Inflammation and Monocyte Recruitment due to Aging and Mechanical Stretch in Alveolar Epithelium are Inhibited by the Molecular Chaperone 4-phenylbutyrate.

INTRODUCTION: Ventilator-Induced lung injury (VILI) is a form of acute lung injury that is initiated or exacerbated by mechanical ventilation. The aging lung is also more susceptible to injury. Harmful mechanical stretch of the alveolar epithelium is a recognized mechanism of VILI, yet little is known about how mechanical stretch affects aged epithelial cells. Disruption to Endoplasmic Reticulum (ER) homeostasis results in a condition known as ER stress that leads to disruption of cellular homeostasis, apoptosis, and inflammation. ER stress is increased with aging and other pathological stimuli. We hypothesized that age and mechanical stretch increase alveolar epithelial cells' proinflammatory responses that are mediated by ER stress. Furthermore, we believed that inhibition of this upstream mechanism with 4PBA, an ER stress reducer, alleviates subsequent inflammation and monocyte recruitment. METHODS: Type II alveolar epithelial cells (ATII) were harvested from C57Bl6/J mice 2 months (young) and 20 months (old) of age. The cells were cyclically stretched at 15% change in surface area for up to 24 hours. Prior to stretch, groups were administered 4PBA or vehicle as a control. RESULTS: Mechanical stretch and age upregulated ER stress and proinflammatory MCP-1/CCL2 and MIP-1ß/CCL4 chemokine expression in ATIIs. Age-matched and mismatched monocyte recruitment by ATII conditioned media was also quantified. CONCLUSIONS: Age increases susceptibility to stretch-induced ER stress and downstream inflammatory gene expression in a primary ATII epithelial cell model. Administration of 4PBA attenuated the increased ER stress and proinflammatory responses from stretch and/or age and significantly reduced monocyte migration to ATII conditioned media.

Absence of a Large Superconductivity-Induced Gap in Magnetic Fluctuations of Sr_{2}RuO_{4}.

Inelastic neutron scattering experiments on Sr_{2}RuO_{4} determine the spectral weight of the nesting induced magnetic fluctuations across the superconducting transition. There is no observable change at the superconducting transition down to an energy of ∼0.35 meV, which is well below the 2Δ values reported in several tunneling experiments. At this and higher energies magnetic fluctuations clearly persist in the superconducting state. Only at energies below ∼0.3 meV can evidence for partial suppression of spectral weight in the superconducting state be observed. This strongly suggests that the one-dimensional bands with the associated nesting fluctuations do not form the active, highly gapped bands in the superconducting pairing in Sr_{2}RuO_{4}.

Optimizing Surveillance for South American Origin Influenza A Viruses Along the United States Gulf Coast Through Genomic Characterization of Isolates from Blue-winged Teal (Anas discors).

Relative to research focused on inter-continental viral exchange between Eurasia and North America, less attention has been directed towards understanding the redistribution of influenza A viruses (IAVs) by wild birds between North America and South America. In this study, we genomically characterized 45 viruses isolated from blue-winged teal (Anas discors) along the Texas and Louisiana Gulf Coast during March of 2012 and 2013, coincident with northward migration of this species from Neotropical wintering areas to breeding grounds in the United States and Canada. No evidence of South American lineage genes was detected in IAVs isolated from blue-winged teal supporting restricted viral gene flow between the United States and southern South America. However, it is plausible that blue-winged teal redistribute IAVs between North American breeding grounds and wintering areas throughout the Neotropics, including northern South America, and that viral gene flow is limited by geographical barriers further south (e.g., the Amazon Basin). Surveillance for the introduction of IAVs from Central America and northern South America into the United States may be further optimized through genomic characterization of viruses resulting from coordinated, concurrent sampling efforts targeting blue-winged teal and sympatric species throughout the Neotropics and along the United States Gulf Coast.

A magnetically shielded room with ultra low residual field and gradient.

A versatile and portable magnetically shielded room with a field of (700 ± 200) pT within a central volume of 1 m × 1 m × 1 m and a field gradient less than 300 pT/m, achieved without any external field stabilization or compensation, is described. This performance represents more than a hundredfold improvement of the state of the art for a two-layer magnetic shield and provides an environment suitable for a next generation of precision experiments in fundamental physics at low energies; in particular, searches for electric dipole moments of fundamental systems and tests of Lorentz-invariance based on spin-precession experiments. Studies of the residual fields and their sources enable improved design of future ultra-low gradient environments and experimental apparatus. This has implications for developments of magnetometry beyond the femto-Tesla scale in, for example, biomagnetism, geosciences, and security applications and in general low-field nuclear magnetic resonance (NMR) measurements.

