bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autophosphorylation of the CK1 kinase domain regulates enzyme activity and function
Authors: Cullati Sierra N. , Chen Jun-Song , Gould Kathleen L. 
Published: June 2019

AbstractCK1 enzymes are conserved, acidophilic serine/threonine kinases with a variety of critical cellular functions; misregulation of CK1 contributes to cancer, neurodegenerative diseases, and sleep phase disorders. Despite this, little is known about how CK1 activity is controlled. Here, we describe a new mechanism of CK1 autoregulation that is conserved in CK1 enzymes from yeast to human – the autophosphorylation of a threonine in the mobile L-EF loop proximal to the active site. Phosphorylation at this site inhibits kinase activity, in contrast to well-characterized T-loop autophosphorylation in other kinase families. Consequently, yeast and human enzymes with phosphoablating mutations at this site are hyperactive. InS. pombe, hyperactive CK1 causes defects in cell growth and morphology at a high level but protection from heat shock at a low level, highlighting the necessity of regulated CK1 function. We propose that phosphorylation on the L-EF loop prevents substrate docking with the kinase domain by shielding the positively charged binding pocket and/or sterically hindering the active site. Due to the strong sequence conservation of this autophosphorylation site and the functional importance of the L-EF loop, which is unique to the CK1 family of kinases, this mechanism is likely to regulate the majority of CK1 enzymes in vivo.Significance StatementKinases in the CK1 family are important signaling enzymes, and they function in multiple pathways within the same cell. Misregulation of CK1 activity contributes to human disease, including cancer, neurodegenerative disease, and sleep phase disorders, yet the mechanisms that control CK1 activity are not well understood. We have identified a conserved autophosphorylation site in the CK1 kinase domain that inhibits substrate phosphorylation. We hypothesize that by using kinase domain autophosphorylation in combination with other regulatory mechanisms, CK1 enzymes can coordinate the phosphorylation of their substrates in different pathways.
Aquila: diploid personal genome assembly and comprehensive variant detection based on linked reads
Authors: Zhou Xin , Zhang Lu , Weng Ziming , Dill David L. , Sidow Arend 
Published: June 2019

AbstractVariant discovery in personal, whole genome sequence data is critical for uncovering the genetic contributions to health and disease. We introduce a new approach, Aquila, that uses linked-read data for generating a high quality diploid genome assembly, from which it then comprehensively detects and phases personal genetic variation. Assemblies cover >95% of the human reference genome, with over 98% in a diploid state. Thus, the assemblies support detection and accurate genotyping of the most prevalent types of human genetic variation, including single nucleotide polymorphisms (SNPs), small insertions and deletions (small indels), and structural variants (SVs), in all but the most difficult regions. All heterozygous variants are phased in blocks that can approach arm-level length. The final output of Aquila is a diploid and phased personal genome sequence, and a phased VCF file that also contains homozygous and a few unphased heterozygous variants. Aquila represents a cost-effective evolution of whole-genome reconstruction that can be applied to cohorts for variation discovery or association studies, or to single individuals with rare phenotypes that could be caused by SVs or compound heterozygosity.
The transcription factor Shox2 shapes thalamocortical neuron firing and synaptic properties
Authors: Yu Diankun , Maroteaux Matthieu , Song Yingnan , Han Xiao , Febbo Isabella , Namboodri Claire , Sun Cheng , Ye Wenduo , Meyer Emily , Rowe Stuart , Chen YP , Schrader LA 
Published: June 2019

