The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin–Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive web-based survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features

The effect of CO2 on the mechanical properties of the Captain Sandstone: Geological storage of CO2 at the Goldeneye field (UK)

Geological storage of CO2 in clastic reservoirs is expected to have a variety of coupled chemical-mechanical effects, which may damage the overlying caprock and/or the near-wellbore area. We performed conventional triaxial creep experiments, combined with fluid flow-through experiments (brine and CO2-rich brine) on samples of poorly consolidated, carbonate- and quartz-cemented Captain Sandstone from the Goldeneye field. The main goal was to study the effect of carbonate cement dissolution on mechanical and ultrasonic properties, as well as on the failure strength of the material. Our experiments were performed under in situ reservoir conditions, mimicking reservoir depletion and injection. Although total dissolution of calcite was observed, and confirmed by microstructural and fluid chemistry analyses, it did not affect the rock mechanical properties, nor was any measurable rock strength reduction observed. This is most likely because grain-to-grain contacts were sufficiently quartz-cemented and quartz is not affected by CO2-rich brine. Failure data for the Captain Sandstone showed that the stress conditions under which CO2 injection will take place remain far away from the failure envelope. Therefore, CO2 injection is not expected to lead to shear failure of the reservoir. However, longer-term chemical reactions, involving minerals such as feldspar, clays or micas, still require more research

The effect of CO2 on the mechanical properties of the Captain Sandstone: Geological storage of CO2 at the Goldeneye field (UK)

Geological storage of CO2 in clastic reservoirs is expected to have a variety of coupled chemical-mechanical effects, which may damage the overlying caprock and/or the near-wellbore area. We performed conventional triaxial creep experiments, combined with fluid flow-through experiments (brine and CO2-rich brine) on samples of poorly consolidated, carbonate- and quartz-cemented Captain Sandstone from the Goldeneye field. The main goal was to study the effect of carbonate cement dissolution on mechanical and ultrasonic properties, as well as on the failure strength of the material. Our experiments were performed under in situ reservoir conditions, mimicking reservoir depletion and injection. Although total dissolution of calcite was observed, and confirmed by microstructural and fluid chemistry analyses, it did not affect the rock mechanical properties, nor was any measurable rock strength reduction observed. This is most likely because grain-to-grain contacts were sufficiently quartz-cemented and quartz is not affected by CO2-rich brine. Failure data for the Captain Sandstone showed that the stress conditions under which CO2 injection will take place remain far away from the failure envelope. Therefore, CO2 injection is not expected to lead to shear failure of the reservoir. However, longer-term chemical reactions, involving minerals such as feldspar, clays or micas, still require more research

Antiproliferative and Calcemic Actions of Trans-Decalin CD-Ring Analogs of 1,25-Dihydroxyvitamin D-3

Background: 1,25-Dihydroxyvitamin D-3 [1,25(OH)(2)D-3] has potent antiproliferative actions but calcemic effects obstruct its application in the treatment of hyperproliferative disorders. Therefore, analogs of 1,25(OH)(2)D-3 are designed with a clear dissociation between both effects. Here the biological activity of the trans-decalin CD-ring analog CY10012 is discussed. Materials and Methods: Proliferation/differentiation/transactivation assays as well as mouse models were used to determine the activity of CY10012 in vitro and in vivo. Results: CY10012, has ten-fold higher antiproliferative actions than 1,25(OH)(2)D-3 but is also twice as calcemic. To determine the role of the Vitamin D Receptor (VDR) in mediating the calcemic actions of CY10012, the analog was daily administered to VDRwt and VDRko mice. This treatment caused drastic weight loss and death in VDRwt mice but not in VDRko mice. Conclusion: Analog CY10012 has greater antiproliferative action but also two-fold higher calcemic effects which depended entirely on VDR-mediated signalling pathways

Structure–property relationships in twist-bend nematogens : the influence of terminal groups

The synthesis and characterisation of a range of non-symmetric liquid crystal dimers designed to exhibit the twist-bend nematic phase is reported. Beginning with 1-(4-cyanobiphenyl-4′-yloxy)-6-(4-cyanobiphenyl-4′-yl) hexane, each nitrile group is exchanged systematically for a methoxy group. The behaviour of these dimers is interpreted in terms of their bent shape being the predominant driving force for the formation of the twist-bend nematic phase, and the small differences between the twist-bend nematic–nematic transition temperatures are attributed to the differences between the interaction strength parameters of the mesogenic units. The 4-alkyloxyphenyl 4-[6-(4′-cyanobiphenyl-4-yl)hexyloxy]benzoates with ethyl, butyl, hexyl and octyl chains show the twist-bend nematic phase, whereas the corresponding 4-alkyloxyphenyl 4-[5-(4′-cyanobiphenyl-4-yloxy)pentyloxy]benzoates do not. This difference in behaviour is attributed to the more bent structure of the former. Increasing the terminal chain length initially decreases the twist-bend nematic–nematic transition temperature and this suggests that the chain disrupts the interactions between the mesogenic units. Subsequent increases in chain length have a smaller effect suggesting that the chain can be accommodated within an intercalated arrangement. The transitional behaviour of 1-(4-cyanobiphenyl-4′-yloxy)-6-(4-butyloxybiphenyl-4′-yl) hexane is compared to that of 1-(4-cyanobiphenyl-4′-yloxy)-6-(4-((S)-2-methyl)butyloxybiphenyl-4′-yl) hexane, and it is shown that chain branching strongly destabilises the twist-bend nematic phase. This is attributed to difficulties associated with packing the dimers

Microarray analysis of MCF-7 breast cancer cells treated with 1,25-dihydroxyvitamin D-3 or a 17-methyl-D-ring analog

Background: 1 alpha,25-dihydroxyvitamin D-3 [1,25-(OH)(2)D-3] is the biological active form of vitamin D. Its antiproliferative capacities make it a potential drug to treat diseases such as cancer. The clinical use of 1,25-(OH)(2)D-3 as an antiproliferative agent is hampered by its calcemic effects. Hence, structural analogs such as the seco-9,11-bisnor-17-methyl analog, WY1112, have been developed with superagonistic capacities. This study aims to distinct the molecular activities of 1,25-(OH)(2)D-3 and WY1112 and identify, possible differences in gene expression. Materials and Methods: Total RNA was extracted from MCF-7 breast cancer cells treated with 1,25-(OH)(2)D-3 Or WY1112 and was used for microarray analysis. Results: The experiments revealed that WY1112 induces the same genes as 1,25(OH)(2)D-3, but the induction level of the individual genes is higher. Microarray analysis did not reveal genes that were exclusively regulated by WY1112. Conclusion: The superagonistic vitamin D analog WY1112 induces the same set of genes as 1,25-(OH)(2)D-3, but the level of induction of the individual genes is higher