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Mary H Patton, Katherine E Padgett, Paige N McKeon, Shao-Gang Lu, Thomas W Abrams, Brian N Mathur
Decades of work in Aplysia californica established the general rule that principles of synaptic plasticity and their molecular mechanisms are evolutionarily conserved from mollusks to mammals. However, an exquisitely sensitive, activity-dependent homosynaptic mechanism that protects against the depression of neurotransmitter release in Aplysia sensory neuron terminals has, to date, not been uncovered in other animals, including mammals. Here, we discover that depression at a mammalian synapse that is implicated in habit formation and habit learning acceleration by ethanol, the fast-spiking interneuron (FSI) to medium spiny principal projection neuron (MSN) synapse of the dorsolateral striatum, is subject to this type of synaptic protection...
October 12, 2018: Neuropharmacology
Qiong Zhang, Xu Han, Jinfeng Chen, Xiaomei Xie, Jiafeng Xu, Yang Zhao, Jie Shen, Lin Hu, Pinglong Xu, Hai Song, Long Zhang, Bin Zhao, Ying-Jie Wang, Zongping Xia
A proper inflammatory response is critical to the restoration of tissue homeostasis after injury or infection, but how such a response is modulated by the physical properties of the cellular and tissue microenvironment is not fully understood. Here, using H358, HeLa and HEK293T cells, we report that cell density can modulate inflammatory responses through the Hippo signaling pathway. We found that NF-κβ activation through the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) is not affected by cell density...
October 12, 2018: Journal of Biological Chemistry
Shangfeng Gao, Tong Zhang, Lei Jin, Dong Liang, Guangwei Fan, Yunnong Song, Paul J Lucassen, Rutong Yu, Dick F Swaab
Aberrant regulation and activity of synaptic proteins may cause synaptic pathology in the prefrontal cortex (PFC) of mood disorder patients. Carboxy-terminal PDZ ligand of NOS1 (CAPON) is a critical scaffold protein linked to synaptic proteins like nitric oxide synthase 1, synapsins. We hypothesized that CAPON is altered together with its interacting synaptic proteins in the PFC in mood disorder patients and may contribute to depression-like behaviors in mice subjected to chronic unpredictable mild stress (CUMS)...
October 11, 2018: Cerebral Cortex
B D Lynn, Xinbo Li, S G Hormuzdi, E K Griffiths, C J McGlade, J I Nagy
Electrical synapses in the mammalian central nervous system (CNS) are increasingly recognized as highly complex structures for mediation of neuronal communication, both with respect to their capacity for dynamic short and long-term modification in efficacy of synaptic transmission and their multi-molecular regulatory and structural components. These two characteristics are inextricably linked, such that understanding of mechanisms that contribute to electrical synaptic plasticity requires knowledge of the molecular composition of electrical synapses and the functions of proteins associated with these synapses...
October 8, 2018: European Journal of Neuroscience
Tzu-Cheng Su, Chun-Yu Chen, Wen-Che Tsai, Hui-Ting Hsu, Hsu-Heng Yen, Wen-Wei Sung, Chih-Jung Chen
OBJECTIVE: PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK) regulates components of the cell cycle, including cell growth, immune responses, DNA damage repair, apoptosis, and inflammation. PBK/TOPK may also accelerate tumorigenesis in colorectal cancer. METHODS: We investigated the impact of PBK/TOPK on the clinical outcome of colorectal cancer patients to further identify its role in colorectal cancer. PBK/TOPK immunoreactivity was analyzed by immunohistochemistry in 162 cancer specimens from primary colorectal cancer patients...
2018: PloS One
Giulia Morra, Massimiliano Meli, Giorgio Colombo
Here, we introduce a novel computational method to identify the protein substructures most likely to support the functionally-oriented structural deformations that occur upon ligand-binding. To this aim, we study of the modulation of protein energetics along the trajectory of a Molecular Dynamics simulation of different proteins in the presence and in the absence of their respective ligands, namely human FGF, human second PDZ from human PTP1E/PTPL1, and the N terminal domain of human Hsp90. The method is based on the idea that a subset of protein residues (hotspots) may initiate the global response via the disassembly and reassembly of interactions, which is reflected in the modulation of the overall protein energetics...
