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Potent antiretroviral therapy (ART) suppresses HIV-1 viral replication and results in decreased morbidity and mortality. However, prolonged treatment is associated with drug-induced toxicity, emergence of drug-resistant viral strains, and financial constraints. Structured therapeutic interruptions (STIs) have been proposed as a strategy that could boost HIV-specific immunity, through controlled exposure to autologous virus over limited time periods, and subsequently control viral replication in the absence of ART. Here, we analyzed the impact of repeated STIs on virological and immunological parameters in a large prospective STI study. We show that: (i) the plateau virus load (VL) reached after STIs correlated with pretreatment VL, the amount of viral recrudescence during the treatment interruptions, and the off-treatment viral rebound rate; (ii) the magnitude and the breadth of the HIV-specific CD8+T lymphocyte response, despite marked interpatient variability, increased overall with STI. However, the quantity and quality of the post-STI response was comparable to the response observed before any therapy; (iii) individuals with strong and broad HIV-specific CD8+T lymphocyte responses at baseline retained these characteristics during and after STI; (iv) the increase in HIV-specific CD8+T lymphocyte frequencies induced by STI was not correlated with decreased viral set point after STI; and (v) HIV-specific CD4+T lymphocyte responses increased with STI, but were subsequently maintained only in patients with low pretreatment and plateau VLs. Overall, these data indicate that STI-induced quantitative boosting of HIV-specific cellular immunity was not associated with substantial change in viral replication and that STI was largely restoring pretherapy CD8+T cell responses in patients with established infection.

The potent ability of current antiretroviral drug regimens to control human immunodeficiency Virus-1 (HIV-1) replication, in conjunction with the clinical practice of structured therapeutic interruptions, provides a system in which virus levels are manipulated during a persistent infection in humans. Here, we exploit this system to examine the impact of variable plasma virus load (pVL) on the functionality of HIV-specific CD8+ T-lymphocyte populations. Using both ELISpot methodology and intracellular cytokine staining for interferon (IFN)-gamma to assess functional status, together with fluorochrome-labeled peptide-major histocompatibility complex (pMHC) class I tetramer analysis to detect the physical presence of CD8+ T lymphocytes expressing cognate T-cell receptors (TCRs), we observed that the proportion of HIV-specific CD8+ T lymphocytes capable of mounting an effector response to antigen challenge directly ex vivo is related to the kinetics of virus exposure. Specifically, (a) after prolonged suppression of pVL with antiretroviral therapy (ART), physical and functional measures of HIV-specific CD8+ T-lymphocyte frequencies approximated; and (b) the percentage of functionally responsive cells in the HIV-specific CD8+ T lymphocyte populations declined substantially when therapy was discontinued and pVL recrudesced in the same patients. These results corroborate and extend observations in animal models that describe nonresponsive CD8+ T lymphocytes in the presence of high levels of antigen load and have implications for the interpretation of quantitative data generated by methods that rely on functional readouts.

The potent ability of current antiretroviral drug regimens to control human immunodeficiency Virus-1 (HIV-1) replication, in conjunction with the clinical practice of structured therapeutic interruptions, provides a system in which virus levels are manipulated during a persistent infection in humans. Here, we exploit this system to examine the impact of variable plasma virus load (pVL) on the functionality of HIV-specific CD8+ T-lymphocyte populations. Using both ELISpot methodology and intracellular cytokine staining for interferon (IFN)-gamma to assess functional status, together with fluorochrome-labeled peptide-major histocompatibility complex (pMHC) class I tetramer analysis to detect the physical presence of CD8+ T lymphocytes expressing cognate T-cell receptors (TCRs), we observed that the proportion of HIV-specific CD8+ T lymphocytes capable of mounting an effector response to antigen challenge directly ex vivo is related to the kinetics of virus exposure. Specifically, (a) after prolonged suppression of pVL with antiretroviral therapy (ART), physical and functional measures of HIV-specific CD8+ T-lymphocyte frequencies approximated; and (b) the percentage of functionally responsive cells in the HIV-specific CD8+ T lymphocyte populations declined substantially when therapy was discontinued and pVL recrudesced in the same patients. These results corroborate and extend observations in animal models that describe nonresponsive CD8+ T lymphocytes in the presence of high levels of antigen load and have implications for the interpretation of quantitative data generated by methods that rely on functional readouts.

Malignant Pleural Mesothelioma (MPM) is typically diagnosed 20–50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory. To elucidate this path, we conducted multi-regional exome sequencing of 90 tumour samples from 22 MPMs acquired at surgery. Here we show that exomic intratumour heterogeneity varies widely across the cohort. Phylogenetic tree topology ranges from linear to highly branched, reflecting a steep gradient of genomic instability. Using transfer learning, we detect repeated evolution, resolving 5 clusters that are prognostic, with temporally ordered clonal drivers. BAP1 /−3p21 and FBXW7 /-chr4 events are always early clonal. In contrast, NF2 /−22q events, leading to Hippo pathway inactivation are predominantly late clonal, positively selected, and when subclonal, exhibit parallel evolution indicating an evolutionary constraint. Very late somatic alteration of NF2 /22q occurred in one patient 12 years after surgery. Clonal architecture and evolutionary clusters dictate MPM inflammation and immune evasion. These results reveal potentially drugable evolutionary bottlenecking in MPM, and an impact of clonal architecture on shaping the immune landscape, with potential to dictate the clinical response to immune checkpoint inhibition. The impact of intratumour heterogeneity on immune surveillance and clinical outcomes has not been adequately explored in malignant pleural mesothelioma (MPM). Here the authors analyse the influence of evolution on the survival and immune landscape of MPM patients using multi-region sequencing data.

