bluuebunny/crossref_metadata_2025_split huggingface dataset:
Top-down attention modulates auditory-evoked neural responses in neurotypical, but not ADHD, young adults
Authors: Kwasa Jasmine A. C. , Noyce Abigail L. , Torres Laura M. , Shinn-Cunningham Barbara G. 
Published: February 2021

AbstractIndividuals differ in their ability to selectively attend to goal-relevant auditory stimuli. People with Attention-Deficit/Hyperactivity Disorder (ADHD) in particular tend to show cognitive deficits associated with distractibility and inefficiencies in inhibition and attention. We hypothesized that people with ADHD would exhibit poorer performance and weaker neural signatures of attentional control when undertaking a challenging auditory task that required strong top-down attention. Neurotypical (N = 20) and ADHD (N = 25) young adults with normal hearing listened to one of three concurrent, spatially separated speech streams and reported the order of the syllables presented while we recorded electroencephalography (EEG). We tested both the ability to sustain attentional focus on a single “target” stream and the ability to monitor the target but flexibly switch attention to an unpredictable “interrupter” stream from another direction if and when it appeared. Although both stimulus structure and task demands affected behavioral performance, ADHD status did not. In both groups, the interrupter evoked larger neural responses when it was to be attended compared to when it was irrelevant, including for the P3a “reorienting” response previously described as involuntary. This attentional modulation was weaker in ADHD listeners, even though their behavioral performance was no lower. Across the entire cohort, individual performance correlated with the degree of top-down modulation of neural responses. These results demonstrate that listeners differ in their ability to modulate neural representations of sound based on task goals. Adults with ADHD have weaker volitional control of attentional processes than their neurotypical counterparts.Significance StatementADHD and neurotypical listeners attended to one speech stream among distractors while neural responses were measured with electroencephalography. Behavioral performance varied with stimulus structure and task demands, but not with ADHD status. In both groups, top-down attention modulated stimulus-evoked neural responses: interrupting sounds elicited weaker responses when the sounds were ignored compared to when they were attended. This modulation affected a late “orienting” response (P3a) that has been previously described as automatic and not dependent on internal state. Importantly, ADHD subjects showed weaker attentional filtering than did neurotypical controls. At the individual level, performance correlated with neural metrics. Our results demonstrate that people vary widely in how flexibly they can use attention to modulate sensory responses based on task goals.
Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down Syndrome-related phenotypes
Authors: Lana-Elola Eva , Cater Heather , Watson-Scales Sheona , Greenaway Simon , Müller-Winkler Jennifer , Gibbins Dorota , Nemes Mihaela , Slender Amy , Hough Tertius , Keskivali-Bond Piia , Scudamore Cheryl L , Herbert Eleanor , Banks Gareth T , Mobbs Helene , Canonica Tara , Tosh Justin , Noy Suzanna , Llorian Miriam , Nolan Patrick M. , Griffin Julian L. , Good Mark , Simon Michelle , Mallon Ann-Marie , Wells Sara , Fisher Elizabeth M. C. , Tybulewicz Victor L. J. 
Published: February 2021

AbstractDown syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, causative genes remain mostly unknown. Animal models enable identification of these genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. Here, we comprehensively phenotype Dp1Tyb mice and find wide-ranging DS-like phenotypes including aberrant megakaryopoiesis, reduced bone density, and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for studies of many complex DS phenotypes.
ChEC-seq produces robust and specific maps of transcriptional regulators
Authors: Zentner Gabriel E. , Policastro Robert A. , Henikoff Steven 
Published: February 2021

AbstractWe previously introduced chromatin endogenous cleavage and high-throughput sequencing (ChEC-seq), which uses fusion of a chromatin-binding protein of interest to micrococcal nuclease (MNase) and high-throughput sequencing to generate genome-wide maps of factor binding. Here, we respond to concerns that have been raised about the specificity of the method relative to its negative control when a single long calcium incubation time is used. Through reanalysis of our previously published datasets, we show that short-duration ChEC-seq experiments provide robust, specific maps of transcriptional regulators across the budding yeast genome. Our analyses also confirm that consideration of MNase digestion kinetics is important for proper design and interpretation of ChEC-seq experiments.
The genetic basis of adaptation through the evolution of self-fertilization
Authors: Xu Kuangyi 
Published: February 2021

