Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe ...visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.
The potential for genome-wide association studies to relate phenotypes to specific genetic variation is greatly increased when data can be combined or compared across multiple studies. To facilitate ...replication and validation across studies, RTI International (Research Triangle Park, North Carolina) and the National Human Genome Research Institute (Bethesda, Maryland) are collaborating on the consensus measures for Phenotypes and eXposures (PhenX) project. The goal of PhenX is to identify 15 high-priority, well-established, and broadly applicable measures for each of 21 research domains. PhenX measures are selected by working groups of domain experts using a consensus process that includes input from the scientific community. The selected measures are then made freely available to the scientific community via the PhenX Toolkit. Thus, the PhenX Toolkit provides the research community with a core set of high-quality, well-established, low-burden measures intended for use in large-scale genomic studies. PhenX measures will have the most impact when included at the experimental design stage. The PhenX Toolkit also includes links to standards and resources in an effort to facilitate data harmonization to legacy data. Broad acceptance and use of PhenX measures will promote cross-study comparisons to increase statistical power for identifying and replicating variants associated with complex diseases and with gene-gene and gene-environment interactions.
Ammonia, if present in the ice shells of icy satellites, could lower the temperature for the onset of melting to 176 K and create a large temperature range where partial melt is thermally stable. The ...evolution of regions of ammonia‐rich partial melt could strongly influence the geological and thermal evolution of icy bodies. For melt to be extracted from partially molten regions, the surrounding solid matrix must deform and compact. Whether ammonia‐rich melts sink to the subsurface ocean or become frozen into the ice shell depends on the compaction rate and thermal evolution. Here we construct a model for the compaction and thermal evolution of a partially molten, ammonia‐rich ice shell in a one‐dimensional geometry. We model the thickening of an initially thin ice shell above an ocean with 10% ammonia. We find that ammonia‐rich melts can freeze into the upper 5 to 10 km of the ice shell, when ice shell thickening is rapid compared to the compaction rate. The trapping of near‐surface volatiles suggests that, upon reheating of the ice shell, eutectic melting events are possible. However, as the ice shell thickening rate decreases, ammonia‐rich melt is efficiently excluded from the ice shell and the bulk of the ice shell is pure water ice. We apply our results to the thermal evolution of Neptune's moon Triton. As Triton's ice shell thickens, the gradual increase of ammonia concentration in Triton's subsurface ocean helps to prevent freezing and increases the predicted final ocean thickness by up to 50 km.
Plain Language Summary
Many icy worlds in the outer solar system are thought to have liquid water beneath their icy crusts. If ammonia is present in the ice, it can lower the melting temperature by nearly 100 °C and allow melt to be present at the cold temperatures found in the outer solar system. However it is not known whether ammonia would be present in the icy crust, or whether it would sink down into the subsurface ocean below. We model the flow of ammonia‐rich liquids through an ice shell, at a time when the ice shell is thickening. We find that ammonia can freeze into the top few kilometers of ice shell; however, most of the ammonia sinks down into the subsurface ocean below. This causes the ocean to become more ammonia‐rich as the world continues to cool and the ice shell continues to thicken. The trapping of some ammonia in the ice shell could allow near‐surface ammonia‐rich liquids to be generated if the ice shell is ever reheated.
Key Points
During ice shell thickening, ammonia‐rich melt can freeze into the upper few kilometers, when the cooling rate exceeds the compaction rate
Most ammonia is excluded from the ice shell and concentrates in the subsurface ocean
The ammonia concentration in Triton's ocean gradually increases as the ice shell thickens, helping to prevent the ocean from freezing.
The design of industrial crystallization processes usually employs laboratory‐scale experimental data which must be correlated with the full‐scale process for effective technology transfer. In this ...context, the measured growth rates of single crystals of ibuprofen in stagnant ethanolic solutions are compared with data recorded for a population of crystals crystallized in an agitated 7‐mL reactor. The single crystal growth rates are found to be rather close to those determined in the agitated reactor, with both being also in good agreement with previously published data at the 750‐mL scale, suggesting that studies on single crystals can have utility for the purpose of crystallization process design and optimization.
Preliminary crystallization science of scale data is reported highlighting some encouraging observed correlations between the growth rates of ibuprofen single crystals in stagnant ethanolic solutions when compared with data recorded for a population of crystals crystallized in an agitated 7‐mL reactor and the data previously published at 750‐mL scale.
Solid tumors often have an inadequate blood supply, which results in large regions that are subjected to hypoxic or anoxic stress. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that ...regulates much of the transcriptional response of cells to hypoxia. Activating transcription factor 3 (ATF3) is another transcription factor that responds to a variety of stresses and is often upregulated in cancer. We investigated the regulation of ATF3 by oxygen deprivation. ATF3 induction occurred most robustly under anoxia, is common, and it is not dependent on presence of HIF-1 or p53, but is sensitive to the inhibition of c-Jun NH2-terminal kinase activation and the antioxidant N-acetylcystein. ATF3 could also be induced by desferrioxamine but not by the mitochondrial poison cyanide or the nonspecific 2-oxoglutarate dioxygenase inhibitor dimethyloxalylglycine. We also show that anoxic ATF3 mRNA is more stable than normoxic mRNA providing a mechanism for this induction. Thus, this study demonstrates that the regulation of ATF3 under anoxia is independent of 2-oxoglutarate dioxygenase, HIF-1 and p53, presumably involving multiple regulatory pathways.
