4,007 research outputs found
Mesoscopic organization reveals the constraints governing C. elegans nervous system
One of the biggest challenges in biology is to understand how activity at the
cellular level of neurons, as a result of their mutual interactions, leads to
the observed behavior of an organism responding to a variety of environmental
stimuli. Investigating the intermediate or mesoscopic level of organization in
the nervous system is a vital step towards understanding how the integration of
micro-level dynamics results in macro-level functioning. In this paper, we have
considered the somatic nervous system of the nematode Caenorhabditis elegans,
for which the entire neuronal connectivity diagram is known. We focus on the
organization of the system into modules, i.e., neuronal groups having
relatively higher connection density compared to that of the overall network.
We show that this mesoscopic feature cannot be explained exclusively in terms
of considerations, such as optimizing for resource constraints (viz., total
wiring cost) and communication efficiency (i.e., network path length).
Comparison with other complex networks designed for efficient transport (of
signals or resources) implies that neuronal networks form a distinct class.
This suggests that the principal function of the network, viz., processing of
sensory information resulting in appropriate motor response, may be playing a
vital role in determining the connection topology. Using modular spectral
analysis, we make explicit the intimate relation between function and structure
in the nervous system. This is further brought out by identifying functionally
critical neurons purely on the basis of patterns of intra- and inter-modular
connections. Our study reveals how the design of the nervous system reflects
several constraints, including its key functional role as a processor of
information.Comment: Published version, Minor modifications, 16 pages, 9 figure
Comparison of serious inhaler technique errors made by device-naïve patients using three different dry powder inhalers: a randomised, crossover, open-label study
Background: Serious inhaler technique errors can impair drug delivery to the lungs. This randomised, crossover, open-label study evaluated the proportion of patients making predefined serious errors with Pulmojet compared with Diskus and Turbohaler dry powder inhalers. Methods: Patients ≥18 years old with asthma and/or COPD who were current users of an inhaler but naïve to the study devices were assigned to inhaler technique assessment on Pulmojet and either Diskus or Turbohaler in a randomised order. Patients inhaled through empty devices after reading the patient information leaflet. If serious errors potentially affecting dose delivery were recorded, they repeated the inhalations after watching a training video. Inhaler technique was assessed by a trained nurse observer and an electronic inhalation profile recorder. Results: Baseline patient characteristics were similar between randomisation arms for the Pulmojet-Diskus (n = 277) and Pulmojet-Turbohaler (n = 144) comparisons. Non-inferiority in the proportions of patients recording no nurse-observed serious errors was demonstrated for both Pulmojet versus Diskus, and Pulmojet versus Turbohaler; therefore, superiority was tested. Patients were significantly less likely to make ≥1 nurse-observed serious errors using Pulmojet compared with Diskus (odds ratio, 0.31; 95 % CI, 0.19–0.51) or Pulmojet compared with Turbohaler (0.23; 0.12–0.44) after reading the patient information leaflet with additional video instruction, if required. Conclusions These results suggest Pulmojet is easier to learn to use correctly than the Turbohaler or Diskus for current inhaler users switching to a new dry powder inhaler
Finding and testing network communities by lumped Markov chains
Identifying communities (or clusters), namely groups of nodes with
comparatively strong internal connectivity, is a fundamental task for deeply
understanding the structure and function of a network. Yet, there is a lack of
formal criteria for defining communities and for testing their significance. We
propose a sharp definition which is based on a significance threshold. By means
of a lumped Markov chain model of a random walker, a quality measure called
"persistence probability" is associated to a cluster. Then the cluster is
defined as an "-community" if such a probability is not smaller than
. Consistently, a partition composed of -communities is an
"-partition". These definitions turn out to be very effective for
finding and testing communities. If a set of candidate partitions is available,
setting the desired -level allows one to immediately select the
-partition with the finest decomposition. Simultaneously, the
persistence probabilities quantify the significance of each single community.
Given its ability in individually assessing the quality of each cluster, this
approach can also disclose single well-defined communities even in networks
which overall do not possess a definite clusterized structure
Evaluation of probabilistic photometric redshift estimation approaches for The Rubin Observatory Legacy Survey of Space and Time (LSST)
Many scientific investigations of photometric galaxy surveys require redshift estimates, whose uncertainty properties are best encapsulated by photometric redshift (photo-z) posterior probability density functions (PDFs). A plethora of photo-z PDF estimation methodologies abound, producing discrepant results with no consensus on a preferred approach. We present the results of a comprehensive experiment comparing 12 photo-z algorithms applied to mock data produced for The Rubin Observatory Legacy Survey of Space and Time Dark Energy Science Collaboration. By supplying perfect prior information, in the form of the complete template library and a representative training set as inputs to each code, we demonstrate the impact of the assumptions underlying each technique on the output photo-z PDFs. In the absence of a notion of true, unbiased photo-z PDFs, we evaluate and interpret multiple metrics of the ensemble properties of the derived photo-z PDFs as well as traditional reductions to photo-z point estimates. We report systematic biases and overall over/underbreadth of the photo-z PDFs of many popular codes, which may indicate avenues for improvement in the algorithms or implementations. Furthermore, we raise attention to the limitations of established metrics for assessing photo-z PDF accuracy; though we identify the conditional density estimate loss as a promising metric of photo-z PDF performance in the case where true redshifts are available but true photo-z PDFs are not, we emphasize the need for science-specific performance metrics
