bluuebunny/crossref_metadata_2025_split huggingface dataset:
Size and structure of the sequence space of repeat proteins
Authors: Marchi Jacopo , Galpern Ezequiel A. , Espada Rocio , Ferreiro Diego U. , Walczak Aleksandra M. , Mora Thierry 
Published: May 2019

AbstractThe coding space of protein sequences is shaped by evolutionary constraints set by requirements of function and stability. We show that the coding space of a given protein family —the total number of sequences in that family— can be estimated using models of maximum entropy trained on multiple sequence alignments of naturally occuring amino acid sequences. We analyzed and calculated the size of three abundant repeat proteins families, whose members are large proteins made of many repetitions of conserved portions of ∼30 amino acids. While amino acid conservation at each position of the alignment explains most of the reduction of diversity relative to completely random sequences, we found that correlations between amino acid usage at different positions significantly impact that diversity. We quantified the impact of different types of correlations, functional and evolutionary, on sequence diversity. Analysis of the detailed structure of the coding space of the families revealed a rugged landscape, with many local energy minima of varying sizes with a hierarchical structure, reminiscent of fustrated energy landscapes of spin glass in physics. This clustered structure indicates a multiplicity of subtypes within each family, and suggests new strategies for protein design.
RNA strand invasion activity of the Polycomb complex PRC2
Authors: Alecki Célia , Chiwara Victoria , Sanz Lionel A. , Grau Daniel , Pérez Osvaldo Arias , Armache Karim-Jean , Chédin Fréderic , Francis Nicole J. 
Published: May 2019

AbstractEpigenetic regulation is conveyed through information encoded by specific chromatin features. Non-canonical nucleic acid structures could in principle also convey biological information but their role(s) in epigenetic regulation is not known. Polycomb Group (PcG) proteins form memory of transient transcriptional repression events that is necessary for development. In Drosophila, PcG proteins are recruited to specific DNA sequences, Polycomb Response Elements (PREs). PREs are switchable memory elements that can exist in repressed, active, or unengaged states 1,2. How PcG activities are targeted to PREs to maintain repressed states only in appropriate developmental contexts has been difficult to elucidate. Biochemically, PcG protein complexes modify chromatin to maintain gene repression 1,3,4. However, PcG proteins also interact with both RNA and DNA, and RNA is implicated in the targeting of PcG function. We find that R-loops, three-stranded nucleic acid structures formed when an RNA hybridizes to its complementary DNA and displaces the other DNA strand 5, form at many PREs in Drosophila embryos, and correlate with the repressive state. R-loops are recognized by the PcG complex PRC1 in vitro. Unexpectedly, we find that the PcG complex PRC2 has RNA strand invasion activity, which can drive formation of RNA-DNA hybrids, the key component of R-loops. Our results suggest a new mechanism for targeting PcG function through R-loop formation by PRC2 and recognition by PRC1. More generally, our findings suggest formation and recognition 6 of non-canonical nucleic acid structures as an epigenetic mechanism.
Loss of F-box Motif Encoding Gene SAF1 and RRM3 Together Leads to Synthetic Growth Defect and Sensitivity to HU, MMS inS.cerevisiae
Authors: Sharma Meenu , Verma V. , Bairwa Narendra K 
Published: May 2019

