Batubara, A.; Carolan, V.A.; Loadman, Paul M.; Sutton, Chris W.; Shnyder, Steven D.; Clench, M.R. (2015-07-15)
RATIONALE: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a low molecular weight drug of the flavonoid group, which has an anti-vascular effect in tumours causing endothelial cell apoptosis and activation of cytokines. Flavonoid-based compounds have been reported to lead to an upregulation in the expression of lysophosphatidylcholines (LPC)-type lipids in solid tumours. A study employing TLC/MALDI-MS and MALDI-MS imaging to examine LS174T colorectal adenocarcinoma xenografts following administration of DMXAA has been conducted into this effect. METHODS: LS174T colorectal adenocarcinoma xenografts grown in male immune-deficient mice were treated with 27.5 mg/kg DMXAA. The control (before treatment) and 4 h and 24 h post-treatment tumours were excised and divided into two. MALDI-MS imaging experiments were carried out on 12 microm cryosections sections taken from one half of the tumours and from the other half the lipids were extracted and analysed by TLC/MALDI-MS. These experiments were carried out in triplicate. RESULTS: Statistical analysis of the MALDI-MS imaging data set indicated an increased amount of LPC in the 24 h post-treated sample and a decreased amount of PC in the 24 h post-treated sample, compared with the 4 h post-treated sample and the control. These effects were confirmed by the TLC/MALDI-MS data. The lipid extracts were separated into six spots on the TLC plate. These were identified as arising from different lipids classes, i.e. LPC, sphingomyelins (SM), phosphatidylcholines (PC) and phosphatidylethanolamines (PE). The TLC/MALDI-MS data indicated that LPC were highly expressed in the 4 h and 24 h post-treated tumour samples compared with the control. Examination of the mass spectrometric images confirms this increase and demonstrates additionally that the increase in the signals arising from LPC appears to be localised primarily within the central areas of the xenograft. CONCLUSIONS: An increase in expression of LPC lipids in solid tumours treated with DMXAA has been demonstrated and shown to be localised in the central area of the tumour.
Amrani, S.; Nacer, A.; Noureddine, N.E.; Seaward, Mark R.D. (2015-04)
Despite more than two centuries of almost uninterrupted surveys and studies of Algerian lichenology, the history and lichen diversity of Algeria are still poorly understood. During the preparation of a forthcoming checklist of Algerian lichens it was considered necessary to provide the present historical overview of lichenological exploration of the country from 1799 to 2013, supported by a reasonably comprehensive annotated bibliography of 171 titles.
Here, we studied how epithelial energy metabolism impacts overall skin development by selectively deleting intraepithelial mtDNA in mice by ablating a key maintenance factor (TfamEKO), which induces loss of function of the electron transport chain (ETC). Quantitative (immuno)histomorphometry demonstrated that TfamEKO mice showed significantly reduced hair follicle (HF) density and morphogenesis, fewer intrafollicular keratin15+ epithelial progenitor cells, increased apoptosis, and reduced proliferation. TfamEKO mice also displayed premature entry into (aborted) HF cycling by apoptosis-driven HF regression (catagen). Ultrastructurally, TfamEKO mice exhibited severe HF dystrophy, pigmentary abnormalities, and telogen-like condensed dermal papillae. Epithelial HF progenitor cell differentiation (Plet1, Lrig1 Lef1, and β-catenin), sebaceous gland development (adipophilin, Scd1, and oil red), and key mediators/markers of epithelial–mesenchymal interactions during skin morphogenesis (NCAM, versican, and alkaline phosphatase) were all severely altered in TfamEKO mice. Moreover, the number of mast cells, major histocompatibility complex class II+, or CD11b+ immunocytes in the skin mesenchyme was increased, and essentially no subcutis developed. Therefore, in contrast to their epidermal counterparts, pilosebaceous unit stem cells depend on a functional ETC. Most importantly, our findings point toward a frontier in skin biology: the coupling of HF keratinocyte mitochondrial function with the epithelial–mesenchymal interactions that drive overall development of the skin and its appendages.
