bluuebunny/crossref_metadata_2025 huggingface dataset:
EIF4A3 associated splicing and nonsense mediated decay defined by a systems analysis with novel small molecule inhibitors
Authors: Mazloomian Alborz , Araki Shinsuke , Ohori Momoko , Yap Damian , Nakao Shoichi , Nakanishi Atsushi , Shah Sohrab , Aparicio Samuel
Published: September 2017

Chemical biology approaches to the global functions of splicing reactions are gaining momentum, with an increasing repertoire of small molecule probes becoming available. Here we map the association of eIF4A3 with transcript expression, NMD and alternative splicing using a set of selective novel small molecule allosteric helicase inhibitors whose synthesis and chemical properties we have recently described. We show through analysis of dose monotonic transcriptional responses to increasing inhibition that both full length and NMD prone transcripts link eIF4A3 to normal functioning of cell division including chromosome segregation and cell cycle checkpoints, pointing to a conserved role of splicing and transcript quality processing in cell cycle functions. Cell cycle analysis and microscopy of inhibitor treated cells demonstrates chromosome mis-segregation and spindle defects, associated with a G2/M arrest, validating this observation. Through analysis of conserved alternative splicing patterns exhibiting monotonic responses, we find that eIF4A3 dependent alternative splicing involves exons that are longer and introns that are shorter than transcripts not modulated by eIF4A3. Moreover we observe conservation of over/under representation of RBP binding motif density over introns and exons implicated eIF4A3 modulated skipped exon and retained introns. The distribution of motif densities over 5’ and branch intron sites and 5’ exons is consistent with function of the exon-junction complex. Taken together we have defined a fraction of the transcrip-tome dependent on eIF4A3 functions and revealed a link between eIF4A3 and cell cycle regulation. The systems approach described here suggests additional avenues for therapeutic exploitation of eIF4A3 functions in cancer and related diseases.
NF90/ILF3 is a transcription factor that promotes proliferation over differentiation by hierarchical regulation in K562 erythroleukemia cells
Authors: Wu Ting-Hsuan , Shi Lingfang , Adrian Jessika , Shi Minyi , Nair Ramesh V. , Snyder Michael P. , Kao Peter N.
Published: September 2017

NF90 and splice variant NF110 are DNA‐ and RNA-binding proteins encoded by the Interleukin enhancer-binding factor 3 (ILF3) gene that regulate RNA splicing, stabilization and export. The role of NF90 in regulating transcription as a DNA-binding protein has not been comprehensively characterized. Here, ENCODE ChIP-seq identified 9,081 genomic sites specifically bound by NF90/110 in K562 cells. One third of binding sites occurred at promoters of annotated genes. NF90/110 binding colocalized with chromatin marks associated with active promoters and strong enhancers. Comparison with 150 ENCODE ChIP-seq experiments revealed that NF90 clustered with transcription factors exhibiting preference for promoters over enhancers (POLR2A,MYC,YY1). Differential gene expression analysis following shRNA knockdown of NF90 in K562 cells revealed that NF90 directly activates transcription factors that drive growth and proliferation (EGR1,MYC), while attenuating differentiation along erythroid lineage (KLF1). NF90/110 binds chromatin to hierarchically regulate transcription factors to promote proliferation and suppress differentiation.
High-throughput identification of RNA nuclear enrichment sequences
Authors: Shukla Chinmay J , McCorkindale Alexandra L , Gerhardinger Chiara , Korthauer Keegan D , Cabili Moran N , Shechner David M , Irizarry Rafael A , Maass Philipp G , Rinn John L
Published: September 2017

One of the biggest surprises since the sequencing of the human genome has been the discovery of thousands of long noncoding RNAs (lncRNAs)1–6. Although lncRNAs and mRNAs are similar in many ways, they differ with lncRNAs being more nuclear-enriched and in several cases exclusively nuclear7,8. Yet, the RNA-based sequences that determine nuclear localization remain poorly understood9–11. Towards the goal of systematically dissecting the lncRNA sequences that impart nuclear localization, we developed a massively parallel reporter assay (MPRA). Unlike previous MPRAs12–15that determine motifs important for transcriptional regulation, we have modified this approach to identify sequences sufficient for RNA nuclear enrichment for 38 human lncRNAs. Using this approach, we identified 109 unique, conserved nuclear enrichment regions, originating from 29 distinct lncRNAs. We also discovered two shorter motifs within our nuclear enrichment regions. We further validated the sufficiency of several regions to impart nuclear localization by single molecule RNA fluorescencein situhybridization (smRNA-FISH). Taken together, these results provide a first systematic insight into the sequence elements responsible for the nuclear enrichment of lncRNA molecules.
S1-seq assay for mapping processed DNA ends
Authors: Mimitou Eleni P. , Keeney Scott
Published: September 2017

