Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells

The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndrome (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). We investigated the functional effects of SF3B1 disruption in myeloid cell lines: SF3B1 knockdown resulted in growth inhibition, cell cycle arrest and impaired erythroid differentiation and deregulation of many genes and pathways, including cell cycle regulation and RNA processing. MDS is a disorder of the hematopoietic stem cell and we thus studied the transcriptome of CD34 + cells from MDS patients with SF3B1 mutations using RNA sequencing. Genes significantly differentially expressed at the transcript andor exon level in SF3B1 mutant compared with wild-type cases include genes that are involved in MDS pathogenesis (ASXL1 and CBL), iron homeostasis and mitochondrial metabolism (ALAS2, ABCB7 and SLC25A37) and RNA splicingprocessing (PRPF8 and HNRNPD). Many genes regulated by a DNA damage-induced BRCA1-BCLAF1-SF3B1 protein complex showed differential expressionsplicing in SF3B1 mutant cases. This is the first study to determine the target genes of SF3B1 mutation in MDS CD34 + cells. Our data indicate that SF3B1 has a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processespathways, many of which are relevant to the known RARS pathophysiology, suggesting a causal link.

UV dosimetry for solar water disinfection (SODIS) carried out in different plastic bottles and bags

Solar water disinfection (SODIS) is a well-established inexpensive means of water disinfection in developing countries, but lacks an indicator to illustrate its end-point. A study of the solar UV dosage required for SODIS, in order to achieve a bacteria concentration below the detection limit for: Escherichia coli, Enterococcus spp. and Clostridium perfringens, in water in PET bottles, PE and PE/EVA bags showed disinfection to be most efficient in PE bags, with a solar UV (290–385 nm) dose of 389 kJ m−2 required. In parallel to the disinfection experiments, a range of polyoxometalate, semiconductor photocatalysis and photodegradable dye-based solar UV dosimeter indicators were tested under the same solar UV irradiation conditions. All three types of dosimeter produced indicators that largely and significantly change colour upon exposure to 389 kJ m−2 solar UV; further indicators are reported which change colour at higher doses and hence would be suitable for the less efficient SODIS containers tested. All indicators tested were robust, easy to use and inexpensive so as not to add significantly to the attractive low cost of SODIS. Furthermore, whilst semiconductor photocatalyst and photodegradable dye based indicators are disposable, one-use systems, the polyoxometalate based indicators recover colour in the dark overnight, allowing them to be reused, and hence further decreasing the cost of using indicators during the implementation of the SODIS method.

CaV3.1 T-Type Ca2+ Channels Contribute to Myogenic Signalling in Rat Retinal Arterioles

Purpose: Although L-type Ca2+ channels are known to play a key role in the myogenic reactivity of retinal arterial vessels, the involvement of other types of voltage-gated Ca2+ channels in this process remains unknown. In the present study we have investigated the contribution of T-type Ca2+ channels to myogenic signalling in arterioles of the rat retinal microcirculation.

Methods: Confocal immunolabelling of wholemount preparations was used to investigate the localisation of CaV3.1-3 channels in retinal arteriolar smooth muscle cells. T-type currents and the contribution of T-type channels to myogenic signalling were assessed by whole-cell patch-clamp recording and pressure myography of isolated retinal arteriole segments.

Results: Strong immunolabelling for CaV3.1 was observed on the plasma membrane of retinal arteriolar smooth muscle cells. In contrast, no expression of CaV3.2 or CaV3.3 could be detected in retinal arterioles, although these channels were present on glial cell end feet surrounding the vessels and retinal ganglion cells, respectively. TTA-A2 sensitive T-type currents were recorded in retinal arteriolar myocytes with biophysical properties distinct from those of the L-type currents present in these cells. Inhibition of T-type channels using TTA-A2 or ML-218 dilated isolated, myogenically active, retinal arterioles.

Conclusions: CaV3.1 T-type Ca2+ channels are functionally expressed on arteriolar smooth muscle cells of retinal arterioles and play an important role in myogenic signalling in these vessels. The work has important implications concerning our understanding of the mechanisms controlling blood flow autoregulation in the retina and its disruption during ocular disease.

Calibration of BAS-TR image plate response to high energy (3-300 MeV) carbon ions

The paper presents the calibration of Fuji BAS-TR image plate (IP) response to high energy carbon ions of different charge states by employing an intense laser-driven ion source, which allowed access to carbon energies up to 270 MeV. The calibration method consists of employing a Thomson parabola spectrometer to separate and spectrally resolve different ion species, and a slotted CR-39 solid state detector overlayed onto an image plate for an absolute calibration of the IP signal. An empirical response function was obtained which can be reasonably extrapolated to higher ion energies. The experimental data also show that the IP response is independent of ion charge states.

Beamed neutron emission driven by laser accelerated light ions

Highly anisotropic, beam-like neutron emission with peak flux of the order of 10^9 n/sr was obtained from light nuclei reactions in a pitcher–catcher scenario, by employing MeV ions driven by subpetawatt laser. The spatial profile of the neutron beam, fully captured for the first time by employing a CR39 nuclear track detector, shows a FWHMdivergence angle of ~70 deg, with a peak flux nearly an order of magnitude higher than the isotropic component elsewhere. The observed beamed flux of neutrons is highly favourable for a wide range of applications, and indeed for further transport and moderation to thermal energies. A systematic study employing various combinations of pitcher–catcher materials indicates the dominant reactions being d(p, n+p)1Hand d(d,n)3He. Albeit insufficient cross-section data are available for modelling, the observed anisotropy in the neutrons’ spatial and spectral profiles are most likely related to the directionality and high energy of the projectile ions.