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Cell Biology
The N-terminal dimerization is required for TDP-43 splicing activity
Jul 22, 2017   Scientific Reports
Jiang LL, Xue W, Hong JY, Zhang JT, Li MJ, Yu SN, He JH, Hu HY
The N-terminal dimerization is required for TDP-43 splicing activity
Jul 22, 2017
Scientific Reports
TDP-43 is a nuclear factor that functions in promoting pre-mRNA splicing. Deletion of the N-terminal domain (NTD) and nuclear localization signal (NLS) (i.e., TDP-35) results in mislocalization to cytoplasm and formation of inclusions. However, how the NTD functions in TDP-43 activity and proteinopathy remains largely unknown. Here, we studied the structure and function of the NTD in inclusion formation and pre-mRNA splicing of TDP-43 by using biochemical and biophysical approaches. We found that TDP-43 NTD forms a homodimer in solution in a concentration-dependent manner, and formation of intermolecular disulfide results in further tetramerization. Based on the NMR structure of TDP-43 NTD, the dimerization interface centered on Leu71 and Val72 around the β7-strand was defined by mutagenesis and size-exclusion chromatography. Cell experiments revealed that the N-terminal dimerization plays roles in protecting TDP-43 against formation of cytoplasmic inclusions and enhancing pre-mRNA splicing activity of TDP-43 in nucleus. This study may provide mechanistic insights into the physiological function of TDP-43 and its related proteinopathies.
Assessment of Hepatocellular Carcinoma Metastasis Glycobiomarkers Using Advanced Quantitative N-glycoproteome Analysis
Jul 24, 2017   Frontiers In Physiology
Liu T, Shang S, Li W, Qin X, Sun L, Zhang S, Liu Y
Assessment of Hepatocellular Carcinoma Metastasis Glycobiomarkers Using Advanced Quantitative N-glycoproteome Analysis
Jul 24, 2017
Frontiers In Physiology
Hepatocelluar carcinoma (HCC) is one of the most common malignant tumors with high incidence of metastasis. Glycosylation is involved in fundamental molecular and cell biology process occurring in cancer including metastasis formation. In this study, lectin microarray, lectin blotting, lectin affinity chromatography and tandem 18O stable isotope labeling coupled with liquid chromatography-mass spectrometer (LC-MS) analysis were applied to quantify the changes in N-glycosite occupancy for HCC metastasis serum. Firstly, lectin microarray was used to screen glycoforms and Phaseolus vulgaris Leucoagglutinin (PHA-L) reactive structure (β1,6-GlcNAc branched N-glycan) was found to be increased significantly in HCC patients with metastasis compared with those with non-metastasis. Then, PHA-L affinity glycoproteins were enriched followed by N-glycosite occupancy measurement with strategy of tandem 18O stable isotope labeling. 11 glycoproteins with significantly changed N-glycosite occupancy were identified, they were associated with cell migration, invasion and adhesion through p38 mitogen-activated protein kinase signaling pathway and nuclear factor kappa B signaling pathway. Quantification of N-glycosite occupancy for PHA-L reactive glycoproteins could help to discover important glycoproteins of potential clinically significance in terms of HCC etiology. Also, understanding of N-glycosite occupancy alterations will aid the characterization of molecular mechanism of HCC metastasis as well as establishment of novel glycobiomarkers.
Meeting report - Emerging Concepts in Cell Organization
Jul 24, 2017   Journal Of Cell Science
Teis D, Kukulski W
Meeting report - Emerging Concepts in Cell Organization
Jul 24, 2017
Journal Of Cell Science
New concepts in cell organization emerged in a medieval castle during a snowy week in January 2017 in the middle of the Austrian Alps. The occasion was the 10th Annaberg EMBO workshop in Goldegg am See; organized by Gabriele Seethaler, Catherine Rabouille and Marino Zerial. There were 95 participants, including many who gave talks and presented posters, enjoying a familial and trusting atmosphere that stimulated lively exchange of (unpublished) results, new ideas and thoughts. © 2017. Published by The Company of Biologists Ltd.