During meiosis, the specialized cell division giving rise to gametes, numerous DNA doublestrand breaks (DSBs) are introduced at multiple places throughout the genome by the topoisomerase-like protein Spo11. Homologous recombination, a highly-conserved DSB repair pathway, is employed for their repair and ensures the formation of chiasmata and the proper segregation of homologous chromosomes. In the initial steps of recombination, end resection takes place, wherein Spo11 is endonucleolytically released and the 5′-terminal strands of each DSB are exonucleolytically processed, exposing the ssDNA necessary to identify a homologous repair template. DNA removed by DSB processing is reconstituted by DNA synthesis, which copies genetic information from the intact homologous template. We developed a next-generation sequencing assay, termed S1-seq, to study DNA end resection genome-wide at high spatial resolution during yeast meiotic recombination. The assay relies on the fact that removal of the ssDNA tails of resected DSBs marks the position where resection stopped. Molecular features of resection are revealed by sequencing of these ssDNA-to-dsDNA junctions and comparison to high-resolution Spo11 DSB maps. We describe the experimental and computational methods for S1-seq as applied to meiosis in the SK1 strain of budding yeastSaccharomyces cerevisiae, and discuss how it can also be applied to map DSBs and recombination intermediates.
Turning vice into virtue: Using Batch-Effects to Detect Errors in Large Genomic Datasets
Authors: Mafessoni Fabrizio , Prasad Rashmi B , Groop Leif , Hansson Ola , Prüfer Kay
Published: September 2017

It is often unavoidable to combine data from different sequencing centers or sequencing platforms when compiling datasets with a large number of individuals. However, the different data are likely to contain specific systematic errors that will appear as SNPs. Here, we devise a method to detect systematic errors in combined datasets. To measure quality differences between individual genomes, we study pairs of variants that reside on different chromosomes and co-occur in individuals. The abundance of these pairs of variants in different genomes is then used to detect systematic errors due to batch effects. Applying our method to the 1000 Genomes dataset, we find that coding regions are enriched for errors, where about 1% of the higher-frequency variants are predicted to be erroneous, whereas errors outside of coding regions are much rarer (<0.001%). As expected, predicted errors are less often found than other variants in a dataset that was generated with a different sequencing technology, indicating that many of the candidates are indeed errors. However, predicted 1000 Genomes errors are also found in other large datasets; our observation is thus not specific to the 1000 Genomes dataset. Our results show that batch effects can be turned into a virtue by using the resulting variation in large scale datasets to detect systematic errors.
Inferring continuous and discrete population genetic structure across space
Authors: Bradburd Gideon S. , Coop Graham M. , Ralph Peter L.
Published: September 2017

A classic problem in population genetics is the characterization of discrete population structure in the presence of continuous patterns of genetic differentiation. Especially when sampling is discontinuous, the use of clustering or assignment methods may incorrectly ascribe differentiation due to continuous processes (e.g., geographic isolation by distance) to discrete processes, such as geographic, ecological, or reproductive barriers between populations. This reflects a shortcoming of current methods for inferring and visualizing population structure when applied to genetic data deriving from geographically distributed populations. Here, we present a statistical framework for the simultaneous inference of continuous and discrete patterns of population structure. The method estimates ancestry proportions for each sample from a set of two-dimensional population layers, and, within each layer, estimates a rate at which relatedness decays with distance. This thereby explicitly addresses the “clines versus clusters” problem in modeling population genetic variation. The method produces useful descriptions of structure in genetic relatedness in situations where separated, geographically distributed populations interact, as after a range expansion or secondary contact. We demonstrate the utility of this approach using simulations and by applying it to empirical datasets of poplars and black bears in North America.

Author summary

One of the first steps in the analysis of genetic data, and a principal mission of biology, is to describe and categorize natural variation. A continuous pattern of differentiation (isolation by distance), where individuals found closer together in space are, on average, more genetically similar than individuals sampled farther apart, can confound attempts to categorize natural variation into groups. This is because current statistical methods for assigning individuals to discrete clusters cannot accommodate spatial patterns, and so are forced to use clusters to describe what is in fact continuous variation. As isolation by distance is common in nature, this is a substantial shortcoming of existing methods. In this study, we introduce a new statistical method for categorizing natural genetic variation - one that describes variation as a combination of continuous and discrete patterns. We demonstrate that this method works well and can capture patterns in population genomic data without resorting to splitting populations where they can be described by continuous patterns of variation.
The drivers and consequences of unstablePlasmodiumdynamics: A long-term study of three malaria species infecting a tropical lizard
Authors: Otero Luisa , Schall Jos. J. , Cruz Virnaliz , Aaltonen Kristen , Acevedo Miguel A.
Published: September 2017

The dynamics of vector-borne parasites are driven by interactions between factors intrinsic to the parasite, its host, as well as environmental fluctuations. Understanding these interactions requires a long-term view, especially to predict the consequences of climate change on parasite dynamics.

The goal of this study is to evaluate temporal fluctuations in individual probability of infection, its environmental drivers and consequences for host body condition, of three malaria parasites (Plasmodium azurophilum,P. leucocytica, andP. floridense) infecting the lizard,Anolis gundlachi, in the rainforest of Puerto Rico.

We conducted 13 surveys totalingN> 8000 lizards over 26 years. During the early years of the study, the lizard’s probability of infection by all threePlasmodiumspecies appeared stable despite disturbances from short droughts and small to moderate hurricanes.