Recently, nanoscale metal-organic frameworks (NMOFs) have started to be developed as a promising platform for bioimaging and drug delivery. On the other hand, combination therapies using multiple approaches are demonstrated to achieve much enhanced efficacy. Herein, we report, for the first time, core-shell nanoparticles consisting of a photodynamic therapeutic (PDT) agent and a MOF shell while simultaneously carrying a chemotherapeutic drug for effective combination therapy. In this work, core-shell nanoparticles of zeolitic-imadazolate framework-8 (ZIF-8) as shell embedded with graphitic carbon nitride (g-C3N4) nanosheets as core are fabricated by growing ZIF-8 in the presence of g-C3N4 nanosheets. Doxorubicin hydrochloride (DOX) is then loaded into the ZIF-8 shell of the core-shell nanoparticles. The combination of the chemotherapeutic effects of DOX and the PDT effect of g-C3N4 nanosheets can lead to considerably enhanced efficacy. Furthermore, the red fluorescence of DOX and the blue fluorescence of g-C3N4 nanosheets provide the additional function of dual-color imaging for monitoring the drug release process.
T-type Ca2+ channels are a distinct family of low voltage-activated Ca2+ channels which serve many roles in different tissues. Several studies have implicated them, for example, in the adaptive responses to chronic hypoxia in the cardiovascular and endocrine systems. Hydrogen sulfide (H2S) was more recently discovered as an important signalling molecule involved in many functions, including O2 sensing. Since ion channels are emerging as an important family of target proteins for modulation by H2S, and both T-type Ca2+ channels and H2S are involved in cellular responses to hypoxia, we have investigated whether recombinant and native T-type Ca2+ channels are a target for modulation by H2S. Using patch-clamp electrophysiology, we demonstrate that the H2S donor, NaHS, selectively inhibits Cav3.2 T-type Ca2+ channels heterologously expressed in HEK293 cells, whilst Cav3.1 and Cav3.3 channels were unaffected. Sensitivity of Cav3.2 channels to H2S required the presence of the redox-sensitive extracellular residue H191, which is also required for tonic binding of Zn2+ to this channel. Chelation of Zn2+ using TPEN prevented channel inhibition by H2S. H2S also selectively inhibited native T-type channels (primarily Cav3.2) in sensory dorsal root ganglion neurons. Our data demonstrate a novel target for H2S regulation, the T-type Ca2+ channel Cav3.2. Results have important implications for the proposed pro-nociceptive effects of this gasotransmitter. Implications for the control of cellular responses to hypoxia await further study.
Ali, Esam M.A.; Edwards, Howell G.M.; Cox, R. (2015)
A novel dispersive system operating at 1064-nm excitation and coupled with transfer electron InGaAs photocathode and electron bombardment CCD technology has been evaluated for the analysis of drugs of abuse and explosives. By employing near-IR excitation at 1064-nm excitation wavelength has resulted in a significant damping of the fluorescence emission compared to 785-nm wavelength excitation. Spectra of street samples of drugs of abuse and plastic explosives, which usually fluoresce with 785-nm excitation, are readily obtained in situ within seconds through plastic packaging and glass containers using highly innovative detector architecture based upon a transfer electron (TE) photocathode and electron bombarded gain (EB) technology that allowed the detection of NIR radiation at 1064nm without fluorescence interference. This dispersive near-IR Raman system has the potential to be an integral part in the armoury of the forensic analyst as a non-destructive tool for the in-situ analysis of drugs of abuse and explosives. Copyright (c) 2015 John Wiley & Sons, Ltd.