Isofraxidin, a coumarin component improves high-fat diet induced hepatic lipid homeostasis disorder and macrophage inflammation in mice
Jul 24, 2017   Food & Function
Li J, Li X, Li Z, Zhang L, Liu Y, Ding H, Yin S
Isofraxidin, a coumarin component improves high-fat diet induced hepatic lipid homeostasis disorder and macrophage inflammation in mice
Jul 24, 2017
Food & Function
Isofraxidin (IF) is a coumarin compound produced in the functional foods Siberian ginseng and Apium graveolens. The first objective of this study was to investigate the protective effects and putative methods of IF in combating lipotoxicity in vitro and in vivo. Oleic acid was used to induce lipid turbulence in human hepatoma cells (HepG2). Alterations in triglyceride metabolism, inflammation and oxidative status were monitored. Results show that IF mainly reduced triglyceride accumulation, TNF-α release and ROS activation in metabolic disordered cells. Next, a high-fat diet, which induced a non-alcoholic fatty liver disease, was used to evaluate the therapeutic action of IF. Our results show that treatment with IF significantly inhibited the high-fat diet-induced elevation in body weight, liver weight, lipid metabolism (TG, TC and HDL-C) and hepatic injury in mice. In biochemical terms, treatment with IF resulted in enhanced phosphorylation of AMPKα and ACC, as well as reduced hepatic expression of FAS and HMGC, suggesting that lipogenesis was compromised. We also found robust evidence that treatment with IF significantly depleted infiltrating inflammatory cells (F4/80+ Kupffer cells and CD68+ macrophages) and inflammatory cytokine release (TNFα and IL-6). Moreover, the anti-inflammatory activity in IF-treated hepatic tissue correlated with down-regulation of TLR4 expression and NF-κB transcription. In sum, these results suggest that IF might play a protective role against lipid metabolism disorder induced by a high-fat diet via inhibition of lipid production and inflammation in the liver.
Cortical forces and CDC-42 control clustering of PAR proteins for Caenorhabditis elegans embryonic polarization
Jul 24, 2017   Nature Cell Biology Add nature.com free-link Cancel
Wang SC, Low TYF, Nishimura Y, Gole L, Yu W, Motegi F
Cortical forces and CDC-42 control clustering of PAR proteins for Caenorhabditis elegans embryonic polarization
Jul 24, 2017
Nature Cell Biology
Cell polarization enables zygotes to acquire spatial asymmetry, which in turn patterns cellular and tissue axes during development. Local modification in the actomyosin cytoskeleton mediates spatial segregation of partitioning-defective (PAR) proteins at the cortex, but how mechanical changes in the cytoskeleton are transmitted to PAR proteins remains elusive. Here we uncover a role of actomyosin contractility in the remodelling of PAR proteins through cortical clustering. During embryonic polarization in Caenorhabditis elegans, actomyosin contractility and the resultant cortical tension stimulate clustering of PAR-3 at the cortex. Clustering of atypical protein kinase C (aPKC) is supported by PAR-3 clusters and is antagonized by activation of CDC-42. Cortical clustering is associated with retardation of PAR protein exchange at the cortex and with effective entrainment of advective cortical flows. Our findings delineate how cytoskeleton contractility couples the cortical clustering and long-range displacement of PAR proteins during polarization. The principles described here would apply to other pattern formation processes that rely on local modification of cortical actomyosin and PAR proteins.
Adrenocorticotropic hormone and 1,25-dihydroxyvitamin D3 enhance human osteogenesis in vitro by synergistically accelerating the expression of bone-specific genes
Jul 24, 2017   Laboratory Investigation; A Journal Of Technical Methods And Pathology
Tourkova IL, Liu L, Sutjarit N, Larrouture QC, Luo J, Robinson LJ, Blair HC
Adrenocorticotropic hormone and 1,25-dihydroxyvitamin D3 enhance human osteogenesis in vitro by synergistically accelerating the expression of bone-specific genes
Jul 24, 2017
Laboratory Investigation; A Journal Of Technical Methods And Pathology
To improve definition of the physical and hormonal support of bone formation, we studied differentiation of human osteoblasts in vitro at varying combinations of ACTH, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D), and extracellular calcium, with and without added cortisol. Bone mineralization, alkaline phosphatase activity, and osteoblast-specific markers RunX2, osterix, and collagen I increased with 10 pM ACTH, 10 nM 1,25(OH)2D, or at 2 mM calcium with important synergistic activity of combinations of any of these stimuli. Signals induced by ACTH at 10-30 min included cAMP, TGF-β, and Erk1/2 phosphorylation. Affymetrix gene expression analysis showed that 2 h treatment of ACTH or 1,25(OH)2D increased the expression of bone regulating and structural mRNAs, including collagen I, biglycan, the vitamin D receptor, and TGF-β. Accelerating expression of these bone-specific genes was confirmed by quantitative PCR. Expression of 1,25(OH)2D 1α-hydroxylase (1α-hydroxylase) increased with 1,25(OH)2D, ACTH, and extracellular calcium from 0.5 to 2 mM. Unlike renal 1α-hydroxylase, in osteoblasts, 1α-hydroxylase activity is independent of parathyroid hormone. In keeping with calcium responsivity, calcium-sensing receptor RNA and protein increased with 10 nM ACTH or 1,25(OH)2D. Inclusion of 200 nM cortisol or 10 nM ACTH in differentiation media blunted osteoblasts alkaline phosphatase response to 1,25(OH)2D and calcium. Our results point to the importance of ACTH in bone maintenance and that extra skeletal (renal) 1,25(OH)2D is required for bone mineralization despite 1α-hydroxylase expression by osteoblasts.Laboratory Investigation advance online publication, 24 July 2017; doi:10.1038/labinvest.2017.62.
