Using Inhabitation in Bounded Combinatory Logic with Intersection Types for Composition Synthesis

We describe ongoing work on a framework for automatic composition synthesis from a repository of software components. This work is based on combinatory logic with intersection types. The idea is that components are modeled as typed combinators, and an algorithm for inhabitation {\textemdash} is there a combinatory term e with type tau relative to an environment Gamma? {\textemdash} can be used to synthesize compositions. Here, Gamma represents the repository in the form of typed combinators, tau specifies the synthesis goal, and e is the synthesized program. We illustrate our approach by examples, including an application to synthesis from GUI-components.Comment: In Proceedings ITRS 2012, arXiv:1307.784

Longest paths in random hypergraphs

The excellent target article of Hamm et al. (2022) raises much food for thought. In this commentary we first discuss what is included in their proposed category of ‘positive evaluations and responses to police assertions of power to attempt social influence’. Given integers k, j with 1 j k − 1, we consider the length of the longest j-tight path in the binomial random k-uniform hypergraph Hk(n, p). We show that this length undergoes a phase transition from logarithmic length to linear and determine the critical threshold, as well as proving upper and lower bounds on the length in the subcritical and supercritical ranges. In particular, for the supercritical case we introduce the Pathfinder algorithm, a depth-first search algorithm which discovers j-tight paths in a k-uniform hypergraph. We prove that, in the supercritical case, with high probability this algorithm will find a long j-tight path

Induced B Cell Development in Adult Mice

We employed the B-Indu-Rag1 model in which the coding exon of recombination-activating gene 1 (Rag1) is inactivated by inversion. It is flanked by inverted loxP sites. Accordingly, B cell development is stopped at the pro/pre B-I cell precursor stage. A B cell-specific Cre recombinase fused to a mutated estrogen receptor allows the induction of RAG1 function and B cell development by application of Tamoxifen. Since Rag1 function is recovered in a non-self-renewing precursor cell, only single waves of development can be induced. Using this system, we could determine that B cells minimally require 5 days to undergo development from pro/preB-I cells to the large and 6 days to the small preB-II cell stage. First immature transitional (T) 1 and T2 B cells could be detected in the bone marrow at day 6 and day 7, respectively, while their appearance in the spleen took one additional day. We also tested a contribution of adult bone marrow to the pool of B-1 cells. Sublethally irradiated syngeneic WT mice were adoptively transferred with bone marrow of B-Indu-Rag1 mice and B cell development was induced after 6 weeks. A significant portion of donor derived B-1 cells could be detected in such adult mice. Finally, early VH gene usage was tested after induction of B cell development. During the earliest time points the VH genes proximal to D/J were found to be predominantly rearranged. At later time points, the large family of the most distal VH prevailed

A genotypic analysis of five P. aeruginosa strains after biofilm infection by phages targeting different cell surface receptors

The Supplementary Material for this article can be found online at: http://journal.frontiersin.org/article/10.3389/fmicb. 2017.01229/full#supplementary-materialAntibiotic resistance constitutes one of the most serious threats to the global public health and urgently requires new and effective solutions. Bacteriophages are bacterial viruses increasingly recognized as being good alternatives to traditional antibiotic therapies. In this study, the efficacy of phages, targeting different cell receptors, against Pseudomonas aeruginosa PAO1 biofilm and planktonic cell cultures was evaluated over the course of 48h. Although significant reductions in the number of viable cells were achieved for both cases, the high level of adaptability of the bacteria in response to the selective pressure caused by phage treatment resulted in the emergence of phage-resistant variants. To further investigate the genetic makeup of phage-resistant variants isolated from biofilm infection experiments, some of these bacteria were selected for phenotypic and genotypic characterization. Whole genome sequencing was performed on five phage-resistant variants and all of them carried mutations affecting the galU gene as well as one of pil genes. The sequencing analysis further revealed that three of the P. aeruginosa PAO1 variants carry large deletions (> 200 kbp) in their genomes. Complementation of the galU mutants with wild-type galU in trans restored LPS expression on the bacterial cell surface of these bacterial strains and rendered the complemented strains to be sensitive to phages. This provides unequivocal evidence that inactivation of galU function was associated with resistance to the phages that uses LPS as primary receptors. Overall, this work demonstrates that P. aeruginosa biofilms can survive phage attack and develop phage-resistant variants exhibiting defective LPS production and loss of type IV pili that are well adapted to the biofilm mode of growth.This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the project PTDC/BBB-BSS/6471/2014; the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER006684) and BioTecNorte operation (NORTE-01-0145-FEDER000004)funded by European Regional Development Fund under the scope of Norte2020 – Programa Operacional Regional do Norte. SS is an FCT investigator (IF/01413/2013). Work done in the lab of JL is supported by Canadian Institutes of Health Research (Grant MOP-14687). YH was a recipient of a postdoctoral fellowship award from Cystic Fibrosis, and JL holds a Canada Research Chair in Cystic Fibrosis and Microbial Glycobiology funded by the Canadian Foundation of Innovation. Work done in the lab of CK is supported by a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada(#371639).info:eu-repo/semantics/publishedVersio

