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https://www.readbyqxmd.com/read/29228025/a-defect-in-the-inner-kinetochore-protein-cenpt-causes-a-new-syndrome-of-severe-growth-failure
#1
Christina Y Hung, Barbara Volkmar, James D Baker, Johann W Bauer, Emanuela Gussoni, Stefan Hainzl, Alfred Klausegger, Jose Lorenzo, Ivana Mihalek, Olaf Rittinger, Mustafa Tekin, Julia E Dallman, Olaf A Bodamer
Primordial growth failure has been linked to defects in the biology of cell division and replication. The complex processes involved in microtubule spindle formation, organization and function have emerged as a dominant patho-mechanism in these conditions. The majority of reported disease genes encode for centrosome and centriole proteins, leaving kinetochore proteins by which the spindle apparatus interacts with the chromosomes largely unaccounted for. We report a novel disease gene encoding the constitutive inner kinetochore member CENPT, which is involved in kinetochore targeting and assembly, resulting in severe growth failure in two siblings of a consanguineous family...
2017: PloS One
https://www.readbyqxmd.com/read/29227648/quinazolinone-based-anticancer-agents-synthesis-anti-proliferative-sar-anti-tubulin-activity-and-tubulin-co-crystal-structure
#2
Wolfgang Dohle, Fabrice L Jourdan, Gregory Menchon, Andrea E Prota, Paul A Foster, Pascoe Mannion, Ernest Hamel, Mark P Thomas, Philip G Kasprzyk, Eric Ferrandis, Michel O Steinmetz, Mathew P Leese, Barry V L Potter
Quinazolinone-based anti-cancer agents were designed, decorated with functional groups from a 2-methoxyestradiol-based microtubule disruptor series, incorporating the aryl sulfamate motif of steroid sulfatase (STS) inhibitors. The steroidal AB-ring system was mimicked, favoring conformations with an N-2 substituent occupying D-ring space. Evaluation against breast and prostate tumor cell lines identified 7b with DU-145 anti-proliferative activity (GI50 300 nM). A preliminary structure-activity relationship afforded compounds (e...
December 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29226866/11c-cft-pet-in-presymptomatic-ftdp-17-a-potential-biomarker-predicting-onset
#3
Liyong Wu, Jia Liu, Xueyan Feng, Jing Dong, Wei Qin, Yang Liu, Jingjuan Wang, Jie Lu, Kewei Chen, Yuping Wang, Jianping Jia
Frontotemporal dementia with parkinsonism-linked to chromosome 17 (FTDP-17) is a rare autosomal dominant neurodegenerative disorder. Most patients with FTDP-17 carry the mutation in the microtubule-associated protein tau (MAPT) gene. Striatum is predominantly and early affected in FTDP-17. Five family members (two symptomatic patients and three presymptomatic mutation carriers) from a Chinese pedigree of FTDP-17 with N279K mutation in MAPT were enrolled. Parkinsonism was the initial symptom for symptomatic patients...
December 6, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29225789/taking-control-reorganization-of-the-host-cytoskeleton-by-chlamydia
#4
REVIEW
Jordan Wesolowski, Fabienne Paumet
Both actin and microtubules are major cytoskeletal elements in eukaryotic cells that participate in many cellular processes, including cell division and motility, vesicle and organelle movement, and the maintenance of cell shape. Inside its host cell, the human pathogen Chlamydia trachomatis manipulates the cytoskeleton to promote its survival and enhance its pathogenicity. In particular, Chlamydia induces the drastic rearrangement of both actin and microtubules, which is vital for its entry, inclusion structure and development, and host cell exit...
2017: F1000Research
https://www.readbyqxmd.com/read/29225022/the-mitotic-function-of-augmin-is-dependent-on-its-microtubule-associated-protein-subunit-ede1-in-arabidopsis-thaliana
#5
Yuh-Ru Julie Lee, Yuji Hiwatashi, Takashi Hotta, Tingting Xie, John H Doonan, Bo Liu
The augmin complex plays an essential role in microtubule (MT)-dependent MT nucleation by recruiting the γ-tubulin complex to MT walls to generate new MTs [1]. The complex contains eight subunits (designated AUG) including AUG8, which is an MT-associated protein (MAP). When this complex is isolated from etiolated seedlings consisting of primarily interphase cells in Arabidopsis thaliana, AUG8 is an integral component [2]. EDE1 (Endosperm DEfective 1) is homologous to AUG8 [3]. Here, we demonstrate that EDE1, but not AUG8, is associated with acentrosomal spindle and phragmoplast MT arrays in patterns indistinguishable from those of the AUG1-7 subunits and the γ-tubulin complex proteins (GCPs) that exhibit biased localization toward MT minus ends...
