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Introduction: There is increasing evidence that phosphorylated tau (P-tau181) is a specific biomarker for Alzheimer's disease (AD) pathology, but its potential utility in non-White patient cohorts and patients with concomitant cerebrovascular disease (CeVD) is unknown. Methods: Single molecule array (Simoa) measurements of plasma P-tau181, total tau, amyloid beta (Aβ)40 and Aβ42, as well as derived ratios were correlated with neuroimaging modalities indicating brain amyloid (Aβ+), hippocampal atrophy, and CeVD in a Singapore-based cohort of non-cognitively impaired (NCI; n = 43), cognitively impaired no dementia (CIND; n = 91), AD (n = 44), and vascular dementia (VaD; n = 22) subjects. Results: P-tau181/Aβ42 ratio showed the highest area under the curve (AUC) for Aβ+ (AUC = 0.889) and for discriminating between AD Aβ+ and VaD Aβ− subjects (AUC = 0.903). In addition, P-tau181/Aβ42 ratio was associated with hippocampal atrophy. None of the biomarkers was associated with CeVD. Discussion: Plasma P-tau181/Aβ42 ratio may be a noninvasive means of identifying AD with elevated brain amyloid in populations with concomitant CeVD.

This paper reports a series of tests for fore- and hind-limb preferences used by cane toads, Rhinella marina, to assist returning to the righted position after being overturned. We confirm the strong and significant right-handedness reported in this species, which under certain conditions exceeded 90% right-hand preference at the group level. Toads were tested under a variety of conditions including horizontal and inclined surfaces, with and without the opportunity for the forelimbs to grasp a support, in order to assess the effects of different vestibular and proprioceptive input on the strength and direction of fore- and hind-limb preferences. A range of behavioural strategies indicated learning effects; however, the strength or direction of limb preferences did not increase significantly with experience, even in toads retested multiple times. Comparisons with the mammalian condition for limb preferences are discussed with relevance to practice effects and established limb preferences, and to effects associated with arousal or stress. In contrast to the expectation that handedness in toads represents intentional or voluntary preferences, the presence of lateralized central pattern generators in the toads is postulated to explain the different forms of lateralization revealed by our tests.

Aims The effectiveness of commercially available wound dressings and a HOCl gel formulation was tested against two- and five-species biofilms in a dynamic in vitro chronic wound infection model. Method Two-species biofilms (Pseudomonas aeruginosa and Staphylococcus aureus) were cultured using a biofilm flow device and treated with wound dressings containing silver, iodine, polyhexamethylene biguanide, crystal violet or HOCl gel at 5 h. Five-species biofilms (P. aeruginosa, S. aureus, Enterococcus faecalis, Streptococcus pyogenes and Escherichia coli) were similarly cultured and treated with HOCl gel at 5 and 24 h. Multidose experiments used two- and five-species biofilms with HOCl applied at 24, 48 and 72 h. Results None of the treatments completely disrupted the biofilms and, with the exception of silver, bacteria recovered in number post-treatment. HOCl was most effective when applied to 24 h established biofilms with most activity against P. aeruginosa. Recovery post-treatment was negligible with HOCl applied at 24 h and multiple doses indicated that bacteria were not becoming tolerant to treatment. Conclusions Realistic models are necessary to test the effectiveness of antimicrobial wound treatments to ensure findings are clinically translatable. HOCl gel shows promise as a new topical antimicrobial for wounds, especially due to its ability to inhibit P. aeruginosa. Significance and impact of the study This study highlights a need for robust in vitro data to support development and use of wound treatments that can only be obtained from the refinement of realistic infection models. Furthermore, it indicates the potential use of HOCl gel for chronic wound management.

Summary Background Patients with systemic lupus erythematosus (SLE) are at risk of developing COVID-19 due to underlying immune abnormalities and regular use of immunosuppressant medications. We aimed to evaluate the presence of SARS-CoV-2 IgG antibodies in patients with SLE with or without previous COVID-19-related symptoms or RT-PCR-confirmed SARS-CoV-2 infection. Methods For this analysis, we included patients with SLE from two cohorts based in New York City: the Web-based Assessment of Autoimmune, Immune-Mediated and Rheumatic Patients during the COVID-19 pandemic (WARCOV) study; and the NYU Lupus Cohort (a prospective registry of patients at NYU Langone Health and NYC Health + Hospitals/Bellevue). Patients in both cohorts were tested for SARS-CoV-2 IgG antibodies via commercially available immunoassays, processed through hospital or outpatient laboratories. Patients recruited from the NYU Lupus Cohort, referred from affiliated providers, or admitted to hospital with COVID-19 were tested for SARS-CoV-2 IgG antibodies as part of routine surveillance during follow-up clinical visits. Findings 329 patients with SLE were included in this analysis, 146 from the WARCOV study and 183 from the NYU Lupus Cohort, and were tested for SARS-CoV-2 antibodies between April 29, 2020, and Feb 9, 2021. 309 (94%) were women and 91 (28%) were of Hispanic ethnicity. 51 (16%) of 329 patients had a positive SARS-CoV-2 IgG antibody test. Seropositive patients were more likely than seronegative patients to be Hispanic (24 [47%] of 51 vsz 67 [24%] of 278). Other demographic variables, SLE-specific factors, and immunosuppressant use were not associated with SARS-CoV-2 positivity. Of the 29 patients with COVID-19 previously confirmed by RT-PCR, 18 (62%) were on immunosuppressants; 24 (83%) of 29 patients tested positive for SARS-CoV-2 IgG antibodies. Of 17 patients who had symptoms of COVID-19 but negative concurrent RT-PCR testing, one (6%) developed an antibody response. Of 26 patients who had COVID-19-related symptoms but did not undergo RT-PCR testing, six (23%) developed an antibody response. Of 83 patients who had no symptoms of COVID-19 and no RT-PCR testing, four (5%) developed an antibody response. Among 36 patients who were initially SARS-CoV-2 IgG positive, the majority maintained reactivity serially (88% up to 10 weeks, 83% up to 20 weeks, and 80% up to 30 weeks). Seven (70%) of ten patients with confirmed COVID-19 had antibody positivity beyond 30 weeks from disease onset. Interpretation Most patients with SLE and confirmed COVID-19 were able to produce and maintain a serological response despite the use of a variety of immunosuppressants, providing reassurance about the efficacy and durability of humoral immunity and possible protection against re-infection with SARS-CoV-2. Funding National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, and Bloomberg Philanthropies COVID-19 Response Initiative Grant.

