Regression-Based Bayesian Estimation and Structure Learning for Nonparanormal Graphical Models.

A nonparanormal graphical model is a semiparametric generalization of a Gaussian graphical model for continuous variables in which it is assumed that the variables follow a Gaussian graphical model only after some unknown smooth monotone transformations. We consider a Bayesian approach to inference in a nonparanormal graphical model in which we put priors on the unknown transformations through a random series based on B-splines. We use a regression formulation to construct the likelihood through the Cholesky decomposition on the underlying precision matrix of the transformed variables and put shrinkage priors on the regression coefficients. We apply a plug-in variational Bayesian algorithm for learning the sparse precision matrix and compare the performance to a posterior Gibbs sampling scheme in a simulation study. We finally apply the proposed methods to a microarray data set. The proposed methods have better performance as the dimension increases, and in particular, the variational Bayesian approach has the potential to speed up the estimation in the Bayesian nonparanormal graphical model without the Gaussianity assumption while retaining the information to construct the graph.

Excitation Spectrum and Superfluid Gap of an Ultracold Fermi Gas.

Ultracold atomic gases are a powerful tool to experimentally study strongly correlated quantum many-body systems. In particular, ultracold Fermi gases with tunable interactions have allowed to realize the famous BEC-BCS crossover from a Bose-Einstein condensate (BEC) of molecules to a Bardeen-Cooper-Schrieffer (BCS) superfluid of weakly bound Cooper pairs. However, large parts of the excitation spectrum of fermionic superfluids in the BEC-BCS crossover are still unexplored. In this work, we use Bragg spectroscopy to measure the full momentum-resolved low-energy excitation spectrum of strongly interacting ultracold Fermi gases. This enables us to directly observe the smooth transformation from a bosonic to a fermionic superfluid that takes place in the BEC-BCS crossover. We also use our spectra to determine the evolution of the superfluid gap and find excellent agreement with previous experiments and self-consistent T-matrix calculations both in the BEC and crossover regime. However, toward the BCS regime a calculation that includes the effects of particle-hole correlations shows better agreement with our data.

Amphibian chytrid prevalence on boreal toads in SE Alaska and NW British Columbia: tests of habitat, life stages, and temporal trends.

Tracking and understanding variation in pathogens such as Batrachochytrium dendrobatidis (Bd), the agent of amphibian chytridiomycosis which has caused population declines globally, is a priority for many land managers. However, relatively little sampling of amphibian communities has occurred at high latitudes. We used skin swabs collected during 2005-2017 from boreal toads Anaxyrus boreas (n = 248), in southeast Alaska (USA; primarily in and near Klondike Gold Rush National Historical Park [KLGO]) and northwest British Columbia (Canada) to determine how Bd prevalence varied across life stages, habitat characteristics, local species richness, and time. Across all years, Bd prevalence peaked in June and was >3 times greater for adult toads (37.5%) vs. juveniles and metamorphs (11.2%). Bd prevalence for toads in the KLGO area, where other amphibian species are rare or absent, was highest from river habitats (55.0%), followed by human-modified upland wetlands (32.3%) and natural upland wetlands (12.7%)-the same rank-order these habitats are used for toad breeding. None of the 12 Columbia spotted frogs Rana luteiventris or 2 wood frogs R. sylvatica from the study area tested Bd-positive, although all were from an area of low host density where Bd has not been detected. Prevalence of Bd on toads in the KLGO area decreased during 2005-2015. This trend from a largely single-species system may be encouraging or concerning, depending on how Bd is affecting vital rates, and emphasizes the need to understand effects of pathogens before translating disease prevalence into management actions.

Design of complex bone internal structure using topology optimization with perimeter control.

