16S ribosomal RNA (rRNA) gene and other environmental sequencing techniques provide snapshots of microbial communities, revealing phylogeny and the abundances of microbial populations across diverse ...ecosystems. While changes in microbial community structure are demonstrably associated with certain environmental conditions (from metabolic and immunological health in mammals to ecological stability in soils and oceans), identification of underlying mechanisms requires new statistical tools, as these datasets present several technical challenges. First, the abundances of microbial operational taxonomic units (OTUs) from amplicon-based datasets are compositional. Counts are normalized to the total number of counts in the sample. Thus, microbial abundances are not independent, and traditional statistical metrics (e.g., correlation) for the detection of OTU-OTU relationships can lead to spurious results. Secondly, microbial sequencing-based studies typically measure hundreds of OTUs on only tens to hundreds of samples; thus, inference of OTU-OTU association networks is severely under-powered, and additional information (or assumptions) are required for accurate inference. Here, we present SPIEC-EASI (SParse InversE Covariance Estimation for Ecological Association Inference), a statistical method for the inference of microbial ecological networks from amplicon sequencing datasets that addresses both of these issues. SPIEC-EASI combines data transformations developed for compositional data analysis with a graphical model inference framework that assumes the underlying ecological association network is sparse. To reconstruct the network, SPIEC-EASI relies on algorithms for sparse neighborhood and inverse covariance selection. To provide a synthetic benchmark in the absence of an experimentally validated gold-standard network, SPIEC-EASI is accompanied by a set of computational tools to generate OTU count data from a set of diverse underlying network topologies. SPIEC-EASI outperforms state-of-the-art methods to recover edges and network properties on synthetic data under a variety of scenarios. SPIEC-EASI also reproducibly predicts previously unknown microbial associations using data from the American Gut project.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To study the pathogenesis of fatal cerebral malaria, we conducted autopsies in 31 children with this clinical diagnosis. We found that 23% of the children had actually died from other causes. The ...remaining patients had parasites sequestered in cerebral capillaries, and 75% of those had additional intra- and perivascular pathology. Retinopathy was the only clinical sign distinguishing malarial from nonmalarial coma. These data have implications for treating malaria patients, designing clinical trials and assessing malaria-specific disease associations.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The immune system can suppress tumour development both by eliminating malignant cells and by preventing the outgrowth and spread of cancer cells that resist eradication
. Clinical and experimental ...data suggest that the latter mode of control-termed cancer-immune equilibrium
-can be maintained for prolonged periods of time, possibly up to several decades
. Although cancers most frequently originate in epithelial layers, the nature and spatiotemporal dynamics of immune responses that maintain cancer-immune equilibrium in these tissue compartments remain unclear. Here, using a mouse model of transplantable cutaneous melanoma
, we show that tissue-resident memory CD8
T cells (T
cells) promote a durable melanoma-immune equilibrium that is confined to the epidermal layer of the skin. A proportion of mice (~40%) transplanted with melanoma cells remained free of macroscopic skin lesions long after epicutaneous inoculation, and generation of tumour-specific epidermal CD69
CD103
T
cells correlated with this spontaneous disease control. By contrast, mice deficient in T
formation were more susceptible to tumour development. Despite being tumour
free at the macroscopic level, mice frequently harboured melanoma cells in the epidermal layer of the skin long after inoculation, and intravital imaging revealed that these cells were dynamically surveyed by T
cells. Consistent with their role in melanoma surveillance, tumour-specific T
cells that were generated before melanoma inoculation conferred profound protection from tumour development independently of recirculating T cells. Finally, depletion of T
cells triggered tumour outgrowth in a proportion (~20%) of mice with occult melanomas, demonstrating that T
cells can actively suppress cancer progression. Our results show that T
cells have a fundamental role in the surveillance of subclinical melanomas in the skin by maintaining cancer-immune equilibrium. As such, they provide strong impetus for exploring these cells as targets of future anticancer immunotherapies.
Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed ...prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, <1% at 6 months, and ≤0.1% from 12 months onward define optimal response, whereas >10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome–positive Ph+ >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.
The enteric nervous system (ENS) consists of glial cells (EGCs) and neurons derived from neural crest precursors. EGCs retain capacity for large-scale neurogenesis in culture, and in vivo lineage ...tracing has identified neurons derived from glial cells in response to inflammation. We thus hypothesize that EGCs possess a chromatin structure poised for neurogenesis. We use single-cell multiome sequencing to simultaneously assess transcription and chromatin accessibility in EGCs undergoing spontaneous neurogenesis in culture, as well as small intestine myenteric plexus EGCs. Cultured EGCs maintain open chromatin at genomic loci accessible in neurons, and neurogenesis from EGCs involves dynamic chromatin rearrangements with a net decrease in accessible chromatin. A subset of in vivo EGCs, highly enriched within the myenteric ganglia and that persist into adulthood, have a gene expression program and chromatin state consistent with neurogenic potential. These results clarify the mechanisms underlying EGC potential for neuronal fate transition.
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•Single-cell RNA and chromatin accessibility profiling of enteric glial cells•Enteric glial cells undergo dynamic chromatin remodeling during neurogenesis•Intraganglionic enteric glial cells have distinct RNA and ATAC profiles•Intraganglionic enteric glia maintain chromatin poised for neurogenesis
By performing comprehensive single-cell transcriptomic and chromatin accessibility profiling of enteric glial cells both in culture and freshly isolated from mouse small intestine, Guyer et al. identify intraganglionic glia as a distinct subpopulation of enteric glial cells that are epigenetically poised for neurogenesis.