Freshwater is a critical input to estuaries but is under increasing demand to support upstream human activities. In this study, otolith biochronology was used to quantify the relationship between river discharge and juvenile growth rates of barramundi (Lates calcarifer) in three regions of the Gulf of Carpentaria in northern Australia. In all regions, river discharge had a strong positive effect on juvenile growth rates. Models were also developed which incorporated the Southern Oscillation Index (SOI) and the Madden–Julian Oscillation (MJO). SOI values corresponding to La Nina events had strong positive consequences for juvenile barramundi growth rates in all regions, and the intensity of positive wet season MJO pulses had a strong positive effect on growth rates in the perennially flowing river, but not the intermittently flowing rivers. The consequences of three hypothetical water development scenarios were estimated for the perennial river. The model predicted a 12%, 8% and 1% reduction in annual barramundi growth rates under proposed scenarios for 18%, 8%, and 3% reduction in river discharge, respectively. Fish growth is a robust, quantitative metric that can be monitored pre and post water resource development to identify the least impactful development scenario and monitor its compliance and success through time.

Alzheimer’s disease (AD) is influenced by both genetic and environmental factors; thus, brain epigenomic alterations may provide insights into AD pathogenesis. Multiple array-based Epigenome-Wide Association Studies (EWASs) have identified robust brain methylation changes in AD; however, array-based assays only test about 2% of all CpG sites in the genome. Here, we develop EWASplus, a computational method that uses a supervised machine learning strategy to extend EWAS coverage to the entire genome. Application to six AD-related traits predicts hundreds of new significant brain CpGs associated with AD, some of which are further validated experimentally. EWASplus also performs well on data collected from independent cohorts and different brain regions. Genes found near top EWASplus loci are enriched for kinases and for genes with evidence for physical interactions with known AD genes. In this work, we show that EWASplus implicates additional epigenetic loci for AD that are not found using array-based AD EWASs., Array-based epigenome-wide association studies only test about 2% of the CpG sites in the genome. Here, the authors describe EWASplus, a supervised machine learning strategy that extends EWAS coverage to the entire genome, and use it to identify novel brain CpGs associated with Alzheimer’s disease.

We thank the A.P. Leventis Conservation Foundation for supporting this work. Female song is widespread across bird species yet rarely reported. Here, we report the first observations and description of female song in the Cyprus Wheatear Oenanthe cypriaca and compare it to male song through the breeding season. Twenty-five percent of colour-ringed females were observed singing at least once, predominantly in April, compared to 71% of males that continued singing through the breeding period. We suggest that female song may have multiple functions in this species, but it may be especially important in territorial defence and mate acquisition. Publisher PDF

Genome-wide association studies (GWAS) have identified many risk loci for Alzheimer's disease (AD)1,2, but how these loci confer AD risk is unclear. Here, we aimed to identify loci that confer AD risk through their effects on brain protein abundance to provide new insights into AD pathogenesis. To that end, we integrated AD GWAS results with human brain proteomes to perform a proteome-wide association study (PWAS) of AD, followed by Mendelian randomization and colocalization analysis. We identified 11 genes that are consistent with being causal in AD, acting via their cis-regulated brain protein abundance. Nine replicated in a confirmation PWAS and eight represent new AD risk genes not identified before by AD GWAS. Furthermore, we demonstrated that our results were independent of APOE e4. Together, our findings provide new insights into AD pathogenesis and promising targets for further mechanistic and therapeutic studies.

Background Bacillus Calmette–Guerin (BCG) vaccine provides partial protection against Buruli ulcer caused by Mycobacterium ulcerans in epidemiological studies. This study aimed to quantify M. ulcerans-specific immune responses induced by BCG immunisation. Methods Intracellular cytokine analysis of in-vitro experiments done 10 weeks after BCG immunisation in 130 Australian infants randomised to one of three BCG vaccine strains given either at birth (BCG-Denmark, BCG-Japan, or BCG-Russia) or at two months of age (BCG-Denmark). Results Proportions of polyfunctional CD4+ T-cells were higher in M. ulcerans-stimulated compared to unstimulated control samples. These proportions were not influenced by the vaccine strain or timing of the immunisation. The M. ulcerans-specific immune responses showed similar patterns to those observed in M. tuberculosis-stimulated samples, although they were of lower magnitude. Conclusions Our data show that BCG immunisation induces M. ulcerans-specific immune responses in infants, likely explaining the cross-protective effect observed in epidemiological studies. (ACTRN12608000227392)

Invasive non-native species and global warming are two of the greatest components of global ecosystem change. The Pacific oyster, Crassostrea gigas, is the world most cultivated shellfish and was introduced throughout the Northwest European Shelf (NWES) under the premise it could not complete its life cycle. Recent warming trends have changed this and wild populations can be found as far north as Nordic Scandinavia. Under the RCP8.5 concentration pathway, we predict that the majority of NWES coastline will be within C. gigas’s thermal recruitment niche by 2100. Given the widespread occurrence of current naturalized C. gigas populations, its large larval dispersal potential and a lack of feasible management solutions, C. gigas will likely undergo a considerable range expansion this century. The time taken to reach maturity is predicted to decrease by up to 60 days, which may lead to precocious spawning events, facilitating expansion further. Crassostrea gigas can form extensive reefs completely transforming native systems. This may compromise native biodiversity, protected habitats, and commercial species. However, naturalization can also deliver a number of beneficial ecosystem goods and services to human society. Whether naturalization is deemed positive or negative will depend on biogeographic context, the perceptions of stakeholders, and the wider management priorities.

Dispersal to efficiently locate future breeding areas in young animals has important consequences for survival, life history and future breeding success, and therefore population dynamics and evolution. Long-distance migrant birds that have little time immediately pre-breeding may use the post-fledging period to locate their future breeding territory. We radio-tracked 37 juvenile Cyprus Wheatears, Oenanthe cypriaca, a long-distance migrant passerine, to investigate movements for 10 weeks post-fledging. We measured how distance from the nest and distance of consecutive movements changed with age. We tested whether distance from the nest stopped increasing and consecutive movement distance became similar to pre-dispersal distances, consistent with a fledgling adopting a post-fledgling home range that could reflect scoping out a future local breeding territory. Fledglings had a very high survival rate. Directed movements away from the natal territory started at about 18 days until about 45 days when individuals adopted a more fixed location on average about 600 m (range 0–1500) from their natal site, and further movements were at a scale equivalent to movements within an adult-sized breeding territory. Our results suggest dispersal followed by settlement in a fixed home range prior to first migration that could function to identify the breeding site location for the following year.