Over a longer timescale, we found that the individual lizard probability of infection and overall prevalence varied significantly over the years, and this fluctuation was driven in non-linear ways by variations in temperature and rainfall. The probability of infection was maximized at intermediate levels of temperature and precipitation. This temporal variability inPlasmodiumprevalence driven by environmental factors had two important consequences. First, temperature-mediated a decrease in body condition in infected female lizards relative to non-infected ones. Second,Plasmodiumparasite species composition varied through time.

Overall, the results show how environmental conditions, such a severe drought, can drive disease dynamics outside of their apparent stable equilibrium and mediate the potential negative effects of parasite infection on the host. Our results also emphasize the need for long-term studies to reveal host-parasite dynamics, their drivers and consequences.
A survey of DNA methylation polymorphism identifies environmentally responsive co-regulated networks of epigenetic variation in the human genome
Authors: Garg Paras , Joshi Ricky S. , Watson Corey , Sharp Andrew J.
Published: September 2017

While studies such as the 1000 Genomes Projects have resulted in detailed maps of genetic variation in humans, to date there are few robust maps of epigenetic variation. We defined sites of common epigenetic variation, termed Variably Methylated Regions (VMRs) in five purified cell types. We observed that VMRs occur preferentially at enhancers and 3’ UTRs. While the majority of VMRs have high heritability, a subset of VMRs within the genome show highly correlated variation intrans, forming co-regulated networks that have low heritability, differ between cell types and are enriched for specific transcription factor binding sites and biological pathways of functional relevance to each tissue. For example, in T cells we defined a network of 72 co-regulated VMRs enriched for genes with roles in T-cell activation; in fibroblasts a network of 21 coregulated VMRs comprising all fourHOXgene clusters enriched for control of tissue growth; and in neurons a network of 112 VMRs enriched for roles in learning and memory. By culturing genetically-identical fibroblasts under varying conditions of nutrient deprivation and cell density, we experimentally demonstrate that some VMR networks are responsive to environmental conditions, with methylation levels at these loci changing in a coordinated fashion intransdependent on cellular growth. Intriguingly these environmentally-responsive VMRs showed a strong enrichment for imprinted loci (p<10−94), suggesting that these are particularly sensitive to environmental conditions. Our study provides a detailed map of common epigenetic variation in the human genome, showing that both genetic and environmental causes underlie this variation.
Alzheimer's disease: the large gene instability hypothesis
Authors: Soheili-Nezhad Sourena
Published: September 2017

All drug trials of the Alzheimer's disease (AD) have failed to slow the progression of dementia in phase III studies, and the most effective therapeutic strategy remains controversial due to the poorly understood disease mechanisms. For AD drug design, amyloid beta (Aβ) and its cascade have been the primary focus since decades ago, but mounting evidence indicates that the underpinning molecular pathways of AD are more complex than the classical reductionist models. Several genome-wide association studies (GWAS) have recently shed light on dark aspects of AD from a hypothesis-free perspective. Here, I use this novel insight to suggest that the amyloid cascade hypothesis may be a wrong model for AD therapeutic design. I review 23 novel genetic risk loci and show that, as a common theme, they code for receptor proteins and signal transducers of cell adhesion pathways, with clear implications in synaptic development, maintenance, and function. Contrary to the Aβ-based interpretation, but further reinforcing the unbiased genome-wide insight, the classical hallmark genes of AD including the amyloid precursor protein (APP), presenilins (PSEN), and APOE also take part in similar pathways of growth cone adhesion and contact-guidance during brain development. On this basis, I propose that a disrupted synaptic adhesion signaling nexus, rather than a protein aggregation process, may be the central point of convergence in AD mechanisms. By an exploratory bioinformatics analysis, I show that synaptic adhesion proteins are encoded by largest known human genes, and these extremely large genes may be vulnerable to DNA damage accumulation in aging due to their mutational fragility. As a prototypic example and an immediately testable hypothesis based on this argument, I suggest that mutational instability of the large Lrp1b tumor suppressor gene may be the primary etiological trigger for APOE-dab1 signaling disruption in late-onset AD. In conclusion, the large gene instability hypothesis suggests that evolutionary forces of brain complexity have led to emergence of large and fragile synaptic genes, and these unstable genes are the bottleneck etiology of aging disorders including senile dementias. A paradigm shift is warranted in AD prevention and therapeutic design.
APC sets the Wnt tone necessary for cerebral cortical progenitor development
Authors: Nakagawa Naoki , Li Jingjun , Yabuno-Nakagawa Keiko , Eom Tae-Yeon , Cowles Martis , Mapp Tavien , Taylor Robin , Anton E.S.
Published: September 2017

