TMG 1 (2014): Pandemic Disease in the Medieval World: Rethinking the Black Death, ed. Monica Green

The plague organism (Yersinia pestis) killed an estimated 40% to 60% of all people when it spread rapidly through the Middle East, North Africa, and Europe in the fourteenth century: an event known as the Black Death. Previous research has shown, especially for Western Europe, how population losses then led to structural economic, political, and social changes. But why and how did the pandemic happen in the first place? When and where did it begin? How was it sustained? What was its full geographic extent? And when did it really end? Pandemic Disease in the Medieval World is the first book to synthesize the new evidence and research methods that are providing fresh answers to these crucial questions. It was only in 2011, thanks to ancient DNA recovered from remains unearthed in London’s East Smithfield cemetery, that the full genome of the plague pathogen was identified. This single-celled organism probably originated 3000-4000 years ago and has caused three pandemics in recorded history: the Justinianic (or First) Plague Pandemic, around 541-750; the Black Death (Second Plague Pandemic), conventionally dated to the 1340s; and the Third Plague Pandemic, usually dated from around 1894 to the 1930s. This ground-breaking book brings together scholars from the humanities and social and physical sci­ences to address the question of how recent work in genetics, zoology, and epi­de­miology can enable a rethinking of the Black Death\u27s global reach and its larger historical significance. It forms the inaugural double issue of The Medieval Globe, a new journal sponsored by the Program in Medieval Studies at the University of Illinois at Urbana-Champaign. This issue of The Medieval Globe is published with the support of the World History Center at the University of Pittsburgh.https://scholarworks.wmich.edu/medieval_globe/1000/thumbnail.jp

A large-scale study on the effects of sex on gray matter asymmetry

Research on sex-related brain asymmetries has not yielded consistent results. Despite its importance to further understanding of normal brain development and mental disorders, the field remains relatively unexplored. Here we employ a recently developed asymmetry measure, based on the Dice coefficient, to detect sex-related gray matter asymmetries in a sample of 457 healthy participants (266 men and 191 women) obtained from 5 independent databases. Results show that women’s brains are more globally symmetric than men’s (p < 0.001). Although the new measure accounts for asymmetries distributed all over the brain, several specific structures were identified as systematically more symmetric in women, such as the thalamus and the cerebellum, among other structures, some of which are typically involved in language production. These sex-related asymmetry differences may be defined at the neurodevelopmental stage and could be associated with functional and cognitive sex differences, as well as with proneness to develop a mental disorder

Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells

Nitric oxide (NO) plays a relevant role during cell death regulation in tumor cells. The overexpression of nitric oxide synthase type III (NOS-3) induces oxidative and nitrosative stress, p53 and cell death receptor expression and apoptosis in hepatoblastoma cells. S-nitrosylation of cell death receptor modulates apoptosis. Sorafenib is the unique recommended molecular-targeted drug for the treatment of patients with advanced hepatocellular carcinoma. The present study was addressed to elucidate the potential role of NO during Sorafenib-induced cell death in HepG2 cells. We determined the intra- and extracellular NO concentration, cell death receptor expression and their S-nitrosylation modifications, and apoptotic signaling in Sorafenib-treated HepG2 cells. The effect of NO donors on above parameters has also been determined. Sorafenib induced apoptosis in HepG2 cells. However, low concentration of the drug (10nM) increased cell death receptor expression, as well as caspase-8 and -9 activation, but without activation of downstream apoptotic markers. In contrast, Sorafenib (10 µM) reduced upstream apoptotic parameters but increased caspase-3 activation and DNA fragmentation in HepG2 cells. The shift of cell death signaling pathway was associated with a reduction of S-nitrosylation of cell death receptors in Sorafenib-treated cells. The administration of NO donors increased S-nitrosylation of cell death receptors and overall induction of cell death markers in control and Sorafenib-treated cells. In conclusion, Sorafenib induced alteration of cell death receptor S-nitrosylation status which may have a relevant repercussion on cell death signaling in hepatoblastoma cells.Instituto de Salud Carlos III PI13/00021Ministerio de Economía y Competitividad BFU2012-32056Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía BIO-0216Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía CTS-6264Consejería de Salud, Junta de Andalucía PI13/ 0002