BackgroundSubstance use and psychiatric illness, particularly psychotic disorders, contribute to violence in emergency healthcare settings. However, there is limited research regarding the relationship between specific substances, psychotic symptoms and violent behaviour in such settings. We investigated the interaction between recent cannabinoid and stimulant use, and acute psychotic symptoms, in relation to violent behaviour in a British emergency healthcare setting.MethodsWe used electronic medical records from detentions of 1089 individuals under Section 136 of the UK Mental Health Act (1983 amended 2007), an emergency police power used to detain people for 24–36 h for psychiatric assessment. The relationship between recent cannabinoids and/or stimulant use, psychotic symptoms, and violent behaviour, was estimated using logistic regression.FindingsThere was evidence of recent alcohol or drug use in 64.5% of detentions. Violent incidents occurred in 12.6% of detentions. Psychotic symptoms increased the odds of violence by 4.0 [95% confidence intervals (CI) 2.2–7.4; p < 0.0001]. Cannabinoid use combined with psychotic symptoms increased the odds of violence further [odds ratios (OR) 7.1, 95% CI 3.7–13.6; p < 0.0001]. Recent use of cannabinoids with stimulants but without psychotic symptoms was also associated with increased odds of violence (OR 3.3, 95% CI 1.4–7.9; p < 0.0001).InterpretationIn the emergency setting, patients who have recently used cannabinoids and exhibit psychotic symptoms are at higher risk of violent behaviour. Those who have used both stimulants and cannabinoids without psychotic symptoms may also be at increased risk. De-escalation protocols in emergency healthcare settings should account explicitly for substance use.

Aim To better understand the marked decrease in serum triglycerides observed with tirzepatide in patients with type 2 diabetes, additional lipoprotein-related biomarkers were measured post hoc in available samples from the same study. Materials and Methods Patients were randomized to receive once-weekly subcutaneous tirzepatide (1, 5, 10 or 15 mg), dulaglutide (1.5 mg) or placebo. Serum lipoprotein profile, apolipoprotein (apo) A-I, B and C-III and preheparin lipoprotein lipase (LPL) were measured at baseline and at 4, 12 and 26 weeks. Lipoprotein particle profile by nuclear magnetic resonance was assessed at baseline and 26 weeks. The lipoprotein insulin resistance (LPIR) score was calculated. Results At 26 weeks, tirzepatide dose-dependently decreased apoB and apoC-III levels, and increased serum preheparin LPL compared with placebo. Tirzepatide 10 and 15 mg decreased large triglyceride-rich lipoprotein particles (TRLP), small low-density lipoprotein particles (LDLP) and LPIR score compared with both placebo and dulaglutide. Treatment with dulaglutide also reduced apoB and apoC-III levels but had no effect on either serum LPL or large TRLP, small LDLP and LPIR score. The number of total LDLP was also decreased with tirzepatide 10 and 15 mg compared with placebo. A greater reduction in apoC-III with tirzepatide was observed in patients with high compared with normal baseline triglycerides. At 26 weeks, change in apoC-III, but not body weight, was the best predictor of changes in triglycerides with tirzepatide, explaining up to 22.9% of their variability. Conclusions Tirzepatide treatment dose-dependently decreased levels of apoC-III and apoB and the number of large TRLP and small LDLP, suggesting a net improvement in atherogenic lipoprotein profile.

OCBIL theory provides a basis for understanding of the evolution and ecology of biota on old, climatically buffered, infertile landscapes (OCBILs) worldwide. Here, we test a genetic hypothesis presented in OCBIL theory that predicts highly differentiated intraspecific population systems on OCBILs vs. more limited differentiation on young, often disturbed, fertile landscapes (YODFELs). We examined patterns of genomic and morphological divergence in Banksia seminuda across OCBILs and YODFELs in south-western Australia. We also used these data to determine whether these OCBIL and YODFEL populations represent distinct subspecific lineages, a point of previous contention among taxonomists. As hypothesized, genomic analyses based on 3466 SNP loci revealed strong structuring within B. seminuda, with high differentiation across narrow geographic scales among OCBIL populations vs. lower differentiation across much larger geographic scales among YODFEL populations. In addition, genomic and morphological divergence was found between OCBIL and YODFEL populations, providing comprehensive quantitative evidence for two subspecies. These findings have taxonomic implications for the species and provide support for OCBIL theory and its insights into the evolution, ecology and conservation of biota on ancient landscapes.

Background Significant developments in stem cell therapy for Parkinson’s disease (PD) have already been achieved; however, methods for reliable assessment of dopamine neuron maturation in vivo are lacking. Establishing the efficacy of new cellular therapies using non-invasive methodologies will be critical for future regulatory approval and application. The current study examines the utility of neuroimaging to characterise the in vivo maturation, innervation and functional dopamine release of transplanted human embryonic stem cell-derived midbrain dopaminergic neurons (hESC-mDAs) in a preclinical model of PD. Methods Female NIH RNu rats received a unilateral stereotaxic injection of 6-OHDA into the left medial forebrain bundle to create the PD lesion. hESC-mDA cell and sham transplantations were carried out 1 month post-lesion, with treated animals receiving approximately 4 × 105 cells per transplantation. Behavioural analysis, [18F]FBCTT and [18F]fallypride microPET/CT, was conducted at 1, 3 and 6 months post-transplantation and compared with histological characterisation at 6 months. Results PET imaging revealed transplant survival and maturation into functional dopaminergic neurons. [18F]FBCTT-PET/CT dopamine transporter (DAT) imaging demonstrated pre-synaptic restoration and [18F]fallypride-PET/CT indicated functional dopamine release, whilst amphetamine-induced rotation showed significant behavioural recovery. Moreover, histology revealed that the grafted cells matured differently in vivo producing high- and low-tyrosine hydroxylase (TH) expressing cohorts, and only [18F]FBCTT uptake was well correlated with differentiation. Conclusions This study provides further evidence for the value of in vivo functional imaging for the assessment of cell therapies and highlights the utility of DAT imaging for the determination of early post-transplant cell maturation and differentiation of hESC-mDAs.