AbstractUnearthing of novel genetic interaction which leads to synthetic growth defects due to inactivation of genes are needed for applications in precision medicine. The genetic interactions among the molecular players involving different biological pathways need to be investigated. The SAF1 gene ofS.cerevisiaeencodes for a protein product which contain N-terminal F-box motif and C-terminal RCC1 domain. The F-box motif interacts with Skp1subunit of the SCF-E3 ligase and C-terminus with Aah1 (adenine deaminase) for ubiquitination and subsequent degradation by 26S proteasome during phase transition from proliferation state to quiescence phase due to nutrient limitation stress. The replication fork associated protein Rrm3 ofS.cerevisiaebelongs to Pif1 family helicase and function in removal of the non-histone proteins during replication fork movement. Here we have investigated the genetic interaction among both the genes (SAF1 and RRM3) and their role in growth fitness and genome stability. The single and double gene knockout strains of SAF1and RRM3 genes was constructed in BY4741 genetic background and checked for the growth fitness in presence of genotoxic stress causing agents such as hydroxyurea and methyl methanesulfonate. The strains were also evaluated for nuclear migration defect by DAPI staining and for HIS3AI marked Ty1 retro-transposition. Thesaf1Δrrm3Δshowed the extremely slow growth phenotype in rich medium and sensitivity to genotoxic agents such as HU and MMS in comparison to single gene mutant (saf1Δ,rrm3Δ) and WT cells. Thesaf1Δrrm3Δalso showed the defects in nuclear migration as evident by multi-nuclei phenotype. Thesaf1Δrrm3Δalso showed the elevated frequency of Ty1 retro-transposition in JC2326 background in comparison to eithersaf1Δ or rrm3Δ. Based on these observations we report that thatSAF1 and RRM3 functions in parallel pathway for growth fitness and stability of the genome.
Quantitative analysis of ZFY and CTCF reveals dependent recognition of tandem zinc finger proteins
Authors: Zuo Zheng , Billings Timothy , Walker Michael , Petkov Petko M. , Stormo Gary D. , Fordyce Polly M. 
Published: May 2019

AbstractThe human genome contains around 800 C2H2 Zinc Finger Proteins (ZFPs), and many of them are composed of long tandem arrays of zinc fingers. Current motif prediction models assume longer finger arrays correspond to longer DNA-binding motifs and higher specificity. However, recent experimental efforts to identify ZFP binding sitesin vivocontradict this assumption, with many having short motifs. Here, we systematically test how multiple zinc fingers contribute to binding for three model ZFPs: Zinc Finger Y (ZFY), CTCF, and ZNF343. Using ZFY, which contains 13 fingers, we quantitatively characterize its binding specificity with several methods, including Affinity-seq, HT-SELEX, Spec-seq and fluorescence anisotropy, and find evidence for ‘dependent recognition’ where downstream fingers can recognize some extended motifs only in the presence of an intact core site. For the genomic insulator CTCF, additional high-throughput affinity measurements reveal that its upstream specificity profile depends on the strength of the core, violating presumed additivity and positionindependence. Moreover, the effect of different epigenetic modifications within the core site depends on the strength of flanking upstream site, providing new insight into how the previously identified intellectual disability-causing and cancer-related mutant R567W disrupts upstream recognition and deregulates CTCF’s methylation sensitivity. Lastly, we used ZNF343 as example to show that a simple iterative motif analysis strategy based on a small set of prefixed cores can reveal the dependent relationship between cores and upstream motifs. These results establish that the current underestimation of ZFPs motif lengths is due to our lack of understanding of intrinsic properties of tandem zinc finger recognition, including irregular motif structure, variable spacing, and dependent recognition between sub-motifs. These results also motivate a need for better recognition models beyond additive, position-weight matrix to predict ZFP specificities, occupancies, and the molecular mechanisms of disease mutations.
Gene-experience correlation during cognitive development: Evidence from the Adolescent Brain Cognitive Development (ABCD) StudySM
Authors: Loughnan Robert J. , Palmer Clare E. , Thompson Wesley K. , Dale Anders M. , Jernigan Terry L. , Fan Chun Chieh 
Published: May 2019

AbstractBackgroundFindings in adults have shown more culturally sensitive ‘crystallized’ measures of intelligence have greater heritability, these results were not able to be shown in children.MethodsWith data from 8,518 participants, aged 9 to 11, from the Adolescent Brain Cognitive Development (ABCD) Study®, we used polygenic predictors of intelligence test performance (based on genome-wide association meta-analyses of data from 269,867 individuals) and of educational attainment (based on data from 1.1 million individuals), associating these predictors with neurocognitive performance. We then assessed the extent of mediation of these associations by a measure of recreational reading.Resultsmore culturally sensitive ‘crystallized’ measures were more strongly associated with the polygenic predictors than were less culturally sensitive ‘fluid’ measures. This mirrored heritability differences reported previously in adults and suggests similar associations in children. Recreational reading more strongly statistically mediated the genetic associations with crystallized than those with fluid measures of cognition.ConclusionThis is consistent with a prominent role of gene-environment correlation in cognitive development measured by “crystallized” intelligence tests. Such experiential mediators may represent malleable targets for improving cognitive outcomes.
Ablation of tanycytes of the arcuate nucleus and median eminence increases visceral adiposity and decreases insulin sensitivity in male mice
Authors: Yoo Sooyeon , Cha David , Kim Soohyun , Jiang Lizhi , Adebesin Mobolanie , Wolfe Andrew , Riddle Ryan , Aja Susan , Blackshaw Seth 
Published: May 2019

