SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2), also known as Brahma homologue (BRM), is a Snf2-family DNA-dependent ATPase. BRM and its ...close homologue Brahma-related gene 1 (BRG1), also known as SMARCA4, are mutually exclusive ATPases of the large ATP-dependent SWI/SNF chromatin-remodeling complexes involved in transcriptional regulation of gene expression. No small molecules have been reported that modulate SWI/SNF chromatin-remodeling activity via inhibition of its ATPase activity, an important goal given the well-established dependence of BRG1-deficient cancers on BRM. Here, we describe allosteric dual BRM and BRG1 inhibitors that downregulate BRM-dependent gene expression and show antiproliferative activity in a BRG1-mutant-lung-tumor xenograft model upon oral administration. These compounds represent useful tools for understanding the functions of BRM in BRG1-loss-of-function settings and should enable probing the role of SWI/SNF functions more broadly in different cancer contexts and those of other diseases.
The authors present exploitation of Multiple Views in Single‐Path (MVSP) Synthetic Aperture Sonar (SAS). The authors demonstrate the interest of MVSP SAS for underwater Mine Counter‐Measures (MCM) ...with unmanned vehicles, to comply with requirements for performances of detection and classification and time constraints. The authors here lay the emphasis on exploitation in reduction of false alarms of classification by alleviating the ambiguity between mines and natural bottom objects. Finally, the authors show that MVSP SAS is offering a pre‐identification tool with high impact on MCM process duration.
Extension of Synthetic Aperture Sonar provides Multiple Views in Single Path: this is useful for performances in detection and classification in Mine Warfare applications with unmanned vehicles. The authors also show that these technology and performances are close to offering a pre‐identification tool.
Polyploidy has had a considerable impact on the evolution of many eukaryotes, especially angiosperms. Indeed, most--if not all-angiosperms have experienced at least one round of polyploidy during the ...course of their evolution, and many important crop plants are current polyploids. The occurrence of 2n gametes (diplogametes) in diploid populations is widely recognised as the major source of polyploid formation. However, limited information is available on the genetic control of diplogamete production. Here, we describe the isolation and characterisation of the first gene, AtPS1 (Arabidopsis thaliana Parallel Spindle 1), implicated in the formation of a high frequency of diplogametes in plants. Atps1 mutants produce diploid male spores, diploid pollen grains, and spontaneous triploid plants in the next generation. Female meiosis is not affected in the mutant. We demonstrated that abnormal spindle orientation at male meiosis II leads to diplogamete formation. Most of the parent's heterozygosity is therefore conserved in the Atps1 diploid gametes, which is a key issue for plant breeding. The AtPS1 protein is conserved throughout the plant kingdom and carries domains suggestive of a regulatory function. The isolation of a gene involved in diplogamete production opens the way for new strategies in plant breeding programmes and progress in evolutionary studies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Despite the dominant role of bone mass in osteoporotic fractures, aging bone tissue properties must be thoroughly understood to improve osteoporosis management. In this context, collagen content and ...integrity are considered important factors, although limited research has been conducted on the tensile behavior of demineralized compact bone in relation to its porosity and elastic properties in the native mineralized state. Therefore, this study aims (i) at examining the age-dependency of mineralized bone and collagen micromechanical properties; (ii) to test whether, and if so to which extent, collagen properties contribute to mineralized bone mechanical properties.
Two cylindrical cortical bone samples from fresh frozen human anatomic donor material were extracted from 80 proximal diaphyseal sections from a cohort of 24 female and 19 male donors (57 to 96 years at death). One sample per section was tested in uniaxial tension under hydrated conditions. First, the native sample was tested elastically (0.25 % strain), and after demineralization, up to failure. Morphology and composition of the second specimen was assessed using micro-computed tomography, Raman spectroscopy, and gravimetric methods. Simple and multiple linear regression were employed to relate morphological, compositional, and mechanical variables with age and sex.
Macro-tensile properties revealed that only elastic modulus of native samples was age dependent whereas apparent elastic modulus was sex dependent (p < 0.01). Compositional and morphological analysis detected a weak but significant age and sex dependency of relative mineral weight (r = −0.24, p < 0.05) and collagen disorder ratio (I∼1670/I∼1640, r = 0.25, p < 0.05) and a strong sex dependency of bone volume fraction while generally showing consistent results in mineral content assessment. Young's modulus of demineralized bone was significantly related to tissue mineral density and Young's modulus of native bone.
The results indicate that mechanical properties of the organic phase, that include collagen and non-collagenous proteins, are independent of donor age. The observed reduction in relative mineral weight and corresponding overall stiffer response of the collagen network may be caused by a reduced number of mineral-collagen connections and a lack of extrafibrillar and intrafibrillar mineralization that induces a loss of waviness and a collagen fiber pre-stretch.
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Abstract
The normal zone propagation velocity (NZPV) of three families of REBCO tape architectures designed for superconducting fault current limiters and to be used in high voltage direct current ...transmission systems has been measured experimentally in liquid nitrogen at atmospheric pressure. The measured NZPVs span more than three orders of magnitude depending on the tape architectures. Numerical simulations based on finite elements allow us to reproduce the experiments well. The dynamic current transfer length (CTL) extracted from the numerical simulations was found to be the dominating characteristic length determining the NZPV instead of the thermal diffusion length. We therefore propose a simple analytical model, whose key parameters are the dynamic CTL, the heat capacity and the resistive losses in the metallic layers, to calculate the NZPV.
Purpose
Recent studies on patients with stable obesity-hypoventilation syndrome have raised concerns about hyperoxia-induced hypercapnia in this population. This study aimed to evaluate whether a ...higher oxygen saturation target would increase arterial partial pressure of carbon dioxide (PaCO
2)
in obese patients after coronary artery bypass grafting surgery (CABG).