German S3 guideline "actinic keratosis and cutaneous squamous cell carcinoma" – long version of the update 2023

Actinic keratosis (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline “actinic keratosis and cutaneous squamous cell carcinoma” was updated and expanded by the topics cutanepus squamous cell carcinoma in situ (Bowen’s disease) and actinic cheilitis. This guideline was developed at the highest evidence level (S3) and is aimed at dermatologists, general practitioners, ear nose and throat specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings, as well as other medical specialties, policy makers and insurance funds involved in the diagnosis and treatment of patients with AK and cSCC

Structures of insect Imp-L2 suggest an alternative strategy for regulating the bioavailability of insulin-like hormones

The insulin/insulin-like growth factor signalling axis is an evolutionary ancient and highly conserved hormonal system involved in the regulation of metabolism, growth and lifespan in animals. Human insulin is stored in the pancreas, while insulin-like growth factor-1 (IGF-1) is maintained in blood in complexes with IGF-binding proteins (IGFBP1–6). Insect insulin-like polypeptide binding proteins (IBPs) have been considered as IGFBP-like structural and functional homologues. Here, we report structures of the Drosophila IBP Imp-L2 in its free form and bound to Drosophila insulin-like peptide 5 and human IGF-1. Imp-L2 contains two immunoglobulin-like fold domains and its architecture is unrelated to human IGFBPs, suggesting a distinct strategy for bioavailability regulation of insulin-like hormones. Similar hormone binding modes may exist in other insect vectors, as the IBP sequences are highly conserved. Therefore, these findings may open research routes towards a rational interference of transmission of diseases such as malaria, dengue and yellow fevers

Use and Characteristics of Antipsychotic/Methylphenidate Combination Therapy in Children and Adolescents with a Diagnosis of Attention-Deficit/Hyperactivity Disorder

OBJECTIVE: Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) frequently have comorbidities that are potential indications for antipsychotics (APs). Some studies have suggested that the combined use of methylphenidate (MPH) and APs is increasing in this population group. Longitudinal analyses and in-depth investigations on the substance level are lacking. This study aimed to estimate the cumulative proportion of concomitant AP/MPH use in children and adolescents with ADHD over a follow-up of up to 9 years and to describe patient characteristics stratified by specific AP drug. METHODS: Based on claims data, concomitant AP/MPH use was identified among 67,595 children and adolescents with ADHD starting MPH treatment between 2005 and 2013. Characteristics and diagnoses—including those indicating appropriateness of AP use according to approved indications and/or guidelines—were examined at the time of first AP/MPH combination therapy. In addition, subsequent use of AP/MPH combination therapy was evaluated. RESULTS: The cumulative proportion of individuals with any AP/MPH combination therapy rose to over 6% within 9 years after initiating MPH. The most frequent APs first used in combination with MPH were risperidone (72%), pipamperone (15%), and tiapride (8%). Percentages of psychiatric hospitalization in the year preceding the first combination therapy with MPH were 33%, 43%, and 19%, respectively. The proportion of individuals with potentially appropriate use was high (>72%) in risperidone/MPH and tiapride/MPH and low (15%) in pipamperone/MPH combination users. Conduct disorders and tic disorders were frequent in users who were prescribed MPH with risperidone and tiapride, respectively. One-quarter of patients with AP/MPH combination therapy were one-time-only combination users. CONCLUSION: Our study suggests that a considerable proportion of children and adolescents with ADHD receive MPH in combination with APs and that this is a factor not only during the first years of MPH treatment. ADHD guidelines should specify algorithms concerning the use of AP medication

Estimating the prevalence of Parkinson's disease (PD) and proportions of patients with associated dementia and depression among the older adults based on secondary claims data

OBJECTIVES: While the epidemiology of Parkinson's disease (PD) has been extensively studied, data on the prevalence of PD among the older adults in Germany are scarce, based on small samples, and limited to primary data designs. This study estimated the PD prevalence among the older adults in Germany in 2006 using secondary data. METHODS: We included 815,573 health insurance members aged ≥65 years from all regions in Germany. PD was identified in case of at least one inpatient or outpatient diagnosis. An outpatient diagnosis had to be confirmed by either a subsequent diagnosis or an antiparkinsonian drug within 12 months. PD was also assumed if a first prescription was confirmed by a diagnosis within 12 months. Cases were checked for a diagnosis of dementia or depression. RESULTS: The standardized prevalence of PD was 1680 (95% confidence interval (CI): 1644–1716) cases per 100,000 persons. The prevalence increased with age and peaked in the age group of ≥90 years (4633 cases; 95% CI: 4227–5068) with higher rates in men (1729; 95% CI: 1684–1776) than in women (1644; 95% CI: 1593–1697). Dementia and depression occurred in 26.6% (95% CI: 25.8–27.5) and 32.6 (95% CI: 31.7–33.5) of PD cases, respectively. CONCLUSIONS: The age‐related increase of PD prevalence and the age‐specific prevalence estimates are in line with other European studies, stressing the public health relevance related to PD. In addition to the minimization of biases that might occur in primary data studies, further strengths of our findings are the large underlying sample size and the coverage of Germany