Antidepressant Exposure and DNA Methylation: Insights from a Methylome-Wide Association Study.

Importance: Understanding antidepressant mechanisms could help design more effective and tolerated treatments. Objective: Identify DNA methylation (DNAm) changes associated with antidepressant exposure. Design: Case-control methylome-wide association studies (MWAS) of antidepressant exposure were performed from blood samples collected between 2006-2011 in Generation Scotland (GS). The summary statistics were tested for enrichment in specific tissues, gene ontologies and an independent MWAS in the Netherlands Study of Depression and Anxiety (NESDA). A methylation profile score (MPS) was derived and tested for its association with antidepressant exposure in eight independent cohorts, alongside prospective data from GS. Setting: Cohorts; GS, NESDA, FTC, SHIP-Trend, FOR2107, LBC1936, MARS-UniDep, ALSPAC, E-Risk, and NTR. Participants: Participants with DNAm data and self-report/prescription derived antidepressant exposure. Main Outcomes and Measures: Whole-blood DNAm levels were assayed by the EPIC/450K Illumina array (9 studies, N exposed = 661, N unexposed = 9,575) alongside MBD-Seq in NESDA (N exposed = 398, N unexposed = 414). Antidepressant exposure was measured by self- report and/or antidepressant prescriptions. Results: The self-report MWAS (N = 16,536, N exposed = 1,508, mean age = 48, 59% female) and the prescription-derived MWAS (N = 7,951, N exposed = 861, mean age = 47, 59% female), found hypermethylation at seven and four DNAm sites (p < 9.42x10 -8 ), respectively. The top locus was cg26277237 ( KANK1, p self-report = 9.3x10 -13 , p prescription = 6.1x10 -3 ). The self-report MWAS found a differentially methylated region, mapping to DGUOK-AS1 ( p adj = 5.0x10 -3 ) alongside significant enrichment for genes expressed in the amygdala, the "synaptic vesicle membrane" gene ontology and the top 1% of CpGs from the NESDA MWAS (OR = 1.39, p < 0.042). The MPS was associated with antidepressant exposure in meta-analysed data from external cohorts (N studies = 9, N = 10,236, N exposed = 661, f3 = 0.196, p < 1x10 -4 ). Conclusions and Relevance: Antidepressant exposure is associated with changes in DNAm across different cohorts. Further investigation into these changes could inform on new targets for antidepressant treatments. 3 Key Points: Question: Is antidepressant exposure associated with differential whole blood DNA methylation?Findings: In this methylome-wide association study of 16,536 adults across Scotland, antidepressant exposure was significantly associated with hypermethylation at CpGs mapping to KANK1 and DGUOK-AS1. A methylation profile score trained on this sample was significantly associated with antidepressant exposure (pooled f3 [95%CI]=0.196 [0.105, 0.288], p < 1x10 -4 ) in a meta-analysis of external datasets. Meaning: Antidepressant exposure is associated with hypermethylation at KANK1 and DGUOK-AS1 , which have roles in mitochondrial metabolism and neurite outgrowth. If replicated in future studies, targeting these genes could inform the design of more effective and better tolerated treatments for depression.

Neutron source reconstruction using a generalized expectation-maximization algorithm on one-dimensional neutron images from the Z facility.

Magnetized Liner Inertial Fusion experiments have been performed at the Z facility at Sandia National Laboratories. These experiments use deuterium fuel, which produces 2.45 MeV neutrons on reaching thermonuclear conditions. To study the spatial structure of neutron production, the one-dimensional imager of neutrons diagnostic was fielded to record axial resolved neutron images. In this diagnostic, neutrons passing through a rolled edge aperture form an image on a CR-39-based solid state nuclear track detector. Here, we present a modified generalized expectation-maximization algorithm to reconstruct an axial neutron emission profile of the stagnated fusion plasma. We validate the approach by comparing the reconstructed neutron emission profile to an x-ray emission profile provided by a time-integrated pinhole camera.

Chytrid infections exhibit historical spread and contemporary seasonality in a declining stream-breeding frog.