November 30, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/29223322/systemic-administration-of-epothilone-d-improves-functional-recovery-of-walking-after-rat-spinal-cord-contusion-injury
#6
Jörg Ruschel, Frank Bradke
Central nervous system (CNS) injuries cause permanent impairments of sensorimotor functions as mature neurons fail to regenerate their severed axons. The poor intrinsic growth capacity of adult CNS neurons and the formation of an inhibitory lesion scar are key impediments to axon regeneration. Systemic administration of the microtubule stabilizing agent epothilone B promotes axon regeneration and recovery of motor function by activating the intrinsic axonal growth machinery and by reducing the inhibitory fibrotic lesion scar...
December 6, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/29223097/recent-advances-in-microtubule-stabilizing-agents
#7
REVIEW
Ya-Nan Cao, Ling-Li Zheng, Dan Wang, Xiao-Xia Liang, Feng Gao, Xian-Li Zhou
Highly dynamic mitotic spindle microtubules are superb therapeutic targets for a group of chemically diverse and clinically successful anticancer drugs. Microtubule-targeted drugs disrupt microtubule dynamics in distinct ways, and they are primarily classified into two groups: microtubule destabilizing agents (MDAs), such as vinblastine, colchicine, and combretastatin-A4, and microtubule stabilizing agents (MSAs), such as paclitaxel and epothilones. Systematic discovery and development of new MSAs have been aided by extensive research on paclitaxel, yielding a large number of promising anticancer compounds...
November 24, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29222800/primary-motor-neuron-culture-to-promote-cellular-viability-and-myelination
#8
Jun-Kyo Francis Suh, Sujin Hyung
A culture system that can recapitulate myelination in vitro will not only help us to better understand the mechanism of myelination and demyelination but also identify possible therapeutic interventions for treating demyelinating diseases. Here, we introduce a simple and reproducible myelination culture system using mouse motor neurons (MNs) and Schwann cells (SCs). Dissociated motor neurons are plated on a feeder layer of SCs, which interact with and wrap around the axons of MNs as they differentiate in culture...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29222784/methods-for-quantitative-analysis-of-axonal-cargo-transport
#9
Matias Alloatti, Luciana Bruno, Tomas L Falzone
Neurons rely on complex axonal transport mechanisms that mediate the intracellular dynamics of proteins, vesicles, and mitochondria along their high polarized structure. The fast improvement of live imaging techniques of fluorescent cargos allowed the identification of the diverse motion properties of different transported molecules. These properties arise as the result of molecular interactions between many players involved in axonal transport. Motor proteins, microtubule tracks, cargo association, and even axonal viscosity contribute to the proper axonal dynamics of different cargos...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29222390/sodium-channel-remodeling-in-subcellular-microdomains-of-murine-failing-cardiomyocytes
#10
Mathilde R Rivaud, Esperanza Agullo-Pascual, Xianming Lin, Alejandra Leo-Macias, Mingliang Zhang, Eli Rothenberg, Connie R Bezzina, Mario Delmar, Carol Ann Remme
BACKGROUND: Cardiac sodium channel (NaV1.5) dysfunction contributes to arrhythmogenesis during pathophysiological conditions. Nav1.5 localizes to distinct subcellular microdomains within the cardiomyocyte, where it associates with region-specific proteins, yielding complexes whose function is location specific. We herein investigated sodium channel remodeling within distinct cardiomyocyte microdomains during heart failure. METHODS AND RESULTS: Mice were subjected to 6 weeks of transverse aortic constriction (TAC; n=32) to induce heart failure...
