Preliminary findings on the paleomicrobiological study of 400 naturally mummified human remains from upper Nubia

We present 400 mummies excavated from two early Christian burial sites at Kulubnarti, between the 2nd and 3rd cataracts of the Nile in Northern Sudan, prior to the flooding caused by the Aswan Dam. One site was on an island in the Nile dated from 550-750 AD. The other was on the Nile western bank and was in use from c.750-1500 AD. Due to the exceptionally dry climate many of the remains were naturally mummified. Analysis of diet, via chemical examination of hair and of coprolites, had indicated possible deficiencies in vitamins B6, B12, folacin and vitamin C, suggesting iron deficiency. The presence of criba orbitalia, a pathological lesion of the roof of the eye socket (orbit), also suggests iron deficiency anaemia but may also be caused by inflammation. Anaemia is found in several infectious diseases, and severe iron deficiency increases susceptibility to disease. Tuberculosis was widespread in ancient and Roman Egypt, and there was historical contact with Upper Nubia via the Nile. The presence of Acacia pollen in coprolites suggested the possibility of leishmaniasis, as these trees are the habitat of the sand fly vector of the protozoan pathogen. The area is known today for the many infectious diseases afflicting its inhabitants, but were these present in antiquity? We have, therefore, undertaken a study of diseases in Kulubnarti. Initially we looked for evidence of tuberculosis and leishmaniasis. We anticipate shortly broadening the search to include brucellosis, malaria, hepatitis and West Nile fever viruses. Schistosomasis was considered but at this level the Nile flows swiftly and the intermediate host snail is not present so was at present not ocnsidered. Ribs were examined for Mycobacterium tuberculosis DNA, using nested PCR targeting a123 bp sequence on the repetitive element IS6110. Material from the heads of the long bones, possible bone marrow, was examined for Leishmania species using a PCR which amplifies a 119 bp-conserved region of the minicircle kinetoplast DNA. Initial results indicate that M. tuberculosis and Leishmania sp were present in both populations

Phosphorothioate oligonucleotides, suramin and heparin inhibit DNA-dependent protein kinase activity

Phosphorothioate oligonucleotides and suramin bind to heparin binding proteins including DNA polymerases, and inhibit their functions. In the present study, we report inhibition of DNA-dependent protein kinase activity by phosphorothioate oligonucleotides, suramin and heparin. Inhibitory effect of phosphorothioate oligonucleotides on DNA-dependent protein kinase activity was increased with length and reached a plateau at 36-mer. The base composition of phosphorothioate oligonucleotides did not affect the inhibitory effect. The inhibitory effect by phosphorothioate oligodeoxycytidine 36-mer can be about 200-fold greater than that by the phosphodiester oligodeoxycytidine 36-mer. The inhibitory effect was also observed with purified DNA-dependent protein kinase, which suggests direct interaction between DNA-dependent protein kinase and phosphorothioate oligonucleotides. DNA-dependent protein kinase will have different binding positions for double-stranded DNA and phosphorothioate oligodeoxycytidine 36-mer because they were not competitive in DNA-dependent protein kinase activation. Suramin and heparin inhibited DNA-dependent protein kinase activity with IC50 of 1.7 μM and 0.27 μg ml−1 respectively. DNA-dependent protein kinase activities and DNA double-stranded breaks repair in cultured cells were significantly suppressed by the treatment with suramin in vivo. Our present observations suggest that suramin may possibly result in sensitisation of cells to ionising radiation by inactivation of DNA-dependent protein kinase and the impairment of double-stranded breaks repair

Ephrin-A5 and EphA5 Interaction Induces Synaptogenesis during Early Hippocampal Development

Synaptogenesis is a fundamental step in neuronal development. For spiny glutamatergic synapses in hippocampus and cortex, synaptogenesis involves adhesion of pre and postsynaptic membranes, delivery and anchorage of pre and postsynaptic structures including scaffolds such as PSD-95 and NMDA and AMPA receptors, which are glutamate-gated ion channels, as well as the morphological maturation of spines. Although electrical activity-dependent mechanisms are established regulators of these processes, the mechanisms that function during early development, prior to the onset of electrical activity, are unclear. The Eph receptors and ephrins provide cell contact-dependent pathways that regulate axonal and dendritic development. Members of the ephrin-A family are glycosyl-phosphatidylinositol-anchored to the cell surface and activate EphA receptors, which are receptor tyrosine kinases.Here we show that ephrin-A5 interaction with the EphA5 receptor following neuron-neuron contact during early development of hippocampus induces a complex program of synaptogenic events, including expression of functional synaptic NMDA receptor-PSD-95 complexes plus morphological spine maturation and the emergence of electrical activity. The program depends upon voltage-sensitive calcium channel Ca2+ fluxes that activate PKA, CaMKII and PI3 kinase, leading to CREB phosphorylation and a synaptogenic program of gene expression. AMPA receptor subunits, their scaffolds and electrical activity are not induced. Strikingly, in contrast to wild type, stimulation of hippocampal slices from P6 EphA5 receptor functional knockout mice yielded no NMDA receptor currents.These studies suggest that ephrin-A5 and EphA5 signals play a necessary, activity-independent role in the initiation of the early phases of synaptogenesis. The coordinated expression of the NMDAR and PSD-95 induced by eprhin-A5 interaction with EphA5 receptors may be the developmental switch that induces expression of AMPAR and their interacting proteins and the transition to activity-dependent synaptic regulation

Not Quite Right: Representations of Eastern Europeans in ECJ Discourse

Although the increasing responsiveness of the Court of Justice of the European Union (the ‘ECJ’) jurisprudence to western Member States’ concerns regarding Central and Eastern European (‘CEE’) nationals’ mobility has garnered academic attention, ECJ discourse has not been scrutinised for how it approaches the CEE region or CEE movers. Applying postcolonial theory, this article seeks to fill this gap and to explore whether there are any indications that ECJ discourse is in line with the historical western-centric inferiorisation of the CEE region. A critical discourse analysis of a set of ECJ judgments and corresponding Advocate General opinions pertaining to CEE nationals illustrates not only how the ECJ adopts numerous discursive strategies to maintain its authority, but also how it tends to prioritise values of the western Member States, while overlooking interests of CEE movers. Its one-sided approach is further reinforced by referring to irrelevant facts and negative assumptions to create an image of CEE nationals as socially and economically inferior to westerners, as not belonging to the proper EU polity and as not quite deserving of EU law’s protections. By silencing CEE nationals’ voices, while disregarding the background of east/west socio-economic and political power differentials and precariousness experienced by many CEE workers in the west, such racialising discourse normalises ethnicity- and class-based stereotypes. These findings also help to contextualise both EU and western policies targeting CEE movers and evidence of their unequal outcomes in the west, and are in line with today’s nuanced expressions of racisms. By illustrating the ECJ’s role in addressing values pertinent to mobile CEE individuals, this study facilitates a fuller appreciation of the ECJ’s power in shaping and reflecting western-centric EU identity and policies. Engaging with such issues will not only allow us to better appreciate—and question—the ECJ’s legitimacy, but might also facilitate a better understanding of power dynamics within the EU. This study also makes significant theoretical and methodological contributions. It expands (and complicates) the application of postcolonial theory to contemporary intra-EU processes, while illustrating the usefulness of applying critical discourse analysis to exploring differentiation, exclusion, subordination and power within legal language

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

This corrects the article DOI: 10.1038/bjc.2017.429