The high-density star formation typical of the merger/starburst events that power the large IR luminosities of ultraluminous infrared galaxies (ULIRGs) (L{sub IR}(8-1000 {mu}m) {approx}>10{sup 12} ...L{sub sun}) throughout the universe results in extraordinarily high cosmic-ray (CR) energy densities of U{sub CR} {approx} few x(10{sup 3}-10{sup 4}) U{sub CR,Gal} permeating their interstellar medium, a direct consequence of the large supernova remnant number densities in such systems. Unlike far-UV photons emanating from numerous star-forming (SF) sites, these large CR energy densities in ULIRGs will volumetrically heat and raise the ionization fraction of dense (n > 10{sup 4} cm{sup -3}) UV-shielded gas cores throughout their compact SF volumes. Such conditions can turn most of the large molecular gas masses found in such systems and their high redshift counterparts ({approx}10{sup 9}-10{sup 10} M {sub sun}) into giant CR-dominated regions (CRDRs) rather than ensembles of photon-dominated regions (PDRs) which dominate in less IR-luminous systems where star formation and molecular gas distributions are much more extended. The molecular gas in CRDRs will have a minimum temperature of T{sub kin} {approx} (80-160) K, and very high ionization fractions of x(e) > 10{sup -6} throughout its UV-shielded dense core, which in turn will fundamentally alter the initial conditions for star formation in such systems. Observational tests of CRDRs can be provided by high-J CO and {sup 13}CO lines or multi-J transitions of any heavy rotor molecules (e.g., HCN) and their isotopologs. Chemical signatures of very high ionization fractions in dense UV-shielded gas such as low DCO{sup +}/HCO{sup +} and high HCO{sup +}/CO abundance ratios would be good probes of CRDRs in extreme starbursts. These tests, along with direct measurements of the high CO line brightness temperatures expected over the areas of compact dense gas disks found in ULIRGs, will soon be feasible as sub-arcsecond interferometric imaging capabilities and sensitivity at millimeter/submillimeter wavelengths improve in the era of ALMA.
The objective of the Apollon 10 PW project is the generation of 10 PW peak power pulses of 15 fs at $1~\text{shot}~\text{min}^{-1}$. In this paper a brief update on the current status of the Apollon ...project is presented, followed by a more detailed presentation of our experimental and theoretical investigations of the temporal characteristics of the laser. More specifically the design considerations as well as the technological and physical limitations to achieve the intended pulse duration and contrast are discussed.
This EAACI position paper aims at providing a state‐of‐the‐art overview on nonallergic rhinitis (NAR). A significant number of patients suffering from persistent rhinitis are defined as nonallergic ...noninfectious rhinitis (NANIR) patients, often denominated in short as having NAR. NAR is defined as a symptomatic inflammation of the nasal mucosa with the presence of a minimum of two nasal symptoms such as nasal obstruction, rhinorrhea, sneezing, and/or itchy nose, without clinical evidence of endonasal infection and without systemic signs of sensitization to inhalant allergens. Symptoms of NAR may have a wide range of severity and be either continuously present and/or induced by exposure to unspecific triggers, also called nasal hyperresponsiveness (NHR). NHR represents a clinical feature of both AR and NAR patients. NAR involves different subgroups: drug‐induced rhinitis, (nonallergic) occupational rhinitis, hormonal rhinitis (including pregnancy rhinitis), gustatory rhinitis, senile rhinitis, and idiopathic rhinitis (IR). NAR should be distinguished from those rhinitis patients with an allergic reaction confined to the nasal mucosa, also called “entopy” or local allergic rhinitis (LAR). We here provide an overview of the current consensus on phenotypes of NAR, recommendations for diagnosis, a treatment algorithm, and defining the unmet needs in this neglected area of research.
Rhinitis is an umbrella term that encompasses many different subtypes, several of which still elude complete characterization. The concept of phenotyping, being the definition of disease subtypes on ...the basis of clinical presentation, has been well established in the last decade. Classification of rhinitis entities on the basis of phenotypes has facilitated their characterization and has helped practicing clinicians to efficiently approach rhinitis patients. Recently, the concept of endotypes, that is, the definition of disease subtypes on the basis of underlying pathophysiology, has emerged. Phenotypes/endotypes are dynamic, overlapping, and may evolve into one another, thus rendering clear‐cut definitions difficult. Nevertheless, a phenotype‐/endotype‐based classification approach could lead toward the application of stratified and personalized medicine in the rhinitis field. In this PRACTALL document, rhinitis phenotypes and endotypes are described, and rhinitis diagnosis and management approaches focusing on those phenotypes/endotypes are presented and discussed. We emphasize the concept of control‐based management, which transcends all rhinitis subtypes.
