566 research outputs found
Explaining the unobserved: why quantum mechanics is not only about information
A remarkable theorem by Clifton, Bub and Halvorson (2003)(CBH) characterizes
quantum theory in terms of information--theoretic principles. According to Bub
(2004, 2005) the philosophical significance of the theorem is that quantum
theory should be regarded as a ``principle'' theory about (quantum) information
rather than a ``constructive'' theory about the dynamics of quantum systems.
Here we criticize Bub's principle approach arguing that if the mathematical
formalism of quantum mechanics remains intact then there is no escape route
from solving the measurement problem by constructive theories. We further
propose a (Wigner--type) thought experiment that we argue demonstrates that
quantum mechanics on the information--theoretic approach is incomplete.Comment: 34 Page
Cytoplasmic LPS Activates Caspase-11: Implications in TLR4-Independent Endotoxic Shock
Inflammatory caspases, such as caspase-1 and -11, mediate innate immune detection of pathogens. Caspase-11 induces pyroptosis, a form of programmed cell death, and specifically defends against bacterial pathogens that invade the cytosol. During endotoxemia, however, excessive caspase-11 activation causes shock. We report that contamination of the cytoplasm by lipopolysaccharide (LPS) is the signal that triggers caspase-11 activation in mice. Specifically, caspase-11 responds to penta- and hexa-acylated lipid A, whereas tetra-acylated lipid A is not detected, providing a mechanism of evasion for cytosol-invasive Francisella. Priming the caspase-11 pathway in vivo resulted in extreme sensitivity to subsequent LPS challenge in both wild type and Tlr4-deficient mice, whereas caspase 11-deficient mice were relatively resistant. Together, our data reveal a new pathway for detecting cytoplasmic LPS
A deep learning framework for the detection and quantification of drusen and reticular pseudodrusen on optical coherence tomography
Purpose - To develop and validate a deep learning (DL) framework for the
detection and quantification of drusen and reticular pseudodrusen (RPD) on
optical coherence tomography scans.
Design - Development and validation of deep learning models for
classification and feature segmentation.
Methods - A DL framework was developed consisting of a classification model
and an out-of-distribution (OOD) detection model for the identification of
ungradable scans; a classification model to identify scans with drusen or RPD;
and an image segmentation model to independently segment lesions as RPD or
drusen. Data were obtained from 1284 participants in the UK Biobank (UKBB) with
a self-reported diagnosis of age-related macular degeneration (AMD) and 250
UKBB controls. Drusen and RPD were manually delineated by five retina
specialists. The main outcome measures were sensitivity, specificity, area
under the ROC curve (AUC), kappa, accuracy and intraclass correlation
coefficient (ICC).
Results - The classification models performed strongly at their respective
tasks (0.95, 0.93, and 0.99 AUC, respectively, for the ungradable scans
classifier, the OOD model, and the drusen and RPD classification model). The
mean ICC for drusen and RPD area vs. graders was 0.74 and 0.61, respectively,
compared with 0.69 and 0.68 for intergrader agreement. FROC curves showed that
the model's sensitivity was close to human performance.
