bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coordination between stochastic and deterministic specification in the Drosophila visual system
Authors: Courgeon Maximilien , Desplan Claude 
Published: June 2019

AbstractMany sensory systems use stochastic fate specification to increase their repertoire of neuronal types. How these stochastic decisions are coordinated with the development of their target post-synaptic neurons in processing centers is not understood. In the Drosophila visual system, two subtypes of the UV-sensitive R7 color photoreceptors called yR7 and pR7 are stochastically specified in the retina. In contrast, the target neurons of photoreceptors in the optic lobes are specified through a highly deterministic program. Here, we identify subtypes of the main postsynaptic target of R7, the Dm8 neurons, that are each specific to the different subtypes of R7s. We show that during development the different Dm8 subtypes are produced in excess by distinct neuronal progenitors, independently from R7 subtype specification. Following matching with their respective R7 target, supernumerary Dm8s are eliminated by apoptosis. We show that the two interacting cell adhesion molecules Dpr11, expressed in yR7s, and its partner DIPγ, expressed in yDm8s, are essential for the matching of the synaptic pair. Loss of either molecule leads to the death of yDm8s or their mis-pairing with the wrong pR7 subtype. We also show that competitive interactions between Dm8 subtypes regulate both cell survival and targeting. These mechanisms allow the qualitative and quantitative matching of R7 subtypes with their target in the brain and thus permit the stochastic choice made in R7 to propagate to the deterministically specified downstream circuit to support color vision.
Toxoplasma gondiibradyzoites induce transcriptional changes to host cells and prevent IFNγ-mediated cell death
Authors: Seizova Simona , Garnham Alexandra L , Coffey Michael J , Whitehead Lachlan W , Rogers Kelly L , Tonkin Christopher J 
Published: June 2019

SummaryToxoplasma gondii, the causative agent of toxoplasmosis, lies dormant for life and is a reservoir for disease reactivation, causing blindness, encephalitis and congenital birth defects. Acute-stage tachyzoites extensively manipulate their host cell by exporting a repertoire of proteins across the parasitophorous vacuolar membrane (PVM). This interferes with the hosts transcriptional program, allowing for persistence during immune attack. It is unknown how bradyzoites persist and what role host manipulation plays in latency. Here we show that bradyzoite-containing host cells have a unique transcriptional landscape when compared to tachyzoite infection. We demonstrate that many of these changes are dependent parasite protein export. Furthermore, we show that bradyzoite effector proteins protect host cell’s from IFNγ-mediated cell death, thus highlighting the functional importance of host manipulation. Together, our work provides the first understanding of howToxoplasmasets up latency to persist in its host.
Tomato yellow leaf curl virus V2 protein plays a critical role in the nuclear export of V1 protein and viral systemic infection
Authors: Zhao Wenhao , Ji Yinghua , Wu Shuhua , Barton Elizabeth , Fan Yongjian , Wang Xiaofeng , Zhou Yijun 
Published: June 2019

