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Biophysics
The association between breast cancer and S100P methylation in peripheral blood by multicenter case-control studies
Apr 20, 2017   Carcinogenesis
Yang R, Stöcker S, Schott S, Heil J, Marme F,   . . . . . .   , Qu B, Bartram CR, Sohn C, Schneeweiss A, Burwinkel B
The association between breast cancer and S100P methylation in peripheral blood by multicenter case-control studies
Apr 20, 2017
Carcinogenesis
Breast cancer (BC) is the leading cancer in women worldwide. Changes in DNA methylation in peripheral blood could be associated with malignant diseases. Making use of screening results by llumina 27K Methylation Assay, we validated demethylation of five CpG sites of S100P gene in blood cell DNA of BC patients by three independent retrospective studies with subjects from different centers (Validation I: 235 familial BC case and 206 controls, odds ratio per -1% methylation > 1.03, and P < 6.00 × 10-8 for all five CpG sites; Validation II: 189 sporadic BC case and 189 controls, odds ratio per -1% methylation > 1.03, P < 8.0 × 10-5 for four CpG sites; Validation III: 156 sporadic BC case and 151 controls, odds ratio per -1% methylation > 1.03, P < 6.0 × 10-4 for four CpG sites). In addition, the blood-based S100P methylation pattern was similar among BC patients with differential clinical characteristics regardless of stage, receptor status and menopause status. The observed BC-associated decreased S100P methylation in blood mainly originates from the leucocytes subpopulations but not B cells. The methylation levels of most S100P CpG sites were inversely correlated with the expression of S100P in leucocytes (P < 1.2 × 10-4) and in tissue (P < 1.1 × 10-4). This study reveals significant association between blood-based decreased S100P methylation and BC, and provides another proof for the application of altered DNA methylation signatures from blood cells as potential markers for the detection of BC, especially for the early stage. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Respiratory chain enzyme deficiency induces mitochondrial location of actin-binding Gelsolin to modulate the oligomerization of VDAC complexes and cell survival
Apr 21, 2017   Human Molecular Genetics
García-Bartolomé A, Peñas A, Marín-Buera L, Lobo-Jarne T, Pérez-Pérez R, Morán M, Arenas J, Martín MA, Ugalde C
Respiratory chain enzyme deficiency induces mitochondrial location of actin-binding Gelsolin to modulate the oligomerization of VDAC complexes and cell survival
Apr 21, 2017
Human Molecular Genetics
Despite considerable knowledge on the genetic basis of mitochondrial disorders, their pathophysiological consequences remain poorly understood. We previously used 2D-DIGE analyses to define a protein profile characteristic for respiratory chain complex III-deficiency that included a significant overexpression of cytosolic Gelsolin (GSN), a cytoskeletal protein that regulates the severing and capping of the actin filaments. Biochemical and immunofluorescence assays confirmed a specific increase of GSN levels in the mitochondria from patientś fibroblasts and from transmitochondrial cybrids with complex III assembly defects. A similar effect was obtained in control cells upon treatment with antimycin A in a dose-dependent manner, showing that the enzymatic inhibition of complex III is sufficient to promote the mitochondrial localization of GSN. Mitochondrial subfractionation showed the localization of GSN to the mitochondrial outer membrane, where it interacts with the voltage-dependent anion channel protein 1 (VDAC1). In control cells, VDAC1 was present in five stable oligomeric complexes, which showed increased levels and a modified distribution pattern in the complex III-deficient cybrids. Downregulation of GSN expression induced cell death in both cell types, in parallel with the specific accumulation of VDAC1 dimers and the release of mitochondrial cytochrome c into the cytosol, indicating a role for GSN in the oligomerization of VDAC complexes and in the prevention of apoptosis. Our results demonstrate that respiratory chain complex III dysfunction induces the physiological upregulation and mitochondrial location of GSN, probably to promote cell survival responses through the modulation of the oligomeric state of the VDAC complexes. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Probing protein flexibility reveals a mechanism for selective promiscuity
Apr 22, 2017   ELife
Pabon NA, Camacho CJ
Probing protein flexibility reveals a mechanism for selective promiscuity
Apr 22, 2017
ELife
Many eukaryotic regulatory proteins adopt distinct bound and unbound conformations, and use this structural flexibility to bind specifically to multiple partners. However, we lack an understanding of how an interface can select some ligands, but not others. Here, we present a molecular dynamics approach to identify and quantitatively evaluate the interactions responsible for this selective promiscuity. We apply this approach to the anti-cancer target PD-1 and its ligands PD-L1 and PD-L2. We discover that while unbound PD-1 exhibits a hard-to-drug hydrophilic interface, conserved specific triggers encoded in the cognate ligands activate a promiscuous binding pathway that reveals a flexible hydrophobic binding cavity. Specificity is then established by additional contacts that stabilize the PD-1 cavity into distinct bound-like modes. Collectively, our studies provide insight into the structural basis and evolution of multiple binding partners, and also suggest a biophysical approach to exploit innate binding pathways to drug seemingly undruggable targets.