ABSTRACTThalamocortical neurons (TCNs) transmit information about sensory stimuli from the thalamus to the cortex. In response to different physiological states and demands TCNs can fire in tonic and/or phasic burst modes. These firing properties of TCNs are supported by precisely timed inhibitory synaptic inputs from the thalamic reticular nucleus and intrinsic currents, including T-type Ca2+ and HCN currents. These intrinsic currents are mediated by Cav3.1 and HCN channel subunits, and alterations in expression or modulation of these channels can have dramatic implications on thalamus function. The factors that regulate these currents controlling the firing patterns important for integration of the sensory stimuli and the consequences resulting from the disruption of these firing patterns are not well understood. Shox2 is a transcription factor known to be important for pacemaker activity in the heart. We show here that Shox2 is also expressed in adult mouse thalamus. We hypothesized that genes regulated by Shox2’s transcriptional activity may be important for physiological properties of TCNs. In this study, we used RNA sequencing on control and Shox2 knockout mice to determine Shox2-affected genes and revealed a network of ion channel genes important for neuronal firing properties. Quantitative PCR confirmed that expression of Hcn2, 4 and Cav3.1 genes were affected by Shox2 KO. Western blotting showed expression of the proteins for these channels was decreased in the thalamus, and electrophysiological recordings showed that Shox2 KO impacted the firing and synaptic properties of TCNs. Finally, behavioral studies revealed that Shox2 expression in TCNs play a role in somatosensory function and object recognition memory. Overall, these results reveal Shox2 as a transcription factor important for TCN firing properties and thalamic function.
Tonic resting-state hubness supports high-frequency activity defined verbal-memory encoding network in epilepsy
Authors: Ganne Chaitanya , Hinds Walter , Kragel James , He Xiaosong , Sideman Noah , Ezzyat Youssef , Sperling Michael R , Sharan Ashwini , Tracy Joseph I 
Published: June 2019

AbstractHigh-frequency gamma activity of verbal-memory encoding using invasive-electroencephalogram coupled has laid the foundation for numerous studies testing the integrity of memory in diseased populations. Yet, the functional connectivity characteristics of networks subserving these HFA-memory linkages remains uncertain. By integrating this electrophysiological biomarker of memory encoding from IEEG with resting-state BOLD fluctuations, we estimated the segregation and hubness of HFA-memory regions in drug-resistant epilepsy patients and matched healthy controls. HFA-memory regions express distinctly different hubness compared to neighboring regions in health and in epilepsy, and this hubness was more relevant than segregation in predicting verbal memory encoding. The HFA-memory network comprised regions from both the cognitive control and primary processing networks, validating that effective verbal-memory encoding requires multiple functions, and is not dominated by a central cognitive core. Our results demonstrate a tonic intrinsic set of functional connectivity, which provides the necessary conditions for effective, phasic, task-dependent memory encoding.HighlightsHigh frequency memory activity in IEEG corresponds to specific BOLD changes in resting-state data.HFA-memory regions had lower hubness relative to control brain nodes in both epilepsy patients and healthy controls.HFA-memory network displayed hubness and participation (interaction) values distinct from other cognitive networks.HFA-memory network shared regional membership and interacted with other cognitive networks for successful memory encoding.HFA-memory network hubness predicted both concurrent task (phasic) and baseline (tonic) verbal-memory encoding success.
A Novel Antenna Protein Complex in the Life Cycle of Cyanobacterial Photosystem II
Authors: Weisz Daniel A. , Johnson Virginia M. , Niedzwiedzki Dariusz M. , Shinn Min Kyung , Liu Haijun , Klitzke Clécio F. , Gross Michael L. , Blankenship Robert E. , Lohman Timothy M. , Pakrasi Himadri B. 
Published: June 2019

ABSTRACTIn oxygenic photosynthetic organisms, photosystem II (PSII) is a unique membrane protein complex that catalyzes light-driven oxidation of water. PSII undergoes frequent damage due to its demanding photochemistry. However, many facets of its repair and reassembly following photodamage remain unknown. We have discovered a novel PSII subcomplex that lacks five key PSII core reaction center polypeptides: D1, D2, PsbE, PsbF, and PsbI. This pigment-protein complex does contain the PSII core antenna proteins CP47 and CP43, as well as most of their associated low–molecular–mass subunits, and the assembly factor Psb27. Immunoblotting analysis, multiple mass spectrometry techniques, and ultrafast spectroscopic results supported the absence of a functional reaction center in this chlorophyll–protein complex. We therefore refer to it as the ‘no reaction center’ complex (NRC). Additionally, genetic deletion of PsbO on the PSII lumenal side resulted in an increased NRC population, indicative of a faulty PSII repair scheme at the cellular level. Analytical ultracentrifugation studies and clear native acrylamide gel analysis showed that the NRC complex is a stable pigment-protein complex and not a mixture of free CP47 and CP43 proteins. Our finding challenges the current model of the PSII repair cycle and implies an alternative PSII repair strategy. We propose that formation of this pigment-protein complex maximizes PSII repair economy by preserving an intact PSII core antenna shell in a single complex that is available for PSII reassembly, thus minimizing the risk of randomly diluting multiple recycling components in the thylakoid membrane following a photodamage event at the RC.Significance statementPhotosystem II (PSII) converts sunlight into chemical energy, powering nearly all life on Earth. The efficiency of this process is maximized under various environmental conditions by a frequent repair and reassembly cycle that follows inevitable PSII damage even during normal oxygenic photosynthesis. We have isolated a novel pigment protein PSII subcomplex in which, surprisingly, the reaction center (RC) components of PSII are absent. Formation of this stable chlorophyll-protein complex suggests a protective mechanism whereby longer-lived PSII subunits are ‘unplugged’ from the damaged RC to prevent harmful, aberrant photochemistry during RC repair. This finding provides intriguing new insight into how PSII is assembled and rebuilt to optimize its performance to optimally catalyze one of the most challenging reactions in biology.
Identification of a master regulator of differentiation inToxoplasma
Authors: Waldman Benjamin S. , Schwarz Dominic , Wadsworth Marc H. , Saeij Jeroen P. , Shalek Alex K. , Lourido Sebastian 
Published: June 2019

