bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripheral blood cell immunophenotyping reveals distinct subgroups of inflamed depression
Authors: Lynall Mary-Ellen , Turner Lorinda , Bhatti Junaid , Cavanagh Jonathan , de Boer Peter , Mondelli Valeria , Jones Declan , Drevets Wayne C. , Cowen Philip , Harrison Neil A. , Pariante Carmine M. , Pointon Linda ,   NIMA Consortium, Clatworthy Menna R. , Bullmore Ed 
Published: July 2019

AbstractDepression has been associated with increased inflammatory proteins but changes in circulating immune cells are less well defined. We used multi-parametric flow cytometry to investigate 14 subsets of peripheral blood cells in 206 cases of major depressive disorder (MDD) and 77 age- and sex-matched controls. There were significant case-control differences, by univariate and multivariate analysis: cases showed increased immune cell counts, especially neutrophils, CD4+ T cells and monocytes, and increased inflammatory proteins (C-reactive protein and interleukin-6). Within-group analysis demonstrated significant association between the severity of depressive symptoms and increased myeloid and CD4+ cell counts. MDD cases could be partitioned into two groups by forced binary clustering of cell counts: the inflamed depression group (N=81 out of 206; 39%) had increased monocyte, CD4+ and neutrophil counts, increased C-reactive protein (CRP) and interleukin 6 (IL-6), and was more depressed than the uninflamed majority of cases. Relaxing the presumption of a binary classification, data-driven clustering identified four subgroups of MDD cases: two of these subgroups (N=38 and N=100; 67% collectively) were associated with increased inflammatory proteins and more severe depression, but differed from each other in the relative weighting of myeloid and lymphoid cell counts. Case-control and within-group results were robust to statistical control for the potentially confounding effects of age, sex, BMI, recent infection status, and tobacco use. Peripheral blood immunophenotyping can be used to identify a candidate cellular biomarker of inflamed depression, and to further decompose that binary partition, suggesting that there is more than one mechanistic pathway underlying inflamed depression.One Sentence SummaryTwo subgroups of depressed cases (about two-thirds of all 206 cases) were identified by peripheral blood biomarker evidence of distinctive cellular immunophenotypes, biased towards the myeloid or lymphoid lineages in different subgroups, but consistently associated with increased blood concentrations of inflammatory proteins and greater severity of depressive symptoms.
IQGAP1 connects phosphoinositide signaling to cytoskeletal reorganization
Authors: Yerramilli V. Siddartha , Ross Alonzo H. , Lindberg Samantha K. , Scarlata Suzanne , Gericke Arne 
Published: July 2019

AbstractIQGAP1 is a multi-domain protein that acts as a scaffold for multiple signaling pathways. IQGAP1 generates the lipid messenger PI(3,4,5)P3 by scaffolding the phosphoinositide kinases PIPKIs and PI3K. The dynamics of this scaffolding protein complex in intact, living cells are unknown. Here, we delineate the role of IQGAP1 in PI(3,4,5)P3-mediated signaling in live cells under basal and stimulated conditions using fluorescence lifetime imaging microscopy. We demonstrate that IQGAP1 interacts strongly with PIPKIγ at intracellular entities and on the plasma membrane, and scaffolds PI3K and PIPKIγ in response to physiological changes. Additionally, we show that IQGAP1 scaffolds phosphoinositides with PI3K, PIPKIγ and EGFR, and forms clusters upon cell stimulation with epidermal growth factor. Importantly, we show that IQGAP1 connects PI(3,4,5)P3-mediated signaling and cytoskeletal signaling pathways by binding PIPKIγ in proximity of the cytoskeletal proteins talin and Cdc42. Our results support a model in which IQGAP1 mediates crosstalk between phosphoinositide signaling and the cytoskeleton to promote directed cell movement.
Context-dependent gene regulation by transcription factor complexes
Authors: Kribelbauer Judith F. , Loker Ryan E. , Feng Siqian , Rastogi Chaitanya , Abe Namiko , Rube H. Tomas , Bussemaker Harmen J. , Mann Richard S. 
Published: July 2019

