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https://www.readbyqxmd.com/read/28339910/rituximab-and-hepatitis-b-reactivation-in-hbsag-negative-anti-hbc-positive-kidney-transplant-recipients
#1
Juhan Lee, Jun Yong Park, Kyu Ha Huh, Beom Seok Kim, Myoung Soo Kim, Soon Il Kim, Hoon Sang Ahn, Yu Seun Kim
Background.: Hepatitis B virus (HBV) reactivation is a well-known complication of immunosuppressive therapy. Although rituximab is increasingly used for desensitization of ABO-incompatible or positive crossmatch kidney transplantation, the risk of HBV reactivation in hepatitis B surface antigen (HBsAg)-negative/hepatitis B core antibody (anti-HBc)-positive kidney transplant patients receiving rituximab desensitization remains undetermined. Methods.: We analysed 172 resolved HBV patients who underwent living donor kidney transplantation between 2008 and 2014...
February 23, 2017: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/28339772/heterologous-desensitization-of-cardiac-%C3%AE-adrenergic-signal-via-hormone-induced-%C3%AE-ar-arrestin-pde4-complexes
#2
Qian Shi, Minghui Li, Delphine Mika, Qin Fu, Sungjin Kim, Jason Phan, Ao Shen, Gregoire Vandecasteele, Yang K Xiang
Aims: Cardiac β-adrenergic receptor (βAR) signaling is susceptible to heterologous desensitization by different neurohormonal stimuli in clinical conditions associated with heart failure. We aim to examine the underlying mechanism of cross talk between βARs and a set of G-protein coupled receptors (GPCRs) activated by hormones/agonists. Methods and results: Rat ventricular cardiomyocytes were used to determine heterologous phosphorylation of βARs under a series of GPCR agonists...
February 21, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28338799/novel-form-of-the-michaelis-menten-equation-that-enables-accurate-estimation-of-kcat-km-ki-with-just-two-rate-measurements-utility-in-directed-evolution
#3
Jian Lu, Yuxia Dong, Emily C Ng, Daniel L Siehl
One of applications of directed evolution is to desensitize an enzyme to an inhibitor. kcat,1/KM and KI are three dimensions that when multiplied measure an enzyme's intrinsic capacity for catalysis in the presence of an inhibitor. The ideal values for the individual dimensions depend on substrate and inhibitor concentrations under the conditions of the application. When attempting to optimize those values by directed evolution, (kcat/KM)*KI can be an informative parameter for evaluating libraries of variants, but throughput is limited...
February 22, 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/28337156/lack-of-evidence-that-neural-empathic-responses-are-blunted-in-excessive-users-of-violent-video-games-an-fmri-study
#4
Gregor R Szycik, Bahram Mohammadi, Thomas F Münte, Bert T Te Wildt
The use of violent video games has been often linked to increase of aggressive behavior. According to the General Aggression Model, one of the central mechanisms for this aggressiveness inducing impact is an emotional desensitization process resulting from long lasting repeated violent game playing. This desensitization should evidence itself in a lack of empathy. Recent research has focused primarily on acute, short term impact of violent media use but only little is known about long term effects. In this study 15 excessive users of violent games and control subjects matched for age and education viewed pictures depicting emotional and neutral situations with and without social interaction while fMRI activations were obtained...
2017: Frontiers in Psychology
https://www.readbyqxmd.com/read/28332600/calmodulin-is-responsible-for-ca-2-dependent-regulation-of-trpa1-channels
#5
Raquibul Hasan, Alasdair T S Leeson-Payne, Jonathan H Jaggar, Xuming Zhang
TRPA1 is a Ca(2+)-permeable ion channel involved in many sensory disorders such as pain, itch and neuropathy. Notably, the function of TRPA1 depends on Ca(2+), with low Ca(2+) potentiating and high Ca(2+) inactivating TRPA1. However, it remains unknown how Ca(2+) exerts such contrasting effects. Here, we show that Ca(2+) regulates TRPA1 through calmodulin, which binds to TRPA1 in a Ca(2+)-dependent manner. Calmodulin binding enhanced TRPA1 sensitivity and Ca(2+)-evoked potentiation of TRPA1 at low Ca(2+), but inhibited TRPA1 sensitivity and promoted TRPA1 desensitization at high Ca(2+)...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28332411/underneath-the-academic-curiosity
#6
Miguel Leal-Rato
As a medical student, I have now almost 6 years of academic studies and clinical interaction with numerous patients, though sometimes brief and superficial. I have found that sometimes it is truly hard to grasp how humane a person is behind their sickness. Fortunately, I have been hitherto able to avoid the almost natural desensitization our degree imposes upon us, either through my own process of thought or through a kind warning of some of "my" patients. Having been particularly thrown aback by the keen eye of a patient I had the opportunity to meet in an Oncology ward, I realized that I had much more to consider when studying a clinical case and that rarely a cancer (or a disease whatever it may be) is but a cancer...
