Heterogeneous Employment Effects of Job Search Programmes: A Machine Learning Approach

We systematically investigate the effect heterogeneity of job search programmes for unemployed workers. To investigate possibly heterogeneous employment effects, we combine non-experimental causal empirical models with Lasso-type estimators. The empirical analyses are based on rich administrative data from Swiss social security records. We find considerable heterogeneities only during the first six months after the start of training. Consistent with previous results of the literature, unemployed persons with fewer employment opportunities profit more from participating in these programmes. Furthermore, we also document heterogeneous employment effects by residence status. Finally, we show the potential of easy-to-implement programme participation rules for improving average employment effects of these active labour market programmes

Effect or Treatment Heterogeneity? Policy Evaluation with Aggregated and Disaggregated Treatments

Binary treatments are often ex-post aggregates of multiple treatments or can be disaggregated into multiple treatment versions. Thus, effects can be heterogeneous due to either effect or treatment heterogeneity. We propose a decomposition method that uncovers masked heterogeneity, avoids spurious discoveries, and evaluates treatment assignment quality. The estimation and inference procedure based on double/debiased machine learning allows for high-dimensional confounding, many treatments and extreme propensity scores. Our applications suggest that heterogeneous effects of smoking on birthweight are partially due to different smoking intensities and that gender gaps in Job Corps effectiveness are largely explained by differences in vocational training

Thermal Storage for High-Power Small Satellites

As the power levels and sizes of small satellites grow, new capabilities become possible along with new challenges for thermal control. Greater amounts of heat must be transported across longer distances, making it more difficult to control component temperatures using simple, passive systems. This paper describes the performance of an innovative thermal storage technology for small satellite thermal control systems. The thermal storage unit helps maintain temperature stability by efficiently incorporating a solid/liquid phase-change material (PCM). This paper describes the results of an analysis and testing program that proved the feasibility of the PCM thermal storage concept. We formulated a simple model for a high-power small satellite in an orbital thermal environment. We found that proper selection of the PCM depends on the thermal environment, thermal control system characteristics, and characteristics of the thermal load. The model shows that a properly designed thermal storage system can dramatically reduce temperature variation. We designed and built a sub-scale PCM thermal storage unit and measured its performance with a heat pipe under conditions that simulate operation in a small satellite thermal control system. Results of these tests demonstrate the capability of the thermal control system to reduce temperature variation during transient operation

Pharmacokinetics and metabolism of eprinomectin in cats when administered in a novel topical combination of fipronil, (S)-methoprene, eprinomectin and praziquantel

AbstractFour studies were conducted to determine the pharmacokinetic characteristics and in vitro metabolism of eprinomectin, a semi-synthetic avermectin, in cats. Pharmacokinetic parameters including bioavailability of eprinomectin were determined in a parallel study design comprised of one group of eight cats which were treated once topically at 0.12mL/kg bodyweight with BROADLINE®, a novel combination product (fipronil 8.3% (w/v), (S)-methoprene 10% (w/v), eprinomectin 0.4% (w/v) and praziquantel 8.3% (w/v)), delivering a dose of 0.5mg eprinomectin per kg body weight, and a group of six cats which received 0.4% (w/v) eprinomectin at 0.4mg/kg bodyweight once by intravenous injection. For cats treated by topical application, the average eprinomectin (B1a component) maximum plasma concentration (Cmax) was 20ng/mL. The maximum concentrations were reached 24h after dosing in the majority of the animals (six of eight cats). The average terminal half-life was 114h due to slow absorption (‘flip-flop’ kinetics). Following intravenous administration the average Cmax was 503ng/mL at 5min post-dose, and the mean elimination half-life was 23h. Eprinomectin was widely distributed with a mean volume of distribution of 2390mL/kg, and the clearance rate was 81mL/h/kg. Mean areas under the plasma concentration versus time curves extrapolated to infinity were 2100ngh/mL and 5160ngh/mL for the topical and intravenous doses, respectively. Topical eprinomectin was absorbed with an average absolute bioavailability of 31%. In a second parallel design study, the dose proportionality of eprinomectin after single topical administration of BROADLINE® was studied. Four groups of eight cats each were treated once topically with 0.5, 1, 2 or 5 times the minimum recommended dose of the combination, 0.12mL/kg bodyweight. Based on comparison of areas under the plasma concentration versus time curves from the time of dosing to the last time point at which eprinomectin B1a was quantified, and Cmax, dose proportionality was established. In addition, the metabolic pathway of eprinomectin using cat liver microsomes, and plasma protein binding using cat, rat, and dog plasma were studied in vitro. Results of the analyses of eprinomectin B1a described here showed that it is metabolically stable and highly protein bound (>99%), and thus likely to be, as with other species, excreted mainly as unchanged parent drug in the feces of cats

Increased large conductance calcium-activated potassium (BK) channel expression accompanied by STREX variant downregulation in the developing mouse CNS

