpur in the Godavari River Basin, India, using Integrated Valuation of Ecosystem Services and Trade-offs (InVEST) ecosystem service modelling tool. The  results revealed that the sediment export yields ranged from 0.75 (Hivra) to 2.77 t/ha/year (Jagdalpur). The mean deviation between modelled values and observed sediment export yield was - 11.11%, which indicated good prediction by the model. The sediment retention ranged from 16.04 (Hivra) to 101.52 t/ha/year (Konta). Most sediment export and retention occurred on cropland or shrubland land use land cover types in all four watersheds. For decision making on soil conservation, soil loss tolerance limits have been established for these watersheds. For aquatic habitats, sediment concentration is considered more important than the total annual sediment export, since water turbidity is an important determinant of water quality, and the aquatic lives therein. Therefore, the temporal distribution of rainfall and corresponding sediment export becomes important, since these two factors determine the sediment concentration as well as turbidity in the waterbody. In current study, "Precipitation Concentration Index adjusted Sediment Export Yield Index" was developed to account for the effects of the temporal rainfall distribution and its impact on sediment export. The index for four watersheds was quantified (Hivra > Satrapur > Konta > Jagdalpur), which is concordant to the turbidity values reported by respective gauge stations. Thus, the proposed index can efficiently capture the impact of temporal rainfall distribution on sediment export, and consequently its effect on water turbidity. The study revealed the potential of InVEST model to quantify the sediment export and retention in the watersheds studied. Together with the proposed index, it would help the policy makers in making informed decisions for planning conservation strategies for aquatic biodiversity., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Host range assessment for emerging invasive insects is a vital step toward fully defining the issues the insect may pose. Spotted lanternfly (SLF) is an invasive species that is rapidly expanding its presence in the United States. The primary hosts facilitating this spread are tree of heaven, a plant from SLF's native range, and the economically important winegrape. Black walnut is also implicated as an important and common host plant. This study investigated the survival and development of SLF on diets that included a variety of crop host plants in the presence or absence of tree of heaven. The following plant species, 'Honeycrisp' apple, 'Reliance' peach, silver maple, and tree of heaven were paired with winegrape or black walnut throughout the study. SLF had strong development and high survival on a diet of winegrape alone, and winegrape or black walnut paired with tree of heaven. Survival parameters were reduced with all other plant pairings. In particular, SLF in the winegrape and peach diet treatment did not develop past the third nymphal instar. A second experiment evaluated the survival of early and late instar nymphs and adult SLF life stages on three specialty crops - 'Cascade' hops, muscadine grapes, and kiwifruit over a two-week period. Nymphs survived longer than adults, with survival of first and second instar nymphs on hops not differing from the control tree of heaven treatment. The adult stage survived best on kiwi and muscadine grape. Our results show tree of heaven and winegrape were the only single plant diets evaluated that are sufficient for complete SLF development, while other host plants may require additional host or hosts of sufficient nutritional quality for SLF survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsensohn, Nixon, Urban, Jones and Leskey.)

The present research aimed to better understand individual differences in attitudes towards emotions with a focus on anger. We report findings of four studies conducted with American and Polish individuals. Results showed that individuals who have more positive attitudes toward anger are higher in trait anger (Studies 1-4), are more likely to think about getting revenge (Study 1), and expect that getting revenge will make them feel good (Studies 1-2). In addition, these individuals are lower in agreeableness and lower in the tendency to engage in avoidance when angered (Studies 1-4). They score lower in humility (Studies 3-4), lower in secure romantic attachment but higher in anxious and avoidance attachment (Study 3). Finally, they are more likely to believe a wide range of conspiracies (Studies 2-4). Discussion focuses on the implications of these results., Competing Interests: Competing interestsThe authors have no relevant financial or non-financial interests to disclose., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The COVID-19 pandemic led to a rapid acceleration in the number of individuals engaging in remote work. This presented an opportunity to study individuals that were not voluntarily working remotely pre-pandemic and examine how they adapted and learned to achieve success in a remote work environment, at an organization that did not have substantial prior experience managing remote work. We used a semi-structured interview process to interview participants ( n = 59) who occupied both Individual Contributor and Leadership levels at an organization and broadly representative across several important demographic characteristics. We asked participants to discuss what factors at individual, team, and organizational levels contributed positively toward their remote work experience, which factors presented challenges to remote work, and what could be done to ensure success with remote work in the future. Interviews were analyzed utilizing a thematic analysis approach and summarized into common themes pertaining to factors that influence success in a remote working environment. Themes were used to identify specific skillsets particularly relevant to remote work that would benefit from training, as well as important organizational culture changes and policies needed to support remote workers and ensure their success. We present these and other findings in relation to current research and provide recommendations for practitioners., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Henke, Jones and O’Neill.)

