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Markus R M Fiedler, Lars Barthel, Christin Kubisch, Corrado Nai, Vera Meyer
BACKGROUND: The lifestyle of filamentous fungi depends on the secretion of hydrolytic enzymes into the surrounding medium, which degrade polymeric substances into monomers that are then taken up to sustain metabolism. This feature has been exploited in biotechnology to establish platform strains with high secretory capacity including Aspergillus niger. The accepted paradigm is that proteins become mainly secreted at the tips of fungal hyphae. However, it is still a matter of debate if the amount of growing hyphal tips in filamentous fungi correlates with an increase in secretion, with previous studies showing either a positive or no correlation...
June 16, 2018: Microbial Cell Factories
Nguyen-Quoc-Khanh Le, Quang-Thai Ho, Yu-Yen Ou
Deep learning has been increasingly used to solve a number of problems with state-of-the-art performance in a wide variety of fields. In biology, deep learning can be applied to reduce feature extraction time and achieve high levels of performance. In our present work, we apply deep learning via two-dimensional convolutional neural networks and position-specific scoring matrices to classify Rab protein molecules, which are main regulators in membrane trafficking for transferring proteins and other macromolecules throughout the cell...
June 13, 2018: Analytical Biochemistry
Rifu Xu, Ning Qin, Xiaoxing Xu, Xue Sun, Xiaoxia Chen, Jinghua Zhao
The SLIT2 ligand and ROBO receptors of the SLIT/ROBO pathway are expressed in hen ovarian follicles and have been shown to play critical roles in ovary development, cell proliferation and apoptosis in mammals. However, the exact roles of SLIT2 and the molecular mechanisms of chicken follicle development remain poorly understood. Here, we discovered that high levels of SLIT2 suppress FSHR, GDF9, STAR and CYP11A1 mRNA and protein expression in granulosa cells (GCs) and cell proliferation (p < 0.01). However, these inhibitory effects can be abolished by the siRNA-mediated knockdown of the ROBO1 and ROBO2 receptors...
June 15, 2018: Scientific Reports
Michael Weykamp, Vahagn C Nikolian, Isabel S Dennahy, Gerald A Higgins, Patrick E Georgoff, Henriette Remmer, Mohamed H Ghandour, Hasan B Alam
BACKGROUND: Histone deacetylase inhibitors such as valproic acid (VPA) improve survival in lethal models of hemorrhagic shock and polytrauma. Although VPA is known to modulate transcription, its ability to reduce mortality within minutes of administration suggests involvement of a rapid, posttranslational mechanism. We hypothesized that VPA treatment would cause proteomic changes within minutes of treatment including quantitative and/or posttranslational differences in structural and/or effector proteins...
August 2018: Journal of Surgical Research
Meiping Lu, Chengyun Xu, Qin Zhang, Xiling Wu, Lanfang Tang, Xiangzhi Wang, Junsong Wu, Ximei Wu
Dendritic cell (DC) trafficking from lung to the draining mediastinal lymph nodes (MLNs) is a key step for initiation of T cell responses in allergic asthma. In the present study, we investigate the role of DC-mediated airway inflammation after inhibition of p21-activated kinase-1 (PAK1), an effector of Rac and Cdc42 small GTPases, in the allergen-induced mouse models of asthma. Systemic administration of PAK1 specific inhibitor IPA-3 significantly attenuates not only the airway inflammation but also the airway hyperresponsiveness in a mouse model of ovalbumin-induced asthma...
June 12, 2018: Biochemical Pharmacology
Alba Manresa-Arraut, Flemming Fryd Johansen, Cord Brakebusch, Shohreh Issazadeh-Navikas, Henrik Hasseldam
T-cells are known to be intimately involved in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). T-cell activation is controlled by a range of intracellular signaling pathways regulating cellular responses such as proliferation, cytokine production, integrin expression, and migration. These processes are crucial for the T-cells' ability to mediate inflammatory processes in autoimmune diseases such as MS. RhoA is a ubiquitously expressed small GTPase well described as a regulator of the actin cytoskeleton...
2018: Frontiers in Immunology
James W Clancy, Colin S Sheehan, Christopher J Tricarico, Crislyn D'Souza-Schorey
Epithelial cells form tissues with many functions, including secretion and environmental separation and protection. Glandular epithelial tissues comprise of cysts and tubules that are formed from a polarized, single-epithelial cell layer surrounding a central, fluid-filled lumen. The pathways regulating key processes in epithelial tissue morphogenesis such as mitotic spindle formation are incompletely understood, but are important to investigate, as their dysregulation is a signature of epithelial tumors. Here, we describe a signaling axis that manifests in a defect in mitotic spindle orientation during epithelial growth and cystogenesis...
