Opposing action of the FLR-2 glycoprotein hormone and DRL-1/FLR-4 MAP kinases balance p38-mediated growth and lipid homeostasis in C. elegans.

Animals integrate developmental and nutritional signals before committing crucial resources to growth and reproduction; however, the pathways that perceive and respond to these inputs remain poorly understood. Here, we demonstrate that DRL-1 and FLR-4, which share similarity with mammalian mitogen-activated protein kinases, maintain lipid homeostasis in the C. elegans intestine. DRL-1 and FLR-4 function in a protein complex at the plasma membrane to promote development, as mutations in drl-1 or flr-4 confer slow growth, small body size, and impaired lipid homeostasis. To identify factors that oppose DRL-1/FLR-4, we performed a forward genetic screen for suppressors of the drl-1 mutant phenotypes and identified mutations in flr-2 and fshr-1, which encode the orthologues of follicle stimulating hormone and its putative G protein-coupled receptor, respectively. In the absence of DRL-1/FLR-4, neuronal FLR-2 acts through intestinal FSHR-1 and protein kinase A signaling to restrict growth. Furthermore, we show that opposing signaling through DRL-1 and FLR-2 coordinates TIR-1 oligomerization, which modulates downstream p38/PMK-1 activity, lipid homeostasis, and development. Finally, we identify a surprising noncanonical role for the developmental transcription factor PHA-4/FOXA in the intestine where it restricts growth in response to impaired DRL-1 signaling. Our work uncovers a complex multi-tissue signaling network that converges on p38 signaling to maintain homeostasis during development

The heavy top quark in the two Higgs doublet model

Constraints on the two Higgs doublet model are presented, assuming a top mass of 174 $\pm$ 17 GeV. We concentrate primarily on the ``type II'' model, where up--type quarks receive their mass from one Higgs doublet, and down--type quarks receive their mass from the second doublet. High energy constraints derived from the $W$ mass, the full width of the $Z$ and the $b \bar b$ partial width of the $Z$ are combined with low energy constraints from $\Gamma(b\to s \gamma)$, $\Gamma(b \to c \tau \bar\nu_\tau)$ and $B^0$-$\bar B^0$ mixing to determine the experimentally favored configurations of the model. This combination of observables rules out small charged Higgs masses and small values of $\tan\beta$, and provides some information about the neutral Higgs masses and the mixing angle $\alpha$. In particular, constraints derived from the $\rho$ parameter rule out configurations where the charged Higgs is much heavier or much lighter than the neutral Higgses. We discuss a scenario where $\Gamma(Z\to b \bar b)$ is enhanced relative to the standard model result, which unfortunately is on the verge of being ruled out by the combination of $\Gamma(b\to s \gamma)$ and $\rho$ parameter constraints. Implications for various extensions of the standard model are briefly discussed.Comment: 26 page

Critical change in the Fermi surface of iron arsenic superconductors at the onset of superconductivity

The phase diagram of a correlated material is the result of a complex interplay between several degrees of freedom, providing a map of the material's behavior. One can understand (and ultimately control) the material's ground state by associating features and regions of the phase diagram, with specific physical events or underlying quantum mechanical properties. The phase diagram of the newly discovered iron arsenic high temperature superconductors is particularly rich and interesting. In the AE(Fe1-xTx)2As2 class (AE being Ca, Sr, Ba, T being transition metals), the simultaneous structural/magnetic phase transition that occurs at elevated temperature in the undoped material, splits and is suppressed by carrier doping, the suppression being complete around optimal doping. A dome of superconductivity exists with apparent equal ease in the orthorhombic / antiferromagnetic (AFM) state as well as in the tetragonal state with no long range magnetic order. The question then is what determines the critical doping at which superconductivity emerges, if the AFM order is fully suppressed only at higher doping values. Here we report evidence from angle resolved photoemission spectroscopy (ARPES) that critical changes in the Fermi surface (FS) occur at the doping level that marks the onset of superconductivity. The presence of the AFM order leads to a reconstruction of the electronic structure, most significantly the appearance of the small hole pockets at the Fermi level. These hole pockets vanish, i. e. undergo a Lifshitz transition, at the onset of superconductivity. Superconductivity and magnetism are competing states in the iron arsenic superconductors. In the presence of the hole pockets superconductivity is fully suppressed, while in their absence the two states can coexist.Comment: Updated version accepted in Nature Physic

Aerosol generation during cadaveric simulation of otologic surgery and live cochlear implantation