AbstractGeminiviruses are an important group of circular, single-stranded DNA viruses that cause devastating diseases in crops. Geminiviruses replicate their genomic DNA in the nucleus. The newly-synthesized viral DNA is subsequently transported to the cytoplasm, moved to adjacent cells through plasmodesmata with the help of viral movement proteins, and, ultimately, moved long-distance to establish systemic infection. Thus, the nucleocytoplasmic transportation is crucial for a successful infection by geminiviruses. For Tomato yellow leaf curl virus (TYLCV), the V1 protein is known to bind and shuttle viral genomic DNA, but the role of V2 protein in this process is still unclear. Here, we report that the nucleus-localized V1 protein dramatically decreases when co-expressed with V2 protein, and that V2-facilitated nuclear export of V1 protein depends on host exportin-α and a specific V1-V2 interaction. Chemical inhibition of exportin-α or a substitutions at cysteine 85 of V2 protein, which abolishes the V1-V2 interaction, blocks the promoted redistribution of V1 protein to the perinuclear region and the cytoplasm. When the V2C85S mutation is incorporated into a TYLCV infectious clone, the TYLCV-C85S causes delayed onset of very mild symptoms compared to wild-type TYLCV, indicating that the V1-V2 interaction and, thus, V2-mediated nuclear export of V1 protein is crucial for viral spread and systemic infection. Our data point to a critical role of the V2 protein in promoting the nuclear export of the V1 protein, likely by promoting V1-mediated nucleocytoplasmic transportation of TYLCV genomic DNA, and in turn, promoting viral systemic infection.Author summaryAs both replication and the transcription of geminiviruses occur in the nucleus, transportation of the viral genomic DNA into and out of the nucleus of the infected cells is essential for a successful infection cycle. However, the nuclear export of geminiviruses is still little known and even less is known about the process for monopartite geminiviruses. We use TYLCV, a typical monopartite begomovirus in the family Geminiviridae, to examine the nucleocytoplasmic transportation. In this study, we found TYLCV V2 is able to redistribute the nucleus-localized V1 protein to the perinuclear region. Moreover, the nuclear export of V1 protein is dependent on the V1-V2 interaction and host exportin-α. Blocking the V1-V2 interaction impeded the V2-mediated V1 protein redistribution and decrease TYLCV infection efficiency with delayed and mild symptoms. This report shows us a new explanation for the role of V2 in the nuclear export of V1 protein and TYLCV viral systemic infection.
Low oxygen enhances trophoblast column growth by potentiating the extravillous lineage and promoting LOX activity
Authors: Treissman Jenna , Yuan Victor , Baltayeva Jennet , Le Hoa T. , Castellana Barbara , Robinson Wendy P. , Beristain Alexander G. 
Published: June 2019

ABSTRACTEarly placental development and the establishment of the invasive trophoblast lineage take place within a low oxygen environment. However, conflicting and inconsistent findings have obscured the role of oxygen in regulating invasive trophoblast differentiation. In this study, the effect of hypoxic, normoxic, and atmospheric oxygen on invasive extravillous pathway progression was examined using a human placental explant model. Here, we show that exposure to low oxygen enhances extravillous column outgrowth and promotes the expression of genes that align with extravillous trophoblast (EVT) lineage commitment. By contrast, super-physiological atmospheric levels of oxygen promote trophoblast proliferation while simultaneously stalling EVT progression. Low oxygen-induced EVT differentiation coincided with elevated transcriptomic levels of lysyl oxidase (LOX) in trophoblast anchoring columns, where functional experiments established a role for LOX activity in promoting EVT column outgrowth. The findings of this work support a role for low oxygen in potentiating the differentiation of trophoblasts along the extravillous pathway. Additionally, these findings generate insight into new molecular processes controlled by oxygen during early placental development.Summary StatementLow oxygen promotes extravillous trophoblast differentiation
A Protein Engineering Approach for Uncovering Cryptic Ubiquitin-binding Sites: from a Ubiquitin-Variant Inhibitor of APC/C to K48 Chain Binding
Authors: Watson Edmond R. , Grace Christy R. R. , Zhang Wei , Miller Darcie J. , Davidson Iain F. , Prabu J. Rajan , Yu Shanshan , Bolhuis Derek L. , Kulko Elizaveta T. , Vollrath Ronnald , Haselbach David , Stark Holger , Peters Jan-Michael , Brown Nicholas G. , Sidhu Sachdev S. , Schulman Brenda A. 
Published: June 2019