Species with extensive geographical ranges pose special challenges to assessing drivers of wildlife disease, necessitating collaborative and large-scale analyses. The imperilled foothill yellow-legged frog (Rana boylii) inhabits a wide geographical range and variable conditions in rivers of California and Oregon (USA), and is considered threatened by the pathogen Batrachochytrium dendrobatidis (Bd). To assess drivers of Bd infections over time and space, we compiled over 2000 datapoints from R. boylii museum specimens (collected 1897-2005) and field samples (2005-2021) spanning 9° of latitude. We observed a south-to-north spread of Bd detections beginning in the 1940s and increase in prevalence from the 1940s to 1970s, coinciding with extirpation from southern latitudes. We detected eight high-prevalence geographical clusters through time that span the species' geographical range. Field-sampled male R. boylii exhibited the highest prevalence, and juveniles sampled in autumn exhibited the highest loads. Bd infection risk was highest in lower elevation rain-dominated watersheds, and with cool temperatures and low stream-flow conditions at the end of the dry season. Through a holistic assessment of relationships between infection risk, geographical context and time, we identify the locations and time periods where Bd mitigation and monitoring will be critical for conservation of this imperilled species.

Comparison of equine paranasal sinus trephination complications and outcome following standing computed tomography, radiography and sinoscopy guided approaches for the treatment of sinusitis.

OBJECTIVE: The recent availability of standing computed tomography (CT) for equine paranasal sinus disease has enhanced diagnosis and enabled more targeted surgery compared to radiography and sinoscopy. To date, there have been no studies which have critically evaluated the benefit of preoperative CT versus radiography and sinoscopy on complications and outcome in horses undergoing sinus trephination. STUDY DESIGN: Retrospective study. ANIMALS: A total of 229 equids. METHODS: The medical records of equids (229) presented for sinusitis treated via trephination that had CT, radiography and/or sinoscopy at time of surgery between 2009 and 2022 were reviewed. Outcome and complications were evaluated for six different pre- and intraoperative imaging modalities. RESULTS: The six groups did not differ in demographics or disease category, though equids with less weight (p = .0179) and shorter disease duration (p = .0075) were more likely to have radiography and sinoscopy based surgical planning. Short-term postoperative complications occurred in 30.1% and were higher in groups using preoperative CT imaging (p = .01), with hemorrhage being the most common surgical complication. Following initial trephination surgery, 57.0% (127/223) of cases resolved and there was no difference between the imaging groups. Final resolution after follow-up medical or surgical treatment increased to 94.6% (211/223) and was not different between the imaging groups or between primary or secondary sinusitis. Additional nasal fenestrations to improve sinonasal drainage, maxillary septal bulla fenestrations and trephinations to treat nasal conchal bullae were made in the CT groups. CLINICAL SIGNIFICANCE: CT provided additional diagnostic information and enabled different surgical approaches but did not improve resolution in this study population.

"They just looked at me like I was human": The experiences of parenting women and providers with substance use disorder treatment.

BACKGROUND: The current US addiction treatment system does not effectively meet the needs of pregnant and parenting women with substance use disorder (SUD). The aim of this research was to identify barriers and facilitators to engagement and retention in SUD residential treatment for pregnant and parenting women. This research was part of a co-design process to collaboratively create a more patient-centered long-term residential program. DESIGN AND METHODS: The study conducted semi-structured individual interviews with both parenting women with lived experience (WWLE) in residential SUD treatment and SUD treatment providers. Interviews aimed to elicit participants' experiences either receiving or providing care. The study team analyzed data in NVivo-12 using a deductive codebook based on the six principles of trauma informed care (TIC). RESULTS: We conducted a total of 32 interviews (WWLE =13, SUD providers =19). The study identified four major themes: 1) peer relationships provide inspiration and diminish shame; 2) providing individuals safe space to stumble in recovery creates opportunities for growth and builds self-efficacy; 3) reasonable, clear boundaries create a structured, protective environment for early recovery; 4) nonjudgmental connections facilitate engagement and build trust. We identified small pivotal moments along the continuum of care that showed how the elements in the four themes enhanced engagement and retention in treatment. These interactions, along the care continuum, are either structural (workflow process) or relational (interpersonal). CONCLUSION: This research increases understanding of the interplay of the structural and relational barriers and facilitators to engagement and retention in treatment. These seemingly minor positive or negative interactions along the care continuum are pivotal to fully operationalizing TIC and optimizing women's engagement in treatment. Improvement strategies that integrate the voices of WWLE and collaboratively co-design a more patient-centered system are critical steps to improving engagement in SUD treatment and more equitable SUD treatment services.

