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hyper direct pathway

David Mathar, Leonora Wilkinson, Anna K Holl, Jane Neumann, Lorenz Deserno, Arno Villringer, Marjan Jahanshahi, Annette Horstmann
Incidental learning of appropriate stimulus-response associations is crucial for optimal functioning within our complex environment. Positive and negative prediction errors (PEs) serve as neural teaching signals within distinct ('direct'/'indirect') dopaminergic pathways to update associations and optimize subsequent behavior. Using a computational reinforcement learning model, we assessed learning from positive and negative PEs on a probabilistic task (Weather Prediction Task - WPT) in three populations that allow different inferences on the role of dopamine (DA) signals: (1) Healthy volunteers that repeatedly underwent [(11)C]raclopride Positron Emission Tomography (PET), allowing for assessment of striatal DA release during learning, (2) Parkinson's disease (PD) patients tested both on and off L-DOPA medication, (3) early Huntington's disease (HD) patients, a disease that is associated with hyper-activation of the 'direct' pathway...
September 19, 2016: Cortex; a Journal Devoted to the Study of the Nervous System and Behavior
Jing Ni, Nan Wang, Lili Gao, Lili Li, Siwen Zheng, Yuejian Liu, Molu Ozukum, Anna Nikiforova, Guangming Zhao, Zhiqi Song
BACKGROUND: The pigmentation of skin and hair in mammals is driven by the intercellular transfer of melanosome from the melanocyte to surrounding keratinocytes However, the detailed molecular mechanism is still a subject of investigation. OBJECTIVE: To investigate the effects of N-methyl-d-aspartate (NMDA) receptor-dependent signaling pathway on melanocyte morphologic change and melanosome transfer between melanocytes and keratinocytes. METHODS: The expression and the intracellular distribution of NMDA receptor in human melanocyte were analyzed by Western blot and immunofluorescence staining...
August 24, 2016: Journal of Dermatological Science
Madeleine J Oudin, Miles A Miller, Joelle A Z Klazen, Tatsiana Kosciuk, Alisha Lussiez, Shannon K Hughes, Jenny Tadros, James E Bear, Douglas A Lauffenburger, Frank B Gertler
Directed cell migration, a key process in metastasis, arises from the combined influence of multiple processes, including chemotaxis-the directional movement of cells to soluble cues-and haptotaxis-the migration of cells on gradients of substrate-bound factors. However, it is unclear how chemotactic and haptotactic pathways integrate with each other to drive overall cell behavior. Mena(INV) has been implicated in metastasis by driving chemotaxis via dysregulation of phosphatase PTP1B and more recently in haptotaxis via interaction with integrin α5β1...
October 15, 2016: Molecular Biology of the Cell
David J Duffy, Aleksandar Krstic, Thomas Schwarzl, Melinda Halasz, Kristiina Iljin, Dirk Fey, Bridget Haley, Jenny Whilde, Saija Haapa-Paananen, Vidal Fey, Matthias Fischer, Frank Westermann, Kai-Oliver Henrich, Steffen Bannert, Desmond G Higgins, Walter Kolch
Wnt signalling is involved in the formation, metastasis and relapse of a wide array of cancers. However, there is ongoing debate as to whether activation or inhibition of the pathway holds the most promise as a therapeutic treatment for cancer, with conflicting evidence from a variety of tumour types. We show that Wnt/β-catenin signalling is a bi-directional vulnerability of neuroblastoma, malignant melanoma and colorectal cancer, with hyper-activation or repression of the pathway both representing a promising therapeutic strategy, even within the same cancer type...
August 11, 2016: Oncotarget
Hong Zheng, Kaushik P Patel
The sympathetic nervous system has been identified as a major contributor to the pathophysiology of chronic heart failure (CHF) and other diseases such as hypertension and diabetes, both in experimental animal models and patients. The kidneys have a dense afferent sensory innervation positioning it to be the origin of multimodal input to the central nervous system. Afferent renal nerve (ARN) signals are centrally integrated, and their activation results in a general increase in sympathetic tone, which is directed toward the kidneys as well as other peripheral organs innervated by the sympathetic nerves...
August 6, 2016: Autonomic Neuroscience: Basic & Clinical
Soheil Rastgou Talemi, Carl-Fredrik Tiger, Mikael Andersson, Roja Babazadeh, Niek Welkenhuysen, Edda Klipp, Stefan Hohmann, Jörg Schaber
Adaptation is an important property of living organisms enabling them to cope with environmental stress and maintaining homeostasis. Adaptation is mediated by signaling pathways responding to different stimuli. Those signaling pathways might communicate in order to orchestrate the cellular response to multiple simultaneous stimuli, a phenomenon called crosstalk. Here, we investigate possible mechanisms of crosstalk between the High Osmolarity Glycerol (HOG) and the Cell Wall Integrity (CWI) pathways in yeast, which mediate adaptation to hyper- and hypo-osmotic challenges, respectively...