Objective The risk of SARS‐CoV‐2 transmission to healthcare workers through airborne aerosolization during otologic surgery has not been characterized. The objective of this study was to describe and quantify the aerosol generation during common otologic procedures in both cadaveric surgical simulation and live patient surgery. Methods The number concentrations of generated aerosols in the particle size range of 0.30 to 10.0 μm were quantified using an optical particle sizer during both a cadaveric simulation of routine otologic procedures as well as cochlear implant surgery on live patients in the operating room. Results In the cadaveric simulation, temporalis fascia graft harvest using cold techniques (without electrocautery) (n = 4) did not generate aerosols above baseline concentrations. Tympanoplasty (n = 3) and mastoidectomy (n = 3) both produced statistically significant increases in concentrations of aerosols (P < 0.05), predominantly submicron particles (< 1.0 μm). High‐speed, powered drilling of the temporal bone during mastoidectomy with a Multi Flute cutting burr resulted in higher peak concentrations and greater number of spikes in aerosols than with a diamond burr. In the operating room, spikes in aerosols occurred during both cochlear implant surgeries. Conclusion In the cadaveric simulation, temporalis fascia graft harvest without electrocautery did not generate aerosol levels above baseline, while significant aerosol levels were generated during mastoidectomy and to a much less degree during tympanoplasty. Aerosol spikes were appreciated during cochlear implantation surgery in live patients

Sox17 Promotes Cell Cycle Progression and Inhibits TGF-β/Smad3 Signaling to Initiate Progenitor Cell Behavior in the Respiratory Epithelium

The Sry-related high mobility group box transcription factor Sox17 is required for diverse developmental processes including endoderm formation, vascular development, and fetal hematopoietic stem cell maintenance. Expression of Sox17 in mature respiratory epithelial cells causes proliferation and lineage respecification, suggesting that Sox17 can alter adult lung progenitor cell fate. In this paper, we identify mechanisms by which Sox17 influences lung epithelial progenitor cell behavior and reprograms cell fate in the mature respiratory epithelium. Conditional expression of Sox17 in epithelial cells of the adult mouse lung demonstrated that cell cluster formation and respecification of alveolar progenitor cells toward proximal airway lineages were rapidly reversible processes. Prolonged expression of Sox17 caused the ectopic formation of bronchiolar-like structures with diverse respiratory epithelial cell characteristics in alveolar regions of lung. During initiation of progenitor cell behavior, Sox17 induced proliferation and increased the expression of the progenitor cell marker Sca-1 and genes involved in cell cycle progression. Notably, Sox17 enhanced cyclin D1 expression in vivo and activated cyclin D1 promoter activity in vitro. Sox17 decreased the expression of transforming growth factor-beta (TGF-β)-responsive cell cycle inhibitors in the adult mouse lung, including p15, p21, and p57, and inhibited TGF-β1-mediated transcriptional responses in vitro. Further, Sox17 interacted with Smad3 and blocked Smad3 DNA binding and transcriptional activity. Together, these data show that a subset of mature respiratory epithelial cells retains remarkable phenotypic plasticity and that Sox17, a gene required for early endoderm formation, activates the cell cycle and reinitiates multipotent progenitor cell behavior in mature lung cells

An empirical analysis of the determinants of mobile instant messaging appropriation in university learning

Published ArticleResearch on technology adoption often profiles device usability (such as perceived usefulness) and user dispositions (such as perceived ease of use) as the prime determinants of effective technology adoption. Since any process of technology adoption cannot be conceived out of its situated contexts, this paper argues that any pre-occupation with technology acceptance from the perspective of device usability and user dispositions potentially negates enabling contexts that make successful adoption a reality. Contributing to contemporary debates on technology adoption, this study presents flexible mobile learning contexts comprising cost (device cost and communication cost), device capabilities (portability, collaborative capabilities), and learner traits (learner control) as antecedents that enable the sustainable uptake of emerging technologies. To explore the acceptance and capacity of mobile instant messaging systems to improve student performance, the study draws on these antecedents, develops a factor model and empirically tests it on tertiary students at a South African University of Technology. The study involved 223 national diploma and bachelor’s degree students and employed partial least squares for statistical analysis. Overall, the proposed model displayed a good fit with the data and rendered satisfactory explanatory power for students’ acceptance of mobile learning. Findings suggest that device portability, communication cost, collaborative capabilities of device and learner control are the main drivers of flexible learning in mobile environments. Flexible learning context facilitated by learner control was found to have a positive influence on attitude towards mobile learning and exhibited the highest path coefficient of the overall model. The study implication is that educators need to create varied learning opportunities that leverage learner control of learning in mobile learning systems to enhance flexible mobile learning. The study also confirmed the statistical significance of the original Technology Acceptance Model constructs

Measurement of three-jet differential cross sections d sigma-3jet / d M-3jet in p anti-p collisions at sqrt(s)=1.96 TeV

We present the first measurement of the inclusive three-jet differential cross section as a function of the invariant mass of the three jets with the largest transverse momenta in an event in p anti-p collisions at sqrt(s) = 1.96 TeV. The measurement is made in different rapidity regions and for different jet transverse momentum requirements and is based on a data set corresponding to an integrated luminosity of 0.7 fb^{-1} collected with the D0 detector at the Fermilab Tevatron Collider. The results are used to test the three-jet matrix elements in perturbative QCD calculations at next-to-leading order in the strong coupling constant. The data allow discrimination between parametrizations of the parton distribution functions of the proton.Comment: 10 pages, 4 figures, 2 tables, submitted to Phys. Lett. B, corrected chi2 values for NNPD

