No / Tissue stem cells and germ line or embryonic stem cells were shown to have reduced oxidative metabolism, which was proposed to be an adaptive mechanism to reduce damage accumulation caused by reactive oxygen species. However, an alternate explanation is that stem cells are less dependent on specialized cytoplasmic functions compared with differentiated cells, therefore, having a high nuclear-to-cytoplasmic volume ratio and consequently a low mitochondrial content. To determine whether stem cells rely or not on mitochondrial respiration, we selectively ablated the electron transport chain in the basal layer of the epidermis, which includes the epidermal progenitor/stem cells (EPSCs). This was achieved using a loxP-flanked mitochondrial transcription factor A (Tfam) allele in conjunction with a keratin 14 Cre transgene. The epidermis of these animals (TfamEKO) showed a profound depletion of mitochondrial DNA and complete absence of respiratory chain complexes. However, despite a short lifespan due to malnutrition, epidermal development and skin barrier function were not impaired. Differentiation of epidermal layers was normal and no proliferation defect or major increase of apoptosis could be observed. In contrast, mice with an epidermal ablation of prohibitin-2, a scaffold protein in the inner mitochondrial membrane, displayed a dramatic phenotype observable already in utero, with severely impaired skin architecture and barrier function, ultimately causing death from dehydration shortly after birth. In conclusion, we here provide unequivocal evidence that EPSCs, and probably tissue stem cells in general, are independent of the mitochondrial respiratory chain, but still require a functional dynamic mitochondrial compartment.

Yes / Polysialic acid (polySia), an α-2,8-glycosidically linked polymer of sialic acid, is a developmentally regulated posttranslational modification predominantly found on NCAM (neuronal cell adhesion molecule). Whilst high levels are expressed during development, peripheral adult organs do not express polySia-NCAM. However, tumours of neural crest-origin re-express polySia-NCAM: its occurrence correlates with aggressive and invasive disease and poor clinical prognosis in different cancer types, notably including small cell lung cancer (SCLC), pancreatic cancer and neuroblastoma. In neuronal development, polySia-NCAM biosynthesis is catalysed by two polysialyltransferases, ST8SiaII and ST8SiaIV, but it is ST8SiaII that is the prominent enzyme in tumours. The aim of this study was to determine the effect of ST8SiaII inhibition by a small molecule on tumour cell migration, utilising cytidine monophosphate (CMP) as a tool compound. Using immunoblotting we showed that CMP reduced ST8iaII-mediated polysialylation of NCAM. Utilizing a novel HPLC-based assay to quantify polysialylation of a fluorescent acceptor (DMB-DP3), we demonstrated that CMP is a competitive inhibitor of ST8SiaII (Ki = 10 μM). Importantly, we have shown that CMP causes a concentration-dependent reduction in tumour cell-surface polySia expression, with an absence of toxicity. When ST8SiaII-expressing tumour cells (SH-SY5Y and C6-STX) were evaluated in 2D cell migration assays, ST8SiaII inhibition led to significant reductions in migration, while CMP had no effect on cells not expressing ST8SiaII (DLD-1 and C6-WT). The study demonstrates for the first time that a polysialyltransferase inhibitor can modulate migration in ST8SiaII-expressing tumour cells. We conclude that ST8SiaII can be considered a druggable target with the potential for interfering with a critical mechanism in tumour cell dissemination in metastatic cancers. / Yorkshire Cancer Research; EPSRC; Association for International Cancer Research; Jordanian Government PhD scholarship

No / We present a series of iterative methods to examine the problems associated with summed probability functions (SPFs) based on archaeological radiocarbon data. As a case study we use an SPF generated from a substantial radiocarbon data-set from the Irish Later Bronze and Iron Ages. We use simple numerical methods to show that real patterns can be deciphered from SPFs that can be used to trace and evaluate patterns of change. However, our results suggest that SPFs should not be used as a simple index of past human activity. / This research forms part of the project ‘Mobility, Climate and Culture: Re-modelling the Irish Iron Age’, funded by the British Academy through their BARDA scheme. Preliminary data collection was conducted as part of a pilot project funded by the Heritage Council of Ireland.