Oceanic heatwaves have significant impacts on disease dynamics in marine ecosystems. Following an extreme heatwave in Nanoose Bay, British Columbia, Canada, a severe sea cucumber wasting event occurred that resulted in the mass mortality of Apostichopus californicus. Here, we sought to determine if heat stress in isolation could trigger wasting symptoms in A. californicus . We exposed sea cucumbers to (i) a simulated marine heatwave (22 °C), (ii) an elevated temperature treatment (17 °C), or (iii) control conditions (12 °C). We measured the presence of skin lesions, mortality, posture maintenance, antipredator defences, spawning, and organ evisceration during the 79-hour thermal exposure, as well as 7-days post-exposure. Both the 22 °C and 17 °C treatments elicited stress responses where individuals exhibited a reduced ability to maintain posture and an increase in stress spawning. The 22 °C heatwave was particularly stressful, as it was the only treatment where mortality was observed. However, none of the treatments induced wasting symptoms as observed in the Nanoose Bay event. This study provides evidence that sea cucumber wasting may not be triggered by heat stress in isolation, leaving the cause of the mass mortality event observed in Nanoose unknown.

Clinical research in neurodevelopmental disorders remains reliant upon clinician and caregiver measures. Limitations of these approaches indicate a need for objective, quantitative, and reliable biomarkers to advance clinical research. Extant research suggests the potential utility of multiple candidate biomarkers; however, effective application of these markers in trials requires additional understanding of replicability, individual differences, and intra-individual stability over time. The Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is a multi-site study designed to investigate a battery of electrophysiological (EEG) and eye-tracking (ET) indices as candidate biomarkers for autism spectrum disorder (ASD). The study complements published biomarker research through: inclusion of large, deeply phenotyped cohorts of children with ASD and typical development; a longitudinal design; a focus on well-evidenced candidate biomarkers harmonized with an independent sample; high levels of clinical, regulatory, technical, and statistical rigor; adoption of a governance structure incorporating diverse expertise in the ASD biomarker discovery and qualification process; prioritization of open science, including creation of a repository containing biomarker, clinical, and genetic data; and use of economical and scalable technologies that are applicable in developmental populations and those with special needs. The ABC-CT approach has yielded encouraging results, with one measure accepted into the FDA's Biomarker Qualification Program to date. Through these advances, the ABC-CT and other biomarker studies in progress hold promise to deliver novel tools to improve clinical trials research in ASD.

ObjectiveDespite advances in the identification of epigenetic alterations in pancreatic cancer, their biological roles in the pathobiology of this dismal neoplasm remain elusive. Here, we aimed to characterise the functional significance of histone lysine methyltransferases (KMTs) and demethylases (KDMs) in pancreatic tumourigenesis.DesignDNA methylation sequencing and gene expression microarrays were employed to investigate CpG methylation and expression patterns of KMTs and KDMs in pancreatic cancer tissues versus normal tissues. Gene expression was assessed in five cohorts of patients by reverse transcription quantitative-PCR. Molecular analysis and functional assays were conducted in genetically modified cell lines. Cellular metabolic rates were measured using an XF24-3 Analyzer, while quantitative evaluation of lipids was performed by liquid chromatography-mass spectrometry (LC-MS) analysis. Subcutaneous xenograft mouse models were used to evaluate pancreatic tumour growth in vivo.ResultsWe define a new antitumorous function of the histone lysine (K)-specific methyltransferase 2D (KMT2D) in pancreatic cancer. KMT2D is transcriptionally repressed in human pancreatic tumours through DNA methylation. Clinically, lower levels of this methyltransferase associate with poor prognosis and significant weight alterations. RNAi-based genetic inactivation of KMT2D promotes tumour growth and results in loss of H3K4me3 mark. In addition, KMT2D inhibition increases aerobic glycolysis and alters the lipidomic profiles of pancreatic cancer cells. Further analysis of this phenomenon identified the glucose transporter SLC2A3 as a mediator of KMT2D-induced changes in cellular, metabolic and proliferative rates.ConclusionTogether our findings define a new tumour suppressor function of KMT2D through the regulation of glucose/fatty acid metabolism in pancreatic cancer.