We report the effects of aspartame on anxiety-like behavior, neurotransmitter signaling and gene expression in the amygdala, a brain region associated with the regulation of anxiety and fear responses. C57BL/6 mice consumed drinking water containing 0.015% or 0.03% aspartame, a dose equivalent of 8 to 15% of the FDA recommended maximum human daily intake, or plain drinking water. Robust anxiety-like behavior (evaluated using open field test and elevated zero maze) was observed in male and female mice consuming the aspartame-containing water. Diazepam, an allosteric modulator of the GABA-A receptor, alleviated the anxiety-like behavior. RNA sequencing of the amygdala followed by KEGG biological pathway analysis of differentially expressed genes showed glutamatergic and GABAergic synapse pathways as significantly enriched. Quantitative PCR showed upregulation of mRNA for the glutamate NMDA receptor subunit 2D ( Grin2d ) and metabotropic receptor 4 ( Grm4 ) and downregulation of the GABA-A receptor associated protein ( Gabarap ) mRNA. Thus, taken together, our diazepam and gene expression data show that aspartame consumption shifted the excitation-inhibition equilibrium in the amygdala toward excitation. Even more strikingly, the anxiety-like behavior, its response to diazepam, and changes in amygdala gene expression were transmitted to male and female offspring in two generations descending from the aspartame-exposed males. Extrapolation of the findings to humans suggests that aspartame consumption at doses below the FDA recommended maximum daily intake may produce neurobehavioral changes in aspartame-consuming individuals and their descendants. Thus, human population at risk of aspartame's potential mental health effects may be larger than current expectations, which only include aspartame-consuming individuals.

Background: Nicotine produces its effects by binding to nicotinic acetylcholine receptors (nAChRs). Variants of genes encoding properties of nAChRs are candidates for affecting likelihood of smoking cessation., Methods: A systematic review was conducted summarizing evidence of associations between single nucleotide polymorphisms (SNPs) of nAChR genes and smoking cessation. From 24 articles meeting inclusion criteria, summary odds ratios (ORs) for associations between nine SNPs and smoking cessation were calculated from 26 studies (N = 233-29,072) stratified by gene, ancestry, study design, and pharmacotherapy; SNPs in linkage disequilibrium were pooled. Results for a tenth SNP from two GWAS were summarized., Results: People of European ancestry with minor alleles of CHRNA5 rs16969968 and CHRNA3 rs1051730 had longer time to cessation [HR = 0.90, 95 % CI 0.88 - 0.92 (n = 2 studies)] and lower odds of cessation [OR = 0.88, 95 % CI 0.80 - 0.97 (n = 5 cohort studies), OR = 0.64, 95 % CI 0.45 - 0.90 (n = 4 placebo arms)]. Risk of persistent smoking associated with these alleles was attenuated in smokers receiving nicotine replacement therapy (NRT). Recipients of bupropion alone or with NRT with these alleles had higher, though not statistically significant, odds of cessation. Results for CHRNA5 rs588765 and rs680244 were similar to rs16969968/rs1051730 findings. Evidence was limited for other SNPs., Conclusion: Evidence consistently indicates the minor alleles of four SNPs within CHRNA3 or CHRNA5 are risk alleles for cessation failure. Analysis by pharmacotherapy revealed bupropion may be the most efficacious intervention for people with these alleles., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest. Dr. Brett Froeliger is a consultant for Promentis Pharmaceuticals, Inc. (BF) for work unrelated to the content of the manuscript. Dr. Matthew Carpenter has received consulting honoraria from both Pfizer and Frutarom for work unrelated to the content of the manuscript., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Managing agricultural landscapes to support biodiversity conservation requires profound structural changes worldwide. Often, discussions are centered on management at the field level. However, a wide and growing body of evidence calls for zooming out and targeting agricultural policies, research, and interventions at the landscape level to halt and reverse the decline in biodiversity, increase biodiversity-mediated ecosystem services in agricultural landscapes, and improve the resilience and adaptability of these ecosystems. We conducted the most comprehensive assessment to date on landscape complexity effects on nondomesticated terrestrial biodiversity through a meta-analysis of 1,134 effect sizes from 157 peer-reviewed articles. Increasing landscape complexity through changes in composition, configuration, or heterogeneity significatively and positively affects biodiversity. More complex landscapes host more biodiversity (richness, abundance, and evenness) with potential benefits to sustainable agricultural production and conservation, and effects are likely underestimated. The few articles that assessed the combined contribution of linear (e.g., hedgerows) and areal (e.g., woodlots) elements resulted in a near-doubling of the effect sizes (i.e., biodiversity level) compared to the dominant number of studies measuring these elements separately. Similarly, positive effects on biodiversity are stronger in articles monitoring biodiversity for at least 2 y compared to the dominant 1-y monitoring efforts. Besides, positive and stronger effects exist when monitoring occurs in nonoverlapping landscapes, highlighting the need for long-term and robustly designed monitoring efforts. Living in harmony with nature will require shifting paradigms toward valuing and promoting multifunctional agriculture at the farm and landscape levels with a research agenda that untangles complex agricultural landscapes' contributions to people and nature under current and future conditions.