Computational microRNA (miRNA) target prediction is one of the key means for deciphering the role of miRNAs in development and disease. Here, we present the DIANA-microT web server as the user ...interface to the DIANA-microT 3.0 miRNA target prediction algorithm. The web server provides extensive information for predicted miRNA:target gene interactions with a user-friendly interface, providing extensive connectivity to online biological resources. Target gene and miRNA functions may be elucidated through automated bibliographic searches and functional information is accessible through Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The web server offers links to nomenclature, sequence and protein databases, and users are facilitated by being able to search for targeted genes using different nomenclatures or functional features, such as the genes possible involvement in biological pathways. The target prediction algorithm supports parameters calculated individually for each miRNA:target gene interaction and provides a signal-to-noise ratio and a precision score that helps in the evaluation of the significance of the predicted results. Using a set of miRNA targets recently identified through the pSILAC method, the performance of several computational target prediction programs was assessed. DIANA-microT 3.0 achieved there with 66% the highest ratio of correctly predicted targets over all predicted targets. The DIANA-microT web server is freely available at www.microrna.gr/microT.
Abstract
We use state-of-the-art chemical models to track the cosmic evolution of the CNO isotopes in the interstellar medium of galaxies, yielding powerful constraints on their stellar initial mass ...function (IMF). We re-assess the relative roles of massive stars, asymptotic giant branch (AGB) stars and novae in the production of rare isotopes such as 13C, 15N, 17O and 18O, along with 12C, 14N and 16O. The CNO isotope yields of super-AGB stars, novae and fast-rotating massive stars are included. Having reproduced the available isotope enrichment data in the solar neighbourhood, and across the Galaxy, and having assessed the sensitivity of our models to the remaining uncertainties, e.g. nova yields and star formation history, we show that we can meaningfully constrain the stellar IMF in galaxies using C, O and N isotope abundance ratios. In starburst galaxies, where data for multiple isotopologue lines are available, we find compelling new evidence for a top-heavy stellar IMF, with profound implications for their star formation rates and efficiencies, perhaps also their stellar masses. Neither chemical fractionation nor selective photodissociation can significantly perturb globally averaged isotopologue abundance ratios away from the corresponding isotope ones, as both these processes will typically affect only small mass fractions of molecular clouds in galaxies. Thus, the Atacama Large Millimeter
Array now stands ready to probe the stellar IMF, and even the ages of specific starburst events in star-forming galaxies across cosmic time unaffected by the dust obscuration effects that plague optical/near-infrared studies.
We report Atacama Large Millimeter Array (ALMA) observations of four high-redshift dusty star-forming galaxy candidates selected from far-infrared (FIR)/submillimeter observations in the COSMOS ...field. We securely detect all galaxies in the continuum and spectroscopically confirm them at z = 3.62-5.85 using ALMA 3 mm line scans, detecting multiple CO and/or C i transitions. This includes the most distant dusty galaxy currently known in the COSMOS field, ID85001929 at z = 5.847. These redshifts are lower than we had expected, as these galaxies have substantially colder dust temperatures (i.e., their spectral energy distributions peak at longer rest-frame wavelengths) than most literature sources at z > 4. The observed cold dust temperatures are best understood as evidence for optically thick dust continuum in the FIR, rather than the result of low star formation efficiency with rapid metal enrichment. We provide direct evidence that, given their cold spectral energy distributions, cosmic microwave background (CMB) plays a significant role in biasing their observed Rayleigh-Jeans (RJ) slopes to unlikely steep values and, possibly, reducing their CO fluxes by a factor of two. We recover standard RJ slopes when the CMB contribution is taken into account. High-resolution ALMA imaging shows compact morphology and evidence for mergers. This work reveals a population of cold dusty star-forming galaxies that were underrepresented in current surveys and are even colder than typical main-sequence galaxies at the same redshift. High FIR dust optical depth might be a widespread feature of compact starbursts at any redshift.