The 2013–2016 outbreak of Ebola virus (EBOV) in West Africa was the largest recorded. It began following the cross-species transmission of EBOV from an animal reservoir, most likely bats, into ...humans, with phylogenetic analysis revealing the co-circulation of several viral lineages. We hypothesized that this prolonged human circulation led to genomic changes that increased viral transmissibility in humans. We generated a synthetic glycoprotein (GP) construct based on the earliest reported isolate and introduced amino acid substitutions that defined viral lineages. Mutant GPs were used to generate a panel of pseudoviruses, which were used to infect different human and bat cell lines. These data revealed that specific amino acid substitutions in the EBOV GP have increased tropism for human cells, while reducing tropism for bat cells. Such increased infectivity may have enhanced the ability of EBOV to transmit among humans and contributed to the wide geographic distribution of some viral lineages.
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•EBOV adapted to humans during the West African outbreak•Amino acid substitutions in the EBOV glycoprotein increase human cell tropism•The same glycoprotein amino acid substitutions decrease tropism for bat cells
The Ebola virus acquired amino acid substitutions in its glycoprotein that increased its tropism for human cells during the West African outbreak of 2013–2016.
Abstract Background While emotion dysregulation represents an important mechanism underpinning psychological responses to trauma, little research has investigated this in refugees. In the current ...study, we examined the mediating role of emotion dysregulation in the relationship between refugee experiences (trauma and living difficulties) and psychological outcomes. Methods Participants were 134 traumatized treatment-seeking refugees who completed measures indexing trauma exposure, post-migration living difficulties, difficulties in emotion regulation, posttraumatic stress disorder, depression, and explosive anger. Results Findings revealed distinctive patterns of emotion dysregulation associated with each of these psychological disorders. Results also indicated that emotion regulation difficulties mediated the association between both trauma and psychological symptoms, and living difficulties and psychological symptoms. Limitations Limitations include a cross-sectional design and the use of measures that had not been validated across all cultural groups in this study. Conclusions These findings underscore the key role of emotion dysregulation in psychological responses of refugees, and highlight potential directions for treatment interventions for traumatized refugees.
Damp and high levels of relative humidity (RH), typically above 70–80%, are known to provide mould-favourable conditions. Exposure to indoor mould contamination has been associated with an increased ...risk of developing and/or exacerbating a range of allergic and non-allergic diseases. The VTT model is a mathematical model of indoor mould growth that was developed based on surface readings of RH and temperature on wood in a controlled laboratory chamber. The model provides a mould index based on the environmental readings. We test the generalisability of this laboratory-based model to less-controlled domestic environments across different values of model parameters. Mould indices were generated using objective measurements of RH and temperature in the air, taken from sensors in a domestic setting every 3–5 min over 1 year in the living room and bedroom across 219 homes. Mould indices were assessed against self-reports from occupants regarding the presence of visible mould growth and mouldy odour in the home. Logistic regression provided evidence for relationships between mould indices and occupant responses. Mould indices were most successful at predicting occupant responses when the model parameters encouraged higher vulnerability to mould growth compared with the original VTT model. A lower critical RH level, above which mould grows, a higher sensitivity, and larger increases in the mould index all consistently increased performance. Using moment-to-moment time-series data for temperature and RH, the model and its developments could help inform smart monitoring or control of RH, for example to counter risks associated with reduced ventilation in energy efficient homes.
•Domestic mould growth can be predicted from air relative humidity and temperature.•Best prediction performance requires a model that is sensitive to relative humidity.•Real-time predictions could inform targeted smart control to improve public health.•Implications for early intervention for contamination, reducing remediation needs.•The data provide a unique set of time-series air measurements and survey responses.
In metastatic melanoma, it is vital to identify and validate biomarkers of prognosis. Previous studies have systematically evaluated protein biomarkers or mRNA-based expression signatures. No such ...analyses have been applied to microRNA (miRNA)-based prognostic signatures. As a first step, we identified two prognostic miRNA signatures from publicly available data sets (Gene Expression Omnibus/The Cancer Genome Atlas) of global miRNA expression profiling information. A 12-miRNA signature predicted longer survival after surgery for resection of American Joint Committee on Cancer stage III disease (>4 years, no sign of relapse) and outperformed American Joint Committee on Cancer standard-of-care prognostic markers in leave-one-out cross-validation analysis (error rates 34% and 38%, respectively). A similar 15-miRNA biomarker derived from The Cancer Genome Atlas miRNA-seq data performed slightly worse (39%) than these current biomarkers. Both signatures were then assessed for replication in two independent data sets and subjected to systematic cross-validation together with the three other miRNA-based prognostic signatures proposed in the literature to date. Five miRNAs (miR-142-5p, miR-150-5p, miR-342-3p, miR-155-5p, and miR-146b-5p) were reproducibly associated with patient outcome and have the greatest potential for application in the clinic. Our extensive validation approach highlighted among multiple independent cohorts the translational potential and limitations of miRNA signatures, and pointed to future directions in the analysis of this emerging class of markers.
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