Large facial bone loss usually requires patient-specific bone implants to restore the structural integrity and functionality that also affects the appearance of each patient. Titanium alloys (e.g., Ti-6Al-4V) are typically used in the interfacial porous coatings between the implant and the surrounding bone to promote stability. There exists a property mismatch between the two that in general leads to complications such as stress-shielding. This biomechanical discrepancy is a hurdle in the design of bone replacements. To alleviate the mismatch, the internal structure of the bone replacements should match that of the bone. Topology optimization has proven to be a good technique for designing bone replacements. However, the complex internal structure of the bone is difficult to mimic using conventional topology optimization methods without additional restrictions. In this work, the complex bone internal structure is recovered using a perimeter control based topology optimization approach. By restricting the solution space by means of the perimeter, the intricate design complexity of bones can be achieved. Three different bone regions with well-known physiological loadings are selected to illustrate the method. Additionally, we found that the target perimeter value and the pattern of the initial distribution play a vital role in obtaining the natural curvatures in the bone internal structures as well as avoiding excessive island patterns.

The Fulde-Ferrell-Larkin-Ovchinnikov state for ultracold fermions in lattice and harmonic potentials: a review.

We review the concepts and the present state of theoretical studies of spin-imbalanced superfluidity, in particular the elusive Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) state, in the context of ultracold quantum gases. The comprehensive presentation of the theoretical basis for the FFLO state that we provide is useful also for research on the interplay between magnetism and superconductivity in other physical systems. We focus on settings that have been predicted to be favourable for the FFLO state, such as optical lattices in various dimensions and spin-orbit coupled systems. These are also the most likely systems for near-future experimental observation of the FFLO state. Theoretical bounds, such as Bloch's and Luttinger's theorems, and experimentally important limitations, such as finite-size effects and trapping potentials, are considered. In addition, we provide a comprehensive review of the various ideas presented for the observation of the FFLO state. We conclude our review with an analysis of the open questions related to the FFLO state, such as its stability, superfluid density, collective modes and extending the FFLO superfluid concept to new types of lattice systems.

Induced p-Wave Pairing in Bose-Fermi Mixtures.

Cooper pairing caused by an induced interaction represents a paradigm in our description of fermionic superfluidity. Here, we present a strong coupling theory for the critical temperature of p-wave pairing between spin polarized fermions immersed in a Bose-Einstein condensate. The fermions interact via the exchange of phonons in the condensate, and our self-consistent theory takes into account the full frequency and momentum dependence of the resulting induced interaction. We demonstrate that both retardation and self-energy effects are important for obtaining a reliable value of the critical temperature. Focusing on experimentally relevant systems, we perform a systematic analysis varying the boson-boson and boson-fermion interaction strength as well as their masses, and identify the most suitable system for realizing a p-wave superfluid. Our results show that such a superfluid indeed is experimentally within reach using light bosons mixed with heavy fermions.

Quality of Life and Compassion Satisfaction in Clinicians: A Pilot Intervention Study for Reducing Compassion Fatigue.

BACKGROUND: Compassion fatigue (CF) is prevalent in healthcare professionals, particularly in those caring for chronic, acutely ill, and/or those patients who might be moving toward comfort care. Over time, CF can lead to burnout (BO) and secondary traumatic stress and an overall decrease in professional quality of life. In this pilot study, participants completed a resiliency program focused on education about CF and self-awareness of its individualized impact and were expected to develop ongoing self-care practices to prevent/address the untoward effects. METHODS: Healthcare professionals ( N = 15) participated in a formalized educational program consisting of three 90-minute educational sessions held 2 weeks apart. Preassessment and postintervention data were collected electronically in survey format. A postprogram evaluation was also offered. RESULTS: Upon completion of the program, participants noted an increase in compassion satisfaction (CS) and a small reduction in BO. Secondary traumatic stress remained unchanged. Feedback about the program was positive, and participants reported the impact on their clinical practice and life to be moderately high. At 6 months, over half of the participants continued to report positive impact on their personal/professional lives. CONCLUSION: While the small sample size of this pilot study limits the generalizability of the findings, there were positive effects for CS and BO in participants over time, indicating possible benefits of providing self-care education to healthcare providers. Additional research with a larger sample size is needed to address how healthcare providers might further benefit from resiliency education and interventions to improve professional quality of life.

Momentum-resolved spectroscopy of a Fermi liquid.