October 3, 2018: Journal of Chemical Theory and Computation
Lívia J Tavares, Erica D de Avila, Marlise I Klein, Beatriz H D Panariello, Denise M P Spolidório, Ana Cláudia Pavarina
Antimicrobial photodynamic therapy (aPDT) kills several planktonic pathogens. However, the susceptibility of biofilm-derived anaerobic bacteria to aPDT is poorly characterized. Here, we evaluated the effect of Photodithazine (PDZ)-mediated aPDT on Fusobacterium nucleatum and Porphyromonas gingivalis biofilms. In addition, aPDT was tested with metronidazole (MTZ) to explore the potential antimicrobial effect of the treatment. The minimum inhibitory concentration (MIC) of MTZ was defined for each bacterial species...
November 2018: Journal of Photochemistry and Photobiology. B, Biology
Hidekazu Hiroaki, Kaori Satomura, Natsuko Goda, Yukako Nakakura, Minami Hiranuma, Takeshi Tenno, Daizo Hamada, Takahisa Ikegami
Background : The tight junction is an intercellular adhesion complex composed of claudins (CLDs), occludin, and the scaffolding proteins zonula occludens 1 (ZO-1) and its two paralogs ZO-2 and ZO-3. ZO-1 is a multifunctional protein that contains three PSD95/Discs large/ZO-1(PDZ) domains. A key functional domain of ZO-1 is the first PDZ domain (ZO-1(PDZ1)) that recognizes the conserved C-termini of CLDs. Methods : In this study, we confirmed that phosphoinositides bound directly to ZO-1(PDZ1) by biochemical and solution NMR experiments...
September 26, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Shengchang Tang, Hao Ma, Hsiu-Chung Tu, Huei-Ren Wang, Po-Chiao Lin, Kristi S Anseth
Hydrogels with tunable viscoelasticity hold promise as materials that can recapitulate many dynamic mechanical properties found in native tissues. Here, covalent adaptable boronate bonds are exploited to prepare hydrogels that exhibit fast relaxation, with relaxation time constants on the order of seconds or less, but are stable for long-term cell culture and are cytocompatible for 3D cell encapsulation. Using human mesenchymal stem cells (hMSC) as a model, the fast relaxation matrix mechanics are found to promote cell-matrix interactions, leading to spreading and an increase in nuclear volume, and induce yes-associated protein/PDZ binding domain nuclear localization at longer times...
September 2018: Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
Amir Kedan, Nandini Verma, Ashish Saroha, Michal Shreberk-Shaked, Anna-Katharina Müller, Nishanth Ulhas Nair, Sima Lev
The tumor suppressor Hippo pathway negatively regulates the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) to inhibit cell growth and control organ size, whereas activation of YAP and TAZ is implicated in tumorigenesis and cancer metastasis. Here, we report that the nonreceptor tyrosine kinase PYK2 positively regulates TAZ and YAP transcriptional activity in triple-negative breast cancer (TNBC). We found that inhibition of PYK2 expression or its kinase activity substantially affects the steady-state level of TAZ and markedly facilitates its proteasomal degradation...
September 24, 2018: Cell Death & Disease
Laurent Gagnoux-Palacios, Hala Awina, Stéphane Audebert, Aurélie Rossin, Magali Mondin, Franck Borgese, Carlota Planas-Botey, Amel Mettouchi, Jean-Paul Borg, Anne-Odile Hueber
Finely tuned regulation of epithelial cell death maintains tissue integrity and homeostasis. At the cellular level, life and death decisions are controlled by environmental stimuli such as the activation of death receptors. We show that cell polarity and adherens junction formation prevent proapoptotic signals emanating from the Fas death receptor. Fas is sequestered in E-cadherin actin-based adhesion structures that are less able to induce downstream apoptosis signaling. Using a proteomic-based approach, we find that the polarity molecule Dlg1 interacts with the C-terminal PDZ-binding site in Fas and that this interaction decreases formation of the death-inducing complex upon engagement with Fas ligand (FasL), thus acting as an additional cell death protection mechanism...