Structure of Fam20A reveals a pseudokinase featuring unique disulfide pattern and inverted ATP-binding
Apr 22, 2017   ELife
Cui J, Zhu Q, Zhang H, Cianfrocco MA, Leschziner AE, Dixon JE, Xiao J
Structure of Fam20A reveals a pseudokinase featuring unique disulfide pattern and inverted ATP-binding
Apr 22, 2017
ELife
Mutations in FAM20A cause tooth enamel defects known as Amelogenesis Imperfecta (AI) and renal calcification. We previously showed that Fam20A is a secretory pathway pseudokinase and allosterically activates the physiological casein kinase Fam20C to phosphorylate secreted proteins important for biomineralization (Cui et al., 2015). Here we report the nucleotide-free and ATP-bound structures of Fam20A. Fam20A exhibits a distinct disulfide bond pattern mediated by a unique insertion region. Loss of this insertion due to abnormal mRNA splicing interferes with the structure and function of Fam20A, resulting in AI. Fam20A binds ATP in the absence of divalent cations, and strikingly, ATP is bound in an inverted orientation compared to other kinases. Fam20A forms a dimer in the crystal, and residues in the dimer interface are critical for Fam20C activation. Together, these results provide structural insights into the function of Fam20A and shed light on the mechanism by which Fam20A mutations cause disease.
Role of the Ion Channel Extracellular Collar in AMPA Receptor Gating
Apr 22, 2017   Scientific Reports
Yelshanskaya MV, Mesbahi-Vasey S, Kurnikova MG, Sobolevsky AI
Role of the Ion Channel Extracellular Collar in AMPA Receptor Gating
Apr 22, 2017
Scientific Reports
AMPA subtype ionotropic glutamate receptors mediate fast excitatory neurotransmission and are implicated in numerous neurological diseases. Ionic currents through AMPA receptor channels can be allosterically regulated via different sites on the receptor protein. We used site-directed mutagenesis and patch-clamp recordings to probe the ion channel extracellular collar, the binding region for noncompetitive allosteric inhibitors. We found position and substitution-dependent effects for introduced mutations at this region on AMPA receptor gating. The results of mutagenesis suggested that the transmembrane domains M1, M3 and M4, which contribute to the ion channel extracellular collar, undergo significant relative displacement during gating. We used molecular dynamics simulations to predict an AMPA receptor open state structure and rationalize the results of mutagenesis. We conclude that the ion channel extracellular collar plays a distinct role in gating and represents a hub for powerful allosteric modulation of AMPA receptor function that can be used for developing novel therapeutics.
Dual histone reader ZMYND8 inhibits cancer cell invasion by positively regulating epithelial genes
Apr 22, 2017   The Biochemical Journal
Basu M, Sengupta I, Khan W, Srivastava DK, Chakrabarti P, Roy S, Das C
Dual histone reader ZMYND8 inhibits cancer cell invasion by positively regulating epithelial genes
Apr 22, 2017
The Biochemical Journal
Enhanced migratory potential and invasiveness of cancer cells attribute crucially.in cancer progression. These phenotypes are achieved by precise alteration of invasion-associated genes through local epigenetic modifications which are recognized by a class of proteins termed as chromatin reader. ZMYND8 (zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8), a key component of transcription regulatory network, has been recently shown to be a novel reader of H3.1K36Me2/H4K16Ac marks. Through differential gene expression analysis upon silencing this chromatin reader, we identified a subset of genes involved in cell proliferation and invasion/migration regulated by ZMYND8. Detailed analysis uncovered its anti-proliferative activity through BrdU incorporation, alteration in the expression of proliferation markers and cell cycle regulating genes and cell viability assays. In addition, performing wound healing and invasion/migration assays, its anti-invasive nature is evident. Interestingly, epithelial-mesenchymal transition, a key mechanism of cellular invasion, is regulated by ZMYND8 where we identified its selective enrichment on promoters of CLDN1 / CDH1 genes, rich in H3K36Me2/H4K16Ac marks, leading to their upregulation. Thus, presence of ZMYND8 could be implicated in maintaining the epithelial phenotype of cells. Further, syngeneic mice, injected with ZMYND8-overexpressed invasive breast cancer cells showed reduction in tumor volume and weight. In concert with this, we observed a significant downregulation of ZMYND8 in invasive ductal and lobular breast cancer tissues compared to normal one. Taken together, our study elucidates a novel function of ZMYND8 in regulating EMT and invasion of cancer cells, possibly through its chromatin reader function. ©2017 The Author(s).