Cerebellar dysfunction has been demonstrated in autism spectrum disorders (ASDs); however, the circuits underlying cerebellar contributions to ASD-relevant behaviors remain unknown. In this study, we demonstrated functional connectivity between the cerebellum and the medial prefrontal cortex (mPFC) in mice; showed that the mPFC mediates cerebellum-regulated social and repetitive/inflexible behaviors; and showed disruptions in connectivity between these regions in multiple mouse models of ASD-linked genes and in individuals with ASD. We delineated a circuit from cerebellar cortical areas Right crus 1 (Rcrus1) and posterior vermis through the cerebellar nuclei and ventromedial thalamus and culminating in the mPFC. Modulation of this circuit induced social deficits and repetitive behaviors, whereas activation of Purkinje cells (PCs) in Rcrus1 and posterior vermis improved social preference impairments and repetitive/inflexible behaviors, respectively, in male PC-Tsc1 mutant mice. These data raise the possibility that these circuits might provide neuromodulatory targets for the treatment of ASD.

Synbiotic ice cream was developed from goat milk by using inulin as a prebiotic and Lactobacillus plantarum (UBLP-40) as a probiotic. The treatment mix was formulated to contain more than 10% fat, 8.6% milk solids not fat, 2% inulin, 15% sugar, 0.4% stabilizer-emulsifier combination and probiotic Lactobacillus plantarum culture. Physico-chemical, microbiological and sensory qualities of control and synbiotic ice cream were compared . Synbiotic ice cream showed higher whipping ability (p

Anthropogenic disturbances in the Chesapeake Bay (USA) have depleted eastern oysterCrassostrea virginicaabundance and altered the estuary’s environment and water quality. Efforts to rehabilitate oyster populations are underway; however, the effect of oyster biodeposits on water quality and plankton community structure are not clear. In July 2017, we used 6 shear turbulence resuspension mesocosms (STURMs) to determine differences in plankton composition with and without the daily addition of oyster biodeposits to a muddy sediment bottom. STURM systems had a volume-weighted root mean square turbulent velocity of 1.08 cm s-1, energy dissipation rate of ~0.08 cm2s-3, and bottom shear stress of ~0.36-0.51 Pa during mixing-on periods during 4 wk of tidal resuspension. Phytoplankton increased their chlorophyllacontent in their cells in response to low light in tanks with biodeposits. The diatomSkeletonema costatumbloomed and had significantly longer chains in tanks without biodeposits. These tanks also had significantly lower concentrations of total suspended solids, zooplankton carbon, and nitrite +nitrate, and higher phytoplankton carbon concentrations. Results suggest that the absence of biodeposit resuspension initiates nitrogen uptake for diatom reproduction, increasing the cell densities ofS. costatum. The low abundance of the zooplankton population in non-biodeposit tanks suggests an inability of zooplankton to graze onS. costatumand negative effects ofS. costatumon zooplankton. A high abundance of the copepodAcartia tonsain biodeposit tanks may have reducedS. costatumchain length. Oyster biodeposit addition and resuspension efficiently transferred phytoplankton carbon to zooplankton carbon, thus supporting the food web in the estuary.

Polyglutamine (polyQ) tract expansion leads to proteotoxic misfolding and drives a family of nine diseases. We study spinal and bulbar muscular atrophy (SBMA), a progressive degenerative disorder of the neuromuscular system caused by the polyQ androgen receptor (AR). Using a knock-in mouse model of SBMA, AR113Q mice, we show that E3 ubiquitin ligases which are a hallmark of the canonical muscle atrophy machinery are not induced in AR113Q muscle. Similarly, we find no evidence to suggest dysfunction of signaling pathways that trigger muscle hypertrophy or impairment of the muscle stem cell niche. Instead, we find that skeletal muscle atrophy is characterized by diminished function of the transcriptional regulator Myocyte Enhancer Factor 2 (MEF2), a regulator of myofiber homeostasis. Decreased expression of MEF2 target genes is age- and glutamine tract length-dependent, occurs due to polyQ AR proteotoxicity, and is associated with sequestration of MEF2 into intranuclear inclusions in muscle. Skeletal muscle from R6/2 mice, a model of Huntington disease which develops progressive atrophy, also sequesters MEF2 into inclusions and displays age-dependent loss of MEF2 target genes. Similarly, SBMA patient muscle shows loss of MEF2 target gene expression, and restoring MEF2 activity in AR113Q muscle rescues fiber size and MEF2-regulated gene expression. This work establishes MEF2 impairment as a novel mechanism of skeletal muscle atrophy downstream of toxic polyglutamine proteins and as a therapeutic target for muscle atrophy in these disorders.

Analysis of expression of the immediate early gene c-Fos in neuronal populations is a commonly used method to assess changes in neuronal activity due to various factors of interest. However, different levels of c-Fos have been observed between control animals across studies. The present investigation assessed whether such differences could reflect different behavioral or physiological states in housing conditions that are typically considered naïve controls. Specifically, we assessed c-Fos expression in 19 brain regions in male C57BL6/J mice that were housed either socially (in groups of four/cage) or individually. c-Fos expression was compared with socially-housed mice under either normal or reverse light conditions to assess the effect of light cycle on neuronal activity. We identified three main patterns of differences between groups. Light, but not social housing conditions, influenced c-Fos expression in the suprachiasmatic nucleus of hypothalamus and the dentate gyrus (DG). A large number of brain regions across cortex, hypothalamus, ventral striatum and midbrain showed increased activity during the dark phase of circadian cycle only in the social, but not individual, housing. Finally, activity in the amygdala appeared to be induced by social housing conditions only during the dark phase of circadian cycle. Taken together, our experiment identified differential regulation of c-Fos expression by basal housing conditions and circadian phase. It also indicates that despite the well-known habituation of c-Fos expression to repeated stimulation, this expression is sensitive to basal housing conditions. This sensitivity needs to be taken into account when analyzing c-Fos data in various studies.

Androgen receptor (AR) action is a hallmark of prostate cancer (PCa) with androgen deprivation being standard therapy. Yet, resistance arises and aberrant AR signaling promotes disease. We sought compounds that inhibited genes driving cancer but not normal growth and hypothesized that genes with consensus androgen response elements (cAREs) drive proliferation but genes with selective elements (sAREs) promote differentiation. In a high-throughput promoter-dependent drug screen, doxorubicin (dox) exhibited this ability, acting on DNA rather than AR. This dox effect was observed at low doses for multiple AR target genes in multiple PCa cell lines and also occurred in vivo. Transcriptomic analyses revealed that low dox downregulated cell cycle genes while high dox upregulated DNA damage response genes. In chromatin immunoprecipitation (ChIP) assays with low dox, AR binding to sARE-containing enhancers increased, whereas AR was lost from cAREs. Further, ChIP-seq analysis revealed a subset of genes for which AR binding in low dox increased at pre-existing sites that included sites for prostate-specific factors such as FOXA1. AR dependence on cofactors at sAREs may be the basis for differential modulation by dox that preserves expression of genes for survival but not cancer progression. Repurposing of dox may provide unique opportunities for PCa treatment.