Histone H3 E50K mutation confers oncogenic activity and supports an EMT phenotype.

Sequencing of human patient tumors has identified recurrent missense mutations in genes encoding core histones. We report that mutations that convert histone H3 amino acid 50 from a glutamate to a lysine (H3E50K) support an oncogenic phenotype in human cells. Expression of H3E50K is sufficient to transform human cells as evidenced by a dramatic increase in cell migration and invasion, and a statistically significant increase in proliferation and clonogenicity. H3E50K also increases the invasive phenotype in the context of co-occurring BRAF mutations, which are present in patient tumors characterized by H3E50K. H3E50 lies on the globular domain surface in a region that contacts H4 within the nucleosome. We find that H3E50K perturbs proximal H3 post-translational modifications globally and dysregulates gene expression, activating the epithelial to mesenchymal transition. Functional studies using S. cerevisiae reveal that, while yeast cells that express H3E50K as the sole copy of histone H3 show sensitivity to cellular stressors, including caffeine, H3E50K cells display some genetic interactions that are distinct from the characterized H3K36M oncohistone yeast model. Taken together, these data suggest that additional histone H3 mutations have the potential to be oncogenic drivers and function through distinct mechanisms that dysregulate gene expression.

White matter, cognition and psychotic-like experiences in UK Biobank.

BACKGROUND: Psychotic-like experiences (PLEs) are risk factors for the development of psychiatric conditions like schizophrenia, particularly if associated with distress. As PLEs have been related to alterations in both white matter and cognition, we investigated whether cognition (g-factor and processing speed) mediates the relationship between white matter and PLEs. METHODS: We investigated two independent samples (6170 and 19 891) from the UK Biobank, through path analysis. For both samples, measures of whole-brain fractional anisotropy (gFA) and mean diffusivity (gMD), as indications of white matter microstructure, were derived from probabilistic tractography. For the smaller sample, variables whole-brain white matter network efficiency and microstructure were also derived from structural connectome data. RESULTS: The mediation of cognition on the relationships between white matter properties and PLEs was non-significant. However, lower gFA was associated with having PLEs in combination with distress in the full available sample (standardized ß = -0.053, p = 0.011). Additionally, lower gFA/higher gMD was associated with lower g-factor (standardized ß = 0.049, p < 0.001; standardized ß = -0.027, p = 0.003), and partially mediated by processing speed with a proportion mediated of 7% (p = < 0.001) for gFA and 11% (p < 0.001) for gMD. CONCLUSIONS: We show that lower global white matter microstructure is associated with having PLEs in combination with distress, which suggests a direction of future research that could help clarify how and why individuals progress from subclinical to clinical psychotic symptoms. Furthermore, we replicated that processing speed mediates the relationship between white matter microstructure and g-factor.

Polygenic prediction of major depressive disorder and related traits in African ancestries UK Biobank participants.