AbstractTanycytes are radial glial cells located in the mediobasal hypothalamus. Recent studies have proposed that tanycytes play an important role in hypothalamic control of energy homeostasis, although this has not been directly tested. Here, we report the phenotype of mice in which tanycytes of the arcuate nucleus and median eminence were conditionally ablated. Although the CSF-hypothalamic barrier was rendered more permeable, the blood-hypothalamic barrier was not altered. The metabolic effects of tanycyte ablation were likewise moderate. However, we consistently observed a significant increase in visceral fat distribution accompanying insulin insensitivity, but only in male mice, and without an effect on either body weight or food intake. A high-fat diet accelerated overall body weight gain in tanycyte-ablated mice, but the development of visceral adiposity and insulin insensitivity was attenuated. These results clarify the extent to which tanycytes regulate energy metabolism, and indicate a role for tanycytes in controlling body adiposity.
Clinical Efficacy and Adverse Effects of Antibiotics Used to Treat Mycobacterium abscessus Pulmonary Disease
Authors: Chen Jianhui , Zhao Lan , Mao Yanhua , Ye Meiping , Guo Qi , Zhang Yongjie , Xu Liyun , Zhang Zhemin , Li Bing , Chu Haiqing 
Published: May 2019

AbstractTreatment of Mycobacterium abscessus pulmonary infection requires long-term administration of multiple antibiotics. Little is known, however, about the impact of each antibiotic on treatment outcomes. A retrospective analysis was conducted to evaluate the efficacy and adverse effects of antibiotics administered in 244 cases of M. abscessus pulmonary disease. Only 110 (45.1%) patients met the criteria for treatment success. Treatment with amikacin (AOR, 3.275; 95% CI, 1.221 - 8.788), imipenem (AOR, 2.078; 95% CI, 1.151 - 3.753), linezolid (AOR, 2.231; 95% CI, 1.078 - 4.616) and tigecycline (AOR, 2.040; 95% CI, 1.079 - 3.857) was successful. The incidence of adverse effects was high (192/244, 78.7%). Severe adverse effects were primarily: ototoxicity (14/60, 23.3%) caused by amikacin; gastrointestinal (14/60, 23.3%) caused by tigecycline; and myelosuppression (5/60, 8.3%) caused by linezolid. In conclusion, the rate of success in treating M. abscessus pulmonary disease is still unsatisfactory; the administration of amikacin, imipenem, linezolid and tigecycline correlated with increased treatment success. Adverse side effects are common due to the long-term and combined antibiotic therapy. Ototoxicity, gastrointestinal and myelosuppression are the most severe.
Nutritional Immunity and Antibiotic Drug Treatments Influence Microbial Composition but Fail to Eliminate Urethral Catheter Biofilms in Recurrently Catheterized Patients
Authors: Yu Yanbao , Singh Harinder , Tsitrin Tamara , Kwon Keehwan , Bekele Shiferaw , Eguez Rodrigo V. , Lin Yi-Han , Sikorski Patricia , Moncera Kelvin J. , Torralba Manolito G. , Morrow Lisa , Wolcott Randall , Nelson Karen E. , Pieper Rembert 
Published: May 2019

