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Abstract The Scibar Cosmic-Ray Telescope (SciCRT) is the most promising detector of the Sierra Negra Cosmic Rays Observatory (SN-CRO). At this location, being a target and a tracker of secondary cosmic rays, the SciCRT offers a high probability of observing solar energetic particles and lower energy galactic cosmic rays (LEGCR); also, it allows the identification of incoming particles by measuring their energy deposition. In this work we present a Geant4-based simulation of the energy deposited by neutrons, $$\gamma $$ γ -rays, protons, electrons and muons in the optimally running SciCRT components. We also calculated the detection efficiency of the SciCRT at its current state. Our simulation results provide new information about the SciCRT detection response that may be used as a basis to estimate and analyze the energy spectra of primary particles.

Abstract The Permo-Triassic mass extinction was linked to catastrophic environmental changes and large igneous province (LIP) volcanism. In addition to the widespread marine losses, the Permo–Triassic event was the most severe terrestrial ecological crisis in Earth’s history and the only known mass extinction among insects, but the cause of extinction on land remains unclear. In this study, high-resolution Hg concentration records and multiple-archive S-isotope analyses of sediments from the Junggar Basin (China) provide evidence of repeated pulses of volcanic-S (acid rain) and increased Hg loading culminating in a crisis of terrestrial biota in the Junggar Basin coeval with the interval of LIP emplacement. Minor S-isotope analyses are, however, inconsistent with total ozone layer collapse. Our data suggest that LIP volcanism repeatedly stressed end-Permian terrestrial environments in the ~300 kyr preceding the marine extinction locally via S-driven acidification and deposition of Hg, and globally via pulsed addition of CO2.

Procedural flexibility is an important skill for algebra. Although prior work has focused on measuring students' procedural flexibility using arithmetic problems, word problems may also capture students' flexibility because of their open-ended nature. To date, no published study has examined the use of word problems as another measure of procedural flexibility. The present study aims to establish flexibility on fraction word problems as a predictor of algebra learning and to determine whether flexibility demonstrated on fraction arithmetic versus fraction word problems differentially predicts two types of algebra learning (e.g., algebraic feature knowledge and algebra equation-solving). Middle-school students (N = 350) completed fraction arithmetic problems, fraction word problems, and algebra measures at the start and end of the school year. We coded fraction arithmetic and word problems for demonstrated procedural flexibility. Path models showed that overall flexibility significantly predicted both algebraic feature knowledge and equation-solving. When examining flexibility by type, procedural flexibility on arithmetic problems significantly predicted end-of-year algebraic feature knowledge and algebra equation-solving, whereas procedural flexibility on word problems significantly predicted algebraic feature knowledge. Procedural flexibility on arithmetic problems was still predictive of performance when accounting for fraction magnitude skill. These findings build on prior literature that establishes procedural flexibility as a crucial predictor of algebra learning and extends measures of procedural flexibility to include word problems.

Despite the documented influence of motivation on mathematics learning for most students, we understand far less about this relation for students identified with learning disabilities. Based on Rogoff's three planes of analysis (i.e., personal, community, and interpersonal), we gathered survey, interview, and video data to understand the motivations of sixth graders in a special education mathematics classroom as well as classroom conditions that supported motivation during a unit on fractions. By the end of that unit, students reported improved ability beliefs and attributed the changes to increased conceptual understanding of fractions, exposure to strategies for sense making, and the additional time and assistance provided to them. Through video analysis, we also found that having students verbalize their thinking about the mathematics can provide opportunities to identify remediation needs and thus support productive participation and positive ability beliefs. These findings highlight the motivational value of effective mathematics instruction for students with learning disabilities.

Biological invasions are one of the main drivers of global biodiversity decline. At the same time, glacial retreat induced by climate warming is occurring at an alarming rate across the globe, threatening unique taxa and ecosystems. However, we know little about how introduced species contribute to the dynamics of colonisation in newly-deglaciated forelands. To answer this question, detailed inventories of plant and invertebrate communities were undertaken during two summer field seasons in the forelands of three tidewater and three inland glaciers that are retreating on the sub-Antarctic Island of South Georgia. The vascular plant communities present included a large proportion of South Georgia’s native flora. As expected, plant richness and cover increased with time since deglaciation along a deglaciation chronosequence. Introduced plants were well represented in the study sites and two species (Poa annua and Cerastium fontanum) were amongst the earliest and most frequent colonisers of recently-deglaciated areas (occurring on more than 75% of transects surveyed). Introduced arthropods were also present around tidewater glaciers, including an important predatory species (Merizodus soledadinus) with known detrimental impacts on native invertebrate communities. Our study provides a rare and detailed picture of developing novel communities along a deglaciation chronosequence in the sub-Antarctic. Introduced species are able to track glacial retreat on South Georgia, indicating that further local colonisation and spread are inevitable as the region’s climate continues to warm.

In seasonal environments conception is timed such that offspring are born at the peak of resource abundance. Although largely determined by photoperiod, reproductive timing can also be modulated by fluctuating environmental conditions. Some studies show that reproduction is occurring earlier, coinciding with an earlier spring as the climate warms. A failure to synchronize parturition with the advancing spring flush of resources can lower reproductive fitness; on the other hand, a longer growing season could be beneficial to some species. We asked whether breeding phenology of white-tailed deer (Odocoileus virginianus) has changed with changing environmental conditions. Using 29 years of wildlife motor-vehicle accident data (1988–2016) as an index of deer rut behaviour in southern Ontario, Canada, we assessed four deer management areas (DMAs) to determine: 1) whether timing of the white-tailed deer rut has changed; 2) whether the growing season has changed; and 3) whether changes in growing season and rut are correlated. We found that in the southwestern-most DMA the peak of the rut is 9 days earlier than in the northeastern-most DMA. The peak of the rut did not change over three decades. We detected an increase in the number of growing degree days, signifying both an earlier start to spring green-up and a later end to fall. The trend toward a longer growing season could have positive impacts on deer populations throughout the province.

Drilling for the International Continental Scientific Drilling Program (ICDP) Early Jurassic Earth System and Timescale project (JET) was undertaken between October 2020 and January 2021. The drill site is situated in a small-scale synformal basin of the latest Triassic to Early Jurassic age that formed above the major Permian–Triassic half-graben system of the Cheshire Basin. The borehole is located to recover an expanded and complete succession to complement the legacy core from the Llanbedr (Mochras Farm) borehole drilled through 1967–1969 on the edge of the Cardigan Bay Basin, North Wales. The overall aim of the project is to construct an astronomically calibrated integrated timescale for the Early Jurassic and to provide insights into the operation of the Early Jurassic Earth system. Core of Quaternary age cover and Early Jurassic mudstone was obtained from two shallow partially cored geotechnical holes (Prees 2A to 32.2 m below surface (m b.s.) and Prees 2B to 37.0 m b.s.) together with Early Jurassic and Late Triassic mudstone from the principal hole, Prees 2C, which was cored from 32.92 to 651.32 m (corrected core depth scale). Core recovery was 99.7 % for Prees 2C. The ages of the recovered stratigraphy range from the Late Triassic (probably Rhaetian) to the Early Jurassic, Early Pliensbachian (Ibex Ammonoid Chronozone). All ammonoid chronozones have been identified for the drilled Early Jurassic strata. The full lithological succession comprises the Branscombe Mudstone and Blue Anchor formations of the Mercia Mudstone Group, the Westbury and Lilstock formations of the Penarth Group, and the Redcar Mudstone Formation of the Lias Group. A distinct interval of siltstone is recognized within the Late Sinemurian of the Redcar Mudstone Formation, and the name “Prees Siltstone Member” is proposed. Depositional environments range from playa lake in the Late Triassic to distal offshore marine in the Early Jurassic. Initial datasets compiled from the core include radiography, natural gamma ray, density, magnetic susceptibility, and X-ray fluorescence (XRF). A full suite of downhole logs was also run. Intervals of organic carbon enrichment occur in the Rhaetian (Late Triassic) Westbury Formation and in the earliest Hettangian and earliest Pliensbachian strata of the Redcar Mudstone Formation, where up to 4 % total organic carbon (TOC) is recorded. Other parts of the succession are generally organic-lean, containing less than 1 % TOC. Carbon-isotope values from bulk organic matter have also been determined, initially at a resolution of ∼ 1 m, and these provide the basis for detailed correlation between the Prees 2 succession and adjacent boreholes and Global Stratotype Section and Point (GSSP) outcrops. Multiple complementary studies are currently underway and preliminary results promise an astronomically calibrated biostratigraphy, magnetostratigraphy, and chemostratigraphy for the combined Prees and Mochras successions as well as insights into the dynamics of background processes and major palaeo-environmental changes.

