Sphingolipids are structural membrane components and important eukaryotic signaling molecules. Sphingolipids regulate inflammation and immunity and were recently identified as the most differentially ...abundant metabolite in stool from inflammatory bowel disease (IBD) patients. Commensal bacteria from the Bacteroidetes phylum also produce sphingolipids, but the impact of these metabolites on host pathways is largely uncharacterized. To determine whether bacterial sphingolipids modulate intestinal health, we colonized germ-free mice with a sphingolipid-deficient Bacteroides thetaiotaomicron strain. A lack of Bacteroides-derived sphingolipids resulted in intestinal inflammation and altered host ceramide pools in mice. Using lipidomic analysis, we described a sphingolipid biosynthesis pathway and revealed a variety of Bacteroides-derived sphingolipids including ceramide phosphoinositol and deoxy-sphingolipids. Annotating Bacteroides sphingolipids in an IBD metabolomic dataset revealed lower abundances in IBD and negative correlations with inflammation and host sphingolipid production. These data highlight the role of bacterial sphingolipids in maintaining homeostasis and symbiosis in the gut.
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•Colonization with a sphingolipid-deficient Bacteroides strain is pro-inflammatory•Metabolomics describe Bacteroides sphingolipids and their biosynthetic pathway•IBD patients have decreased Bacteroides sphingolipids but increased host sphingolipids
In this issue, Brown et al. discover a number of bacterial sphingolipid metabolites and demonstrate that sphingolipid production by Bacteroides species in the gut microbiome promotes symbiosis with the host. Bacterial sphingolipid deficiency correlates with inflammatory bowel disease and increased host-produced sphingolipid abundance in the human intestine.
The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor ...signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Almost immediately after a human being is born, so too is a new microbial ecosystem, one that resides in that person's gastrointestinal tract. Although it is a universal and integral part of human ...biology, the temporal progression of this process, the sources of the microbes that make up the ecosystem, how and why it varies from one infant to another, and how the composition of this ecosystem influences human physiology, development, and disease are still poorly understood. As a step toward systematically investigating these questions, we designed a microarray to detect and quantitate the small subunit ribosomal RNA (SSU rRNA) gene sequences of most currently recognized species and taxonomic groups of bacteria. We used this microarray, along with sequencing of cloned libraries of PCR-amplified SSU rDNA, to profile the microbial communities in an average of 26 stool samples each from 14 healthy, full-term human infants, including a pair of dizygotic twins, beginning with the first stool after birth and continuing at defined intervals throughout the first year of life. To investigate possible origins of the infant microbiota, we also profiled vaginal and milk samples from most of the mothers, and stool samples from all of the mothers, most of the fathers, and two siblings. The composition and temporal patterns of the microbial communities varied widely from baby to baby. Despite considerable temporal variation, the distinct features of each baby's microbial community were recognizable for intervals of weeks to months. The strikingly parallel temporal patterns of the twins suggested that incidental environmental exposures play a major role in determining the distinctive characteristics of the microbial community in each baby. By the end of the first year of life, the idiosyncratic microbial ecosystems in each baby, although still distinct, had converged toward a profile characteristic of the adult gastrointestinal tract.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Identifying immunodominant T cell epitopes remains a significant challenge in the context of infectious disease, autoimmunity, and immuno-oncology. To address the challenge of antigen discovery, we ...developed a quantitative proteomic approach that enabled unbiased identification of major histocompatibility complex class II (MHCII)-associated peptide epitopes and biochemical features of antigenicity. On the basis of these data, we trained a deep neural network model for genome-scale predictions of immunodominant MHCII-restricted epitopes. We named this model bacteria originated T cell antigen (BOTA) predictor. In validation studies, BOTA accurately predicted novel CD4 T cell epitopes derived from the model pathogen Listeria monocytogenes and the commensal microorganism Muribaculum intestinale. To conclusively define immunodominant T cell epitopes predicted by BOTA, we developed a high-throughput approach to screen DNA-encoded peptide-MHCII libraries for functional recognition by T cell receptors identified from single-cell RNA sequencing. Collectively, these studies provide a framework for defining the immunodominance landscape across a broad range of immune pathologies.