Acute Hepatopancreatic Necrosis Disease (AHPND)-causing Vibrio parahaemolyticus strains maintain an antibacterial Type VI Secretion System with versatile effector repertoires
Apr 22, 2017   Applied And Environmental Microbiology
Li P, Kinch LN, Ray A, Dalia AB, Cong Q, Nunan LM, Camilli A, Grishin NV, Salomon D, Orth K
Acute Hepatopancreatic Necrosis Disease (AHPND)-causing Vibrio parahaemolyticus strains maintain an antibacterial Type VI Secretion System with versatile effector repertoires
Apr 22, 2017
Applied And Environmental Microbiology
Acute hepatopancreatic necrosis disease (AHPND) is a newly emerging shrimp disease that has severely damaged the global shrimp industry. AHPND is caused by toxic strains of Vibrio parahaemolyticus (V. parahaemolyticus) that have acquired a "selfish plasmid" encoding the deadly binary toxins PirAvp/PirBvp To better understand the repertoire of virulence factors in AHPND-causing V. parahaemolyticus, we conducted a comparative analysis using genome sequences of the clinical strain RIMD2210633, environmental non-AHPND and toxic AHPND isolates of V. parahaemolyticus Interestingly, we found that all of the AHPND strains, but none of the non-AHPND strains, harbor the antibacterial type VI secretion system 1 (T6SS1) which we previously identified and characterized in the clinical isolate RIMD2210633. This finding suggests that the acquisition of this T6SS might confer AHPND-causing V. parahaemolyticus a fitness advantage over competing bacteria and facilitate shrimp infection. Additionally, we find highly dynamic effector loci in the T6SS1 of AHPND-causing strains, leading to diverse effector repertoires. Our discovery provides novel insights into AHPND-causing pathogens and reveals a potential target for disease control.Importance Acute hepatopancreatic necrosis disease (AHPND) is a serious disease that has caused severe damage and significant financial losses to the global shrimp industry. To better understand and prevent this shrimp disease, it is essential to thoroughly characterize its causative agent, Vibrio paraehaemolyticus (V. parahaemolyticus). Although the plasmid-encoded binary toxins PirAvp/PirBvp have been shown to be the primary cause of AHPND, it remains unknown whether other virulent factors are commonly present in V. parahaemolyticus and might play important roles during shrimp infection. Here, we analyzed the genome sequences of clinical, non-AHPND and AHPND strains to characterize their repertoires of key virulence determinants. Our studies reveal that an antibacterial type VI secretion system is associated with the AHPND strains and differentiates them from non-AHPND strains, similar to the PirA/PirB toxins. We propose that T6SS1 provides a selective advantage during shrimp infections. Copyright © 2017 American Society for Microbiology.
NINJ2- A novel regulator of endothelial inflammation and activation
Apr 22, 2017   Cellular Signalling
Wang J, Fa J, Wang P, Jia X, Peng H, Chen J, Wang Y, Wang C, Chen Q, Tu X, Wang QK, Xu C
NINJ2- A novel regulator of endothelial inflammation and activation
Apr 22, 2017
Cellular Signalling
Previous genetic studies suggested that variants in NINJ2 (encode ninjurin2) confer risk to ischemic stroke or large artery atherosclerotic stroke. However, the underlying mechanisms of NINJ2 in ischemic stroke or atherosclerosis are still unknown. In this study, we hypothesized that NINJ2 may play a role in endothelial inflammation and activation, and regulate the process of atherosclerosis. Here, we demonstrated that NINJ2 can regulate the expression of a panel of genes that are associated with inflammation and atherosclerosis (e.g. IL-1β, TNF-α, IL-8, IL-6, ICAM-1 and E-selectin) in human vascular endothelial cells (HUVECs). Moreover, we found the expression of ninjurin2 is upregulated in LPS stimulated HUVECs and mouse aorta, and it can regulate LPS-induced endothelial activation and the adhesion of monocytes to endothelial cells. We also found that NINJ2 can regulate NF-κB and c-jun through interacting with TLR4. In conclusion, our study suggests that ninjurin2 is a novel regulator of endothelia inflammation and activation through TLR4 signaling pathways, and these data provided new insights into the mechanisms between NINJ2 and atherosclerosis. Copyright © 2017. Published by Elsevier Inc.