Here, we examined retrospective reports of adults' earliest autobiographical memory, the age of this report and whether the reported age was associated with exposure to early life adversity, current anxiety and childhood attachment. Across four studies, we found that reporting a later 'earliest' memory was associated with higher self-reported anxiety in both American (Studies 1, 2 and 4) and Australian (Study 3) samples. Furthermore, in Studies 2-4, we found that reporting a later earliest memory uniquely predicted anxiety when controlling for number of adverse childhood events (a risk factor for the development of anxiety). In Study 4, we established that this relation is partially mediated by childhood anxious attachment. Although we consistently demonstrated that later earliest memories were associated with current anxiety, we found little evidence for a relation between reported age at the time of earliest memory and childhood adversity. We also found no evidence of gender differences in the associations of interest. These results suggest that poorer memory of early childhood is associated with greater childhood anxious attachment and anxiety in adulthood. The implications of this work are discussed in terms of the adaptive nature of autobiographical memory and the development of a coherent life narrative., (© 2021 The British Psychological Society.)

Introduction: Identifying genetic factors associated with smoking cessation could inform precision cessation interventions. Of major interest is genetic variation in nicotine metabolism, largely predicted by CYP2A6 variations., Aims and Methods: We conducted a systematic literature review to summarize the population-based evidence of the association between CYP2A6 and smoking cessation. In the 12 studies meeting the inclusion criteria, the known functional metabolic effect of CYP2A6 variants was used to classify nicotine metabolism as normal (>75% metabolic activity), intermediate (50.1%-75% activity), slow (25%-50% activity), and poor (<25% activity). Summary odds ratios of smoking cessation were calculated across metabolic groups, stratified by ancestry and whether participants received pharmacotherapy or placebo/no treatment., Results: Among untreated people of European ancestry (n = 4 studies), those with CYP2A6 reduced metabolism were more likely to quit smoking than those with normal metabolism (Summary OR = 2.05, 95% CI 1.23 to 3.42) and the likelihood of cessation increased as nicotine metabolism decreased. Nicotine replacement therapy attenuated the association at end-of-treatment, while bupropion modified the association such that intermediate/slow metabolizers were less likely to quit than normal metabolizers (Summary OR = 0.86, 95% CI 0.79 to 0.94). Among untreated Asian people (n = 3 studies), results differed compared with those with European ancestry: those with slow metabolism were less likely to have quit smoking than normal metabolizers (Summary OR = 0.52, 95% CI 0.38 to 0.71). Evidence for people of African ancestry (n = 1 study) suggested the CYP2A6 association with cessation may differ compared with those of European ancestry., Conclusions and Implications: Most studies included in this review were of European ancestry populations; these showed slower nicotine metabolism was associated with increased likelihood of smoking cessation in a dose-related manner. Pharmacotherapy appeared to attenuate or modify this association among people of European ancestry, but it is unclear whether the change in the association remains consistent after treatment ceases. This finding has implications for precision medicine cessation interventions. Based on only a few studies of people of Asian or African ancestry, the association between CYP2A6 variants and cessation may differ from that observed among those of European ancestry, but more evidence is needed., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The S. pyogenes (Sp) Cas9 endonuclease is an important gene-editing tool. SpCas9 is directed to target sites based on complementarity to a complexed single-guide RNA (sgRNA). However, SpCas9-sgRNA also binds and cleaves genomic off-targets with only partial complementarity. To date, we lack the ability to predict cleavage and binding activity quantitatively, and rely on binary classification schemes to identify strong off-targets. We report a quantitative kinetic model that captures the SpCas9-mediated strand-replacement reaction in free-energy terms. The model predicts binding and cleavage activity as a function of time, target, and experimental conditions. Trained and validated on high-throughput bulk-biochemical data, our model predicts the intermediate R-loop state recently observed in single-molecule experiments, as well as the associated conversion rates. Finally, we show that our quantitative activity predictor can be reduced to a binary off-target classifier that outperforms the established state-of-the-art. Our approach is extensible, and can characterize any CRISPR-Cas nuclease - benchmarking natural and future high-fidelity variants against SpCas9; elucidating determinants of CRISPR fidelity; and revealing pathways to increased specificity and efficiency in engineered systems., (© 2022. The Author(s).)