Despite its importance to everyday functioning, reasoning is underexplored in developmental dyslexia. The current study investigated verbal deductive reasoning on the Wason selection task, not previously used in dyslexia research despite its well-established pedigree. Reasoning rule was manipulated, with the conditional rules varying in the logical values presented. The word frequency and imageability of the word terms was also manipulated. Twenty-six adults with dyslexia and 31 adults without dyslexia completed Wason selection task problems. No group difference in reasoning accuracy or completion time was found. However, the participants were most accurate when reasoning with the rule type “If p, then not q” and least accurate with the rule type “If p then q”. More trials were also answered correctly when the word terms were highly imageable but of average word frequency. These findings are in line with the general reasoning literature. Dyslexia status did not interact with either rule type or word term type. The study expands upon previous research by testing verbal deductive reasoning in dyslexia, highlighting the role of imageability in facilitating reasoning performance for all, regardless of the presence or absence of dyslexia. Implications for the design of educational materials are considered.

Introduction The benefits of exercise in reducing treatment-related morbidity and improving quality of life following a primary diagnosis of cancer have been well documented and have led to exercise being recommended by oncology societies for all people with a cancer diagnosis. However, these recommendations are derived from research typically involving cohorts with more common cancers and relatively good prognosis, such as breast and prostate. Evidence from these cancers may not apply to women with recurrent ovarian cancer. Therefore, the primary objective of this trial is to evaluate the feasibility and safety of a home-based, telephone-delivered exercise intervention for women undergoing chemotherapy for recurrent ovarian cancer.Methods and analysis The Exercise During Chemotherapy for Recurrent Ovarian Cancer (ECHO-R) trial is a single-arm, phase II, pre/postintervention trial of a 6-month, telephone-delivered exercise intervention (consistent with recommended exercise oncology prescription). The target sample size is 80 women who are currently undergoing (or are scheduled to receive) chemotherapy for recurrent ovarian cancer. Recruitment is through participating hospital sites in Queensland, Australia, or via self-referral. The exercise intervention comprises 12 telephone sessions over a 6-month period delivered by trial-trained exercise professionals and supplemented (where feasible) by five sessions face to face. Exercise prescription is individualised and works towards an overall goal of achieving a weekly target of 150 min of moderate-intensity, mixed-mode exercise. Assessments via self-administered survey and physical fitness and function tests occur at baseline and then at 6 and 9 months postbaseline. Data to inform feasibility and safety are recorded as case notes by the exercise professional during each session.Ethics and dissemination Ethics approval for the ECHO-R trial was granted by the Metro North Human Research Ethics Committee (HREC/2020/QRBW/67223) on 6 November 2020. Findings from the trial are planned to be disseminated via peer-reviewed publications and both national and international exercise and oncology conferences.Trial registration number ACTRN12621000042842.

The expansion of copper mining on the hyper-arid pacific slope of Southern Peru has precipitated growing concern for scarce water resources in the region. Located in the headwaters of the Torata river, in the department of Moquegua, the Cuajone mine, owned by Southern Copper, provides a unique opportunity in a little-studied region to examine the relative impact of the landscape-scale mining on water resources in the region. Principal component and cluster analyses of the water chemistry data from 16 sites, collected over three seasons during 2017 and 2018, show distinct statistical groupings indicating that, above the settlement of Torata, water geochemistry is a function of chemical weathering processes acting upon underlying geological units, and confirming that the Cuajone mine does not significantly affect water quality in the Torata river. Impact mitigation strategies that firstly divert channel flow around the mine and secondly divert mine waste to the Toquepala river and tailings dam at Quebrada Honda remove the direct effects on the water quality in the Torata river for the foreseeable future. In the study area, our results further suggest that water quality has been more significantly impacted by urban effluents and agricultural runoff than the Cuajone mine. The increase in total dissolved solids in the waters of the lower catchment reflects the cumulative addition of dissolved ions through chemical weathering of the underlying geological units, supplemented by rapid recharge of surface waters contaminated by residues associated with agricultural and urban runoff through the porous alluvial aquifer. Concentrations in some of the major ions exceeded internationally recommended maxima for agricultural use, especially in the coastal region. Occasionally, arsenic and manganese contamination also reached unsafe levels for domestic consumption. In the lower catchment, below the Cuajone mine, data and multivariate analyses point to urban effluents and agricultural runoff rather than weathering of exposed rock units, natural or otherwise, as the main cause of contamination.

ABSTRACT Corrosion inhibitors, including zinc orthophosphate, sodium orthophosphate, and sodium silicate, are commonly used to prevent the corrosion of drinking water infrastructure. Metals such as zinc are known stressors for antibiotic resistance selection, and phosphates can increase microbial growth in drinking water distribution systems (DWDS). Yet, the influence of corrosion inhibitor type on antimicrobial resistance in DWDS is unknown. Here, we show that sodium silicates can decrease antibiotic resistant bacteria (ARB) and antibiotic-resistance genes (ARGs), while zinc orthophosphate increases ARB and ARGs in source water microbial communities. Based on controlled bench-scale studies, zinc orthophosphate addition significantly increased the abundance of ARB resistant to ciprofloxacin, sulfonamides, trimethoprim, and vancomycin, as well as the genes sul1, qacEΔ1, an indication of resistance to quaternary ammonium compounds, and the integron-integrase gene intI1. In contrast, sodium silicate dosage at 10 mg/L resulted in decreased bacterial growth and antibiotic resistance selection compared to the other corrosion inhibitor additions. Source water collected from the drinking water treatment plant intake pipe resulted in less significant changes in ARB and ARG abundance due to corrosion inhibitor addition compared to source water collected from the pier at the recreational beach. In tandem with the antibiotic resistance shifts, significant microbial community composition changes also occurred. Overall, the corrosion inhibitor sodium silicate resulted in the least selection for antibiotic resistance, which suggests it is the preferred corrosion inhibitor option for minimizing antibiotic resistance proliferation in DWDS. However, the selection of an appropriate corrosion inhibitor must also be appropriate for the water chemistry of the system (e.g., pH, alkalinity) to minimize metal leaching first and foremost and to adhere to the lead and copper rule. IMPORTANCE Antibiotic resistance is a growing public health concern across the globe and was recently labeled the silent pandemic. Scientists aim to identify the source of antibiotic resistance and control points to mitigate the spread of antibiotic resistance. Drinking water is a direct exposure route to humans and contains antibiotic-resistant bacteria and associated resistance genes. Corrosion inhibitors are added to prevent metallic pipes in distribution systems from corroding, and the type of corrosion inhibitor selected could also have implications on antibiotic resistance. Indeed, we found that sodium silicate can minimize selection of antibiotic resistance while phosphate-based corrosion inhibitors can promote antibiotic resistance. These findings indicate that sodium silicate is a preferred corrosion inhibitor choice for mitigation of antibiotic resistance.

Abstract Biological invasions represent a growing threat to islands and their biodiversity across the world. The isolated sub‐Antarctic island of South Georgia in the South Atlantic Ocean is a highly protected area that relies on effective biosecurity including prevention, surveillance and eradication to limit the risk of biological invasions. Based on an opportunistic field discovery, we provide the first report of an introduced ladybird beetle on South Georgia. All specimens discovered belong to the Eurasian species Coccinella undecimpunctata Linnaeus (1758) (Coleoptera: Coccinellidae). Tens of individuals of both sexes were discovered at a single location, indicating that the species may already be established on South Georgia. Transport connectivity with this site suggests that the species most likely arrived recently from the Falkland Islands as a stowaway on a ship. We discuss the implications of our discovery for the continued development of South Atlantic biosecurity.