AbstractPolymicrobial biofilms that form on indwelling urethral catheters used by neurogenic bladder patients are known to recur following catheter replacements. Uropathogens dominate in catheter biofilms (CBs), grow and disperse as multi-cellular aggregates. Their microbial complexity, the characteristics of host immune responses and the molecular crosstalk in this ecosystem are incompletely understood. By surveying eight patients over up to six months with meta-omics analysis methods, we shed new light on the longitudinal microbial dynamics in CBs and the microbial-host crosstalk. There was evidence of chronic innate immune responses in all patients. Pathogens dominated the microbial contents.Proteus mirabilisoften out-competed other species in cases of salt encrustation of catheters. The examination of proteomes in CBs and associated urinary pellets revealed many abundant bacterial systems for transition metal ion (TMI) acquisition. TMIs are sequestered by effector proteins released by activated neutrophils and urothelial cells, such as lactotransferrin and calgranulins, which were abundant in the host proteomes. We identified positive quantitative correlations among systems responsible for siderophore biosynthesis, TMI/siderophore uptake and TMI cellular import in bacterial species, suggesting competition for TMIs to support their metabolism and growth in CBs.Enterococcus faecaliswas prevalent as a cohabitant of CBs and expressed three lipoproteins with apparent TMI acquisition functions. Fastidious anaerobic bacteria such asVeillonella,Actinobaculum, andBifidobacteriumgrew in CB communities that appeared to be oxygen starved. Finally, antibiotic drug treatments were shown to influence microbial composition of CBs but failed to prevent re-colonization of urethral catheters with persisting and/or drug-resistant newly emerging pathogens.
A microparticulate based formulation to protect therapeutic enzymes from proteolytic digestion: phenylalanine ammonia lyase as case study
Authors: de Sousa Irene Pereira , Gourmel Charlotte , Berkovska Olena , Burger Michael , Leroux Jean-Christophe 
Published: May 2019

AbstractPhenylketonuria is a genetic disorder affecting the metabolism of phenylalanine (phe) due to a deficiency in the enzyme phenylalanine hydroxylase. This disorder is characterized by an elevated phe blood level, which can lead to severe intellectual disabilities in newborns. The current strategy to prevent these devastating consequences is limited to a life-long phe-free diet, which implies major lifestyle changes and restrictions. Recently, an injectable enzyme replacement therapy, Pegvaliase, has been approved for treating phenylketonuria, but is associated with significant side-effects. In this study a phe-metabolizing system suitable for oral delivery is designed to overcome the need for daily injections. Active phenylalanine ammonia-lyase (PAL), an enzyme that catalyzes phe metabolism, is loaded into mesoporous silica microparticles (MSPs) with pore sizes ranging from 10 to 35 nm. The surface of the MSPs is lined with a semipermeable barrier to allow permeation of phe while blocking digestive enzymes that degrade PAL. The enzymatic activity can be partially preserved in vitro by coating the MSPs with poly(allylamine) and poly(acrylic acid)-bowman birk (protease inhibitor) conjugate. The carrier system presented herein may provide a general approach to overcome gastro-intestinal proteolytic digestion and to deliver active enzymes to the intestinal lumen for prolonged local action.
Chromatin accessibility established by Pou5f3, Sox19b and Nanog primes genes for activity during zebrafish genome activation
Authors: Pálfy Máté , Schulze Gunnar , Valen Eivind , Vastenhouw Nadine L. 
Published: May 2019

ABSTRACTIn many organisms, early embryonic development is driven by maternally provided factors until the controlled onset of transcription during zygotic genome activation. The regulation of chromatin accessibility and its relationship to gene activity during this transition remains poorly understood. Here, we generated chromatin accessibility maps from genome activation until the onset of lineage specification. During this period, chromatin accessibility increases at regulatory elements. This increase is independent of RNA polymerase II-mediated transcription, with the exception of the hyper-transcribed miR-430 locus. Instead, accessibility often precedes the transcription of associated genes. Loss of the maternal transcription factors Pou5f3, Sox19b, and Nanog, which are known to be required for zebrafish genome activation, results in decreased accessibility at regulatory elements. Importantly, the accessibility of regulatory regions, especially when established by Pou5f3, Sox19b and Nanog, is predictive for future transcription. Our results show that the maternally provided transcription factors Pou5f3, Sox19b, and Nanog open up chromatin and prime genes for activity during zygotic genome activation in zebrafish.
Spatial and semantic regularities produce interactive effects in early stages of visual orientation
Authors: Notaro Giuseppe , Hasson Uri 
Published: May 2019