AbstractAlthough adaptation can be realized through the fixation of beneficial alleles that increase viability, many plant populations may adapt through the evolution of self-fertilization, especially when pollination becomes inefficient. However, the genetic basis of adaptation through the evolution of selfing remains unclear. Using population genetic models, I study adaptation through the fixation of alleles that increase the selfing rate (selfing modifiers) from new mutations or/and standing variation. For adaptive alleles unrelated to selfing, it is known that selfing promotes adaptation from a new mutation only when the beneficial alleles are recessive, and the probability of adaptation from standing variation is nearly independent of dominance, and always decreases with the selfing rate. In contrast, for adaptation through the evolution of selfing, when it occurs by fixation of a newly arisen mutation, a population that already has a high selfing rate may be more (less) likely to adapt than outcrossers even when the modifier is dominant (recessive) if the modifier is weakly (strongly) selected. Also, adaptation from standing variation is more likely through recessive modifier alleles, with the highest fixation probability found in partially selfing populations, but fixation is fastest when dominance is intermediate. When there are multiple modifiers, adaptation through new mutations is more likely when selfing is controlled by few large-effect rather than many slight-effect modifiers. This study suggests that to understand the genetic basis of adaptation, it is necessary to determine the ecological and genetic advantages of adaptive alleles.Significance statementThis study, by deriving the selective coefficient and effective population size, investigated the genetic basis of adaptation through fixation of modifier alleles that increase the selfing rate, which is shown to differ in several aspects from that through evolution of mating-unrelated alleles. Specifically, when adaptation is from new mutations, the dominance of a selfing modifier allele below which selfing increases the fixation probability depends on the strength of pollen limitation and pollen discounting. Adaptation from standing variation is more likely through recessive modifier alleles and in populations with an intermediate selfing rate. This work suggests it is important to have a mechanistic understanding of how adaptive alleles increase individual fitness in environment that is unfavorable to the population.
Annotation of snoRNA abundance across human tissues reveals complex snoRNA-host gene relationships
Authors: Fafard-Couture Étienne , Bergeron Danny , Couture Sonia , Abou Elela Sherif , Scott Michelle S 
Published: February 2021

AbstractBackgroundSmall nucleolar RNAs (snoRNAs) are mid-size non-coding RNAs required for ribosomal RNA modification, implying a ubiquitous tissue distribution linked to ribosome synthesis. However, increasing numbers of studies identify extra-ribosomal roles of snoRNAs in modulating gene expression, suggesting more complex snoRNA abundance patterns. Therefore, there is a great need for mapping the snoRNome in different human tissues as the blueprint for snoRNA functions.ResultsWe used a low structure bias RNA-Seq approach to accurately quantify snoRNAs and compare them to the entire transcriptome in seven healthy human tissues (breast, ovary, prostate, testis, skeletal muscle, liver and brain). We identified 475 expressed snoRNAs categorized in two abundance classes that differ significantly in their function, conservation level and correlation with their host gene: 390 snoRNAs are uniformly expressed and 85 are enriched in the brain or reproductive tissues. Most tissue-enriched snoRNAs are embedded in lncRNAs and display strong correlation of abundance with them, whereas uniformly expressed snoRNAs are mostly embedded in protein-coding host genes and are mainly non- or anticorrelated with them. 59% of the non-correlated or anticorrelated protein-coding host gene/snoRNA pairs feature dual-initiation promoters, as opposed to only 16% of the correlated non-coding host gene/snoRNA pairs.ConclusionsOur results demonstrate that snoRNAs are not a single homogeneous group of housekeeping genes but include highly regulated tissue-enriched RNAs. Indeed, our work indicates that the architecture of snoRNA host genes varies to uncouple the host and snoRNA expressions in order to meet the different snoRNA abundance levels and functional needs of human tissues.
The structure of the human cell cycle
Authors: Stallaert Wayne , Kedziora Katarzyna M. , Taylor Colin D. , Zikry Tarek M. , Sobon Holly K. , Taylor Sovanny R. , Young Catherine L. , Limas Juanita C. , Cook Jeanette G. , Purvis Jeremy E. 
Published: February 2021