Conclusions - The models achieved high classification and segmentation
performance, similar to human performance. Application of this robust framework
will further our understanding of RPD as a separate entity from drusen in both
research and clinical settings.Comment: 26 pages, 7 figure
Caspase-11 Protects Against Bacteria That Escape the Vacuole
Caspases are either apoptotic or inflammatory. The inflammatory Caspases-1 and -11 trigger pyroptosis, a form of programmed cell death. Whereas both can be detrimental in inflammatory disease, only Caspase-1 has an established protective role during infection. Herein, we report that Caspase-11 is required for innate immunity to cytosolic, but not vacuolar, bacteria. While Salmonella typhimurium and Legionella pneumophila normally reside in the vacuole, specific mutants (sifA and sdhA, respectively) that aberrantly enter the cytosol triggered Caspase-11, enhancing clearance of S. typhimurium sifA in vivo. This response did not require NLRP3, NLRC4, or ASC inflammasome pathways. Burkholderia species that naturally invade the cytosol also triggered Caspase-11, protecting mice from lethal challenge with B. thailandensis and B. pseudomallei. Thus, Caspase-11 is critical for surviving exposure to ubiquitous environmental pathogens
USP27X variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms
Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no definitive cure. X-linked intellectual disability disorder 105 (XLID105, #300984; OMIM) is a ND/ID driven by hemizygous variants in the USP27X gene encoding a protein deubiquitylase with a role in cell proliferation and neural development. Currently, only four genetically diagnosed individuals from two unrelated families have been described with limited clinical data. Furthermore, the mechanisms underlying the disorder are unknown. Here, we report 10 new XLID105 individuals from nine families and determine the impact of gene variants on USP27X protein function. Using a combination of clinical genetics, bioinformatics, biochemical, and cell biology approaches, we determined that XLID105 variants alter USP27X protein biology via distinct mechanisms including changes in developmentally relevant protein-protein interactions and deubiquitylating activity. Our data better define the phenotypic spectrum of XLID105 and suggest that XLID105 is driven by USP27X functional disruption. Understanding the pathogenic mechanisms of XLID105 variants will provide molecular insight into USP27X biology and may create the potential for therapy development.</p
Differential IL-1ÎČ secretion by monocyte subsets is regulated by Hsp27 through modulating mRNA stability.
Monocytes play a central role in regulating inflammation in response to infection or injury, and during auto-inflammatory diseases. Human blood contains classical, intermediate and non-classical monocyte subsets that each express characteristic patterns of cell surface CD16 and CD14; each subset also has specific functional properties, but the mechanisms underlying many of their distinctive features are undefined. Of particular interest is how monocyte subsets regulate secretion of the apical pro-inflammatory cytokine IL-1ÎČ, which is central to the initiation of immune responses but is also implicated in the pathology of various auto-immune/auto-inflammatory conditions. Here we show that primary human non-classical monocytes, exposed to LPS or LPSâ+âBzATP (3'-O-(4-benzoyl)benzyl-ATP, a P2X7R agonist), produce approx. 80% less IL-1ÎČ than intermediate or classical monocytes. Despite their low CD14 expression, LPS-sensing, caspase-1 activation and P2X7R activity were comparable in non-classical monocytes to other subsets: their diminished ability to produce IL-1ÎČ instead arose from 50% increased IL-1ÎČ mRNA decay rates, mediated by Hsp27. These findings identify the Hsp27 pathway as a novel therapeutic target for the management of conditions featuring dysregulated IL-1ÎČ production, and represent an advancement in understanding of both physiological inflammatory responses and the pathogenesis of inflammatory diseases involving monocyte-derived IL-1ÎČ
The cytoskeleton in cell-autonomous immunity: structural determinants of host defence
Host cells use antimicrobial proteins, pathogen-restrictive compartmentalization and cell death in their defence against intracellular pathogens. Recent work has revealed that four components of the cytoskeleton â actin, microtubules, intermediate filaments and septins, which are well known for their roles in cell division, shape and movement â have important functions in innate immunity and cellular self-defence. Investigations using cellular and animal models have shown that these cytoskeletal proteins are crucial for sensing bacteria and for mobilizing effector mechanisms to eliminate them. In this Review, we highlight the emerging roles of the cytoskeleton as a structural determinant of cell-autonomous host defence
Cancer recurrence times from a branching process model
As cancer advances, cells often spread from the primary tumor to other parts
of the body and form metastases. This is the main cause of cancer related
mortality. Here we investigate a conceptually simple model of metastasis
formation where metastatic lesions are initiated at a rate which depends on the
size of the primary tumor. The evolution of each metastasis is described as an
independent branching process. We assume that the primary tumor is resected at
a given size and study the earliest time at which any metastasis reaches a
minimal detectable size. The parameters of our model are estimated
independently for breast, colorectal, headneck, lung and prostate cancers. We
use these estimates to compare predictions from our model with values reported
in clinical literature. For some cancer types, we find a remarkably wide range
of resection sizes such that metastases are very likely to be present, but none
of them are detectable. Our model predicts that only very early resections can
prevent recurrence, and that small delays in the time of surgery can
significantly increase the recurrence probability.Comment: 26 pages, 9 figures, 4 table
Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy
AbstractDevelopmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patientsâ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.</jats:p
- âŠ