Enhanced neuroinvasion by smaller, soluble prions
Apr 22, 2017   Acta Neuropathologica Communications
Bett C, Lawrence J, Kurt TD, Orru C, Aguilar-Calvo P, Kincaid AE, Surewicz WK, Caughey B, Wu C, Sigurdson CJ
Enhanced neuroinvasion by smaller, soluble prions
Apr 22, 2017
Acta Neuropathologica Communications
Infectious prion aggregates can propagate from extraneural sites into the brain with remarkable efficiency, likely transported via peripheral nerves. Yet not all prions spread into the brain, and the physical properties of a prion that is capable of transit within neurons remain unclear. We hypothesized that small, diffusible aggregates spread into the CNS via peripheral nerves. Here we used a structurally diverse panel of prion strains to analyze how the prion conformation impacts transit into the brain. Two prion strains form fibrils visible ultrastructurally in the brain in situ, whereas three strains form diffuse, subfibrillar prion deposits and no visible fibrils. The subfibrillar strains had significantly higher levels of soluble prion aggregates than the fibrillar strains. Primary neurons internalized both the subfibrillar and fibril-forming prion strains by macropinocytosis, and both strain types were transported from the axon terminal to the cell body in vitro. However in mice, only the predominantly soluble, subfibrillar prions, and not the fibrillar prions, were efficiently transported from the tongue to the brain. Sonicating a fibrillar prion strain increased the solubility and enabled prions to spread into the brain in mice, as evident by a 40% increase in the attack rate, indicating that an increase in smaller particles enhances prion neuroinvasion. Our data suggest that the small, highly soluble prion particles have a higher capacity for transport via nerves. These findings help explain how prions that predominantly assemble into subfibrillar states can more effectively traverse into and out of the CNS, and suggest that promoting fibril assembly may slow the neuron-to-neuron spread of protein aggregates.
Macrophages Facilitate Electrical Conduction in the Heart
Apr 21, 2017   Cell
Hulsmans M, Clauss S, Xiao L, Aguirre AD, King KR,   . . . . . .   , Kohl P, Vinegoni C, Milan DJ, Ellinor PT, Nahrendorf M
Macrophages Facilitate Electrical Conduction in the Heart
Apr 21, 2017
Cell
Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown. Here, we show that cardiac macrophages facilitate electrical conduction through the distal atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43. When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization. Photostimulation of channelrhodopsin-2-expressing macrophages improves atrioventricular conduction, whereas conditional deletion of connexin 43 in macrophages and congenital lack of macrophages delay atrioventricular conduction. In the Cd11bDTR mouse, macrophage ablation induces progressive atrioventricular block. These observations implicate macrophages in normal and aberrant cardiac conduction. Copyright © 2017 Elsevier Inc. All rights reserved.
Cryo-EM Structure of the Open Human Ether-à-go-go-Related K+ Channel hERG
Apr 21, 2017   Cell
Wang W, MacKinnon R
Cryo-EM Structure of the Open Human Ether-à-go-go-Related K+ Channel hERG
Apr 21, 2017
Cell
The human ether-à-go-go-related potassium channel (hERG, Kv11.1) is a voltage-dependent channel known for its role in repolarizing the cardiac action potential. hERG alteration by mutation or pharmacological inhibition produces Long QT syndrome and the lethal cardiac arrhythmia torsade de pointes. We have determined the molecular structure of hERG to 3.8 Å using cryo-electron microscopy. In this structure, the voltage sensors adopt a depolarized conformation, and the pore is open. The central cavity has an atypically small central volume surrounded by four deep hydrophobic pockets, which may explain hERG's unusual sensitivity to many drugs. A subtle structural feature of the hERG selectivity filter might correlate with its fast inactivation rate, which is key to hERG's role in cardiac action potential repolarization. Copyright © 2017 Elsevier Inc. All rights reserved.