There is a lack of FDA-approved tocolytics for the management of preterm labor (PL). In prior drug discovery efforts, we identified mundulone and mundulone acetate (MA) as inhibitors of in vitro intracellular Ca2+-regulated myometrial contractility. In this study, we probed the tocolytic potential of these compounds using human myometrial samples and a mouse model of preterm birth. In a phenotypic assay, mundulone displayed greater efficacy, while MA showed greater potency and uterine-selectivity in the inhibition of intracellular-Ca2+ mobilization. Cell viability assays revealed that MA was significantly less cytotoxic. Organ bath and vessel myography studies showed that only mundulone exerted inhibition of myometrial contractions and that neither compounds affected vasoreactivity of ductus arteriosus. A high-throughput combination screen identified that mundulone exhibits synergism with two clinical-tocolytics (atosiban and nifedipine), and MA displayed synergistic efficacy with nifedipine. Of these combinations, mundulone+atosiban demonstrated a significant improvement in the in vitro therapeutic index compared to mundulone alone. The ex vivo and in vivo synergism of mundulone+atosiban was substantiated, yielding greater tocolytic efficacy and potency on myometrial tissue and reduced preterm birth rates in a mouse model of PL compared to each single agent. Treatment with mundulone after mifepristone administration dose-dependently delayed the timing of delivery. Importantly, mundulone+atosiban permitted long-term management of PL, allowing 71% dams to deliver viable pups at term (>day 19, 4–5 days post-mifepristone exposure) without visible maternal and fetal consequences. Collectively, these studies provide a strong foundation for the development of mundulone as a single or combination tocolytic for management of PL.

The Pliocene-Recent is associated with many important climatic and paleoceanographic changes, which have shaped the biotic and abiotic nature of the modern world. The closure of the Central American Seaway and the development and intensification of Northern Hemisphere ice sheets had profound global impacts on the latitudinal and vertical structure of the oceans, triggering the extinction and radiation of many marine groups. In particular, marine calcifying planktonic foraminifera, which are highly sensitive to water column structure, exhibited a series of extinctions as global temperatures fell. By analyzing high-resolution (∼ 5 kyr) sedimentary records from the Eastern Equatorial Pacific Ocean, complemented with global records from the novel Triton dataset, we document the biotic changes in this microfossil group, within which three species displayed isochronous co-extinction, and species with cold-water affinity increased in dominance as meridional temperature gradients steepened. We suggest that these changes were associated with the terminal stages of the closure of the Central American Seaway, where following the sustained warmth of the mid-Pliocene Warm Period, bipolar ice sheet expansion initiated a world in which cold- and deep-dwelling species became increasingly more successful. Such global-scale paleoecological and macroevolutionary variations between the Pliocene and the modern icehouse climate would suggest significant deviations from pre-industrial baselines within modern and future marine plankton communities as anthropogenic climate forcing continues.

Staphylococcus aureus infections are associated with high mortality rates. Often considered an extracellular pathogen, S. aureus can persist and replicate within host cells, evading immune responses, and causing host cell death. Classical methods for assessing S. aureus cytotoxicity are limited by testing culture supernatants and endpoint measurements that do not capture the phenotypic diversity of intracellular bacteria. Using a well-established epithelial cell line model, we have developed a platform called InToxSa (intracellular toxicity of S. aureus) to quantify intracellular cytotoxic S. aureus phenotypes. Studying a panel of 387 S. aureus bacteraemia isolates, and combined with comparative, statistical, and functional genomics, our platform identified mutations in S. aureus clinical isolates that reduced bacterial cytotoxicity and promoted intracellular persistence. In addition to numerous convergent mutations in the Agr quorum sensing system, our approach detected mutations in other loci that also impacted cytotoxicity and intracellular persistence. We discovered that clinical mutations in ausA, encoding the aureusimine non-ribosomal peptide synthetase, reduced S. aureus cytotoxicity, and increased intracellular persistence. InToxSa is a versatile, high-throughput cell-based phenomics platform and we showcase its utility by identifying clinically relevant S. aureus pathoadaptive mutations that promote intracellular residency.

Antibiotic resistance remains one of the most pressing public health issues facing the world today. At the forefront of this battle lies the ever-increasing identification of extended-spectrum beta-lactamases and carbapenemases within human pathogens, conferring resistance towards broad-spectrum and last-resort antimicrobials. This study was prompted due to the identification of a pathogenic Aeromonas hydrophila isolate (strain MAH-4) collected from abdominal fluid, which presented a robust resistance pattern against second-, third-, and fourth-generation cephalosporins, ertapenem, ciprofloxacin, gentamicin, levofloxacin and moxifloxacin, and beta lactam/beta-lactamase inhibitor combinations. Whole genome sequencing was performed and identified a 328 kb plasmid (pMAH4) encoding 10 antibiotic resistance genes, including blaSFO-1, blaTEM-1, and blaOXA-1 of A. hydrophia MAH-4. This is the first report of beta-lactamase SFO-1 within a clinical strain of Aeromonas. Due to the remarkable sequence identity of pMAH4 to plasmids associated with Enterobacterales genera like Klebsiella and the extensive capabilities of Aeromonas for horizontal gene transfer, our identification of a clinical isolate encoding SFO-1 on a plasmid suggests antibiotic resistance gene mobility between Enterobacterales and non-Enterobacterales species.

Microplastics are emergent contaminants threatening aquatic organisms including aquacultured fish. This study investigated the effects of high-density polyethylene (HDPE, 100 to 125 μm) on yellow perch (Perca flavescens) based on integrative evaluation including growth performance, nutritional status, nutrient metabolism, fish health, and gut microbial community. Five test diets (0, 1, 2, 4, or 8 g HDPE/100 g diet) containing 41% protein and 10.5% lipid were fed to juvenile perch (average body weight, 25.9 ± 0.2 g; n = 15) at a feeding rate of 1.5% to 2.0% body weight daily. The feeding trial was conducted in a flow-through water system for 9 wk with 3 tanks per treatment and 15 yellow perch per tank. No mortality or HDPE accumulation in the fish was found in any treatments. Weight gain and condition factor of fish were not significantly impacted by HDPE (P > 0.05). Compared to the control group, fish fed the 8% HDPE diet had significantly decreased levels of protein and ash (P

Prior research has shown that the home learning environment (HLE) is critical in the development of spatial skills and that various parental beliefs influence the HLE. However, a comprehensive analysis of the impact of different parental beliefs on the spatial HLE remains lacking, leaving unanswered questions about which specific parental beliefs are most influential and whether inducing a growth mindset can enhance the spatial HLE. To address these gaps, we conducted an online study with parents of 3- to 5-year-olds. We found that parents’ growth mindset about their children’s ability strongly predicted the spatial HLE after controlling for parents’ motivational beliefs about their children, beliefs about their own ability, children’s age, children’s gender, and family SES. Further, reading an article about growth mindset led parents to choose more challenging spatial learning activities for their children. These findings highlight the critical role of parents’ growth mindset in the spatial HLE. Crucially, these findings demonstrate that general growth mindset messages without specific suggestions for parental practices can influence parental behavior intentions. Further, these effects were also observed in the control domain of literacy, underscoring the broad relevance of the growth mindset in the HLE.

