Recent advances in the genetics of idiopathic pulmonary fibrosis

Purpose of reviewGenetics contributes substantially to the susceptibility to idiopathic pulmonary fibrosis (IPF). Genetic studies in sporadic and familial disease have identified several IPF-associated variants, mainly in telomere-related and surfactant protein genes.Here, we review the most recent literature on genetics of IPF and discuss how it may contribute to disease pathogenesis.Recent findingsRecent studies implicate genes involved in telomere maintenance, host defence, cell growth, mammalian target of rapamycin signalling, cell-cell adhesion, regulation of TGF-& beta; signalling and spindle assembly as biological processes involved in the pathogenesis of IPF. Both common and rare genetic variants contribute to the overall risk of IPF; however, while common variants (i.e. polymorphisms) account for most of the heritability of sporadic disease, rare variants (i.e. mutations), mainly in telomere-related genes, are the main contributors to the heritability of familial disease. Genetic factors are likely to also influence disease behaviour and prognosis. Finally, recent data suggest that IPF shares genetic associations - and probably some pathogenetic mechanisms - with other fibrotic lung diseases.Common and rare genetic variants are associated with susceptibility and prognosis of IPF. However, many of the reported variants fall in noncoding regions of the genome and their relevance to disease pathobiology remains to be elucidated

Generalised discrete torsion and mirror symmetry for G_2 manifolds

A generalisation of discrete torsion is introduced in which different discrete torsion phases are considered for the different fixed points or twist fields of a twisted sector. The constraints that arise from modular invariance are analysed carefully. As an application we show how all the different resolutions of the T^7/Z_2^3 orbifold of Joyce have an interpretation in terms of such generalised discrete torsion orbifolds. Furthermore, we show that these manifolds are pairwise identified under G_2 mirror symmetry. From a conformal field theory point of view, this mirror symmetry arises from an automorphism of the extended chiral algebra of the G_2 compactification.Comment: LaTeX, 25 pages, 1 figure; v2: one reference added and comment about higher loop modular invariance corrected, version to be publishe

Self-assembling nanoparticles containing dexamethasone as a novel therapy in allergic airways inflammation.

Nanocarriers can deliver a wide variety of drugs, target them to sites of interest, and protect them from degradation and inactivation by the body. They have the capacity to improve drug action and decrease undesirable systemic effects. We have previously developed a well-defined non-toxic PEG-dendritic block telodendrimer for successful delivery of chemotherapeutics agents and, in these studies, we apply this technology for therapeutic development in asthma. In these proof-of-concept experiments, we hypothesized that dexamethasone contained in self-assembling nanoparticles (Dex-NP) and delivered systemically would target the lung and decrease allergic lung inflammation and airways hyper-responsiveness to a greater degree than equivalent doses of dexamethasone (Dex) alone. We found that ovalbumin (Ova)-exposed mice treated with Dex-NP had significantly fewer total cells (2.78 ± 0.44 × 10(5) (n = 18) vs. 5.98 ± 1.3 × 10(5) (n = 13), P<0.05) and eosinophils (1.09 ± 0.28 × 10(5) (n = 18) vs. 2.94 ± 0.6 × 10(5) (n = 12), p<0.05) in the lung lavage than Ova-exposed mice alone. Also, lower levels of the inflammatory cytokines IL-4 (3.43 ± 1.2 (n = 11) vs. 8.56 ± 2.1 (n = 8) pg/ml, p<0.05) and MCP-1 (13.1 ± 3.6 (n = 8) vs. 28.8 ± 8.7 (n = 10) pg/ml, p<0.05) were found in lungs of the Dex-NP compared to control, and they were not lower in the Dex alone group. In addition, respiratory system resistance was lower in the Dex-NP compared to the other Ova-exposed groups suggesting a better therapeutic effect on airways hyperresponsiveness. Taken together, these findings from early-stage drug development studies suggest that the encapsulation and protection of anti-inflammatory agents such as corticosteroids in nanoparticle formulations can improve efficacy. Further development of novel drugs in nanoparticles is warranted to explore potential treatments for chronic inflammatory diseases such as asthma

Type 1 diabetes in very young children: a model of parent and child influences on management and outcomes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135479/1/pedi12351.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135479/2/pedi12351_am.pd

Special Lagrangian cones with higher genus links

For every odd natural number g=2d+1 we prove the existence of a countably infinite family of special Lagrangian cones in C^3 over a closed Riemann surface of genus g, using a geometric PDE gluing method.Comment: 48 page

