3,881 research outputs found
Comparative transcriptomic analysis of whole blood mycobacterial growth assays and tuberculosis patients’ blood RNA profiles
In vitro whole blood infection models are used for elucidating the immune response to Mycobacterium tuberculosis (Mtb). They exhibit commonalities but also differences, to the in vivo blood transcriptional response during natural human Mtb disease. Here, we present a description of concordant and discordant components of the immune response in blood, quantified through transcriptional profiling in an in vitro whole blood infection model compared to whole blood from patients with tuberculosis disease. We identified concordantly and discordantly expressed gene modules and performed in silico cell deconvolution. A high degree of concordance of gene expression between both adult and paediatric in vivo-in vitro tuberculosis infection was identified. Concordance in paediatric in vivo vs in vitro comparison is largely characterised by immune suppression, while in adults the comparison is marked by concordant immune activation, particularly that of inflammation, chemokine, and interferon signalling. Discordance between in vitro and in vivo increases over time and is driven by T-cell regulation and monocyte-related gene expression, likely due to apoptotic depletion of monocytes and increasing relative fraction of longer-lived cell types, such as T and B cells. Our approach facilitates a more informed use of the whole blood in vitro model, while also accounting for its limitations
SKELESIM: an extensible, general framework for population genetic simulation in R
CAUL read and publish agreementPublishe
A Stochastic Approach to Shortcut Bridging in Programmable Matter
In a self-organizing particle system, an abstraction of programmable matter,
simple computational elements called particles with limited memory and
communication self-organize to solve system-wide problems of movement,
coordination, and configuration. In this paper, we consider a stochastic,
distributed, local, asynchronous algorithm for "shortcut bridging", in which
particles self-assemble bridges over gaps that simultaneously balance
minimizing the length and cost of the bridge. Army ants of the genus Eciton
have been observed exhibiting a similar behavior in their foraging trails,
dynamically adjusting their bridges to satisfy an efficiency trade-off using
local interactions. Using techniques from Markov chain analysis, we rigorously
analyze our algorithm, show it achieves a near-optimal balance between the
competing factors of path length and bridge cost, and prove that it exhibits a
dependence on the angle of the gap being "shortcut" similar to that of the ant
bridges. We also present simulation results that qualitatively compare our
algorithm with the army ant bridging behavior. Our work gives a plausible
explanation of how convergence to globally optimal configurations can be
achieved via local interactions by simple organisms (e.g., ants) with some
limited computational power and access to random bits. The proposed algorithm
also demonstrates the robustness of the stochastic approach to algorithms for
programmable matter, as it is a surprisingly simple extension of our previous
stochastic algorithm for compression.Comment: Published in Proc. of DNA23: DNA Computing and Molecular Programming
- 23rd International Conference, 2017. An updated journal version will appear
in the DNA23 Special Issue of Natural Computin
Coherent Signal Amplification in Bistable Nanomechanical Oscillators by Stochastic Resonance
Stochastic resonance is a counter-intuitive concept[1,2], ; the addition of
noise to a noisy system induces coherent amplification of its response. First
suggested as a mechanism for the cyclic recurrence of ice ages, stochastic
resonance has been seen in a wide variety of macroscopic physical systems:
bistable ring lasers[3], SQUIDs[4,5], magnetoelastic ribbons[6], and
neurophysiological systems such as the receptors in crickets[7] and
crayfish[8]. Although it is fundamentally important as a mechanism of coherent
signal amplification, stochastic resonance is yet to be observed in nanoscale
systems. Here we report the observation of stochastic resonance in bistable
nanomechanical silicon oscillators, which can play an important role in the
realization of controllable high-speed nanomechanical memory cells. Our
nanomechanical systems were excited into a dynamic bistable state and modulated
in order to induce controllable switching; the addition of white noise showed a
marked amplification of the signal strength. Stochastic resonance in
nanomechanical systems paves the way for exploring macroscopic quantum
coherence and tunneling, and controlling nanoscale quantum systems for their
eventual use as robust quantum logic devices.Comment: 18 pages, 4 figure
Manganese toxicity with ephedrone abuse manifesting as parkinsonism: a case report
Introduction: Neurologic consequences of manganese toxicity have been recognized since 1837. A new form of presumed manganese poisoning has been reported in drug addicted persons from Eastern Europe and the Baltic states who have intravenously injected self-prepared methcathinone hydrochloride (ephedrone), which is synthesized from pseudoephedrine hydrochloride using potassium permanganate as a potent oxidant. This clinical syndrome is under-recognized in Western Europe and there are no reported cases in the literature from Ireland.