ABSTRACTThe human cell cycle is conventionally depicted as a five-phase model consisting of four proliferative phases (G1, S, G2, M) and a single state of arrest (G0). However, recent studies show that individual cells can take different paths through the cell cycle and exit into distinct arrest states, thus necessitating an update to the canonical model. We combined time lapse microscopy, highly multiplexed single cell imaging and manifold learning to determine the underlying “structure” of the human cell cycle under multiple growth and arrest conditions. By visualizing the cell cycle as a complete biological process, we identified multiple points of divergence from the proliferative cell cycle into distinct states of arrest, revealing multiple mechanisms of cell cycle exit and re-entry and the molecular routes to senescence, endoreduplication and polyploidy. These findings enable the visualization and comparison of alternative cell cycles in development and disease.One-sentence summaryA systems-level view of single-cell states reveals the underlying architecture of the human cell cycle
Gys1 antisense therapy rescues neuropathological bases of murine Lafora disease
Authors: Ahonen Saija , Nitschke Silvia , Grossman Tamar R. , Kordasiewicz Holly , Wang Peixiang , Zhao Xiaochu , Guisso Dikran R. , Kasiri Sahba , Nitschke Felix , Minassian Berge A. 
Published: February 2021

AbstractLafora disease is a fatal progressive myoclonus epilepsy. At root, it is due to constant acquisition of branches that are too long in a subgroup of glycogen molecules, leading them to precipitate and accumulate into Lafora bodies, which drive a neuroinflammatory response and neurodegeneration. As a potential therapy, we aimed to downregulate glycogen synthase, the enzyme responsible for glycogen branch elongation, in the disease’s mouse models. We synthesized an antisense oligonucleotide (Gys1-ASO) that targets the mRNA of the brain-expressed glycogen synthase 1 gene (Gys1). We administered Gys1-ASO by intracerebroventricular injection and analyzed the pathological hallmarks of Lafora disease, namely glycogen accumulation, Lafora body formation, and neuroinflammation. Gys1-ASO prevented Lafora body formation in young mice that had not yet formed them. In older mice that already exhibited Lafora bodies, Gys1-ASO inhibited further accumulation, markedly preventing large Lafora bodies characteristic of advanced disease. Inhibition of Lafora body formation was associated with prevention of astrogliosis and strong trends towards correction of dysregulated expression of disease immune and neuroinflammatory markers. Lafora disease manifests gradually in previously healthy teenagers. Our work provides proof of principle that an antisense oligonucleotide targeting the GYS1 mRNA could prevent, and halt progression of, this catastrophic epilepsy.
A versatile Tn7 transposon-based bioluminescence tagging tool for quantitative and spatial detection of bacteria in plants
Authors: Matsumoto Ayumi , Schlüter Titus , Melkonian Katharina , Takeda Atsushi , Nakagami Hirofumi , Mine Akira 
Published: February 2021