Correlated decay of triplet excitations in the Shastry-Sutherland compound SrCu2(BO3)2.

The temperature dependence of the gapped triplet excitations (triplons) in the 2D Shastry-Sutherland quantum magnet SrCu(2)(BO(3))(2) is studied by means of inelastic neutron scattering. The excitation amplitude rapidly decreases as a function of temperature, while the integrated spectral weight can be explained by an isolated dimer model up to 10 K. Analyzing this anomalous spectral line shape in terms of damped harmonic oscillators shows that the observed damping is due to a two-component process: one component remains sharp and resolution limited while the second broadens. We explain the underlying mechanism through a simple yet quantitatively accurate model of correlated decay of triplons: an excited triplon is long lived if no thermally populated triplons are nearby but decays quickly if there are. The phenomenon is a direct consequence of frustration induced triplon localization in the Shastry-Sutherland lattice.

Climate change and violent conflict.

Current debates over the relation between climate change and conflict originate in a lack of data, as well as the complexity of pathways connecting the two phenomena.

Magnetic-field-induced soft-mode quantum phase transition in the high-temperature superconductor La1.855Sr0.145CuO4: an inelastic neutron-scattering study.

Inelastic neutron-scattering experiments on the high-temperature superconductor La1.855Sr0.145CuO4 reveal a magnetic excitation gap Delta that decreases continuously upon application of a magnetic field perpendicular to the CuO2 planes. The gap vanishes at the critical field required to induce long-range incommensurate antiferromagnetic order, providing compelling evidence for a field-induced soft-mode driven quantum phase transition.

Quantum effects in a weakly frustrated s=1/2 two-dimensional heisenberg antiferromagnet in an applied magnetic field.

We have studied the two-dimensional S=1/2 square-lattice antiferromagnet Cu(pz)_{2}(ClO4)_{2} (where pz denotes pyrazine), using neutron inelastic scattering and series expansion calculations. We show that the presence of antiferromagnetic next-nearest-neighbor interactions enhances quantum fluctuations associated with resonating valence bonds. Intermediate magnetic fields lead to a selective tuning of resonating valence bonds and a spectacular inversion of the zone-boundary dispersion, providing novel insight into 2D antiferromagnetism in the quantum limit.

Genetic dissection of quantitative trait locus for ethanol sensitivity in long- and short-sleep mice.

Interval-specific congenic strains (ISCS) allow fine mapping of a quantitative trait locus (QTL), narrowing its confidence interval by an order of magnitude or more. In earlier work, we mapped four QTL specifying differential ethanol sensitivity, assessed by loss of righting reflex because of ethanol (LORE), in the inbred long-sleep (ILS) and inbred short-sleep (ISS) strains, accounting for approximately 50% of the genetic variance for this trait. Subsequently, we generated reciprocal congenic strains in which each full QTL interval from ILS was bred onto the ISS background and vice versa. An earlier paper reported construction and results of the ISCS on the ISS background; here, we describe this process and report results on the ILS background. We developed multiple ISCS for each Lore QTL in which the QTL interval was broken into a number of smaller intervals. For each of the four QTL regions (chromosomes 1, 2, 11 and 15), we were successful in reducing the intervals significantly. Multiple, positive strains were overlapped to generate a single, reduced interval. Subsequently, this reduced region was overlaid on previous reductions from the ISS background congenics, resulting in substantial reductions in all QTL regions by approximately 75% from the initial mapping study. Genes with sequence or expression polymorphisms in the reduced intervals are potential candidates; evidence for these is presented. Genetic background effects can be important in detection of single QTL; combining this information with the generation of congenics on both backgrounds, as described here, is a powerful approach for fine mapping QTL.

Magnetic excitations in multiferroic TbMnO3: evidence for a hybridized soft mode.

The magnetic excitations in multiferroic TbMnO3 have been studied by inelastic neutron scattering in the spiral and sinusoidally ordered phases. At the incommensurate magnetic zone center of the spiral phase, we find three low-lying magnons whose character has been fully determined using neutron-polarization analysis. The excitation at the lowest energy is the sliding mode of the spiral, and two modes at 1.1 and 2.5 meV correspond to rotations of the spiral rotation plane. These latter modes are expected to couple to the electric polarization. The 2.5 meV mode is in perfect agreement with recent infrared-spectroscopy data giving strong support to its interpretation as a hybridized phonon-magnon excitation.

Field-induced paramagnons at the metamagnetic transition of Ca1.8Sr0.2RuO4.