Structural and Functional Analysis of a β2-Adrenergic Receptor Complex with GRK5
Apr 21, 2017   Cell
Komolov KE, Du Y, Duc NM, Betz RM, Rodrigues JPGLM, Leib RD, Patra D, Skiniotis G, Adams CM, Dror RO, Chung KY, Kobilka BK, Benovic JL
Structural and Functional Analysis of a β2-Adrenergic Receptor Complex with GRK5
Apr 21, 2017
Cell
The phosphorylation of agonist-occupied G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) functions to turn off G-protein signaling and turn on arrestin-mediated signaling. While a structural understanding of GPCR/G-protein and GPCR/arrestin complexes has emerged in recent years, the molecular architecture of a GPCR/GRK complex remains poorly defined. We used a comprehensive integrated approach of cross-linking, hydrogen-deuterium exchange mass spectrometry (MS), electron microscopy, mutagenesis, molecular dynamics simulations, and computational docking to analyze GRK5 interaction with the β2-adrenergic receptor (β2AR). These studies revealed a dynamic mechanism of complex formation that involves large conformational changes in the GRK5 RH/catalytic domain interface upon receptor binding. These changes facilitate contacts between intracellular loops 2 and 3 and the C terminus of the β2AR with the GRK5 RH bundle subdomain, membrane-binding surface, and kinase catalytic cleft, respectively. These studies significantly contribute to our understanding of the mechanism by which GRKs regulate the function of activated GPCRs. PAPERCLIP. Copyright © 2017 Elsevier Inc. All rights reserved.
A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma
Apr 21, 2017   Human Molecular Genetics
Siibak T, Clemente P, Bratic A, Bruhn H, Kauppila TES,   . . . . . .   , Wedell A, Peter B, Freyer C, Falkenberg M, Wredenberg A
A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma
Apr 21, 2017
Human Molecular Genetics
Mutations in the mitochondrial DNA polymerase, POLG, are associated with a variety of clinical presentations, ranging from early onset fatal brain disease in Alpers syndrome to chronic progressive external ophthalmoplegia. The majority of mutations are linked with disturbances of mitochondrial DNA (mtDNA) integrity and maintenance. On a molecular level, depending on their location within the enzyme, mutations either lead to mtDNA depletion or the accumulation of multiple mtDNA deletions, and in some cases these molecular changes can be correlated to the clinical presentation. We identified a patient with a dominant p.Y955H mutation in POLG, presenting with a severe, early-onset multi-systemic mitochondrial disease with bilateral sensorineural hearing loss, cataract, myopathy, and liver failure. Using a combination of disease models of Drosophila melanogaster (Dm) and in vitro biochemistry analysis, we compare the molecular consequences of the p.Y955H mutation to the well-documented p.Y955C mutation. We demonstrate that both mutations affect mtDNA replication and display a dominant negative effect, with the p.Y955H allele resulting in a more severe polymerase dysfunction. © The Author 2017. Published by Oxford University Press.
iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases
Apr 20, 2017   Neuron
Abud EM, Ramirez RN, Martinez ES, Healy LM, Nguyen CHH,   . . . . . .   , Antel JP, Mortazavi A, Carson MJ, Poon WW, Blurton-Jones M
iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases
Apr 20, 2017
Neuron
Microglia play critical roles in brain development, homeostasis, and neurological disorders. Here, we report that human microglial-like cells (iMGLs) can be differentiated from iPSCs to study their function in neurological diseases, like Alzheimer's disease (AD). We find that iMGLs develop in vitro similarly to microglia in vivo, and whole-transcriptome analysis demonstrates that they are highly similar to cultured adult and fetal human microglia. Functional assessment of iMGLs reveals that they secrete cytokines in response to inflammatory stimuli, migrate and undergo calcium transients, and robustly phagocytose CNS substrates. iMGLs were used to examine the effects of Aβ fibrils and brain-derived tau oligomers on AD-related gene expression and to interrogate mechanisms involved in synaptic pruning. Furthermore, iMGLs transplanted into transgenic mice and human brain organoids resemble microglia in vivo. Together, these findings demonstrate that iMGLs can be used to study microglial function, providing important new insight into human neurological disease. Copyright © 2017 Elsevier Inc. All rights reserved.