Case presentation: We report a 30-year-old Eastern European man who presented with a two-year history of gait disturbance. A neurological assessment revealed features of parkinsonism which included hypophonia, hypomimia, mild bradykinesia and rigidity with no resting tremor. He held his arms slightly abducted from his sides when walking, with a reduction in arm swing. Magnetic resonance imaging of his brain showed a high signal on T1 in the globus pallidus and serum manganese levels were raised. He had no response to levodopa.
Conclusion: Manganism secondary to ephedrone abuse causing parkinsonism has emerged in Western Europe in recent years due to mass immigration and often remains unrecognized. This paper highlights the various features of this rare cause of parkinsonism and aids in its recognition and subsequent diagnosis. Neurologists in Western Europe will increasingly encounter such patients
A single nucleotide polymorphism in the Bax gene promoter affects transcription and influences retinal ganglion cell death
Pro-apoptotic Bax is essential for RGC (retinal ganglion cell)
death. Gene dosage experiments in mice, yielding a single wild-type
Bax allele, indicated that genetic background was able to
influence the cell death phenotype. DBA/2JBax+/− mice exhibited complete resistance to nerve damage after 2 weeks
(similar to Bax−/− mice), but 129B6Bax+/− mice exhibited significant cell loss (similar to wild-type mice). The
different cell death phenotype was associated with the level of
Bax expression, where 129B6 neurons had twice the level of
endogenous Bax mRNA and protein as DBA/2J neurons. Sequence
analysis of the Bax promoters between these strains revealed a
single nucleotide polymorphism (T129B6 to CDBA/2J) at
position −515. A 1.5- to 2.5-fold increase in transcriptional
activity was observed from the 129B6 promoter in transient transfection assays
in a variety of cell types, including RGC5 cells derived from rat RGCs. Since
this polymorphism occurred in a p53 half-site, we investigated the requirement
of p53 for the differential transcriptional activity. Differential
transcriptional activity from either 129B6 or DBA/2J Bax
promoters were unaffected in p53−/− cells, and
addition of exogenous p53 had no further effect on this difference, thus a role
for p53 was excluded. Competitive electrophoretic mobility-shift assays
identified two DNA–protein complexes that interacted with the
polymorphic region. Those forming Complex 1 bound with higher affinity to the
129B6 polymorphic site, suggesting that these proteins probably comprised a
transcriptional activator complex. These studies implicated quantitative
expression of the Bax gene as playing a possible role in
neuronal susceptibility to damaging stimuli
Nasty Viruses, Costly Plasmids, Population Dynamics, and the Conditions for Establishing and Maintaining CRISPR-Mediated Adaptive Immunity in Bacteria
Clustered, Regularly Interspaced Short Palindromic Repeats (CRISPR) abound in the genomes of almost all archaebacteria and nearly half the eubacteria sequenced. Through a genetic interference mechanism, bacteria with CRISPR regions carrying copies of the DNA of previously encountered phage and plasmids abort the replication of phage and plasmids with these sequences. Thus it would seem that protection against infecting phage and plasmids is the selection pressure responsible for establishing and maintaining CRISPR in bacterial populations. But is it? To address this question and provide a framework and hypotheses for the experimental study of the ecology and evolution of CRISPR, I use mathematical models of the population dynamics of CRISPR-encoding bacteria with lytic phage and conjugative plasmids. The results of the numerical (computer simulation) analysis of the properties of these models with parameters in the ranges estimated for Escherichia coli and its phage and conjugative plasmids indicate: (1) In the presence of lytic phage there are broad conditions where bacteria with CRISPR-mediated immunity will have an advantage in competition with non-CRISPR bacteria with otherwise higher Malthusian fitness. (2) These conditions for the existence of CRISPR are narrower when there is envelope resistance to the phage. (3) While there are situations where CRISPR-mediated immunity can provide bacteria an advantage in competition with higher Malthusian fitness bacteria bearing deleterious conjugative plasmids, the conditions for this to obtain are relatively narrow and the intensity of selection favoring CRISPR weak. The parameters of these models can be independently estimated, the assumption behind their construction validated, and the hypotheses generated from the analysis of their properties tested in experimental populations of bacteria with lytic phage and conjugative plasmids. I suggest protocols for estimating these parameters and outline the design of experiments to evaluate the validity of these models and test these hypotheses
Genetics of height and risk of atrial fibrillation: A Mendelian randomization study.