Metabolism and development must be closely coupled to meet the changing physiological needs of each stage in the life cycle. The molecular mechanisms that link these pathways, however, remain poorly understood. Here we show that the Drosophila estrogen-related receptor (dERR) directs a transcriptional switch in mid-pupae that promotes glucose oxidation and lipogenesis in young adults. dERR mutant adults are viable but display reduced locomotor activity, susceptibility to starvation, elevated glucose, and an almost complete lack of stored triglycerides. Molecular profiling by RNA-seq, ChIP-seq, and metabolomics revealed that glycolytic and pentose phosphate pathway genes are induced by dERR, and their reduced expression in mutants is accompanied by elevated glycolytic intermediates, reduced TCA cycle intermediates, and reduced levels of long chain fatty acids. Unexpectedly, we found that the central pathways of energy metabolism, including glycolysis, the tricarboxylic acid cycle, and electron transport chain, are coordinately induced at the transcriptional level in mid-pupae and maintained into adulthood, and this response is partially dependent on dERR, leading to the metabolic defects observed in mutants. Our data support the model that dERR contributes to a transcriptional switch during pupal development that establishes the metabolic state of the adult fly.

Population dynamics of marine species that are sessile as adults are driven by oceanographic dispersal of larvae from spawning to nursery grounds. This is mediated by life-history traits such as the timing and frequency of spawning, larval behaviour and duration, and settlement success. Here, we use 1725 single nucleotide polymorphisms (SNPs) to study the fine scale spatial genetic structure in the commercially important cockle species Cerastoderma edule and compare it to environmental variables and current-mediated larval dispersal within a modelling framework. Hydrodynamic modelling employing the NEMO Atlantic Margin Model (AMM15) was used to simulate larval transport and estimate connectivity between populations during spawning months (April - September), factoring in larval duration and seasonal variability of ocean currents. Results at neutral loci reveal the existence of three separate genetic clusters (mean FST=0.021) within a relatively fine spatial scale in the northwest Atlantic. Environmental association (EA) analysis indicates that oceanographic currents and geographical distance between the populations explain over 20% of the variance observed at neutral loci, while genetic variance (71%) at outlier loci was explained by sea surface temperatures extremes. These results fill an important knowledge gap in the management of a commercially important, overexploited species, and bring us closer to understanding the role of larval dispersal in connecting populations at a fine geographical scale.

Polyglutamine (polyQ) tract polymorphism within the human androgen receptor (AR) shows population heterogeneity. African American men possess short polyQ tracts significantly more frequently than Caucasian American men. The length of polyQ tracts is inversely correlated with the risk of prostate cancer, age of onset, and aggressiveness at diagnosis. Aberrant activation of Wnt signaling also reveals frequently in advanced prostate cancer, and an enrichment of androgen and Wnt signaling activation has been observed in African American patients. Here, we assessed aberrant expression of AR bearing different polyQ tracts and stabilized β-catenin in prostate tumorigenesis using newly generated mouse models. We observed an early onset oncogenic transformation, accelerated tumor cell growth, and aggressive tumor phenotypes in the compound mice bearing short polyQ tract AR and stabilized β-catenin. RNA sequencing analysis showed a robust enrichment of Myc-regulated downstream genes in tumor samples bearing short polyQ AR versus those with longer polyQ tract AR. Upstream regulator analysis further identified Myc as the top candidate of transcriptional regulators in tumor cells from the above mouse samples with short polyQ tract AR and β-catenin. Chromatin immunoprecipitation analyses revealed increased recruitment of β-catenin and AR on the c-Myc gene regulatory locus in the tumor tissues expressing stabilized β-catenin and shorter polyQ tract AR. These data demonstrate a promotional role of aberrant activation of Wnt/β-catenin in combination with short polyQ AR expression in prostate tumorigenesis and suggest a potential mechanism underlying aggressive prostatic tumor development, which has been frequently observed in African American patients.

CD4+ and CD8+ T cells are dichotomous lineages in adaptive immunity. While conventionally viewed as distinct fates that are fixed after thymic development, accumulating evidence indicates that these two populations can exhibit significant lineage plasticity, particularly upon TCR-mediated activation. We define a novel CD4-CD8αβ+ MHC II-recognizing population generated by lineage conversion from effector CD4+ T cells. CD4-CD8αβ+ effector T cells downregulated the expression of T helper cell-associated costimulatory molecules and increased the expression of cytotoxic T lymphocyte-associated cytotoxic molecules. This shift in functional potential corresponded with a CD8+-lineage skewed transcriptional profile. TCRβ repertoire sequencing and in vivo genetic lineage tracing in acutely infected wild-type mice demonstrated that CD4-CD8αβ+ effector T cells arise from fundamental lineage reprogramming of bona fide effector CD4+ T cells. Impairing autophagy via functional deletion of the initiating kinase Vps34 or the downstream enzyme Atg7 enhanced the generation of this cell population. These findings suggest that effector CD4+ T cells can exhibit a previously unreported degree of skewing towards the CD8+ T cell lineage, which may point towards a novel direction for HIV vaccine design.

Phenotypic plasticity is an important driver of species resilience. Often mediated by epigenetic changes, phenotypic plasticity enables individual genotypes to express variable phenotypes in response to environmental change. Barramundi (Lates calcarifer) is a protandrous (male-first) sequential hermaphrodite that exhibit plasticity in length-at-sex change between geographic regions. This plasticity is likely to be mediated by changes in DNA methylation (DNAm), a well-studied epigenetic modification. However, region-specific relationships between length, sex and DNAm in sequential hermaphrodites were previously unreported. To investigate these relationships, here we compare DNAm in four conserved vertebrate sex-determining genes in male and female barramundi of differing lengths from three regions of northern Australia. Despite a strong association between increasing length and male-to-female sex change, the data reveal that DNAm becomes more sex-specific (rather than more female-specific) with length. Significant differences in DNAm between males and females of similar lengths suggest that female-specific DNAm arises rapidly during sex change, rather than gradually with growth. The findings also reveal that region-specific differences in length-at-sex change are accompanied by differences in DNAm, and were concurrent with variability in remotely sensed sea temperature and salinity. Together, these findings provide the first in situ evidence for epigenetically and environmentally mediated sex change in a protandrous hermaphrodite, and offer significant insight into the molecular and ecological processes governing the marked and unique plasticity of sex in fish.