Adenomatous polyposis coli (APC) regulates the activity of β-catenin, an integral component of Wnt signaling. However, the selective role of the APC–β-catenin pathway in cerebral cortical development is unknown. Here we genetically dissected the relative contributions of APC-regulated β-catenin signaling in cortical progenitor development, a necessary early step in cerebral cortical formation. Radial progenitor-specific inactivation of the APC–β-catenin pathway indicates that the maintenance of appropriate β-catenin-mediated Wnt tone is necessary for the orderly differentiation of cortical progenitors and the resultant formation of the cerebral cortex. APC deletion deregulates β-catenin, leads to high Wnt tone, and disrupts Notch1 signaling and primary cilium maintenance necessary for radial progenitor functions. β-Catenin deregulation directly disrupts cilium maintenance and signaling via Tulp3, essential for intraflagellar transport of ciliary signaling receptors. Surprisingly, deletion of β-catenin or inhibition of β-catenin activity in APC-null progenitors rescues the APC-null phenotype. These results reveal that APC-regulated β-catenin activity in cortical progenitors sets the appropriate Wnt tone necessary for normal cerebral cortical development.
Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element
Authors: Huang Peng , Keller Cheryl A. , Giardine Belinda , Grevet Jeremy D. , Davies James O.J. , Hughes Jim R. , Kurita Ryo , Nakamura Yukio , Hardison Ross C. , Blobel Gerd A.
Published: September 2017

Chromatin structure is tightly intertwined with transcription regulation. Here we compared the chromosomal architectures of fetal and adult human erythroblasts and found that, globally, chromatin structures and compartments A/B are highly similar at both developmental stages. At a finer scale, we detected distinct folding patterns at the developmentally controlled β-globin locus. Specifically, new fetal stage-specific contacts were uncovered between a region separating the fetal (γ) and adult (δ and β) globin genes (encompassing the HBBP1 and BGLT3 noncoding genes) and two distal chromosomal sites (HS5 and 3′HS1) that flank the locus. In contrast, in adult cells, the HBBP1–BGLT3 region contacts the embryonic ε-globin gene, physically separating the fetal globin genes from the enhancer (locus control region [LCR]). Deletion of the HBBP1 region in adult cells alters contact landscapes in ways more closely resembling those of fetal cells, including increased LCR–γ-globin contacts. These changes are accompanied by strong increases in γ-globin transcription. Notably, the effects of HBBP1 removal on chromatin architecture and gene expression closely mimic those of deleting the fetal globin repressor BCL11A, implicating BCL11A in the function of the HBBP1 region. Our results uncover a new critical regulatory region as a potential target for therapeutic genome editing for hemoglobinopathies and highlight the power of chromosome conformation analysis in discovering new cis control elements.
Comparative analysis of alternative polyadenylation in S. cerevisiae and S. pombe
Authors: Liu Xiaochuan , Hoque Mainul , Larochelle Marc , Lemay Jean-François , Yurko Nathan , Manley James L. , Bachand François , Tian Bin
Published: September 2017

Alternative polyadenylation (APA) is a widespread mechanism that generates mRNA isoforms with distinct properties. Here we have systematically mapped and compared cleavage and polyadenylation sites (PASs) in two yeast species, S. cerevisiae and S. pombe. Although >80% of the mRNA genes in each species were found to display APA, S. pombe showed greater 3′ UTR size differences among APA isoforms than did S. cerevisiae. PASs in different locations of gene are surrounded with distinct sequences in both species and are often associated with motifs involved in the Nrd1-Nab3-Sen1 termination pathway. In S. pombe, strong motifs surrounding distal PASs lead to higher abundances of long 3′ UTR isoforms than short ones, a feature that is opposite in S. cerevisiae. Differences in PAS placement between convergent genes lead to starkly different antisense transcript landscapes between budding and fission yeasts. In both species, short 3′ UTR isoforms are more likely to be expressed when cells are growing in nutrient-rich media, although different gene groups are affected in each species. Significantly, 3′ UTR shortening in S. pombe coordinates with up-regulation of expression for genes involved in translation during cell proliferation. Using S. pombe strains deficient for Pcf11 or Pab2, we show that reduced expression of 3′-end processing factors lengthens 3′ UTR, with Pcf11 having a more potent effect than Pab2. Taken together, our data indicate that APA mechanisms in S. pombe and S. cerevisiae are largely different: S. pombe has many of the APA features of higher species, and Pab2 in S. pombe has a different role in APA regulation than its mammalian homolog, PABPN1.
Massive reshaping of genome–nuclear lamina interactions during oncogene-induced senescence
Authors: Lenain Christelle , de Graaf Carolyn A. , Pagie Ludo , Visser Nils L. , de Haas Marcel , de Vries Sandra S. , Peric-Hupkes Daniel , van Steensel Bas , Peeper Daniel S.
Published: September 2017

Cellular senescence is a mechanism that virtually irreversibly suppresses the proliferative capacity of cells in response to various stress signals. This includes the expression of activated oncogenes, which causes Oncogene-Induced Senescence (OIS). A body of evidence points to the involvement in OIS of chromatin reorganization, including the formation of senescence-associated heterochromatic foci (SAHF). The nuclear lamina (NL) is an important contributor to genome organization and has been implicated in cellular senescence and organismal aging. It interacts with multiple regions of the genome called lamina-associated domains (LADs). Some LADs are cell-type specific, whereas others are conserved between cell types and are referred to as constitutive LADs (cLADs). Here, we used DamID to investigate the changes in genome–NL interactions in a model of OIS triggered by the expression of the common BRAFV600E oncogene. We found that OIS cells lose most of their cLADS, suggesting the loss of a specific mechanism that targets cLADs to the NL. In addition, multiple genes relocated to the NL. Unexpectedly, they were not repressed, implying the abrogation of the repressive activity of the NL during OIS. Finally, OIS cells displayed an increased association of telomeres with the NL. Our study reveals that senescent cells acquire a new type of LAD organization and suggests the existence of as yet unknown mechanisms that tether cLADs to the NL and repress gene expression at the NL.
The impact of threat of shock-induced anxiety on memory encoding and retrieval
Authors: Bolton Sorcha , Robinson Oliver J.
Published: September 2017