SUMMARYToxoplasma gondiichronically infects a quarter of the world’s population, and its recrudescence can cause life-threatening disease in immunocompromised individuals and recurrent ocular lesions in the immunocompetent. Chronic stages are established by differentiation of rapidly replicating tachyzoites into slow-growing bradyzoites, which form intracellular cysts resistant to immune clearance and existing therapies. Despite its central role in infection, the molecular basis of chronic differentiation is not understood. Through Cas9-mediated genetic screening and single-cell transcriptional profiling, we identify and characterize a putative transcription factor (BFD1) as necessary and sufficient for differentiation. Translation of BFD1 appears to be stress regulated, and its constitutive expression elicits differentiation in the absence of stress. As a Myb-like factor, BFD1 provides a counterpoint to the ApiAP2 factors which dominate our current view of parasite gene regulation. Overall, BFD1 provides a genetic switch to study and controlToxoplasmadifferentiation, and will inform prevention and treatment of chronic infection.
Increase in ribosomal proteins activity: Translational reprogramming inVanilla planifoliaJacks., againstFusariuminfection
Authors: Solano de la Cruz Marco Tulio , Adame-García Jacel , Gregorio-Jorge Josefat , Jiménez-Jacinto Verónica , Vega-Alvarado Leticia , Iglesias-Andreu Lourdes , Escobar-Hernández Esteban Elías , Luna-Rodríguez Mauricio 
Published: June 2019

ABSTRACTBackgroundUpon exposure to unfavorable environmental conditions, plants need to respond quickly to maintain their homeostasis. For instance, physiological, biochemical and transcriptomical changes must occur during interactions with pathogens, this causing the triggering of pathogen- and plant-derived molecules. In the case ofVanilla planifoliaJacks., a worldwide economically important crop, it is susceptible toFusarium oxysporumf. sp.vanillae. This pathogen causes root and stem rot in vanilla plants that finally leads to plant death. To further investigate how vanilla plants respond at the transcriptional level upon infection withF.oxysporumf. sp.vanillae, we employed the RNA-Seq approach to analyze the dynamics of whole-transcriptome changes during two-time frames of the infection.ResultsAnalysis of global gene expression profiles indicated that a major transcriptional change occurs at 2 dpi, in comparison to 10 dpi, whereas 3420 genes were found with a differential expression at 2 dpi, only 839 were identified at 10 dpi. The analysis of the transcriptional profile at 2 dpi suggests that vanilla plants prepare to counter the infection by gathering a pool of translational regulation-related transcripts.ConclusionsWe propose that the plant-pathogen interaction at early stages causes a transcriptional reprogramming coupled with a translational regulation. Altogether, this study provides the identification of molecular players that could help to fight the most damaging disease of vanilla, where ribosomal proteins and regulation of the translational mechanism are critical. These are insights into the defense responses ofV. planifoliaJacks., providing the basis for the understanding of the plant early response towards biotic stress.
Measuring the distribution of fitness effects in somatic evolution by combining clonal dynamics with dN/dS ratios
Authors: Williams Marc J , Zapata Luiz , Werner Benjamin , Barnes Chris , Sottoriva Andrea , Graham Trevor A 
Published: June 2019