Glutamate receptor-like channels are essential for chemotaxis and reproduction in mosses
Jul 24, 2017   Nature Add nature.com free-link Cancel
Ortiz-Ramírez C, Michard E, Simon AA, Damineli DSC, Hernández-Coronado M, Becker JD, Feijó JA
Glutamate receptor-like channels are essential for chemotaxis and reproduction in mosses
Jul 24, 2017
Nature
Glutamate receptors are well characterized channels that mediate cell-to-cell communication during neurotransmission in animals. Nevertheless, information regarding their functional role in organisms without nervous systems is still limited. In plants, Glutamate Receptor-like (GLR) genes have been implicated in defence against pathogens, reproduction, control of stomata aperture and light signal transduction1-5. However, the numerous GLR genes present in angiosperm genomes (20 to 70)6 has prevented the observation of strong phenotypes in loss-of-function mutants. Here, we show that in the moss Physcomitrella patens, a basal land plant, mutation of GLR genes cause sperm failure in targeting the female reproductive organs. In addition, we show that GLR genes encode non-selective Ca2+ permeable channels that can regulate cytoplasmic Ca2+ and are needed to induce the expression of a BELL1-like transcription factor essential for zygote development. Our work reveals novel functions for GLRs in sperm chemotaxis and transcriptional regulation. Sperm chemotaxis is essential for fertilization in both animals and early land plants like bryophytes and pteridophytes. Therefore, our results are suggestive that ionotropic glutamate receptors may have been conserved throughout plant evolution to mediate cell-to-cell communication during sexual reproduction.
Cell biology of spinal cord injury and repair
Jul 24, 2017   The Journal Of Clinical Investigation
O'Shea TM, Burda JE, Sofroniew MV
Cell biology of spinal cord injury and repair
Jul 24, 2017
The Journal Of Clinical Investigation
Spinal cord injury (SCI) lesions present diverse challenges for repair strategies. Anatomically complete injuries require restoration of neural connectivity across lesions. Anatomically incomplete injuries may benefit from augmentation of spontaneous circuit reorganization. Here, we review SCI cell biology, which varies considerably across three different lesion-related tissue compartments: (a) non-neural lesion core, (b) astrocyte scar border, and (c) surrounding spared but reactive neural tissue. After SCI, axon growth and circuit reorganization are determined by neuron-cell-autonomous mechanisms and by interactions among neurons, glia, and immune and other cells. These interactions are shaped by both the presence and the absence of growth-modulating molecules, which vary markedly in different lesion compartments. The emerging understanding of how SCI cell biology differs across lesion compartments is fundamental to developing rationally targeted repair strategies.
Towards a unified analysis of brain maturation and aging across the entire lifespan: A MRI analysis
Jul 24, 2017   Human Brain Mapping
Coupé P, Catheline G, Lanuza E, Manjón JV, Alzheimer's Disease Neuroimaging Initiative
Towards a unified analysis of brain maturation and aging across the entire lifespan: A MRI analysis
Jul 24, 2017
Human Brain Mapping
There is no consensus in literature about lifespan brain maturation and senescence, mainly because previous lifespan studies have been performed on restricted age periods and/or with a limited number of scans, making results instable and their comparison very difficult. Moreover, the use of nonharmonized tools and different volumetric measurements lead to a great discrepancy in reported results. Thanks to the new paradigm of BigData sharing in neuroimaging and the last advances in image processing enabling to process baby as well as elderly scans with the same tool, new insights on brain maturation and aging can be obtained. This study presents brain volume trajectory over the entire lifespan using the largest age range to date (from few months of life to elderly) and one of the largest number of subjects (N = 2,944). First, we found that white matter trajectory based on absolute and normalized volumes follows an inverted U-shape with a maturation peak around middle life. Second, we found that from 1 to 8-10 y there is an absolute gray matter (GM) increase related to body growth followed by a GM decrease. However, when normalized volumes were considered, GM continuously decreases all along the life. Finally, we found that this observation holds for almost all the considered subcortical structures except for amygdala which is rather stable and hippocampus which exhibits an inverted U-shape with a longer maturation period. By revealing the entire brain trajectory picture, a consensus can be drawn since most of the previously discussed discrepancies can be explained. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
Bioinformatics Analysis in Menopause transition promotes distinct modulation in calvaria and bone marrow osteoblastic cells
Jul 24, 2017   Cell Biology International
Li C, Wang Y, Luan H, Zhang H, Xu Y
Bioinformatics Analysis in Menopause transition promotes distinct modulation in calvaria and bone marrow osteoblastic cells
Jul 24, 2017
Cell Biology International
We read with great interest the recent report by Semeghini et al., "Menopause transition promotes distinct modulation of mRNAs and miRNAs expression in calvaria and bone marrow osteoblastic cells," which appeared on 24 May 2017 in Cell Biology International. The results of the report are very helpful for us, however, from our perspective, the author's methods in bioinformatics analysis is inappropriate: Student's t-tests is an inappropriate statistical method for detecting differentially expressed mRNA or miRNA in osteoblastic cells from calvaria of ovariectomized rats compared to control or in osteoblastic cells from bone marrow of ovariectomized rats compared to control. This article is protected by copyright. All rights reserved.