ABSTRACTUbiquitin-mediated proteolysis is a fundamental mechanism used by eukaryotic cells to maintain homeostasis and protein quality, and to control timing in biological processes. Two essential aspects of ubiquitin regulation are conjugation through E1-E2-E3 enzymatic cascades, and recognition by ubiquitin-binding domains. An emerging theme in the ubiquitin field is that these two properties are often amalgamated in conjugation enzymes. In addition to covalent thioester linkage to ubiquitin’s C-terminus for ubiquitin transfer reactions, conjugation enzymes often bind non-covalently and weakly to ubiquitin at “exosites”. However, identification of such sites is typically empirical and particularly challenging in large molecular machines. Here, studying the 1.2 MDa E3 ligase Anaphase-Promoting Complex/Cyclosome (APC/C), which controls cell division and many aspects of neurobiology, we discover a method for identifying unexpected ubiquitin-binding sites. Using a panel of ubiquitin variants (UbVs) we identify a protein-based inhibitor that blocks ubiquitin ligation to APC/C substrates in vitro and ex vivo. Biochemistry, NMR, and cryo EM structurally define the UbV interaction, explain its inhibitory activity through binding the surface on the APC2 subunit that recruits the E2 enzyme UBE2C, and ultimately reveal that this APC2 surface is also a ubiquitin-binding exosite with preference for K48-linked chains. The results provide a new tool for probing APC/C activity, have implications for the coordination of K48-linked Ub chain binding by APC/C with the multistep process of substrate polyubiquitylation, and demonstrate the power of UbV technology for identifying cryptic ubiquitin binding sites within large multiprotein complexes.SIGNIFICANCE STATEMENTUbiquitin-mediated interactions influence numerous biological processes. These are often transient or a part of multivalent interactions. Therefore, unmasking these interactions remains a significant challenge for large, complicated enzymes such as the Anaphase-Promoting Complex/Cyclosome (APC/C), a multisubunit RING E3 ubiquitin (Ub) ligase. APC/C activity regulates numerous facets of biology by targeting key regulatory proteins for Ub-mediated degradation. Using a series of Ub variants (UbVs), we identified a new Ub-binding site on the APC/C that preferentially binds to K48-linked Ub chains. More broadly, we demonstrate a workflow that can be exploited to uncover Ub-binding sites within ubiquitylation machinery and other associated regulatory proteins to interrogate the complexity of the Ub code in biology.
Chemical precision glyco-mutagenesis by glycosyltransferase engineering in living cells
Authors: Schumann Benjamin , Malaker Stacy A. , Wisnovsky Simon P. , Debets Marjoke F. , Agbay Anthony J. , Fernandez Daniel , Wagner Lauren J. S. , Lin Liang , Choi Junwon , Fox Douglas M. , Peh Jessie , Gray Melissa A. , Pedram Kayvon , Kohler Jennifer J. , Mrksich Milan , Bertozzi Carolyn R. 
Published: June 2019

AbstractStudying posttranslational modifications classically relies on experimental strategies that oversimplify the complex biosynthetic machineries of living cells. Protein glycosylation contributes to essential biological processes, but correlating glycan structure, underlying protein and disease-relevant biosynthetic regulation is currently elusive. Here, we engineer living cells to tag glycans with editable chemical functionalities while providing information on biosynthesis, physiological context and glycan fine structure. We introduce a non-natural substrate biosynthetic pathway and use engineered glycosyltransferases to incorporate chemically tagged sugars into the cell surface glycome of the living cell. We apply the strategy to a particularly redundant yet disease-relevant human glycosyltransferase family, the polypeptideN-acetylgalactosaminyl transferases. This approach bestows a gain-of-function modification on cells where the products of individual glycosyltransferases can be selectively characterized or manipulated at will.
Host circadian rhythms are disrupted during malaria infection in parasite genotype-specific manners
Authors: Prior Kimberley F. , O’Donnell Aidan J. , Rund Samuel S. C. , Savill Nicholas J. , van der Veen Daan R. , Reece Sarah E. 
Published: June 2019

AbstractInfection can dramatically alter behavioural and physiological traits as hosts become sick and subsequently return to health. Such “sickness behaviours” include disrupted circadian rhythms in both locomotor activity and body temperature. Host sickness behaviours vary in pathogen species-specific manners but the influence of pathogen intraspecific variation is rarely studied. We examine how infection with the murine malaria parasite, Plasmodium chabaudi, shapes sickness in terms of parasite genotype-specific effects on host circadian rhythms. We reveal that circadian rhythms in host locomotor activity patterns and body temperature become differentially disrupted and in parasite genotype-specific manners. Locomotor activity and body temperature in combination provide more sensitive measures of health than commonly used virulence metrics for malaria (e.g. anaemia). Moreover, patterns of host disruption cannot be explained simply by variation in replication rate across parasite genotypes or the severity of anaemia each parasite genotype causes. It is well known that disruption to circadian rhythms is associated with non-infectious diseases, including cancer, type 2 diabetes, and obesity. Our results reveal that disruption of host circadian rhythms is a genetically variable virulence trait of pathogens with implications for host health and disease tolerance.
Familiarity increases processing speed in the visual system
Authors: Manahova Mariya E. , Spaak Eelke , de Lange Floris P. 
Published: June 2019