Benefit finding among parents of young children with type 1 diabetes

Benefit finding, perceived positive effects of adversity, has been associated with psychological well‐being in people with chronic illnesses and with better adherence for adolescents with type 1 diabetes (T1D). Our qualitative research with parents of young children (< 6 years old) with T1D indicated that benefit finding (BF) is a common parental coping mechanism, but no tools exist to measure BF in parents. We determined psychometric properties of the Diabetes Benefit Finding Scale for Parents (DBFS‐P), a 16‐item questionnaire adapted from the validated adolescent version. Parents of young children with T1D (n = 172) were participants in a randomized trial of an online intervention. We examined the DBFS‐P factor structure through principal component analysis (PCA); internal consistency through Cronbach’s alpha; convergent validity via bivariate correlations between the DBFS‐P and measures of parental depression, anxiety, T1D self‐efficacy, and hypoglycemia fear; and discriminant validity via bivariate correlations between the DBFS‐P and measures of parental somatization and child behavior problems. PCA revealed one factor (56.47% variance) with Cronbach’s α = 0.95. Convergent validity of the DBFS‐P was supported by significant correlations with parental depression (r = −0.35, P < 0.001), anxiety (r = −0.20, P = 0.008), T1D self‐efficacy (r = 0.36, P < 0.001), and hypoglycemia fear (r = 0.27, P < 0.001). Non‐significant correlations with parental somatization (r = −0.06, P = 0.42) and child behavior problems (r = −0.12, P = 0.14) support its discriminant validity. The DBFS‐P demonstrated good psychometric properties as a tool for assessing BF among caregivers.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150510/1/pedi12860_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150510/2/pedi12860.pd

On the mean-field spherical model

Exact solutions are obtained for the mean-field spherical model, with or without an external magnetic field, for any finite or infinite number N of degrees of freedom, both in the microcanonical and in the canonical ensemble. The canonical result allows for an exact discussion of the loci of the Fisher zeros of the canonical partition function. The microcanonical entropy is found to be nonanalytic for arbitrary finite N. The mean-field spherical model of finite size N is shown to be equivalent to a mixed isovector/isotensor sigma-model on a lattice of two sites. Partial equivalence of statistical ensembles is observed for the mean-field spherical model in the thermodynamic limit. A discussion of the topology of certain state space submanifolds yields insights into the relation of these topological quantities to the thermodynamic behavior of the system in the presence of ensemble nonequivalence.Comment: 21 pages, 5 figure

A New Method for Searching for Free Fractional Charge Particles in Bulk Matter

We present a new experimental method for searching for free fractional charge in bulk matter; this new method derives from the traditional Millikan liquid drop method, but allows the use of much larger drops, 20 to 100 mm in diameter, compared to the traditional method that uses drops less than 15 mm in diameter. These larger drops provide the substantial advantage that it is then much easier to consistently generate drops containing liquid suspensions of powdered meteorites and other special minerals. These materials are of great importance in bulk searches for fractional charge particles that may have been produced in the early universe.Comment: 17 pages, 5 figures in a singl PDF file (created from WORD Doc.). Submitted to Review of Scientific Instrument

Axonal transport maintains taste responses

Transection of the gerbil's IXth nerve causes gustatory action potentials to decline in 1-6 h; the rate of decline is a linear function of the length of the nerve stump remaining attached to the tongue18. To test the implication that taste discharge mechanisms depend upon axonal transport in the IXth nerve, we injected 40 nl of [3H]leucine into the petrosal ganglion of one IXth nerve of the gerbil, Meriones unguiculatus. Subsequent liquid scintillation counting of the petrosal ganglion, IXth nerve segments, and representative areas of the tongue indicated that labeled materials were transported down the IXth nerve primarily to the vallate and ipsilateral foliate taste papillae of the tongue. A significant impairment of axonal transport and a substantial decline in summated IXth nerve taste responses occurred within 2-3 h a after colchicine was applied to the IXth nerve trunk between the tongue and the petrosal ganglion. Similarly, cooling the IXth nerve with a 3-10 [deg]C thermocouple junction or metal probe impaired axonal transport and caused a taste response decline. Since impulse mechanisms of the nerve trunk continued to function distal to these sites of treatment, we concluded that the maintenance of taste discharges at the level of the taste bud depends upon unimpeded axonal transport.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24253/1/0000516.pd

Mixing-induced CP violating sources for electroweak baryogenesis from a semiclassical approach

The effects of flavor mixing in electroweak baryogenesis is investigated in a generalized semiclassical WKB approach. Through calculating the nonadiabatic corrections to the particle currents it is shown that extra CP violation sources arise from the off-diagonal part of the equation of motion of particles moving inside the bubble wall. This type of mixing-induced source is of the first order in derivative expansion of the Higgs condensate, but is oscillation suppressed. The numerical importance of the mixing-induced source is discussed in the Minimal Supersymmetric Standard Model and compared with the source term induced by semiclassical force. It is found that in a large parameter space where oscillation suppression is not strong enough, the mixing-induced source can dominate over that from the semiclassical force.Comment: 19 pp, 2 figs, 1 table, some comments added, to appear in Eur.Phys.J.