Oxytocin and its paralogue, vasopressin, are widely studied biomarkers in relation to pregnancy and birth, maternal and social behavior, and mental health. Epigenetics is a biological mechanism that mediates the link between environmental influences and behavioral patterns. In a candidate gene approach, we describe here a DNA methylation assay of two regions within the oxytocin system, using human buccal cells and next-generation sequencing. Two nanograms of DNA were sufficient to assess the DNA methylation status of 28 CpG sites (22 corresponding to the oxytocin receptor and 6 corresponding to the vasopressin/oxytocin intergenic region). This method proved to be non-invasive for the participants, and reproducible; its validity remains to be confirmed alongside other biomarkers of gene function.

This study examined the associations between PM (2.5 and 10) and global DNA methylation among 100 e-waste workers and 51 non-e-waste workers serving as controls. Long interspersed nucleotide repetitive elements-1 (LINE-1) was measured by pyrosequencing. Personal PM

Lyme disease, the most common tick-borne illness in the United States, is most frequently caused by infection withBorrelia burgdorferi. Although early antibiotic treatment can prevent development of severe illness and late manifestations, diagnosis is challenging in patients who do not present with a typical erythema migrans rash. To support a diagnosis of Lyme disease in such cases, guidelines recommend 2-tiered serologic testing. However, 2-tiered testing has numerous limitations, including ambiguity in interpretation and lower sensitivity in early disease. We developed a diagnostic approach for Lyme disease based on the T-cell response toB. burgdorferiinfection by immunosequencing T-cell receptor (TCR) repertoires in blood samples from 3 independent cohorts of patients with laboratory-confirmed or clinically diagnosed early Lyme disease, as well as endemic and non-endemic controls. We identified 251 public, Lyme-associated TCRs that were used to train a classifier for detection of early Lyme disease with 99% specificity. In a validation cohort of individuals with early Lyme disease, TCR testing demonstrated a 1.9-fold increase in sensitivity compared to standard 2-tiered testing (STTT; 56% versus 30%), with a 3.1-fold increase ≤4 days from the onset of symptoms (44% versus 14%). TCR positivity predicted subsequent seroconversion in 37% of initially STTT-negative patients, suggesting that the T-cell response is detectable before the humoral response. While positivity for both tests declined after treatment, greater declines in posttreatment sensitivity were observed for STTT compared to TCR testing. Higher TCR scores were associated with clinical measures of disease severity, including abnormal liver function test results, disseminated rash, and number of symptoms. A subset of Lyme-associated TCRs mapped toB. burgdorferiantigens, demonstrating high specificity of a TCR immunosequencing approach. These results support the clinical utility of T-cell‒based testing as a sensitive and specific diagnostic for early Lyme disease, particularly in the initial days of illness.

Cancer immunotherapy has shown huge potential in the fight against cancer, but only a small proportion of patients respond successfully to treatment. Non-invasive methods to stratify responders from non-responders are critically important as immune therapies are often associated with immune-related side effects. Currently, conventional clinical imaging modalities do not provide a useful measure of immune therapy efficacy. Sensitive imaging biomarkers that provide information about the tumoural microenvironment may provide useful insights allowing for improved patient management. We have assessed the ability of a number of radiopharmaceuticals to non-invasively measure different aspects of the tumour microenvironment and correlated tumour uptake to immune therapy response in a syngeneic model of colon cancer, CT26-WT. Four radiopharmaceuticals, [18F]FDG (a glucose analogue), [18F]FEPPA (a marker for macrophage activation), [18F]FB-IL2 (a marker for CD25+ cells) and [68Ga] Ga-mNOTA-GZP (a marker for granzyme B, the serine protease downstream effector of cytotoxic T cells), were assessed as potential biomarkers to help stratify response to PD-1 monotherapy or combined anti-PD1 and CLTA4 therapy in vivo correlating tumour uptake with changes in tumour-associated immune cell populations. [18F]FDG, [18F]FEPPA and [18F]FB-IL2 (a marker for CD25+ cells) showed limited ability to determine therapy response and showed little correlation to tumour-associated immune cell changes. However, [68Ga] Ga-mNOTA-GZP showed good predictive ability and correlated well with changes in tumour-associated T cells, especially CD8+ T cells. [68Ga]Ga-mNOTA-GZP uptake correlates well with changes in CD8+ T cell populations supporting continued development of granzyme B-based imaging agents for stratification of response to immunotherapy. Early assessment of immunotherapy efficacy with [68Ga]Ga-mNOTA-GZP may allow for the reduction of unnecessary side effects while significantly improving patient management.

Background and Purpose Mitragyna speciosa, more commonly known as kratom, is a plant that contains opioidergic alkaloids but is unregulated in most countries. Kratom is used in the self‐medication of chronic pain and to reduce illicit and prescription opioid dependence. Kratom may be less dangerous than typical opioids because of the stronger preference of kratom alkaloids to induce receptor interaction with G proteins over β‐arrestin proteins. We hypothesized that kratom (alkaloids) can also reduce alcohol intake. Experimental Approach We pharmacologically characterized kratom extracts, kratom alkaloids (mitragynine, 7‐hydroxymitragynine, paynantheine, and speciogynine) and synthetic carfentanil‐amide opioids for their ability to interact with G proteins and β‐arrestin at μ, δ, and κ opioid receptors in vitro. We used C57BL/6 mice to assess to which degree these opioids could reduce alcohol intake and whether they had rewarding properties. Key Results Kratom alkaloids were strongly G protein‐biased at all three opioid receptors and reduced alcohol intake, but kratom and 7‐hydroxymitragynine were rewarding. Several results indicated a key role for δ opioid receptors, including that the synthetic carfentanil‐amide opioid MP102—a G protein‐biased agonist with modest selectivity for δ opioid receptors—reduced alcohol intake, whereas the G protein‐biased μ opioid agonist TRV130 did not. Conclusion and Implications Our results suggest that kratom extracts can decrease alcohol intake but still carry significant risk upon prolonged use. Development of more δ opioid‐selective synthetic opioids may provide a safer option than kratom to treat alcohol use disorder with fewer side effects., ▪

A new species of squat lobster, Mesogalathea ardua sp. nov., is described on the basis of newly collected dorsal carapaces from an Upper Jurassic reefal limestone olistolith at Velika Strmica. The fossiliferous olistolith is situated within Upper Cretaceous flysch-type deposits, but originally formed within the central parastromatoporoid zone of a Jurassic reef complex. Mesogalathea ardua sp. nov. represents the first formal description of a Jurassic squat lobster from Slovenia and extends the known palaeobiogeographical distribution of galatheoid anomurans.

