The serine protease hepsin mediates urinary secretion and polymerisation of Zona Pellucida domain protein uromodulin.

Uromodulin is the most abundant protein in the urine. It is exclusively produced by renal epithelial cells and it plays key roles in kidney function and disease. Uromodulin mainly exerts its function as an extracellular matrix whose assembly depends on a conserved, specific proteolytic cleavage leading to conformational activation of a Zona Pellucida (ZP) polymerisation domain. Through a comprehensive approach, including extensive characterisation of uromodulin processing in cellular models and in specific knock-out mice, we demonstrate that the membrane-bound serine protease hepsin is the enzyme responsible for the physiological cleavage of uromodulin. Our findings define a key aspect of uromodulin biology and identify the first in vivo substrate of hepsin. The identification of hepsin as the first protease involved in the release of a ZP domain protein is likely relevant for other members of this protein family, including several extracellular proteins, as egg coat proteins and inner ear tectorins

Differences in the carcinogenic evaluation of glyphosate between the International Agency for Research on Cancer (IARC) and the European Food Safety Authority (EFSA)

The International Agency for Research on Cancer (IARC) Monographs Programme identifies chemicals, drugs, mixtures, occupational exposures, lifestyles and personal habits, and physical and biological agents that cause cancer in humans and has evaluated about 1000 agents since 1971. Monographs are written by ad hoc Working Groups (WGs) of international scientific experts over a period of about 12 months ending in an eight-day meeting. The WG evaluates all of the publicly available scientific information on each substance and, through a transparent and rigorous process,1 decides on the degree to which the scientific evidence supports that substance's potential to cause or not cause cancer in humans. For Monograph 112,2 17 expert scientists evaluated the carcinogenic hazard for four insecticides and the herbicide glyphosate.3 The WG concluded that the data for glyphosate meet the criteria for classification as a probable human carcinogen. The European Food Safety Authority (EFSA) is the primary agency of the European Union for risk assessments regarding food safety. In October 2015, EFSA reported4 on their evaluation of the Renewal Assessment Report5 (RAR) for glyphosate that was prepared by the Rapporteur Member State, the German Federal Institute for Risk Assessment (BfR). EFSA concluded that ?glyphosate is unlikely to pose a carcinogenic hazard to humans and the evidence does not support classification with regard to its carcinogenic potential?. Addendum 1 (the BfR Addendum) of the RAR5 discusses the scientific rationale for differing from the IARC WG conclusion. Serious flaws in the scientific evaluation in the RAR incorrectly characterise the potential for a carcinogenic hazard from exposure to glyphosate. Since the RAR is the basis for the European Food Safety Agency (EFSA) conclusion,4 it is critical that these shortcomings are corrected

Lezioni di Matematiche complementari di F. Speranza (A.A. 1995-‘96)