BACKGROUND: Observational studies have identified height as a strong risk factor for atrial fibrillation, but this finding may be limited by residual confounding. We aimed to examine genetic variation in height within the Mendelian randomization (MR) framework to determine whether height has a causal effect on risk of atrial fibrillation. METHODS AND FINDINGS: In summary-level analyses, MR was performed using summary statistics from genome-wide association studies of height (GIANT/UK Biobank; 693,529 individuals) and atrial fibrillation (AFGen; 65,446 cases and 522,744 controls), finding that each 1-SD increase in genetically predicted height increased the odds of atrial fibrillation (odds ratio [OR] 1.34; 95% CI 1.29 to 1.40; p = 5 × 10-42). This result remained consistent in sensitivity analyses with MR methods that make different assumptions about the presence of pleiotropy, and when accounting for the effects of traditional cardiovascular risk factors on atrial fibrillation. Individual-level phenome-wide association studies of height and a height genetic risk score were performed among 6,567 European-ancestry participants of the Penn Medicine Biobank (median age at enrollment 63 years, interquartile range 55-72; 38% female; recruitment 2008-2015), confirming prior observational associations between height and atrial fibrillation. Individual-level MR confirmed that each 1-SD increase in height increased the odds of atrial fibrillation, including adjustment for clinical and echocardiographic confounders (OR 1.89; 95% CI 1.50 to 2.40; p = 0.007). The main limitations of this study include potential bias from pleiotropic effects of genetic variants, and lack of generalizability of individual-level findings to non-European populations. CONCLUSIONS: In this study, we observed evidence that height is likely a positive causal risk factor for atrial fibrillation. Further study is needed to determine whether risk prediction tools including height or anthropometric risk factors can be used to improve screening and primary prevention of atrial fibrillation, and whether biological pathways involved in height may offer new targets for treatment of atrial fibrillation
Extinction times in the subcritical stochastic SIS logistic epidemic
Many real epidemics of an infectious disease are not straightforwardly super-
or sub-critical, and the understanding of epidemic models that exhibit such
complexity has been identified as a priority for theoretical work. We provide
insights into the near-critical regime by considering the stochastic SIS
logistic epidemic, a well-known birth-and-death chain used to model the spread
of an epidemic within a population of a given size . We study the behaviour
of the process as the population size tends to infinity. Our results cover
the entire subcritical regime, including the "barely subcritical" regime, where
the recovery rate exceeds the infection rate by an amount that tends to 0 as but more slowly than . We derive precise asymptotics for
the distribution of the extinction time and the total number of cases
throughout the subcritical regime, give a detailed description of the course of
the epidemic, and compare to numerical results for a range of parameter values.
We hypothesise that features of the course of the epidemic will be seen in a
wide class of other epidemic models, and we use real data to provide some
tentative and preliminary support for this theory.Comment: Revised; 34 pages; 6 figure
- …