We studied the role of oceanographic conditions and life history strategies on recovery after extinction in a metapopulation of marine organisms dispersing as pelagic larvae. We combined an age‐structured model with scenarios defined by realistic oceanographic conditions and species distribution along the Irish Sea coast (North Europe). Species life history strategies were modeled combining the dispersal behaviors with two levels of fecundity. Recovery times were quantified after simulating extinction in four regions. Two alternative strategies (high fecundity or larval tidal transport) led to short recovery times, irrespective of the effects of other drivers. Other strategies and low larval survival exacerbated the effects of oceanographic conditions on recovery times: longer times were associated with for example the presence of frontal zones isolating regions of extinction. Recovery times were well explained by the connectivity of each focal population with those located outside the area of extinction (which was higher in the so‐called small world topologies), but not by subsidies (direct connections with populations located nearby). Our work highlights the complexities involved in population recovery: specific trait combinations may blur the effects of the habitat matrix on recovery times; K‐strategists (i.e., with low fecundities) may achieve quick recovery if they possess the appropriate dispersal traits. High larval mortality can exacerbate the effect of oceanographic conditions and lead to heterogeneity in recovery times. Overall, processes driving whole network topologies rather than conditions surrounding local populations are the key to understand patterns of recovery.

Summary: Identifying T cell clones associated with human autoimmunity has remained challenging. Intriguingly, many autoimmune diseases, including multiple sclerosis (MS), show strongly diminished activity during pregnancy, providing a unique research paradigm to explore dynamics of immune repertoire changes during active and inactive disease. Here, we characterize immunomodulation at the single-clone level by sequencing the T cell repertoire in healthy women and female MS patients over the course of pregnancy. Clonality is significantly reduced from the first to third trimester in MS patients, indicating that the T cell repertoire becomes less dominated by expanded clones. However, only a few T cell clones are substantially modulated during pregnancy in each patient. Moreover, relapse-associated T cell clones identified in an individual patient contract during pregnancy and expand during a postpartum relapse. Our data provide evidence that profiling the T cell repertoire during pregnancy could serve as a tool to discover and track “private” T cell clones associated with disease activity in autoimmunity. : Ramien et al. interrogate the immune repertoire in multiple sclerosis (MS) during pregnancy. They report a shift in T cell repertoire composition driven by a small number of “private” clones. This specific rather than global immunomodulation may help to explain the protective effect of pregnancy in human autoimmunity. Keywords: multiple sclerosis, pregnancy, T cell receptor α and β pairing, immunosequencing, repertoire sequencing, immune phenotyping, immune tolerance, human

Galatheoid decapod crustaceans consist of ~1250 species today, but their evolutionary history and origin are poorly known. We studied the largest known fossil galatheoid assemblage, from the Late Jurassic of Ernstbrunn, Austria. This coral-associated assemblage yielded 2348 specimens, arranged in 53 species, 22 genera and six families. Rarefaction analyses show that nearly all taxa have been collected. In addition to abundant Munidopsidae, this assemblage also contains the oldest members of four of the six galatheoid families, including Galatheidae, Munididae, Paragalatheidae and Porcellanidae. We describe the oldest Porcellanidae and Galatheidae to date, and a catillogalatheid: Vibrissalana jurassica gen. et sp. nov., ?Galathea genesis sp. nov. and Galatheites britmelanarum sp. nov. Our re-examination of the oldest claimed porcellanid, Jurellana tithonia, from Ernstbrunn, indicates that it represents a homolodromioid brachyuran, ascribed to Jurellanidae fam. nov. along with Ovalopus gen. nov. The second-oldest claimed porcellanid, Early Cretaceous Petrolisthes albianicus, is transferred to the catillogalatheid Hispanigalathea. We further document that 10.4% of Ernstbrunn galatheoid specimens were parasitized by epicaridean isopods, as shown by swellings in the gill region. Statistical analyses indicate that infestation is near non-random, varying from 0 to 33% for common species. Thus, Late Jurassic coral-associated habitats were key ecosystems in the evolution of galatheoids and their parasites.

Background Ankylosing spondylitis (AS) is a chronic inflammatory disease with worldwide high prevalence. Although AS is strongly associated with HLA-B27 MHC-I antigen presentation, the role played by αβ T cells in AS remains elusive. Methods Utilizing TCRβ repertoire sequencing and bioinformatics tools developed in house, we analyzed overall TCR repertoire structures and antigen-recognizing CDR3 motifs in AS patients with different disease activities. Findings We found that disease progression is associated with both CD4+ and CD8+ T cell oligo-clonal expansion, which suggests that αβ T cell activation may mediate AS disease progression. By developing a bioinformatics platform to dissect antigen-specific responses, we discovered a cell population consisting of both CD4+ and CD8+ T cells expressing identical TCRs, herein termed CD4/8 T cells. CD4/8 clonotypes were highly enriched in the spondyloarthritic joint fluid of patients, and their expansion correlated with the activity of disease. Interpretation These results provide evidence on the T cell clone side to reveal the potential role of CD4/8 T cells in the etiology of AS development.

Summary The temporal order of DNA replication is regulated during development and is highly correlated with gene expression, histone modifications and 3D genome architecture. We tracked changes in replication timing, gene expression, and chromatin conformation capture (Hi-C) A/B compartments over the first two cell cycles during differentiation of human embryonic stem cells to definitive endoderm. Remarkably, transcriptional programs were irreversibly reprogrammed within the first cell cycle and were largely but not universally coordinated with replication timing changes. Moreover, changes in A/B compartment and several histone modifications that normally correlate strongly with replication timing showed weak correlation during the early cell cycles of differentiation but showed increased alignment in later differentiation stages and in terminally differentiated cell lines. Thus, epigenetic cell fate transitions during early differentiation can occur despite dynamic and discordant changes in otherwise highly correlated genomic properties., Graphical Abstract, Highlights • Stable transcriptional reprogramming toward endoderm within one cell cycle • Replication timing can change in the first S phase of a cell fate change • Early discordance between Replication timing and Hi-C compartments • Alignment of replication timing to compartments increases in later cell cycles, The temporal order of DNA replication is regulated during development, and is highly correlated with gene expression, chromatin structure, and 3D-genome architecture. Gilbert and colleagues find that stable transcriptional changes of human embryonic stem cells to endoderm can occur within a single cell cycle, accompanied by discordance in replication timing and chromatin compartment that align in later differentiation stages.