Actomyosin drives cancer cell nuclear dysmorphia and threatens genome stability
Jul 24, 2017   Nature Communications
Takaki T, Montagner M, Serres MP, Le Berre M, Russell M, Collinson L, Szuhai K, Howell M, Boulton SJ, Sahai E, Petronczki M
Actomyosin drives cancer cell nuclear dysmorphia and threatens genome stability
Jul 24, 2017
Nature Communications
Altered nuclear shape is a defining feature of cancer cells. The mechanisms underlying nuclear dysmorphia in cancer remain poorly understood. Here we identify PPP1R12A and PPP1CB, two subunits of the myosin phosphatase complex that antagonizes actomyosin contractility, as proteins safeguarding nuclear integrity. Loss of PPP1R12A or PPP1CB causes nuclear fragmentation, nuclear envelope rupture, nuclear compartment breakdown and genome instability. Pharmacological or genetic inhibition of actomyosin contractility restores nuclear architecture and genome integrity in cells lacking PPP1R12A or PPP1CB. We detect actin filaments at nuclear envelope rupture sites and define the Rho-ROCK pathway as the driver of nuclear damage. Lamin A protects nuclei from the impact of actomyosin activity. Blocking contractility increases nuclear circularity in cultured cancer cells and suppresses deformations of xenograft nuclei in vivo. We conclude that actomyosin contractility is a major determinant of nuclear shape and that unrestrained contractility causes nuclear dysmorphia, nuclear envelope rupture and genome instability.
Label-free photoacoustic imaging of the cardio-cerebrovascular development in the embryonic zebrafish
Jul 24, 2017   Biomedical Optics Express
Chen Q, Jin T, Qi W, Mo X, Xi L
Label-free photoacoustic imaging of the cardio-cerebrovascular development in the embryonic zebrafish
Jul 24, 2017
Biomedical Optics Express
Zebrafish play an important role in biology, pharmacology, toxicology, and medicine. The cardio-cerebrovascular development of zebrafish is particularly critical to understand both brain disorders and cardiovascular diseases in human. In this paper, we applied optical resolution photoacoustic microscopy (ORPAM) to image the whole-body vasculature of the embryonic zebrafish with a special focus on the development of the cardio-cerebrovascular system. Using the intrinsic optical absorption contrast of the embryo, we successfully visualized the formation of the cardio-cerebrovascular network in high-resolution using a 10 × objective, and monitored the whole-body vascular development using a 4 × objective. In addition, we evaluated the impact of the eggshell and pigment inhibitor on the image quality. Our results suggest that ORPAM is capable of studying the cardio-cerebrovascular development of zebrafish in the embryonic stage, and thus has the potential to investigate the cardiovascular and cerebrovascular diseases of human in the future.