June 14, 2018: Journal of Biological Chemistry
Tamunonengiyeofori Lawson, Sean Mayes, Grantley W Lycett, Chiew Foan Chin
Fruit ripening is a complex developmental process that involves the synthesis and modification of the cell wall leading up to the formation of an edible fruit. During the period of fruit ripening, new cell wall polymers and enzymes are synthesized and trafficked to the apoplast. Vesicle trafficking has been shown to play a key role in facilitating the synthesis and modification of cell walls in fruits. Through reverse genetics and gene expression studies, the importance of Rab guanosine triphosphatases (GTPases) as integral regulators of vesicle trafficking to the cell wall has been revealed...
June 14, 2018: Biotechnology & Genetic Engineering Reviews
Satoshi Sugita, Hideki Enokida, Hirofumi Yoshino, Kazutaka Miyamoto, Masaya Yonemori, Takashi Sakaguchi, Yoichi Osako, Masayuki Nakagawa
The active form of the small GTPase RAS binds to downstream effectors to promote cell growth and proliferation. RAS signal enhancement contributes to tumorigenesis, invasion, and metastasis in various different cancers. HRAS proto-oncogene GTPase (HRAS), one of the RAS isoforms, was the first human oncogene for which mutations were reported in T24 bladder cancer (BC) cells in 1982, and HRAS mutation or upregulation has been reported in several cancers. According to data from The Cancer Genome Atlas, HRAS expression was significantly upregulated in clinical BC samples compared to healthy samples (P=0...
June 11, 2018: International Journal of Oncology
Marzia Ognibene, Gabriella Pagnan, Danilo Marimpietri, Davide Cangelosi, Michele Cilli, Maria Chiara Benedetti, Renata Boldrini, Alberto Garaventa, Francesco Frassoni, Alessandra Eva, Luigi Varesio, Vito Pistoia, Annalisa Pezzolo
Neuroblastoma is an aggressive, relapse-prone childhood tumor of the sympathetic nervous system that accounts for 15% of pediatric cancer deaths. A distal portion of human chromosome 3p is often deleted in neuroblastoma, this region may contain one or more putative tumor suppressor genes. A 2.54 Mb region at 3p26.3 encompassing the smallest region of deletion pinpointed CHL1 gene, the locus for neuronal cell adhesion molecule close homolog of L1. We found that low CHL1 expression predicted poor outcome in neuroblastoma patients...
May 25, 2018: Oncotarget
Elizabeth Ntantie, Michaela J Allen, Jerrine Fletcher, Augustine T Nkembo, Nazarius S Lamango, Offiong F Ikpatt
Migratory cells form extracellular matrix attachments called focal-adhesions. Focal adhesion assembly and disassembly are regulated by the Rho family of small GTPases. We previously reported that polyisoprenylated cysteinyl amide inhibitors (PCAIs) suppress Rho protein levels, disrupting F-actin cytoskeleton remodeling in the formation of lamellipodia and filopodia. In this study, we investigated whether these observations effect focal adhesion formation, which involves cell surface receptors known as integrins and several signaling/adaptor proteins such as vinculin, α-actinin, Rock kinases and phospho-Myosin Light Chain-2 (p-MLC-2), that foster the linkage of the actin cytoskeleton to the extracellular matrix...
May 25, 2018: Oncotarget
Raghav Kalia, Ray Yu-Ruei Wang, Ali Yusuf, Paul V Thomas, David A Agard, Janet M Shaw, Adam Frost
Mitochondrial inheritance, genome maintenance and metabolic adaptation depend on organelle fission by dynamin-related protein 1 (DRP1) and its mitochondrial receptors. DRP1 receptors include the paralogues mitochondrial dynamics proteins of 49 and 51 kDa (MID49 and MID51) and mitochondrial fission factor (MFF); however, the mechanisms by which these proteins recruit and regulate DRP1 are unknown. Here we present a cryo-electron microscopy structure of full-length human DRP1 co-assembled with MID49 and an analysis of structure- and disease-based mutations...
June 13, 2018: Nature
Najla El Fissi, Manuel Rojo, Aїcha Aouane, Esra Karatas, Gabriela Poliacikova, Claudine David, Julien Royet, Thomas Rival
Charcot-Marie-Tooth disease type 2A (CMT2A) is caused by dominant alleles of the mitochondrial pro-fusion factor Mitofusin 2 (MFN2). To address the consequences of these mutations on mitofusin activity and neuronal function, we generate Drosophila models expressing in neurons the two most frequent substitutions (R94Q and R364W, the latter never studied before) and two others localizing to similar domains (T105M and L76P). All alleles trigger locomotor deficits associated with mitochondrial depletion at neuromuscular junctions, decreased oxidative metabolism and increased mtDNA mutations, but they differently alter mitochondrial morphology and organization...
June 13, 2018: EMBO Reports
Jennifer L Larson-Casey, Linlin Gu, Patricia L Jackson, David E Briles, Joanetha Y Hale, J Edwin Blalock, J Michael Wells, Jessy S Deshane, Yong Wang, Dana Davis, Veena B Antony, Adriana V F Massicano, Suzanne E Lapi, A Brent Carter
RATIONALE: Cigarette smoking is prevalent in the U.S. and is the leading cause of preventable diseases. A prominent complication of smoking is an increase in lower respiratory tract infections (LRTI). Although LRTIs are known to be increased in subjects that smoke, the mechanism(s) by which this occurs is poorly understood. OBJECTIVES: Determine how cigarette smoke (CS) reduced reactive oxygen species (ROS) production by the phagocytic NADPH oxidase (NOX2), which is essential for innate immunity in lung macrophages...