Anxiety disorders are the most common mental health disorders, and daily transient feelings of anxiety (or “stress”) are ubiquitous. However, the precise impact of both transient and pathological anxiety on higher-order cognitive functions, including short- and long-term memory, is poorly understood. A clearer understanding of the anxiety–memory relationship is important as one of the core symptoms of anxiety, most prominently in post-traumatic stress disorder (PTSD), is intrusive reexperiencing of traumatic events in the form of vivid memories. This study therefore aimed to examine the impact of induced anxiety (threat of shock) on memory encoding and retrieval. Eighty-six healthy participants completed tasks assessing: visuospatial working memory, verbal recognition, face recognition, and associative memory. Critically, anxiety was manipulated within-subjects: information was both encoded and retrieved under threat of shock and safe (no shock) conditions. Results revealed that visuospatial working memory was enhanced when information was encoded and subsequently retrieved under threat, and that threat impaired the encoding of faces regardless of the condition in which it was retrieved. Episodic memory and verbal short-term recognition were, however, unimpaired. These findings indicate that transient anxiety in healthy individuals has domain-specific, rather than domain-general, impacts on memory. Future studies would benefit from expanding these findings into anxiety disorder patients to delineate the differences between adaptive and maladaptive responding.
Interactions between medial prefrontal cortex and dorsomedial striatum are necessary for odor span capacity in rats: role of GluN2B-containing NMDA receptors
Authors: Davies Don A. , Greba Quentin , Selk Jantz C. , Catton Jillian K. , Baillie Landon D. , Mulligan Sean J. , Howland John G.
Published: September 2017

Working memory is involved in the maintenance and manipulation of information essential for complex cognition. While the neural substrates underlying working memory capacity have been studied in humans, considerably less is known about the circuitry mediating working memory capacity in rodents. Therefore, the present experiments tested the involvement of medial prefrontal cortex (mPFC) and dorsal striatum (STR) in the odor span task (OST), a task proposed to assay working memory capacity in rodents. Initially, Long Evans rats were trained to dig in scented sand for food following a serial delayed nonmatching-to-sample rule. Temporary inactivation of dorsomedial (dm) STR significantly reduced span in well trained rats. Inactivation of mPFC or contralateral disconnection of the mPFC and dmSTR also reduced span. Infusing the GluN2B-containing NMDA receptor antagonist Ro 25-6981 into mPFC did not affect span; however, span was significantly reduced following bilateral Ro 25-6981 infusions into dmSTR or contralateral disconnection of mPFC (inactivation) and dmSTR (Ro 25-6981). These results suggest that span capacity in rats depends on GluN2B-containing NMDA receptor-dependent interactions between the mPFC and the dmSTR. Therefore, interventions targeting this circuit may improve the working memory capacity impairments in patients with schizophrenia, Alzheimer's disease, and Parkinson's disease.
Transcriptional correlates of memory maintenance following long-term sensitization of Aplysia californica
Authors: Conte Catherine , Herdegen Samantha , Kamal Saman , Patel Jency , Patel Ushma , Perez Leticia , Rivota Marissa , Calin-Jageman Robert J. , Calin-Jageman Irina E.
Published: September 2017

We characterized the transcriptional response accompanying maintenance of long-term sensitization (LTS) memory in the pleural ganglia of Aplysia californica using microarray (N = 8) and qPCR (N = 11 additional samples). We found that 24 h after memory induction there is strong regulation of 1198 transcripts (748 up and 450 down) in a pattern that is almost completely distinct from what is observed during memory encoding (1 h after training). There is widespread up-regulation of transcripts related to all levels of protein production, from transcription (e.g., subunits of transcription initiation factors) to translation (e.g., subunits of eIF1, eIF2, eIF3, eIF4, eIF5, and eIF2B) to activation of components of the unfolded protein response (e.g., CREB3/Luman, BiP, AATF). In addition, there are widespread changes in transcripts related to cytoskeleton function, synaptic targeting, synaptic function, neurotransmitter regulation, and neuronal signaling. Many of the transcripts identified have previously been linked to memory and plasticity (e.g., Egr, menin, TOB1, IGF2 mRNA binding protein 1/ZBP-1), though the majority are novel and/or uncharacterized. Interestingly, there is regulation that could contribute to metaplasticity potentially opposing or even eroding LTS memory (down-regulation of adenylate cyclase and a putative serotonin receptor, up-regulation of FMRFa and a FMRFa receptor). This study reveals that maintenance of a “simple” nonassociative memory is accompanied by an astonishingly complex transcriptional response.
Experience during early adulthood shapes the learning capacities and the number of synaptic boutons in the mushroom bodies of honey bees (Apis mellifera)
Authors: Cabirol Amélie , Brooks Rufus , Groh Claudia , Barron Andrew B. , Devaud Jean-Marc
Published: September 2017