Group-Level Progressive Alterations in Brain Connectivity Patterns Revealed by Diffusion-Tensor Brain Networks across Severity Stages in Alzheimer's Disease
Jul 24, 2017   Frontiers In Aging Neuroscience
Rasero J, Alonso-Montes C, Diez I, Olabarrieta-Landa L, Remaki L, Escudero I, Mateos B, Bonifazi P, Fernandez M, Arango-Lasprilla JC, Stramaglia S, Cortes JM, Alzheimer’s Disease Neuroimaging Initiative
Group-Level Progressive Alterations in Brain Connectivity Patterns Revealed by Diffusion-Tensor Brain Networks across Severity Stages in Alzheimer's Disease
Jul 24, 2017
Frontiers In Aging Neuroscience
Alzheimer's disease (AD) is a chronically progressive neurodegenerative disease highly correlated to aging. Whether AD originates by targeting a localized brain area and propagates to the rest of the brain across disease-severity progression is a question with an unknown answer. Here, we aim to provide an answer to this question at the group-level by looking at differences in diffusion-tensor brain networks. In particular, making use of data from Alzheimer's Disease Neuroimaging Initiative (ADNI), four different groups were defined (all of them matched by age, sex and education level): G1 (N1 = 36, healthy control subjects, Control), G2 (N2 = 36, early mild cognitive impairment, EMCI), G3 (N3 = 36, late mild cognitive impairment, LMCI) and G4 (N4 = 36, AD). Diffusion-tensor brain networks were compared across three disease stages: stage I (Control vs. EMCI), stage II (Control vs. LMCI) and stage III (Control vs. AD). The group comparison was performed using the multivariate distance matrix regression analysis, a technique that was born in genomics and was recently proposed to handle brain functional networks, but here applied to diffusion-tensor data. The results were threefold: First, no significant differences were found in stage I. Second, significant differences were found in stage II in the connectivity pattern of a subnetwork strongly associated to memory function (including part of the hippocampus, amygdala, entorhinal cortex, fusiform gyrus, inferior and middle temporal gyrus, parahippocampal gyrus and temporal pole). Third, a widespread disconnection across the entire AD brain was found in stage III, affecting more strongly the same memory subnetwork appearing in stage II, plus the other new subnetworks, including the default mode network, medial visual network, frontoparietal regions and striatum. Our results are consistent with a scenario where progressive alterations of connectivity arise as the disease severity increases and provide the brain areas possibly involved in such a degenerative process. Further studies applying the same strategy to longitudinal data are needed to fully confirm this scenario.
A gene network regulated by FGF signalling during ear development
Jul 22, 2017   Scientific Reports
Anwar M, Tambalo M, Ranganathan R, Grocott T, Streit A
A gene network regulated by FGF signalling during ear development
Jul 22, 2017
Scientific Reports
During development cell commitment is regulated by inductive signals that are tightly controlled in time and space. In response, cells activate specific programmes, but the transcriptional circuits that maintain cell identity in a changing signalling environment are often poorly understood. Specification of inner ear progenitors is initiated by FGF signalling. Here, we establish the genetic hierarchy downstream of FGF by systematic analysis of many ear factors combined with a network inference approach. We show that FGF rapidly activates a small circuit of transcription factors forming positive feedback loops to stabilise otic progenitor identity. Our predictive network suggests that subsequently, transcriptional repressors ensure the transition of progenitors to mature otic cells, while simultaneously repressing alternative fates. Thus, we reveal the regulatory logic that initiates ear formation and highlight the hierarchical organisation of the otic gene network.
High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain
Jul 24, 2017   Cell Stem Cell
Zhou T, Tan L, Cederquist GY, Fan Y, Hartley BJ, Mukherjee S, Tomishima M, Brennand KJ, Zhang Q, Schwartz RE, Evans T, Studer L, Chen S
High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain
Jul 24, 2017
Cell Stem Cell
Zika virus (ZIKV) infects fetal and adult human brain and is associated with serious neurological complications. To date, no therapeutic treatment is available to treat ZIKV-infected patients. We performed a high-content chemical screen using human pluripotent stem cell-derived cortical neural progenitor cells (hNPCs) and found that hippeastrine hydrobromide (HH) and amodiaquine dihydrochloride dihydrate (AQ) can inhibit ZIKV infection in hNPCs. Further validation showed that HH also rescues ZIKV-induced growth and differentiation defects in hNPCs and human fetal-like forebrain organoids. Finally, HH and AQ inhibit ZIKV infection in adult mouse brain in vivo. Strikingly, HH suppresses viral propagation when administered to adult mice with active ZIKV infection, highlighting its therapeutic potential. Our approach highlights the power of stem cell-based screens and validation in human forebrain organoids and mouse models in identifying drug candidates for treating ZIKV infection and related neurological complications in fetal and adult patients. Copyright © 2017 Elsevier Inc. All rights reserved.