ABSTRACTEukaryotic transcription factors (TFs) form complexes with various partner proteins to recognize their genomic target sites. Yet, how the DNA sequence determines which TF complex forms at any given site is poorly understood. Here we demonstrate that high-throughputin vitrobinding assays coupled with unbiased computational analysis provides unprecedented insight into how complexes of homeodomain proteins adapt their stoichiometry and configuration to the bound DNA. Using inferred knowledge about minor groove width readout, we design targeted protein mutations that destabilize homeodomain binding in a complex-specific manner. By performing parallel SELEX-seq, ChIP-seq, RNA-seq and Hi-C assays, we not only reveal complex-specific functions, but also show that TF binding sites that lack a canonical sequence motif emerge as a consequence of direct interaction with functionally bound sites.
PacBio amplicon sequencing method to measure pilin antigenic variation frequencies ofNeisseria gonorrhoeae
Authors: Ozer Egon A. , Prister Lauren L. , Yin Shaohui , Ward Billy H. , Ivanov Stanimir , Seifert H Steven 
Published: July 2019

ABSTRACTGene diversification is a common mechanism pathogens use to alter surface structures to aid in immune avoidance.Neisseria gonorrhoeaeuses a gene conversion-based diversification system to alter the primary sequence of the gene encoding the major subunit of the pilus, pilE. Antigenic variation occurs when one of the non-expressed 19 silent copies donates part of its DNA sequence topilE. We have developed a method using Pacific Biosciences amplicon sequencing and custom software to determine pilin antigenic variation frequencies. The program analyzes 37 variable regions across the strain FA1090 1-81-S2pilEgene and can be modified to determine sequence variation from other startingpilEsequences or other diversity generation systems. Using this method, we measured pilin antigenic variation frequencies for various derivatives of strain FA1090 and showed we can also analyze pilin antigenic variation frequencies during macrophage infection.
Single-gene resolution of locally adaptive genetic variation in Mexican maize
Authors: Gates Daniel J , Runcie Dan , Janzen Garrett M. , Navarro Alberto Romero , Willcox Martha , Sonder Kai , Snodgrass Samantha J. , Rodríguez-Zapata Fausto , Sawers Ruairidh J. H. , Rellán-Álvarez Rubén , Buckler Edward S. , Hearne Sarah , Hufford Matthew B. , Ross-Ibarra Jeffrey 
Published: July 2019

AbstractThreats to crop production due to climate change are one of the greatest challenges facing plant breeders today. While considerable adaptive variation exists in traditional landraces, natural populations of crop wild relatives, and ex situ germplasm collections, separating adaptive alleles from linked deleterious variants that impact agronomic traits is challenging and has limited the utility of these diverse germplasm resources. Modern genome editing techniques such as CRISPR offer a potential solution by targeting specific alleles for transfer to new backgrounds, but such methods require a higher degree of precision than traditional mapping approaches can achieve. Here we present a high-resolution genome-wide association analysis to identify loci exhibiting adaptive patterns in a large panel of more than 4500 traditional maize landraces representing the breadth of genetic diversity of maize in Mexico. We evaluate associations between genotype and plant performance in 13 common gardens across a range of environments, identifying hundreds of candidate genes underlying genotype by environment interaction. We further identify genetic associations with environment across Mexico and show that such loci are associated with variation in yield and flowering time in our field trials and predict performance in independent drought trials. Our results indicate that the variation necessary to adapt crops to changing climate exists in traditional landraces that have been subject to ongoing environmental adaptation and can be identified by both phenotypic and environmental association.
Interaction between induced and natural variation atoil yellow1delays reproductive maturity in maize
Authors: Khangura Rajdeep S. , Venkata Bala P. , Marla Sandeep R. , Mickelbart Michael V. , Dhungana Singha , Braun David M. , Dilkes Brian P. , Johal Gurmukh S. 
Published: July 2019

AbstractWe previously demonstrated that maize (Zea mays) locusvery oil yellow1 (vey1)encodes a putative cis-regulatory expression polymorphism at the magnesium chelatase subunit I gene (akaoil yellow1) that strongly modifies the chlorophyll content of the semi-dominantOy1-N1989mutants. Thevey1allele of Mo17 inbred line reduces chlorophyll content in the mutants leading to reduced photosynthetic output.Oy1-N1989mutants in B73 reached reproductive maturity four days later than wild-type siblings. Enhancement ofOy1-N1989by the Mo17 allele at thevey1QTL delayed maturity further, resulting in detection of a flowering time QTL in two bi-parental mapping populations crossed toOy1-N1989. The near isogenic lines of B73 harboring thevey1allele from Mo17 delayed flowering ofOy1-N1989mutants by twelve days. Just as previously observed for chlorophyll content,vey1had no effect on reproductive maturity in the absence of theOy1-N1989allele. Loss of chlorophyll biosynthesis inOy1-N1989mutants and enhancement byvey1reduced CO2assimilation. We attempted to separate the effects of photosynthesis on the induction of flowering from a possible impact of chlorophyll metabolites and retrograde signaling by manually reducing leaf area. Removal of leaves, independent of theOy1-N1989mutant, delayed flowering but surprisingly reduced chlorophyll contents of emerging leaves. Thus, defoliation did not completely separate the identity of the signal(s) that regulates flowering time from changes in chlorophyll content in the foliage. These findings illustrate the necessity to explore the linkage between metabolism and the mechanisms that connect it to flowering time regulation.
Societal attention toward extinction threats
Authors: Jarić Ivan , Bellard Céline , Courchamp Franck , Kalinkat Gregor , Meinard Yves , Roberts David L. , Correia Ricardo A. 
Published: July 2019