Introduction: Genome-Wide Association Studies (GWAS) over-represent European ancestries compared to the global population, neglecting all other ancestry groups and low-income nations. Consequently, polygenic risk scores (PRS) more accurately predict complex traits in Europeans than African Ancestries groups. Very few studies have looked at the transferability of European-derived PRS for behavioural and mental health phenotypes to non-Europeans. We assessed the comparative accuracy of PRS for Major Depressive Disorder (MDD) trained on European and African Ancestries GWAS studies to predict MDD and related traits in African Ancestries participants from the UK Biobank. Methods: UK Biobank participants were selected based on Principal component analysis (PCA) clustering with an African genetic similarity reference population and MDD was assessed with the Composite International Diagnostic Interview (CIDI). Polygenic Risk Scores (PRS) were computed using PRSice2 using either European or African Ancestries GWAS summary statistics. Results: PRS trained on European ancestry samples (246,363 cases) predicted case control status in Africans of the UK Biobank with similar accuracies (190 cases, R2=2%) to PRS trained on far much smaller samples of African Ancestries participants from 23andMe, Inc. (5045 cases, R2=1.8%). This suggests that prediction of MDD status from Africans to Africans had greater efficiency per unit increase in the discovery sample size than prediction of MDD from Europeans to Africans. Prediction of MDD status in African UK Biobank participants using GWAS findings of causal risk factors from European ancestries was non-significant. Conclusion: GWAS studies of MDD in European ancestries are an inefficient means of improving polygenic prediction accuracy in African samples.

Experimental evidence of early-time saturation of the ion-Weibel instability in counterstreaming plasmas of CH, Al, and Cu.

The collisionless ion-Weibel instability is a leading candidate mechanism for the formation of collisionless shocks in many astrophysical systems, where the typical distance between particle collisions is much larger than the system size. Multiple laboratory experiments aimed at studying this process utilize laser-driven (I≳10^{15} W/cm^{2}), counterstreaming plasma flows (V≲2000 km/s) to create conditions unstable to Weibel-filamentation and growth. This technique intrinsically produces temporally varying plasma conditions at the midplane of the interaction where Weibel-driven B fields are generated and studied. Experiments discussed herein demonstrate robust formation of Weibel-driven B fields under multiple plasma conditions using CH, Al, and Cu plasmas. Linear theory based on benchmarked radiation-hydrodynamic FLASH calculations is compared with Fourier analyses of proton images taken ∼5-6 linear growth times into the evolution. The new analyses presented here indicate that the low-density, high-velocity plasma-conditions present during the first linear-growth time (∼300-500 ps) sets the spectral characteristics of Weibel filaments during the entire evolution. It is shown that the dominant wavelength (∼300µm) at saturation persists well into the nonlinear phase, consistent with theory under these experimental conditions. However, estimates of B-field strength, while difficult to determine accurately due to the path-integrated nature of proton imaging, are shown to be in the ∼10-30 T range, an order of magnitude above the expected saturation limit in homogenous plamas but consistent with enhanced B fields in the midplane due to temporally varying plasma conditions in experiments.

The feasibility and effectiveness of a novel online mental health literacy course in supporting university student mental health: a pilot study.

BACKGROUND: There is a need for effective universal approaches to promote and support university student mental health that are scalable and sustainable. In this pilot study we assess the feasibility and acceptability of a fully-digitalized, comprehensive mental health literacy course co-created with and tailored to the needs of undergraduate students. We also explore preliminary associations with mental health and positive behaviour change. METHODS: An accredited online mental health literacy course was developed using state-of-the-art pedagogical principles and a reverse mentorship approach. The course was offered as an interdisciplinary undergraduate elective. Students completed an online survey before and after the 12-week course that collected demographic information and assessed mental health knowledge, emotional self-awareness, mental health, stigma, and health-related behaviors using validated measures. Dependent group t-tests were used to compare pre- and post-course levels of knowledge, mental health, sleep quality and substance use. Mental health outcomes of students who completed the course were compared to an age and sex-matched sample of students not enrolled in the course and who completed the same survey measures over the same academic year. Multivariable linear regression was used to examine the effect of course participation on outcomes at follow-up. RESULTS: The course had good uptake and was positively reviewed by participants. Specifically, students found the course engaging, relevant, and applicable, and agreed they would recommend it to their peers. Among course participants there was improvement in mental health knowledge (p < 0.001) and emotional self-awareness (p = 0.02) at course completion. Compared to the matched comparison group, taking the course was associated with reduced alcohol (ß = - 0.41, p = 0.01) and cannabis use (ß = - 0.35, p = 0.03), and improved sleep quality (ß = 1.56, p = 0.09) at the end of the term. CONCLUSIONS: Findings suggest that delivering mental health literacy as an online accredited course may be an acceptable and effective way of promoting university student mental health through improved knowledge, emotional self-awareness, and healthy lifestyle choices. As the course is expanded to larger and more diverse student cohorts we will be able to further examine the short and long-term effectiveness of the course in supporting student mental health and the underlying mechanisms.