December 8, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29222186/new-splicing-variants-of-mitochondrial-rho-gtpase-1-miro1-transport-peroxisomes
#11
Kanji Okumoto, Tatsuaki Ono, Ryusuke Toyama, Ayako Shimomura, Aiko Nagata, Yukio Fujiki
Microtubule-dependent long-distance movement of peroxisomes occurs in mammalian cells. However, its molecular mechanisms remain undefined. In this study, we identified three distinct splicing variants of human mitochondrial Rho GTPase-1 (Miro1), each containing amino acid sequence insertions 1 (named Miro1-var2), 2 (Miro1-var3), and both 1 and 2 (Miro1-var4), respectively, at upstream of the transmembrane domain. Miro1-var4 and Miro1-var2 are localized to peroxisomes in a manner dependent on the insertion 1 that is recognized by the cytosolic receptor Pex19p...
December 8, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29222174/phosphatase-pp2a-and-microtubule-mediated-pulling-forces-disassemble-centrosomes-during-mitotic-exit
#12
Stephen J Enos, Martin Dressler, Beatriz Ferreira Gomes, Anthony A Hyman, Jeffrey B Woodruff
Centrosomes are microtubule-nucleating organelles that facilitate chromosome segregation and cell division in metazoans. Centrosomes comprise centrioles that organize a micron-scale mass of protein called pericentriolar material (PCM) from which microtubules nucleate. During each cell cycle, PCM accumulates around centrioles through phosphorylation-mediated assembly of PCM scaffold proteins. During mitotic exit, PCM swiftly disassembles by an unknown mechanism. Here, we used Caenorhabditis elegans embryos to determine the mechanism and importance of PCM disassembly in dividing cells...
December 8, 2017: Biology Open
https://www.readbyqxmd.com/read/29222167/cytoplasmic-linker-protein-clip170-negatively-regulates-tlr4-signaling-by-targeting-the-tlr-adaptor-protein-tirap
#13
Padmaja Jakka, Bindu Bhargavi, Swapna Namani, Subathra Murugan, Gary Splitter, Girish Radhakrishnan
Cytoplasmic linker protein 170 (CLIP170) is a CAP-Gly domain-containing protein that is associated with the plus end of growing microtubules and implicated in various cellular processes, including the regulation of microtubule dynamics, cell migration, and intracellular transport. Our studies revealed a previously unrecognized property and role of CLIP170. We identified CLIP170 as one of the interacting partners of Brucella effector protein TcpB that negatively regulates TLR2 and TLR4 signaling. In this study, we demonstrate that CLIP170 interacts with the TLR2 and TLR4 adaptor protein TIRAP...
December 8, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29221437/evolutionary-characterization-and-transcript-profiling-of-%C3%AE-tubulin-genes-in-flax-linum-usitatissimum-l-during-plant-development
#14
Floriana Gavazzi, Gaia Pigna, Luca Braglia, Silvia Gianì, Diego Breviario, Laura Morello
BACKGROUND: Microtubules, polymerized from alpha and beta-tubulin monomers, play a fundamental role in plant morphogenesis, determining the cell division plane, the direction of cell expansion and the deposition of cell wall material. During polarized pollen tube elongation, microtubules serve as tracks for vesicular transport and deposition of proteins/lipids at the tip membrane. Such functions are controlled by cortical microtubule arrays. Aim of this study was to first characterize the flax β-tubulin family by sequence and phylogenetic analysis and to investigate differential expression of β-tubulin genes possibly related to fibre elongation and to flower development...
December 8, 2017: BMC Plant Biology
https://www.readbyqxmd.com/read/29220790/2-alkoxycarbonyl-3-arylamino-5-substituted-thiophenes-as-a-novel-class-of-antimicrotubule-agents-design-synthesis-cell-growth-and-tubulin-polymerization-inhibition
#15
Romeo Romagnoli, Maria Kimatrai Salvador, Santiago Schiaffino Ortega, Pier Giovanni Baraldi, Paola Oliva, Stefania Baraldi, Luisa Carlota Lopez-Cara, Andrea Brancale, Salvatore Ferla, Ernest Hamel, Jan Balzarini, Sandra Liekens, Elena Mattiuzzo, Giuseppe Basso, Giampietro Viola
Microtubules are recognized as crucial components of the mitotic spindle during cell division, and, for this reason, the microtubule system is an attractive target for the development of anticancer agents. Continuing our search strategy for novel tubulin targeting-compounds, a new series of 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)-5-aryl/heteroarylthiophene derivatives was designed, synthesized and demonstrated to act as tubulin polymerization inhibitors at the colchicine site. A structure-activity relationship study on the phenyl at the 5-position of the thiophene ring was performed by introducing a variety of substituents containing electron-releasing and electron-withdrawing groups, with the 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold being the minimum structural requirement for activity...