The magnetic excitations in Ca1.8Sr0.2RuO4 were studied across the metamagnetic transition and as a function of temperature using inelastic neutron scattering. At low temperature and low magnetic field the magnetic response is dominated by a complex superposition of incommensurate antiferromagnetic fluctuations. Upon increasing the magnetic field across the metamagnetic transition, paramagnon and finally well-defined magnon scattering is induced, partially suppressing the incommensurate signals. The high-field phase in Ca1.8Sr0.2RuO4, therefore, has to be considered as an intrinsically ferromagnetic state stabilized by the magnetic field.

Replication of small effect quantitative trait loci for behavioral traits facilitated by estimation of effect size from independent cohorts.

Quantitative trait locus (QTL) mapping is often done in a single segregating population, such as a backcross or an intercross. Both QTL location and effect size are then estimated from the same dataset. This approach results in an over-estimate of effect size for two reasons: (1) LOD scores, which are maximized over numerous point-wise tests, are correlated with estimated effect size and (2) small effect QTLs are often undetected in underpowered experiments, yielding inflated effect sizes for detected QTLs (the Beavis effect). When it is impractical to maintain or generate large population sizes, an alternative is to use two populations, one for initial detection and localization and a second for a locus-matched estimate of effect size, not conditioned on significance. Recombinant inbred (RI) panels are eminently suitable for this approach, as each strain genotype can be sampled repeatedly. We present mapping results from the LXS RI panel for two behavioral phenotypes relating to ethanol response: low-dose ethanol activation and loss of righting following high-dose injection. Both the phenotypes were measured in two or three independent cohorts, which were then used to re-estimate effect size. Many small-effect QTLs replicated using this approach, but in all cases, effect size, in the replicate cohorts, was reduced from the initial estimate, often substantially. Such a reduction will have important consequences for power analyses in which sample sizes are determined for subsequent confirmation studies.

Epigenetic regulation of X-linked cancer/germline antigen genes by DNMT1 and DNMT3b.

We examined the function of two key DNA methyltransferase (DNMT) enzymes in epigenetic regulation of X-linked cancer/germline (CG-X) antigen genes in human cancer cells, using MAGE-A1, NY-ESO-1, and XAGE-1 as models. In HCT116 cells, genetic knockout of DNMT1 caused moderate activation of CG-X genes, DNMT3b knockout had a negligible effect, and double knockout of both enzymes caused robust gene induction. Similarly, dual DNMT knockout caused dramatic hypomethylation of the MAGE-A1 and NY-ESO-1 promoters, DNMT1 knockout showed moderate hypomethylation, and DNMT3b knockout elicited only slight methylation changes. In contrast, both single and double knockout cells showed significant hypomethylation of the XAGE-1 promoter. RNA interference (RNAi) targeting of DNMT1 in HCT116 cells validated the results seen using genetic knockout cells; however, RNAi targeting of DNMT1 in a different colorectal cancer cell line revealed a greater independent role for DNMT1 in mediating CG-X gene repression and promoter methylation in other cell types. Notably, the histone H3 modification pattern at CG-X promoters was altered following DNMT knockout. DNMT1 or DNMT3b knockout reduced dimethylated lysine-9 (diMe-H3K9) levels, but did not significantly affect dimethylated lysine-4 (diMe-H3K4) or acetylated lysine-9 (Ac-H3-K9) levels. In contrast, dual DNMT1/3b knockout reduced the level of diMe-H3K9 and dramatically increased the levels of diMe-H3K4 and Ac-H3K9 at CG-X gene loci. In summary, DNMT1 and DNMT3b were found to perform both redundant and independent functions in epigenetic regulation of CG-X antigen genes in human cancer cells.

Chemostratigraphy of predominantly siliciclastic Neoproterozoic successions: a case study of the Pocatello Formation and Lower Brigham Group, Idaho, USA