Background Eye tracking (ET) is a powerful methodology for studying attentional processes through quantification of eye movements. The precision, usability, and cost-effectiveness of ET render it a promising platform for developing biomarkers for use in clinical trials for autism spectrum disorder (ASD). Methods The Autism Biomarkers Consortium for Clinical Trials conducted a multisite, observational study of 6–11-year-old children with ASD ( n = 280) and typical development (TD, n = 119). The ET battery included: Activity Monitoring, Social Interactive, Static Social Scenes, Biological Motion Preference, and Pupillary Light Reflex tasks. A priori, gaze to faces in Activity Monitoring, Social Interactive, and Static Social Scenes tasks were aggregated into an Oculomotor Index of Gaze to Human Faces (OMI) as the primary outcome measure. This work reports on fundamental biomarker properties (data acquisition rates, construct validity, six-week stability, group discrimination, and clinical relationships) derived from these assays that serve as a base for subsequent development of clinical trial biomarker applications. Results All tasks exhibited excellent acquisition rates, met expectations for construct validity, had moderate or high six-week stabilities, and highlighted subsets of the ASD group with distinct biomarker performance. Within ASD, higher OMI was associated with increased memory for faces, decreased autism symptom severity, and higher verbal IQ and pragmatic communication skills. Limitations No specific interventions were administered in this study, limiting information about how ET biomarkers track or predict outcomes in response to treatment. This study did not consider co-occurrence of psychiatric conditions nor specificity in comparison with non-ASD special populations, therefore limiting our understanding of the applicability of outcomes to specific clinical contexts-of-use. Research-grade protocols and equipment were used; further studies are needed to explore deployment in less standardized contexts. Conclusions All ET tasks met expectations regarding biomarker properties, with strongest performance for tasks associated with attention to human faces and weakest performance associated with biological motion preference. Based on these data, the OMI has been accepted to the FDA’s Biomarker Qualification program, providing a path for advancing efforts to develop biomarkers for use in clinical trials.

We present the dust module in the Multiscale Online Non-hydrostatic AtmospheRe CHemistry model (MONARCH) version 2.0, a chemical weather prediction system that can be used for regional and global modeling at a range of resolutions. The representations of dust processes in MONARCH were upgraded with a focus on dust emission (emission parameterizations, entrainment thresholds, considerations of soil moisture and surface cover), lower boundary conditions (roughness, potential dust sources), and dust–radiation interactions. MONARCH now allows modeling of global and regional mineral dust cycles using fundamentally different paradigms, ranging from strongly simplified to physics-based parameterizations. We present a detailed description of these updates along with four global benchmark simulations, which use conceptually different dust emission parameterizations, and we evaluate the simulations against observations of dust optical depth. We determine key dust parameters, such as global annual emission/deposition flux, dust loading, dust optical depth, mass-extinction efficiency, single-scattering albedo, and direct radiative effects. For dust-particle diameters up to 20 µm, the total annual dust emission and deposition fluxes obtained with our four experiments range between about 3500 and 6000 Tg, which largely depend upon differences in the emitted size distribution. Considering ellipsoidal particle shapes and dust refractive indices that account for size-resolved mineralogy, we estimate the global total (longwave and shortwave) dust direct radiative effect (DRE) at the surface to range between about -0.90 and -0.63 Wm-2 and at the top of the atmosphere between -0.20 and -0.28 Wm-2. Our evaluation demonstrates that MONARCH is able to reproduce key features of the spatiotemporal variability of the global dust cycle with important and insightful differences between the different configurations.

Biomarker development is currently a high priority in neurodevelopmental disorder research. For many types of biomarkers (particularly biomarkers of diagnosis), reliability over short periods is critically important. In the field of autism spectrum disorder (ASD), resting electroencephalography (EEG) power spectral densities (PSD) are well-studied for their potential as biomarkers. Classically, such data have been decomposed into pre-specified frequency bands (e.g., delta, theta, alpha, beta, and gamma). Recent technical advances, such as the Fitting Oscillations and One-Over-F (FOOOF) algorithm, allow for targeted characterization of the features that naturally emerge within an EEG PSD, permitting a more detailed characterization of the frequency band-agnostic shape of each individual's EEG PSD. Here, using two resting EEGs collected a median of 6 days apart from 22 children with ASD and 25 typically developing (TD) controls during the Feasibility Visit of the Autism Biomarkers Consortium for Clinical Trials, we estimate test-retest reliability based on the characterization of the PSD shape in two ways: (1) Using the FOOOF algorithm we estimate six parameters (offset, slope, number of peaks, and amplitude, center frequency and bandwidth of the largest alpha peak) that characterize the shape of the EEG PSD; and (2) using nonparametric functional data analyses, we decompose the shape of the EEG PSD into a reduced set of basis functions that characterize individual power spectrum shapes. We show that individuals exhibit idiosyncratic PSD signatures that are stable over recording sessions using both characterizations. Our data show that EEG activity from a brief 2-min recording provides an efficient window into characterizing brain activity at the single-subject level with desirable psychometric characteristics that persist across different analytical decomposition methods. This is a necessary step towards analytical validation of biomarkers based on the EEG PSD and provides insights into parameters of the PSD that offer short-term reliability (and thus promise as potential biomarkers of trait or diagnosis) vs. those that are more variable over the short term (and thus may index state or other rapidly dynamic measures of brain function). Future research should address the longer-term stability of the PSD, for purposes such as monitoring development or response to treatment.