To cite this article: Bousquet J, Heinzerling L, Bachert C, Papadopoulos NG, Bousquet PJ, Burney PG, Canonica GW, Carlsen KH, Cox L, Haahtela T, Lodrup Carlsen KC, Price D, Samolinski B, Simons FER, ...Wickman M, Annesi‐Maesano I, Baena‐Cagnani CE, Bergmann KC, Bindslev‐Jensen C, Casale TB, Chiriac A, Cruz AA, Dubakiene R, Durham SR, Fokkens WJ, Gerth‐van‐Wijk R, Kalayci O, Kowalski ML, Mari A, Mullol J, Nazamova‐Baranova L, O’Hehir RE, Ohta K, Panzner P, Passalacqua G, Ring J, Rogala B, Romano A, Ryan D, Schmid‐Grendelmeier P, Todo‐Bom A, Valenta R, Woehrl S, Yusuf OM, Zuberbier T, Demoly P. Practical guide to skin prick tests in allergy to aeroallergens. Allergy 2012; 67: 18–24.
This pocket guide is the result of a consensus reached between members of the Global Allergy and Asthma European Network (GA2LEN) and Allergic Rhinitis and its Impact on Asthma (ARIA). The aim of the current pocket guide is to offer a comprehensive set of recommendations on the use of skin prick tests in allergic rhinitis–conjunctivitis and asthma in daily practice. This pocket guide is meant to give simple answers to the most frequent questions raised by practitioners in Europe, including ‘practicing allergists’, general practitioners and any other physicians with special interest in the management of allergic diseases. It is not a long or detailed scientific review of the topic. However, the recommendations in this pocket guide were compiled following an in‐depth review of existing guidelines and publications, including the 1993 European Academy of Allergy and Clinical Immunology position paper, the 2001 ARIA document and the ARIA update 2008 (prepared in collaboration with GA2LEN). The recommendations cover skin test methodology and interpretation, allergen extracts to be used, as well as indications in a variety of settings including paediatrics and developing countries.
State‐of‐the‐art documents like ARIA and EPOS provide clinicians with evidence‐based treatment algorithms for allergic rhinitis (AR) and chronic rhinosinusitis (CRS), respectively. The currently ...available medications can alleviate symptoms associated with AR and RS. In real life, a significant percentage of patients with AR and CRS continue to experience bothersome symptoms despite adequate treatment. This group with so‐called severe chronic upper airway disease (SCUAD) represents a therapeutic challenge. The concept of control of disease has only recently been introduced in the field of AR and CRS. In case of poor control of symptoms despite guideline‐directed pharmacotherapy, one needs to consider the presence of SCUAD but also treatment‐related, diagnosis‐related and/or patient‐related factors. Treatment‐related issues of uncontrolled upper airway disease are linked with the correct choice of treatment and route of administration, symptom‐oriented treatment and the evaluation of the need for immunotherapy in allergic patients. The diagnosis of AR and CRS should be reconsidered in case of uncontrolled disease, excluding concomitant anatomic nasal deformities, global airway dysfunction and systemic diseases. Patient‐related issues responsible for the lack of control in chronic upper airway inflammation are often but not always linked with adherence to the prescribed medication and education. This review is an initiative taken by the ENT section of the EAACI in conjunction with ARIA and EPOS experts who felt the need to provide a comprehensive overview of the current state of the art of control in upper airway inflammation and stressing the unmet needs in this domain.
Next-generation sequencing has identified actionable genetic aberrations in intrahepatic cholangiocarcinomas (iCCA), including the fibroblast growth factor receptor 2 (FGFR2) fusions. Derazantinib ...(ARQ 087), an orally bioavailable, multi-kinase inhibitor with potent pan-FGFR activity, has shown preliminary therapeutic activity against FGFR2 fusion-positive iCCA.
This multicentre, phase 1/2, open-label study enrolled adult patients with unresectable iCCA with FGFR2 fusion, who progressed, were intolerant or not eligible to first-line chemotherapy (NCT01752920). Subjects received derazantinib in continuous daily doses. Tumour response was assessed according to RECIST 1.1 every 8 weeks.
Twenty-nine patients (18 women/11 men; median age, 58.7 years), 2 treatment-naive and 27 who progressed after at least one prior systemic therapy, were enrolled. Overall response rate was 20.7%, disease control rate was 82.8%. Estimated median progression-free survival was 5.7 months (95% CI: 4.04-9.2 months). Treatment-related adverse events (AE) were observed in 27 patients (93.1%, all grades), including asthenia/fatigue (69.0%), eye toxicity (41.4%), and hyperphosphatemia (75.9%). Grade ≥ 3 AEs occurred in 8 patients (27.6%).
Derazantinib demonstrated encouraging anti-tumour activity and a manageable safety profile in patients with advanced, unresectable iCCA with FGFR2 fusion who progressed after chemotherapy. A pivotal trial of derazantinib in iCCA is ongoing (NCT03230318).
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