Compositional nonblocking verification with always enabled events and selfloop-only events

This paper proposes to improve compositional nonblocking verification through the use of always enabled and selfloop-only events. Compositional verification involves abstraction to simplify parts of a system during verification. Normally, this abstraction is based on the set of events not used in the remainder of the system, i.e., in the part of the system not being simplified. Here, it is proposed to exploit more knowledge about the system and abstract events even though they are used in the remainder of the system. Abstraction rules from previous work are generalised, and experimental results demonstrate the applicability of the resulting algorithm to verify several industrial-scale discrete event system models, while achieving better state-space reduction than before

The crystal structure of the Hazara virus nucleocapsid protein

Background: Hazara virus (HAZV) is a member of the Bunyaviridae family of segmented negative stranded RNA viruses, and shares the same serogroup as Crimean-Congo haemorrhagic fever virus (CCHFV). CCHFV is responsible for fatal human disease with a mortality rate approaching 30 %, which has an increased recent incidence within southern Europe. There are no preventative or therapeutic treatments for CCHFV-mediated disease, and thus CCHFV is classified as a hazard group 4 pathogen. In contrast HAZV is not associated with serious human disease, although infection of interferon receptor knockout mice with either CCHFV or HAZV results in similar disease progression. To characterise further similarities between HAZV and CCHFV, and support the use of HAZV as a model for CCHFV infection, we investigated the structure of the HAZV nucleocapsid protein (N) and compared it to CCHFV N. N performs an essential role in the viral life cycle by encapsidating the viral RNA genome, and thus, N represents a potential therapeutic target. Results: We present the purification, crystallisation and crystal structure of HAZV N at 2.7 Å resolution. HAZV N was expressed as an N-terminal glutathione S-transferase (GST) fusion protein then purified using glutathione affinity chromatography followed by ion-exchange chromatography. HAZV N crystallised in the P212121 space group with unit cell parameters a = 64.99, b = 76.10, and c = 449.28 Å. HAZV N consists of a globular domain formed mostly of alpha helices derived from both the N- and C-termini, and an arm domain comprising two long alpha helices. HAZV N has a similar overall structure to CCHFV N, with their globular domains superposing with an RMSD = 0.70 Å, over 368 alpha carbons that share 59 % sequence identity. Four HAZV N monomers crystallised in the asymmetric unit, and their head-to-tail assembly reveals a potential interaction site between monomers. Conclusions: The crystal structure of HAZV N reveals a close similarity to CCHFV N, supporting the use of HAZV as a model for CCHFV. Structural similarity between the N proteins should facilitate study of the CCHFV and HAZV replication cycles without the necessity of working under containment level 4 (CL-4) conditions

Imaging of acute appendicitis in children: EU versus US ... or US versus CT? A European perspective

There is substantial evidence that imaging may reduce the negative appendectomy rate, also in children. However, controversy exists about the preferred method: US or CT, and the choice appears to be determined by the side of the Atlantic Ocean. This review brings forth several arguments in favour of U

Identification of Hammerhead Ribozymes in All Domains of Life Reveals Novel Structural Variations

Hammerhead ribozymes are small self-cleaving RNAs that promote strand scission by internal phosphoester transfer. Comparative sequence analysis was used to identify numerous additional representatives of this ribozyme class than were previously known, including the first representatives in fungi and archaea. Moreover, we have uncovered the first natural examples of “type II” hammerheads, and our findings reveal that this permuted form occurs in bacteria as frequently as type I and III architectures. We also identified a commonly occurring pseudoknot that forms a tertiary interaction critical for high-speed ribozyme activity. Genomic contexts of many hammerhead ribozymes indicate that they perform biological functions different from their known role in generating unit-length RNA transcripts of multimeric viroid and satellite virus genomes. In rare instances, nucleotide variation occurs at positions within the catalytic core that are otherwise strictly conserved, suggesting that core mutations are occasionally tolerated or preferred

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Detection of Leishmania infantum DNA mainly in Rhipicephalus sanguineus male ticks removed from dogs living in endemic areas of canine leishmaniosis

