HAGE, a cancer/testis antigen expressed at the protein level in a variety of cancers

The search for novel tumour antigens that are either uniquely expressed or over-expressed in a wide variety of tumours is still ongoing. Because of their expression in a broad spectrum of cancers and limited expression in normal tissues, cancer/testis antigens are considered to be potentially reliable targets for immunotherapy of cancer in general. The helicase antigen HAGE has been identified as a cancer/testis antigen. However, little is known about its expression in normal and cancer tissues. Using a newly developed antibody against HAGE, specific staining of its expression by immunohistochemistry was validated and optimised on murine tumours transfected to express the HAGE protein. The antibody was subsequently used to determine HAGE expression in normal human and cancer tissue microarrays. HAGE protein expression was confirmed in 75% (12/16) of carcinomas as compared to normal tissues, which either did not express HAGE at all or expressed HAGE at very low levels with the exception of testis. Interestingly, discrepancies were also found between mRNA analysis by real time quantitative PCR (RT-qPCR) and protein analysis by immunohistochemistry, emphasising the need to validate the expression of cancer/testis antigens at the protein level prior to the development of new vaccine strategies. HAGE is therefore proposed to be a valid candidate for designing a broad spectrum vaccine against cancer

Pregabalin silences oxaliplatin-activated sensory neurons to relieve cold allodynia

Oxaliplatin is a platinum-based chemotherapeutic agent that causes cold and mechanical allodynia in up to 90% of patients. Silent Nav1.8-positive nociceptive cold sensors have been shown to be unmasked by oxaliplatin, and this event has been causally linked to the development of cold allodynia. We examined the effects of pregabalin on oxaliplatin-evoked unmasking of cold sensitive neurons using mice expressing GCaMP-3 in all sensory neurons. Intravenous injection of pregabalin significantly ameliorates cold allodynia, while decreasing the number of cold sensitive neurons by altering their excitability and temperature thresholds. The silenced neurons are predominantly medium/large mechano-cold sensitive neurons, corresponding to the 'silent' cold sensors activated during neuropathy. Deletion of α2δ1 subunits abolished the effects of pregabalin on both cold allodynia and the silencing of sensory neurons. Thus, these results define a novel, peripheral inhibitory effect of pregabalin on the excitability of 'silent' cold-sensing neurons in a model of oxaliplatin-dependent cold allodynia.Significance StatementPregabalin is an analgesic drug in the clinic, that is supposed to act by blocking neurotransmitter release. Here we show that silent nociceptors that are activated by chemotherapeutic insults like oxaliplatin are silenced by pregabalin, which blocks the associated pain. This mode of action suggests that peripheral acting pregabalin-like drugs could be very useful for pain during chemotherapy, as they would have no CNS side effects - a problem for many patients with pregabalin. This novel effect of pregabalin is mediated by its interaction with the α2δ1 calcium channel subunit, but how this works is not yet understood

Fabrication of free standing collagen membranes by pulsed-electrophoretic deposition.

This work reports an important new development in the production of collagen membranes, based on pulsed electrophoretic deposition (P-EPD), suitable for a wide range of biomedical applications. Collagen membranes are of great interest as a biomaterial and in a range of other industries, though current production techniques suffer from limitations with scaling up, homogeneity, and complex shapes. P-EPD can be used to rapidly create detachable, large-area, homogeneous products with controlled thickness in a wide variety of shapes. We provide a new understanding of the influence of a range of parameters (pulse width, voltage, duty cycle, solvent additions) and their effects on membrane structure. Characterisation by AFM, SEM, and cryoSEM revealed the ability to produce dense, structurally defect-free membranes, and significantly, we show and discuss the ability to produce thicker membranes by sequential deposition without seeing a corresponding increase in cell electrical resistance. We anticipate this novel, rapid, and controllable method for the production of collagen membranes to be of interest for a wide range of fields.The authors wish to acknowledge the support of theEngineering and Physical Sciences Research Council(EPSRC)grants EP/K503009/1, EP/J500380/1, EP/L504920/1, EP/M506485/1, and EP/M508007/1,Geistlich Pharma AG, and the European ResearchCouncil(ERC)Advanced Grant 320598 3D-