December 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29219729/drought-stress-responses-in-maize-are-diminished-by-piriformospora-indica
#16
Wenying Zhang, Jun Wang, Le Xu, Aiai Wang, Lan Huang, Hewei Du, Lijuan Qiu, Ralf Oelmüller
As an endophytic fungus of Sebacinales, Piriformospora indica promotes plant growth and resistance to abiotic stress, including drought. Colonization of maize roots promoted the leaf size, root length and number of tap roots. Under drought stress, the maize seedlings profited from the presence of the fungus and performed visibly better than the uncolonized controls. To identify genes and biological processes involved in growth promotion and drought tolerance conferred by P. indica, the root transcriptome of colonized and uncolonized seedlings was analyzed 0, 6 and 12 h after drought stress (20% polyethylene glycol 6000)...
December 8, 2017: Plant Signaling & Behavior
https://www.readbyqxmd.com/read/29219183/mechanical-unloading-reduces-microtubule-actin-crosslinking-factor-1-expression-to-inhibit-%C3%AE-catenin-signaling-and-osteoblast-proliferation
#17
Chong Yin, Yan Zhang, Lifang Hu, Ye Tian, Zhihao Chen, Dijie Li, Fan Zhao, Peihong Su, Xiaoli Ma, Ge Zhang, Zhiping Miao, Liping Wang, Airong Qian, Cory J Xian
Mechanical unloading was considered a major threat to bone homeostasis, and has been shown to decrease osteoblast proliferation although the underlying mechanism is unclear. Microtubule actin crosslinking factor 1 (MACF1) is a cytoskeletal protein that regulates cellular processes and Wnt/β-catenin pathway, an essential signaling pathway for osteoblasts. However, the relationship between MACF1 expression and mechanical unloading, and the function and the associated mechanisms of MACF1 in regulating osteoblast proliferation are unclear...
December 8, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29219017/eribulin-in-advanced-breast-cancer-safety-efficacy-and-new-perspectives
#18
Ornella Garrone, Emanuela Miraglio, Anna Maria Vandone, Paola Vanella, Daniele Lingua, Marco C Merlano
Eribulin is a synthetic analog of halichondrin B belonging to microtubule-targeted agents with a distinct mechanism of inhibition of microtubule dynamics. This molecule has multiple nonmitotic effects on tumor biology, exhibiting effects on epithelial-mesenchimal transition and tumor vasculature. We review here preclinical and clinical studies on eribulin. The mitotic and nonmitotic effects together with its favorable safety profile make eribulin a unique drug with high potential in the treatment of metastatic breast cancer...
December 2017: Future Oncology
https://www.readbyqxmd.com/read/29218765/deregulation-of-autophagy-in-postmortem-brains-of-machado-joseph-disease-patients
#19
Annie Sittler, Marie-Paule Muriel, Martina Marinello, Alexis Brice, Wilfred den Dunnen, Sandro Alves
Autophagy, the major pathway for protein turnover, is critical to maintain cellular homeostasis and has been implicated in neurodegenerative diseases. The aim of this research was to analyze the expression of autophagy markers in postmortem brains from Machado-Joseph disease (MJD) patients. The expression of autophagy markers in the cerebellum and the oculomotor nucleus from MJD patients and age-matched controls with no signs of neuropathology was inspected postmortem by immunohistochemistry (IHC) and Western blot...
December 8, 2017: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/29217824/soluble-tau-has-devastating-effects-on-the-structural-plasticity-of-hippocampal-granule-neurons
#20
M Bolós, N Pallas-Bazarra, J Terreros-Roncal, J R Perea, J Jurado-Arjona, J Ávila, M Llorens-Martín
Tau is a neuronal microtubule-associated protein with countless physiological functions. Although the detrimental effects of insoluble aggregated Tau have been widely studied, recent evidence supports the notion that soluble Tau (composed mostly of monomers and dimers) is also toxic for neurons. Here we evaluated the long-term impact of a single stereotaxic injection of human soluble Tau on hippocampal granule neurons in mice. At the ultrastructural level, soluble Tau reduced the number of afferent synapses and caused a dramatic depletion of synaptic vesicles both in afferent and efferent synapses...
December 8, 2017: Translational Psychiatry
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