Epigenetic silencing of SOCS3 expression contributes to fibrosis in Crohn’s disease

Identified risk polymorphisms affecting the Jak-STAT3 pathway in patients with Crohn’s disease could affect TGF-β1 and collagen I expression and in the pathway’s negative regulator, SOCS3. Genetic factors, however, account for only ~25% of disease. Epigenetic events also shape gene expression. Recent experiments showed that autocrine IL-6 production in mesenchymal cells, subepithelial myofibroblasts (SEMF) and muscle cells, of patients with fibrostenotic Crohn’s disease causes sustained Jak-STAT3 activity, excess TGF-β1 and Collagen I production and fibrosis. SOCS3 paradoxically decreased in these cells. We now identify epigenetic mechanisms that silence SOCS3 expression in SEMF of patients with fibrostenotic Crohn’s disease. In a previous experiment, using isolated SEMF of normal ileum and affected ileum from patients with each Crohn’s phenotype, inflammatory (Montreal B1), fibrostenotic (B2) and penetrating (B3), we confirmed decreased SOCS3 protein levels were unique to B2 patients. Expression of miR-19b increased in SEMF of affected ileum. SOCS3 transcriptional activity decreased after transfection of miR-19b mimic and increased when antagomiR-19b was expressed. Epigenetic silencing of SOCS3 in ileal SEMF of patients with fibrostenotic Crohn’s disease occurs by increased miR-19b mediated inhibition of SOCS3

A solution NMR approach to determine the chemical structures of carbohydrates using the hydroxyl groups as starting points

An efficient NMR approach is described for determining the chemical structures of the monosaccharide glucose and four disaccharides, namely, nigerose, gentiobiose, leucrose and isomaltulose. This approach uses the 1H resonances of the −OH groups, which are observable in the NMR spectrum of a supercooled aqueous solution, as the starting point for further analysis. The 2D-NMR technique, HSQC-TOCSY, is then applied to fully define the covalent structure (i.e., the topological relationship between C–C, C–H, and O–H bonds) that must be established for a novel carbohydrate before proceeding to further conformational studies. This process also leads to complete assignment of all 1H and 13C resonances. The approach is exemplified by analyzing the monosaccharide glucose, which is treated as if it were an “unknown”, and also by fully assigning all the NMR resonances for the four disaccharides that contain glucose. It is proposed that this technique should be equally applicable to the determination of chemical structures for larger carbohydrates of unknown composition, including those that are only available in limited quantities from biological studies. The advantages of commencing the structure elucidation of a carbohydrate at the −OH groups are discussed with reference to the now well-established 2D-/3D-NMR strategy for investigation of peptides/proteins, which employs the −NH resonances as the starting point

Polyglutamine inclusion body toxicity

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141741/1/mds27226_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141741/2/mds27226.pd

Venture Capital in Japan: A Financial Instrument Supporting the Innovativeness of the Japanese Economy

Two factors: First, the relatively small number of new companies as well as the number of companies subject to liquidation over the year ("firm turnover") in Japan, and second, the insignificant prestige associated with the profession of entrepreneur do not foster growth in the dynamics of this form of financing ventures. The cited indicator for Japan in among the lowest in comparison with other highly developed countries1, while the profession of entrepreneur is not the foremost dream of college graduates. They would much rather prefer realizing their professional careers as members of the government bureaucracy or employees of a major corporation2. However, this mindset is slowly changing, if for no other reason then, in spite of popular conviction, because most small companies are not established during periods of prosperity, but near the end of the downward phase of the economic cycle. That is exactly the phase Japan has been dealing with for several years now. Young, creative people, recruited from the unemployed, are seeking self-employment, using all possible opportunities embedded in the "again starting up" machinery of the economy.Dwa czynniki: pierwszy - stosunkowo mała liczba nowych firm, a także firm likwidowanych w skali roku ("firm turnover") w Japonii oraz drugi - niewielki prestiż, jakim cieszy się zawód przedsiębiorcy, nie sprzyjają dynamizacji omawianej formy finansowania przedsięwzięć. Cytowany wskaźnik, dla Japonii należy do najniższych w porównaniu z innymi krajami wysoko rozwiniętymi (Grabowiecki 2000), zaś profesja przedsiębiorcy nie jest szczytem marzeń ludzi po studiach. Znacznie bardziej chcieliby oni swoją karierę zawodową realizować jako członkowie rządowej biurokracji lub pracownicy dużej korporacji (Corver 2008, s. 2). Ta świadomość ulega jednak stopniowej zmianie, chociażby dlatego, że wbrew popularnym przekonaniom, większość niewielkich przedsiębiorstw, powstaje nie w okresie prosperity, lecz pod koniec spadkowej fazy cyklu koniunkturalnego. Z taką fazą mamy do czynienia w Japonii od paru lat. Młodzi, kreatywni ludzie, rekrutujący się z bezrobotnych, poszukują samozatrudnienia, wykorzystują wszelakie szanse, tkwiące w "ruszającej na powrót" maszynerii gospodark (Yonekura, Lynskey 2003, s. 11)