AbstractPublic attention and interest in the fate of endangered species is a crucial prerequisite for effective conservation programs. Societal awareness and values will largely determine whether conservation initiatives receive necessary support and lead to adequate policy change. Using text data mining, we assessed general public attention toward climate change and biological invasions, which represent two key threats for endangered amphibian, reptile, bird and mammal species in three European countries (France, Germany and the United Kingdom). Our analysis revealed that public attention patterns differed among species groups and countries but was globally higher for climate change than for biological invasions. Both threats received better recognition in threatened than in non-threatened species, as well as in native species than in species from other countries and regions. The relative level of attention toward the two threats corresponded well with the listing of the threats and their severity within the IUCN Red List. We conclude that more efficient communication regarding the threat from biological invasions should be developed, and that conservation practitioners should take advantage of the existing attention toward the threat of climate change.
Engineered Dendritic Cell-Directed Concurrent Activation of Multiple T cell Inhibitory Pathways Induces Robust Immune Tolerance
Authors: Gudi Radhika R. , Karumuthil-Melethil Subha , Perez Nicolas , Li Gongbo , Vasu Chenthamarakshan 
Published: July 2019

AbstractInhibitory/repressor-receptors are upregulated significantly on activated T cells, and have been the molecules of attention as targets for inducing immune tolerance. Induction of effective antigen specific tolerance depends on concurrent engagement of the TCR and one or more of these inhibitory receptors. Here, we show, for the first time that dendritic cells (DCs) can be efficiently engineered to express multiple T cell inhibitory ligands, and enhanced engagement of T cell inhibitory receptors, upon antigen presentation, by these DCs can induce effective CD4+ T cell tolerance and suppress autoimmunity. Compared to control DCs, antigen presentation by DCs that ectopically express CTLA4, PD1 and BTLA selective ligands (B7.1wa, PD-L1, and HVEM-CRD1 respectively) individually (mono-ligand DCs) or in combination (multi-ligand DCs) causes an inhibition of CD4+ T cell proliferation and pro-inflammatory cytokine response, as well as increase in Foxp3+ Treg frequency and immune regulatory cytokine production. Administration of self-antigen (mouse thyroglobulin; mTg) loaded multi-ligand DCs caused hyporesponsiveness to mTg challenge, suppression of autoantibody production, and amelioration of experimental autoimmune thyroiditis. Overall, this study shows that engineered DC-directed enhanced concurrent activation of multiple T cell coinhibitory pathways is an effective way to induce self-antigen specific T cell tolerance to suppress ongoing autoimmunity.
Crystal structure of Sulfolobus solfataricus topoisomerase III reveals a novel carboxyl-terminal zinc finger domain essential for decatenation activity
Authors: Wang Hanqian , Zhang Junhua , Gao Zengqiang , Zheng Xin , Zhu Keli , Zhang Zhenfeng , Zhang Zhiyong , Dong Yuhui , Huang Li , Gong Yong 
Published: July 2019