March 23, 2017: Medical Teacher
https://www.readbyqxmd.com/read/28331448/antibody-mediated-rejection-a-review
#7
Jorge Carlos Garces, Sixto Giusti, Catherine Staffeld-Coit, Humberto Bohorquez, Ari J Cohen, George E Loss
BACKGROUND: Chronic antibody injury is a serious threat to allograft outcomes and is therefore the center of active research. In the continuum of allograft rejection, the development of antibodies plays a critical role. In recent years, an increased recognition of molecular and histologic changes has provided a better understanding of antibody-mediated rejection (AMR), as well as potential therapeutic interventions. However, several pathways are still unknown, which accounts for the lack of efficacy of some of the currently available agents that are used to treat rejection...
2017: Ochsner Journal
https://www.readbyqxmd.com/read/28331048/g-protein-coupled-receptor-kinase-3-and-protein-kinase-c-phosphorylate-the-distal-c-terminal-tail-of-the-chemokine-receptor-cxcr4-and-mediate-recruitment-of-beta-arrestin
#8
Jiansong Luo, John M Busillo, Ralf Stumm, Jeffrey L Benovic
Phosphorylation of G protein-coupled receptors (GPCRs) is a key event for cell signaling and regulation of receptor function. Previously, using tandem mass spectrometry, we identified two phosphorylation sites at the distal C-terminal tail of the chemokine receptor CXCR4, but were unable to determine which specific residues were phosphorylated. Here, we demonstrate that serines 346 and/or 347 (Ser-346/7) of CXCR4 are phosphorylated upon stimulation with the agonist CXCL12 as well as a CXCR4 pepducin, ATI-2341...
March 22, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28328746/cross-talk-between-insulin-signaling-and-gpcrs
#9
Qin Fu, Qian Shi, Toni M West, Yang K Xiang
Diabetes is a major risk factor for the development of heart failure. One of the hallmarks of diabetes is insulin resistance associated with hyperinsulinemia. The literature shows that insulin and adrenergic signaling is intimately linked to each other; however, whether and how insulin may modulate cardiac adrenergic signaling and cardiac function remains unknown. Notably, recent studies have revealed that insulin receptor and β2 adrenergic receptor (β2AR) forms a membrane complex in animal hearts, bringing together the direct contact between two receptor signaling systems, and forming an integrated and dynamic network...
March 17, 2017: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28325178/corticosteroids-and-immune-suppressive-therapies-in-horses
#10
REVIEW
Mathilde Leclere
Immune suppressive therapies target exaggerated and deleterious responses of the immune system. Triggered by exogenous or endogenous factors, these improper responses can lead to immune or inflammatory manifestations, such as urticaria, equine asthma, or autoimmune and immune-mediated diseases. Glucocorticoids are the most commonly used immune suppressive drugs and the only ones supported by robust evidence of clinical efficacy in equine medicine. In some conditions, combining glucocorticoids with other pharmacologic and nonpharmacologic treatments, such as azathioprine, antihistamine, bronchodilators, environmental management, or desensitization, can help to decrease dosages and associated side effects...