Mapping Genes for Calcium Signaling and Their Associated Human Genetic Disorders
Apr 21, 2017   Bioinformatics (Oxford, England)
Hörtenhuber M, Toledo EM, Smedler E, Arenas E, Malmersjö S, Louhivuori L, Uhlén P
Mapping Genes for Calcium Signaling and Their Associated Human Genetic Disorders
Apr 21, 2017
Bioinformatics (Oxford, England)
Signal transduction via calcium ions (Ca 2+ ) represents a fundamental signaling pathway in all eukaryotic cells. A large portion of the human genome encodes proteins used to assemble signaling systems that can transduce signals with diverse spatial and temporal dynamics. Here, we provide a map of all of the genes involved in Ca 2+ signaling and link these genes to human genetic disorders. Using Gene Ontology terms and genome databases, 1,805 genes were identified as regulators or targets of intracellular Ca 2+ signals. Associating these 1,805 genes with human genetic disorders uncovered 1,470 diseases with mutated "Ca 2+ genes". A network with scale-free properties appeared when the Ca 2+ genes were mapped to their associated genetic disorders. The Ca 2+ genome database is freely available at http://cagedb.uhlenlab.org and will foster studies of gene functions and genetic disorders associated with Ca 2+ signaling. per.uhlen@ki.se. Supplementary data are available at Bioinformatics online.
Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium
Apr 21, 2017   PLoS Genetics
Ng MCY, Graff M, Lu Y, Justice AE, Mudgal P,   . . . . . .   , Bowden DW, Cupples LA, Haiman CA, Loos RJF, North KE
Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium
Apr 21, 2017
PLoS Genetics
Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (
Dissection of the interaction between the intrinsically disordered YAP protein and the transcription factor TEAD
Apr 21, 2017   ELife
Mesrouze Y, Bokhovchuk F, Meyerhofer M, Fontana P, Zimmermann C, Martin T, Delaunay C, Erdmann D, Schmelzle T, Chène P
Dissection of the interaction between the intrinsically disordered YAP protein and the transcription factor TEAD
Apr 21, 2017
ELife
TEAD (TEA/ATTS domain) transcription factors are the most distal effectors of the Hippo pathway. YAP (Yes-associated protein) is a coactivator protein which, upon binding to TEAD proteins, stimulates their transcriptional activity. Since the Hippo pathway is deregulated in various cancers, designing inhibitors of the YAP:TEAD interaction is an attractive therapeutic strategy for oncology. Understanding the molecular events that take place at the YAP:TEAD interface is therefore important not only to devise drug discovery approaches, but also to gain knowledge on TEAD regulation. In this report, combining single site-directed mutagenesis and double mutant analyses, we conduct a detailed analysis on the role of several residues located at the YAP:TEAD interface. Our results provide quantitative understanding of the interactions taking place at the YAP:TEAD interface and give insights into the formation of the YAP:TEAD complex and more particularly on the interaction between TEAD and the Ω-loop found in YAP.
Arf GAPs and molecular motors
Apr 21, 2017   Small GTPases
Luo R, Reed CE, Sload JA, Wordeman L, Randazzo PA, Chen PW
Arf GAPs and molecular motors
Apr 21, 2017
Small GTPases
Arf GTPase-activating proteins (Arf GAPs) were first identified as regulators of the small GTP-binding proteins ADP-ribosylation factors (Arfs). The Arf GAPs are a large family of proteins in metazoans, outnumbering the Arfs that they regulate. The members of the Arf GAP family have complex domain structures and some have been implicated in particular cellular functions, such as cell migration, or with particular pathologies, such as tumor invasion and metastasis. The specific effects of Arfs sometimes depend on the Arf GAP involved in their regulation. These observations have led to speculation that the Arf GAPs themselves may affect cellular activities in capacities beyond the regulation of Arfs. Recently, 2 Arf GAPs, ASAP1 and AGAP1, have been found to bind directly to and influence the activity of myosins and kinesins, motor proteins associated with filamentous actin and microtubules, respectively. The Arf GAP-motor protein interaction is critical for cellular behaviors involving the actin cytoskeleton and microtubules, such as cell migration and other cell movements. Arfs, then, may function with molecular motors through Arf GAPs to regulate microtubule and actin remodeling.
Sites of overt and covert attention define simultaneous spatial reference centers for visuomotor response
Apr 21, 2017   Scientific Reports
Zhou Y, Liang L, Pan Y, Qian N, Zhang M
Sites of overt and covert attention define simultaneous spatial reference centers for visuomotor response
Apr 21, 2017
Scientific Reports
The site of overt attention (fixation point) defines a spatial reference center that affects visuomotor response as indicated by the stimulus-response-compatibility (SRC) effect: When subjects press, e.g., a left key to report stimuli, their reaction time is shorter when stimuli appear to the left than to the right of the fixation. Covert attention to a peripheral site appears to define a similar reference center but previous studies did not control for confounding spatiotemporal factors or investigate the relationship between overt- and covert-attention-defined centers. Using an eye tracker to monitor fixation, we found an SRC effect relative to the site of covert attention induced by a flashed cue dot, and a concurrent reduction, but not elimination, of the overt-attention SRC effect. The two SRC effects jointly determined the overall motor reaction time. Since trials with different cue locations were randomly interleaved, the integration of the two reference centers must be updated online. When the cue was invalid and diminished covert attention, the covert-attention SRC effect disappeared and the overt-attention SRC effect retained full strength, excluding non-attention-based interpretations. We conclude that both covert- and overt-attention sites define visual reference centers that simultaneously contribute to motor response.