Relationship of EMAST and Microsatellite Instability Among Patients with Rectal Cancer

Elevated microsatellite instability at selected tetranucleotide repeats (EMAST) is a genetic signature identified in 60% of sporadic colon cancers and may be linked with heterogeneous expression of the DNA mismatch repair (MMR) protein hMSH3. Unlike microsatellite instability-high (MSI-H) in which hypermethylation of hMLH1 occurs followed by multiple susceptible gene mutations, EMAST may be associated with inflammation and subsequent relaxation of MMR function with the biological consequences not known. We evaluated the prevalence of EMAST and MSI in a population-based cohort of rectal cancers, as EMAST has not been previously determined in rectal cancers. We analyzed 147 sporadic cases of rectal cancer using five tetranucleotide microsatellite markers and National-Cancer-Institute-recommended MSI (mononucleotide and dinucleotide) markers. EMAST and MSI determinations were made on analysis of DNA sequences of the polymerase chain reaction products and determined positive if at least two loci were found to have frame-shifted repeats upon comparison between normal and cancer samples from the same patient. We correlated EMAST data with race, gender, and tumor stage and examined the samples for lymphocyte infiltration. Among this cohort of patients with rectal cancer (mean age 62.2 ± 10.3 years, 36% female, 24% African American), 3/147 (2%) showed MSI (three males, two African American) and 49/147 (33%) demonstrated EMAST. Rectal tumors from African Americans were more likely to show EMAST than Caucasians (18/37, 49% vs. 27/104, 26%, p = 0.014) and were associated with advanced stage (18/29, 62% EMAST vs. 18/53, 37%, non-EMAST p = 0.02). There was no association between EMAST and gender. EMAST was more prevalent in rectal tumors that showed peri-tumoral infiltration compared to those without (30/49, 60% EMAST vs. 24/98, 25% non-EMAST, p = 0.0001). EMAST in rectal cancer is common and MSI is rare. EMAST is associated with African-American race and may be more commonly seen with metastatic disease. The etiology and consequences of EMAST are under investigation, but its association with immune cell infiltration suggests that inflammation may play a role for its development

Clique-Finding for Heterogeneity and Multidimensionality in Biomarker Epidemiology Research: The CHAMBER Algorithm

Commonly-occurring disease etiology may involve complex combinations of genes and exposures resulting in etiologic heterogeneity. We present a computational algorithm that employs clique-finding for heterogeneity and multidimensionality in biomedical and epidemiological research (the "CHAMBER" algorithm).This algorithm uses graph-building to (1) identify genetic variants that influence disease risk and (2) predict individuals at risk for disease based on inherited genotype. We use a set-covering algorithm to identify optimal cliques and a Boolean function that identifies etiologically heterogeneous groups of individuals. We evaluated this approach using simulated case-control genotype-disease associations involving two- and four-gene patterns. The CHAMBER algorithm correctly identified these simulated etiologies. We also used two population-based case-control studies of breast and endometrial cancer in African American and Caucasian women considering data on genotypes involved in steroid hormone metabolism. We identified novel patterns in both cancer sites that involved genes that sulfate or glucuronidate estrogens or catecholestrogens. These associations were consistent with the hypothesized biological functions of these genes. We also identified cliques representing the joint effect of multiple candidate genes in all groups, suggesting the existence of biologically plausible combinations of hormone metabolism genes in both breast and endometrial cancer in both races.The CHAMBER algorithm may have utility in exploring the multifactorial etiology and etiologic heterogeneity in complex disease

Localized Populations of CD8low/− MHC Class I Tetramer+ SIV-Specific T Cells in Lymphoid Follicles and Genital Epithelium

CD8 T cells play an important role in controlling viral infections. We investigated the in situ localization of simian immunodeficiency virus (SIV)-specific T cells in lymph and genital tissues from SIV-infected macaques using MHC-class I tetramers. The majority of tetramer-binding cells localized in T cell zones and were CD8+. Curiously, small subpopulations of tetramer-binding cells that had little to no surface CD8 were detected in situ both early and late post-infection, and in both vaginally and rectally inoculated macaques. These tetramer+CD8low/− cells were more often localized in apparent B cell follicles relative to T cell zones and more often found near or within the genital epithelium than the submucosa. Cells analyzed by flow cytometry showed similar populations of cells. Further immunohistological characterization revealed small populations of tetramer+CD20− cells inside B cell follicles and that tetramer+ cells did not stain with γδ-TCR nor CD4 antibodies. Negative control tetramer staining indicated that tetramer+CD8low/− cells were not likely NK cells non-specifically binding to MHC tetramers. These findings have important implications for SIV-specific and other antigen-specific T cell function in these specific tissue locations, and suggest a model in which antigen-specific CD8+ T cells down modulate CD8 upon entering B cell follicles or the epithelial layer of tissues, or alternatively a model in which only antigen-specific CD8 T cells that down-modulate CD8 can enter B cell follicles or the epithelium