The honey bee mushroom bodies (MBs) are brain centers required for specific learning tasks. Here, we show that environmental conditions experienced as young adults affect the maturation of MB neuropil and performance in a MB-dependent learning task. Specifically, olfactory reversal learning was selectively impaired following early exposure to an impoverished environment lacking some of the sensory and social interactions present in the hive. In parallel, the overall number of synaptic boutons increased within the MB olfactory neuropil, whose volume remained unaffected. This suggests that experience of the rich in-hive environment promotes MB maturation and the development of MB-dependent learning capacities.
Contextual fear conditioning in zebrafish
Authors: Kenney Justin W. , Scott Ian C. , Josselyn Sheena A. , Frankland Paul W.
Published: September 2017

Zebrafish are a genetically tractable vertebrate that hold considerable promise for elucidating the molecular basis of behavior. Although numerous recent advances have been made in the ability to precisely manipulate the zebrafish genome, much less is known about many aspects of learning and memory in adult fish. Here, we describe the development of a contextual fear conditioning paradigm using an electric shock as the aversive stimulus. We find that contextual fear conditioning is modulated by shock intensity, prevented by an established amnestic agent (MK-801), lasts at least 14 d, and exhibits extinction. Furthermore, fish of various background strains (AB, Tu, and TL) are able to acquire fear conditioning, but differ in fear extinction rates. Taken together, we find that contextual fear conditioning in zebrafish shares many similarities with the widely used contextual fear conditioning paradigm in rodents. Combined with the amenability of genetic manipulation in zebrafish, we anticipate that our paradigm will prove to be a useful complementary system in which to examine the molecular basis of vertebrate learning and memory.
False memories for shape activate the lateral occipital complex
Authors: Karanian Jessica M. , Slotnick Scott D.
Published: September 2017

Previous functional magnetic resonance imaging evidence has shown that false memories arise from higher-level conscious processing regions rather than lower-level sensory processing regions. In the present study, we assessed whether the lateral occipital complex (LOC)—a lower-level conscious shape processing region—was associated with false memories for shape. During encoding, participants viewed intact or scrambled colored abstract shapes. During retrieval, colored disks were presented and participants indicated whether the corresponding item was previously “intact” or “scrambled.” False memories for shape (“intact”/scrambled > “scrambled”/scrambled) activated LOC, which indicates lower-level sensory processing regions can support false memory.
Histone deacetylase inhibition induces odor preference memory extension and maintains enhanced AMPA receptor expression in the rat pup model
Authors: Bhattacharya Sriya , Mukherjee Bandhan , Doré Jules J.E. , Yuan Qi , Harley Carolyn W. , McLean John H.
Published: September 2017

Histone deacetylase (HDAC) plays a role in synaptic plasticity and long-term memory formation. We hypothesized that trichostatin-A (TSA), an HDAC inhibitor, would promote long-term odor preference memory and maintain enhanced GluA1 receptor levels that have been hypothesized to support memory. We used an early odor preference learning model in neonate rat pups that normally produces only 24-h memory to test behavior and examine receptor protein expression. Our behavioral studies showed that intrabulbar infusion of TSA, prior to pairing of the conditioned stimulus (peppermint odor) with the unconditioned stimulus (tactile stimulation), prolonged 24-h odor preference memory for at least 9 d. The prolonged odor preference memory was selective for the paired odor and was also observed using a specific HDAC6 inhibitor, tubacin, supporting a role for histone acetylation in associative memory. Immunoblot analysis showed that GluA1 receptor membrane expression in the olfactory bulbs of the TSA-treated group was significantly increased at 48 h unlike control rats without TSA. Immunohistochemistry revealed significant increase of GluA1 expression in olfactory bulb glomeruli 5 d after training. These results extend previous evidence for a close relationship between enhanced GluA1 receptor membrane expression and memory expression. Together, these findings provide a new single-trial appetitive model for understanding the support and maintenance of memories of varying duration.
Development and characterization of 24 microsatellite markers in Primula tosaensis, an endangered primrose, using MiSeq
Authors: Yamamoto Masaya , Handa Yoshihiro , Aihara Hiroki , Setoguchi Hiroaki
Published: September 2017

Primula tosaensis (Primulaceae) is an endangered primrose endemic to Japan. In this study, 24 novel microsatellite markers were developed using Illumina MiSeq sequencing to facilitate conservation of this endangered species. The genetic diversity and polymorphisms of these novel markers were measured in 32 individuals from a wild P. tosaensis population. The number of alleles and expected heterozygosities ranged from 2 to 5 (mean = 2.8) and from 0.119 to 0.724 (mean = 0.395), respectively. All loci were in Hardy–Weinberg equilibrium. The markers developed in this study will provide a powerful and practical tool for investigating the population structure and genetic diversity of P. tosaensis.
Metaproteomics of marine viral concentrates reveals key viral populations and abundant periplasmic proteins in the oligotrophic deep chlorophyll maximum of the South China Sea
Authors: Xie Zhang‐Xian , Chen Feng , Zhang Shu‐Feng , Wang Ming‐Hua , Zhang Hao , Kong Ling‐Fen , Dai Min‐Han , Hong Hua‐Sheng , Lin Lin , Wang Da‐Zhi
Published: September 2017