AbstractFamiliarity with a stimulus leads to an attenuated neural response to the stimulus. Alongside this attenuation, recent studies have also observed a truncation of stimulus-evoked activity for familiar visual input. One proposed function of this truncation is to rapidly put neurons in a state of readiness to respond to new input. Here, we examined this hypothesis by presenting human participants with target stimuli that were embedded in rapid streams of familiar or novel distractor stimuli at different speeds of presentation, while recording brain activity using magnetoencephalography (MEG) and measuring behavioral performance. We investigated the temporal and spatial dynamics of signal truncation and whether this phenomenon bears relationship to participants’ ability to categorize target items within a visual stream. Behaviorally, target categorization performance was markedly better when the target was embedded within familiar distractors, and this benefit became more pronounced with increasing speed of presentation. Familiar distractors showed a truncation of neural activity in the visual system, and this truncation was strongest for the fastest presentation speeds. Moreover, neural processing of the target was stronger when it was preceded by familiar distractors. Taken together, these findings suggest that truncation of neural responses for familiar items may result in stronger processing of relevant target information, resulting in superior perceptual performance.Significance statementThe visual response to familiar input is attenuated more rapidly than for novel input. Here we find that this truncation of the neural response for familiar input is strongest for very fast image presentations. We also find a tentative function for this truncation: the neural response to a target image that is embedded within distractors is much greater when the distractors are familiar than when they are novel. Similarly, target categorization performance is much better when the target is embedded within familiar distractors, and this advantage is most obvious for very fast image presentations. This suggests that neural truncation helps to rapidly put neurons in a state of readiness to respond to new input.
Multifaceted genome-wide study identifies novel regulatory loci for body mass index in Indians
Authors: Giri Anil K , Prasad Gauri , Bandesh Khushdeep , Parekatt Vaisak , Mahajan Anubha , Banerjee Priyanka , Kauser Yasmeen , Chakraborty Shraddha , Rajashekar Donaka ,   INDICO, Sharma Abhay , Mathur Sandeep Kumar , Basu Analabha , McCarthy Mark I , Tandon Nikhil , Bharadwaj Dwaipayan 
Published: June 2019

AbstractObesity, a risk factor for various human diseases originates through complex interactions between genes and prevailing environment that varies across populations. Indians exhibit a unique obesity phenotype likely attributed by specific gene pool and environmental factors. Here, we present genome-wide association study (GWAS) of 7,259 Indians to understand the genetic architecture of body mass index (BMI) in the population. Our study revealed novel association of variants in BAI3 (rs6913677) and SLC22A11 (rs2078267) at GWAS significance, and of ZNF45 (rs8100011) with near GWAS significance. As genetic loci may dictate the phenotype through modulation of epigenetic processes, we overlapped discovered genetic signatures with DNA methylation patterns of 236 Indian individuals, and analyzed expression of the candidate genes using publicly available data. The variants in BAI3 and SLC22A11 were found to dictate methylation patterns at unique CpGs harboring critical cis- regulatory elements. Further, BAI3, SLC22A11 and ZNF45 variants were found to overlie repressive chromatin, active enhancer, and active chromatin regions, in that order, in human subcutaneous adipose tissue in ENCODE database. Besides, the identified genomic regions represented potential binding sites for key transcription factors implicated in obesity and/or metabolic disorders. Interestingly, rs8100011 (ZNF45) acted as a robust cis-expression quantitative trait locus (cis-eQTL) in subcutaneous adipose tissue in GTEx portal, and ZNF45 gene expression showed an inverse correlation with BMI in skeletal muscle of Indian subjects. Further, gene-based GWAS analysis revealed CPS1 and UPP2 as additional leads regulating BMI in Indians. Our study decodes potential genomic mechanisms underlying obesity phenotype in Indians.
Evolution of C4 photosynthesis predicted by constraint-based modelling
Authors: Blätke Mary-Ann , Bräutigam Andrea 
Published: June 2019