Ancient Chinese methods are remarkably effective for the preparation of artemisinin-rich extracts of Qing Hao with potent antimalarial activity.

yesAncient Chinese herbal texts as far back as the 4th Century Zhou hou bei ji fang describe methods for the use of Qing Hao (Artemisia annua) for the treatment of intermittent fevers. Today, the A. annua constituent artemisinin is an important antimalarial drug and the herb itself is being grown and used locally for malaria treatment although this practice is controversial. Here we show that the ancient Chinese methods that involved either soaking, (followed by wringing) or pounding, (followed by squeezing) the fresh herb are more effective in producing artemisinin-rich extracts than the usual current method of preparing herbal teas from the dried herb. The concentrations of artemisinin in the extracts was up to 20-fold higher than that in a herbal tea prepared from the dried herb, but the amount of total artemisinin extracted by the Chinese methods was much less than that removed in the herbal tea. While both extracts exhibited potent in vitro activities against Plasmodium falciparum, only the pounded juice contained sufficient artemisinin to suppress parasitaemia in P. berghei infected mice. The implications of these results are discussed in the context of malaria treatment using A. annua infusions

Microplastics and synthetic particles ingested by deep-sea amphipods in six of the deepest marine ecosystems on Earth

Funding Funding for the laboratory work and analysis was from Newcastle University internal support. This work was supported by the 2007–2010 HADEEP project, funded by the Nippon Foundation (2009765188) and the Natural Environmental Research Council (NE/E007171/1). The 2011–2013 Kermadec Trench sampling was supported by the TOTAL Foundation (France) through the projects ‘Multi-disciplinary investigations of the deepest scavengers on Earth’ (2010–2012) and ‘Trench Connection’ (2013–2015). The Mariana samples were derived from the ‘FISH2017’ expedition (RV Shinyo-Maru SY1615) supported by the Tokyo University for Marine Science and Technology. Acknowledgements We thank the captain, crew and company of the research expeditions who assisted in the collection of the amphipods between 2008 and 2017, namely the Japanese Hakuho-Maru, Tansei Maru and Shinyo-Maru, the German Sonne and the RV Kaharoa in New Zealand. The assistance of David Whitaker and Peter McParlin from The School of Marine Science and Technology at Newcastle University are much appreciated. We are extremely grateful to Bob Keighley and Dan Parnaby at Shimadzu UK Limited for facilitating the FTIR analysis and access to their material database. We also thank Heather Stewart from the British Geological Survey for calculating the distances between trenches.Peer reviewedPublisher PD

Distribution, composition and functions of gelatinous tissues in deep-sea fishes

Many deep-sea fishes have a gelatinous layer, or subdermal extracellular matrix, below the skin or around the spine. We document the distribution of gelatinous tissues across fish families (approx. 200 species in ten orders), then review and investigate their composition and function. Gelatinous tissues from nine species were analysed for water content (96.53 ± 1.78% s.d.), ionic composition, osmolality, protein (0.39 ± 0.23%), lipid (0.69 ± 0.56%) and carbohydrate (0.61 ± 0.28%). Results suggest that gelatinous tissues are mostly extracellular fluid, which may allow animals to grow inexpensively. Further, almost all gelatinous tissues floated in cold seawater, thus their lower density than seawater may contribute to buoyancy in some species. We also propose a new hypothesis: gelatinous tissues, which are inexpensive to grow, may sometimes be a method to increase swimming efficiency by fairing the transition from trunk to tail. Such a layer is particularly prominent in hadal snailfishes (Liparidae); therefore, a robotic snailfish model was designed and constructed to analyse the influence of gelatinous tissues on locomotory performance. The model swam faster with a watery layer, representing gelatinous tissue, around the tail than without. Results suggest that the tissues may, in addition to providing buoyancy and low-cost growth, aid deep-sea fish locomotion. © 2017 The Authors

Fishes of the hadal zone including new species, in situ observations and depth records of Liparidae