BACKGROUND: Large conductance calcium- and voltage activated potassium (BK) channels are important determinants of neuronal excitability through effects on action potential duration, frequency and synaptic efficacy. The pore- forming subunits are encoded by a single gene, KCNMA1, which undergoes extensive alternative pre mRNA splicing. Different splice variants can confer distinct properties on BK channels. For example, insertion of the 58 amino acid stress-regulated exon (STREX) insert, that is conserved throughout vertebrate evolution, encodes channels with distinct calcium sensitivity and regulation by diverse signalling pathways compared to the insertless (ZERO) variant. Thus, expression of distinct splice variants may allow cells to differentially shape their electrical properties during development. However, whether differential splicing of BK channel variants occurs during development of the mammalian CNS has not been examined. RESULTS: Using quantitative real-time polymerase chain reaction (RT-PCR) Taqman™ assays, we demonstrate that total BK channel transcripts are up regulated throughout the murine CNS during embryonic and postnatal development with regional variation in transcript levels. This upregulation is associated with a decrease in STREX variant mRNA expression and an upregulation in ZERO variant expression. CONCLUSION: As BK channel splice variants encode channels with distinct functional properties the switch in splicing from the STREX phenotype to ZERO phenotype during embryonic and postnatal CNS development may provide a mechanism to allow BK channels to control distinct functions at different times of mammalian brain development

Mitochondrial genome sequences illuminate maternal lineages of conservation concern in a rare carnivore

<p>Abstract</p> <p>Background</p> <p>Science-based wildlife management relies on genetic information to infer population connectivity and identify conservation units. The most commonly used genetic marker for characterizing animal biodiversity and identifying maternal lineages is the mitochondrial genome. Mitochondrial genotyping figures prominently in conservation and management plans, with much of the attention focused on the non-coding displacement ("D") loop. We used massively parallel multiplexed sequencing to sequence complete mitochondrial genomes from 40 fishers, a threatened carnivore that possesses low mitogenomic diversity. This allowed us to test a key assumption of conservation genetics, specifically, that the D-loop accurately reflects genealogical relationships and variation of the larger mitochondrial genome.</p> <p>Results</p> <p>Overall mitogenomic divergence in fishers is exceedingly low, with 66 segregating sites and an average pairwise distance between genomes of 0.00088 across their aligned length (16,290 bp). Estimates of variation and genealogical relationships from the displacement (<it>D</it>) loop region (299 bp) are contradicted by the complete mitochondrial genome, as well as the protein coding fraction of the mitochondrial genome. The sources of this contradiction trace primarily to the near-absence of mutations marking the D-loop region of one of the most divergent lineages, and secondarily to independent (recurrent) mutations at two nucleotide position in the D-loop amplicon.</p> <p>Conclusions</p> <p>Our study has two important implications. First, inferred genealogical reconstructions based on the fisher D-loop region contradict inferences based on the entire mitogenome to the point that the populations of greatest conservation concern cannot be accurately resolved. Whole-genome analysis identifies Californian haplotypes from the northern-most populations as highly distinctive, with a significant excess of amino acid changes that may be indicative of molecular adaptation; D-loop sequences fail to identify this unique mitochondrial lineage. Second, the impact of recurrent mutation appears most acute in closely related haplotypes, due to the low level of evolutionary signal (unique mutations that mark lineages) relative to evolutionary noise (recurrent, shared mutation in unrelated haplotypes). For wildlife managers, this means that the populations of greatest conservation concern may be at the highest risk of being misidentified by D-loop haplotyping. This message is timely because it highlights the new opportunities for basing conservation decisions on more accurate genetic information.</p

Characterization of Fibrodysplasia Ossificans Progessiva relevant Acvr1/Acvr2 Activin receptors in medaka (Oryzias latipes)

Activin and Bone Morphogenetic Protein (BMP) signaling plays crucial roles in vertebrate organ formation, including osteo- and angiogenesis, and tissue homeostasis, such as neuronal maintenance. Activin and BMP signaling needs to be precisely controlled by restricted expression of shared receptors, stoichiometric composition of receptor-complexes and presence of regulatory proteins. A R206H mutation in the human (hs) BMP type I receptor hsACVR1, on the other hand, leads to excessive phosphorylation of Sons of mothers against decapentaplegic (SMAD) 1/5/8. This in turn causes increased inflammation and heterotopic ossification in soft tissues of patients suffering from Fibrodysplasia Ossificans Progressiva (FOP). Several animal models have been established to understand the spontaneous and progressive nature of FOP, but often have inherent limitations. The Japanese medaka (Oryzias latipes, ola) has recently emerged as popular model for bone research. To assess whether medaka is suitable as a potential FOP animal model, we determined the expression of Activin receptor type I (ACVR1) orthologs olaAcvr1 and olaAcvr1l with that of Activin type II receptors olaAcvr2ab, olaAcvr2ba and olaAcvr2bb in embryonic and adult medaka tissues by in situ hybridization. Further, we showed that Activin A binding properties are conserved in olaAcvr2, as are the mechanistic features in the GS-Box of both olaAcvr1 and olaAcvr1l. This consequently leads to FOP-typical elevated SMAD signaling when the medaka type I receptors carry the R206H equivalent FOP mutation. Together, this study therefore provides experimental groundwork needed to establish a unique medaka model to investigate mechanisms underlying FOP