BackgroundRegular physical activity is important for arthritis self-management and could be promoted through tailoring community leisure and fitness centers' customer-relationship management (CRM) strategies.ObjectivesThis study investigates the influence of two CRM strategies on individuals with arthritis reaching or maintaining two moderate-to-vigorous physical activity (MVPA) thresholds (≥150 and ≥45 minutes/week) from baseline-to-12 months and 12-to-24 months as well as mean changes in total minutes/week of MVPA. It also explores time-dependent variations in the influence of socio-cognitive variables on MVPA outcomes.MethodsSurvey data from 374 participants with arthritis in a two-year randomized controlled trial (control versus two CRM strategies: IncentiveOnly and Incentive+Support) were used. Participants reported measures of physical activity participation, socio-cognitive decision-making, mental and physical wellbeing, friendship, community connectedness, sense of trust in others, and demographics.Findings/discussionReceiving the Incentive+Support CRM strategy (versus control) increased participants' likelihood of reaching/maintaining both physical activity thresholds from 12-to-24 months (≥150 MVPA minutes/week, p < .001; ≥45 MVPA minutes/week, p < .032) but not from baseline-to-12 months. However, receiving the IncentiveOnly CRM strategy (versus control) did not predict reaching/maintaining these thresholds. Importantly, socio-cognitive decision-making variables' influence on reaching/maintaining these MVPA thresholds varied over time, suggesting CRM strategies may require further tailoring based on time-specific profiles. Perhaps because of new facility induced excitement, the mean change in total MVPA minutes/week for the control group significantly increased (26.8 minute/week, p = .014, 95% CI [5.5, 48.0]) from baseline-to-12 months, but subsequently declined by 11.4 minute/week from 12-to-24 months (p = .296, 95% CI [-32.7, 9.9]). Mean changes in total MVPA minutes/week were non-significant for those receiving IncentiveOnly content but significant for those receiving Incentive+Support content: baseline-to-12 months (38.2 minute/week increase, p = .023, 95% CI [4.9, 71.4]) and baseline-to-24-months (45.9 minute/week increase, p = .007, 95% CI [12.7, 79.1]).

BackgroundAlthough fieldwork supervisors and culturally and linguistically diverse (CALD) students can experience challenges during allied health placements, there is little holistic understanding of how they view and use support resources to address these challenges. This study sought to identify, codify, and map the perceived value attached to support resources used or sought by CALD students and fieldwork supervisors and to ascertain areas where they could be optimised and better presented to users.MethodsWe conducted a thematic analysis to examine interview and open-ended survey responses from CALD students (n = 18) and fieldwork supervisors (n = 161) respectively.FindingsThe six generated themes depicted different patterns of perceived value in university and non-university support resources and spanned three levels of specificity: general, discipline-contextualised, and individualised. Fieldwork supervisors valued a staged approach to support resource design and use for CALD students commencing with general level resources to build foundational language skills and socio-cultural familiarisation and moving on to include disciple-contextualised supports, preplacement mechanisms to monitor student readiness, and formalised mechanisms to enable tailoring of placements. CALD students, however, often undervalued institutional general resources relative to discipline-contextualised resources. The commonality of support resources valued and sought by supervisors from different fields suggests they could be optimised for delivery via an inter-professional community of practice.ConclusionIdentifying and mapping the perceived value attached to support resources provides actionable insights into how to enhance the 'fit' between resources and user needs. Drawing the often-fragmented support resources into a cohesive ecosystem focused around perceived value at different levels of specificity allows CALD students and educators to better conceptualise the types of benefits that can accrue from taking a broader and staged approach to fieldwork placement preparations. Knowing this ecosystem encapsulates what prior uses find of value may enhance perceptions of resource relevance in the minds of new users.

Abstract Invasive wild pigs (Sus scrofa) are considered one of the most damaging species globally, and once they become established in an area, they are notoriously difficult to eliminate. As such, identifying the potential pathways of invasion, especially in places with emerging populations, is critical for preventing new or continued invasion. Wild pigs have been reported in Ontario, Canada, in recent years. We tested four nonexclusive hypotheses about the source of wild pigs in Ontario: (a) escapees from captive sources within Ontario; (b) invasion from neighboring jurisdictions; (c) existing wild populations within Ontario; and (d) translocation and illegal release. We found that sightings of Eurasian wild boar were closer to premises with wild boar than were random locations; wild boar sightings were an average of 16.3 km (SD = 25.4 km, min = 0.2 km, n = 20) from premises with wild boar. We also found that sightings of domestic pigs were closer to domestic pig farms than expected. Sightings of wild pigs in groups of more than four animals were rare. Our results suggest that wild pigs observed in Ontario are recent escapes from captivity, recognizing that there may be established groups of wild pigs that we have not yet detected. While not common, we also received reports indicating that in the past, wild pigs have been translocated and illegally released. Other North American jurisdictions that have been successful at eliminating wild pigs have removed existing populations and changed regulations to limit future invasion, such as prohibiting possession and transport of wild boar and prohibiting hunting of wild pigs.

Global climate changes triggered by massive output of greenhouse gases led to mass extinctions in Earth’s past. Here, the authors show that widespread release of methane at the time of the end-Triassic mass extinction was caused by interaction of a Large Igneous Province with sedimentary host-rocks.

BackgroundMechanisms contributing to tissue remodeling of the infarcted heart following cell-based therapy remain elusive. While cell-based interventions have the potential to influence the cardiac healing process, there is little direct evidence of preservation of functional myocardium.AimThe aim of the study was to investigate tissue remodeling in the infarcted heart following human embryonic stem cell-derived endothelial cell product (hESC-ECP) therapy.Materials and methodsFollowing coronary artery ligation (CAL) to induce cardiac ischemia, we investigated infarct size at 1 day post-injection in media-injected controls (CALM, n = 11), hESC-ECP-injected mice (CALC, n = 10), and dead hESC-ECP-injected mice (CALD, n = 6); echocardiography-based functional outcomes 14 days post-injection in experimental (CALM, n = 13; CALC, n = 17) and SHAM surgical mice (n = 4); and mature infarct size (CALM and CALC, both n = 6). We investigated ligand–receptor interactions (LRIs) in hESC-ECP cell populations, incorporating a publicly available C57BL/6J mouse cardiomyocyte-free scRNAseq dataset with naive, 1 day, and 3 days post-CAL hearts.ResultsHuman embryonic stem cell-derived endothelial cell product injection reduces the infarct area (CALM: 54.5 ± 5.0%, CALC: 21.3 ± 4.9%), and end-diastolic (CALM: 87.8 ± 8.9 uL, CALC: 63.3 ± 2.7 uL) and end-systolic ventricular volume (CALM: 56.4 ± 9.3 uL, CALC: 33.7 ± 2.6 uL). LRI analyses indicate an alternative immunomodulatory effect mediated via viable hESC-ECP-resident signaling.ConclusionDelivery of the live hESC-ECP following CAL modulates the wound healing response during acute pathological remodeling, reducing infarct area, and preserving functional myocardium in this relatively acute model. Potential intrinsic myocardial cellular/hESC-ECP interactions indicate that discreet immunomodulation could provide novel therapeutic avenues to improve cardiac outcomes following myocardial infarction.

Abstract Extinction rates in the modern world are currently at their highest in 66 million years and are likely to increase with projections of future climate change. Our knowledge of modern-day extinction risk is largely limited to decadal-centennial terrestrial records, while data from the marine realm is typically applied to high-order (> 1 million year) timescales. At present, it is unclear whether fossil organisms with common ancestry and ecological niche exhibit consistent indicators of ecological stress prior to extinction. The marine microfossil record, specifically that of the planktonic foraminifera, allows for high-resolution analyses of large numbers of fossil individuals with incredibly well-established ecological and phylogenetic history. Here, analysis of the isochronous extinction of two members of the planktonic foraminiferal genus Dentoglobigerina shows disruptive selection differentially compounded by permanent ecological niche migration, “pre-extinction gigantism”, and photosymbiont bleaching prior to extinction. Despite shared ecological and phylogenetic affinity, and timing of extinction, the marked discrepancies observed within the pre-extinction phenotypic responses are species-specific. These behaviours may provide insights into the nature of evolution and extinction in the open ocean and can potentially assist in the recognition and understanding of marine extinction risk in response to global climate change.

