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Wolfgang Miehsler, Clemens Dejaco, Hans-Peter Gröchenig, Harry Fuchssteiner, Christoph Högenauer, Lili Kazemi-Shirazi, Harald Maier, Andreas Mayer, Alexander Moschen, Walter Reinisch, Wolfgang Petritsch, Reingard Platzer, Pius Steiner, Herbert Tilg, Harald Vogelsang, Heimo Wenzl, Gottfried Novacek
Anti-TNFα-antibodies have revolutionized the therapy of inflammatory bowel diseases and other immune-mediated inflammatory diseases. Due to the increasing application of these substances, the Working Group of Inflammatory Bowel Diseases of the Austrian Association of Gastroenterology and Hepatology intended to update their consensus report on the safe use of Infliximab (published in 2010) and to enlarge its scope to cover all anti-TNFα-antibodies. The present consensus report summarizes the current evidence on the safe use of anti-TNFα-antibodies and covers the following topics: general risk of infection, bacterial infections (i...
March 2018: Zeitschrift Für Gastroenterologie
William M McGuigan, Jack A Luchette, Roxanne Atterholt
Research has established that childhood maltreatment experiences are associated with negative outcomes in adolescence, including violent and antisocial behavior (Chapple et al., 2005). Neglect is the most prevalent form of childhood maltreatment (U.S. DHHS, 2012), the consequences of which require further investigation. This study used archival data to explore whether childhood physical neglect increased the likelihood of violent behavior in a random sample of 85 males between the ages of 12-19 held at a long-term detention facility in the Northeastern United States...
March 9, 2018: Child Abuse & Neglect
George Vavougios, Sotirios G Zarogiannis, Triantafylos Doskas
Recent research has outlined that Dimethyl Fumarate (DMF) functions as a gene regulator via multiple pathways, critical among which is the NRF2 cytoprotective cascade. PARK7/DJ-1 is a multifunctional protein that acts as a redox sensor and effector of multiple cytoprotective pathways, including NRF2. Specifically, it prevents the association of NRF2 with its inhibitor KEAP1, allowing NRF2 to enter the nucleus and mediate cytoprotective and antioxidant cascades. It is our hypothesis that while the NRF2-KEAP1 inhibitory complex is reported the main pharmacological target for DMF's NRF dependent functions, no study to date has explored the effects of DMF on DJ-1's expression, and vice-versa, the possibility of a regulatory inadequacy in the upstream, oxidant-responsive DJ-1 activator of the NRF2 cascade...
February 26, 2018: Multiple Sclerosis and related Disorders
Valerie L Kinner, Oliver T Wolf, Christian J Merz
Relapses represent a major limitation to the long-term remission of pathological fear and anxiety. Stress modulates the acquisition and expression of fear memories and appears to promote fear recovery in patients with anxiety disorders. However, the neural correlates underlying stress hormone effects on the return of fear in humans remain unexplored. Likewise, little is known about the interactions between sex and stress hormones on return of fear phenomena. In this functional magnetic resonance imaging study, 32 men and 32 women were exposed to a fear renewal paradigm with fear acquisition in context A and extinction in context B...
February 21, 2018: Psychoneuroendocrinology
Allison K Farrell, Richard B Slatcher, Erin T Tobin, Ledina Imami, Derek E Wildman, Francesca Luca, Samuele Zilioli
The glucocorticoid receptor gene NR3C1 is an important down-regulator of inflammation and is typically under-expressed in individuals with low socioeconomic status (SES). Negative emotionality has been suggested as a potential mediator of SES disparities in health outcomes. In this study, we expand this literature by naturalistically assessing negative emotionality in a key emotional environment: the family. In a sample of 104 youth with asthma (10-17 years) and their primary caregiver, we assessed SES via caregiver report, emotional expression by youth and parents in the home over four days using the electronically activated recorder (EAR), and NR3C1 expression via blood collected from youth...
February 15, 2018: Psychoneuroendocrinology
Lillian H Krantz, Shelley McMain, Janice R Kuo
The current research tested whether four dimensions of mindfulness - acceptance without judgment, observing, describing and acting with awareness - predicted frequency of nonsuicidal self-injury (NSSI) and mediate the relationship with NSSI outcomes during 20-weeks of Dialectical Behaviour Therapy (DBT) skills training for borderline personality disorder (BPD). Eighty-four self-harming individuals with BPD were randomized to either DBT skills training or to a waitlist control group. A series of regressions revealed no relationship between dimensions of mindfulness and NSSI at baseline...
March 1, 2018: Behaviour Research and Therapy
Renren Bai, Jian Sun, Zhongxing Liang, Younghyoun Yoon, Eric Salgado, Amber Feng, Yoonhyeun Oum, Yuanyuan Xie, Hyunsuk Shim
The CXCR4/CXCL12 chemokine axis can chemotactically accumulate inflammatory cells to local tissues and regulate the release of inflammatory factors. Developing novel CXCR4 modulators may provide a desirable strategy to control the development of inflammation. A series of novel hybrids were designed by integrating the key pharmacophores of three CXCR4 modulators. The majority of compounds displayed potent CXCR4 binding affinity. Compound 7a exhibited 1000-fold greater affinity than AMD3100 and significantly inhibited invasion of CXCR4-positive tumor cells...