IgG fractions from patients with antiphospholipid syndrome and systemic lupus erythematosus bind to platelets, but do not affect collagen-induced platelet activation.

Anti-beta-2 glycoprotein 1 (anti-ß2GP1) is an antiphospholipid antibody found in patients with antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). Its presence commonly is associated with thrombosis; however, the mechanisms of interaction of anti-ß2GP1 antibodies and platelets remain unclear. We investigated the effects of APS and SLE patient-derived IgG fractions on collagen-mediated platelet aggregation and examined the binding of patient-derived IgG to platelets before and after activation by collagen. IgG fractions, 150, 200, 300 or 350 µg/ml, isolated from 11 patients with APS and SLE were incubated with two sets of platelet-rich plasma (PRP) in the incubation wells of an aggregometer. The first set was activated by collagen and the other set was incubated for an additional 10 min. All platelets were collected by centrifugation and fixed in cell blocks. We assessed binding of IgG to platelets using immunocytochemistry (ICC). Patient-derived IgG fractions did not affect collagen-induced platelet aggregation. ICC staining using anti-human IgG antibodies demonstrated that patient-derived IgG fractions had greater affinity for non-activated platelets than those activated by 0.75 µg/ml collagen. Patient-derived IgG fractions bound to the surface of platelets and potentially could be internalized by platelets. IgG fractions from APS and SLE patients may sensitize non-activated platelets, which could increase platelet reactivity and thrombotic risk in patients. We did not detect secondary effects of patient-derived IgG fractions.

Associations of social cohesion and quality of life with objective and perceived built environments: a latent profile analysis among seniors.

BACKGROUND: Healthy aging requires support from local built and social environments. Using latent profile analysis, this study captured the multidimensionality of the built environment and examined relations between objective and perceived built environment profiles, neighborhood social cohesion and quality of life among seniors. METHODS: In total, 693 participants aged 66-97 were sampled from two US locales in 2005-2008 as part of the Senior Neighborhood Quality of Life Study (SNQLS). Perceived social cohesion and quality of life were assessed using validated surveys. Six objective (geographic information system (GIS)-based) and seven perceived built environment latent profiles generated in previous SNQLS publications were used for analyses. Mixed-effects models estimated social cohesion and quality of life separately as a function of the built environment profiles. RESULTS: More walkable and destination-rich perceived built environment profiles were associated with higher social cohesion and quality of life. Objective built environment profiles were not associated with social cohesion and only positively associated with quality of life in only one locale (Baltimore/DC). CONCLUSIONS: Latent profile analysis offered a comprehensive approach to assessing the built environment. Seniors who perceived their neighborhoods to be highly walkable and recreationally dense experienced higher neighborhood social cohesion and quality of life, which may set the stage for healthier aging.

Amoebic gill disease increases energy requirements and decreases hypoxia tolerance in Atlantic salmon (Salmo salar) smolts.

Globally, Atlantic salmon (Salmo salar Linnaeus) aquaculture is now routinely affected by amoebic gill disease (AGD; Neoparamoeba perurans). The disease proliferates throughout the summer and is implicated in decreasing tolerance of salmon to environmental perturbations, yet little empirical evidence exists to support these observations. Using salmon acclimated to 15 or 19 °C, our aim was to determine the effects of clinically light-moderate (industry-relevant) AGD on metabolism (MO2rest and MO2max), aerobic scope (MO2max - MO2rest), excess post-exercise oxygen consumption (EPOC), and hypoxia tolerance. An increase in MO2rest (~8% and ~ 13% increase within the 15 and 19 °C acclimation groups, respectively) with increasing disease signs demonstrated an increase in baseline energy requirements as the disease progressed. Conversely, MO2max remained stable at both temperatures (~364 mg O2 kg-1 h-1), resulting in a decline in aerobic scope by 13 and 19% in the 15 and 19 °C groups, respectively. There was evidence of a decrease in hypoxia tolerance as the dissolved oxygen concentrations at loss of equilibrium increased by ~8% with more severe lesion coverage of the gills. These results suggest an increase in basal energy requirements and reduction in hypoxia tolerance as AGD proliferates, lending support to the idea that AGD reduces environmental tolerance. However, the lack of an effect of acclimation temperature indicates that the temperature-disease interaction may be more complicated than currently thought.