Abatacept in difficult-to-treat juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children and an important cause of short-term and long-term disability. Gene changes in the immune system can predispose to JIA and regulation of the immune system is crucial in the pathogenesis. The goal of therapy is complete disease control using disease-modifying antirheumatic drugs (DMARDS). Activated T-cells may play a role in the immunopathology of JIA. Therefore, targeting T-cell activation is a rational approach for the treatment of JIA. Abatacept (ABA), a selective co-stimulation modulator, has been shown to be effective in treating all JIA subtypes and is generally safe and well tolerated in JIA. Neutralizing antibodies were found in 6/9 (67%) of seropositive patients, but anti-ABA antibodies did not appear to be associated with disease flare, serious adverse events, acute infusional adverse events, hypersensitivity, autoimmune disorders, or low ABA serum concentrations. Anti-ABA antibodies were more frequent when ABA concentrations were below therapeutic levels. Although information on ABA in JIA is still limited, available data suggest a potential role in difficult to treat JIA patients previously treated with other biologic agents and for non-responders to TNF-blockade

An Outcome-Oriented, Social-Ecological Framework for Assessing Protected Area Effectiveness

Both the number and the extent of protected areas have grown considerably in recent years, but evaluations of their effectiveness remain partial and are hard to compare across cases. To overcome this situation, first, we suggest reserving the term effectiveness solely for assessing protected area outcomes, to clearly distinguish this from management assessments (e.g., sound planning). Second, we propose a multidimensional conceptual framework, rooted in social–ecological theory, to assess effectiveness along three complementary dimensions: ecological outcomes (e.g., biodiversity), social outcomes (e.g., well-being), and social–ecological interactions (e.g., reduced human pressures). Effectiveness indicators can subsequently be evaluated against contextual and management elements (e.g., design and planning) to shed light on management performance (e.g., cost-effectiveness). We summarize steps to operationalize our framework to foster more holistic effectiveness assessments while improving comparability across protected areas. All of this can ensure that protected areas make real contributions toward conservation and sustainability goals.Peer Reviewe

Effects of different matrix representations and connectivity measures on habitat network assessments

Assessing landscape connectivity is important to understand the ecology of landscapes and to evaluate alternative conservation strategies. The question is though, how to quantify connectivity appropriately, especially when the information available about the suitability of the matrix surrounding habitat is limited. Our goal here was to investigate the effects of matrix representation on assessments of the connectivity among habitat patches and of the relative importance of individual patches for the connectivity within a habitat network. We evaluated a set of 50 × 50 km^2 test areas in the Carpathian Mountains and considered three different matrix representations (binary, categorical and continuous) using two types of connections among habitat patches (shortest lines and least-cost paths). We compared connections, and the importance of patches, based on (1) isolation, (2) incidence-functional, and (3) graph measures. Our results showed that matrix representation can greatly affect assessments of connections (i.e., connection length, effective distance, and spatial location), but not patch prioritization. Although patch importance was not much affected by matrix representation, it was influenced by the connectivity measure and its parameterization. We found the biggest differences in the case of the integral index of connectivity and equally weighted patches, but no consistent pattern in response to changing dispersal distance. Connectivity assessments in more fragmented landscapes were more sensitive to the selection of matrix representation. Although we recommend using continuous matrix representation whenever possible, our results indicated that simpler matrix representations can be also used as a proxy to delineate those patches that are important for overall connectivity, but not to identify connections among habitat patches

Resource pulses and human–wildlife conflicts

Pulsed resources have prominent effects on community and ecosystem dynamics; however, there is little research on how resource pulses affect human–wildlife interactions. Tree masting is a common type of pulsed resource that represents a crucial food for many species and has important bottom-up effects in food webs. In anthropogenic landscapes, years of food shortage after mast years can have negative outcomes for both people and wildlife, for instance when an increased use of anthropogenic foods by animals exacerbates human–wildlife conflicts. Here, we used novel remote sensing indicators of forest productivity and phenology, together with weather cues and ground measures of mast production, to assess whether years of masting and crop failures lead to changes in human–wildlife conflict occurrence. We used a unique 14-year dataset including the production of European beech Fagus sylvatica seeds and brown bear Ursus arctos damage in the northeastern Carpathians as our model system. Linking these data in a panel regression framework, we found that temporal fluctuations in damage occurrence were sensitive to the year-to-year variation in beechnut production. Specifically, the number of damages during bear hyperphagia (i.e., September to December, when bears need to accumulate fat reserves prior to hibernation) was significantly higher in years with low beechnut production than in normal or mast years. Furthermore, we provide evidence that beech masting and failure can be predicted through a combination of remote-sensing, weather, and field indicators of forest productivity and phenology. We demonstrate how pulsed resources, such as tree masting, can percolate through food webs to amplify human–wildlife conflict in human-dominated landscapes. Given the recent range expansion of large carnivores and herbivores in many regions, including Europe, predicting years of natural food shortage can provide a pathway to proactive damage prevention, and thus to foster coexistence between wildlife and people.Peer Reviewe

Becoming With, in Life and Death

Abstract: Based on a life-long relationship between trust and domination of human and horse, this essay is a personal reflection on how perceptions and relationships shape the way we (as humans and non-humans in shared relationships) deal with implemented mercy deaths. What can we learn from our non-human companions when it comes to the decision of putting them down? This essay explores, on one hand, the relation between domination and compassion as a way of dealing with an animal’s life and death. On the other hand it investigates trust and correspondence beyond borders of human exceptionalism as a different, more open way of becoming with each other, focussing on the transformative potential of co-responding relationships