April 2017: Veterinary Clinics of North America. Equine Practice
https://www.readbyqxmd.com/read/28324237/cyclosporine-a-induces-endoplasmic-reticulum-stress-and-influences-pro-apoptotic-factors-in-human-gingival-fibroblasts
#11
Suresh Ranga Rao, Shiyamali Sundararajan, Rajasekaran Subbarayan, Dinesh Murugan Girija
Cyclosporine-A (CsA) induces gingival overgrowth. Cyclosporine's anti-apoptotic activity in human gingival fibroblast is due to desensitization of mitochondrial permeability transition pore (MPTP) and augmentation of anti-apoptotic, Bcl2. Alternative mechanisms of apoptosis exist involving enzymes like calcium-dependent Calpain and signaling events related to apoptosis, like Glycogen synthase kinase 3β (GSK3β) and protein kinase A (PKA). Cyclosporine-A in renal tubular cells induces endoplasmic reticulum stress (ER stress) which has not been explored in gingival overgrowth...
March 21, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28323425/structure-based-design-of-highly-selective-and-potent-g-protein-coupled-receptor-kinase-2-inhibitors-based-on-paroxetine
#12
Helen V Waldschmidt, Kristoff T Homan, Marilyn C Cato, Osvaldo Cruz-Rodríguez, Alessandro Cannavo, Michael W Wilson, Jianliang Song, Joseph Y Cheung, Walter J Koch, John J G Tesmer, Scott D Larsen
In heart failure, the β-adrenergic receptors (βARs) become desensitized and uncoupled from heterotrimeric G proteins. This process is initiated by G protein-coupled receptor kinases (GRKs), some of which are upregulated in the failing heart making them desirable therapeutic targets. The selective serotonin reuptake inhibitor, paroxetine, was previously identified as a GRK2 inhibitor. Utilizing a structure based drug design approach we modified paroxetine to generate a small compound library. Included in this series is a highly potent and selective GRK2 inhibitor, 14as, with an IC50 of 30 nM against GRK2 and greater than 230-fold selectivity over other GRKs and kinases...
March 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28322331/targeted-disruption-of-tc-ptp-in-the-proliferative-compartment-augments-stat3-and-akt-signaling-and-skin-tumor-development
#13
Hyunseung Lee, Mihwa Kim, Minwoo Baek, Liza D Morales, Ik-Soon Jang, Thomas J Slaga, John DiGiovanni, Dae Joon Kim
Tyrosine phosphorylation is a vital mechanism that contributes to skin carcinogenesis. It is regulated by the counter-activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Here, we report the critical role of T-cell protein tyrosine phosphatase (TC-PTP), encoded by Ptpn2, in chemically-induced skin carcinogenesis via the negative regulation of STAT3 and AKT signaling. Using epidermal specific TC-PTP knockout (K14Cre.Ptpn2(fl/fl)) mice, we demonstrate loss of TC-PTP led to a desensitization to tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA)-induced apoptosis both in vivo epidermis and in vitro keratinocytes...
March 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28321223/abo-incompatible-kidney-transplantation
#14
REVIEW
Christian Morath, Martin Zeier, Bernd Döhler, Gerhard Opelz, Caner Süsal
ABO-incompatible (ABOi) kidney transplantation has long been considered a contraindication to successful kidney transplantation. During the last 25 years, increasing organ shortage enforced the development of strategies to overcome the ABO antibody barrier. In the meantime, ABOi kidney transplantation has become a routine procedure with death-censored graft survival rates comparable to the rates in compatible transplantations. Desensitization is usually achieved by apheresis and B cell-depleting therapies that are accompanied by powerful immunosuppression...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28320963/conformational-dynamics-and-role-of-the-acidic-pocket-in-asic-ph-dependent-gating
#15
Sabrina Vullo, Gaetano Bonifacio, Sophie Roy, Niklaus Johner, Simon Bernèche, Stephan Kellenberger
Acid-sensing ion channels (ASICs) are proton-activated Na(+) channels expressed in the nervous system, where they are involved in learning, fear behaviors, neurodegeneration, and pain sensation. In this work, we study the role in pH sensing of two regions of the ectodomain enriched in acidic residues: the acidic pocket, which faces the outside of the protein and is the binding site of several animal toxins, and the palm, a central channel domain. Using voltage clamp fluorometry, we find that the acidic pocket undergoes conformational changes during both activation and desensitization...