March 2, 2018: European Journal of Medicinal Chemistry
Rosita Gabbianelli, Elisabetta Damiani
Neurodegeneration represents a global problem due to the progressive increase in the aging population all over the world. The quality of life in aging and the cost for the health care system require actions to promote healthy aging. In this regard, several risk factors associated with the development of neurodegeneration can be identified, and programs to educate people on the key role of prevention could significantly ameliorate the future picture of the aging population. Here we describe the key role of the pre- and postnatal period of life during the first 1000 days of life, focusing on the importance of nutrition and a healthy lifestyle of mother and offspring for the prevention of neurodegeneration later in life...
February 9, 2018: Journal of Nutritional Biochemistry
Brij Bhushan Mehta, Anil Tiwari, Saniya Sharma, Ashu Shukla, Maryada Sharma, Rakesh K Vasishta, Ramesh K Sen, Aman Sharma, Manni Luthra-Guptasarma
Tenascin-C (TN-C) levels are elevated in the synovial tissue and fluid, as well as cartilage of rheumatoid arthritis (RA) patients. In addition, the presence of TN-C fragments has also been documented in arthritic cartilage. We have previously shown that a single chain variable fragment antibody (TN64), directed against the fibronectin type III repeats 1-5 (TNfnIII 1-5) of TN-C, effectively inhibits fibrotic pathology. Given that fibrosis results from chronic inflammation, and the fact that increased levels of TN-C in the synovial fluid of patients with RA contributes to synovial inflammation and joint destruction, we aimed to investigate the role of TNfnIII 1-5 region of TN-C in RA pathogenesis...
March 9, 2018: International Immunopharmacology
Ryan J Post, Melissa R Warden
Major depressive disorder can manifest as different combinations of symptoms, ranging from a profound and incapacitating sadness, to a loss of interest in daily life, to an inability to engage in effortful, goal-directed behavior. Recent research has focused on defining the neural circuits that mediate separable features of depression in patients and preclinical animal models, and connections between frontal cortex and brainstem neuromodulators have emerged as candidate targets. The development of methods permitting recording and manipulation of neural circuits defined by connectivity has enabled the investigation of prefrontal-neuromodulatory circuit dynamics in animal models of depression with exquisite precision, a systems-level approach that has brought new insights by integrating these fields of depression research...
March 9, 2018: Current Opinion in Neurobiology
Nicola Salvarese, Barbara Spolaore, Selena Marangoni, Anna Pasin, Alessandro Galenda, Sergio Tamburini, Gianfranco Cicoria, Fiorenzo Refosco, Cristina Bolzati
An assessment study involving the use of the transglutaminase (TGase) conjugation method and the nitride-technetium-99m labelling on a bis(thiosemicarbazone) (BTS) bifunctional chelating agent is presented. The previously described chelator diacetyl-2-(N4 -methyl-3-thiosemicarbazone)-3-(N4 -amino-3-thiosemicarbazone), H2 ATSM/A, has been functionalized with 6-aminohexanoic acid (ε-Ahx) to generate the bifunctional chelating agent diacetyl-2-(N4 -methyl-3-thiosemicarbazone)-3-[N4 -(amino)-(6-aminohexanoic acid)-3-thiosemicarbazone], H2 ATSM/A-ε-Ahx (1), suitable for conjugation to glutamine (Gln) residues of bioactive molecules via TGase...
March 2, 2018: Journal of Inorganic Biochemistry
Paula C Dos Reis Oliveira, Michiel H S Kraak, Harm G van der Geest, Sofia Naranjo, Piet F M Verdonschot
Despite the widely acknowledged connection between terrestrial and aquatic ecosystems, the contribution of runoff to the sediment composition in lowland stream deposition zones and the subsequent effects on benthic invertebrates remain poorly understood. The aim of this study was therefore to investigate the mechanisms by which runoff affects sediment composition and macroinvertebrates in deposition zones of lowland stream ecosystems. To this end, sediment from runoff and adjacent instream deposition zones from streams with different land use was chemically characterized and the biological effects were assessed at the species, community and ecosystem level...
March 9, 2018: Science of the Total Environment
Srinivasulu Cheemanapalli, Anuradha C M, Suresh Babu Pakala, Suresh Kumar Chitta
Although BAX, which is a molecular hit squad that incentive apoptosis was found to be an attractive emerging target for anticancer agents. The molecular mechanism of small molecules/peptides involved in the BAX activation was remain unknown. The present focus of the study is to identification and development of novel molecules which are precisely activates BAX mediated apoptosis. In this process we identified some syringic acid analogues associated with the BAX hydrophobic groove by a virtual-screen approach...