SUMMARYInvestigation of plant-bacteria interactions requires quantification ofin plantabacterial titers by means of colony counting assays. However, colony counting assays are cumbersome and time-consuming, and are unable to detect spatial patterns of bacterial colonization in plants. Here, to overcome these shortcomings, we devised a broadly applicable genetic engineering tool for bioluminescence-based quantitative and spatial detection of bacteria in plants. We developed plasmid vectors that have broad host ranges and enable Tn7transposon-mediated integration of theluxCDABEluciferase operon into a specific genomic location ubiquitously found across bacterial phyla. These vectors allowed for generation of bioluminescent transformants of various plant pathogenic bacteria belonging to the generaPseudomonas, Rhizobium(Agrobacterium), andRalstonia. The bioluminescent transformant ofPseudomonas syringaepv.tomatoDC3000 (Pto-lux) was as virulent inArabidopsis thalianaas its parental strain. Direct luminescence measurements ofPto-lux-inoculated plant tissues reported bacterial titers inA. thaliana, Solanum lycopersicum, Nicotiana benthamiana, andMarchantia polymorphaas accurately as conventional colony counting assays. We further showed the utility of our vectors for converting the previously generatedPtoderivatives to isogenic bioluminescent strains. Importantly, quantitative bioluminescence assays using thesePto-lux strains accurately reported the effects of plant immunity and bacterial effectors on bacterial growth with a dynamic range of 4 orders of magnitude. Moreover, macroscopic bioluminescence imaging illuminated spatial colonization patterns of thePto-lux in/on inoculated plant tissues. Taken together, our vectors offer untapped opportunities for developing bioluminescence-based quantitative and spatial analysis of bacterial growth in a variety of plant-bacteria interactions.SIGNIFICANCE STATEMENTWe developed broad-host-range plasmid vectors that integrate the luciferase operon,luxCDABE, into a specific genomic location ubiquitously found across bacterial phyla. Using these vectors, we established a high-throughput method for bioluminescence-based quantitative assays ofin plantabacterial growth with a dynamic range of 4 orders of magnitude and visualized spatiotemporal patterns of bacterial colonization in/on inoculated plant tissues.
The relationship between affective visual mismatch negativity and interpersonal difficulties across autism and schizotypal traits
Authors: Ford Talitha C. , Hugrass Laila E. , Jack Bradley N. 
Published: February 2021

AbstractObjectiveSensory deficits are a feature of autism and schizophrenia, as well as the upper end of their non-clinical spectra. The mismatch negativity (MMN), an index of pre-attentive auditory processing, is particularly sensitive in detecting such deficits; however, little is known about the relationship between the visual MMN (vMMN) to emotional faces and autism and schizophrenia spectrum symptom domains.MethodsWe probed the vMMN to happy, sad, and neutral faces in 77 young adults (18-40 years, 41 female), and evaluated their degree of autism and schizophrenia spectrum traits using the Autism Spectrum Quotient (AQ) and Schizotypal Personality Questionnaire (SPQ). Results: The vMMN to happy faces was significantly larger than the vMMNs to sad and neutral faces (p> 0.05). The vMMN to happy faces was associated with interpersonal difficulties as indexed by AQ Communication and Attention to Detail subscales, and SPQ Interpersonal Features (p< 0.05,uncorrected), such that a larger vMMN was associated with more interpersonal difficulties.ConclusionsPre-attentive processing of positive affect might be more specific to the interpersonal features associated with autism and schizophrenia.SignificanceThese findings add valuable insights into the growing body of literature investigating symptom-specific neurobiological markers of autism and schizophrenia spectrum conditions.Highlights-The visual Mismatch Negativity (vMMN) is larger in response to happy compared to sad or neutral facial expressions-The vMMN to happy facial expressions is specifically associated with more social communication difficulties-vMMN to positive affect may be a neural mechanism associated with social communication difficulties in autism and schizophrenia
Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry
Authors: Wei Tiantian , Wang Jue , Liang Ruqi , Chen Wendong , He An , Du Yifei , Zhou Wenjing , Zhang Zhiying , Ma Mingzhe , Lu Jin , Guo Xing , Chen Xiaowei , Tian Ruijun , Xiao Junyu , Lei Xiaoguang 
Published: February 2021