Isotopic chemostratigraphy has proven successful in the correlation of carbonate-rich Neoproterozoic successions. In successions dominated by siliciclastic rocks, chemostratigraphy can be problematic, but if thin carbonates punctuate siliciclastic strata, useful isotopic data may be obtained. The upper Pocatello Formation and lower Brigham Group of southeastern Idaho provide an opportunity to assess the potential and limitations of isotopic chemostratigraphy in overwhelmingly siliciclastic successions. The 5000 m thick succession consists predominantly of siliciclastic lithologies, with only three intervals that contain thin intercalated carbonates. Its depositional age is only broadly constrained by existing biostratigraphic, sequence stratigraphic and geochronometric data. The lowermost carbonates include a cap dolomite atop diamictites and volcanic rocks of the Pocatello Formation. The delta 13C values of these carbonates are distintly negative (-5 to -3), similar to carbonates that overlie Neoproterozoic glaciogenic rocks worldwide. Stratigraphically higher carbonates record a major positive delta 13C excursion to values as high as +8.8 within the carbonate member of the Caddy Canyon Quartzite. The magnitude of this excusion is consistent with post-Sturtian secular variation recorded elsewhere in the North American Cordillera, Australia, Svalbard, Brazil and Nambia, and exceeds the magnitude of any post-Varanger delta 13C excursion documented to date. In most samples, Sr-isotopic abundances have been altered by diagenesis and greenschist facies metamorphism, but a least-altered value of approximately 0.7076 supports a post-Sturtian and pre-Marinoan/Varanger age for upper Pocatello and lower Brigham rocks that lie above the Pocatello diamictite. Thus, even though available chemostratigraphic data are limited, they corroborate correlations of Pocatello Formation diamictites and overlying units with Sturtian glaciogenic rocks and immediately post-Sturtian successions in western North America and elsewhere.

Polarized intestinal hybrid cell lines derived from primary culture: establishment and characterization.

A cell culture system has been developed that produces stable gastrointestinal (GI) polarized cell lines capable of maintaining hormone secretion. A spontaneously transformed rat mucosal epithelial cell was selected for hypoxanthine/guanine phosphoribosyltransferase deficiency and transfected with a plasmid conferring hygromycin resistance (BRIE 291 cells). Fusion of these cells with dispersed small intestinal epithelia cells resulted in hybrid cell lines that retained characteristic properties of the native GI cell more effectively than the transformed tumorigenic parental cell line. Hybrid hBRIE 380 cells are uniformly cuboidal with microvilli, contain villin, are contact inhibited, are anchorage dependent, require serum supplementation for growth, and are more sensitive to virus infection than the parental BRIE 291 cells. Fusion of BRIE 291 with dispersed pancreatic islet cells has resulted in a variety of pancreatic-hormone-producing cell lines. One of these, hybrid hBRIE 291-i2, forms confluent monolayers capable of synthesizing insulin-like immunoreactivity. These studies demonstrate that functionally polarized GI cells can be generated from primary cultures of nondividing committed epithelial cells by somatic cell hybridization and make feasible the selection and maintenance of specific GI epithelial cell types in confluent monolayer cultures.

Radical prostatectomy after definitive radiation therapy for prostate cancer.

Radical prostatectomy was performed in 14 patients following local failure of radiation therapy for adenocarcinoma of the prostate. Ten patients were treated with external beam and 4 with interstitial radiation. The interval from beginning radiation therapy to biopsy-proved residual or recurrent disease was twenty-four to one hundred fourteen months (mean 61 months). Ten patients had significant anterior and lateral fibrosis. Five patients had loss of tissue planes between the prostate and rectum, however, no rectal injuries occurred. Estimated blood loss was 300-8,000 cc (median 1,000 cc). Operative time was one hundred ten to three hundred seventy-five minutes (median 185 minutes). Significant late complications are impotence (100%) and incontinence (55%). Tumor volume was 1.1-27.2 cc (mean 11.1 cc). Seven patients had seminal vesicle involvement, 9 had level III capsule penetration, and 6 had positive surgical margins. Follow-up ranges from one to fifty-two months (median 18 months). Currently, 6 patients are clinically without disease and have serum prostate-specific antigen (PSA) of 0.0 ng/mL. Four patients have no clinical evidence of disease but do have detectable serum PSA, and 4 patients have evidence of metastatic bone disease on bone scan with elevated serum PSA levels. Radical prostatectomy following radiation therapy has no greater immediate morbidity or mortality compared with radical prostatectomy without prior irradiation and takes only slightly longer to perform. However, there is a marked increased risk of impotence and incontinence. More patients followed for a longer time are needed to assess the benefit of radical prostatectomy on survival of patients who fail radiation therapy.

Adjuvant radiation therapy in patients with detectable prostate specific antigen following radical prostatectomy.