Draft Nuclear Genome Sequence of the Liquid Hydrocarbon-Accumulating Green Microalga Botryococcus braunii Race B (Showa)
Apr 21, 2017   Genome Announcements
Browne DR, Jenkins J, Schmutz J, Shu S, Barry K,   . . . . . .   , Fox DT, Dhungana S, Okada S, Chappell J, Devarenne TP
Draft Nuclear Genome Sequence of the Liquid Hydrocarbon-Accumulating Green Microalga Botryococcus braunii Race B (Showa)
Apr 21, 2017
Genome Announcements
Botryococcus braunii has long been known as a prodigious producer of liquid hydrocarbon oils that can be converted into combustion engine fuels. This draft genome for the B race of B. braunii will allow researchers to unravel important hydrocarbon biosynthetic pathways and identify possible regulatory networks controlling this unusual metabolism. Copyright © 2017 Browne et al.
The Role of Minimal Residual Disease Testing in Myeloma Treatment Selection and Drug Development: Current Value and Future Applications
Apr 21, 2017   Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research
Anderson KC, Auclair D, Kelloff GJ, Sigman CC, Avet-Loiseau H,   . . . . . .   , Reaman GH, Robbins MD, Sasser AK, Valente N, Zamagni E
The Role of Minimal Residual Disease Testing in Myeloma Treatment Selection and Drug Development: Current Value and Future Applications
Apr 21, 2017
Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research
Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10-5‒10-6 cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents, while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions. Copyright ©2017, American Association for Cancer Research.
Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults
Apr 21, 2017   Fluids And Barriers Of The CNS
Patton SM, Wang Q, Hulgan T, Connor JR, Jia P,   . . . . . .   , Franklin DR, Kaur H, Iudicello J, Grant I, Kallianpur AR
Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults
Apr 21, 2017
Fluids And Barriers Of The CNS
HIV-associated neurocognitive disorder (HAND) remains common, despite antiretroviral therapy (ART). HIV dysregulates iron metabolism, but cerebrospinal fluid (CSF) levels of iron and iron-transport proteins in HIV-infected (HIV+) persons are largely unknown. The objectives of this study were to characterize CSF iron-related biomarkers in HIV+ adults and explore their relationships to known predictors of HAND. We quantified total iron, transferrin and heavy-chain (H)-ferritin by immunoassay in CSF sampled by lumbar puncture in 403 HIV+ participants in a multi-center, observational study and evaluated biomarker associations with demographic and HIV-related correlates of HAND [e.g., age, sex, self-reported race/ethnicity, ART, and detectable plasma virus and CSF viral load (VL)] by multivariable regression. In a subset (N = 110) with existing CSF: serum albumin (QAlb) measurements, QAlb and comorbidity severity were also included as covariates to account for variability in the blood-CSF-barrier. Among 403 individuals (median age 43 years, 19% women, 56% non-Whites, median nadir CD4+ T cell count 180 cells/µL, 46% with undetectable plasma virus), men had 25% higher CSF transferrin (median 18.1 vs. 14.5 µg/mL), and 71% higher H-ferritin (median 2.9 vs. 1.7 ng/mL) than women (both p-values ≤0.01). CSF iron was 41% higher in self-reported Hispanics and 27% higher in (non-Hispanic) Whites than in (non-Hispanic) Blacks (median 5.2 and 4.7 µg/dL in Hispanics and Whites, respectively, vs. 3.7 µg/dL in Blacks, both p ≤ 0.01); these findings persisted after adjustment for age, sex, and HIV-specific factors. Median H-ferritin was 25% higher (p  50 years) than in younger persons (age ≤ 35 years; both p 
Association of BRM promoter polymorphisms and esophageal adenocarcinoma outcome
Apr 21, 2017   Oncotarget
Korpanty GJ, Eng L, Qiu X, Olusesan Faluyi O, Renouf DJ,   . . . . . .   , Darling G, Reisman D, Cuffe S, Liu G, Xu W
Association of BRM promoter polymorphisms and esophageal adenocarcinoma outcome
Apr 21, 2017
Oncotarget