ObjectiveChildren with developmental disabilities are associated with a high risk of poor school enrollment and educational attainment without timely and appropriate support. Epidemiological data on cerebral palsy and associated comorbidities required for policy intervention in global health are lacking. This paper set out to report the best available evidence on the global and regional prevalence of cerebral palsy (CP) and developmental intellectual disability and the associated “years lived with disability” (YLDs) among children under 5 years of age in 2019.MethodsWe analyzed the collaborative 2019 Rehabilitation Database of the Global Burden of Disease (GBD) Study and World Health Organization for neurological and mental disorders available for 204 countries and territories. Point prevalence and YLDs with 95% uncertainty intervals (UI) are presented.ResultsGlobally, 8.1 million (7.1–9.2) or 1.2% of children under 5 years are estimated to have CP with 16.1 million (11.5–21.0) or 2.4% having intellectual disability. Over 98% resided in low-income and middle-income countries (LMICs). CP and intellectual disability accounted for 6.5% and 4.5% of the aggregate YLDs from all causes of adverse health outcomes respectively. African Region recorded the highest prevalence of CP (1.6%) while South-East Asia Region had the highest prevalence of intellectual disability. The top 10 countries accounted for 57.2% of the global prevalence of CP and 62.0% of the global prevalence of intellectual disability.ConclusionBased on this Database, CP and intellectual disability are highly prevalent and associated with substantial YLDs among children under 5 years worldwide. Universal early detection and support services are warranted, particularly in LMICs to optimize school readiness for these children toward inclusive education as envisioned by the United Nations' Sustainable Development Goals.

ABSTRACT Microbes have inhabited the oceans and soils for millions of years and are uniquely adapted to their habitat. In contrast, sewer infrastructure in modern cities dates back only ~150 years. Sewer pipes transport human waste and provide a view into public health, but the resident organisms that likely modulate these features are relatively unexplored. Here, we show that the bacterial assemblages sequenced from untreated wastewater in 71 U.S. cities were highly coherent at a fine sequence level, suggesting that urban infrastructure separated by great spatial distances can give rise to strikingly similar communities. Within the overall microbial community structure, temperature had a discernible impact on the distribution patterns of closely related amplicon sequence variants, resulting in warm and cold ecotypes. Two bacterial genera were dominant in most cities regardless of their size or geographic location; on average, Arcobacter accounted for 11% and Acinetobacter 10% of the entire community. Metagenomic analysis of six cities revealed these highly abundant resident organisms carry clinically important antibiotic resistant genes blaCTX-M, blaOXA, and blaTEM. In contrast, human fecal bacteria account for only ~13% of the community; therefore, antibiotic resistance gene inputs from human sources to the sewer system could be comparatively small, which will impact measurement capabilities when monitoring human populations using wastewater. With growing awareness of the metabolic potential of microbes within these vast networks of pipes and the ability to examine the health of human populations, it is timely to increase our understanding of the ecology of these systems. IMPORTANCE Sewer infrastructure is a relatively new habitat comprised of thousands of kilometers of pipes beneath cities. These wastewater conveyance systems contain large reservoirs of microbial biomass with a wide range of metabolic potential and are significant reservoirs of antibiotic resistant organisms; however, we lack an adequate understanding of the ecology or activity of these communities beyond wastewater treatment plants. The striking coherence of the sewer microbiome across the United States demonstrates that the sewer environment is highly selective for a particular microbial community composition. Therefore, results from more in-depth studies or proven engineering controls in one system could be extrapolated more broadly. Understanding the complex ecology of sewer infrastructure is critical for not only improving our ability to treat human waste and increasing the sustainability of our cities but also to create scalable and effective sewage microbial observatories, which are inevitable investments of the future to monitor health in human populations.

Abstract Various methods exist to monitor wildlife populations and estimate trends in their distribution and abundance. For American beaver (Castor canadensis), aerial surveys provide a means to obtain abundance data over large areas and typically involve observers searching watercourses and shorelines for active beaver presence. Here, we describe a systematic aerial photographic census we designed and executed in autumn to quantify annual beaver colony abundance on the 184‐km2 Michipicoten Island, Ontario, from 2015 to 2019. Aerial photographs were stitched together into orthophotomosaics after each census and visually searched for beaver food caches, with each food cache representing an independent beaver colony. Our methods revealed that beaver colony abundance declined substantially from a peak of 6.1 colonies/km2 in 2015, the highest reported across North America, to 0.4 colonies/km2 in 2018. Beaver abundance remained low through 2019. Although photographing the entire isolated study area required relatively little time and effort, even when beaver density was very high, post‐census processing work was time‐consuming. Lessons learned will improve efficiencies of our future censuses and aid other researchers. Our method is advantageous over traditional aerial wildlife surveys in that it provides a digital and visual record that can be used for additional analyses.

ABSTRACT Microbial nitrification is a critical process governing nitrogen availability in aquatic systems. Freshwater nitrifiers have received little attention, leaving many unanswered questions about their taxonomic distribution, functional potential, and ecological interactions. Here, we reconstructed genomes to infer the metabolism and ecology of free-living picoplanktonic nitrifiers across the Laurentian Great Lakes, a connected series of five of Earth’s largest lakes. Surprisingly, ammonia-oxidizing bacteria (AOB) related to Nitrosospira dominated over ammonia-oxidizing archaea (AOA) at nearly all stations, with distinct ecotypes prevailing in the transparent, oligotrophic upper lakes compared to Lakes Erie and Ontario. Unexpectedly, one ecotype of Nitrosospira encodes proteorhodopsin, which could enhance survival under conditions where ammonia oxidation is inhibited or substrate limited. Nitrite-oxidizing bacteria (NOB) “Candidatus Nitrotoga” and Nitrospira fluctuated in dominance, with the latter prevailing in deeper, less-productive basins. Genome reconstructions reveal highly reduced genomes and features consistent with genome streamlining, along with diverse adaptations to sunlight and oxidative stress and widespread capacity for organic nitrogen use. Our findings expand the known functional diversity of nitrifiers and establish their ecological genomics in large lake ecosystems. By elucidating links between microbial biodiversity and biogeochemical cycling, our work also informs ecosystem models of the Laurentian Great Lakes, a critical freshwater resource experiencing rapid environmental change. IMPORTANCE Microorganisms play critical roles in Earth’s nitrogen cycle. In lakes, microorganisms called nitrifiers derive energy from reduced nitrogen compounds. In doing so, they transform nitrogen into a form that can ultimately be lost to the atmosphere by a process called denitrification, which helps mitigate nitrogen pollution from fertilizer runoff and sewage. Despite their importance, freshwater nitrifiers are virtually unexplored. To understand their diversity and function, we reconstructed genomes of freshwater nitrifiers across some of Earth’s largest freshwater lakes, the Laurentian Great Lakes. We discovered several new species of nitrifiers specialized for clear low-nutrient waters and distinct species in comparatively turbid Lake Erie. Surprisingly, one species may be able to harness light energy by using a protein called proteorhodopsin, despite the fact that nitrifiers typically live in deep dark water. Our work reveals the unique biodiversity of the Great Lakes and fills key gaps in our knowledge of an important microbial group, the nitrifiers.

Global projections for ocean conditions in 2100 predict that the North Pacific will experience some of the largest changes. Coastal processes that drive variability in the region can alter these projected changes but are poorly resolved by global coarse-resolution models. We quantify the degree to which local processes modify biogeochemical changes in the eastern boundary California Current System (CCS) using multi-model regionally downscaled climate projections of multiple climate-associated stressors (temperature, O2, pH, saturation state (Ω), and CO2). The downscaled projections predict changes consistent with the directional change from the global projections for the same emissions scenario. However, the magnitude and spatial variability of projected changes are modified in the downscaled projections for carbon variables. Future changes in pCO2 and surface Ω are amplified, while changes in pH and upper 200 m Ω are dampened relative to the projected change in global models. Surface carbon variable changes are highly correlated to changes in dissolved inorganic carbon (DIC), pCO2 changes over the upper 200 m are correlated to total alkalinity (TA), and changes at the bottom are correlated to DIC and nutrient changes. The correlations in these latter two regions suggest that future changes in carbon variables are influenced by nutrient cycling, changes in benthic–pelagic coupling, and TA resolved by the downscaled projections. Within the CCS, differences in global and downscaled climate stressors are spatially variable, and the northern CCS experiences the most intense modification. These projected changes are consistent with the continued reduction in source water oxygen; increase in source water nutrients; and, combined with solubility-driven changes, altered future upwelled source waters in the CCS. The results presented here suggest that projections that resolve coastal processes are necessary for adequate representation of the magnitude of projected change in carbon stressors in the CCS.