Questo volume si basa sugli appunti a suo tempo (A.A. 1996/97) redatti da Luca Ferrari, oggi docente all’Università di Firenze, allora studente frequentante il corso di Matematiche Complementari della Facoltà di Scienze dell’Università di Parma. Questo volume, però, è una viva testimonianza dei corsi di Matematiche Complementari tenuti da Francesco Speranza ed in particolare del penultimo tenuto integralmente da Speranza, prima della prematura scomparsa avvenuta il 18 dicembre del 1998. Gli appunti infatti rispecchiano fedelmente l’impostazione generale del corso, sia come scelta degli argomenti sia come equilibrio delle singole parti. Ma non finisce qui. Come apparirà chiaro a chi ha avuto la fortuna ed il piacere di seguire le lezioni di Speranza, da questi appunti:–esce viva la voce del Nostro, con le sue cadenze ed il suo stile di presentazione degli argomenti e dei contenuti; –emergono distinti la sua pacatezza ed il suo equilibrio espositivo;–si nota la forte attenzione ai valori storici, filosofici e contenutistici degli argomenti trattati; –traspare non poco il suo continuo riflettere sulle proprie vedute ed il suo confrontarsi con quelle degli altri;e, ultimo non ultimo, sorprendentemente: –si vede il docente che entra in classe con la sua cultura, l’idea delle cose che deve dire secondo un suo progetto, lo svolgimento della lezione in cui talvolta lo schema si perde e si arricchisce, perché il docente è reattivo agli sguardi e alle domande degli studenti e trova buona l'occasione di contribuire non solo alla conoscenza, ma anche alla cultura dei suoi ascoltatori.I curatori al fine di conservare e rinsaldare le opportunità offerte dagli appunti, da un lato si sono preoccupati di mantenere, per quanto possibile, il testo di Ferrari così come era, correggendo solo alcuni refusi, senza segnalarlo; dall’altro lato per rinsaldarlo, a integrazione del testo, hanno aggiunto, al termine di ciascun capitolo, appendici e note scritte allo scopo di offrire al lettore suggerimenti o riferimenti bibliografici.Ci si augura che questa convergenza di intenti onori la memoria di Speranza e, soprattutto, dia la possibilità di usufruire del suo magistero a chi l’ha conosciuto ma anche alle nuove leve di studenti ed insegnanti

Immunohistochemical detection of polyductin and co-localization with liver progenitor cell markers during normal and abnormal development of the intrahepatic biliary system and in adult hepatobiliary carcinomas

The longest open reading frame of PKHD1 (polycystic kidney and hepatic disease 1), the autosomal recessive polycystic kidney disease (ARPKD) gene, encodes a single-pass, integral membrane protein named polyductin or fibrocystin. A fusion protein comprising its intracellular C-terminus, FP2, was previously used to raise a polyclonal antiserum shown to detect polyductin in several human tissues, including liver. In the current study, we aimed to investigate by immunohistochemistry the detailed polyductin localization pattern in normal (ductal plate [DP], remodelling ductal plate [RDP], remodelled bile ducts) and abnormal development of the primitive intrahepatic biliary system, known as ductal plate malformation (DPM). This work also included the characterization of polyductin expression profile in various histological forms of neonatal and infantile cholestasis, and in cholangiocellular carcinoma (CCC) and hepatocellular carcinoma (HCC). We detected polyductin expression in the intrahepatic biliary system during the DP and the RDP stages as well as in DPM. No specific staining was found at the stage of remodelled bile ducts. Polyductin was also detected in liver biopsies with neonatal cholestasis, including mainly biliary atresia and neonatal hepatitis with ductular reaction as well as congenital hepatic fibrosis. In addition, polyductin was present in CCC, whereas it was absent in HCC. Polyductin was also co-localized in some DP cells together with oval stem cell markers. These results represent the first systematic study of polyductin expression in human pathologies associated with abnormal development of intrahepatic biliary tree, and support the following conclusions: (i) polyductin expression mirrors developmental properties of the primitive intrahepatic biliary system; (ii) polyductin is re-expressed in pathological conditions associated with DPM and (iii) polyductin might be a potential marker to distinguish CCC from HCC.Tyrolean Perinatal Program, Innsbruck, AustriaOsterreichische Krebshilfe Tirol (Austrian Cancer Research Tyrol)Medical University of Innsbruck, Austri

Bridging the gap between the technological singularity and mainstream medicine : highlighting a course on technology and the future of medicine

The “technological singularity” is defined as that putative point in time forecasted to occur in the mid twenty-first century when machines will become smarter than humans, leading humans and machines to merge. It is hypothesized that this event will have a profound influence on medicine and population health. This work describes a new course on Technology and the Future of Medicine developed by a diverse, multi-disciplinary group of faculty members at a Canadian university. The course began as a continuous professional learning course and was later established as a recognized graduate course. We describe the philosophy of the course, the barriers encountered in course development, and some of the idiosyncratic solutions that were developed to overcome these, including the use of YouTube audience retention analytics. We hope that this report might provide a useful template for other institutions attempting to set up similar programs