ABSTRACTLearning environmental regularities allows predicting multiple dimensions of future events such as their location and semantic features. However, few studies have examined how multi-dimensional predictions are implemented, and mechanistic accounts are absent. Using eye tracking study, we evaluated whether predictions of object-location and object-category interact during the earliest stages of orientation. We presented stochastic series so that across four conditions, participants could predict either the location of the next image, its semantic category, both dimensions, or neither. Participants observed images in absence of any task. We modeled saccade latencies using ELATER, a rise-to-threshold model that accounts for accumulation rate (AR), variance of AR over trials, and decision threshold. The main findings were: 1) accumulation-rate scaled with the degree of surprise associated with location of target-presentation (confirmatory result); 2) predictability of semantic-category hindered latencies, but only when images were presented at a surprising location, suggesting a bottleneck in implementing joint predictions; 3) saccades to images that satisfied semantic expectations were associated with larger variance of accumulation-rate than saccades to semantically-surprising images, consistent with a richer repertoire of early evaluative processes for semantically-expected images. Joint impacts of location and target-identity regularity were also identified in analyses of anticipatory fixation offsets. The results indicate a strong interaction between the processing of regularities in object location and identity during stimulus-guided saccades, and suggest these regularities also impact anticipatory, non-stimulus-guided processes.
Cerebral oxygenation during locomotion is modulated by respiration
Authors: Zhang Qingguang , Roche Morgane , Gheres Kyle W. , Chaigneau Emmanuelle , Haselden William D. , Charpak Serge , Drew Patrick J. 
Published: May 2019

AbstractIn the brain, increased neural activity is correlated with an increase of cerebral blood flow and increased tissue oxygenation. However, how cerebral oxygen dynamics are controlled in the behaving animals remains unclear. Here, we investigated to what extent the cerebral oxygenation varies during natural behaviors that change the whole-body homeostasis, specifically exercise. We measured oxygen levels in the cortex of awake, head-fixed mice during locomotion using polarography, spectroscopy, and two-photon phosphorescence lifetime measurements of oxygen sensors. We found that locomotion significantly and globally increases cerebral oxygenation, specifically in areas involved in locomotion, as well as in the frontal cortex and the olfactory bulb. The oxygenation increase persisted when neural activity and functional hyperemia were blocked, occurred both in the tissue and in arteries feeding the brain, and was tightly correlated with respiration rate and the phase of respiration cycle. Thus, respiration provides a dynamic pathway for modulating cerebral oxygenation.
Integrins control tissue morphogenesis and homeostasis by sustaining the different types of intracellular actin networks
Authors: Mateos Carmen Santa-Cruz , Valencia-Expósito Andrea , Míguez David G. , Palacios Isabel M. , Martín-Bermudo María D. 
Published: May 2019

AbstractForces generated by the actomyosin cytoskeleton are key contributors to the generation of tissue shape. Within the cell, the actomyosin cytoskeleton organizes in different types of networks, each of them performing distinct roles. In addition, although they normally localize to precise regions of the cells, they are rarely independent and often their dynamics influence each other. In fact, the reorganization of a given structure can promote the formation of another, conversions that govern many morphogenetic processes. In addition, maintenance of a specific actomyosin network organization in a differentiated tissue might be equally important. Failure to do so could lead to undesired cell state transitions, which in turn would have drastic consequences on the homeostasis of the tissue. Still, little is known about the mechanisms that ensure controlled transitions between actomyosin networks during morphogenesis or their maintenance in a differentiated tissue. Here, we use theDrosophilafollicular epithelium to show that cell-ECM interactions mediated by integrins are necessary for the establishment and maintenance of the different actomyosin networks present in these epithelial cells. Elimination of integrins in a group of follicle cells results in changes in the F-actin levels and physical properties of their intracellular actomyosin networks. Integrin mutant follicle cells have reduced number of basal stress fibers. They also show increased cortical F-actin levels and tension, which interferes with proper basal surface growth. Finally, clonal elimination of integrins also triggers non-autonomous behavioural changes in neighbouring wild types cells, which now reorganize their actin cytoskeleton and spread and overlay the mutant ones. Based on these results, we propose that cell-ECM interactions mediated by integrins regulate epithelia morphogenesis and homesostasis by preserving the different types of intracellular actin networks.