Abstract Background Microorganisms in urban sanitary sewers exhibit community properties that suggest sewers are a novel ecosystem. Sewer microorganisms present both an opportunity as a control point for wastewater treatment and a risk to human health. If treatment processes are to be improved and health risks quantified, then it is necessary to understand microbial distributions and dynamics within this community. Here, we use 16S rRNA gene sequencing to characterize raw influent wastewater bacterial communities in a 5-year time series from two wastewater treatment plants in Milwaukee, WI; influent wastewater from 77 treatment plants across the USA; and wastewater in 12 Milwaukee residential sewers. Results In Milwaukee, we find that in transit from residences to treatment plants, the human bacterial component of wastewater decreases in proportion and exhibits stochastic temporal variation. In contrast, the resident sewer community increases in abundance during transit and cycles seasonally according to changes in wastewater temperature. The result is a bacterial community that assembles into two distinct community states each year according to the extremes in wastewater temperature. Wastewater bacterial communities from other northern US cities follow temporal trends that mirror those in Milwaukee, but southern US cities have distinct community compositions and differ in their seasonal patterns. Conclusions Our findings provide evidence that environmental conditions associated with seasonal change and climatic differences related to geography predictably structure the bacterial communities residing in below-ground sewer pipes. Video abstract

Abstract Background Social interactions, reproductive demands and intrinsic constraints all influence foraging decisions in animals. Understanding the relative importance of these factors in shaping the way that coexisting species within communities use and partition resources is central to knowledge of ecological and evolutionary processes. However, in marine environments, our understanding of the mechanisms that lead to and allow coexistence is limited, particularly in the tropics. Methods Using simultaneous data from a suite of animal-borne data loggers (GPS, depth recorders, immersion and video), dietary samples and stable isotopes, we investigated interspecific and intraspecific differences in foraging of two closely-related seabird species (the red-footed booby and brown booby) from neighbouring colonies on the Cayman Islands in the Caribbean. Results The two species employed notably different foraging strategies, with marked spatial segregation, but limited evidence of interspecific dietary partitioning. The larger-bodied brown booby foraged within neritic waters, with the smaller-bodied red-footed booby travelling further offshore. Almost no sex differences were detected in foraging behaviour of red-footed boobies, while male and female brown boobies differed in their habitat use, foraging characteristics and dietary contributions. We suggest that these behavioural differences may relate to size dimorphism and competition: In the small brown booby population (n 2000 individuals) and avoidance of kleptoparasitism may be more prevalent in driving movements for both sexes. Conclusions Our results reveal how, in an environment where opportunities for prey diversification are limited, neighbouring seabird species segregate at-sea, while exhibiting differing degrees of sexual differentiation. While the mechanisms underlying observed patterns remain unclear, our data are consistent with the idea that multiple factors involving both conspecifics and heterospecifics, as well as reproductive pressures, may combine to influence foraging differences in these neighbouring tropical species.

Sweet corn is one of the most important vegetables in North America and has undergone different selection pressures than non-sweet cultivars. Here, the authors report its genome assembly and reveal the evolutionary history of modern sweet corn through population genomic analyses.

ABSTRACT Fungal infections are a global threat, but treatments are limited due to a paucity in antifungal drug targets and the emergence of drug-resistant fungi such as Candida auris. Metabolic adaptations enable microbial growth in nutrient-scarce host niches, and they further control immune responses to pathogens, thereby offering opportunities for therapeutic targeting. Because it is a relatively new pathogen, little is known about the metabolic requirements for C. auris growth and its adaptations to counter host defenses. Here, we establish that triggering metabolic dysfunction is a promising strategy against C. auris. Treatment with pyrvinium pamoate (PP) induced metabolic reprogramming and mitochondrial dysfunction evident in disrupted mitochondrial morphology and reduced tricarboxylic acid (TCA) cycle enzyme activity. PP also induced changes consistent with disrupted iron homeostasis. Nutrient supplementation experiments support the proposition that PP-induced metabolic dysfunction is driven by disrupted iron homeostasis, which compromises carbon and lipid metabolism and mitochondria. PP inhibited C. auris replication in macrophages, which is a relevant host niche for this yeast pathogen. We propose that PP causes a multipronged metabolic hit to C. auris: it restricts the micronutrient iron to potentiate nutritional immunity imposed by immune cells, and it further causes metabolic dysfunction that compromises the utilization of macronutrients, thereby curbing the metabolic plasticity needed for growth in host environments. Our study offers a new avenue for therapeutic development against drug-resistant C. auris, shows how complex metabolic dysfunction can be caused by a single compound triggering antifungal inhibition, and provides insights into the metabolic needs of C. auris in immune cell environments. IMPORTANCE Over the last decade, Candida auris has emerged as a human pathogen around the world causing life-threatening infections with wide-spread antifungal drug resistance, including pandrug resistance in some cases. In this study, we addressed the mechanism of action of the antiparasitic drug pyrvinium pamoate against C. auris and show how metabolism could be inhibited to curb C. auris proliferation. We show that pyrvinium pamoate triggers sweeping metabolic and mitochondrial changes and disrupts iron homeostasis. PP-induced metabolic dysfunction compromises the utilization of both micro- and macronutrients by C. auris and reduces its growth in vitro and in immune phagocytes. Our findings provide insights into the metabolic requirements for C. auris growth and define the mechanisms of action of pyrvinium pamoate against C. auris, demonstrating how this compound works by inhibiting the metabolic flexibility of the pathogen. As such, our study characterizes credible avenues for new antifungal approaches against C. auris.

Mercury exposure constitutes an acute risk to human health and the environment. Driven by the requirement to monitor trace-level mercury, we report a highly sensitive mercury(II) DNA sensor enhanced by silver(I) activation, followed by mercury(II)-specific oligonucleotides (MSO) molecular configuration switch and mercury(II)-modulated FRET. Activating the MSO strands with silver(I), mismatched cytosine–silver(I)–cytosine bridges induce individual MSO strands to fold readily in response to mercury(II) resulting in enhanced fluorescence signal. The structural switches were studied by 2D 1H–1H NOESY and TOCSY NMR spectroscopy, and 260 nm absorbance. The signal decreases with increasing mercury(II) concentration from 100 pM to 0.1 mM. The approach affords outstanding mercury(II) selectivity over other environmentally associated metals. Furthermore, the methodology was deployed for detection of mercury(II) in spiked pond waters with 97.9–100.6% recovery. The simple and feasible format has great potential for developing a cost effective and useful tool for environmental monitoring.

Background: Inspired by intense challenges encountered by patients and clinicians, we examined the experiences of living with sarcoidosis in three of the hardest impacted English-speaking cities during the early COVID-19 pandemic: London, New Orleans, and New York. Methods: A multi-disciplinary, multi-national research team including 6 patient leaders conducted qualitative investigations with analyses rooted in grounded theory. Recruitment occurred by self-referral through patient advocacy groups. Results: A total of 28 people living with sarcoidosis participated. The majority of patients had multi-system and severe sarcoidosis. Dominant themes were consistent across groups with differences expressed in spirituality and government and health systems. Racial, gender, and able-bodied inequity were voiced regarding healthcare access and intervention, societal interactions, and COVID-19 exposure and contraction. Agreement regarding extreme disruption in care and communication created concern for disability and survival. Concerns of COVID-19 exposure triggering new sarcoidosis cases or exacerbating established sarcoidosis were expressed. Pre-COVID-19 impediments in sarcoidosis healthcare delivery, medical knowledge, and societal burdens were intensified during the pandemic. Conversely, living with sarcoidosis cultivated personal and operational preparedness for navigating the practicalities and uncertainties of the pandemic. Optimism prevailed that knowledge of sarcoidosis, respiratory, and multi-organ diseases could provide pathways for COVID-19-related therapy and support; however, remorse was expressed regarding pandemic circumstances to draw long-awaited attention to multi-organ system and respiratory conditions. Conclusion: Participants expressed concepts warranting infrastructural and scientific attention. This framework reflects pre- and intra-pandemic voiced needs in sarcoidosis and may be an agent of sensitization and strategy for other serious health conditions. A global query into sarcoidosis will be undertaken.