AbstractObservations and records for fish exceeding 6000m deep are few and often spurious. Recent developments in accessing and sampling the hadal zone 6000–11,000m) have led to an acceleration in new findings in the deep subduction trenches, particularly in the Pacific Ocean. This study describes the discovery of two new species of snailfish (Liparidae) from the Mariana Trench; the ‘Mariana snailfish’ (6198–8076m) and the ‘Ethereal snailfish’ (7939–8145m). These new findings represent respectively the deepest known specimen caught with corroborating depth data, and the deepest fish seen alive. Further specimens and observations of the Kermadec Trench snailfish, Notoliparis kermadecensis, are also presented, as well as the first hadal records of Synaphobranchidae and Zoarcidae (6068 and 6145m respectively) and a depth extension for the Macrouridae (maximum depth now 7012m). Details of these new snailfish specimens caught by baited trap and behaviour observations filmed by baited cameras are presented. An updated assessment of fishes from hadal depths is also reported

The development of the Meaning in Life Index (MILI) and its relationship with personality and religious behaviours and beliefs among UK undergraduate students

The scales available for assessing meaning in life appear to be confounded with several related constructs, including purpose in life, satisfaction with life, and goal-directed behaviour. The Meaning in Life Index (MILI), a new instrument devised as a specific measure of meaning in life, was developed from responses to a pool of 22 items rated by a sample of 501 undergraduate students in Wales. The nine-item scale demonstrated sufficient face validity, internal consistency, and scale reliability to commend the instrument for future use. With respect to personality, the MILI scores were most strongly predicted by neuroticism (negatively), and less strongly by extraversion (positively) and psychoticism (negatively). With respect to several religious behavioural variables, those who attended church at least weekly returned significantly higher MILI scores than those who attended church less frequently. Intrinsic religiosity was the only orientation to be significantly associated with the MILI scale scores, although the magnitude of the association was smaller than anticipated. These results suggest that meaning in life is associated more strongly with individual differences in personality than with specific religious behaviours and attitudes. The implications of these results are discussed in terms of individual's personal values and attitudes that might underlie their experience of a meaning in life

Natural history study of glycan accumulation in large animal models of GM2 gangliosidoses

beta-hexosaminidase is an enzyme responsible for the degradation of gangliosides, glycans, and other glycoconjugates containing beta-linked hexosamines that enter the lysosome. GM2 gangliosidoses, such as Tay-Sachs and Sandhoff, are lysosomal storage disorders characterized by beta-hexosaminidase deficiency and subsequent lysosomal accumulation of its substrate metabolites. These two diseases result in neurodegeneration and early mortality in children. A significant difference between these two disorders is the accumulation in Sandhoff disease of soluble oligosaccharide metabolites that derive from N- and O-linked glycans. In this paper we describe our results from a longitudinal biochemical study of a feline model of Sandhoff disease and an ovine model of Tay-Sachs disease to investigate the accumulation of GM2/GA2 gangliosides, a secondary biomarker for phospholipidosis, bis-(monoacylglycero)-phosphate, and soluble glycan metabolites in both tissue and fluid samples from both animal models. While both Sandhoff cats and Tay-Sachs sheep accumulated significant amounts of GM2 and GA2 gangliosides compared to age-matched unaffected controls, the Sandhoff cats having the more severe disease, accumulated larger amounts of gangliosides compared to Tay-Sachs sheep in their occipital lobes. For monitoring glycan metabolites, we developed a quantitative LC/MS assay for one of these free glycans in order to perform longitudinal analysis. The Sandhoff cats showed significant disease-related increases in this glycan in brain and in other matrices including urine which may provide a useful clinical tool for measuring disease severity and therapeutic efficacy. Finally, we observed age-dependent increasing accumulation for a number of analytes, especially in Sandhoff cats where glycosphingolipid, phospholipid, and glycan levels showed incremental increases at later time points without signs of peaking. This large animal natural history study for Sandhoff and Tay-Sachs is the first of its kind, providing insight into disease progression at the biochemical level. This report may help in the development and testing of new therapies to treat these disorders