Viral concentrates (VCs), containing bioinformative DNA and proteins, have been used to study viral diversity, viral metagenomics and virus–host interactions in natural ecosystems. Besides viruses, VCs also contain many noncellular biological components including diverse functional proteins. Here, we used a shotgun proteomic approach to characterize the proteins of VCs collected from the oligotrophic deep chlorophyll maximum (DCM) of the South China Sea. Proteins of viruses infecting picophytoplankton, that is, cyanobacteria and prasinophytes, and heterotrophic bacterioplankton, such as SAR11 and SAR116, dominated the viral proteome. Almost no proteins from RNA viruses or known gene transfer agents were detected, suggesting that they were not abundant at the sampling site. Remarkably, nonviral proteins made up about two thirds of VC proteins, including overwhelmingly abundant periplasmic transporters for nutrient acquisition and proteins for diverse cellular processes, that is, translation, energy metabolism and one carbon metabolism. Interestingly, three 56 kDa selenium‐binding proteins putatively involved in peroxide reduction from gammaproteobacteria were abundant in the VCs, suggesting active removal of peroxide compounds at DCM. Our study demonstrated that metaproteomics provides a valuable avenue to explore the diversity and structure of the viral community and also the pivotal biological functions affiliated with microbes in the natural environment.
To Lube or not to Lube: The Effect of Intrapartum Lubricant use on Vaginal Microbiota
Authors: McElroy Katie Gresia , Regan Mary
Published: September 2017

Purpose

This study aimed to characterize the composition of vaginal microbiota during labor and to investigate the effect of lubricant use on its bacterial composition.

Research Questions

What is the composition of vaginal microbiota in late pregnancy, throughout labor, and in the postpartum period? Does intrapartum lubricant use affect the composition of vaginal microbiota during labor?

Significance

The composition of vaginal microbiota is critically important during pregnancy because maternal microbes transferred at birth form the basis of the neonate's microbiome. Vaginal dysbiosis, a disruption in composition, is linked with many biological and behavioral factors, including use of personal lubricants. Studies show that lubricants can alter microbial composition and damage the integrity of vaginal epithelium. These findings are concerning because similar lubricants are frequently used during labor. However, the effect of lubricant use on vaginal microbiota during labor has not been studied.

Methods

The prospective cohort study was nested within a federally‐funded study (R01NR014826). Fifteen participants collected mid‐vaginal specimens during pregnancy, labor, and in the postpartum period, and clinical labor data were extracted from medical records. 16S rRNA gene profiling was used for bacterial composition, and multiple linear regression was used to investigate the effect of intrapartum lubricant use.

Results

The composition of vaginal microbiota varied among participants, with a notable high abundance of Lactobacillus iners and Gardnerella vaginalis. A significant bivariate negative correlation between lubricant use and relative abundance of L. crispatus disappeared when controlling for time since ruptured membranes. A trend between lubricant use and changes in the composition of vaginal microbiota as measured by the Jensen‐Shannon distance was noted but not significant.

Discussion

The study offers novel information about the composition of vaginal microbiota during labor and the effect of lubricant use on its composition. The potential relationship between increased lubricant use and decreased L. crispatus has important clinical significance for perinatal providers and can be used to begin to build evidence that supports a less invasive approach to perinatal practice. The study was limited by a small sample, a lack of control group, and the analysis of relative abundance, as opposed to absolute abundance. A larger study is needed to further elucidate the association between lubricant use and vaginal dysbiosis.
Mathematical Model for Tissue-Level Hypoxic Response in Microfluidic Environment
Authors: Morshed Adnan , Dutta Prashanta
Published: September 2017

Availability of essential species like oxygen is critical in shaping the dynamics of tumor growth. When the intracellular oxygen level falls below normal, it initiates major cascades in cellular dynamics leading to tumor cell survival. In a cellular block with cells growing away from the blood vessel, the scenario can be aggravated for the cells further inside the block. In this study, the dynamics of intracellular species inside a colony of tumor cells are investigated by varying the cell-block thickness and cell types in a microfluidic cell culture device. The oxygen transport across the cell block is modeled through diffusion, while ascorbate (AS) transport from the extracellular medium is addressed by a concentration-dependent uptake model. The extracellular and intracellular descriptions were coupled through the consumption and traffic of species from the microchannel to the cell block. Our model shows that the onset of hypoxia is possible in HeLa cell within minutes depending on the cell location, although the nutrient supply inside the channel is maintained in normoxic levels. This eventually leads to total oxygen deprivation inside the cell block in the extreme case, representing the development of a necrotic core that maintains a dynamic balance with growing cells and scarce supply. The numerical model reveals that species concentration and hypoxic response are different for HeLa and HelaS3 cells. Results also indicate that the long-term hypoxic response from a microfluidic cellular block stays within 5% of the values of a tissue with the basal layer. The hybrid model can be very useful in designing microfluidic experiments to satisfactorily predict the tissue-level response in cancer research.
Modeling
the Deformation of the Elastin Network in the Aortic
Valve
Authors: Anssari-Benam Afshin , Bucchi Andrea
Published: September 2017