An Actomyosin-Arf-GEF Negative Feedback Loop for Tissue Elongation under Stress
Jul 24, 2017   Current Biology : CB
West JJ, Zulueta-Coarasa T, Maier JA, Lee DM, Bruce AEE, Fernandez-Gonzalez R, Harris TJC
An Actomyosin-Arf-GEF Negative Feedback Loop for Tissue Elongation under Stress
Jul 24, 2017
Current Biology : CB
In response to a pulling force, a material can elongate, hold fast, or fracture. During animal development, multi-cellular contraction of one region often stretches neighboring tissue. Such local contraction occurs by induced actomyosin activity, but molecular mechanisms are unknown for regulating the physical properties of connected tissue for elongation under stress. We show that cytohesins, and their Arf small G protein guanine nucleotide exchange activity, are required for tissues to elongate under stress during both Drosophila dorsal closure (DC) and zebrafish epiboly. In Drosophila, protein localization, laser ablation, and genetic interaction studies indicate that the cytohesin Steppke reduces tissue tension by inhibiting actomyosin activity at adherens junctions. Without Steppke, embryogenesis fails, with epidermal distortions and tears resulting from myosin misregulation. Remarkably, actomyosin network assembly is necessary and sufficient for local Steppke accumulation, where live imaging shows Steppke recruitment within minutes. This rapid negative feedback loop provides a molecular mechanism for attenuating the main tension generator of animal tissues. Such attenuation relaxes tissues and allows orderly elongation under stress. Copyright © 2017 Elsevier Ltd. All rights reserved.
A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45
Jul 24, 2017   Molecular Cell
Courtney AH, Amacher JF, Kadlecek TA, Mollenauer MN, Au-Yeung BB, Kuriyan J, Weiss A
A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45
Jul 24, 2017
Molecular Cell
The Src Family kinase Lck sets a critical threshold for T cell activation because it phosphorylates the TCR complex and the Zap70 kinase. How a T cell controls the abundance of active Lck molecules remains poorly understood. We have identified an unappreciated role for a phosphosite, Y192, within the Lck SH2 domain that profoundly affects the amount of active Lck in cells. Notably, mutation of Y192 blocks critical TCR-proximal signaling events and impairs thymocyte development in retrogenic mice. We determined that these defects are caused by hyperphosphorylation of the inhibitory C-terminal tail of Lck. Our findings reveal that modification of Y192 inhibits the ability of CD45 to associate with Lck in cells and dephosphorylate the C-terminal tail of Lck, which prevents its adoption of an active open conformation. These results suggest a negative feedback loop that responds to signaling events that tune active Lck amounts and TCR sensitivity. Copyright © 2017 Elsevier Inc. All rights reserved.
Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements
Jul 24, 2017   American Journal Of Human Genetics
Zepeda-Mendoza CJ, Ibn-Salem J, Kammin T, Harris DJ, Rita D,   . . . . . .   , Ordulu Z, Talkowski ME, Andrade-Navarro MA, Robinson PN, Morton CC
Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements
Jul 24, 2017
American Journal Of Human Genetics
Interpretation of variants of uncertain significance, especially chromosomal rearrangements in non-coding regions of the human genome, remains one of the biggest challenges in modern molecular diagnosis. To improve our understanding and interpretation of such variants, we used high-resolution three-dimensional chromosomal structural data and transcriptional regulatory information to predict position effects and their association with pathogenic phenotypes in 17 subjects with apparently balanced chromosomal abnormalities. We found that the rearrangements predict disruption of long-range chromatin interactions between several enhancers and genes whose annotated clinical features are strongly associated with the subjects' phenotypes. We confirm gene-expression changes for a couple of candidate genes to exemplify the utility of our analysis of position effect. These results highlight the important interplay between chromosomal structure and disease and demonstrate the need to utilize chromatin conformational data for the prediction of position effects in the clinical interpretation of non-coding chromosomal rearrangements. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
A Requirement for Mena, an Actin Regulator, in Local mRNA Translation in Developing Neurons
Jul 24, 2017   Neuron
Vidaki M, Drees F, Saxena T, Lanslots E, Taliaferro MJ, Tatarakis A, Burge CB, Wang ET, Gertler FB
A Requirement for Mena, an Actin Regulator, in Local mRNA Translation in Developing Neurons
Jul 24, 2017
Neuron
During neuronal development, local mRNA translation is required for axon guidance and synaptogenesis, and dysregulation of this process contributes to multiple neurodevelopmental and cognitive disorders. However, regulation of local protein synthesis in developing axons remains poorly understood. Here, we uncover a novel role for the actin-regulatory protein Mena in the formation of a ribonucleoprotein complex that involves the RNA-binding proteins HnrnpK and PCBP1 and regulates local translation of specific mRNAs in developing axons. We find that translation of dyrk1a, a Down syndrome- and autism spectrum disorders-related gene, is dependent on Mena, both in steady-state conditions and upon BDNF stimulation. We identify hundreds of additional mRNAs that associate with the Mena complex, suggesting that it plays broader role(s) in post-transcriptional gene regulation. Our work establishes a dual role for Mena in neurons, providing a potential link between regulation of actin dynamics and local translation. Copyright © 2017 Elsevier Inc. All rights reserved.
