Cryo-EM structure of a helicase loading intermediate containing ORC-Cdc6-Cdt1-MCM2-7 bound to DNA

In eukaryotes, the Cdt1-bound replicative helicase core MCM2-7 is loaded onto DNA by the ORC-Cdc6 ATPase to form a prereplicative complex (pre-RC) with an MCM2-7 double hexamer encircling DNA. Using purified components in the presence of ATP-γS, we have captured in vitro an intermediate in pre-RC assembly that contains a complex between the ORC-Cdc6 and Cdt1-MCM2-7 heteroheptamers called the OCCM. Cryo-EM studies of this 14-subunit complex reveal that the two separate heptameric complexes are engaged extensively, with the ORC-Cdc6 N-terminal AAA+ domains latching onto the C-terminal AAA+ motor domains of the MCM2-7 hexamer. The conformation of ORC-Cdc6 undergoes a concerted change into a right-handed spiral with helical symmetry that is identical to that of the DNA double helix. The resulting ORC-Cdc6 helicase loader shows a notable structural similarity to the replication factor C clamp loader, suggesting a conserved mechanism of action

Study on performance of compression engine operated by biodiesel fuel

The analysis of the performance of biofuel is aimed at evaluating the energy efficiency of operating the engine with the use of biodiesel fuel as function of the fuel’s composition and other physical-and-chemical parameters. The mathematical models and analysis techniques known to the authors do not take into account the effect that the use of different bio-diesel fuels has on the operation of the engine and, therefore, need refinement in terms of the mathematical expressions and empirical formulae that describe the physical processes taking place in the engine’s cylinders. The aim of the study is to improve the mathematical relations taking into consideration the physical-and-chemical parameters of different types of fuel. The research methods proposed in the article are based on step-by-step consideration of the mathematical models of processes that follow each other, with due account for their possible overlapping, which jointly have an effect on the engine’s output indices. The boundary conditions and parameter increments are pre-set in electronic work sheets. Thus, it becomes possible, using the refined mathematical model, to calculate the main performance indices of the diesel engine with due account for the changes in the physical-and-chemical parameters of the fuel. The novelty of the described approach is in the possibility, through the use of the refined model and taking into account the data on the composition of the fuel and the design and operation parameters of the engine, to calculate the indices that allow evaluating the efficiency of use of specific fuels in the internal combustion engine under consideration. In results, formulas for the calculation of the effective power of the engine, fresh air charge density, excess air factor, effective specific fuel consumption and combustion pressure have been developed. Combustion pressure modelling and experimental data is presented

Structural validity of the foot and ankle outcome score for orthopaedic pathologies with Rasch Measurement Theory

Publisher Copyright: © 2021 The AuthorsA B S T R A C T Background: The Foot and Ankle Outcome Score (FAOS) is one of the most frequently used patient reported outcome measures for foot and ankle conditions. The aim is to test the structural validity of the Finnish version of the FAOS using Rasch Measurement Theory. Methods: FAOS scores were obtained from 218 consecutive patients who received operative treatment for foot and ankle conditions. The FAOS data were fitted into the Rasch model and person separation index (PSI) calculated. Results: All the five subscales provided good coverage and targeting. Three subscales presented unidimensional structure. Thirty-eight of the 42 items had ordered response category thresholds. Three of the 42 items had differential item functioning towards gender. All subscales showed sufficient fit to the Rasch model. PSI ranged from 0.73 to 0.94 for the subscales. Conclusions: The Finnish version of the FAOS shows acceptable structural validity for assessing complaints in orthopaedic foot and ankle patients. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of European Foot and Ankle Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Peer reviewe

Factors predicting chronic pain after open inguinal hernia repair : a regression analysis of randomized trial comparing three different meshes with three fixation methods (FinnMesh Study)

Correction: Volume: 22 Issue: 5 Pages: 819-819 DOI: 10.1007/s10029-018-1788-y WOS:000446065400016Chronic pain after inguinal hernioplasty is the foremost side-effect up to 10-30% of patients. Mesh fixation may influence on the incidence of chronic pain after open anterior mesh repairs. Some 625 patients who underwent open anterior mesh repairs were randomized to receive one of the three meshes and fixations: cyanoacrylate glue with low-weight polypropylene mesh (n = 216), non-absorbable sutures with partially absorbable mesh (n = 207) or self-gripping polyesther mesh (n = 202). Factors related to chronic pain (visual analogue scores; VAS ae 30, range 0-100) at 1 year postoperatively were analyzed using logistic regression method. A second analysis using telephone interview and patient records was performed 2 years after the index surgery. At index operation, all patient characteristics were similar in the three study groups. After 1 year, chronic inguinal pain was found in 52 patients and after 2 years in only 16 patients with no difference between the study groups. During 2 years' follow-up, three (0.48%) patients with recurrences and five (0.8%) patients with chronic pain were re-operated. Multivariate regression analysis indicated that only new recurrent hernias and high pain scores at day 7 were predictive factors for longstanding groin pain (p = 0.001). Type of mesh or fixation, gender, pre-operative VAS, age, body mass index or duration of operation did not predict chronic pain. Only the presence of recurrent hernia and early severe pain after index operation seemed to predict longstanding inguinal pain.Peer reviewe

CUL-2^LRR-1 and UBXN-3 drive replisome disassembly during DNA replication termination and mitosis

Replisome disassembly is the final step of DNA replication in eukaryotes, involving the ubiquitylation and CDC48-dependent dissolution of the CMG helicase (CDC45-MCM-GINS). Using Caenorhabditis elegans early embryos and Xenopus laevis egg extracts, we show that the E3 ligase CUL-2(LRR-1) associates with the replisome and drives ubiquitylation and disassembly of CMG, together with the CDC-48 cofactors UFD-1 and NPL-4. Removal of CMG from chromatin in frog egg extracts requires CUL2 neddylation, and our data identify chromatin recruitment of CUL2(LRR1) as a key regulated step during DNA replication termination. Interestingly, however, CMG persists on chromatin until prophase in worms that lack CUL-2(LRR-1), but is then removed by a mitotic pathway that requires the CDC-48 cofactor UBXN-3, orthologous to the human tumour suppressor FAF1. Partial inactivation of lrr-1 and ubxn-3 leads to synthetic lethality, suggesting future approaches by which a deeper understanding of CMG disassembly in metazoa could be exploited therapeutically

Pulmonary toxicity of synthetic amorphous silica–effects of porosity and copper oxide doping

Materials can be modified for improved functionality. Our aim was to test whether pulmonary toxicity of silica nanomaterials is increased by the introduction of: a) porosity; and b) surface doping with CuO; and whether c) these modifications act synergistically. Mice were exposed by intratracheal instillation and for some doses also oropharyngeal aspiration to: 1) solid silica 100 nm; 2) porous silica 100 nm; 3) porous silica 100 nm with CuO doping; 4) solid silica 300 nm; 5) porous silica 300 nm; 6) solid silica 300 nm with CuO doping; 7) porous silica 300 nm with CuO doping; 8) CuO nanoparticles 9.8 nm; or 9) carbon black Printex 90 as benchmark. Based on a pilot study, dose levels were between 0.5 and 162 µg/mouse (0.2 and 8.1 mg/kg bw). Endpoints included pulmonary inflammation (neutrophil numbers in bronchoalveolar fluid), acute phase response, histopathology, and genotoxicity assessed by the comet assay, micronucleus test, and the gamma-H2AX assay. The porous silica materials induced greater pulmonary inflammation than their solid counterparts. A similar pattern was seen for acute phase response induction and histologic changes. This could be explained by a higher specific surface area per mass unit for the most toxic particles. CuO doping further increased the acute phase response normalized according to the deposited surface area. We identified no consistent evidence of synergism between surface area and CuO doping. In conclusion, porosity and CuO doping each increased the toxicity of silica nanomaterials and there was no indication of synergy when the modifications co-occurred

AXIN2-related oligodontia-colorectal cancer syndrome with cleft palate as a possible new feature

Background: Pathogenic variants in AXIN2 have been associated with tooth agenesis, colon polyps, and colon cancer. Given the rare nature of this phenotype, we set out to collect additional genotypic and phenotypic information. Methods: Data were collected via a structured questionnaire. Sequencing was performed in these patients mostly due to diagnostic purpose. A little more than half of the AXIN2 variant carriers were identified by NGS; other six were family members. Results: Here, we report 13 individuals with a heterozygous AXIN2 pathogenic/likely pathogenic variant who have a variable expression of oligodontia-colorectal cancer syndrome (OMIM 608615) or oligodontia-cancer predisposition syndrome (ORPHA 300576). Three individuals from one family also had cleft palate, which might represent a new clinical feature of AXIN2 phenotype, also given the fact that AXIN2 polymorphisms have been found in association with oral clefting in population studies. AXIN2 has already been added to multigene cancer panel tests; further research should be conducted to determine whether it should be added to cleft lip/palate multigene panels. Conclusion: More clarity about oligodontia-colorectal cancer syndrome, about the variable expression, and associated cancer risks is needed to improve clinical management and to establish guidelines for surveillance. We collected information about the surveillance that was advised, which might support clinical management of these patients.</p

Online Survey on Novel Designs for Supporting Self-Reflection and Emotion Regulation in Online News Commenting

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User-centred quality of UI interventions aiming to influence online news commenting behaviour

While HCI literature offers general frameworks for understanding user-centred quality, specific application areas may call for more detailed contextualisation of it. This paper focuses on socio-technical context of online news commenting by investigating speculative UI interventions intended to influence users’ emotions and social behaviour. To understand the aspects of quality that matter to users in such UI interventions, we conducted an international online survey (N = 439) and qualitatively analysed respondents’ first impressions of eight different design proposals. The findings describe contextually relevant socio-technical viewpoints and offer actionable considerations for design. For example, the findings imply that designers should be mindful of possible unintentional misuse that may result from the UI reinforcing specific emotional states or affording stigmatisation of individual users. The study advances understanding of which aspects of quality should be considered when designing and deploying UI interventions for digital media services and evaluating them with potential end-users.publishedVersionPeer reviewe