Adnan, X.; Suheimat, M.; Efron, N.; Edwards, K.; Pritchard, N.; Mathur, A.; Mallen, Edward A.H.; Atchison, D.A. (2015)
This is a comprehensive study of a large range of biometric and optical parameters in people with type 1 diabetes. The parameters of 74 people with type 1 diabetes and an age matched control group were assessed. Most of the people with diabetes had low levels of neuropathy, retinopathy and nephropathy. Marginal or no significant differences were found between groups for corneal shape, corneal thickness, pupil size, and pupil decentrations. Relative to the control group, the diabetes group demonstrated smaller anterior chamber depths, more curved lenses, greater lens thickness and lower lens equivalent refractive index. While the optics of diabetic eyes make them appear as older eyes than those of people of the same age without diabetes, the differences did not increase significantly with age. Age-related changes in the optics of the eyes of people with diabetes need not be accelerated if the diabetes is well controlled.
Schmidtmann, G.; Logan, Andrew J.; Kennedy, Graeme J.; Gordon, G.E.; Loffler, G. (2015-04)
Humans manipulate objects chiefly within their lower visual field, a consequence of upright posture and the anatomical position of hands and arms.This study tested the hypothesis of enhanced sensitivity to a range of stimuli within the lower visual field. Following current models of hierarchical processing within the ventral steam, discrimination sensitivity was measured for orientation, curvature, shape (radial frequency patterns), and faces at various para-central locations (horizontal, vertical, and main diagonal meridians) and eccentricities (5° and 10°). Peripheral sensitivity was isotropic for orientation and curvature. By contrast, observers were significantly better at discriminating shapes throughout the lower visual field compared to elsewhere. For faces, however, peak sensitivity was found in the left visual field, corresponding to the right hemispheric localization of human face processing. Presenting head outlines without any internal features (e.g., eyes, mouth) recovered the lower visual field advantage found for simple shapes. A lower visual field preference for the shape of an object, which is absent for more localized information (orientation and curvature) but also for more complex objects (faces), is inconsistent with a strictly feed-forward model and poses a challenge for multistage models of object perception. The distinct lower visual field preference for contour shapes is, however, consistent with an asymmetry at intermediate stages of visual processing, which may play a key role in representing object characteristics that are particularly relevant to visually guided actions.
After more than 3500 years of occupation in the Neolithic and Bronze Age, the many lake-dwellings’ around the Circum-Alpine region ‘suddenly’ came to an end. Throughout that period alternating phases of occupation and abandonment illustrate how resilient lacustrine populations were against change: cultural/environmental factors might have forced them to relocate temporarily, but they always returned to the lakes. So why were the lake-dwellings finally abandoned and what exactly happened towards the end of the Late Bronze Age that made the lake-dwellers change their way of life so drastically? The new research presented here draws upon the results of a four-year-long project dedicated to shedding light on this intriguing conundrum. Placing a particular emphasis upon the Bronze Age, a multidisciplinary team of researchers has studied the lake-dwelling phenomenon inside out, leaving no stones unturned, enabling identification of all possible interactive socio-economic and environmental factors that can be subsequently tested against each other to prove (or disprove) their validity. By re-fitting the various pieces of the jigsaw a plausible, but also rather unexpected, picture emerges.
The epidermal differentiation program is regulated at several levels including signaling pathways, lineage-specific transcription factors, and epigenetic regulators that establish well-coordinated process of terminal differentiation resulting in formation of the epidermal barrier. The epigenetic regulatory machinery operates at several levels including modulation of covalent DNA/histone modifications, as well as through higher-order chromatin remodeling to establish long-range topological interactions between the genes and their enhancer elements. Epigenetic regulators exhibit both activating and repressive effects on chromatin in keratinocytes (KCs): whereas some of them promote terminal differentiation, the others stimulate proliferation of progenitor cells, as well as inhibit premature activation of terminal differentiation-associated genes. Transcription factor-regulated and epigenetic mechanisms are highly connected, and the p63 transcription factor has an important role in the higher-order chromatin remodeling of the KC-specific gene loci via direct control of the genome organizer Satb1 and ATP-dependent chromatin remodeler Brg1. However, additional efforts are required to fully understand the complexity of interactions between distinct transcription factors and epigenetic regulators in the control of KC differentiation. Further understanding of these interactions and their alterations in different pathological skin conditions will help to progress toward the development of novel approaches for the treatment of skin disorders by targeting epigenetic regulators and modulating chromatin organization in KCs.
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