Impact of Preimplantation Genetic Screening on Donor oocyte-recipient cycles in the United States
Jul 24, 2017   American Journal Of Obstetrics And Gynecology
Barad DH, Darmon SK, Kushnir VA, Albertini DF, Gleicher N
Impact of Preimplantation Genetic Screening on Donor oocyte-recipient cycles in the United States
Jul 24, 2017
American Journal Of Obstetrics And Gynecology
Our objective was to estimate the contribution of Preimplantation genetic screening to in-vitro fertilization pregnancy outcomes in donor oocyte-recipient cycles. This is a retrospective cross-sectional study of United States national data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System between 2005-2013. Society for Assisted Reproductive Technology Clinic Outcome Reporting relies on voluntarily annual reports by over 90% of United States in-vitro fertilization centers. We evaluated pregnancy and live birth rates in donor oocyte-recipient cycles after first embryo transfer with day 5/6 embryos. Statistical models, adjusted for patient and donor ages, number of embryos transferred, race, infertility diagnosis and cycle year were created to compare live birth rates in 392 Preimplantation genetic screening and 20,616 Control cycles. Overall, pregnancy and live birth rates were significantly lower in Preimplantation genetic screening cycles than in control cycles. Adjusted odds of live birth for Preimplantation genetic screening cycles were reduced by 35% (OR 0.65, 95% CI 0.53 to 0.80; P < 0.001). Preimplantation Genetic Screening, as practiced in donor oocyte-recipient cycles over the past nine years, has not been associated with improved odds of live birth or reduction in miscarriage rates. Copyright © 2017 Elsevier Inc. All rights reserved.
Histone demethylase PHF8 regulates hypoxia signaling through HIF1α and H3K4me3
Jul 23, 2017   Biochimica Et Biophysica Acta
Maina PK, Shao P, Jia X, Liu Q, Umesalma S, Marin M, Long D, Concepción-Román S, Qi HH
Histone demethylase PHF8 regulates hypoxia signaling through HIF1α and H3K4me3
Jul 23, 2017
Biochimica Et Biophysica Acta
Hypoxia through transcription factor HIF1α plays a critical role in cancer development. In prostate cancer, HIF1α interplays with androgen receptor (AR) to contribute to the progression of this disease to its lethal form-castration-resistant prostate cancer (CRPC). Hypoxia upregulates several epigenetic factors including histone demethylase KDM3A which is a critical co-factor of HIF1α. However, how histone demethylases regulate hypoxia signaling is not fully understood. Here, we report that histone demethylase PHF8 plays an essential role in hypoxia signaling. Knockdown or knockout of PHF8 by RNAi or CRISPR-Cas9 system reduced the activation of HIF1α and the induction of HIF1α target genes including KDM3A. Mechanistically, PHF8 regulates hypoxia inducible genes mainly through sustaining the level of trimethylated histone 3 lysine 4 (H3K4me3), an active mark in transcriptional regulation. The positive role of PHF8 in hypoxia signaling extended to hypoxia-induced neuroendocrine differentiation (NED), wherein PHF8 cooperates with KDM3A to regulate the expression of NED genes. Moreover, we discovered that the role of PHF8 in hypoxia signaling is associated with the presence of full-length AR in CRPC cells. Collectively, our study identified PHF8 as a novel epigenetic factor in hypoxia signaling, and the underlying regulatory mechanisms likely apply to general cancer development involving HIF1α. Therefore, targeting PHF8 can potentially be a novel therapeutic strategy in cancer therapy. Copyright © 2017. Published by Elsevier B.V.
Development of new ganglioside probes and unraveling of raft domain structure by single-molecule imaging
Jul 23, 2017   Biochimica Et Biophysica Acta
Suzuki KGN, Ando H, Komura N, Fujiwara T, Kiso M, Kusumi A
Development of new ganglioside probes and unraveling of raft domain structure by single-molecule imaging
Jul 23, 2017
Biochimica Et Biophysica Acta
Gangliosides are involved in a variety of biological roles and are a component of lipid rafts found in cell plasma membranes (PMs). Gangliosides are especially abundant in neuronal PMs and are essential to their physiological functions. However, the dynamic behaviors of gangliosides have not been investigated in living cells due to a lack of fluorescent probes that behave like their parental molecules. We have recently developed, using an entirely chemical method, four new ganglioside probes (GM1, GM2, GM3, and GD1b) that act similarly to their parental molecules in terms of raft partitioning and binding affinity. Using single fluorescent-molecule imaging, we have found that ganglioside probes dynamically enter and leave rafts featuring CD59, a GPI-anchored protein. This occurs both before and after stimulation. The residency time of our ganglioside probes in rafts with CD59 oligomers was 48 ms, after stimulation. The residency times in CD59 homodimer and monomer rafts were 40 ms and 12 ms, respectively. In this review, we introduce an entirely chemical-based ganglioside analog synthesis method and describe its application in single-molecule imaging and for the study of the dynamic behavior of gangliosides in cell PMs. Finally, we discuss how raft domains are formed, both before and after receptor engagement. This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa. Copyright © 2017. Published by Elsevier B.V.