Numerous human genetic diseases are caused by mutations that give rise to aberrant alternative splicing. Recently, several of these debilitating disorders have been shown to be amenable for ...splice-correcting oligonucleotides (SCOs) that modify splicing patterns and restore the phenotype in experimental models. However, translational approaches are required to transform SCOs into usable drug products. In this study, we present a new cell-penetrating peptide, PepFect14 (PF14), which efficiently delivers SCOs to different cell models including HeLa pLuc705 and mdx mouse myotubes; a cell culture model of Duchenne's muscular dystrophy (DMD). Non-covalent PF14-SCO nanocomplexes induce splice-correction at rates higher than the commercially available lipid-based vector Lipofectamine™ 2000 (LF2000) and remain active in the presence of serum. Furthermore, we demonstrate the feasibility of incorporating this delivery system into solid formulations that could be suitable for several therapeutic applications. Solid dispersion technique is utilized and the formed solid formulations are as active as the freshly prepared nanocomplexes in solution even when stored at an elevated temperatures for several weeks. In contrast, LF2000 drastically loses activity after being subjected to same procedure. This shows that using PF14 is a very promising translational approach for the delivery of SCOs in different pharmaceutical forms.
During the last 25 years, antibody-mediated rejection of the cardiac allograft has evolved from a relatively obscure concept to a recognized clinical complication in the management of heart ...transplant patients. Herein we report the consensus findings from a series of meetings held between 2010-2012 to develop a Working Formulation for the pathologic diagnosis, grading, and reporting of cardiac antibody-mediated rejection. The diagnostic criteria for its morphologic and immunopathologic components are enumerated, illustrated, and described in detail. Numerous challenges and unresolved clinical, immunologic, and pathologic questions remain to which a Working Formulation may facilitate answers.
This paper aims to clarify the genetic mechanism that is responsible for the accumulation of cannabigerol (CBG) in certain phenotypes of Cannabis sativa L. CBG is the direct precursor of the ...cannabinoids CBD, THC and CBC. Plants strongly predominant in CBG have been found in different fibre hemp accessions. Inbred offspring derived from one such individual were crossed with true breeding THC predominant- and CBD predominant plants, respectively. The segregations in the cross progenies indicate that CBG accumulation is due to the homozygous presence of a minimally functional allele, tentatively called B sub(0), at the single locus B that normally controls the conversion of CBG into THC (allele B sub(T)) and/or CBD (allele B sub(D)). The fact that CBG accumulating plants have so far been found in European fibre hemp populations that are generally composed of B sub(D)/B sub(D) plants, and the observation that the here investigated B sub(0) allele possesses a residual ability to convert small amounts of CBG into CBD, make it plausible that this B sub(0) is a mutation of normally functional B sub(D). Therefore, B sub(0) is considered as a member of the B sub(D) allelic series encoding a CBD synthase isoform with greatly weakened substrate affinity and/or catalytic capacity.
The mechanism that controls the proportion of cannabichromene (CBC), a potential pharmaceutical, in the cannabinoid fraction of Cannabis sativa L. is explored. As with tetrahydrocannabinol (THC) and ...cannabidiol (CBD), CBC is an enzymatic conversion product of the precursor cannabigerol (CBG). CBC is reported to dominate the cannabinoid fraction of juveniles and to decline with maturation. This ontogeny was confirmed in inbred lines with different mature chemotypes. A consistent CBC presence was found in early leaves from a diverse clone collection, suggesting that CBC synthase is encoded by a fixed locus. Morphological variants possessing a 'prolonged juvenile chemotype' (PJC), a substantial proportion of CBC persisting up to maturity, are presented. PJC is associated with a reduced presence of floral bracts, bracteoles, and capitate-stalked trichomes. Genetic factors causing these features were independent of the allelic chemotype locus B that was previously postulated and regulates THC and CBD synthesis and CBG accumulation. In contrast to previously described Cannabis chemotypes, the cannabinoid composition of PJCs showed plasticity in that reduced light levels increased the CBC proportion. The ability of PJC plants to enable the production of pharmaceutical raw material with high CBC purity is demonstrated.
To identify and prioritise uncertainties regarding epilepsy treatment from people with epilepsy, their carers and epilepsy clinicians.
Failure to acknowledge and address genuine treatment ...uncertainties has caused unnecessary iatrogenic harm. The authors define an uncertainty as a question that cannot be sufficiently answered by a systematic review of the literature. The database of the uncertainties of the effects of treatment (DUETs) is a collection of 'known unknowns' that enables patient-prioritised research.
The authors organised five separate focus groups (two consisting of clinicians, three of patients and carers) to garner questions on epilepsy treatment uncertainties; these yielded 398 potential research questions. Participants were asked to rank the questions in terms of importance. The authors then performed a thematic analysis.
Patients rated questions concerning cognitive drug side effects, managing the consequences of side effects and improving public awareness about the treatment of epilepsy through improved services as most important. For clinicians, the most important themes were treatment programmes for non-epileptic attack disorder (NEAD), concerns about side effects in utero and uncertainties regarding prescribing in pregnancy.
Patient uncertainties were often focussed on very practical considerations-how to take prescribed medication, access to services and how to minimise drug side effects. Clinicians' questions were also practical but clustered around 'the challenging consultation'-for example, NEAD, sudden unexplained death in epilepsy and prescribing in pregnancy. The authors have published the research questions on NHS Evidence and are working with them to identify those questions which represent genuine uncertainties. The authors encourage other clinicians to seek patient and carers' priorities in order to shape their research agenda.
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