Odderon Exchange from Elastic Scattering Differences between pp and pp[over ¯] Data at 1.96 TeV and from pp Forward Scattering Measurements.

We describe an analysis comparing the pp[over ¯] elastic cross section as measured by the D0 Collaboration at a center-of-mass energy of 1.96 TeV to that in pp collisions as measured by the TOTEM Collaboration at 2.76, 7, 8, and 13 TeV using a model-independent approach. The TOTEM cross sections, extrapolated to a center-of-mass energy of sqrt[s]=1.96 TeV, are compared with the D0 measurement in the region of the diffractive minimum and the second maximum of the pp cross section. The two data sets disagree at the 3.4σ level and thus provide evidence for the t-channel exchange of a colorless, C-odd gluonic compound, also known as the odderon. We combine these results with a TOTEM analysis of the same C-odd exchange based on the total cross section and the ratio of the real to imaginary parts of the forward elastic strong interaction scattering amplitude in pp scattering for which the significance is between 3.4σ and 4.6σ. The combined significance is larger than 5σ and is interpreted as the first observation of the exchange of a colorless, C-odd gluonic compound.

[External Quality Assessment of Thick and Thin Blood Smear Slides for the Diagnosis of Malaria in the Lomé and Gulf Health Districts of Togo]. / Évaluation Externe de la Qualité de la Goutte Épaisse/Frottis Sanguin pour le Diagnostic du Paludisme dans les Districts Sanitaires de Lomé et du Golfe au Togo.

Objective: In sub-Saharan Africa where 90% of malaria cases are concentrated, the control of this disease constitutes a major challenge whose diagnosis by thick and thin smear deserves to be exact and reproducible. The purpose of this study is to assess the performance of thick/thin blood smear in order to improve its implementation process. Material and methods: This was a descriptive and analytical study that took place from May to June 2017 and involved participating laboratories (PL) coming from public, liberal and confessional sectors in Lomé. A set of 13 blood smear slides of variable parasite densities (PD) with assigned values (AV) of parasite densities and the Plasmodium species assigned was used. The criterion for establishing the parasite densities compliance interval was assigned values ± 25% and the performance rates were compared to the 80% recommended by the WHO for Africa region. Results: 41.9% (13/31) of the PLs had a compliance rate greater than 80% including four with a performance of 100% for the ability to identify the Plasmodium species. For the parasitaemia < 100/µl, 51.6% of participating laboratories had a performance rate less than 80% and for parasitaemia > 2000/µl, 100% of these laboratories had a performance rate greater than 80%. Conclusion: The evaluated laboratories had insufficient ability for the identification of Plasmodium falciparum and the correct estimation of low parasitaemia. A need to strength the technical skills, adapted to the context of low parasitaemia are essential to improve the biological diagnosis of malaria in Togo.

Comparison of bacterial diversity and distribution on the gills of Atlantic salmon (Salmo salar L.): an evaluation of sampling techniques.