We consider a recent momentum-resolved radio-frequency spectroscopy experiment, in which Fermi liquid properties of a strongly interacting atomic Fermi gas were studied. Here we show that by extending the Brueckner-Goldstone model, we can formulate a theory that goes beyond basic mean-field theories and that can be used for studying spectroscopies of dilute atomic gases in the strongly interacting regime. The model hosts well-defined quasiparticles and works across a wide range of temperatures and interaction strengths. The theory provides excellent qualitative agreement with the experiment. Comparing the predictions of the present theory with the mean-field Bardeen-Cooper-Schrieffer theory yields insights into the role of pair correlations, Tan's contact, and the Hartree mean-field energy shift.

Alteration of fibroblast phenotype by asbestos-induced autoantibodies.

Pulmonary fibrosis is a relentlessly progressive disease for which the etiology can be idiopathic or associated with environmental or occupational exposures. There is not a clear explanation for the chronic and progressive nature of the disease, leaving treatment and prevention options limited. However, there is increasing evidence of an autoimmune component, since fibrotic diseases are often accompanied by production of autoantibodies. Because exposure to silicates such as silica and asbestos can lead to both autoantibodies and pulmonary/pleural fibrosis, these exposures provide an excellent tool for examining the relationship between these outcomes. This study explored the possibility that autoantibodies induced by asbestos exposure in mice would affect fibroblast phenotype. L929 fibroblasts and primary lung fibroblasts were treated with serum IgG from asbestos- or saline-treated mice, and tested for binding using cell-based ELISA, and for phenotypic changes using immunofluorescence, laser scanning cytometry and Sirius Red collagen assay. Autoantibodies in the serum of C57Bl/6 mice exposed to asbestos (but not sera from untreated mice) bound to mouse fibroblasts. The autoantibodies induced differentiation to a myofibroblast phenotype, as demonstrated by increased expression of smooth muscle α-actin (SMA), which was lost when the serum was cleared of IgG. Cells treated with purified IgG of exposed mice produced excess collagen. Using ELISA, we tested serum antibody binding to DNA topoisomerase (Topo) I, vimentin, TGFß-R, and PDGF-Rα. Antibodies to DNA Topo I and to PDGF-Rα were detected, both of which have been shown by others to be able to affect fibroblast phenotype. The anti-fibroblast antibodies (AFA) also induced STAT-1 activation, implicating the PDGF-R pathway as part of the response to AFA binding. These data support the hypothesis that asbestos induces AFA that modify fibroblast phenotype, and suggest a mechanism whereby autoantibodies may mediate some of the fibrotic manifestations of asbestos exposure.

Asbestos-induced autoimmunity in C57BL/6 mice.

Environmental impacts on autoimmunity have significant public health implications. Epidemiological studies have shown associations between exposure to airborne silicates, such as crystalline silica or asbestos, and autoimmunity, but the etiology remains unclear. The purpose of this study was to test the hypothesis that asbestos could lead to a specific pattern of autoantibodies and pathology indicative of systemic autoimmune disease (SAID). Female C57Bl/6 mice were instilled intratracheally with 2 doses x 60 microg/mouse of amphibole asbestos (tremolite), wollastonite (a non-fibrogenic control fiber), or saline alone. Serum samples were collected and urine was checked for protein bi-weekly for 7 months. By 26 weeks, the asbestos-instilled animals had a significantly higher frequency of positive anti-nuclear antibody (ANA) tests compared to wollastonite and saline groups. The majority of positive ANAs showed homogeneous or combined homogeneous/speckled patterns, and tested positive for antibodies to dsDNA and SSA/Ro 52. Serum isotyping showed no significant changes in IgM, IgA, or IgG subclasses. However, there was an overall decrease in the mean IgG serum concentration in asbestos-instilled mice. IgG immune complex deposition was demonstrated in the kidneys of asbestos-instilled mice, with evidence of glomerular and tubule abnormalities suggestive of glomerulonephritis. Flow cytometry demonstrated moderate changes in the percentages of CD25+ T-suppressor cells and B1a B-cells in the superficial cervical lymph nodes of the asbestos-instilled mice. These data demonstrate that asbestos leads to immunologic changes consistent with the development of autoimmunity. This study provides a non-autoimmune prone murine model for use in future elucidation of mechanisms involved in asbestos-induced autoimmune disease.