Tauopathic Changes in the Striatum of A53T α-Synuclein Mutant Mouse Model of Parkinson's Disease

Tauopathic pathways lead to degenerative changes in Alzheimer's disease and there is evidence that they are also involved in the neurodegenerative pathology of Parkinson's disease [PD]. We have examined tauopathic changes in striatum of the α-synuclein (α-Syn) A53T mutant mouse. Elevated levels of α-Syn were observed in striatum of the adult A53T α-Syn mice. This was accompanied by increases in hyperphosphorylated Tau [p-Tau], phosphorylated at Ser202, Ser262 and Ser396/404, which are the same toxic sites also seen in Alzheimer's disease. There was an increase in active p-GSK-3β, hyperphosphorylated at Tyr216, a major and primary kinase known to phosphorylate Tau at multiple sites. The sites of hyperphosphorylation of Tau in the A53T mutant mice were similar to those seen in post-mortem striata from PD patients, attesting to their pathophysiological relevance. Increases in p-Tau were not due to alterations on protein phosphatases in either A53T mice or in human PD, suggesting lack of involvement of these proteins in tauopathy. Extraction of striata with Triton X-100 showed large increases in oligomeric forms of α-Syn suggesting that α-Syn had formed aggregates the mutant mice. In addition, increased levels of p-GSK-3β and pSer396/404 were also found associated with aggregated α-Syn. Differential solubilization to measure protein binding to cytoskeletal proteins demonstrated that p-Tau in the A53T mutant mouse were unbound to cytoskeletal proteins, consistent with dissociation of p-Tau from the microtubules upon hyperphosphorylation. Interestingly, α-Syn remained tightly bound to the cytoskeleton, while p-GSK-3β was seen in the cytoskeleton-free fractions. Immunohistochemical studies showed that α-Syn, pSer396/404 Tau and p-GSK-3β co-localized with one another and was aggregated and accumulated into large inclusion bodies, leading to cell death of Substantia nigral neurons. Together, these data demonstrate an elevated state of tauopathy in striata of the A53T α-Syn mutant mice, suggesting that tauopathy is a common feature of synucleinopathies

First comprehensive contribution to medical ethnobotany of Western Pyrenees

<p>Abstract</p> <p>Background</p> <p>An ethnobotanical and medical study was carried out in the Navarre Pyrenees, an area known both for its high biological diversity and its cultural significance.</p> <p>As well as the compilation of an ethnopharmacological catalogue, a quantitative ethnobotanical comparison has been carried out in relation to the outcomes from other studies about the Pyrenees. A review of all drugs used in the area has also been carried out, through a study of the monographs published by the institutions and organizations responsible for the safety and efficacy of medicinal plants (WHO, ESCOP, and the E Commission of the German Department of Health) in order to ascertain the extent to which the Navarre Pyrenees ethnopharmacology has been officially evaluated.</p> <p>Methods</p> <p>Fieldwork was carried out over two years, from November 2004 to December 2006. During that time we interviewed 88 local people in 40 villages. Information was collected using semi-structured ethnobotanical interviews and the data was analyzed using quantitave indexes: Ethnobotonicity Index, Shannon-Wiener's Diversity, Equitability and The Informant Consensus Factor. The official review has been performed using the official monographs published by the WHO, ESCOP and the E Commission of the German Department of Health.</p> <p>Results</p> <p>The ethnobotanical and medical catalogue of the Navarre Pyrenees Area comprises 92 species, of which 39 have been mentioned by at least three interviewees. The quantitative ethnobotany results show lower values than those found in other studies about the Pyrenees; and 57.6% of the Pyrenees medical ethnobotany described does not figure in documents published by the above mentioned institutions.</p> <p>Conclusion</p> <p>The results show a reduction in the ethnobotanical and medical knowledge in the area of study, when compared to other studies carried out in the Pyrenees. Nevertheless, the use of several species that may be regarded as possible sources for pharmacological studies is reported here such as the bark of <it>Sambucus nigra</it>, the roots of <it>Fragaria vesca</it>, or the leaves of <it>Scrophularia nodosa</it>. These species are not currently approved by the WHO, ESCOP and the E Commission of the German Department of Health, institutions that, apart from encouraging the greater use of plants for medicinal purposes, may help in the design of development plans for these rural areas by validating their traditional medicine.</p

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies