1,771 research outputs found
Clinical utility of NGS diagnosis and disease stratification in a multi-ethnic primary ciliary dyskinesia cohort
Background: Primary ciliary dyskinesia (PCD), a genetically heterogeneous condition enriched in some consanguineous populations, results from recessive mutations affecting cilia biogenesis and motility. Currently, diagnosis requires multiple expert tests.
Methods: The diagnostic utility of multigene panel next-generation sequencing (NGS) was evaluated in 161 unrelated families from multiple population ancestries.
Results: Most (82%) families had affected individuals with biallelic or hemizygous (75%) or single (7%) pathogenic causal alleles in known PCD genes. Loss-of-function alleles dominate (73% frameshift, stop-gain, splice site), most (58%) being homozygous, even in non-consanguineous families. Although 57% (88) of the total 155 diagnostic disease variants were novel, recurrent mutations and mutated genes were detected. These differed markedly between white European (52% of families carry DNAH5 or DNAH11 mutations), Arab (42% of families carry CCDC39 or CCDC40 mutations) and South Asian (single LRRC6 or CCDC103 mutations carried in 36% of families) patients, revealing a striking genetic stratification according to population of origin in PCD. Genetics facilitated successful diagnosis of 81% of families with normal or inconclusive ultrastructure and 67% missing prior ultrastructure results.
Conclusions: This study shows the added value of high-throughput targeted NGS in expediting PCD diagnosis. Therefore, there is potential significant patient benefit in wider and/or earlier implementation of genetic screening
Novel steady state of a microtubule assembly in a confined geometry
We study the steady state of an assembly of microtubules in a confined
volume, analogous to the situation inside a cell where the cell boundary forms
a natural barrier to growth. We show that the dynamical equations for growing
and shrinking microtubules predict the existence of two steady states, with
either exponentially decaying or exponentially increasing distribution of
microtubule lengths. We identify the regimes in parameter space corresponding
to these steady states. In the latter case, the apparent catastrophe frequency
near the boundary was found to be significantly larger than that in the
interior. Both the exponential distribution of lengths and the increase in the
catastrophe frequency near the cell margin is in excellent agreement with
recent experimental observations.Comment: 8 pages, submitted to Phys. Rev.
Probing the dynamic structure factor of a neutral Fermi superfluid along the BCS-BEC crossover using atomic impurity qubits
We study an impurity atom trapped by an anharmonic potential, immersed within
a cold atomic Fermi gas with attractive interactions that realizes the
crossover from a Bardeen-Cooper-Schrieffer (BCS) superfluid to a Bose-Einstein
condensate (BEC). Considering the qubit comprising the lowest two vibrational
energy eigenstates of the impurity, we demonstrate that its dynamics probes the
equilibrium density fluctuations encoded in the dynamic structure factor of the
superfluid. Observing the impurity's evolution is thus shown to facilitate
nondestructive measurements of the superfluid order parameter and the contact
between collective and single-particle excitation spectra. Our setup
constitutes a novel model of an open quantum system interacting with a thermal
reservoir, the latter supporting both bosonic and fermionic excitations that
are also coupled to each other.Comment: Updated to final author version. 9+7 pages, 18 figure
The time-profile of cell growth in fission yeast: model selection criteria favoring bilinear models over exponential ones
BACKGROUND: There is considerable controversy concerning the exact growth profile of size parameters during the cell cycle. Linear, exponential and bilinear models are commonly considered, and the same model may not apply for all species. Selection of the most adequate model to describe a given data-set requires the use of quantitative model selection criteria, such as the partial (sequential) F-test, the Akaike information criterion and the Schwarz Bayesian information criterion, which are suitable for comparing differently parameterized models in terms of the quality and robustness of the fit but have not yet been used in cell growth-profile studies. RESULTS: Length increase data from representative individual fission yeast (Schizosaccharomyces pombe) cells measured on time-lapse films have been reanalyzed using these model selection criteria. To fit the data, an extended version of a recently introduced linearized biexponential (LinBiExp) model was developed, which makes possible a smooth, continuously differentiable transition between two linear segments and, hence, allows fully parametrized bilinear fittings. Despite relatively small differences, essentially all the quantitative selection criteria considered here indicated that the bilinear model was somewhat more adequate than the exponential model for fitting these fission yeast data. CONCLUSION: A general quantitative framework was introduced to judge the adequacy of bilinear versus exponential models in the description of growth time-profiles. For single cell growth, because of the relatively limited data-range, the statistical evidence is not strong enough to favor one model clearly over the other and to settle the bilinear versus exponential dispute. Nevertheless, for the present individual cell growth data for fission yeast, the bilinear model seems more adequate according to all metrics, especially in the case of wee1Δ cells