Background: Sand flies are the only biologically adapted vectors of Leishmania parasites, however, a possible role in the transmission of Leishmania has been proposed for other hematophagous ectoparasites such as ticks. In order to evaluate natural infection by Leishmania infantum in Rhipicephalus sanguineus ticks, taking into account its close association with dogs, 128 adult R. sanguineus ticks removed from 41 dogs living in endemic areas of canine leishmaniosis were studied. Methods: Individual DNA extraction was performed from each tick and whole blood taken from dogs. Dog sera were tested for IgG antibodies to L. infantum antigen by ELISA and L. infantum real-time PCR was performed from canine whole blood samples and ticks. Results: Leishmania infantum PCR was positive in 13 ticks (10.1%) including one female, (2.0%) and 12 males (15.2%), and in only five dogs (12.2%). Male ticks had a significantly higher infection rate when compared to female R. sanguineus. The percentage of L. infantum seroreactive dogs was 19.5%. All but two PCR positive dogs were seroreactive. Leishmania infantum PCR positive ticks were removed from seropositive and seronegative dogs with a variety of PCR results. Conclusions: This study demonstrates high prevalence of L. infantum DNA in R. sanguineus ticks removed from L. infantum seropositive and seronegative dogs. The presence of L. infantum DNA was detected mainly in male ticks possibly due to their ability to move between canine hosts and feed on several canine hosts during the adult life stage. Additional studies are needed to further explore the role of R. sanguineus ticks and in particular, male adults, in both the epidemiology and immunology of L. infantum infection in dogs in endemic areas

Quality and reporting of clinical guidelines for breast cancer treatment: A systematic review

Background: High-quality, well-reported clinical practice guidelines (CPGs) and consensus statements (CSs) underpinned by systematic reviews are needed. We appraised the quality and reporting of CPGs and CSs for breast cancer (BC) treatment. Methods: Following protocol registration (Prospero no: CRD42020164801), CPGs and CSs on BC treatment were identified, without language restrictions, through a systematic search of bibliographic databases (MEDLINE, EMBASE, Web of Science, Scopus, CDSR) and online sources (12 guideline databases and 51 professional society websites) from January 2017 to June 2020. Data were extracted in duplicate assessing overall quality using AGREE II (% of maximum score) and reporting compliance using RIGHT (% of total 35 items); reviewer agreement was 98% and 96% respectively. Results: There were 59 relevant guidance documents (43 CPGs, 16 CSs), of which 20 used systematic reviews for evidence synthesis. The median overall quality was 54.0% (IQR 35.9e74.3) and the median overall reporting compliance was 60.9% (IQR 44.5e84.4). The correlation between quality and reporting was 0.9. Compared to CSs, CPGs had better quality (55.4% vs 44.2%; p ¼ 0.032) and reporting (67.18% vs 44.5%; p ¼ 0.005). Compared to subjective methods of evidence analysis, guidance documents that used systematic reviews had better quality (76.3% vs 51.4%; p ¼ 0.001) and reporting (87.1% vs 59.4%; p ¼ 0.001). Conclusion: The quality and reporting of CPGs and CSs in BC treatment were moderately strong. Systematic reviews should be used to improve the quality and reporting of CPGs and CSs.Beatriz Galindo (senor modality) Program by the Ministry of Science, Innovation, and Universities of the Spanish Governmen

Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice

The NLRP3 inflammasome complex is responsible for maturation of the pro-inflammatory cytokine, IL-1β. Mutations in NLRP3 are responsible for the cryopyrinopathies, a spectrum of conditions including neonatal-onset multisystem inflammatory disease (NOMID). While excessive production of IL-1β and systemic inflammation are common to all cryopyrinopathy disorders, skeletal abnormalities, prominently in the knees, and low bone mass are unique features of patients with NOMID. To gain insights into the mechanisms underlying skeletal abnormalities in NOMID, we generated knock-in mice globally expressing the D301N NLRP3 mutation (ortholog of D303N in human NLRP3). NOMID mice exhibit neutrophilia in blood and many tissues, including knee joints, and high levels of serum inflammatory mediators. They also exhibit growth retardation and severe postnatal osteopenia stemming at least in part from abnormally accelerated bone resorption, attended by increased osteoclastogenesis. Histologic analysis of knee joints revealed abnormal growth plates, with loss of chondrocytes and growth arrest in the central region of the epiphyses. Most strikingly, a tissue “spike" was observed in the mid-region of the growth plate in the long bones of all NOMID mice that may be the precursor to more severe deformations analogous to those observed in NOMID patients. These findings provide direct evidence linking a NOMID-associated NLRP3-activating mutation to abnormalities of postnatal skeletal growth and bone remodeling