AbstractThe dual-specificity tyrosine phosphorylation-regulated kinase DYRK2 has emerged as a key regulator of cellular processes such as proteasome-mediated protein degradation. To gain further insights into its function, we took a chemical biology approach and developed C17, a potent small-molecule DYRK2 inhibitor, through multiple rounds of structure-based optimization guided by a number of co-crystallized structures. C17 displayed an effect on DYRK2 at a single-digit nanomolar IC50and showed outstanding selectivity for the human kinome containing 467 other human kinases. Using C17 as a chemical probe, we further performed quantitative phosphoproteomic assays and identified several novel DYRK2 targets, including eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and stromal interaction molecule 1 (STIM1). DYRK2 phosphorylated 4E-BP1 at multiple sites, and the combined treatment of C17 with AKT and MEK inhibitors showed synergistic 4E-BP1 phosphorylation suppression. The phosphorylation of STIM1 by DYRK2 substantially increased the interaction of STIM1 with the ORAI1 channel, and C17 impeded the store-operated calcium entry process. Collectively, these studies further expand our understanding of DYRK2 and provide a valuable tool to further pinpoint its biological function.
Elucidating vimentin interaction with zinc ions and its interplay with oxidative modifications through crosslinking assays and molecular dynamics simulations
Authors: Mónico Andreia , Guzmán-Caldentey Joan , Pajares María A. , Martín-Santamaría Sonsoles , Pérez-Sala Dolores 
Published: February 2021

AbstractThe intermediate filament protein vimentin is involved in essential cellular processes, including cell division and stress responses. Vimentin oxidative modifications impact network reorganization and its single cysteine residue, Cys328, acts as a redox sensor. Vimentin binds zinc, which influences its assembly by undefined mechanisms. Here, results from combined biochemical and molecular dynamics studies support that zinc ions interact with Cys328 in its thiolate form, whereas Glu329 and Asp331 stabilize zinc coordination. Vimentin oxidation can induce disulfide crosslinking, implying a close proximity of cysteine residues in certain vimentin associations, validated by our computational models. Notably, micromolar zinc concentrations selectively prevent Cys328 alkylation and crosslinking. These effects are not mimicked by magnesium, consistent with the fewer magnesium ions hosted at the cysteine region. Altogether, our results pinpoint the region surrounding Cys328, highly conserved in type III intermediate filaments, as a hot spot for zinc binding, which modulates Cys328 reactivity and vimentin assembly.
The bacterial iron sensor IdeR recognizes its DNA targets by indirect readout
Authors: Marcos-Torres Francisco Javier , Maurer Dirk , Griese Julia J. 
Published: February 2021

ABSTRACTIdeR is the main transcriptional regulator controlling iron homeostasis genes in Actinobacteria, including species from theCorynebacterium, Mycobacterium, andStreptomycesgenera, as well as the erythromycin-producing bacteriumSaccharopolyspora erythraea.Despite being a well-studied transcription factor since the identification of the Diphtheria toxin repressor DtxR three decades ago, the details of how IdeR proteins recognize their highly conserved 19-bp DNA target remain to be elucidated. The results of our structural and mutational studies support a model wherein IdeR uses an indirect readout mechanism, identifying its targets via the sequence-specific DNA backbone structure rather than through direct contacts with the DNA bases. Furthermore, we show that IdeR efficiently recognizes a shorter palindromic sequence corresponding to a half binding site as compared to the full 19-bp target previously reported, expanding the number of potential target genes controlled by IdeR proteins.
Building organizational resilience through human capital management strategy
Authors: Douglas Stephanie 
Published: February 2021

Purpose
This paper examines the role of human capital management strategy in shaping organizational resilience. Resilient organizations thrive in uncertain and adverse conditions. The organization’s capacity for resilience can be developed through human capital management strategies that are focused on employee capabilities, training, and development. When individual capabilities and resilience are developed, those can be aggregated at an organizational level to develop the capacity in an organization for resilience.

Design/methodology/approach
A review of relevant studies and literature was conducted to develop strategies and insight into developing the human capital of an organization to support organizational resilience.

Findings
Supporting individual capability development and resilience builds the organization’s capacity for resilience. By shifting human capital management strategies to building capabilities and then skills, organizations develop individual resilience and then organizational resilience. The implications of how to build such human capital management strategies are presented.

Originality/value
This paper provides support and guidelines for building individual capability and resilience to enhance an organization’s resilience.