Background: As medical professional roles diversify, it is essential to understand what makes effective medical leaders. This study develops and validates a medical leadership competency framework that can be used to develop and evaluate leaders across all levels of medical organisations., Method: In Phase One, the authors derived desired leadership traits and behaviours in the medical context from a panel of subject matter experts (SMEs). Traits and behaviours were then combined into multifaceted competencies which were ranked and further refined through evaluation with additional SMEs. In Phase Two, the final seven competencies were evaluated with 181 medical trainees and 167 supervisors between 2017 and 2018 to determine the validity of rapid-form and long-form leadership assessments of medical trainees. Self and supervisor reports of the seven competencies were compared with validated trait and leadership behaviour measures as well as clinical performance evaluations., Results: The final seven leadership competencies were: Ethical and Social Responsibility, Civility, Self-Leadership, Team Management, Vision and Strategy, Creativity and Innovation, and Communication and Interpersonal Influence. Results demonstrate initial validity for rapid-form and long-form leadership evaluations; however, perceptions of good leadership may differ between trainees and supervisors. Further, negative leadership behaviours (eg, incivility) are generally not punished by supervisors and some positive leadership behaviours (eg, ethical leadership) were associated with poor leadership and clinical performance evaluations by supervisors. Supervisor perceptions of leadership were significantly driven by trainee scores on social boldness (a facet of extraversion)., Conclusions: A multicompetency framework effectively evaluates leadership in medicine. To more effectively reinforcepositive leadership behaviours and discourage negative leadership behaviours in medical students and resident physicians, we recommend that medical educators:: (1) Use validated frameworks to build leadership curriculum and evaluations. (2) Use short-term and long-term assessment tools. (3) Teach assessors how to evaluate leaders and encourage positive leadership behaviours early in training., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The invasive spotted lanternfly, Lycorma delicatula, (White Hemiptera: Fulgoridae) continues to spread throughout the Eastern United States. This species exhibits a broad host range, with tree of heaven, Ailanthus altissima (Mill.) Swingle, commonly referred to as the preferred host. Here, we evaluated 2-wk survivorship of early nymphal instars, late nymphal instars, and adult L. delicatula on single diets of ten wild and cultivated hosts: tree of heaven; apple, Malus domestica; peach, Prunus persica; black cherry, P. serotina Ehrh; black locust, Robinia pseudoacacia L.; black walnut, Juglans nigra L.; common hackberry Celtis occidentalis L.; mulberry Morus alba L.; sugar maple Acer saccharum Marshall; white oak, Quercus alba L.. Among them, early and late instars had significantly greater survivorship on tree of heaven and black walnut and adults had greatest survivorship on tree of heaven. Additionally, we evaluated development and survivorship of L. delicatula from newly hatched nymphs to adulthood on single diets of tree of heaven, black walnut, grapevine, apple, and peach, and mixed diets of tree of heaven plus one other host. Single host diets that supported L. delicatula development to adulthood were tree of heaven and black walnut. Interestingly, mixed diets also supported development, and reduced development time to adults by up to 12% compared with the single tree of heaven diet. Our results suggest that within agroecosystems and across landscapes, L. delicatula can develop on single hosts such as tree of heaven, but also on multiple host plants, yielding adults earlier in the growing season., (Published by Oxford University Press on behalf of Entomological Society of America 2021.)