Abstract Motion‐activated wildlife cameras (or “camera traps”) are frequently used to remotely and noninvasively observe animals. The vast number of images collected from camera trap projects has prompted some biologists to employ machine learning algorithms to automatically recognize species in these images, or at least filter‐out images that do not contain animals. These approaches are often limited by model transferability, as a model trained to recognize species from one location might not work as well for the same species in different locations. Furthermore, these methods often require advanced computational skills, making them inaccessible to many biologists. We used 3 million camera trap images from 18 studies in 10 states across the United States of America to train two deep neural networks, one that recognizes 58 species, the “species model,” and one that determines if an image is empty or if it contains an animal, the “empty‐animal model.” Our species model and empty‐animal model had accuracies of 96.8% and 97.3%, respectively. Furthermore, the models performed well on some out‐of‐sample datasets, as the species model had 91% accuracy on species from Canada (accuracy range 36%–91% across all out‐of‐sample datasets) and the empty‐animal model achieved an accuracy of 91%–94% on out‐of‐sample datasets from different continents. Our software addresses some of the limitations of using machine learning to classify images from camera traps. By including many species from several locations, our species model is potentially applicable to many camera trap studies in North America. We also found that our empty‐animal model can facilitate removal of images without animals globally. We provide the trained models in an R package (MLWIC2: Machine Learning for Wildlife Image Classification in R), which contains Shiny Applications that allow scientists with minimal programming experience to use trained models and train new models in six neural network architectures with varying depths.

The environmental changes at the Permian–Triassic boundary are thought to have been caused primarily by volcanic eruptions. Here the authors develop a model to show that the loss of ecosystems on land and consequent massive terrestrial biomass oxidation triggered large biogeochemical changes in the oceans at the time of the marine mass extinction.

Many major mass extinction events have been associated with large volcanic eruption events, with the argument that large volumes of volcanic degassing could trigger past global climate changes. Here, the authors find that during the end-Triassic extinction event volcanic pulses emitted large amounts of CO2 comparable to projected anthropogenic emissions for the 21st century in the future 2 °C warming scenario.

A hallmark of Listeria (L.) monocytogenes pathogenesis is bacterial escape from maturing entry vacuoles, which is required for rapid bacterial replication in the host cell cytoplasm and cell-to-cell spread. The bacterial transcriptional activator PrfA controls expression of key virulence factors that enable exploitation of this intracellular niche. The transcriptional activity of PrfA within infected host cells is controlled by allosteric coactivation. Inhibitory occupation of the coactivator site has been shown to impair PrfA functions, but consequences of PrfA inhibition for L. monocytogenes infection and pathogenesis are unknown. Here we report the crystal structure of PrfA with a small molecule inhibitor occupying the coactivator site at 2.0 Å resolution. Using molecular imaging and infection studies in macrophages, we demonstrate that PrfA inhibition prevents the vacuolar escape of L. monocytogenes and enables extensive bacterial replication inside spacious vacuoles. In contrast to previously described spacious Listeria-containing vacuoles, which have been implicated in supporting chronic infection, PrfA inhibition facilitated progressive clearance of intracellular L. monocytogenes from spacious vacuoles through lysosomal degradation. Thus, inhibitory occupation of the PrfA coactivator site facilitates formation of a transient intravacuolar L. monocytogenes replication niche that licenses macrophages to effectively eliminate intracellular bacteria. Our findings encourage further exploration of PrfA as a potential target for antimicrobials and highlight that intra-vacuolar residence of L. monocytogenes in macrophages is not inevitably tied to bacterial persistence. Author summary Listeria monocytogenes is a bacterial pathogen that causes severe, often fatal disease in vulnerable individuals. Listeria monocytogenes infects host cells, where it needs to escape from its entry vacuole to replicate inside the host cell cytoplasm and spread to neighboring cells. Inability of Listeria to escape from vacuoles has been associated with long-term bacterial survival inside infected immune cells and chronic infection. We discovered that inhibition of the master regulator of the bacterial factors that orchestrate the intracellular lifestyle of Listeria monocytogenes traps the bacteria inside their entry vacuoles and facilitates extensive bacterial replication in spacious vacuoles. Yet, the majority of infected host immune cells survive the infection and ultimately clear the bacteria. Thus, our data demonstrate that intra-vacuolar existence of Listeria monocytogenes in immune cells is not inevitably tied to bacterial persistence and chronic infection. We provide high resolution structural insights into how an effective inhibitory molecule interacts with the master regulator of Listeria virulence, which may be exploited for rational drug design.

The importance of working memory (WM) in reading and mathematics performance has been widely studied, with recent research examining the components of WM (i.e., storage and processing) and their roles in these educational outcomes. However, the differing relationships between these abilities and the foundational skills involved in the development of reading and mathematics have received less attention. Additionally, the separation of verbal, visual and spatial storage and processing and subsequent links with foundational skills and downstream reading and mathematics has not been widely examined. The current study investigated the separate contributions of processing and storage from verbal, visual and spatial tasks to reading and mathematics, whilst considering influences on the underlying skills of verbal comprehension and counting, respectively. Ninety-two children aged 7- to 8-years were assessed. It was found that verbal comprehension (with some caveats) was predicted by verbal storage and reading was predicted by verbal and spatial storage. Counting was predicted by visual processing and storage, whilst mathematics was related to verbal and spatial storage. We argue that resources for tasks relying on external representations of stimuli related mainly to storage, and were largely verbal and spatial in nature. When a task required internal representation, there was a draw on visual processing and storage abilities. Findings suggest a possible meaningful separability of types of processing. Further investigation of this could lead to the development of an enhanced WM model, which might better inform interventions and reasonable adjustments for children who struggle with reading and mathematics due to WM deficits.

ABSTRACT Microbial water quality is generally monitored by culturable fecal indicator bacteria (FIB), which are intended to signal human health risk due to fecal pollution. However, FIB have limited utility in most urbanized watersheds as they do not discriminate among fecal pollution sources, tend to make up a small fraction of the total microbial community, and do not inform on pollution impacts on the native ecosystem. To move beyond these limitations, we assessed entire bacterial communities and investigated how bacterial diversity relates to traditional ecological and human health-relevant water quality indicators throughout the Milwaukee River Basin. Samples were collected from 16 sites on 5 days during the summer, including both wet and dry weather events, and were processed by 16S rRNA gene amplicon sequencing. Historical water quality at each sampling location, as opposed to upstream land use, was associated significantly with bacterial community alpha diversity. Source partitioning the sequence data was important for determining water quality relationships. Sewage-associated bacterial sequences were detected in all samples, and the relative abundance of sewage sequences was strongly associated with the human Bacteroides fecal marker. From this relationship, we developed a preliminary threshold for human sewage pollution when using bacterial community sequence data. Certain abundant freshwater bacterial sequences were also associated with human fecal pollution, suggesting their possible utility in water quality monitoring. This study sheds light on how bacterial community analysis can be used to supplement current water quality monitoring techniques to better understand interactions between ecological water quality and human health indicators. IMPORTANCE Surface waters in highly developed mixed-use watersheds are frequently impacted by a wide variety of pollutants, leading to a range of impairments that must be monitored and remediated. With advancing technologies, microbial community sequencing may soon become a feasible method for routine evaluation of the ecological quality and human health risk of a water body. In this study, we partnered with a local citizen science organization to evaluate the utility of microbial community sequencing for identifying pollution sources and ecological impairments in a large mixed-use watershed. We show that changes in microbial community diversity and composition are indicative of both long-term ecological impairments and short-term fecal pollution impacts. By source partitioning the sequence data, we also estimate a threshold target for human sewage pollution, which may be useful as a starting point for future development of sequencing-based water quality monitoring techniques.