Against all odds: designing and implementing a grassroots, community-designed RHIO in a rural region.

Community Health Information Networks have provided lessons learned for RHIOs by bringing attention to issues of trust, buy-in, ownership and financing. This article reports the formation of a new rural RHIO, East Kern County Integrated Technology Association (EKCITA) and addresses unique rural demands and success themes specificto rural environments. A case study approach-grounded in action research and utilizing techniques of key informant interviews, participant observations and content review of written data sources from 2006-was utilized. Through a process of grassroots governance, transparency and consensus decision-making, EKCITA was incorporated in 2006. Taking lessons learned from past initiatives, this rural RHIO used a transparent and participative process while addressing unique challenges faced by rural regions. Through this process, seven additional success themes were identified, five of which are unique to rural regions. Rural communities can develop dynamic entities that address a host ofissues in addition to information technology.

Assessment of autoimmune responses associated with asbestos exposure in Libby, Montana, USA.

Systemic autoimmune responses are associated with certain environmental exposures, including crystalline particles such as silica. Positive antinuclear antibody (ANA) tests have been reported in small cohorts exposed to asbestos, but many questions remain regarding the prevalence, pattern, and significance of autoantibodies associated with asbestos exposures. The population in Libby, Montana, provides a unique opportunity for such a study because of both occupational and environmental exposures that have occurred as a result of the mining of asbestos-contaminated vermiculite near the community. As part of a multifaceted assessment of the impact of asbestos exposures on this population, this study explored the possibility of exacerbated autoimmune responses. Age- and sex-matched sets of 50 serum samples from Libby and Missoula, Montana (unexposed), were tested for ANA on HEp-2 cells using indirect immunofluorescence. Data included frequency of positive tests, ANA titers, staining patterns, and scored fluorescence intensity, all against known controls. Serum immunoglobulin A (IgA), rheumatoid factor, and antibodies to extractable nuclear antigen (ENA) were also tested. The Libby samples showed significantly higher frequency of positive ANA and ENA tests, increased mean fluorescence intensity and titers of the ANAs, and higher serum IgA, compared with Missoula samples. In the Libby samples, positive correlations were found between ANA titers and both lung disease severity and extent of exposure. The results support the hypothesis that asbestos exposure is associated with autoimmune responses and suggests that a relationship exists between those responses and asbestos-related disease processes.

Differential expression and imprinting status of Ins1 and Ins2 genes in extraembryonic tissues of laboratory mice.

There are two functional insulin genes in the mouse genome. The Ins2 gene is imprinted and expressed monoallelically from the paternal allele in the yolk sac. In the present study we have re-examined the imprinting status of Ins1. We found that Ins1 is not expressed in the yolk sac of several laboratory mouse strains. The asynchrony of replication at the wild type locus was significantly lower than at imprinted loci and was more similar to non-imprinted loci. Finally, we have taken the advantage of the Ins1(neo) allele created by homologous recombination to examine the allelic usage at this locus. We observed that the neo gene inserted at the Ins1 locus was expressed from both the paternally and the maternally transmitted allele. Therefore, the Ins1 gene does not share any of the basic properties of imprinted genes. On the basis of these data, we concluded that Ins1 locus is unlikely to be imprinted in common laboratory mice.

Improved metabolic disorders of insulin receptor-deficient mice by transgenic overexpression of glucokinase in the liver.