AbstractThe distribution of fitness effects (DFE) defines how new mutations spread through an evolving population. The ratio of non-synonymous to synonymous mutations (dN/dS) has become a popular method to detect selection in somatic cells, however the link, in somatic evolution, between dN/dS values and fitness coefficients is missing. Here we present a quantitative model of somatic evolutionary dynamics that yields the selective coefficients from individual driver mutations from dN/dS estimates, and then measure the DFE for somatic mutant clones in ostensibly normal oesophagus and skin. We reveal a broad distribution of fitness effects, with the largest fitness increases found for TP53 and NOTCH1 mutants (proliferative bias 1-5%). Accurate measurement of the per-gene DFE in cancer evolution is precluded by the quality of currently available sequencing data. This study provides the theoretical link between dN/dS values and selective coefficients in somatic evolution, and reveals the DFE for mutations in human tissues.
Motoneuron-derived Activinβ regulates Drosophila body size and tissue-scaling during larval growth and adult development
Authors: Moss-Taylor Lindsay , Upadhyay Ambuj , Pan Xueyang , Kim Myung-Jun , O’Connor Michael B. 
Published: June 2019

AbstractCorrect scaling of body and organ size is crucial for proper development and survival of all organisms. Perturbations in circulating hormones, including insulins and steroids, are largely responsible for changing body size in response to both genetic and environmental factors. Such perturbations typically produce adults whose organs and appendages scale proportionately with final size. The identity of additional factors that might contribute to scaling of organs and appendages with body size is unknown. Here we report that loss-of-function mutations in Drosophila Activinβ (Actβ), a member of the TGF-β superfamily, lead to production of small larvae/pupae and undersized rare adult escapers. Morphometric measurements of escaper adult appendage size (wings, legs), as well as heads, thoraxes, and abdomens, reveal a disproportional reduction in abdominal size compared to other tissues. Similar size measurements of selected Actβ mutant larval tissues demonstrate that somatic muscle size is disproportionately smaller when compared to fat body, salivary glands, prothoracic glands, imaginal discs and brain. We also show that Actβ control of body size is dependent on canonical signaling through the transcription-factor dSmad2 and that it modulates the growth rate, but not feeding behavior, during the third instar period. Tissue and cell-specific knockdown and overexpression studies reveal that motoneuron derived Actβ is essential for regulating proper body size and tissue scaling. These studies suggest that, unlike in vertebrates where Myostatin, and certain other Activin-like factors act as systemic negative regulators of muscle mass, in Drosophila Actβ is a positive regulator of muscle mass that is directly delivered to muscles by motoneurons. We discuss the importance of these findings in coordinating proportional scaling of insect muscle mass to appendage size.
Calcium dobesilate reduces VEGF signaling by interfering with heparan sulfate binding site and protects from vascular complications in diabetic mice
Authors: Njau Florence , Shushakova Nelli , Schenk Heiko , Wulfmeyer Vera Christine , Bollin Robin , Menne Jan , Haller Hermann 
Published: June 2019

AbstractInhibiting vascular endothelial growth factor (VEGF) is a therapeutic option in diabetic microangiopathy. However, VEGF is needed at physiological concentrations to maintain glomerular integrity; complete VEGF blockade has deleterious effects on glomerular structure and function. Anti-VEGF therapy in diabetes raises the challenge of reducing VEGF-induced pathology without accelerating endothelial cell injury. Heparan sulfate (HS) can act as a co-receptor for VEGF. Calcium dobesilate (CaD) is a small molecule with vasoprotective properties that has been used for the treatment of diabetic microangiopathy. Preliminary evidence suggests that CaD interferes with HS binding sites of fibroblast growth factor. We therefore tested the hypotheses that (1) CaD inhibits VEGF signaling in endothelial cells, (2) that this effect is mediated via interference between CaD and HS, and (3) that CaD ameliorates diabetic nephropathy in a streptozotocin-induced diabetic mouse model by VEGF inhibition. We found that CaD significantly inhibited VEGF165-induced endothelial cell migration, proliferation, and permeability. CaD significantly inhibited VEGF165-induced phosphorylation of VEGFR-2 and suppressed the activity of VEGFR-2 mediated signaling cascades. The effects of CaD in vitro were abrogated by heparin, suggesting the involvement of heparin-like domain in the interaction with CaD. In addition, VEGF121, an isoform which does not bind to heparin, was not inhibited by CaD. By applying proximity ligation assays to endothelial cells, we show inhibition of interaction in situ between HS and VEGF and between VEGF and VEGFR-2. Moreover, CaD reduced VEGF signaling in diabetic kidneys and ameliorated diabetic nephropathy and neuropathy, suggesting CaD as a VEGF inhibitor without the negative effects of complete VEGF blockade and therefore could be useful as a strategy in treating diabetic nephropathy.
Health Conditions Associated with Overweight in Climacteric Women
Authors: Marques Maria Suzana , Freitas Ronilson Ferreira , Araújo Veloso Popoff Daniela , Piana Santos Lima de Oliveira Fernanda , Rodrigues Moreira Maria Helena , Araújo Drummond Andreia Maria , Schmidt França Dorothéa , Nogueira dos Santos Luís Antônio , de Siqueira e Rocha Marcelo Eustáquio , Brant Rocha João Pedro , Brant Rocha Maria Clara , Santos Figueiredo Brito Maria Fernanda , Prates Caldeira Antônio , Maria Borborema Fabiana Aparecida , Santos Viviane Maria , Santos Brant Rocha Josiane 
Published: June 2019