Dental task trainer simulators using haptics (virtual touch) offers a cost-effective method of teaching certain clinical skills. The purpose of this study is to evaluate students’ performance in removing artificial caries after training with either a haptic dental chair simulator with virtual reality or a traditional dental chair simulator with a mannequin head. Cluster Randomized Controlled Trials in two cohorts, both Year 1 dental students. Students taught using traditional dental chair simulators were compared with students taught using haptic-based simulators on their ability to cut a cavity in a plastic tooth following training. Across both cohorts, there was no difference in the quality of cavity cut, though students’ technique differed across the two simulator groups in some respects. No difference was seen across both cohorts in the quality of cavity cut for a simple preparation, though students in the haptic condition performed less well in the more demanding task. Moreover, students in the haptic group were also less likely to be perceived to be ‘holding the instrument appropriately’. These findings suggest further investigation is needed into the differences in handling of instruments and level of clinical task difficulty between the simulators.

Though endocytosed dietary cholesterol is transferred to the endoplasmic reticulum (ER), how this is regulated is unclear. Here, the authors report a role for Niemann-Pick Type C Protein 1 (NPC1) in tethering endocytic organelles to the ER, which may contribute to interorganelle cholesterol transport.

Abstract Background The built environment is reported to influence physical activity in populations, but longitudinal evidence about the impact of building new physical activity infrastructure is limited. This study aimed to prospectively investigate the uptake and usage of the newly established Peninsula Aquatic and Recreation Centre (PARC), a large multi-purpose recreation facility in Melbourne, Australia. Methods Physically inactive adults (n = 549) from the City of Frankston were recruited before the opening of PARC and followed up 12 months later to measure frequency of attendance at the Centre, and the purposes and barriers to use. Multivariable methods were used to identity the demographic, cognitive and social predictors of attendance, and the relationship between PARC use and improvements in leisure-time physical activity. Results Over 12 months 8.7% of the sampled residents used PARC once per month or more, 17.5% attended less than once per month, and 73.8% did not use the Centre. Lap swimming was the dominant purpose for attendance, and the major barriers were cost of transport and cost of entry. Independent predictors of usage were being female, having children, living within 5 km of the Centre, and expressing strong intentions for use prior to its opening. Use of PARC was not associated with progression to a higher level of total leisure-time physical activity. Conclusions While installation of multi-purpose aquatic and recreation facilities may be considered an investment towards physical activity in populations, regular use by inactive people is likely to be low. Strategies to reduce barriers, including cost and transport, and to motivate use should be trialled in order to improve the public health impacts of this form of infrastructure.

Abstract Background Many parts of Africa have witnessed reductions in Plasmodium falciparum transmission over the last 15 years. Since immunity to malaria is acquired more rapidly at higher transmission, the slower acquisition of immunity at lower transmission may partially offset the benefits of reductions in transmission. We examined the clinical spectrum of disease and predictors of mortality after sustained changes in transmission intensity, using data collected from 1989 to 2016. Methods We conducted a temporal observational analysis of 18,000 children, aged 14 days to 14 years old, who were admitted to Kilifi County Hospital, Kenya, from 1989 to 2016 with malaria. We describe the trends over time of the clinical and laboratory criteria for severe malaria and associated risk of mortality. Results During the time periods 1989–2003, 2004–2008, and 2009–2016, Kilifi County Hospital admitted averages of 657, 310, and 174 cases of severe malaria per year including averages of 48, 14, and 12 malaria-associated deaths per year, respectively. The median ages in years of children admitted with cerebral malaria, severe anaemia, and malaria-associated mortality were 3.0 (95% confidence interval (CI) 2.2–3.9), 1.1 (95% CI 0.9–1.4), and 1.1 (95% CI 0.3–2.2) in the year 1989, rising to 4.9 (95% CI 3.9–5.9), 3.8 (95% CI 2.5–7.1), and 5 (95% CI 3.3–6.3) in the year 2016. The ratio of children with cerebral malaria to severe anaemia rose from 1:2 before 2004 to 3:2 after 2009. Hyperparasitaemia was a risk factor for death after 2009 but not in earlier time periods. Conclusion Despite the evidence of slower acquisition of immunity, continued reductions in the numbers of cases of severe malaria resulted in lower overall mortality. Our temporal data are limited to a single site, albeit potentially applicable to a secular trend present in many parts of Africa.

Substantial cross-sectional evidence and limited longitudinal research indicates that the availability of recreational facilities (e.g., parks, fitness centres) is associated with physical activity participation. However, few intervention trials have investigated how recreational infrastructure can be used to reduce inactivity levels in communities. The MOVE Frankston study aimed to assess the impact of low intensity strategies to promote use of a multi-purpose leisure and aquatic centre in a socioeconomically diverse, metropolitan community. This randomised controlled trial of two years' duration compared public awareness raising (control condition) with two interventions: mailed information about the centre and a free entry pass (I-O); and this minimal intervention supplemented by customer relations management support through telephone contact, mailed promotional materials and additional incentives (I+S). Participants (n = 1320) were inactive adults living in the City of Frankston, Melbourne Australia. There were 928 people (70.3%) followed up at 12 months (61.2% female, 52% ≥55 yrs). Compared with controls, attendance at the Centre once or more was higher in both the I-O (OR 1.79, 95% CI 1.28-2.50) and I+S groups (OR 1.46, 95% CI 1.03-2.07). The proportion of people using the centre weekly did not differ by group. The odds of being in contemplation or preparation to use the Centre were higher in both the I-O (OR 1.76, 95% CI 1.28-2.42) and I+S groups (OR 1.48, 95% CI 1.07-2.06). Total physical activity and related social and cognitive factors did not differ between the groups. The findings show that the low intensity promotional strategies prompted occasional attendance and increased readiness to use this recreational facility, a level of behaviour change unlikely to reduce non-communicable disease risk. It is recommended that more frequent customer relations contact, and involvement of healthcare providers, be tested as strategies to encourage inactive adults to take up physical activity opportunities at recreational facilities of this type.

The zoonotic pathogen Coxiella burnetii, the causative agent of the human disease Q fever, is an ever-present danger to global public health. Investigating novel metabolic pathways necessary for C. burnetii to replicate within its unusual intracellular niche may identify new therapeutic targets. Recent studies employing stable isotope labelling established the ability of C. burnetii to synthesize lactate, despite the absence of an annotated synthetic pathway on its genome. A noncanonical lactate synthesis pathway could provide a novel anti-Coxiella target if it is essential for C. burnetii pathogenesis. In this study, two C. burnetii proteins, CBU1241 and CBU0823, were chosen for analysis based on their similarities to known lactate synthesizing enzymes. Recombinant GST-CBU1241, a putative malate dehydrogenase (MDH), did not produce measurable lactate in in vitro lactate dehydrogenase (LDH) activity assays and was confirmed to function as an MDH. Recombinant 6xHis-CBU0823, a putative NAD+-dependent malic enzyme, was shown to have both malic enzyme activity and MDH activity, however, did not produce measurable lactate in either LDH or malolactic enzyme activity assays in vitro. To examine potential lactate production by CBU0823 more directly, [13C]glucose labelling experiments compared label enrichment within metabolic pathways of a cbu0823 transposon mutant and the parent strain. No difference in lactate production was observed, but the loss of CBU0823 significantly reduced 13C-incorporation into glycolytic and TCA cycle intermediates. This disruption to central carbon metabolism did not have any apparent impact on intracellular replication within THP-1 cells. This research provides new information about the mechanism of lactate biosynthesis within C. burnetii, demonstrating that CBU1241 is not multifunctional, at least in vitro, and that CBU0823 also does not synthesize lactate. Although critical for normal central carbon metabolism of C. burnetii, loss of CBU0823 did not significantly impair replication of the bacterium inside cells.