AIMS/HYPOTHESIS: Insulin receptor null mutant mice develop severe diabetes, ketoacidosis and liver steatosis and die within 1 week after birth. Since the liver plays an essential role in the control of glucose homeostasis, we examined in this work whether the metabolic disorders of insulin receptor-deficient mice could be improved upon restoration of hepatic glucose metabolism by transgenic constitutive overexpression of glucokinase selectively in the liver. METHODS: We first generated transgenic mice overexpressing rat glucokinase cDNA under control of the liver-specific phenylalanine hydroxylase gene promoter. These transgenic mice were crossed with heterozygous insulin-receptor-null mutants to produce homozygous insulin-receptor-null mice overexpressing glucokinase in the liver. RESULTS: The transgenic mice overexpressing glucokinase in the liver showed improved glucose tolerance and were mildly hypoglycaemic and hyperlipidaemic under starved conditions. The introduction of the glucokinase transgene in insulin receptor null mice did not prevent the development of glycosuria. However, ketoacidosis was delayed by more than 1 week and survival was prolonged to 10 to 16 days in 16% of the pups. In these longer surviving pups, serum glucose and triglyceride concentrations were lowered, hepatic glycogen stores were reconstituted and liver steatosis was absent as compared with the pups which had developed strong ketoacidosis and died earlier. CONCLUSIONS/INTERPRETATION: These results show that overexpression of hepatic glucokinase can compensate, in part, for the metabolic disorders developed by insulin receptor-deficient mice. This shows the importance of improving hepatic function in diabetes and must revive interest in enhancement of glucokinase activity as a therapeutic strategy for the treatment of diabetes.

Increased islet cell proliferation, decreased apoptosis, and greater vascularization leading to beta-cell hyperplasia in mutant mice lacking insulin.

The targeted disruption of the two nonallelic insulin genes in mouse was reported previously to result in intrauterine growth retardation, severe diabetes immediately after suckling, and death within 48 h of birth. We have further used these animals to investigate the morphology and cell biology of the endocrine pancreas in late gestation and at birth when insulin is absent throughout development. Pancreatic beta-cells were identified by detecting the activity of the LacZ gene inserted at the Ins2 locus. A significant increase in the mean area of the islets was found at embryonic d 18.5 (E18.5) and in the newborn in Ins1-/-, Ins2-/- animals compared with Ins1-/-, Ins2+/- and wild-type controls, whereas the blood glucose levels were unaltered. The individual size of the beta-cells in the insulin-deficient fetuses was similar to controls, suggesting that the relative increase in islet size was due to an increase in cell number. Immunohistochemistry for proliferating cell nuclear antigen within the pancreatic ductal epithelium showed no differences in labeling index between insulin-deficient and control mice, and no change in the number of beta-cells associated with ducts, but the relative size distribution of the islets was altered so that fewer islets under 5,000 microm(2) and more islets greater than 10,000 microm(2) were present in Ins1-/-, Ins2-/- animals. This suggests that the greater mean islet size seen in insulin-deficient animals represented an enlargement of formed islets and was not associated with an increase in islet neogenesis. The proportional contribution of alpha- and beta-cells to the islets was not altered. This was supported by an increase in the number of cells containing immunoreactive proliferating cell nuclear antigen in both islet alpha- and beta-cells at E18.5 in insulin-deficient mice, and a significantly lower incidence of apoptotic cells, as determined by molecular histochemistry using the terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling reaction. The density of blood vessels within sections of whole pancreas, or within islets, was determined by immunohistochemistry for the endothelial cell marker CD31 and was found to be increased 2-fold in insulin-deficient mice compared with controls at E18.5. However, no changes were found in the steady-state expression of mRNAs encoding vascular endothelial growth factor, its receptor Flk-1, IGF-I or -II, the IGF-I and insulin receptors, or insulin receptor substrates-1 or -2 in pancreata from Ins1-/-, Ins2-/- mice compared with Ins1-/-, Ins2+/- controls. Thus, we conclude that the relative hyperplasia of the islets in late gestation in the insulin-deficient mice was due to an increased islet cell proliferation coupled with a reduced apoptosis, which may be related to an increased vascularization of the pancreas.

Endocrine pancreas in insulin receptor-deficient mouse pups.

