King and Baronage (A.D. 1135-1327) by HUTTON, William Holden

William Holden Hutton (1860-1930) was a British historian and Dean of Winchester Cathedral. In this slim volume, Hutton writes of the long period of feudal anarchy following the death of King Henry I in 1135, during which Henry’s implacable daughter, Mathilda, battled the ineffectual King Stephen. Hutton then describes the turbulent reign of the great King Henry II, the reigns of Kings Richard, John, Henry III, and of the first two Edwards, rulers who whether weak or strong, rigid or resourceful, were grimly opposed by their powerful barons. – Summary by Pamela Nagami
This title is avalable for free download at: www.librivox.org.

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Audizione sottosegretario Bressa in Commissione Federalismo fiscale

Venerdì 15 12 2017

La Commissione Federalismo fiscale, sui principi del federalismo fiscale e il processo di attuazione dell’articolo 116, terzo comma, della Costituzione, mercoledì 20 dicembre alle 8, ha in programma l’audizione del Sottosegretario agli affari regionali e le autonomie, Gianclaudio Bressa.

Tratto da www.senato.it.
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Analysis of the efficacy of Taiwanese freeze-dried neurotoxic antivenom against <i>Naja kaouthia</i>, <i>Naja siamensis</i> and <i>Ophiophagus hannah</i> through proteomics and animal model approaches

by Chien-Chun Liu, Chen-Hsien You, Po-Jung Wang, Jau-Song Yu, Guo-Jen Huang, Chien-Hsin Liu, Wen-Chin Hsieh, Chih-Chuan Lin

In Southeast Asia, envenoming resulting from cobra snakebites is an important public health issue in many regions, and antivenom therapy is the standard treatment for the snakebite. Because these cobras share a close evolutionary history, the amino acid sequences of major venom components in different snakes are very similar. Therefore, either monovalent or polyvalent antivenoms may offer paraspecific protection against envenomation of humans by several different snakes. In Taiwan, a bivalent antivenom—freeze-dried neurotoxic antivenom (FNAV)—against Bungarus multicinctus and Naja atra is available. However, whether this antivenom is also capable of neutralizing the venom of other species of snakes is not known. Here, to expand the clinical application of Taiwanese FNAV, we used an animal model to evaluate the neutralizing ability of FNAV against the venoms of three common snakes in Southeast Asia, including two ‘true’ cobras Naja kaouthia (Thailand) and Naja siamensis (Thailand), and the king cobra Ophiophagus hannah (Indonesia). We further applied mass spectrometry (MS)-based proteomic techniques to characterize venom proteomes and identify FNAV-recognizable antigens in the venoms of these Asian snakes. Neutralization assays in a mouse model showed that FNAV effectively neutralized the lethality of N. kaouthia and N. siamensis venoms, but not O. hannah venom. MS-based venom protein identification results further revealed that FNAV strongly recognized three-finger toxin and phospholipase A2, the major protein components of N. kaouthia and N. siamensis venoms. The characterization of venom proteomes and identification of FNAV-recognizable venom antigens may help researchers to further develop more effective antivenom designed to block the toxicity of dominant toxic proteins, with the ultimate goal of achieving broadly therapeutic effects against these cobra snakebites.

Tratto da: www.plos.org.
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Genotyping of <i>Mycobacterium leprae</i> for better understanding of leprosy transmission in Fortaleza, Northeastern Brazil

by Amanda N. B. Fontes, Luana N. G. C. Lima, Rosa M. S. Mota, Rosa L. F. Almeida, Maria A. Pontes, Heitor de S. Gonçalves, Cristiane C. Frota, Varalakshmi D. Vissa, Patrick J. Brennan, Ricardo J. P. S. Guimaraes, Carl Kendall, Ligia R. F. S. Kerr, Philip N. Suffys

Leprosy is endemic in large part of Brazil with 28,761 new patients in 2015, the second largest number worldwide and reaches 9/10.000 in highly endemic regions and 2.7/10.000 in the city of Fortaleza, Ceará, Northeast Brazil. For better understanding of risk factors for leprosy transmission, we conducted an epidemiologic study supplemented by 17 locus VNTR and SNP 1–4 typing of Mycobacterium leprae in skin biopsy samples from new multibacillary (MB) patients diagnosed at a reference center in 2009 and 2010. Among the 1,519 new patients detected during the study period, 998 (65.7%) were MB and we performed DNA extraction and genotyping on 160 skin biopsy samples, resulting in 159 (16%) good multilocus VNTR types. Thirty-eight of these patients also provided VNTR types from M. leprae in nasal swabs. The SNP-Type was obtained for 157 patients and 87% were of type 4. Upon consideration all VNTR markers, 156 different genotypes and three pairs with identical genotypes were observed; no epidemiologic relation could be observed between individuals in these pairs. Considerable variability in differentiating index (DI) was observed between the different markers and the four with highest DI [(AT)15, (TA)18, (AT)17 and (GAA)21] frequently demonstrated differences in copy number when comparing genotypes from both type of samples. Excluding these markers from analysis resulted in 83 genotypes, 20 of which included 96 of the patients (60.3%). These clusters were composed of two (n = 8), three (n = 6), four (n = 1), five (n = 2), six (n = 1), 19 (n = 1) and 23 (n = 23) individuals and suggests that recent transmission is contributing to the maintenance of leprosy in Fortaleza. When comparing epidemiological and clinical variables among patients within clustered or with unique M. leprae genotypes, a positive bacterial index in skin biopsies and knowledge of working with someone with the disease were significantly associated with clustering. A tendency to belong to a cluster was observed with later notification of disease (mean value of 3.4 months) and having disability grade 2. A tendency for lack of clustering was observed for patients who reported to have lived with another leprosy case but this might be due to lack of inclusion of household contacts in the study. Although clusters were spread over the city, kernel analysis revealed that some of the patients belonging to the two major clusters were spatially related to some neighborhoods that report poverty and high disease incidence in children. Finally, inclusion of genotypes from nasal swabs might be warranted. A major limitation of the study is that sample size of 160 patients from a two year period represents only 15% of the new patients and this could have weakened statistical outcomes. This is the first molecular epidemiology study of leprosy in Brazil and although the high clustering level suggests that recent transmission is the major cause of disease in Fortaleza; the existence of two large clusters needs further investigation.