Methods
Obese patients having CABG were recruited. With a randomized crossover design, we compared two oxygenation strategies for 30 min each, immediately after extubation: a peripheral oxygen saturation (SpO
2
) target of ≥ 95% achieved with manual oxygen titration (liberal) and a SpO
2
target of 90% achieved with FreeO
2
, an automated oxygen titration device (conservative). The main outcome was end-of-period arterial PaCO
2
.
Results
Thirty patients were included. Mean (standard deviation SD) body mass index (BMI) was 34 (3) kg·m
−2
and mean (SD) baseline partial pressure of carbon dioxide (PCO
2
) was 40.7 (3.1) mmHg. Mean (SD) end-of-period PaCO
2
was 42.0 (5.4) mmHg in the conservative period, compared with 42.6 (4.6) mmHg in the liberal period mean difference − 0.6 (95% confidence interval − 2.2 to 0.9) mmHg;
P
= 0.4. Adjusted analysis for age, BMI, narcotics, and preoperative PaCO
2
did not substantively change the results. Fourteen patients were retainers, showing an elevation in mean (SD) PaCO
2
in the liberal period of 3.3 (4.1) mmHg. Eleven patients had the opposite response, with a mean (SD) end-of-period PaCO
2
decrease of 1.8 (2.2) mmHg in the liberal period. Five patients had a neutral response.
Conclusion
This study did not show a clinically important increase in PaCO
2
associated with higher SpO
2
values in this specific population of obese patients after CABG. Partial pressure of carbon dioxide increased with liberal oxygen administration in almost half of the patients, but no predictive factor was identified.
Trial registration
www.clinicaltrials.gov
(NCT02917668); registered 25 September, 2016.
Clinical multicenter imaging studies are frequent and rely on a wide range of existing tools for sharing data and processing pipelines. This is not the case for preclinical (small animal) studies. ...Animal population imaging is still in infancy, especially because a complete standardization and control of initial conditions in animal models across labs is still difficult and few studies aim at standardization of acquisition and post-processing techniques. Clearly, there is a need of appropriate tools for the management and sharing of data, post-processing and analysis methods dedicated to small animal imaging. Solutions developed for Human imaging studies cannot be directly applied to this specific domain. In this paper, we present the Small Animal Shanoir (SAS) solution for supporting animal population imaging using tools compatible with open data. The integration of automated workflow tools ensures accessibility and reproducibility of research outputs. By sharing data and imaging processing tools, hosted by SAS, we promote data preparation and tools for reproducibility and reuse, and participation in multicenter or replication "
" studies contributing to the improvement of quality science in preclinical domain. SAS is a first step for promoting open science for small animal imaging and a contribution to the valorization of data and pipelines of reference.
High-resolution peripheral quantitative computed tomography (HR-pQCT) based micro-finite element (μFE) analysis allows accurate prediction of stiffness and ultimate load of standardised (∼1 cm) ...distal radius and tibia sections. An alternative homogenized finite element method (hFE) was recently validated to compute the ultimate load of larger (∼2 cm) distal radius sections that include Colles' fracture sites. Since the mechanical integrity of the weight-bearing distal tibia is gaining clinical interest, it has been shown that the same properties can be used to predict the strength of both distal segments of the radius and the tibia. Despite the capacity of hFE to predict structural properties of distal segments of the radius and the tibia, the limitations of such homogenization scheme remain unclear. Therefore, the objective of this study is to build a complete mechanical data set of the compressive behavior of distal segments of the tibia and to compare quantitatively the structural properties with the hFE predictions. As a further aim, it is intended to verify whether hFE is also able to capture the post-yield strain localisation or fracture zones in such a bone section, despite the absence of strain softening in the constitutive model.
Twenty-five fresh-frozen distal parts of tibias of human donors were used in this study. Sections were cut corresponding to an in-house triple-stack protocol HR-pQCT scan, lapped, and scanned using micro computed tomography (μCT). The sections were tested in compression until failure, unloaded and scanned again in μCT. Volumetric bone mineral density (vBMD) and bone mineral content (BMC) were correlated to compression test results. hFE analysis was performed in order to compare computational predictions (stiffness, yield load and plastic deformation field pattern) with the compressive experiment. Namely, strain localization was assessed based on digital volume correlation (DVC) results and qualitatively compared to hFE predictions by comparing mid-slices patterns.
Bone mineral content (BMC) showed a good correlation with stiffness (R2 = 0.92) and yield (R2 = 0.88). Structural parameters also showed good agreement between the experiment and hFE for both stiffness (R2 = 0.96, slope = 1.05 with 95 % CI 0.97, 1.14) and yield (R2 = 0.95, slope = 1.04 0.94, 1.13). The qualitative comparison between hFE and DVC strain localization patterns allowed the classification of the samples into 3 categories: bad (15 sections), semi (8), and good agreement (2).
The good correlations between BMC or hFE and experiment for structural parameters were similar to those obtained previously for the distal part of the radius. The failure zones determined by hFE corresponded to registration only in 8 % of the cases. We attribute these discrepancies to local elastic/plastic buckling effects that are not captured by the continuum-based FE approach exempt from strain softening. A way to improve strain localization hFE prediction would be to use longer distal segments with intact cortical shells, as done for the radius. To conclude, the used hFE scheme captures the elastic and yield response of the tibia sections reliably but not the subsequent failure process.
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MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to ...growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.
The surgical management of life-threatening perioperative hemoptysis has been vastly replaced by radiologic embolization. In some situations, surgical therapy can prove useful. This case report ...describes life-threatening hemoptysis of an unusual cause during coronary artery bypass grafting, managed through an original technique of temporary pulmonary vascular exclusion by thoracotomy.
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