June 13, 2018: American Journal of Respiratory and Critical Care Medicine
Kyung-Ran Park, Eun-Cheol Kim, Jin Tae Hong, Hyung-Mun Yun
Rationale: Characterizing the regulation of bone-resorbing osteoclasts is central to the understanding of the pathogenesis and treatment of bone diseases, such as osteoporosis and periodontitis. 5-hydroxytryptamine (5-HT) has drawn considerable attention for its role in bone; however, it remains unknown whether the intracellular signaling of 5-HT receptors (5-HTRs) is linked to any of the regulatory mechanisms in osteoclasts. Herein, we report 5-HT6 R to be a key regulatory receptor for osteoclastogenesis. Methods: In order to explore the critical role of 5-HT6 R in bone-resorbing osteoclasts, in vitro experiments were performed using mouse whole bone marrow cells isolated from femora and tibiae and In vivo animal experiments were performed using 5-HT6 R-deficient (5-HT6 RKO-/- ) mice, bone resorption mice model, and osteoporosis mice model...
2018: Theranostics
Jonathan S Duke-Cohan, Yuki Ishikawa, Akihiro Yoshizawa, Young-Il Choi, Chin-Nien Lee, Oreste Acuto, Stephan Kissler, Ellis L Reinherz
Multiple autoimmune pathologies are associated with single-nucleotide polymorphisms of the human gene TAGAP , which encodes TAGAP, a guanosine triphosphatase (GTPase)-activating protein. We showed in mice that Tagap-mediated signaling by the sema3E/plexin-D1 ligand-receptor complex attenuates thymocytes' adhesion to the cortex through their β1 -containing integrins. By promoting thymocyte detachment within the cortex of the thymus, Tagap-mediated signaling enabled their translocation to the medulla, which is required for continued thymic selection...
June 12, 2018: Science Signaling
Jingjing Li, Enrique Amaya
The African clawed frog Xenopus has remarkable capacities to heal wounds rapidly and to regenerate complex tissues. Because of its experimental tractability, studies using Xenopus oocytes, embryos, and larvae have contributed extensively to our understanding of the molecular and cellular mechanisms underpinning wound healing and tissue regeneration. In this protocol, we describe wound-healing assays following mechanical or laser injuries of oocytes and multicellular epithelia in Xenopus laevis embryos. We also explain how to perform assays aimed at investigating the cellular and molecular events during wound healing, including gene knockdown and overexpression experiments...
June 12, 2018: Cold Spring Harbor Protocols
Alex M Abel, Aradhana A Tiwari, Zachary J Gerbec, Jason R Siebert, Chao Yang, Nathan J Schloemer, Kate J Dixon, Monica S Thakar, Subramaniam Malarkannan
Natural killer (NK) cells are innate lymphocytes that play essential roles in mediating antitumor immunity. NK cells respond to various inflammatory stimuli including cytokines and stress-induced cellular ligands which activate germline-encoded activation receptors (NKRs), such as NKG2D. The signaling molecules activated downstream of NKRs are well defined; however, the mechanisms that regulate these pathways are not fully understood. IQ domain-containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffold protein...
2018: Frontiers in Immunology
Alejandro López Tobón, Megalakshmi Suresh, Jing Jin, Alessandro Vitriolo, Thorben Pietralla, Kerry Tedford, Michael Bossenz, Kristina Mahnken, Friedemann Kiefer, Giuseppe Testa, Klaus-Dieter Fischer, Andreas W Püschel
The characteristic six layers of the mammalian neocortex develop sequentially as neurons are generated by neural progenitors and subsequently migrate past older neurons to their final position in the cortical plate. One of the earliest steps of neuronal differentiation is the formation of an axon. Small GTPases play essential roles during this process by regulating cytoskeletal dynamics and intracellular trafficking. While the function of GTPases has been studied extensively in cultured neurons and in vivo much less is known about their upstream regulators...
June 11, 2018: Scientific Reports
Jing Cai, Xuewen Song, Wei Wang, Terry Watnick, York Pei, Feng Qian, Duojia Pan
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder caused by mutations in PKD1 or PKD2 and affects one in 500-1000 humans. Limited treatment is currently available for ADPKD. Here we identify the Hippo signaling effector YAP and its transcriptional target, c-Myc, as promoters of cystic kidney pathogenesis. While transgenic overexpression of YAP promotes proliferation and tubule dilation in mouse kidneys, loss of YAP/TAZ or c-Myc suppresses cystogenesis in a mouse ADPKD model resulting from Pkd1 deficiency...
June 11, 2018: Genes & Development
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