New advances in autophagy in plants: regulation, selectivity and function
Jul 23, 2017   Seminars In Cell & Developmental Biology
Wang P, Mugume Y, Bassham DC
New advances in autophagy in plants: regulation, selectivity and function
Jul 23, 2017
Seminars In Cell & Developmental Biology
Autophagy is a major and conserved pathway for delivering unwanted proteins or damaged organelles to the vacuole for degradation and recycling. In plants, it functions as a housekeeping process to maintain cellular homeostasis under normal conditions and is induced by stress and senescence; it thus plays important roles in development, stress tolerance and metabolism. Autophagy can both execute bulk degradation and be highly selective in targeting cargos under specific environmental conditions or during certain developmental processes. Here, we review recent research on autophagy in plants, and discuss new insights into its core mechanism, regulation, selectivity and physiological roles. Potential future directions are also highlighted. Copyright © 2017. Published by Elsevier Ltd.
Effect of calcium phosphate nanocomposite on in vitro remineralization of human dentin lesions
Jul 23, 2017   Dental Materials : Official Publication Of The Academy Of Dental Materials
Weir MD, Ruan J, Zhang N, Chow LC, Zhang K, Chang X, Bai Y, Xu HHK
Effect of calcium phosphate nanocomposite on in vitro remineralization of human dentin lesions
Jul 23, 2017
Dental Materials : Official Publication Of The Academy Of Dental Materials
Secondary caries is a primary reason for dental restoration failures. The objective of this study was to investigate the remineralization of human dentin lesions in vitro via restorations using nanocomposites containing nanoparticles of amorphous calcium phosphate (NACP) or NACP and tetracalcium phosphate (TTCP) for the first time. NACP was synthesized by a spray-drying technique and incorporated into a resin consisting of ethoxylated bisphenol A dimethacrylate (EBPADMA) and pyromellitic glycerol dimethacrylate (PMGDM). After restoring the dentin lesions with nanocomposites as well as a non-releasing commercial composite control, the specimens were treated with cyclic demineralization (pH 4, 1h per day) and remineralization (pH 7, 23h per day) for 4 or 8 weeks. Calcium (Ca) and phosphate (P) ion releases from composites were measured. Dentin lesion remineralization was measured at 4 and 8 weeks by transverse microradiography (TMR). Lowering the pH increased ion release of NACP and NACP-TTCP composites. At 56 days, the released Ca concentration in mmol/L (mean±SD; n=3) was (13.39±0.72) at pH 4, much higher than (1.19±0.06) at pH 7 (p
cGAS surveillance of micronuclei links genome instability to innate immunity
Jul 24, 2017   Nature Add nature.com free-link Cancel
Mackenzie KJ, Carroll P, Martin CA, Murina O, Fluteau A,   . . . . . .   , Nowotny M, Gilbert N, Chandra T, Reijns MAM, Jackson AP
cGAS surveillance of micronuclei links genome instability to innate immunity
Jul 24, 2017
Nature
DNA is strictly compartmentalized within the nucleus to prevent autoimmunity; despite this, cyclic GMP-AMP synthase (cGAS), a cytosolic sensor of double-stranded DNA, is activated in autoinflammatory disorders and by DNA damage. Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS localizes to micronuclei arising from genome instability in a mouse model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells. Such micronuclei occur after mis-segregation of DNA during cell division and consist of chromatin surrounded by its own nuclear membrane. Breakdown of the micronuclear envelope, a process associated with chromothripsis, leads to rapid accumulation of cGAS, providing a mechanism by which self-DNA becomes exposed to the cytosol. cGAS is activated by chromatin, and consistent with a mitotic origin, micronuclei formation and the proinflammatory response following DNA damage are cell-cycle dependent. By combining live-cell laser microdissection with single cell transcriptomics, we establish that interferon-stimulated gene expression is induced in micronucleated cells. We therefore conclude that micronuclei represent an important source of immunostimulatory DNA. As micronuclei formed from lagging chromosomes also activate this pathway, recognition of micronuclei by cGAS may act as a cell-intrinsic immune surveillance mechanism that detects a range of neoplasia-inducing processes.

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