September 21, 2018: Journal of Cell Biology
Anne Y Warren, Charlie E Massie, Kate Watt, Katarina Luko, Folake Orafidiya, Luke A Selth, Hisham Mohammed, Brinder S Chohan, Suraj Menon, Ajoeb Baridi, Wanfeng Zhao, Carles Escriu, Thanakorn Pungsrinont, Clive D'Santos, Xiaoping Yang, Chris Taylor, Arham Qureshi, Vincent R Zecchini, Greg L Shaw, Scott M Dehm, Ian G Mills, Jason S Carroll, Wayne D Tilley, Iain J McEwan, Aria Baniahmad, David E Neal, Mohammad Asim
Elucidation of mechanisms underlying the increased androgen receptor (AR) activity and subsequent development of aggressive prostate cancer (PrCa) is pivotal in developing new therapies. Using a systems biology approach, we interrogated the AR-regulated proteome and identified PDZ binding kinase (PBK) as a novel AR-regulated protein that regulates full-length AR and AR variants (ARVs) activity in PrCa. PBK overexpression in aggressive PrCa is associated with early biochemical relapse and poor clinical outcome...
September 20, 2018: Oncogene
He Shen, Nuo Yang, Alexander M Truskinovsky, Yanmin Chen, Ashley L Mussell, Norma Nowak, Lester Kobzik, Costa Frangou, Jianmin Zhang
Deregulated expression of the transcriptional co-activator with PDZ-binding motif (WWTR1/TAZ) is a common feature of basal-like breast cancer (BLBC). Yet, how oncogenic TAZ regulates cell cycle progression and proliferation in breast cancer remains poorly understood, and whether TAZ is required for tumor maintenance has not been established. Here, using an integrative oncogenomic approach, TAZ-dependent cellular programs essential for tumor growth and progression were identified. Significantly, TAZ-driven tumor cells required sustained TAZ expression, given that its withdrawal impaired both genesis and maintenance of solid tumors...
September 20, 2018: Molecular Cancer Research: MCR
Kiminori Hori, Kasumi Ajioka, Natsuko Goda, Asako Shindo, Maki Takagishi, Takeshi Tenno, Hidekazu Hiroaki
Most solid tumors have their own cancer stem cells (CSCs), which are resistant to standard chemo-therapies. Recent reports have described that Wnt pathway plays a key role in self-renewal and tumorigenesis of CSCs. Regarding the Wnt/β-catenin pathway, Dvl (mammalian Disheveled) is an attractive target of drug discovery. After analyzing the PDZ domain of human Dvl1 (Dvl1-PDZ) using NMR, we subjected it to preliminary NMR titration studies with 17 potential PDZ-binding molecules including CalBioChem-322338, a commercially available Dvl PDZ domain inhibitor...
2018: Frontiers in Pharmacology
Qiqi Wang, Ran Song, Chunjuan Zhao, Hua Liu, Ying Yang, Siyu Gu, Duiping Feng, Junqi He
HPV16 is the predominant type of HPV causing invasive cervical cancer. However, the underlying molecular mechanism of the unparalleled carcinogenic power of HPV16 compared with other types of High-risk (HR)-HPV including HPV18 is still elusive. The PDZ binding motif (PBM) of high-risk HPV E6 plays an important role in neoplasia and progression of cervical cancer. HPV16 E6 rather than HPV18 E6, interacted with NHERF1 by its PBM region, and induced degradation of NHERF1. NHERF1 retarded the assembly of cytoskeleton by downregulation of ACTN4, thereby inhibited the migration and invasion of cervical cancer cells in both cell and mouse model...