Adjuvant radiation therapy following radical prostatectomy for adenocarcinoma of the prostate was given to 25 patients. Of these patients 8 had microscopic lymph node metastasis, 8 had seminal vesicle invasion without positive lymph nodes, 6 had positive surgical margins and 3 had only capsule penetration. Their only evidence of residual disease was detectable serum prostate specific antigen (PSA) by the Yang assay. A total of 15 patients (60%) had a subsequent decrease in PSA to less than 0.3 ng./ml. and an additional 5 (20%) had a decrease in PSA by more than 50%. Currently 8 patients have no detectable PSA after a median followup of 18 months (17 to 38 months) since initiating radiation therapy. Only 1 of 12 patients with detectable PSA immediately after radical prostatectomy has had a durable response to adjuvant radiation therapy. In contrast 7 of 13 patients with a delayed increase in PSA had a durable response. The ability of adjuvant radiation therapy to eliminate serum PSA in patients with a delayed increase in PSA after radical prostatectomy is encouraging. However, longer followup, including the use of nonradiated control subjects, is needed to assess the ability of adjuvant radiation therapy to control local disease and prolong patient survival.

Positive surgical margins at radical prostatectomy: importance of the apical dissection.

Positive margins were analyzed in 189 clinical stage B radical retropubic prostatectomies. Margins were identified by serially blocking the entire specimens in planes selected for optimum demonstration of capsule surface. Positive margins were divided into 2 categories: 1) those associated with capsular penetration of cancer and 2) those caused by inadvertent surgical incisions through the capsule into intracapsular cancer. Data were analyzed separately at each of 6 anatomical sites. Frequency of positive margins was related to the volume of cancer. Cancer of greater than 12 cc constituted a distinctive category in which seminal vesicle invasion, lymph node metastases and multiple positive margins were found in the majority of cases, signifying minimal possibility of cure. However, 31 positive margins occurred among 136 patients (23%) who were potentially curable by the criteria of normal seminal vesicles and absence of pelvic lymph node metastases; 17, of these 31 surgically positive margins (55%) occurred at the apex. Positive capsular penetration margins at the apex were volume-related, while negative margins were not. Site specific recommendations for avoiding positive and negative capsular penetration margins are suggested. The prostate apex, rectal and lateral surfaces, bladder neck and superior pedicles accounted for 48, 24, 16 and 10% of all positive margins, respectively. Dissection of the apical prostate and Denonvilliers' fascia require modifications of current surgical techniques if positive margins are to be avoided. Serum levels of prostate specific antigen may require as long as 5 years to become detectable when only 1 positive margin is the only evidence of nonorgan-confined disease.

Colorado IDDM Registry: lower incidence of IDDM in Hispanics. Comparison of disease characteristics and care patterns in biethnic population.

The Colorado IDDM Registry identifies newly diagnosed cases of insulin-dependent diabetes mellitus (IDDM) throughout the state. Hispanics in Colorado are a racial mixture of American Indian and White populations. Because American Indians have a low risk of IDDM, and differing frequencies of HLA antigens and haplotypes are reported for Hispanics and non-Hispanics, we compared incidence rates and disease characteristics. Eligible participants were less than 18 yr of age and Colorado residents at time of diagnosis, diagnosed between 1 January 1978 and 31 December 1983, and on insulin within 2 wk of diagnosis. Subjects were reported by their physicians, and statewide validation of reporting was conducted through review of hospital discharge indexes. Incidence rates for Hispanics (n = 76) were significantly lower than those for non-Hispanics (n = 628), although 95% confidence intervals overlapped for children aged 10-17 yr. Age-adjusted rates were significantly lower in Hispanic than non-Hispanic males, whereas age-adjusted rates for females did not differ. The cumulative risk of IDDM was less for Hispanic males aged 0-17 yr than for non-Hispanic males (P less than .001); cumulative risk among females was males (P less than .001); cumulative risk among females was not different (P = .10). Clinical onset characteristics and medical care at diagnosis were similar. After diagnosis, hospitalizations per 100 person-yr appeared higher in Hispanics, but ketoacidosis and insulin reactions per 100 person-yr were similar. Difference in rate of hospitalizations may have been due to lower response rates among older non-Hispanics.(ABSTRACT TRUNCATED AT 250 WORDS)

Couples undergoing treatment for infertility: dimensions of life satisfaction.

The purpose of this study was to investigate the perceived life, marital, and sexual satisfaction of married couples undergoing treatment for infertility. A survey research design was utilized involving the responses of 43 husband-wife pairs. The findings indicated that wives had a significantly lower level of satisfaction with life than their husbands and that there were significant relationships between husband-wife pairs for both marital and sexual satisfaction. In comparison to paired wives, the responses of 17 wives whose husbands chose not to respond to the survey indicated higher levels of dissatisfaction in all three dimensions of life satisfaction. Furthermore, a majority of the scores for this group indicated clinical levels of depression. It was evident that individuals, especially females, undergoing treatment for infertility experienced stress in various areas of their lives. Hence, suggestions are given to assist caregivers in their endeavor to enhance the quality of life for infertile couples.