2016: Scientific Reports
Regina Célia de Souza, Mario Pansini, Gisele Arruda, Caroline Valente, Marcos Leal Brioschi
The acupuncture meridians represent the flow of corporal energy which contains the acupuncture points. Laser acupuncture is a form of acupuncture stimulation by the use of laser. Thermographic images represent the propagation of heat in micro-environmental systems. The objective of this study was to investigate the use of thermographic images to document the changes on the small intestine meridian (S.I.M.) when submitted to laser acupuncture. Another important issue regards to the analysis of the flow direction if it is upward when stimulated by acupuncture points...
November 2016: Lasers in Medical Science
Valentina Vellecco, Emma Mitidieri, Antonella Gargiulo, Vincenzo Brancaleone, Danilo Matassa, Thomas Klein, Franca Esposito, Giuseppe Cirino, Mariarosaria Bucci
AIM: To test the effect of linagliptin in non-obese diabetic (NOD) mice, a murine model of type 1 diabetes, to unveil a possible direct cardiovascular action of dipeptidyl peptidase 4 (DPP-4) inhibitors beyond glycaemia control. METHODS: NOD mice were grouped according to glycosuria levels as NODI: none; NODII: high; NODIII: severe. Linagliptin treatment was initiated once they reached NODII levels. Vascular reactivity was assessed ex vivo on aorta harvested from mice upon reaching NODIII level...
July 27, 2016: Diabetes, Obesity & Metabolism
Pierachille Santus, Dejan Radovanovic
INTRODUCTION: Asthma is a chronic inflammatory disease characterized by bronchial hyper-reactivity. Although many currently available treatment regimens are effective, poor symptom control and refractory severe disease still represent major unmet needs. In the last years, numerous molecular therapeutic targets that interfere with the innate inflammatory response in asthma have been identified. Promising preliminary results concern the signaling cascade promoted by prostaglandin D2 (PGD2) and its receptor antagonists...
September 2016: Expert Opinion on Investigational Drugs
Ali Al-Bayati, Dhanisha Lukka, Audrey E Brown, Mark Walker
BACKGROUND: Hyper-coagulability (elevated thrombin) is a feature of type 2 diabetes and contributes to an increased risk of thrombotic and vascular events. Skeletal muscle is the key peripheral tissue site of insulin resistance in type 2 diabetes. Cultured human skeletal muscle cells were used to explore the effects of thrombin on insulin signalling and glucose uptake. We hypothesized that thrombin affects insulin activity in human skeletal muscle cells which could link the hypercoagulability and insulin resistance in type 2 diabetes...
September 2016: Journal of Diabetes and its Complications
Makoto K Shimada, Ryoko Sanbonmatsu, Yumi Yamaguchi-Kabata, Chisato Yamasaki, Yoshiyuki Suzuki, Ranajit Chakraborty, Takashi Gojobori, Tadashi Imanishi
Short Tandem Repeats (STRs) comprise repeats of one to several base pairs. Because of the high mutability due to strand slippage during DNA synthesis, rapid evolutionary change in the number of repeating units directly shapes the range of repeat-number variation according to selection pressure. However, the remaining questions include: Why are STRs causing repeat expansion diseases maintained in the human population; and why are these limited to neurodegenerative diseases? By evaluating the genome-wide selection pressure on STRs using the database we constructed, we identified two different patterns of relationship in repeat-number polymorphisms between DNA and amino-acid sequences, although both patterns are evolutionary consequences of avoiding the formation of harmful long STRs...
October 2016: Molecular Genetics and Genomics: MGG
Marco Leibinger, Anastasia Andreadaki, Philipp Gobrecht, Evgeny Levin, Heike Diekmann, Dietmar Fischer
Retinal ganglion cells (RGCs) do not normally regenerate injured axons, but die upon axotomy. Although IL-6-like cytokines are reportedly neuroprotective and promote optic nerve regeneration, their overall regenerative effects remain rather moderate. Here, we hypothesized that direct activation of the gp130 receptor by the designer cytokine hyper-IL-6 (hIL-6) might induce stronger RGC regeneration than natural cytokines. Indeed, hIL-6 stimulated neurite growth of adult cultured RGCs with significantly higher efficacy than CNTF or IL-6...
June 28, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
Shaina N Porter, Andrew S Cluster, Robert A J Signer, Jenna Voigtmann, Darlene A Monlish, Laura G Schuettpelz, Jeffrey A Magee
Pten negatively regulates the phosphatidylinositol 3-kinase (PI3K) pathway and is required to maintain quiescent adult hematopoietic stem cells (HSCs). Pten has been proposed to regulate HSCs cell autonomously and non-cell autonomously, but the relative importance of each mechanism has not been directly tested. Furthermore, the cytokines that activate the PI3K pathway upstream of Pten are not well defined. We sought to clarify whether Pten cell autonomously or non-cell autonomously regulates HSC mobilization...