The dopamine transporter (DAT) mediates the inactivation of released dopamine (DA) through its reuptake, and thereby plays an important homeostatic role in dopaminergic neurotransmission. Amphetamines exert their stimulant effects by targeting DAT and inducing the reverse transport of DA, leading to a dramatic increase of extracellular DA. Animal models have proven critical to investigating the molecular and cellular mechanisms underlying transporter function and its modulation by psychostimulants such as amphetamine. Here we establish a behavioral model for amphetamine action using adult Drosophila melanogaster. We use it to characterize the effects of amphetamine on sleep and sleep architecture. Our data show that amphetamine induces hyperactivity and disrupts sleep in a DA-dependent manner. Flies that do not express a functional DAT (dDAT null mutants) have been shown to be hyperactive and to exhibit significantly reduced sleep at baseline. Our data show that, in contrast to its action in control flies, amphetamine decreases the locomotor activity of dDAT null mutants and restores their sleep by modulating distinct aspects of sleep structure. To begin to explore the circuitry involved in the actions of amphetamine on sleep, we also describe the localization of dDAT throughout the fly brain, particularly in neuropils known to regulate sleep. Together, our data establish Drosophila as a robust model for studying the regulatory mechanisms that govern DAT function and psychostimulant action., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Reproductive experience leads to long-lasting changes in anxiety-like behaviour and fear extinction, the laboratory model of exposure therapy for anxiety disorders. For example, fear extinction is influenced by estrous cycle in nulliparous (no reproductive experience) female rats, but this effect is abolished in primiparous (one reproductive experience) females. It is unclear whether such changes are driven by pregnancy, maternal experience of caring for offspring during the postpartum period, or a combination of both experiences. The present study sought to determine the influence of maternal experience (i.e., exposure to pups and mother-pup interactions) on fear extinction in primiparous rats. In Experiment 1, we tested whether pup exposure is necessary to mitigate estrous effects on fear extinction in primiparous rats. Age-matched nulliparous rats, primiparous rats, and primiparous rats who experienced pregnancy but not pup exposure, underwent fear conditioning on day 1 (2 months post-parturition), extinction training during proestrus (high sex hormones) or metestrus (low sex hormones) on day 2, and extinction recall on day 3. Replicating past research, nulliparous rats showed impaired extinction recall when they were extinguished during metestrus compared to proestrus. In contrast, primiparous rats with and without pup exposure showed comparable extinction recall irrespective of estrous phase. In Experiment 2, we assessed whether naturally-occurring variation in mother-pup interactions predict future fear extinction performance and anxiety-like behaviour. During the first week of lactation, primiparous rats were measured for maternal behaviours toward pups. Primiparous rats were then tested on the light-dark box and elevated plus maze to measure anxiety-like behaviour and underwent a fear extinction protocol 1 month post-weaning. We found no significant correlations between maternal behaviour and fear extinction outcomes or anxiety-like behaviour. Our findings suggest that pregnancy, not maternal experience, mitigates the impact of estrous cycle on fear extinction. In addition, natural variation in maternal experience does not appear to contribute to variability in future fear extinction outcomes or anxiety-like behaviour in primiparous rats., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pestana, McCutcheon, Harmon-Jones, Richardson and Graham.)

Ecological forecasts will be best suited to inform intervention strategies if they are accessible to a diversity of decision-makers. Researchers are developing intuitive forecasting interfaces to guide stakeholders through the development of intervention strategies and visualization of results. Yet, few studies to date have evaluated how user interface design facilitates the coordinated, cross-boundary management required for controlling biological invasions. We used a participatory approach to develop complementary tangible and online interfaces for collaboratively forecasting biological invasions and devising control strategies. A diverse group of stakeholders evaluated both systems in the real-world context of controlling sudden oak death, an emerging forest disease killing millions of trees in California and Oregon. Our findings suggest that while both interfaces encouraged adaptive experimentation, tangible interfaces are particularly well suited to support collaborative decision-making. Reflecting on the strengths of both systems, we suggest workbench-style interfaces that support simultaneous interactions and dynamic geospatial visualizations., (© 2021 The Authors. Ecological Applications published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)