AbstractThis study aims to investigate the association between health conditions and overweight in climacteric women assisted by primary care professionals. It is a cross-sectional study conducted with 874 women from 40 to 65 years of age, selected by probabilistic sampling between August 2014 and August 2015. In addition to the outcome variable, other variables such as overweight/obesity, sociodemographic, reproductive, clinical, eating and behavioural factors were evaluated. Descriptive analyses of the variables investigated through their frequency distributions were performed. Then, bivariate analyses were performed through Poisson regression. For the multiple analyses, the hierarchical Poisson regression was used to identify factors associated with overweight/obesity in the climacteric period. The prevalence of overweight/obesity was 74%. Attending public school (PR: 1.30 - 95% CI 1.14 - 1.50), low schooling (PR: 1.11 - 95% CI 1.01 - 1.23), gout (PR: 1.18 - 95% CI 1.16-1.44), kidney disease (PR: 1.18 - 95% CI 1.05 - 1.32), metabolic syndrome - MS (PR: 1.19 - 95% CI 1.05 - 1.34) and fat intake (PR: 1.12 - 95% CI 1.02 - 1.23) were considered risk factors for overweight. Having the first birth after 18 years (PR: 0.89 - 95% CI 0.82 to 0.97) was shown to be a protective factor for overweight and obesity. The presence of overweight and obesity is associated with socio-demographic, reproductive, clinical and eating habits.
The small GTPase Rab11F represents a molecular marker within the secretory pathway required for the nitrogen-fixing symbiosis
Authors: Nounurai Prachumporn , Densow Holger , Bednarz Hanna , Niehaus Karsten 
Published: June 2019

AbstractThe nitrogen-fixing root nodule is generally derived through a successful symbiotic interaction between legume plants and bacteria of the genusRhizobium. A root nodule shelter hundreds ofRhizobia, which are thought to invade into the plant cells through an endocytosis-like process despite the existence of turgor pressure. Each invadingRhizobiumis surrounded by the peribacteroid membrane to form the symbiosome, which results in the higher acquisition of host membrane materials. In this study, we show the localization of Rab11F, a RabA6b homolog with the large Rab-GTPase family, which was highly expressed in root nodules ofMedicago sativaandM. truncatula. Rab11F-labeled organelles accumulated the membrane specific dye FM4-64 and were sensitive to Brefeldin A by forming aggregates after treatment with this drug. By co-localization with the cis-Golgi marker, GmMan1-mCherry, Rab11F-organelles formed tri-colored organelles, whereby Rab11F was located to the opposite side of GmMan1-mCherry indicating that Rab11F-labeled structures were localized within the trans-Golgi network (TGN). In root nodules, Rab11F was localized transiently at the infection thread-covering membrane on the side of infection droplets and the peribacteroid membranes. The symbiosome acquires Rab11F during the entry process and differentiation. However, the symbiosome did not recruit Rab11F after cessation of division. In conclusion, thelegumeplant seemed to use a specialized secretion pathway from the TGN, which was marked by Rab11F, to proliferate the symbiosome membrane.