September 19, 2018: International Journal of Cancer. Journal International du Cancer
Gian Marco Elisi, Matteo Santucci, Domenico D'Arca, Angela Lauriola, Gaetano Marverti, Lorena Losi, Laura Scalvini, Maria Laura Bolognesi, Marco Mor, Maria Paola Costi
Drug repurposing is a fast and consolidated approach for the research of new active compounds bypassing the long streamline of the drug discovery process. Several drugs in clinical practice have been reported for modulating the major Hippo pathway's terminal effectors, namely YAP (Yes1-associated protein), TAZ (transcriptional co-activator with PDZ-binding motif) and TEAD (transcriptional enhanced associate domains), which are directly involved in the regulation of cell growth and tissue homeostasis. Since this pathway is known to have many cross-talking phenomena with cell signaling pathways, many efforts have been made to understand its importance in oncology...
September 14, 2018: Cancers
Nelly R Hajizadeh, Joanna Pieprzyk, Petr Skopintsev, Ali Flayhan, Dmitri I Svergun, Christian Löw
The scaffolding protein PDZK1 has been associated with the regulation of membrane transporters. It contains four conserved PDZ domains, which typically recognize a 3-5-residue long motif at the C terminus of the binding partner. The atomic structures of the individual domains are available but their spatial arrangement in the full-length context influencing the binding properties remained elusive. Here we report a systematic study of full-length PDZK1 and deletion constructs using small-angle X-ray scattering, complemented with biochemical and functional studies on PDZK1 binding to known membrane protein partners...
August 16, 2018: Structure
Zonghui Ding, Harshil Dhruv, Aneta Kwiatkowska-Piwowarczyk, Rosamaria Ruggieri, Jean Kloss, Marc Symons, Patrick Pirrotte, Jennifer M Eschbacher, Nhan L Tran, Joseph C Loftus
Glioblastoma multiforme (GBM) is the most common type of malignant brain tumors in adults and has a dismal prognosis. The highly aggressive invasion of malignant cells into the normal brain parenchyma renders complete surgical resection of GBM tumors impossible, increases resistance to therapeutic treatment, and leads to near-universal tumor recurrence. We have previously demonstrated that TROY (TNFRSF19) plays an important role in glioblastoma cell invasion and therapeutic resistance. However, the potential downstream effectors of TROY signaling have not been fully characterized...
October 2018: Neoplasia: An International Journal for Oncology Research
Inna S Yanez Orozco, Frank A Mindlin, Junyan Ma, Bo Wang, Brie Levesque, Matheu Spencer, Soheila Rezaei Adariani, George Hamilton, Feng Ding, Mark E Bowen, Hugo Sanabria
Previous studies of the N-terminal PDZ tandem from PSD-95 produced divergent models and failed to identify interdomain contacts stabilizing the structure. We used ensemble and single-molecule FRET along with replica-exchange molecular dynamics to fully characterize the energy landscape. Simulations and experiments identified two conformations: an open-like conformation with a small contact interface stabilized by salt bridges, and a closed-like conformation with a larger contact interface stabilized by surface-exposed hydrophobic residues...
September 13, 2018: Nature Communications
Khundrakpam Herojit Singh, Savita Yadav, Deepak Kumar, Bichitra Kumar Biswal
High-temperature requirement A (HtrA) proteins, which are members of the heat-shock-induced serine protease family, are involved in extracytoplasmic protein quality control and bacterial survival strategies under stress conditions, and are associated with the virulence of several pathogens; they are therefore major drug targets. Mycobacterium tuberculosis possesses three putative HtrAs: HtrA1 (Rv1223), HtrA2 (Rv0983) and HtrA3 (Rv0125). Each has a cytoplasmic region, a transmembrane helix and a periplasmic region...
September 1, 2018: Acta Crystallographica. Section D, Structural Biology
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