Brahma (BRM) is a critical catalytic subunit of the SWI/SNF chromatin remodeling complex; expression of BRM is commonly lost in various cancer types. BRM promoter polymorphisms (BRM-741; BRM-1321) are associated with loss of BRM expression, and with cancer risk/survival. We evaluated these two polymorphisms in the overall survival (OS) of esophageal adenocarcinoma (EAC) patients. Of 270 patients, 37% were stage IV. Minor allele frequencies were 47-49%; 15% were double-homozygotes. When compared to the wild-type genotype, the homozygous variant of BRM-741 carried an adjusted OS hazard ratio (aHR) of 1.64 (95% CI:1.1-2.4); for BRM-1321, the aHR was 2.09 (95% CI:1.4-3.0). Compared to the double wild-type, carrying homozygous variants of both promoter polymorphisms (double-homozygote) yielded an aHR of 2.21 (95% CI:1.4-3.6). Directions/magnitudes of associations were similar in subsets by age, gender, smoking status, use of platinum agents, and disease stage, and for progression-free survival. In a cohort of EAC patients of all stages (84% male; median age of 64 years), two BRM polymorphisms were genotyped. Cox proportional hazards models, adjusted for known prognostic variables, estimated the association of polymorphisms with OS. BRM polymorphisms were associated with OS in EAC in this study. Validation studies are warranted.
Activity-induced spontaneous spikes in GABAergic neurons suppress seizure discharges: an implication of computational modeling
Apr 21, 2017   Oncotarget
Lu W, Feng J, Wen B, Wang K, Wang JH
Activity-induced spontaneous spikes in GABAergic neurons suppress seizure discharges: an implication of computational modeling
Apr 21, 2017
Oncotarget
Epilepsy, a prevalent neurological disorder, appears self-termination. The endogenous mechanism for seizure self-termination remains to be addressed in order to develop new strategies for epilepsy treatment. We aim to examine the role of activity-induced spontaneous spikes at GABAergic neurons as an endogenous mechanism in the seizure self-termination. Neuronal spikes were induced by depolarization pulses at cortical GABAergic neurons from temporal lobe epilepsy patients and mice, in which some of these neurons fired activity-induced spontaneous spikes. Neural networks including excitatory and inhibitory neurons were computationally constructed, and their functional properties were based on our studies from whole-cell recordings. With the changes in the portion and excitability of inhibitory neurons that generated activity-induced spontaneous spike, the efficacies to suppress synchronous seizure activity were analyzed, such as its onset time, decay slope and spike frequency. The increases in the proportion and excitability of inhibitory neurons that generated activity-induced spontaneous spikes effectively suppressed seizure activity in neural networks. These factors synergistically strengthened the efficacy of seizure activity suppression. Our study supports a notion that activity-induced spontaneous spikes in GABAergic neurons may be an endogenous mechanism for seizure self-termination. A potential therapeutic strategy for epilepsy is to upregulate the cortical inhibitory neurons that generate activity-induced spontaneous spikes.
Single-molecule visualization of fast polymerase turnover in the bacterial replisome
Apr 22, 2017   ELife
Lewis JS, Spenkelink LM, Jergic S, Wood EA, Monachino E, Horan NP, Duderstadt KE, Cox MM, Robinson A, Dixon NE, van Oijen AM
Single-molecule visualization of fast polymerase turnover in the bacterial replisome
Apr 22, 2017
ELife
The Escherichia coli DNA replication machinery has been used as a road map to uncover design rules that enable DNA duplication with high efficiency and fidelity. Although the enzymatic activities of the replicative DNA Pol III are well understood, its dynamics within the replisome are not. Here we test the accepted view that the Pol III holoenzyme remains stably associated within the replisome. We use in vitro single-molecule assays with fluorescently labeled polymerases to demonstrate that the Pol III* complex (holoenzyme lacking the β2 sliding clamp), is rapidly exchanged during processive DNA replication. Nevertheless, the replisome is highly resistant to dilution in the absence of Pol III* in solution. We further show similar exchange in live cells containing labeled clamp loader and polymerase. These observations suggest a concentration-dependent exchange mechanism providing a balance between stability and plasticity, facilitating replacement of replisomal components dependent on their availability in the environment.

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