Intestinal adaptive immune responses influence host health, yet only a few intestinal bacteria species that induce cognate adaptive immune responses during homeostasis have been identified. Here, we ...show that
, an intestinal bacterium associated with systemic effects on host metabolism and PD-1 checkpoint immunotherapy, induces immunoglobulin G1 (IgG1) antibodies and antigen-specific T cell responses in mice. Unlike previously characterized mucosal responses, T cell responses to
are limited to T follicular helper cells in a gnotobiotic setting, without appreciable induction of other T helper fates or migration to the lamina propria. However,
-specific responses are context dependent and adopt other fates in conventional mice. These findings suggest that, during homeostasis, contextual signals influence T cell responses to the microbiota and modulate host immune function.
ABSTRACT
The CMB B-mode polarization signal – both the primordial gravitational wave signature and the signal sourced by lensing – is subject to many contaminants from systematic effects. Of ...particular concern are systematics that result in mixing of signals of different ‘spin’, particularly leakage from the much larger spin-0 intensity signal to the spin-2 polarization signal. We present a general formalism, which can be applied to arbitrary focal plane setups, that characterizes signals in terms of their spin. We provide general expressions to describe how spin-coupled signals observed by the detectors manifest at map-level, in the harmonic domain, and in the power spectra, focusing on the polarization spectra – the signals of interest for upcoming CMB surveys. We demonstrate the presence of a previously unidentified cross-term between the systematic and the intrinsic sky signal in the power spectrum, which in some cases can be the dominant source of contamination. The formalism is not restricted to intensity to polarization leakage but provides a complete elucidation of all leakage including polarization mixing, and applies to both full and partial (masked) sky surveys, thus covering space-based, balloon-borne, and ground-based experiments. Using a pair-differenced setup, we demonstrate the formalism by using it to completely characterize the effects of differential gain and pointing systematics, incorporating both intensity leakage and polarization mixing. We validate our results with full time ordered data simulations. Finally, we show in an Appendix that an extension of simple binning map-making to include additional spin information is capable of removing spin-coupled systematics during the map-making process.
Sleepiness may account for up to 20% of crashes on monotonous roads, especially highways. Obstructive sleep apnea (OSA) is the most common medical disorder that causes excessive daytime sleepiness, ...increasing the risk for drowsy driving two to three times. The purpose of these guidelines is to update the 1994 American Thoracic Society Statement that described the relationships among sleepiness, sleep apnea, and driving risk.
A multidisciplinary panel was convened to develop evidence-based clinical practice guidelines for the management of sleepy driving due to OSA. Pragmatic systematic reviews were performed, and the Grading of Recommendations, Assessment, Development, and Evaluation approach was used to formulate and grade the recommendations. Critical outcomes included crash-related mortality and real crashes, whereas important outcomes included near-miss crashes and driving performance.
A strong recommendation was made for treatment of confirmed OSA with continuous positive airway pressure to reduce driving risk, rather than no treatment, which was supported by moderate-quality evidence. Weak recommendations were made for expeditious diagnostic evaluation and initiation of treatment and against the use of stimulant medications or empiric continuous positive airway pressure to reduce driving risk. The weak recommendations were supported by very low-quality evidence. Additional suggestions included routinely determining the driving risk, inquiring about additional causes of sleepiness, educating patients about the risks of excessive sleepiness, and encouraging clinicians to become familiar with relevant laws.
The recommendations presented in this guideline are based on the current evidence, and will require an update as new evidence and/or technologies becomes available.
The first international goal for establishing marine protected areas (MPAs) to conserve the ocean's biodiversity was set in 2002. Since 2006, the Convention on Biological Diversity (CBD) has driven ...MPA establishment, with 193 parties committed to protecting >10% of marine environments globally by 2020, especially 'areas of particular importance for biodiversity' (Aichi target 11). This has resulted in nearly 10 million km(2) of new MPAs, a growth of ~360% in a decade. Unlike on land, it is not known how well protected areas capture marine biodiversity, leaving a significant gap in our understanding of existing MPAs and future protection requirements. We assess the overlap of global MPAs with the ranges of 17,348 marine species (fishes, mammals, invertebrates), and find that 97.4% of species have <10% of their ranges represented in stricter conservation classes. Almost all (99.8%) of the very poorly represented species (<2% coverage) are found within exclusive economic zones, suggesting an important role for particular nations to better protect biodiversity. Our results offer strategic guidance on where MPAs should be placed to support the CBD's overall goal to avert biodiversity loss. Achieving this goal is imperative for nature and humanity, as people depend on biodiversity for important and valuable services.
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