March 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28320308/binding-of-smoothelin-like-1-to-tropomyosin-and-calmodulin-is-mutually-exclusive-and-regulated-by-phosphorylation
#16
Annegret Ulke-Lemée, David Hao Sun, Hiroaki Ishida, Hans J Vogel, Justin A MacDonald
BACKGROUND: The smoothelin-like 1 protein (SMTNL1) can associate with tropomyosin (Tpm) and calmodulin (CaM), two proteins essential to the smooth muscle contractile process. SMTNL1 is phosphorylated at Ser301 by protein kinase A during calcium desensitization in smooth muscle, yet the effect of SMTNL1 phosphorylation on Tpm- and CaM-binding has yet to be investigated. RESULTS: Using pull down studies with Tpm-Sepharose and CaM-Sepharose, we examined the interplay between Tpm binding, CaM binding, phosphorylation of SMTNL1 and calcium concentration...
March 21, 2017: BMC Biochemistry
https://www.readbyqxmd.com/read/28319482/immunotherapy-for-food-allergy
#17
William R Reisacher, Wesley Davison
PURPOSE OF REVIEW: The current review discusses strategies for administering specific immunotherapy (SIT) for the treatment of food allergy. It focuses on three delivery routes for food allergens, immunomodulatory adjuvants and allergen modifications. RECENT FINDINGS: Interest in SIT for food allergy has been increasing significantly. Sublingual immunotherapy is effective for desensitization with a very favorable adverse event profile. Epicutaneous immunotherapy is also effective, most notably in younger children, with a high rate of local reactions...
March 17, 2017: Current Opinion in Otolaryngology & Head and Neck Surgery
https://www.readbyqxmd.com/read/28319053/alternatively-spliced-mu-opioid-receptor-c-termini-impact-the-diverse-actions-of-morphine
#18
Jin Xu, Zhigang Lu, Ankita Narayan, Valerie P Le Rouzic, Mingming Xu, Amanda Hunkele, Taylor G Brown, William F Hoefer, Grace C Rossi, Richard C Rice, Arlene Martínez-Rivera, Anjali M Rajadhyaksha, Luca Cartegni, Daniel L Bassoni, Gavril W Pasternak, Ying-Xian Pan
Extensive 3' alternative splicing of the mu opioid receptor gene OPRM1 creates multiple C-terminal splice variants. However, their behavioral relevance remains unknown. The present study generated 3 mutant mouse models with truncated C termini in 2 different mouse strains, C57BL/6J (B6) and 129/SvEv (129). One mouse truncated all C termini downstream of Oprm1 exon 3 (mE3M mice), while the other two selectively truncated C-terminal tails encoded by either exon 4 (mE4M mice) or exon 7 (mE7M mice). Studies of these mice revealed divergent roles for the C termini in morphine-induced behaviors, highlighting the importance of C-terminal variants in complex morphine actions...
March 20, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28315585/eye-movement-during-recall-reduces-objective-memory-performance-an-extended-replication
#19
Arne Leer, Iris M Engelhard, Bert Lenaert, Dieter Struyf, Bram Vervliet, Dirk Hermans
Eye Movement Desensitization and Reprocessing (EMDR) therapy for posttraumatic stress disorder involves making eye movements (EMs) during recall of a traumatic image. Experimental studies have shown that the dual task decreases self-reported memory vividness and emotionality. However valuable, these data are prone to demand effects and little can be inferred about the mechanism(s) underlying the observed effects. The current research aimed to fill this lacuna by providing two objective tests of memory performance...
March 9, 2017: Behaviour Research and Therapy
https://www.readbyqxmd.com/read/28306593/current-concepts-for-sensitized-patients-before-transplantation
#20
Dael Geft, Jon Kobashigawa
PURPOSE OF REVIEW: Antibody allosensitization poses a major immunologic challenge for patients awaiting heart transplantation. It is associated with significant morbidity and mortality for both pretransplant and posttransplant patients by prolonging wait times to transplant and increasing posttransplant rejection and vasculopathy. Many questions remain regarding methods and interpretation of antibody detection, the relevance of sensitization in specific patient populations such as those with mechanical circulatory support and the ideal strategies for desensitization...
March 16, 2017: Current Opinion in Organ Transplantation
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