Insulin receptor (IR)-deficient pups rapidly become hyperglycemic and hyperinsulinemic and die of diabetic ketoacidosis within a few days. Immunocytochemical analysis of the endocrine pancreas revealed that IR deficiency did not alter islet morphology or the number of beta-, alpha-, delta-, and pancreatic polypeptide (PP) cells. The lack of IR did not result in major changes in the expression of islet hormone genes or of beta-cell-specific marker genes encoding pancreas duodenum homeobox-containing transcription factor-1 (PDX-1), glucokinase (GCK), and GLUT2, as shown by reverse transcriptase-polymerase chain reaction analysis. The serum glucagon levels in IR-deficient and nondiabetic littermates were comparable. Finally, total insulin content in the pancreas of IR-deficient pups was gradually depleted, indicating sustained insulin secretion, not compensated for by increased insulin biosynthesis. These findings are discussed in light of recent results suggesting a role of IR in beta-cell function.

Compensatory responses in mice carrying a null mutation for Ins1 or Ins2.

Intrauterine growth retardation and postnatal acute diabetes result from insulin deficiency in double homozygous null mutants for Ins1 and Ins2 (Duvillié B, et al., Proc. Natl. Acad. Sci. USA 94:5137-5140, 1997). The characterization of single homozygous null mutants for Ins1 or Ins2 is described here. Neither kind of mutant mice was diabetic. Immunocytochemical analysis of the islets showed normal distribution of the endocrine cells producing insulin, glucagon, somatostatin, or pancreatic polypeptide. Analysis of the expression of the functional insulin gene in Ins1-/- or Ins2-/- mice revealed a dramatic increase of Ins1 transcripts in Ins2-/- mutants. This compensatory response was quantitatively reflected by total pancreatic insulin content similar for both types of mutants and wild-type mice. Moreover, both mutants had normal plasma insulin levels and normal glucose tolerance tests. The determination of beta-cell mass by morphometry indicated beta-cell hyperplasia in the mutant mice. The beta-cell mass in Ins2-/- mice was increased almost threefold, which accounts for the increase of Ins1 transcripts in Ins2-/-mutants. This study thus contributes to evaluate the potential of increasing the beta-cell mass to compensate for low insulin production.

IGF-1 receptor as an alternative receptor for metabolic signaling in insulin receptor-deficient muscle cells.

We have derived skeletal muscle cell lines from wild-type (wt) and insulin receptor (IR) knockout mice to unravel the metabolic potential of IGF-1 receptor (IGF-1R). Both wt and IR(-/-) myoblasts differentiated into myotubes with similar patterns of expression of muscle-specific genes such as MyoD, myogenin and MLC1A indicating that IR is not required for this process. Binding of 125I-IGF-1 on wt and IR(-/-) myotubes was similar showing that IGF-1R was not upregulated in the absence of IR. Stimulation of IR(-/-) myotubes with IGF-1 (10(-10) to 10(-7) M) increased glucose uptake and incorporation into glycogen, induced IRS-1 phosphorylation and activated PI 3-kinase and MAP kinase, two enzymes of major signaling pathways. These effects were comparable to those obtained with wt myotubes using insulin or IGF-1 or with IR(-/-) myotubes using insulin at higher concentrations. This study provides a direct evidence that IGF-1R can represent an alternative receptor for metabolic signaling in muscle cells.

Biallelic transcription of Igf2 and H19 in individual cells suggests a post-transcriptional contribution to genomic imprinting.

The H19 and insulin-like growth factor 2 (Igf2) genes in the mouse are models for genomic imprinting during development. The genes are located only 90 kb apart in the same transcriptional orientation [1], but are reciprocally imprinted: Igf2 is paternally expressed while H19 is maternally expressed. It has been suggested that expression of H19 and repression of Igf2 (or the converse) on a given chromosome are mechanistically linked and that the parental imprint operates at the level of transcription [2]. Although expression of Igf2 and H19 is thought to be monoallelic, the data have so far been obtained exclusively by looking at steady-state RNA levels using techniques that reflect the average activity of the genes in a cell population [3] [4]. Here, we have adapted a fluorescent in situ hybridisation (FISH) method to detect nascent RNA molecules of Igf2 and H19 at the initial transcription sites in the nuclei of wild-type mouse embryonic liver cells. Nine different transcription patterns were observed, reflecting a high heterogeneity of transcription at the single-cell level. Our observations suggest that regulation of Igf2 and H19 by parental imprinting is much more complex than previously proposed and acts at both transcriptional and post-transcriptional levels.