Learning from Minimum Entropy Queries in a Large Committee Machine
In supervised learning, the redundancy contained in random examples can be
avoided by learning from queries. Using statistical mechanics, we study
learning from minimum entropy queries in a large tree-committee machine. The
generalization error decreases exponentially with the number of training
examples, providing a significant improvement over the algebraic decay for
random examples. The connection between entropy and generalization error in
multi-layer networks is discussed, and a computationally cheap algorithm for
constructing queries is suggested and analysed.Comment: 4 pages, REVTeX, multicol, epsf, two postscript figures. To appear in
Physical Review E (Rapid Communications
Altered Cerebellar Short-Term Plasticity but No Change in Postsynaptic AMPA-Type Glutamate Receptors in a Mouse Model of Juvenile Batten Disease
Juvenile Batten disease is the most common progressive neurodegenerative disorder of childhood. It is associated with mutations in the CLN3 gene, causing loss of function of CLN3 protein and degeneration of cerebellar and retinal neurons. It has been proposed that changes in granule cell AMPA-type glutamate receptors (AMPARs) contribute to the cerebellar dysfunction. In this study we compared AMPAR properties and synaptic transmission in cerebellar granule cells from wild-type and Cln3 knockout mice. In Cln3Δex1–6 cells the amplitude of AMPA-evoked whole-cell currents was unchanged. Similarly, we found no change in the amplitude, kinetics, or rectification of synaptic currents evoked by individual quanta, or in their underlying single-channel conductance. We found no change in cerebellar expression of GluA2 or GluA4 protein. By contrast, we observed a reduced number of quantal events following mossy-fiber stimulation in Sr2+, altered short-term plasticity in conditions of reduced extracellular Ca2+, and reduced mossy fiber vesicle number. Thus, while our results suggest early presynaptic changes in the Cln3Δex1–6 mouse model of juvenile Batten disease, they reveal no evidence for altered postsynaptic AMPARs
Loci for primary ciliary dyskinesia map to chromosome 16p12.1-12.2 and 15q13.1-15.1 in Faroe Islands and Israeli Druze genetic isolates
The detection of airborne transmission of tuberculosis from HIV-infected patients, using an in vivo air sampling model
Background. Nosocomial transmission of tuberculosis remains an important public health problem. We created an in vivo air sampling model to study airborne transmission of tuberculosis from patients coinfected with human immunodeficiency virus (HIV) and to evaluate environmental control measures.
Methods. An animal facility was built above a mechanically ventilated HIV‐tuberculosis ward in Lima, Peru. A mean of 92 guinea pigs were continuously exposed to all ward exhaust air for 16 months. Animals had tuberculin skin tests performed at monthly intervals, and those with positive reactions were removed for autopsy and culture for tuberculosis.
Results. Over 505 consecutive days, there were 118 ward admissions by 97 patients with pulmonary tuberculosis, with a median duration of hospitalization of 11 days. All patients were infected with HIV and constituted a heterogeneous group with both new and existing diagnoses of tuberculosis. There was a wide variation in monthly rates of guinea pigs developing positive tuberculin test results (0%–53%). Of 292 animals exposed to ward air, 159 developed positive tuberculin skin test results, of which 129 had laboratory confirmation of tuberculosis. The HIV‐positive patients with pulmonary tuberculosis produced a mean of 8.2 infectious quanta per hour, compared with 1.25 for HIV‐negative patients with tuberculosis in similar studies from the 1950s. The mean monthly patient infectiousness varied greatly, from production of 0–44 infectious quanta per hour, as did the theoretical risk for a health care worker to acquire tuberculosis by breathing ward air.
Conclusions. HIV‐positive patients with tuberculosis varied greatly in their infectiousness, and some were highly infectious. Use of environmental control strategies for nosocomial tuberculosis is therefore a priority, especially in areas with a high prevalence of both tuberculosis and HIV infection
Finite size scaling in neural networks
We demonstrate that the fraction of pattern sets that can be stored in
single- and hidden-layer perceptrons exhibits finite size scaling. This feature
allows to estimate the critical storage capacity \alpha_c from simulations of
relatively small systems. We illustrate this approach by determining \alpha_c,
together with the finite size scaling exponent \nu, for storing Gaussian
patterns in committee and parity machines with binary couplings and up to K=5
hidden units.Comment: 4 pages, RevTex, 5 figures, uses multicol.sty and psfig.st
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