No / The growing demand for high-quality middle distillates is increasing worldwide, whereas the demand for low-value oil products, such as heavy oils and residues, is decreasing. Thus, maximizing the production of more liquid distillates of very high quality is of immediate interest to refiners. At the same time, environmental legislation has led to more strict specifications of petroleum derivatives. Hydrotreatment (HDT) of crude oil is one of the most challenging tasks in the petroleum refining industry, which has not been reported widely in the literature. In this work, crude oil was hydrotreated upon a commercial cobalt¿molybdenum on alumina (Co¿Mo/¿-Al2O3) catalyst presulfided at specified conditions. Detailed pilot-plant experiments were conducted in a continuous-flow isothermal trickle-bed reactor (TBR), and the main hydrotreating reactions were hydrodesulfurization (HDS), hydrodenitrogenation (HDN), hydrodeasphaltenization (HDAs), and hydrodemetallization (HDM), which includes hydrodevanadization (HDV) and hydrodenickelation (HDNi). The reaction temperature (T), the hydrogen pressure (P), and the liquid hourly space velocity (LHSV) were varied with certain ranges, with constant hydrogen to oil (H2/Oil) ratio. The effects of T, P, and LHSV on the conversion of sulfur, nitrogen, vanadium, nickel, and asphaltene were studied. The results showed that high T and P and low LHSV in HDS, HDN, HDV, HDNi, and HDAs of crude oil improve the sulfur (S), nitrogen (N), metals [vanadium (V) and nickel (Ni)], and asphaltene (Asph) conversion. The hydrotreated crude oil has been distilled into the following fractions: light naphtha (LN), heavy naphtha (HN), heavy kerosene (HK), light gas oil (LGO), and reduced crude residue (RCR), to compare the yield of these fractions produced by distillation after the HDT process to those produced by conventional methods (i.e., HDT of each fraction separately after the distillation). The yield of the middle distillate showed greater yield compared to the middle distillate produced by conventional methods. The properties of RCR produced using both methods are also discussed.

This work presents a technique for shape modelling of cylindrical and spherical tablets subject to compression. This technique is based on the use of partial differential equations (PDEs), the biharmonic equation in particular. The deformation of the compressed elastic-plastic tablet of both shapes was obtained using the existing contact models found in literature. The mathematical properties of the biharmonic equation have been exploited to achieve simple mathematical expressions characterising the shape of the distorted tablet. Thus, the height, radius and contact area of both configurations due to uniaxial compression are represented by analytic expressions relating the coefficients associated with the solution of the biharmonic equation. The results obtained from the PDE-based simulation are compared with the theoretical ones. It is found that the analytic solution of the elliptic PDE can be utilised to represent the physical changes of the deformed object.

This paper considers a study of the thermo-elastic behaviour of a disc brake during heavy braking. The work is concerned with working towards developing design advice that provides uniform heating of the disc, and equally important, even dissipation of heat from the disc blade. The material presented emanates from a combination of modeling, on-vehicle testing but mainly laboratory observations and subsequent investigations. The experimental work makes use of a purpose built high speed brake dynamometer which incorporates the full vehicle suspension for controlled simulation of the brake and vehicle operating conditions. Advanced instrumentation allows dynamic measurement of brake pressure fluctuations, disc surface temperature and discrete vibration measurements. Disc run-out measurements using non-contacting displacement transducers show the disc taking up varying orders of deformation ranging from first to third order during high speed testing. This surface interrogation during braking identifies disc deformation including disc warping, 'ripple' and the effects of 'hot spotting'. The mechanical measurements are complemented by thermal imaging of the brake, these images showing the vane and vent patterns on the surface of the disc. The results also include static surface scanning, or geometry analysis, of the disc which is carried out at appropriate stages during testing. The work includes stress relieving of finished discs and subsequent dynamometer testing. This identifies that in-service stress relieving, due to high heat input during braking, is a strong possibility for the cause of disc 'warping'. It is also seen that an elastic wave is established during a braking event, the wave disappearing on release of the brake.