June 14, 2016: Stem Cell Reports
John Chapin, Hunter S Terry, Dorothy Kleinert, Jeffrey Laurence
OBJECTIVE: The objective of this study was to describe complement activation in hemostatic and pathologic states of coagulation and in the acquired and congenital hemolytic anemias. METHODS AND RESULTS: We review published and emerging data on the involvement of the classic, alternative and lectin-based complement pathways in coagulation and the hemolytic anemias. The alternative pathway in particular is always "on," at low levels, and is particularly sensitive to hyper-activation in a variety of physiologic and pathologic states including infection, autoimmune disorders, thrombosis and pregnancy, requiring tight control predicated on a variety of soluble and membrane bound regulatory proteins...
April 2016: Transfusion and Apheresis Science
Ling Chen, Gen Zou, Jingzhi Wang, Jin Wang, Rui Liu, Yanping Jiang, Guoping Zhao, Zhihua Zhou
Calcium signaling plays pivotal roles in the hyphal growth, conidiation, and osmosis sensitivity of fungi through the Ca(2+) /calmodulin-calcineurin-dependent pathway. This study found that an appropriate extracellular Ca(2+) concentration markedly stimulated the hyphal growth, cellulase production, and total protein secretion of the cellulase hyper-producing strain, Trichoderma reesei Rut-C30. Transcription analysis revealed upregulation of not only encoding genes of cellulases and the transcriptional activator XYR1 but also several genes encoding endoplasmic reticulum-chaperones after Ca(2+) addition...
May 2016: Molecular Microbiology
Eleen Y Shum, Samantha H Jones, Ada Shao, Jennifer Dumdie, Matthew D Krause, Wai-Kin Chan, Chih-Hong Lou, Josh L Espinoza, Hye-Won Song, Mimi H Phan, Madhuvanthi Ramaiah, Lulu Huang, John R McCarrey, Kevin J Peterson, Dirk G De Rooij, Heidi Cook-Andersen, Miles F Wilkinson
Gene duplication is a major evolutionary force driving adaptation and speciation, as it allows for the acquisition of new functions and can augment or diversify existing functions. Here, we report a gene duplication event that yielded another outcome--the generation of antagonistic functions. One product of this duplication event--UPF3B--is critical for the nonsense-mediated RNA decay (NMD) pathway, while its autosomal counterpart--UPF3A--encodes an enigmatic protein previously shown to have trace NMD activity...
April 7, 2016: Cell
Pim R A Heckman, Marlies A van Duinen, Eva P P Bollen, Akinori Nishi, Lawrence P Wennogle, Arjan Blokland, Jos Prickaerts
BACKGROUND: The fronto-striatal circuits are the common neurobiological basis for neuropsychiatric disorders, including schizophrenia, Parkinson's disease, Huntington's disease, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and Tourette's syndrome. Fronto-striatal circuits consist of motor circuits, associative circuits, and limbic circuits. All circuits share 2 common features. First, all fronto-striatal circuits consist of hyper direct, direct, and indirect pathways...
April 30, 2016: International Journal of Neuropsychopharmacology
Tina N Ploss, Ewoud Reilman, Carmine G Monteferrante, Emma L Denham, Sjouke Piersma, Anja Lingner, Jari Vehmaanperä, Patrick Lorenz, Jan Maarten van Dijl
BACKGROUND: Bacillus subtilis is an important cell factory for the biotechnological industry due to its ability to secrete commercially relevant proteins in large amounts directly into the growth medium. However, hyper-secretion of proteins, such as α-amylases, leads to induction of the secretion stress-responsive CssR-CssS regulatory system, resulting in up-regulation of the HtrA and HtrB proteases. These proteases degrade misfolded proteins secreted via the Sec pathway, resulting in a loss of product...
2016: Microbial Cell Factories
Jin Chu, Domenico Praticò
Alzheimer's disease (AD) is an age-related, neurodegenerative disorder characterized by cognitive impairment with memory loss, extracellular amyloid beta (Aβ) peptides aggregation, and intracellular hyper-phosphorylated tau neurofibrillary tangles (NFT) accumulation. Although the 5- lipoxygenase (5LO) protein enzyme is well known as an important modulators of oxidation and inflammation, recent work has highlighted the potential role that this pathway may play a direct role in AD pathogenesis. In this review article, we will discuss how the 5LO via the γ-secretase influences Aβ peptides formation, and other molecular pathologies including neuroinflammation, synaptic integrity, and cognitive functions, and provide an assessment of how targeting this protein could lead to novel therapeutics for AD and other related neurodegenerative disorders...
March 19, 2016: Brain Research Bulletin
N Bomer, W den Hollander, H Suchiman, E Houtman, R C Slieker, B T Heijmans, P E Slagboom, R G H H Nelissen, Y F M Ramos, I Meulenbelt
OBJECTIVES: To compare the epigenetic landscape of 3D cell models of human primary articular chondrocytes (hPACs) and human bone-marrow derived mesenchymal stem cells (hBMSCs) and their respective autologous articular cartilage. DESIGN: Using Illumina Infinium HumanMethylation450 BeadChip arrays, the DNA methylation landscape of the different cell sources and autologous cartilage was determined. Pathway enrichment was analyzed using DAVID. RESULTS: Principal Component Analysis (PCA) of methylation data revealed separate clustering of hBMSC samples...
August 2016: Osteoarthritis and Cartilage
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