This paper is concerned with proposing a suitable structurally motivated strain energy function, denoted by Weelastin network, for modeling the deformation of the elastin network within the aortic valve (AV) tissue. The AV elastin network is the main noncollagenous load-bearing component of the valve matrix, and therefore, in the context of continuum-based modeling of the AV, the Weelastin network strain energy function would essentially serve to model the contribution of the “isotropic matrix.” To date, such a function has mainly been considered as either a generic neo-Hookean term or a general exponential function. In this paper, we take advantage of the established structural analogy between the network of elastin chains and the freely jointed molecular chain networks to customize a structurally motivated Weelastin network function on this basis. The ensuing stress–strain (force-stretch) relationships are thus derived and fitted to the experimental data points reported by (Vesely, 1998, “The Role of Elastin in Aortic Valve Mechanics,” J. Biomech., 31, pp. 115–123) for intact AV elastin network specimens under uniaxial tension. The fitting results are then compared with those of the neo-Hookean and the general exponential models, as the frequently used models in the literature, as well as the “Arruda–Boyce” model as the gold standard of the network chain models. It is shown that our proposed Weelastin network function, together with the general exponential and the Arruda–Boyce models provide excellent fits to the data, with R2 values in excess of 0.98, while the neo-Hookean function is entirely inadequate for modeling the AV elastin network. However, the general exponential function may not be amenable to rigorous interpretation, as there is no structural meaning attached to the model. It is also shown that the parameters estimated by the Arruda–Boyce model are not mathematically and structurally valid, despite providing very good fits. We thus conclude that our proposed strain energy function Weelastin network is the preferred choice for modeling the behavior of the AV elastin network and thereby the isotropic matrix. This function may therefore be superimposed onto that of the anisotropic collagen fibers family in order to develop a structurally motivated continuum-based model for the AV.
Primary and Secondary Consequences of Rotator Cuff Injury on Joint Stabilizing Tissues in the Shoulder
Authors: Rahman Hafizur , Currier Eric , Johnson Marshall , Goding Rick , Johnson Amy Wagoner , Kersh Mariana E.
Published: September 2017

Rotator cuff tears (RCTs) are one of the primary causes of shoulder pain and dysfunction in the upper extremity accounting over 4.5 million physician visits per year with 250,000 rotator cuff repairs being performed annually in the U.S. While the tear is often considered an injury to a specific tendon/tendons and consequently treated as such, there are secondary effects of RCTs that may have significant consequences for shoulder function. Specifically, RCTs have been shown to affect the joint cartilage, bone, the ligaments, as well as the remaining intact tendons of the shoulder joint. Injuries associated with the upper extremities account for the largest percent of workplace injuries. Unfortunately, the variable success rate related to RCTs motivates the need for a better understanding of the biomechanical consequences associated with the shoulder injuries. Understanding the timing of the injury and the secondary anatomic consequences that are likely to have occurred are also of great importance in treatment planning because the approach to the treatment algorithm is influenced by the functional and anatomic state of the rotator cuff and the shoulder complex in general. In this review, we summarized the contribution of RCTs to joint stability in terms of both primary (injured tendon) and secondary (remaining tissues) consequences including anatomic changes in the tissues surrounding the affected tendon/tendons. The mechanical basis of normal shoulder joint function depends on the balance between active muscle forces and passive stabilization from the joint surfaces, capsular ligaments, and labrum. Evaluating the role of all tissues working together as a system for maintaining joint stability during function is important to understand the effects of RCT, specifically in the working population, and may provide insight into root causes of shoulder injury.
The Influence of Carrier Air Preheating on Autoignition of Inline-Injected Hydrogen–Nitrogen Mixtures in Vitiated Air of High Temperature
Authors: Schmalhofer Christoph A. , Griebel Peter , Aigner Manfred
Published: September 2017

The use of highly reactive hydrogen-rich fuels in lean premixed combustion systems strongly affects the operability of stationary gas turbines (GT) resulting in higher autoignition and flashback risks. The present study investigates the autoignition behavior and ignition kernel evolution of hydrogen–nitrogen fuel mixtures in an inline co-flow injector configuration at relevant reheat combustor operating conditions. High-speed luminosity and particle image velocimetry (PIV) measurements in an optically accessible reheat combustor are employed. Autoignition and flame stabilization limits strongly depend on temperatures of vitiated air and carrier preheating. Higher hydrogen content significantly promotes the formation and development of different types of autoignition kernels: More autoignition kernels evolve with higher hydrogen content showing the promoting effect of equivalence ratio on local ignition events. Autoignition kernels develop downstream a certain distance from the injector, indicating the influence of ignition delay on kernel development. The development of autoignition kernels is linked to the shear layer development derived from global experimental conditions.