A paradigm shifting study demonstrated that induction of MHC class E and II-restricted CD8+ T cells was associated with the clearance of SIV infection in rhesus macaques. Another recent study highlighted the presence of HIV-1-specific class II-restricted CD8+ T cells in HIV-1 patients who naturally control infection (virus controllers; VCs). However, questions regarding class II-restricted CD8+ T cells ontogeny, distribution across different HIV-1 disease states and their role in viral control remain unclear. In this study, we investigated the distribution and anti-viral properties of HLA-DRB1*0701 and DQB1*0501 class II-restricted CD8+ T cells in different HIV-1 patient cohorts; and whether class II-restricted CD8+ T cells represent a unique T cell subset. We show that memory class II-restricted CD8+ T cell responses were more often detectable in VCs than in chronically infected patients, but not in healthy seronegative donors. We also demonstrate that VC CD8+ T cells inhibit virus replication in both a class I- and class II-dependent manner, and that in two VC patients the class II-restricted CD8+ T cells with an anti-viral gene signature expressed both CD4+ and CD8+ T cell lineage-specific genes. These data demonstrated that anti-viral memory class II-restricted CD8+ T cells with hybrid CD4+ and CD8+ features are present during natural HIV-1 infection.

The pneumococcus remains a common cause of otitis media (OM) despite the widespread introduction of pneumococcal conjugate vaccines. In mice, a pneumococcal whole cell vaccine (WCV) induces serotype-independent protection against pneumococcal colonisation and invasive disease via TH17- and antibody-mediated immunity, respectively. We investigated the effect of WCV on influenza A-induced pneumococcal OM in an infant mouse model. C57BL/6 mice were immunised subcutaneously with a single dose of WCV or adjuvant at 6 days of age, infected with pneumococci (EF3030 [serotype 19F] or PMP1106 [16F]) at 12 days of age, and given influenza A virus (A/Udorn/72/307 [H3N2], IAV) at 18 days of age to induce pneumococcal OM. Pneumococcal density in middle ear and nasopharyngeal tissues was determined 6 and 12 days post-virus. Experiments were repeated in antibody (B6.μMT-/-)- and CD4+ T-cell-deficient mice to investigate the immune responses involved. A single dose of WCV did not prevent the development of pneumococcal OM, nor accelerate pneumococcal clearance compared with mice receiving adjuvant alone. However, WCV reduced the density of EF3030 in the middle ear at 6 days post-viral infection (p = 0.022), and the density of both isolates in the nasopharynx at 12 days post-viral infection (EF3030, p = 0.035; PMP1106, p = 0.011), compared with adjuvant alone. The reduction in density in the middle ear required antibodies and CD4+ T cells: WCV did not reduce EF3030 middle ear density in B6.μMT-/- mice (p = 0.35) nor in wild-type mice given anti-CD4 monoclonal antibody before and after IAV inoculation (p = 0.91); and WCV-immunised CD4+ T cell-deficient GK1.5 mice had higher levels of EF3030 in the middle ear than their adjuvant-immunised counterparts (p = 0.044). A single subcutaneous dose of WCV reduced pneumococcal density in the middle ears of co-infected mice in one of two strains tested, but did not prevent OM from occurring in this animal model.

Orchardgrass, or cocksfoot (Dactylis glomerata L.), is a cool-season forage grass susceptible to the choke disease caused by Epichloë typhina. Choke has been reported in orchardgrass seed production fields across the temperate regions of the world, but fungicides have not been efficacious in reducing choke incidence or prevalence. To assess the potential for genetic resistance or tolerance of orchardgrass to choke, we evaluated the variation in orchardgrass cultivars and accessions for choke prevalence and characterized infected plants for endophyte secondary metabolite and mating type gene presence. Significant variation was detected across years and locations. Choke prevalence did not always increase with the age of the stand, nor did choke prevalence correlate with flowering time or swathing time of the entries. Both mating types of E. typhina were detected in approximately equal proportions, and no evidence for loline, ergot alkaloid, or indole-diterpene biosynthesis was found. Plants with multiple infected tillers often showed more than one mating type present in the plant, indicating multiple infection events rather than a single infection event that spread to multiple tillers. Both accessions and cultivars with significant choke, and no choke, were detected, which constitute sources of germplasm for further testing and breeding.

Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a severe complication of malaria that occurs despite effective antimalarial treatment. Currently, noninvasive imaging procedures such as chest X-rays are used to assess edema in established MA-ARDS, but earlier detection methods are needed to reduce morbidity and mortality. The early stages of MA-ARDS are characterized by the infiltration of leukocytes, in particular monocytes/macrophages; thus, monitoring of immune infiltrates may provide a useful indicator of early pathology. In this study, Plasmodium berghei ANKA-infected C57BL/6 mice, a rodent model of MA-ARDS, were longitudinally imaged using the 18-kDa translocator protein (TSPO) imaging agent [(18)F]FEPPA as a marker of macrophage accumulation during the development of pathology and in response to combined artesunate and chloroquine diphosphate (ART+CQ) therapy. [(18)F]FEPPA uptake was compared to blood parasitemia levels and to levels of pulmonary immune cell infiltrates by using flow cytometry. Infected animals showed rapid increases in lung retention of [(18)F]FEPPA, correlating well with increases in blood parasitemia and pulmonary accumulation of interstitial inflammatory macrophages and major histocompatibility complex class II (MHC-II)-positive alveolar macrophages. Treatment with ART+CQ abrogated this increase in parasitemia and significantly reduced both lung uptake of [(18)F]FEPPA and levels of macrophage infiltrates. We conclude that retention of [(18)F]FEPPA in the lungs is well correlated with changes in blood parasitemia and levels of lung-associated macrophages during disease progression and in response to ART+CQ therapy. With further development, TSPO biomarkers may have the potential to accurately assess the early onset of MA-ARDS.