ABSTRACTDNA topoisomerases are essential enzymes for a variety of cellular processes involved in DNA transactions. Mechanistic insights into type IA DNA topoisomerases have come principally from studies on bacterial and eukaryotic enzymes. A structural understanding of type IA topoisomerases in Archaea is lacking. Here, we present a 2.1-angstrom crystal structure of full-length Sulfolobus solfataricus topoisomerase III (Sso topo III), an archaeal member of type IA topoisomerases. The structure shows that Sso topo III adopts a characteristic torus-like architecture consisting of a four-domain core region and a novel carboxyl-terminal zinc finger domain (domain V). Structure-based mutation analyses reveal that a novel zinc-binding motif in domain V is essential for the DNA decatenation activity of Sso topo III. Our data indicate that Sso topo III represents a subclass of Type IA topoisomerases capable of resolving DNA catenates using a domain V-dependent mechanism.IMPORTANCEType IA topoisomerases are omnipresent in all cellular life forms and serve pivotal roles in cellular processes involved in DNA transactions. While considerable insights have been gained into Type IA topoisomerases from bacteria and eukaryotes, a structural understanding of type IA topoisomerases in Archaea remains elusive. we first determined the crystal structure of full-length Sulfolobus solfataricus topoisomerase III (Sso topo III), an archaeal member of type IA topoisomerases. Our structure provides the first molecular view of this archaeal topoisomerase, which removes negative supercoils and decatenates DNA catenane. Our findings manifest that Sso topo III may serve as an alternative prototype of type IA topoisomerases, whose decatenation mechanism differs from that of known bacterial and eukaryotic topoisomerases III such as Escherichia coli topoisomerase III (EcTOP3).
Visual speed compensation of pitch-constrained blue-bottle flies under retinal-image velocity perturbation in a flight mill
Authors: Hsu Shih-Jung , Cheng Bo 
Published: July 2019

ABSTRACTIn the presence of wind or background image motion, flies are able to maintain a constant retinal-image velocity via regulating flight speed to the extent permitted by their locomotor capacity. Here we investigated the speed regulation of semi-tethered blue-bottle flies (Calliphora vomitoria) flying along an annular corridor in a magnetically levitated flight mill enclosed by two motorized cylindrical walls. We perturbed the flies’ retinal-image motion via spinning the cylindrical walls, generating bilaterally-averaged velocity perturbations from -0.3 to 0.3 m·s-1. Flies compensated retinal-image velocity perturbations by adjusting airspeed up to 20%, thereby maintaining a relatively constant retinal-image velocity. When the retinal-image velocity perturbation became greater than ∼0.1 m·s-1, the compensation weakened as airspeed plateaued, suggesting that flies were unable to further change airspeed. The compensation gain, i.e., the ratio of airspeed compensation and retinal-image velocity perturbation, depended on the spatial frequency of the grating patterns, being the largest at 12 m-1.
TheC. elegansRIG-I homologdrh-1mediates the Intracellular Pathogen Response upon viral infection
Authors: Sowa Jessica N. , Jiang Hongbing , Somasundaram Lakshmi , Xu Guorong , Wang David , Troemel Emily R. 
Published: July 2019

AbstractMammalian RIG-I-like receptors detect viral dsRNA and 5’ triphosphorylated RNA to activate transcription of interferon genes and promote antiviral defense. TheC. elegansRIG-I-like receptor DRH-1 promotes defense through antiviral RNA interference, but less is known about its role in regulating transcription. Here we describe a role fordrh-1in directing a transcriptional response inC. eleganscalled the Intracellular Pathogen Response (IPR), which is associated with increased pathogen resistance. The IPR includes a set of genes induced by diverse stimuli including intracellular infection and proteotoxic stress. Previous work suggested that the proteotoxic stress caused by intracellular infections might be the common trigger of the IPR, but here we demonstrate that different stimuli act through distinct pathways. Specifically, we demonstrate that DRH-1/RIG-I is required for inducing the IPR in response to Orsay virus infection, but not in response to other triggers like microsporidian infection or proteotoxic stress. Furthermore,drh-1appears to be acting independently of its known role in RNAi. Interestingly, expression of the replication competent Orsay virus RNA1 segment alone is sufficient to induce most of the IPR genes in a manner dependent on RNA dependent RNA polymerase activity and ondrh-1. Altogether, these results suggest that DRH-1 is a pattern-recognition receptor that detects viral replication products to activate the IPR stress/immune program inC. elegans.ImportanceC. eleganslacks homologs of most mammalian pattern recognition receptors, and how nematodes detect pathogens is poorly understood. We show that theC. elegansRIG-I homologdrh-1mediates induction of the Intracellular Pathogen Response (IPR), a novel transcriptional defense program, in response to infection by the naturalC. elegansviral pathogen Orsay virus.drh-1appears to act as a pattern-recognition receptor to induce the IPR transcriptional defense program by sensing the products of viral RNA-dependent RNA polymerase activity. Interestingly, this signaling role ofdrh-1is separable from its previously known role in antiviral RNAi. In addition, we show that there are multiple host pathways for inducing the IPR, shedding light on the regulation of this novel transcriptional immune response.
Rapid evolution of antiviral APOBEC3 genes driven by the conflicts with ancient retroviruses
Authors: Ito Jumpei , Gifford Robert J. , Sato Kei 
Published: July 2019