No / Bone morphogenetic protein (BMP) signaling plays a key role in the control of skin development and postnatal remodeling by regulating keratinocyte proliferation, differentiation, and apoptosis. To study the role of BMPs in wound-induced epidermal repair, we used transgenic mice overexpressing the BMP downstream component Smad1 under the control of a K14 promoter as an in vivo model, as well as ex vivo and in vitro assays. K14-caSmad1 (transgenic mice overexpressing a constitutively active form of Smad1 under K14 promoter) mice exhibited retarded wound healing associated with significant inhibition of proliferation and increased apoptosis in healing wound epithelium. Furthermore, microarray and quantitative real-time reverse-transcriptase-PCR (qRT-PCR) analyses revealed decreased expression of a number of cytoskeletal/cell motility-associated genes including wound-associated keratins (Krt16, Krt17) and Myosin VA (Myo5a), in the epidermis of K14-caSmad1 mice versus wild-type (WT) controls during wound healing. BMP treatment significantly inhibited keratinocyte migration ex vivo, and primary keratinocytes of K14-caSmad1 mice showed retarded migration compared with WT controls. Finally, small interfering RNA (siRNA)-mediated silencing of BMPR-1B in primary mouse keratinocytes accelerated cell migration and was associated with increased expression of Krt16, Krt17, and Myo5a compared with controls. Thus, this study demonstrates that BMPs inhibit keratinocyte proliferation, cytoskeletal organization, and migration in regenerating skin epithelium during wound healing, and raises a possibility for using BMP antagonists for the management of chronic wounds.

Yes / Purpose. A recent study suggested that updated spectacles could increase falls rate in older people. We hypothesized that this may be due to changes in spectacle magnification and this study assessed the effects of spectacle magnification on adaptive gait. Methods. Adaptive gait and visual function was measured in 10 older adults (mean age 77.1 ¿ 4.3 years) with the participants¿ optimal refractive correction and when blurred with +1.00DS, +2.00DS, -1.00DS and -2.00DS lenses. Adaptive gait measurements for the lead and trail foot included foot position before the step, toe clearance of the step edge and foot position on the step. Vision measurements included visual acuity, contrast sensitivity and stereoacuity. Results. The blur lenses led to equal decrements in visual acuity and stereoacuity for the +1.00DS and -1.00DS and the +2.00DS and -2.00DS lenses. However, they had very different effects on adaptive gait compared to the optimal correction: Positive blur lenses led to an increased distance of the feet from the step, increased vertical toe clearance and reduced distance of the lead heel position on the step. Negative lenses led to the opposite of these changes. Conclusion. The adaptive gait changes did not mirror the effects of blur on vision, but were driven by the magnification changes of the lenses. Steps appear closer and larger with positive lenses and further away and smaller with negative ones. Magnification likely explains the mobility problems some older adults have with updated spectacles and after cataract surgery. / Federation of Ophthalmic and Dispensing Opticians

Yes / Background: Descending kerbs during locomotion involves the regulation of appropriate foot placement before the kerb-edge and foot clearance over it. It also involves the modulation of gait output to ensure the body-mass is safely and smoothly lowered to the new level. Previous research has shown that vision is used in such adaptive gait tasks for feedforward planning, with vision from the lower visual field (lvf) used for online updating. The present study determined when lvf information is used to control/update locomotion when stepping from a kerb. Methodology/Principal Findings: 12 young adults stepped down a kerb during ongoing gait. Force sensitive resistors (attached to participants' feet) interfaced with an high-speed PDLC 'smart glass' sheet, allowed the lvf to be unpredictably occluded at either heel-contact of the penultimate or final step before the kerb-edge up to contact with the lower level. Analysis focussed on determining changes in foot placement distance before the kerb-edge, clearance over it, and in kinematic measures of the step down. Lvf occlusion from the instant of final step contact had no significant effect on any dependant variable (p>0.09). Occlusion of the lvf from the instant of penultimate step contact had a significant effect on foot clearance and on several kinematic measures, with findings consistent with participants becoming uncertain regarding relative horizontal location of the kerb-edge. Conclusion/Significance: These findings suggest concurrent feedback of the lower limb, kerb-edge, and/or floor area immediately in front/below the kerb is not used when stepping from a kerb during ongoing gait. Instead heel-clearance and pre-landing-kinematic parameters are determined/planned using lvf information acquired in the penultimate step during the approach to the kerb-edge, with information related to foot placement before the kerb-edge being the most salient.

No / This communication reports a novel solvent free method to generate and stabilise the triclinic form of artemisinin. We show that the stability of the triclinic form obtained by high temperature extrusion is greater than that of material made using a solvent based technique.