110 research outputs found
Epidemic centrality - is there an underestimated epidemic impact of network peripheral nodes?
In the study of disease spreading on empirical complex networks in SIR model,
initially infected nodes can be ranked according to some measure of their
epidemic impact. The highest ranked nodes, also referred to as
"superspreaders", are associated to dominant epidemic risks and therefore
deserve special attention. In simulations on studied empirical complex
networks, it is shown that the ranking depends on the dynamical regime of the
disease spreading. A possible mechanism leading to this dependence is
illustrated in an analytically tractable example. In systems where the
allocation of resources to counter disease spreading to individual nodes is
based on their ranking, the dynamical regime of disease spreading is frequently
not known before the outbreak of the disease. Therefore, we introduce a
quantity called epidemic centrality as an average over all relevant regimes of
disease spreading as a basis of the ranking. A recently introduced concept of
phase diagram of epidemic spreading is used as a framework in which several
types of averaging are studied. The epidemic centrality is compared to
structural properties of nodes such as node degree, k-cores and betweenness.
There is a growing trend of epidemic centrality with degree and k-cores values,
but the variation of epidemic centrality is much smaller than the variation of
degree or k-cores value. It is found that the epidemic centrality of the
structurally peripheral nodes is of the same order of magnitude as the epidemic
centrality of the structurally central nodes. The implications of these
findings for the distributions of resources to counter disease spreading are
discussed
Alternative splicing in a presenilin 2 variant associated with Alzheimer disease
Objective: Autosomal-dominant familial Alzheimer disease (AD) is caused by by variants in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP). Previously, we reported a rare PSEN2 frameshift variant in an early-onset AD case (PSEN2 p.K115Efs*11). In this study, we characterize a second family with the same variant and analyze cellular transcripts from both patient fibroblasts and brain lysates. Methods: We combined genomic, neuropathological, clinical, and molecular techniques to characterize the PSEN2 K115Efs*11 variant in two families. Results: Neuropathological and clinical evaluation confirmed the AD diagnosis in two individuals carrying the PSEN2 K115Efs*11 variant. A truncated transcript from the variant allele is detectable in patient fibroblasts while levels of wild-type PSEN2 transcript and protein are reduced compared to controls. Functional studies to assess biological consequences of the variant demonstrated that PSEN2 K115Efs*11 fibroblasts secrete less AÎČâ-ââ compared to controls, indicating abnormal Îł-secretase activity. Analysis of PSEN2 transcript levels in brain tissue revealed alternatively spliced PSEN2 products in patient brain as well as in sporadic AD and age-matched control brain. Interpretation: These data suggest that PSEN2 K115Efs*11 is a likely pathogenic variant associated with AD. We uncovered novel PSEN2 alternative transcripts in addition to previously reported PSEN2 splice isoforms associated with sporadic AD. In the context of a frameshift, these alternative transcripts return to the canonical reading frame with potential to generate deleterious protein products. Our findings suggest novel potential mechanisms by which PSEN variants may influence AD pathogenesis, highlighting the complexity underlying genetic contribution to disease risk.Jacquelyn E. Braggin, Stephanie A. Bucks, Meredith M. Course, Carole L. Smith, Bryce Sopher, Leah Osnis, Kiel D. Shuey, Kimiko Domoto-Reilly, Christina Caso, Chizuru Kinoshita, Kathryn P. Scherpelz, Chloe Cross, Thomas Grabowski, Seyyed H.M. Nik, Morgan Newman, Gwenn A. Garden, James B. Leverenz, Debby Tsuang, Caitlin Latimer, Luis F. Gonzalez-Cuyar, Christopher Dirk Keene, Richard S. Morrison, Kristoffer Rhoads, Ellen M. Wijsman, Michael O. Dorschner, Michael Lardelli, Jessica E. Young, Paul N. Valdmanis, Thomas D. Bird, Suman Jayade
The delivery of personalised, precision medicines via synthetic proteins
Introduction:
The design of advanced drug delivery systems based on synthetic and su-pramolecular chemistry has been very successful. Liposomal doxorubicin (CaelyxÂź), and liposomal daunorubicin (DaunoXomeÂź), estradiol topical emulsion (EstrasorbTM) as well as soluble or erodible polymer systems such as pegaspargase (OncasparÂź) or goserelin acetate (ZoladexÂź) represent considerable achievements.