Tratto da: www.plos.org.
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Tongue-driven sonar beam steering by a lingual-echolocating fruit bat

by Wu-Jung Lee, Benjamin Falk, Chen Chiu, Anand Krishnan, Jessica H. Arbour, Cynthia F. Moss

Animals enhance sensory acquisition from a specific direction by movements of head, ears or eyes. As active sensing animals, echolocating bats also aim their directional sonar beam to selectively “illuminate” a confined volume of space, facilitating efficient information processing by reducing echo interference and clutter. Such sonar beam control is generally achieved by head movements or shape changes of the sound-emitting mouth or nose. However, lingual-echolocating Egyptian fruit bats, Rousettus aegyptiacus, which produce sound by clicking their tongue, can dramatically change beam direction at very short temporal intervals without visible morphological changes. The mechanism supporting this capability has remained a mystery. Here we measured signals from free-flying Egyptian fruit bats and discovered a systematic angular sweep of beam focus across increasing frequency. This unusual signal structure has not been observed in other animals, and cannot be explained by the conventional and widely used “piston model” that describes the emission pattern of other bat species. Through modeling we show that the observed beam features can be captured by an array of tongue-driven sound sources located along the side of the mouth, and that the sonar beam direction can be steered parsimoniously by inducing changes to the pattern of phase differences through moving tongue location. The effects are broadly similar to those found in a phased array–an engineering design widely found in human-made sonar systems that enables beam direction changes without changes in the physical transducer assembly. Our study reveals an intriguing parallel between biology and human engineering in solving problems in fundamentally similar ways.

Tratto da: www.plos.org.
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Conditional knockout mice for the distal appendage protein CEP164 reveal its essential roles in airway multiciliated cell differentiation

by Saul S. Siller, Himanshu Sharma, Shuai Li, June Yang, Yong Zhang, Michael J. Holtzman, Wipawee Winuthayanon, Holly Colognato, Bernadette C. Holdener, Feng-Qian Li, Ken-Ichi Takemaru

Multiciliated cells of the airways, brain ventricles, and female reproductive tract provide the motive force for mucociliary clearance, cerebrospinal fluid circulation, and ovum transport. Despite their clear importance to human biology and health, the molecular mechanisms underlying multiciliated cell differentiation are poorly understood. Prior studies implicate the distal appendage/transition fiber protein CEP164 as a central regulator of primary ciliogenesis; however, its role in multiciliogenesis remains unknown. In this study, we have generated a novel conditional mouse model that lacks CEP164 in multiciliated tissues and the testis. These mice show a profound loss of airway, ependymal, and oviduct multicilia and develop hydrocephalus and male infertility. Using primary cultures of tracheal multiciliated cells as a model system, we found that CEP164 is critical for multiciliogenesis, at least in part, via its regulation of small vesicle recruitment, ciliary vesicle formation, and basal body docking. In addition, CEP164 is necessary for the proper recruitment of another distal appendage/transition fiber protein Chibby1 (Cby1) and its binding partners FAM92A and FAM92B to the ciliary base in multiciliated cells. In contrast to primary ciliogenesis, CEP164 is dispensable for the recruitment of intraflagellar transport (IFT) components to multicilia. Finally, we provide evidence that CEP164 differentially controls the ciliary targeting of membrane-associated proteins, including the small GTPases Rab8, Rab11, and Arl13b, in multiciliated cells. Altogether, our studies unravel unique requirements for CEP164 in primary versus multiciliogenesis and suggest that CEP164 modulates the selective transport of membrane vesicles and their cargoes into the ciliary compartment in multiciliated cells. Furthermore, our mouse model provides a useful tool to gain physiological insight into diseases associated with defective multicilia.

Tratto da: www.plos.org.
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MAGPIE: Simplifying access and execution of computational models in the life sciences

by Christoph Baldow, Sebastian Salentin, Michael Schroeder, Ingo Roeder, Ingmar Glauche

Over the past decades, quantitative methods linking theory and observation became increasingly important in many areas of life science. Subsequently, a large number of mathematical and computational models has been developed. The BioModels database alone lists more than 140,000 Systems Biology Markup Language (SBML) models. However, while the exchange within specific models classes has been supported by standardisation and database efforts, the generic application and especially the re-use of models is still limited by practical issues such as easy and straight forward model execution. MAGPIE, a Modeling and Analysis Generic Platform with Integrated Evaluation, closes this gap by providing a software platform for both, publishing and executing computational models without restrictions on the programming language, thereby combining a maximum on flexibility for programmers with easy handling for non-technical users. MAGPIE goes beyond classical SBML platforms by including all models, independent of the underlying programming language, ranging from simple script models to complex data integration and computations. We demonstrate the versatility of MAGPIE using four prototypic example cases. We also outline the potential of MAGPIE to improve transparency and reproducibility of computational models in life sciences. A demo server is available at magpie.imb.medizin.tu-dresden.de.

Tratto da: www.plos.org.
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We are not Charlie and we will never be.