AbstractThe evolution of antiviral genes has been fundamentally shaped by antagonistic interactions with ancestral viruses. The AID/APOBEC family genes (AID and APOBEC1-4) encode cellular cytosine deaminases that target nucleic acids and catalyze C-to-U mutations. In the case of retroviral replication, APOBEC3 proteins induce C-to-U mutations in minus-stranded viral DNA, which results in G-to-A mutations in the viral genome. Previous studies have indicated that the expansion and rapid evolution of mammalian APOBEC3 genes has been driven by an arms race with retroviral parasites, but this has not been thoroughly investigated. Endogenous retroviruses (ERVs) are retrotransposons originated from ancient retroviral infections. These sequences sometimes bear the hallmarks of APOBEC3-mediated mutations, and therefore serve as a record of the ancient conflict between retroviruses and APOBEC3 genes. Here we systematically investigated the sequences of ERVs and APOBEC3 genes in mammals to reconstruct details of the evolutionary conflict between them. We identified 1,420 AID/APOBEC family genes in a comprehensive screen of mammalian genome. Of the AID/APOBEC family genes, APOBEC3 genes have been selectively amplified in mammalian genomes and disclose evidence of strong positive selection - whereas the catalytic domain was highly conserved across species, the structure loop 7, which recognizes viral DNA/RNA substrates, was shown to be evolving under strong positive selection. Although APOBEC3 genes have been amplified by tandem gene duplication in most mammalian lineages, the retrotransposition-mediated gene amplification was found in several mammals including New World monkeys and prosimian primates. Comparative analysis revealed that G-to-A mutations are accumulated in ERVs, and that the G-to-A mutation signatures on ERVs is concordant with the target preferences of APOBEC3 proteins. Importantly, the number of APOBEC3 genes was significantly correlated with the frequency of G-to-A mutations in ERVs, suggesting that the amplification of APOBEC3 genes led to stronger attacks on ERVs and/or their ancestral retroviruses by APOBEC3 proteins. Furthermore, the numbers of APOBEC3 genes and ERVs in mammalian genomes were positively correlated, and in primates, the timings of APOBEC3 gene amplification was concordant with that of ERV invasions. Our findings suggest that conflict with ancient retroviruses was a major selective pressure driving the rapid evolution of APOBEC3 genes in mammals.
Kinase inhibition of G2019S-LRRK2 restores autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions
Authors: Obergasteiger Julia , Frapporti Giulia , Lamonaca Giulia , Pizzi Sara , Picard Anne , Pischedda Francesca , Piccoli Giovanni , Lobbestael Evy , Baekelandt Veerle , Hicks Andrew A. , Corti Corrado , Pramstaller Peter P. , Volta Mattia 
Published: July 2019

AbstractThe Parkinson’s disease (PD)-associated kinase Leucine-Rich Repeat Kinase 2 (LRRK2) is a potent modulator of autophagy and impacts on lysosome biology and function, but unclarity exists on the precise mechanics of its role and the direction of this modulation. LRRK2 is also involved in the degradation of pathological alpha-synuclein, with pathogenic mutations precipitating neuropathology in cellular and animal models of PD, and most LRRK2 familial cases manifesting with Lewy neuropathology. Defects in autophagic processing and lysosomal degradation of alpha-synuclein have been postulated to underlie its accumulation and onset of neuropathology. Thus, it is critical to reconcile these independent pieces of information to obtain a comprehensive knowledge on LRRK2-associated pathology that could also be generalized to the idiopathic disease.Here, we report a focused investigation on the role of PD-causing G2019S-LRRK2 in the autophagy-lysosome pathway in a recombinant cell line model. Initially, we evaluated the effect of LRRK2 expression on autophagy-related transcriptome. Then, we found that G2019S-LRRK2 leads to accumulation of autophagosomes with no net effect on autophagy induction. This is linked to abnormalities in lysosome morphology and proteolytic activity that are associated with a decrease in the successful formation of autolysosomes. Despite some of these features being shared by WT-LRRK2, alpha-synuclein intracellular inclusions are specifically found in G2019S-LRRK2 cells. Pharmacological kinase inhibition is capable of rescuing defects in the autophagy-lysosome pathway and reducing the number of inclusions. Notably, this effect is prevented by upstream blockade of autophagosome-lysosome fusion events, highlighting this step of the process as critical for alpha-synuclein clearance.