Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease ...phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.
Perennial species with the C-4 pathway hold promise for biomass-based energy sources. We have explored the extent that CO2 uptake of such species may be limited by light in a temperate climate. One ...energetic cost of the C-4 pathway is the leakiness (phi) of bundle sheath tissues, whereby a variable proportion of the CO2, concentrated in bundle sheath cells, retrodiffuses back to the mesophyll. In this study, we scale phi from leaf to canopy level of a Miscanthus crop (Miscanthus x giganteus hybrid) under field conditions and model the likely limitations to CO2 fixation. At the leaf level, measurements of photosynthesis coupled to online carbon isotope discrimination showed that leaves within a 3.3-m canopy (leaf area index = 8.3) show a progressive increase in both carbon isotope discrimination and phi as light decreases. A similar increase was observed at the ecosystem scale when we used eddy covariance net ecosystem CO2 fluxes, together with isotopic profiles, to partition photosynthetic and respiratory isotopic flux densities (isofluxes) and derive canopy carbon isotope discrimination as an integrated proxy for phi at the canopy level. Modeled values of canopy CO2 fixation using leaf-level measurements of phi suggest that around 32% of potential photosynthetic carbon gain is lost due to light limitation, whereas using phi determined independently from isofluxes at the canopy level the reduction in canopy CO2 uptake is estimated at 14%. Based on these results, we identify phi as an important limitation to CO2 uptake of crops with the C-4 pathway.
Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage ...genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2(V617F)-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10(-10)) and rs2201862 (MECOM; meta-analysis P=1.96 × 10(-9)). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ(2) P=7.3 × 10(-7)). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype.
Objective
To investigate whether antidrug antibodies and/or drug non‐trough levels predict the long‐term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with ...adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions.
Methods
A total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme‐linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non‐trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated.
Results
Among patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 95% confidence interval (95% CI) 0.57, 0.85). Antidrug antibody–positive patients received lower median dosages of methotrexate compared with antidrug antibody–negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 95% CI 0.015, 0.10, P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 95% CI 0.019, 0.16, P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m2 and poor adherence were associated with lower drug levels.
Conclusion
Pharmacologic testing in anti–tumor necrosis factor–treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months.
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•A new approach to piperidines by acid-catalysed cyclisation of amine derivatives.•Determination of suitable N-protecting groups which lead to acid-stable piperidines.•A novel ring ...contraction of N-sulfonyl piperidines to give pyrrolidines.•Derivation of the likely mechanism of the ring contraction.
The success of acid-catalysed cyclisations of alka-4-enylamine derivatives to piperidines depends very much on the nature of the amine protecting group: while carbamates and related amides can usually be readily and cleanly transformed, the corresponding sulfonamides react further by ring contraction leading to pyrrolidines, especially when such substrates are sterically crowded.
Report of a combined working party of British Society for Antimicrobial Chemotherapy, Hospital Infection Society and Infection Control Nurses Association. (BNI unique abstract) 135 references
Summary
Ageing populations have greater incidences of dementia. People with dementia present for emergency and, increasingly, elective surgery, but are poorly served by the lack of available guidance ...on their peri‐operative management, particularly relating to pharmacological, medico‐legal, environmental and attitudinal considerations. These guidelines seek to deliver such guidance, by providing information for peri‐operative care providers about dementia pathophysiology, specific difficulties anaesthetising patients with dementia, medication interactions, organisational and medico‐legal factors, pre‐, intra‐ and postoperative care considerations, training, sources of further information and care quality improvement tools.
We have studied the transport properties of a large graphene double quantum dot under the influence of a background disorder potential and a magnetic field. At low temperatures, the evolution of the ...charge-stability diagram as a function of the B field is investigated up to 10 T. Our results indicate that the charging energy of the quantum dot is reduced, and hence the effective size of the dot increases at a high magnetic field. We provide an explanation of our results using a tight-binding model, which describes the charge redistribution in a disordered graphene quantum dot via the formation of Landau levels and edge states. Our model suggests that the tunnel barriers separating different electron/hole puddles in a dot become transparent at high B fields, resulting in the charge delocalization and reduced charging energy observed experimentally.
Striae distensae (striae: stretch marks) are a common disfiguring condition associated with continuous and progressive stretching of the skin—as occurs during pregnancy. The pathogenesis of striae is ...unknown but probably relates to changes in those structures that provide skin with its tensile strength and elasticity. Such structures are components of the extracellular matrix, including fibrillin, elastin and collagens. Using a variety of histological techniques, we assessed the distribution of these extracellular matrix components in skin affected by striae. Pregnant women were assessed for the presence of striae, and punch biopsies were obtained from lesional striae and adjacent normal skin. Biopsies were processed for electron microscopy, light microscopy and immunohistochemistry. For histological examination, 7 μm frozen sections were stained so as to identify the elastic fibre network and glycosaminoglycans. Biopsies were also examined with a panel of polyclonal antibodies against collagens I and III, and fibrillin and elastin. Ultrastructural analysis revealed alterations in the appearance of skin affected by striae compared with that of normal skin in that the dermal matrix of striae was looser and more floccular. Light microscopy revealed an increase in glycosaminoglycan content in striae. Furthermore, the number of vertical fibrillin fibres subjacent to the dermal–epidermal junction (DEJ) and elastin fibres in the papillary dermis was significantly reduced in striae compared with normal skin. The orientation of elastin and fibrillin fibres in the deep dermis showed realignment in that the fibres ran parallel to the DEJ. However, no significant alterations were observed in any other extracellular matrix components. This study identifies a reorganization and diminution of the elastic fibre network of skin affected by striae. Continuous strain on the dermal extracellular matrix, as occurs during pregnancy, may remodel the elastic fibre network in susceptible individuals and manifest clinically as striae distensae.
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