AIMS: Assess bacterial diversity and richness in mucus samples from the gills of Atlantic salmon in comparison to preserved or fixed gill filament tissues. Ascertain whether bacterial diversity and richness are homogeneous upon different arches of the gill basket. METHODS AND RESULTS: Bacterial communities contained within gill mucus were profiled using 16S rRNA gene sequencing. No significant difference in taxa richness, alpha (P > 0·05) or beta diversity indices (P > 0·05) were found between the bacterial communities of RNAlater preserved gill tissues and swab-bound mucus. A trend of lower richness and diversity indices were observed in bacterial communities from posterior hemibranchs. CONCLUSIONS: Non-lethal swab sampling of gill mucus provides a robust representation of bacterial communities externally upon the gills. Bacterial communities from the fourth arch appeared to be the least representative overall. SIGNIFICANCE AND IMPACT OF THE STUDY: The external mucosal barriers of teleost fish (e.g. gill surface) play a vital role as a primary defence line against infection. While research effort on the role of microbial communities on health and immunity of aquaculture species continues, the collection and sampling processes to obtain these data require evaluation so methodologies are consistently applied across future studies that aim to evaluate the composition of branchial microbiomes.

Toxicity of Herbicide Mixtures to Tropical Freshwater Microalgae Using a Multispecies Test.

Agriculture within the Great Barrier Reef catchment area has contributed to pesticide contamination of adjacent freshwater ecosystems that flow into the Great Barrier Reef World Heritage Area. A novel multispecies toxicity test was used to assess the toxicity of diuron and hexazinone, 2 herbicides commonly detected within the Great Barrier Reef catchment area, to a community of 3 tropical freshwater microalgae: Monoraphidium arcuatum, Nannochloropsis-like sp., and Pediastrum duplex. Diuron was the most toxic herbicide, with 10% inhibition concentration (IC10) values of 4.3, 7.1, and 29 µg/L for P. duplex, M. arcuatum, and Nannochloropsis-like sp., respectively, followed by hexazinone, with IC10 values of 15, 18, and 450 µg/L, respectively Toxicity testing on 2 commercial formulations (Barrage, 13.2% hexazinone and 48.6% diuron; Diurex, 90% diuron) showed that additives in the commercial formulations did not significantly increase the toxicity of diuron. Direct toxicity assessments were carried out on water samples from the herbicide-contaminated Sandy Creek, which discharges to the Great Barrier Reef lagoon, and a clean reference site, Tully Gorge in the Tully River. Toxicity was observed in several Sandy Creek samples. Artificial herbicide mixtures were assessed in synthetic soft water and natural freshwaters, with toxic responses being observed at environmentally relevant concentrations. The present study successfully applied a novel multispecies tropical microalgal toxicity test, indicating that it is an effective tool for the assessment of herbicide toxicity in both natural and synthetic freshwaters. Environ Toxicol Chem 2021;40:473-486. © 2020 SETAC.

Platelet PD-L1 suppresses anti-cancer immune cell activity in PD-L1 negative tumors.

Strategies that interfere with the binding of the receptor programmed cell death protein-1 (PD-1) to programmed death ligand-1 (PD-L1) have shown marked efficacy against many advanced cancers, including those that are negative for PD-L1. Precisely why patients with PD-L1 negative tumors respond to PD-1/PD-L1 checkpoint inhibition remains unclear. Here, we show that platelet-derived PD-L1 regulates the growth of PD-L1 negative tumors and that interference with platelet binding to PD-L1 negative cancer cells promotes T cell-induced cancer cytotoxicity. These results suggest that the successful outcomes of PD-L1 based therapies in patients with PD-L1 negative tumors may be explained, in part, by the presence of intra-tumoral platelets. Altogether, our findings demonstrate the impact of non-cancer/non-immune cell sources of PD-L1 in the tumor microenvironment in the promotion of cancer cell immune evasion. Our study also provides a compelling rationale for future testing of PD-L1 checkpoint inhibitor therapies in combination with antiplatelet agents, in patients with PD-L1 negative tumors.

A universal scaling law of mammalian touch.

For most mammals, touch is the first sense to develop. They must feel vibrations on the surface of their skin to enable them to respond to various stimuli in their environment, a process called vibrotaction. But how do mammals perceive these vibrations? Through mathematical modeling of the skin and touch receptors, we show that vibrotaction is dominated by "surface" Rayleigh waves traveling cooperatively through all layers of the skin and bone. Applying our model to experimental data, we identify a universal scaling law for the depth of touch receptors across multiple species, indicating an evolutionarily conserved constant in the sensation of vibrations.