FOXN1 forms higher-order nuclear condensates displaced by mutations causing immunodeficiency
The transcription factor FOXN1 is a master regulator of thymic epithelial cell (TEC) development and function. Here, we demonstrate that FOXN1 expression is differentially regulated during organogenesis and participates in multimolecular nuclear condensates essential for the factor’s transcriptional activity. FOXN1’s C-terminal sequence regulates the diffusion velocity within these aggregates and modulates the binding to proximal gene regulatory regions. These dynamics are altered in a patient with a mutant FOXN1 that is modified in its C-terminal sequence. This mutant is transcriptionally inactive and acts as a dominant negative factor displacing wild-type FOXN1 from condensates and causing athymia and severe lymphopenia in heterozygotes. Expression of the mutated mouse ortholog selectively impairs mouse TEC differentiation, revealing a gene dose dependency for individual TEC subtypes. We have therefore identified the cause for a primary immunodeficiency disease and determined the mechanism by which this FOXN1 gain-of-function mutant mediates its dominant negative effect
Collaborative Enhancement of Antibody Binding to Distinct PECAM-1 Epitopes Modulates Endothelial Targeting
Antibodies to platelet endothelial cell adhesion molecule-1 (PECAM-1) facilitate targeted drug delivery to endothelial cells by “vascular immunotargeting.” To define the targeting quantitatively, we investigated the endothelial binding of monoclonal antibodies (mAbs) to extracellular epitopes of PECAM-1. Surprisingly, we have found in human and mouse cell culture models that the endothelial binding of PECAM-directed mAbs and scFv therapeutic fusion protein is increased by co-administration of a paired mAb directed to an adjacent, yet distinct PECAM-1 epitope. This results in significant enhancement of functional activity of a PECAM-1-targeted scFv-thrombomodulin fusion protein generating therapeutic activated Protein C. The “collaborative enhancement” of mAb binding is affirmed in vivo, as manifested by enhanced pulmonary accumulation of intravenously administered radiolabeled PECAM-1 mAb when co-injected with an unlabeled paired mAb in mice. This is the first demonstration of a positive modulatory effect of endothelial binding and vascular immunotargeting provided by the simultaneous binding a paired mAb to adjacent distinct epitopes. The “collaborative enhancement” phenomenon provides a novel paradigm for optimizing the endothelial-targeted delivery of therapeutic agents
A unified data representation theory for network visualization, ordering and coarse-graining
Representation of large data sets became a key question of many scientific
disciplines in the last decade. Several approaches for network visualization,
data ordering and coarse-graining accomplished this goal. However, there was no
underlying theoretical framework linking these problems. Here we show an
elegant, information theoretic data representation approach as a unified
solution of network visualization, data ordering and coarse-graining. The
optimal representation is the hardest to distinguish from the original data
matrix, measured by the relative entropy. The representation of network nodes
as probability distributions provides an efficient visualization method and, in
one dimension, an ordering of network nodes and edges. Coarse-grained
representations of the input network enable both efficient data compression and
hierarchical visualization to achieve high quality representations of larger
data sets. Our unified data representation theory will help the analysis of
extensive data sets, by revealing the large-scale structure of complex networks
in a comprehensible form.Comment: 13 pages, 5 figure
Detecting Network Communities: An Application to Phylogenetic Analysis
This paper proposes a new method to identify communities in generally weighted
complex networks and apply it to phylogenetic analysis. In this case, weights
correspond to the similarity indexes among protein sequences, which can be used
for network construction so that the network structure can be analyzed to
recover phylogenetically useful information from its properties. The analyses
discussed here are mainly based on the modular character of protein similarity
networks, explored through the Newman-Girvan algorithm, with the help of the
neighborhood matrix . The most relevant
networks are found when the network topology changes abruptly revealing distinct
modules related to the sets of organisms to which the proteins belong. Sound
biological information can be retrieved by the computational routines used in
the network approach, without using biological assumptions other than those
incorporated by BLAST. Usually, all the main bacterial phyla and, in some cases,
also some bacterial classes corresponded totally (100%) or to a great
extent (>70%) to the modules. We checked for internal consistency in
the obtained results, and we scored close to 84% of matches for community
pertinence when comparisons between the results were performed. To illustrate
how to use the network-based method, we employed data for enzymes involved in
the chitin metabolic pathway that are present in more than 100 organisms from an
original data set containing 1,695 organisms, downloaded from GenBank on May 19,
2007. A preliminary comparison between the outcomes of the network-based method
and the results of methods based on Bayesian, distance, likelihood, and
parsimony criteria suggests that the former is as reliable as these commonly
used methods. We conclude that the network-based method can be used as a
powerful tool for retrieving modularity information from weighted networks,
which is useful for phylogenetic analysis
Measurement of the Forward-Backward Asymmetry in the B -> K(*) mu+ mu- Decay and First Observation of the Bs -> phi mu+ mu- Decay
We reconstruct the rare decays , , and in a data sample
corresponding to collected in collisions at
by the CDF II detector at the Fermilab Tevatron
Collider. Using and decays we report the branching ratios. In addition, we report
the measurement of the differential branching ratio and the muon
forward-backward asymmetry in the and decay modes, and the
longitudinal polarization in the decay mode with respect to the squared
dimuon mass. These are consistent with the theoretical prediction from the
standard model, and most recent determinations from other experiments and of
comparable accuracy. We also report the first observation of the {\mathcal{B}}(B^0_s \to
\phi\mu^+\mu^-) = [1.44 \pm 0.33 \pm 0.46] \times 10^{-6}27 \pm 6B^0_s$ decay observed.Comment: 7 pages, 2 figures, 3 tables. Submitted to Phys. Rev. Let
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