March 9, 2018: Computational Biology and Chemistry
Dechao Xu, Jiayi Lv, Liangliang He, Lili Fu, Ruikun Hu, Ying Cao, Changlin Mei
Polarity complexes, including the PAR (Partitioning-defective), CRB (Crumbs) and SCRIB (Scribble) complexes, are required for the physiologic establishment, stabilization, and maintenance of a functional apical-basolateral polarity. Inactivation of some of the polarity complexes results in cystic kidneys, and apical-basolateral polarity defects are commonly observed in autosomal-dominant polycystic kidney disease (ADPKD); however, little is known about the role that polarity complexes play in ADPKD. Here, we demonstrate that Scribble, a core protein of the SCRIB complex, is down-regulated in ADPKD cell lines and the zebrafish model of this disease ( pkd2 morphants)...
March 12, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Shaoyong Zhuang, Xiangwei Hua, Kang He, Tao Zhou, Jiang Zhang, Haoyu Wu, Xiong Ma, Qiang Xia, Jianjun Zhang
The contribution of glycogen synthase kinase-3β (GSK-3β) to cholestatic liver disease (CLD) remains unknown. We investigated the role and mechanism of GSK-3β in vivo in liver tissues of patients with CLD and the bile duct ligation (BDL) mouse model and in vitro using a hepatic progenitor cell (HPC) and hepatic stellate cell (HSC) coculture system. In liver tissues of patients with CLD, expression of the inactive form of GSK-3β, phospho-GSK-3β(Ser9), was increased in HPCs. GSK-3β inhibition by SB216763 treatment aggravated liver fibrosis and elevated the expression of osteopontin (OPN) in the BDL mouse model...
March 12, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Aernoud A van Batenburg, Karin M Kazemier, Ton Peeters, Matthijs F M van Oosterhout, Joanne J van der Vis, Jan C Grutters, Roel Goldschmeding, Coline H M van Moorsel
Telomeres are small repetitive DNA sequences at the ends of chromosomes which act as a buffer in age-dependent DNA shortening. Insufficient telomere repeats will be recognized as double-strand breaks. Presently, it is becoming more evident that telomere attrition, whether or not caused by mutations in telomere maintenance genes, plays an important role in many inflammatory and age-associated diseases. In this report, a method to (semi)quantitatively assess telomere length and DNA double-strand breaks in formalin-fixed paraffin-embedded (FFPE) tissue is described...
March 1, 2018: Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society
Stephan Block, Srdjan S Aćimović, Nils Odebo Länk, Mikael Käll, Fredrik Höök
Fluorescence correlation spectroscopy (FCS) has provided a wealth of information on the composition, structure, and dynamics of cell membranes. However, it has proved challenging to reach the spatial resolution required to resolve biophysical interactions at the nm-scale relevant to many crucial membrane processes. In this work, we form artificial cell membranes on dimeric, nanoplasmonic antennas, which shrink the FCS probe volume down to the ~20 nm length-scale. By analysing the autocorrelation functions (ACFs) associated with the fluorescence bursts from individual fluorescently tagged lipids moving through the antenna "hot spots", we show that the confinement of the optical readout volume below the diffraction limit allows the temporal resolution of FCS to be increased by up to 3 orders of magnitude...
March 12, 2018: ACS Nano
Mário R Martins, Rogério L D Santos, Kleber D N Jatahy, Marina C D Matta, Thales P Batista, José Iran C Júnior, Maria D F S Begnami, Leuridan C Torres
BACKGROUND AND OBJECTIVES: OX40, a membrane-bound molecule of the tumor-necrosis-factor-receptor superfamily, is a critical costimulatory receptor during the immune response, especially to T cells, but studies described their presence of OX-40 on neutrophils and monocytes, suggesting a potential role in the activation of immune response. Our aim was to characterize costimulatory receptors OX40 expression on circulating leukocytes in gastric cancer to identify novel targets for immunotherapy...
March 12, 2018: Journal of Surgical Oncology
Varun V Gadkari, Sophie R Harvey, Austin T Raper, Wen-Ting Chu, Jin Wang, Vicki H Wysocki, Zucai Suo
Proliferating cell nuclear antigen (PCNA) is a trimeric ring-shaped clamp protein that encircles DNA and interacts with many proteins involved in DNA replication and repair. Despite extensive structural work to characterize the monomeric, dimeric, and trimeric forms of PCNA alone and in complex with interacting proteins, no structure of PCNA in a ring-open conformation has been published. Here, we use a multidisciplinary approach, including single-molecule Förster resonance energy transfer (smFRET), native ion mobility-mass spectrometry (IM-MS), and structure-based computational modeling, to explore the conformational dynamics of a model PCNA from Sulfolobus solfataricus (Sso), an archaeon...
February 26, 2018: Nucleic Acids Research
Frank J Simutis, Thomas P Sanderson, Gary D Pilcher, Michael J Graziano
The toxicity of avagacestat, a sulfonamide-based gamma (γ)-secretase inhibitor that was in development as a treatment for Alzheimer's disease, was evaluated in a comprehensive nonclinical toxicology program that included 6-month and 1-year repeat-dose toxicity studies in rats and dogs, respectively. There was a spectrum of mechanism-based changes attributed to inhibition of Notch signaling that regulates the differentiation and proliferation of cells throughout development and in adult tissues. In both rats and dogs, ovarian follicular degeneration and atrophy and a low incidence of granulosa cell hyperplasia and benign granulosa-thecal cell tumors were observed...
February 24, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
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