The Problem:
As deliverables have evolved from low molecular weight drugs to biologics (currently representing approximately 30% of the market), so too have the demands made of advanced drug delivery technology. In parallel, the field of membrane trafficking (and endocytosis) has also matured. The trafficking of specific receptors i.e. material to be recycled or destroyed, as well as the trafficking of protein toxins has been well characterized. This, in conjunction with an ability to engineer synthetic, recombinant proteins provides several possibilities.
The Solution:
The first is using recombinant proteins as drugs i.e. denileukin diftitox (OntakÂź) or agalsidase beta (FabrazymeÂź). The second is the opportunity to use protein toxin architecture to reach targets that are not normally accessible. This may be achieved by grafting regulatory domains from multiple species to form synthetic proteins, engineered to do multiple jobs. Examples include access to the nucleocytosolic compartment. Herein the use of synthetic proteins for drug delivery has been reviewed
Measurement of CP observables in B± â D(â)K± and B± â D(â)ϱ decays
Measurements of CP observables in B ± âD (â) K ± and B ± âD (â) Ï Â± decays are presented, where D (â) indicates a neutral D or D â meson that is an admixture of D (â)0 and DÂŻ (â)0 states. Decays of the D â meson to the DÏ 0 and DÎł final states are partially reconstructed without inclusion of the neutral pion or photon, resulting in distinctive shapes in the B candidate invariant mass distribution. Decays of the D meson are fully reconstructed in the K ± Ï â , K + K â and Ï + Ï â final states. The analysis uses a sample of charged B mesons produced in pp collisions collected by the LHCb experiment, corresponding to an integrated luminosity of 2.0, 1.0 and 2.0 fb â1 taken at centre-of-mass energies of s=7, 8 and 13 TeV, respectively. The study of B ± âD â K ± and B ± âD â Ï Â± decays using a partial reconstruction method is the first of its kind, while the measurement of B ± âDK ± and B ± âDÏ Â± decays is an update of previous LHCb measurements. The B ± âDK ± results are the most precise to date
First observation of forward production in collisions at TeV
The decay ZâbbÂŻ is reconstructed in pp collision data, corresponding to 2 fb â1 of integrated luminosity, collected by the LHCb experiment at a centre-of-mass energy of s=8 TeV. The product of the Z production cross-section and the ZâbbÂŻ branching fraction is measured for candidates in the fiducial region defined by two particle-level b -quark jets with pseudorapidities in the range 2.220 GeV and dijet invariant mass in the range 452045 < m_{jj} < 1655462 \pm 763Z \rightarrow b \bar{b}332 \pm 46 \pm 59Z \rightarrow b \bar{b}pp$ collisions
Preliminary Findings from Efforts to Model Pulsed Inductive Theta-Pinch Plasmas Via Particle-In-Cell
A method is pursued to approximately model the electron energy distribution of pulsed inductive plasma devices with Particle-In-Cell code to elucidate formation physics during early times (t \u3c 1 ”s). Specifically, reported results from AFRL-Kirtland\u27s pulsed inductive device, FRCHX, are used as a test case to validate results. An r-z slab approximation is outlined and gyro-frequency, Larmor radius, and EĂB guiding center drift are verified against theory to within 1% difference. The analyses presented, using both single electron and Particle-In-Cell modeling, agree with FRCHX reported results by showing that average electron kinetic energy does not exceed the ionization threshold of 15.47 eV for gaseous deuterium until after the first ÂŒ cycle of the ringing pre-ionization stage (when net magnetic field is approximately nullified). These results provide supportive evidence for the concept that bias field actually inhibits ionization if improperly implemente
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