AbstractConstraint-based modelling (CBM) is a powerful tool for the analysis of evolutionary trajectories. Evolution, especially evolution in the distant past, is not easily accessible to laboratory experimentation. Modelling can provide a window into evolutionary processes by allowing the examination of selective pressures which lead to particular optimal solutions in the model. To study the evolution of C4 photosynthesis from a ground state of C3 photosynthesis, we initially construct a C3 model. After duplication into two cells to reflect typical C4 leaf architecture, we allow the model to predict the optimal metabolic solution under various conditions. The model thus identifies resource limitation in conjunction with high photorespiratory flux as a selective pressure relevant to the evolution of C4. It also predicts that light availability and distribution play a role in guiding the evolutionary choice of possible decarboxylation enzymes. The data shows evolutionary CBM in eukaryotes predicts molecular evolution with precision.
Effect of sampling frequency on fractal fluctuations during treadmill walking
Authors: Marmelat Vivien , Duncan Austin , Meltz Shane 
Published: June 2019

AbstractThe temporal dynamics of stride-to-stride fluctuations in steady-state walking reveal important information about locomotor control and can be quantified using so-called fractal analyses, notably the detrended fluctuation analysis (DFA). Gait dynamics are often collected during treadmill walking using 3-D motion capture to identify gait events from kinematic data. The sampling frequency of motion capture systems may impact the precision of event detection and consequently impact the quantification of stride-to-stride variability. This study aimed i) to determine if collecting multiple walking trials with different sampling frequency affects DFA values of spatiotemporal parameters during treadmill walking, and ii) to determine the reliability of DFA values across downsampled conditions. Seventeen healthy young adults walked on a treadmill while their gait dynamics was captured using different sampling frequency (60, 120 and 240 Hz) in each condition. We also compared data from the highest sampling frequency to downsampled versions of itself. We applied DFA to the following time series: step length, time and speed, and stride length, time and speed. Reliability between experimental conditions and between downsampled conditions were measured with 1) intraclass correlation estimates and their 95% confident intervals, calculated based on a single-measurement, absolute-agreement, two-way mixed-effects model (ICC 3,1), and 2) Bland-Altman bias and limits of agreement. Both analyses revealed a poor reliability of DFA results between conditions using different sampling frequencies, but a relatively good reliability between original and downsampled spatiotemporal variables. Collectively, our results suggest that using sampling frequencies of 120 Hz or 240 Hz provide similar results, but that using 60 Hz may alter DFA values. We recommend that gait kinematics should be collected at around 120 Hz, which provides a compromise between event detection accuracy and processing time.
The role of transporters and synaptic cleft morphology in glutamate and GABA homeostasis and their effect on neuronal function
Authors: Ullah Ghanim 
Published: June 2019

AbstractThe spatiotemporal dynamics of glutamate and gama-aminobutyric acide (GABA) in the synaptic cleft plays a key role in the signal integration in the brain. Since there is no extracellular metabolism of glutamate and GABA, cellular uptake through transporters and diffusion to extracellular space (ECS) regulates the concentration of both neurotransmitters in the cleft. We use the most up to date information about the transporters and synaptic cleft to model the homeostasis of both glutamate and GABA. We show that the models can be used to investigate the role played by different isoforms of transporters, uptake by different neuronal compartments or glia cells, and key parameters determining the morphology of synaptic cleft in the neurotransmitter concentration in the cleft and ECS, and how they shape synaptic responses through postsynaptic receptors. We demonstrate the utility of our models by application to simple neuronal networks and showing that varying the neurotransmitter uptake capacity and synaptic cleft parameters within experimentally observed range can lead to significant changes in neuronal behavior such as the transition of the network between gamma and beta rhythms. The modular form of the models allows easy extension in the future and integration with other computational models of normal and pathological neuronal functions.