High-Q Tuneable 10-GHz Bragg Resonator for Oscillator Applications

This paper describes the design, simulation, and measurement of a tuneable 9.365-GHz aperiodic Bragg resonator. The resonator utilizes an aperiodic arrangement of non (λ/4) low-loss alumina plates (εr = 9.75, loss tangent of 1×10−5 to 2 × 10−5) mounted in a cylindrical metal waveguide. Tuning is achieved by varying the length of the center section of the cavity. A multi-element bellows/probe assembly is presented. A tuning range of 130 MHz (1.39%) is demonstrated. The insertion loss S21 varies from −2.84 to −12.03 dB while the unloaded Q varies from 43 788 to 122 550 over this tuning range. At 10 of the 13 measurement points, the unloaded Q exceeds 100 000, and the insertion loss is above −7 dB. Two modeling techniques are discussed; these include a simple ABCD circuit model for rapid simulation and optimization and a 2.5-D field solver, which is used to plot the field distribution inside the cavity

The Alvarez impact theory of mass extinction; limits to its applicability and the „great expectations syndrome”

For the past three decades, the Alvarez impact theory of mass extinction, causally related to catastrophic meteorite impacts, has been recurrently applied to multiple extinction boundaries. However, these multidisciplinary research efforts across the globe have been largely unsuccessful to date, with one outstanding exception: the Cretaceous-Paleogene boundary. The unicausal impact scenario as a leading explanation, when applied to the complex fossil record, has resulted in force-fitting of data and interpretations ("great expectations syndrome". The misunderstandings can be grouped at three successive levels of the testing process, and involve the unreflective application of the impact paradigm: (i) factual misidentification, i.e., an erroneous or indefinite recognition of the extraterrestrial record in sedimentological, physical and geochemical contexts, (ii) correlative misinterpretation of the adequately documented impact signals due to their incorrect dating, and (iii) causal overestimation when the proved impact characteristics are doubtful as a sufficient trigger of a contemporaneous global cosmic catastrophe. Examples of uncritical belief in the simple cause-effect scenario for the Frasnian-Famennian, Permian-Triassic, and Triassic-Jurassic (and the Eifelian-Givetian and Paleocene-Eocene as well) global events include mostly item-1 pitfalls (factual misidentification), with Ir enrichments and shocked minerals frequently misidentified. Therefore, these mass extinctions are still at the first test level, and only the F-F extinction is potentially seen in the context of item-2, the interpretative step, because of the possible causative link with the Siljan Ring crater (53 km in diameter). The erratically recognized cratering signature is often marked by large timing and size uncertainties, and item-3, the advanced causal inference, is in fact limited to clustered impacts that clearly predate major mass extinctions. The multi-impact lag-time pattern is particularly clear in the Late Triassic, when the largest (100 km diameter) Manicouagan crater was possibly concurrent with the end-Carnian extinction (or with the late Norian tetrapod turnover on an alternative time scale). The relatively small crater sizes and cratonic (crystalline rock basement) setting of these two craters further suggest the strongly insufficient extraterrestrial trigger of worldwide environmental traumas. However, to discuss the kill potential of impact events in a more robust fashion, their location and timing, vulnerability factors, especially target geology and palaeogeography in the context of associated climate-active volatile fluxes, should to be rigorously assessed. The current lack of conclusive impact evidence synchronous with most mass extinctions may still be somewhat misleading due to the predicted large set of undiscovered craters, particularly in light of the obscured record of oceanic impact events

Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor

Objectives: Apremilast, an oral phosphodiesterase 4 inhibitor, regulates inflammatory mediators. Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy. Methods: In the 24-week, placebo-controlled phase of PALACE 1, patients (N=504) were randomised (1:1:1) to placebo, apremilast 20 mg twice a day (BID) or apremilast 30 mg BID. At week 16, patients without ≥20% reduction in swollen and tender joint counts were required to be re-randomised equally to either apremilast dose if initially randomised to placebo or remained on their initial apremilast dose. Patients on background concurrent DMARDs continued stable doses (methotrexate, leflunomide and/or sulfasalazine). Primary outcome was the proportion of patients achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20) at week 16. Results: At week 16, significantly more apremilast 20 mg BID (31%) and 30 mg BID (40%) patients achieved ACR20 versus placebo (19%) (p<0.001). Significant improvements in key secondary measures (physical function, psoriasis) were evident with both apremilast doses versus placebo. Across outcome measures, the 30-mg group generally had higher and more consistent response rates, although statistical comparison was not conducted. The most common adverse events were gastrointestinal and generally occurred early, were self-limiting and infrequently led to discontinuation. No imbalance in major adverse cardiac events, serious or opportunistic infections, malignancies or laboratory abnormalities was observed. Conclusions: Apremilast was effective in the treatment of psoriatic arthritis, improving signs and symptoms and physical function. Apremilast demonstrated an acceptable safety profile and was generally well tolerated. Clinical trial registration number NCT01172938

Human and mouse essentiality screens as a resource for disease gene discovery.

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery

Identification of genetic elements in metabolism by high-throughput mouse phenotyping.

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome

Alternative predictors for dealing with the diversity-validity dilemma in personnel selection: The constructed response multimedia test

In the context of the diversity-validity dilemma in personnel selection, the present field study compared ethnic subgroup differences on an innovative constructed response multimedia test to other commonly used selection instruments. Applicants (N=245, 27% ethnic minorities) for entry-level police jobs completed a constructed response multimedia test, cognitive ability test, language proficiency test, personality inventory, structured interview, and role play. Results demonstrated minor ethnic subgroup differences on constructed response multimedia test scores as compared to other instruments. Constructed response multimedia test scores were related to the selection decision, and no evidence for predictive bias was found. Subgroup differences were also examined on the dimensional level, with cognitively loaded dimension scores displaying larger differences

Human and mouse essentiality screens as a resource for disease gene discovery

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery