bluuebunny/crossref_metadata_2025 huggingface dataset:
Caenorhabditis elegansnematodes are not attracted to the terrestrial isopodPorcellio scaber
Authors: Archer Heather , Deiparine Selina , Andersen Erik C.
Published: March 2020

Phoresy is a behavior in which an organism, the phoront, travels from one location to another by ‘hitching a ride’ on the body of a host as it disperses. Some phoronts are generalists, taking advantage of any available host. Others are specialists and travel only when specific hosts are located using chemical cues to identify and move (chemotax) toward the preferred host. Free-living nematodes, likeCaenorhabditis elegans, are often found in natural environments that contain terrestrial isopods and other invertebrates. Additionally, theC. eleganswild strain PB306 was isolated associated with the isopodPorcellio scaber. However, it is currently unclear ifC. elegansis a phoront of terrestrial isopods, and if so, whether it is a specialist, generalist, or developmental stage-specific combination of both strategies. Because the relevant chemical stimuli might be secreted compounds or volatile odorants, we used different types of chemotaxis assays across diverse extractions of compounds or odorants to test whetherC. elegansis attracted toP. scaber. We show that two different strains – the wild isolate PB306 and the laboratory-adapted strain N2 – are not attracted toP. scaberduring either the dauer or adult life stages. Our results indicate thatC. eleganswas not attracted to chemical compounds or volatile odorants fromP. scaber, providing valuable empirical evidence to suggest that any associations between these two species are likely opportunistic rather than specific phoresy.
Injectable Nanoelectrodes Enable Wireless Deep Brain Stimulation of Native Tissue in Freely Moving Mice
Authors: Kozielski Kristen L. , Jahanshahi Ali , Gilbert Hunter B. , Yu Yan , Erin Önder , Francisco David , Alosaimi Faisal , Temel Yasin , Sitti Metin
Published: March 2020

Devices that electrically modulate the central nervous system have enabled important breakthroughs in the management of neurological and psychiatric disorders. Such devices typically have centimeter-scale dimensions, requiring surgical implantation and wired-in powering. Using smaller, remotely powered materials could lead to less invasive neuromodulation. Herein, we present injectable magnetoelectric nanoelectrodes that wirelessly transmit electrical signals to the brain in response to an external magnetic field. Importantly, this mechanism of modulation requires no genetic modification of the brain, and allows animals to freely move during stimulation. Using these nanoelectrodes, we demonstrate neuronal modulationin vitroand in deep brain targetsin vivo. We also show that local thalamic modulation promotes modulation in other regions connected via basal ganglia circuitry, leading to behavioral changes in mice. Magnetoelectric materials present a versatile platform technology for less invasive, deep brain neuromodulation.
Assessment of mapping strategies for determining the 5□-end of mRNAs and long-noncoding RNAs with short read sequences
Authors: Noguchi Shuhei , Kawaji Hideya , Kasukawa Takeya
Published: March 2020

Background

Genome mapping is an essential step in data processing for transcriptome analysis, and many previous studies have evaluated various methods and strategies for mapping RNA-seq data. Cap Analysis of Gene Expression (CAGE) is a sequencing-based protocol particularly designed to capture the 5□-ends of transcripts for quantitatively measuring the expression levels of transcription start sites genome-wide. Because CAGE analysis can also predict the activities of promoters and enhancers, this protocol has been an essential tool in studies of transcriptional regulation. Typically, the same mapping software is used to align both RNA-seq data and CAGE reads to a reference genome, but which mapping software and options are most appropriate for mapping the 5□-end sequence reads obtained through CAGE has not previously been evaluated systematically.

Results

Here we assessed various strategies for aligning CAGE reads, particularly ∼50-bp sequences, with the human genome by using the HISAT2, LAST, and STAR programs both with and without a reference transcriptome. One of the major inconsistencies among the tested strategies involves alignments to pseudogenes and parent genes: some of the strategies prioritized alignments with pseudogenes even when the read could be aligned with coding genes with fewer mismatches. Another inconsistency concerned the detection of exon-exon junctions. These preferences depended on the program applied and whether a reference transcriptome was included. Overall, the choice of strategy yielded different mapping results for approximately 2% of all promoters.

Conclusions

Although the various alignment strategies produced very similar results overall, we noted several important and measurable differences. In particular, using the reference transcriptome in STAR yielded alignments with the fewest mismatches. In addition, the inconsistencies among the strategies were especially noticeable regarding alignments to pseudogenes and novel splice junctions. Our results indicate that the choice of alignment strategy is important because it might affect the biological interpretation of the data.
Expression of FoxP2 in the Basal Ganglia Regulates Vocal Motor Sequences in the Adult Songbird
Authors: Xiao Lei , Merullo Devin P. , Cao Mou , Co Marissa , Kulkarni Ashwinikumar , Konopka Genevieve , Roberts Todd F.
Published: March 2020

Disruption of the transcription factor FoxP2, which is enriched in the basal ganglia, impair vocal development in humans and songbirds. The basal ganglia are essential for the selection and sequencing of motor actions, but the circuit mechanisms governing accurate sequencing of learned vocalizations are unknown. Here, we show expression of FoxP2 in the basal ganglia is vital for the fluent initiation and termination of birdsong, and the maintenance of song syllable sequencing in adulthood. Knockdown of FoxP2 imbalances dopamine receptor expression across striatal direct-like and indirect-like pathways, suggesting a role of dopaminergic signaling in regulating vocal-motor sequencing. Confirming this prediction, we show that phasic dopamine activation, and not inhibition, during singing drives repetition of song syllables, thus also impairing fluent initiation and termination of birdsong. These findings demonstrate discrete circuit origins for the dysfluent repetition of vocal elements, a phenotype commonly observed in speech disorders.
Human dorsal anterior cingulate neurons signal conflict by amplifying task-relevant information
Authors: Ebitz R. Becket , Smith Elliot H. , Horga Guillermo , Schevon Catherine A. , Yates Mark J. , McKhann Guy M. , Botvinick Matthew M. , Sheth Sameer A. , Hayden Benjamin Y.
Published: March 2020

Hemodynamic activity in dorsal anterior cingulate cortex (dACC) correlates with conflict, suggesting it contributes to conflict processing. This correlation could be explained by multiple neural processes that can be disambiguated by population firing rates patterns. We usedtargeted dimensionality reductionto characterize activity of populations of single dACC neurons as humans performed a task that manipulates two forms of conflict. Although conflict enhanced firing rates, this enhancement did not come from a discrete population of domain-general conflict-encoding neurons, nor from a distinct conflict-encoding response axis. Nor was it the epiphenomenal consequence of simultaneous coactivation of action plans. Instead, conflict amplified the task-relevant information encoded across the neuronal population. Effects of conflict were weaker and more heterogeneous in the dorsolateral prefrontal cortex (dlPFC), suggesting that dACC’s role in conflict processing may be somewhat specialized. Overall, these results support the theory that conflict biases competition between sensorimotor transformation processes occurring in dACC.
Development of A Novel Highly Selective TLR8 Agonist for Cancer Immunotherapy
Authors: Wang Yuxun , Yang Heping , Li Huanping , Zhao Shuda , Zeng Yikun , Zhang Panpan , Lin Xiaoqin , Sun Xiaoxiang , Wang Longsheng , Fu Guangliang , Gao Yaqiao , Wang Pei , Gao Daxin
Published: March 2020

Toll-like receptors (TLRs) are a family of proteins that recognize pathogen associated molecular patterns (PAMPs). Their primary function is to activate innate immune responses while also involved in facilitating adaptive immune responses. Different TLRs exert distinct functions by activating varied immune cascades. Several TLRs are being pursued as cancer drug targets. We discovered a novel, highly potent and selective small molecule TLR8 agonist DN052. DN052 exhibited strong in vitro cellular activity with EC50 at 6.7 nM and was highly selective for TLR8 over other TLRs including TLR4, 7 and 9. The selectivity profile distinguished DN052 from all other TLR agonists currently in clinical development. DN052 displayed excellent in vitro ADMET and in vivo PK profiles. DN052 potently inhibited tumor growth as a single agent. Moreover, combination of DN052 with the immune checkpoint inhibitor, selected targeted therapeutics or chemotherapeutic drugs further enhanced efficacy of single agents. Mechanistically, treatment with DN052 resulted in strong induction of pro-inflammatory cytokines in ex vivo human PBMC assay and in vivo monkey study. GLP toxicity studies in rats and monkeys demonstrated favorable safety profile. This led to the advancement of DN052 into phase I clinical trials.
Lipid availability influences the metabolic maturation of human pluripotent stem cell-derived cardiomyocytes
Authors: Zhang Hui , Badur Mehmet G. , Spiering Sean , Divakaruni Ajit , Meurs Noah E. , Yu Michael S. , Colas Alexandre R. , Murphy Anne N. , Mercola Mark , Metallo Christian M.
Published: March 2020

Objectives

Pluripotent stem cell-derived cardiomyocytes are phenotypically immature, which limits their utility in downstream applications. Metabolism is dramatically reprogramed during cardiac maturationin vivoand presents a potential avenue to drivein vitromaturation. We aimed to identify and address metabolic bottlenecks in the generation of human pluripotent stem cell (hPSC)-derived cardiomyocytes.

Methods

hPSCs were differentiated into cardiomyocytes using an established, chemically-defined differentiation protocol. We applied 13C metabolic flux analysis (MFA) and targeted transcriptomics to characterize cardiomyocyte metabolism in during differentiation in the presence or absence of exogenous lipids.

Results

hPSC-derived cardiomyocytes induced some cardiometabolic pathways (i.e. ketone body and branched-chain amino acid oxidation) but failed to effectively activate fatty acid oxidation. MFA studies indicated that lipid availability in cultures became limited during differentiation, suggesting potential issues with nutrient availability. Exogenous supplementation of lipids improved cardiomyocyte morphology, mitochondrial function, and promoted increased fatty acid oxidation in hPSC-derivatives.

Conclusion

hPSC-derived cardiomyocytes are dependent upon exogenous sources of lipids for metabolic maturation. Proper supplementation removes a potential roadblock in the generation of metabolically mature cardiomyocytes. These studies further highlight the importance of considering and exploiting metabolic phenotypes in thein vitroproduction and utilization of functional hPSC-derivatives.
Autism-linked gene FoxP1 selectively regulates the cultural transmission of learned vocalizations
Authors: Garcia-Oscos Francisco , Koch Therese , Pancholi Harshida , Trusel Massimo , Daliparthi Vamsi , Ayhan Fatma , Co Marissa , Alam Danyal H. , Holdway Jennifer E. , Konopka Genevieve , Roberts Todd F.
Published: March 2020

Autism spectrum disorders (ASD) are characterized by impaired learning of culturally transmitted behaviors like social skills, speech, and language1–3. These behaviors are learned by copying parents and other social models during development, a two-stage process that involves forming memories of appropriate behaviors during social experiences and then using those memories to guide imitation. How ASD-linked genes impair these often-intertwined aspects of learning is not known, thereby limiting our understanding of the developmental progression of ASD and the targeting of therapeutic interventions. Here we show that these aspects of learning are dissociable and that the ASD-linked geneFoxP1selectively impairs learning from social experience, but not behavioral imitation. Haploinsufficiency ofFOXP1in humans causes FOXP1 syndrome, a neurodevelopmental disorder typified by severe disruptions in speech and language development, and other ASD-associated symptoms4,5. We tested how knockdown ofFoxP1(FP1-KD) affects the cultural transmission of vocal behaviors in zebra finches, a songbird that learns by memorizing and vocally copying the song of an adult ‘song-tutor’. We find that FP1-KD blocks song learning in juvenile birds by selectively impairing their ability to encode a memory during social experiences with a songtutor. These learning deficits are linked to disruptions in experience-driven structural and functional plasticity. However, if birds are exposed to tutor-song prior to FP1-KD, their ability to imitate that song during development is unaffected. Thus, FP1-KD impairs cultural transmission of vocalizations by disrupting the ability to form appropriate vocal memories, yet spares the ability to use previously acquired memories to guide vocal learning. This indicates that learning from social experience may be particularly vulnerable in FOXP1 syndrome.
Biochemical computation underlying behavioral decision-making
Authors: Thornquist Stephen C. , Pitsch Maximilian J. , Auth Charlotte S. , Crickmore Michael A.
Published: March 2020

Computations in the brain are broadly assumed to emerge from patterns of fast electrical activity. Challenging this view, we show that a male fly’s decision to persist in mating, even through a potentially lethal threat, hinges on biochemical computations that enable processing over minutes to hours. Each neuron in a recurrent network measuring time into mating contains slightly different internal molecular estimates of elapsed time. Protein Kinase A (PKA) activity contrasts this internal measurement with input from the other neurons to represent evidence that the network’s goal has been achieved. When consensus is reached, PKA pushes the network toward a large-scale and synchronized burst of calcium influx, which we call an eruption. The eruption functions like an action potential at the level of the network, transforming deliberation within the network into an all-or-nothing output, after which the male will no longer sacrifice his life to continue mating. We detail the continuous transformation between interwoven molecular and electrical information over long timescales in this system, showing how biochemical activity, invisible to most large scale recording techniques, is the key computational currency directing a life-or-death decision.
RRE-Finder: A Genome-Mining Tool for Class-Independent RiPP Discovery
Authors: Kloosterman Alexander M. , Shelton Kyle E. , van Wezel Gilles P. , Medema Marnix H. , Mitchell Douglas A.
Published: March 2020

Nearly half of the classes of natural products known as ribosomally synthesized and post-translationally modified peptides (RiPPs) are reliant on a protein domain called the RiPP recognition element (RRE) for peptide maturation. The RRE binds specifically to a linear precursor peptide and directs the post-translational modification enzymes to their substrate. Given its prevalence across various types of RiPP biosynthetic gene clusters (BGCs), the RRE could theoretically be used as a bioinformatic handle to identify novel classes of RiPPs. In addition, due to the high affinity and specificity of most RRE:precursor peptide complexes, a thorough understanding of the RRE domain could be exploited for biotechnological applications. However, sequence divergence of the RRE domain across RiPP classes has precluded automated identification of RREs based solely on sequence similarity. Here, we introduce RRE-Finder, a novel tool for identifying RRE domains with high sensitivity. RRE-Finder can be used in “precision” mode to confidently identify RREs in a class-specific manner or in “exploratory” mode, which was designed to assist in the discovery of novel RiPP classes. RRE-Finder operating in precision mode on the UniProtKB protein database retrieved over 30,000 high-confidence RREs spanning all characterized RRE-dependent RiPP classes, as well as several yet-uncharacterized RiPP, putatively novel gene cluster architectures that will require future experimental work. Finally, RRE-Finder was used in precision mode to explore a possible evolutionary origin of the RRE domain. Altogether, RRE-Finder provides a powerful new method to probe RiPP biosynthetic diversity and delivers a rich dataset of RRE sequences that will provide a foundation for deeper biochemical studies into this intriguing and versatile protein domain.
Learning to Control the Brain through Adaptive Closed-Loop Patterned Stimulation
Authors: Tafazoli Sina , MacDowell Camden J. , Che Zongda , Letai Katherine C. , Steinhardt Cynthia , Buschman Timothy J.
Published: March 2020

Stimulation of neural activity is an important scientific and clinical tool, causally testing hypotheses and treating neurodegenerative and neuropsychiatric diseases. However, current stimulation approaches cannot flexibly control the pattern of activity in populations of neurons. To address this, we developed an adaptive, closed-loop stimulation (ACLS) system that uses patterned, multi-site electrical stimulation to control the pattern of activity in a population of neurons. Importantly, ACLS is a learning system; it monitors the response to stimulation and iteratively updates the stimulation pattern to produce a specific neural response.In silicoandin vivoexperiments showed ACLS quickly learns to produce specific patterns of neural activity (∼15 minutes) and was robust to noise and drift in neural responses. In visual cortex of awake mice, ACLS learned electrical stimulation patterns that produced responses similar to the natural response evoked by visual stimuli. Similar to how repetition of a visual stimulus causes an adaptation in the neural response, the response to electrical stimulation was adapted when it was preceded by the associated visual stimulus. Altogether, our results show ACLS can learn, in real-time, to generate specific patterns of neural activity, providing a framework for using closed-loop learning to control neural activity.
Unbiased homeologous recombination during pneumococcal transformation allows for multiple chromosomal integration events
Authors: Kurushima Jun , Campo Nathalie , van Raaphorst Renske , Cerckel Guillaume , Polard Patrice , Veening Jan-Willem
Published: March 2020

The rapid spread of antimicrobial resistance and vaccine escape in the opportunistic human pathogenStreptococcus pneumoniaecan be largely attributed to competence-induced transformation. To better understand the dynamics of competence-induced transformation, we studied this process at the single-cell level. We show that within isogenic populations, all cells become naturally competent and bind exogenous DNA. In addition, we find that transformation is highly efficient and that the chromosomal location of the integration site or whether the transformed gene is encoded on the leading or lagging strand has limited influence on recombination efficiency. Indeed, we have observed multiple recombination events in single recipients in real-time. However, because of saturation of the DNA uptake and integration machinery and because a single stranded donor DNA replaces the original allele, we find that transformation efficiency has an upper threshold of approximately 50% of the population. Counterintuitively, in the presence of multiple transforming DNAs, the fraction of untransformed cells increases to more than 50%. The fixed mechanism of transformation results in a fail-safe strategy for the population as half of the population generally keeps an intact copy of the original genome. Together, this work advances our understanding of pneumococcal genome plasticity.
Distinctive Gene and Protein Characteristics of Extremely PiezophilicColwellia
Authors: Peoples Logan M. , Kyaw Than S. , Ugalde Juan A. , Mullane Kelli K. , Chastain Roger A. , Yayanos A. Aristides , Kusube Masataka , Methé Barbara A. , Bartlett Douglas H.
Published: March 2020

Background

The deep ocean is characterized by low temperatures, high hydrostatic pressures, and low concentrations of organic matter. While these conditions likely select for distinct genomic characteristics within prokaryotes, the attributes facilitating adaptation to the deep ocean are relatively unexplored. In this study, we compared the genomes of seven strains within the genusColwellia, including some of the most piezophilic microbes known, to identify genomic features that enable life in the deep sea.

Results

Significant differences were found to exist between piezophilic and non-piezophilic strains ofColwellia. PiezophilicColwelliahave a more basic and hydrophobic proteome. The piezophilic abyssal and hadal isolates have more genes involved in replication/recombination/repair, cell wall/membrane biogenesis, and cell motility. The characteristics of respiration, pilus generation, and membrane fluidity adjustment vary between the strains, with operons for anuodehydrogenase and atadpilus only present in the piezophiles. In contrast, the piezosensitive members are unique in having the capacity for dissimilatory nitrite and TMAO reduction. A number of genes exist only within deep-sea adapted species, such as those encoding d-alanine-d-alanine ligase for peptidoglycan formation, alanine dehydrogenase for NADH/NAD+homeostasis, and archaeal methyltransferase for tRNA modification. Many of these piezophile-specific genes are in variable regions of the genome near genomic islands, transposases, and toxin-antitoxin systems.

Conclusions

We identified a number of adaptations that may facilitate deep-sea radiation in members of the genusColwellia,as well as in other piezophilic bacteria. An enrichment in more basic and hydrophobic amino acids could help piezophiles stabilize and limit water intrusion into proteins as a result of high pressure. Variations in genes associated with the membrane, including those involved in unsaturated fatty acid production and respiration, indicate that membrane-based adaptations are critical for coping with high pressure. The presence of many piezophile-specific genes near genomic islands highlights that adaptation to the deep ocean may be facilitated by horizontal gene transfer through transposases or other mobile elements. Some of these genes are amenable to further study in genetically tractable piezophilic and piezotolerant deep-sea microorganisms.
PsiCLIP reveals dynamic RNA binding by DEAH-box helicases before and after exon ligation
Authors: Strittmatter Lisa M. , Capitanchik Charlotte , Newman Andrew J. , Hallegger Martina , Norman Christine M. , Fica Sebastian M. , Oubridge Chris , Luscombe Nicholas M. , Ule Jernej , Nagai Kiyoshi
Published: March 2020

Eight RNA helicases remodel the spliceosome to effect pre-mRNA splicing but their mechanism of action remains poorly understood. We have developed “purified spliceosome iCLIP” (psiCLIP) to define helicase-RNA contacts in specific spliceosomal states. psiCLIP reveals previously unappreciated dynamics of spliceosomal helicases. The binding profile of the helicase Prp16 is influenced by the distance between the branch-point and 3’ splice site, while Prp22 binds diffusely on the intron before exon ligation but switches to more narrow binding downstream of the exon junction after exon ligation. Notably, depletion of the exon-ligation factor Prp18 destabilizes Prp22 binding to the pre-mRNA, demonstrating that psiCLIP can be used to study the relationships between helicases and auxiliary splicing factors. Thus, psiCLIP is sensitive to spliceosome dynamics and complements the insights from structural and imaging studies by providing crucial positional information on helicase-RNA contacts during spliceosomal remodeling.
Alzheimer’s disease brain-derived tau-containing extracellular vesicles: Pathobiology and GABAergic neuronal transmission
Authors: Ruan Zhi , Pathak Dhruba , Kalavai Srinidhi Venkatesan , Yoshii-Kitahara Asuka , Muraoka Satoshi , Takamatsu-Yukawa Kayo , Bhatt Nemil , Hu Jianqiao , Wang Yuzhi , Hersh Samuel , Gorantla Santhi , Kayed Rakez , Gendelman Howard E. , Ikezu Seiko , Luebke Jennifer I. , Ikezu Tsuneya
Published: March 2020

Extracellular vesicles (EVs) propagate tau pathology for Alzheimer’s disease (AD). How EV transmission influences AD are, nonetheless, poorly understood. To these ends, the physicochemical and molecular structure-function relationships of human brain-derived EVs, from AD and prodromal AD (pAD), were compared to non-demented controls (CTRL). AD EVs were shown to be significantly enriched in epitope-specific tau oligomers versus pAD or CTRL EVs assayed by dot-blot and atomic force microscopy tests. AD EVs were efficiently internalized by murine cortical neurons and transferred tau with higher aggregation potency than pAD and CTRL EVs. Strikingly, inoculation of tau-containing AD EVs into the outer molecular layer of the dentate gyrus induced tau propagation throughout the hippocampus. This was seen in 22 months-old C57BL/6 mice at 4.5 months post-injection by semiquantitative brain-wide immunohistochemistry tests with multiple anti-phospho-tau (p-tau) antibodies. Inoculation of the equal amount of tau from CTRL EVs or as oligomer or fibril-enriched fraction from the same AD donor showed little propagation. AD EVs induced tau accumulation in the hippocampus as oligomers or sarkosyl-insoluble proteins. Unexpectedly, p-tau cells were mostly GAD67+ GABAergic neurons and to a lesser extent, GluR2/3+ excitatory mossy cells, showing preferential EV-mediated GABAergic neuronal tau propagation. Whole-cell patch clamp recording of Cornu Ammonis (CA1) pyramidal cells showed significant reduction in the amplitude of spontaneous inhibitory post-synaptic currents. This was accompanied by reductions in c-fos+ GAD67+GABAergic neurons and GAD67+ GABAergic neuronal puncta surrounding pyramidal neurons in the CA1 region confirming reduced interneuronal projections. Our study posits a novel tau-associated pathological mechanism for brain-derived EVs.
Two antagonistic effect genes mediate separation of sexes in a fully dioecious plant
Authors: Xue Liangjiao , Wu Huaitong , Chen Yingnan , Li Xiaoping , Hou Jing , Lu Jing , Wei Suyun , Dai Xiaogang , Olson Matthew S. , Liu Jianquan , Wang Mingxiu , Charlesworth Deborah , Yin Tongming
Published: March 2020

Plant sex determining systems and sex chromosomes are often evolutionarily young. Here, we present the early stage of sex chromosome in a fully dioecious plant,P. deltoides, by determining separate sequences of the physically small X- and Y-linked regions. Intriguingly, two Y genes are absent from the X counterpart. One gene represses female structures by producing siRNAs that block expression of a gene necessary for development of female structures, via RNA-directed DNA methylation and siRNA-guided mRNA cleavage. The other gene generates long non-coding RNA transcripts that, in males, soak up miRNAs that specifically inhibit androecium development. Transformation experiments inArabidopsis thalianashow that the two genes affect gynoecium and androecium development independently and antagonistically. Sex determination in the poplar therefore has the properties proposed for the first steps in the evolution of dioecy in flowering plants, with two genes whose joint effects favor close linkage, as is observed in poplar.
A novel neural stem cell-derived immunocompetent mouse model of glioblastoma for preclinical studies
Authors: Costa Barbara , Fletcher Michael , Boskovic Pavle , Ivanova Ekaterina L. , Eisemann Tanja , Lohr Sabrina , Bunse Lukas , Löwer Martin , Burchard Stefanie , Korshunov Andrey , Liu Hai-Kun , Platten Michael , Radlwimmer Bernhard , Angel Peter , Peterziel Heike
Published: March 2020

Glioblastomas are the most lethal tumors affecting the central nervous system in adults. Simple and inexpensive syngeneicin vivomodels that closely mirror human glioblastoma, including interactions between tumor and immune cells, are urgently needed for deciphering glioma biology and developing more effective treatments. Here, we generated glioblastoma cell lines by repeatedin-vivopassaging of cells isolated from a neural stem cell-specific Pten/p53 double-knockout genetic mouse brain tumor model. Transcriptome and genome analyses of the cell lines revealed molecular heterogeneity comparable to that observed in human glioblastoma. Upon orthotopic transplantation into syngeneic hosts they formed high-grade gliomas that faithfully recapitulated the histopathological features, invasiveness and myeloid cell infiltration characteristic of human glioblastoma. These features make our cell lines unique and useful tools to study multiple aspects of glioblastoma pathomechanism and test novel treatments, especially immunotherapies in syngeneic preclinical models.
Asymmetric chromosome segregation and cell division in DNA damage-induced bacterial filaments
Authors: Raghunathan Suchitha , Chimthanawala Afroze , Krishna Sandeep , Vecchiarelli Anthony G. , Badrinarayanan Anjana
Published: March 2020

Faithful propagation of life requires coordination of DNA replication and segregation with cell growth and division. In bacteria, this results in cell size homeostasis and periodicity in replication and division. The situation is perturbed under stress such as DNA damage, which induces filamentation as cell cycle progression is blocked to allow for repair. Mechanisms that release this morphological state for re-entry into wild type growth are unclear. Here we show that damage recovery is mediated via asymmetric division ofEscherichia colifilaments, producing short daughter cells with wild type size and growth dynamics. Division restoration at this polar site is governed by coordinated action of divisome positioning by the Min system and modulation of division licensing by theterminusregion of the chromosome, with MatP playing a central role in this process. Collectively, our study highlights a key role for concurrency between chromosome (and specificallyterminus)segregation and cell division in daughter cell size maintenance during filamentous divisions and suggests a central function for asymmetric division in mediating cellular recovery from a stressed state.
Identification of FMR1-regulated molecular networks in human neurodevelopment
Authors: Li Meng , Shin Junha , Risgaard Ryan D. , Parries Molly J. , Wang Jianyi , Chasman Deborah , Liu Shuang , Roy Sushmita , Bhattacharyya Anita , Zhao Xinyu
Published: March 2020

RNA-binding proteins (RNA-BPs) play critical roles in development and disease to regulate gene expression. However, genome-wide identification of their targets in primary human cells has been challenging. Here, we applied a modified CLIP-seq strategy to identify genome-wide targets of the FMRP translational regulator 1 (FMR1), a brain-enriched RNA-BP, whose deficiency leads to Fragile X Syndrome (FXS), the most prevalent inherited intellectual disability. We identified FMR1 targets in human dorsal and ventral forebrain neural progenitors and excitatory and inhibitory neurons differentiated from human pluripotent stem cells. In parallel, we measured the transcriptomes of the same four cell types upon FMR1 gene deletion. We discovered that FMR1 preferentially binds long transcripts in human neural cells. FMR1 targets include genes unique to human neural cells and associated with clinical phenotypes of FXS and autism. Integrative network analysis using graph diffusion and multitask clustering of FMR1 CLIP-seq and transcriptional targets reveals critical pathways regulated by FMR1 in human neural development. Our results demonstrate that FMR1 regulates a common set of targets among different neural cell types but also operates in a cell type–specific manner targeting distinct sets of genes in human excitatory and inhibitory neural progenitors and neurons. By defining molecular subnetworks and validating specific high-priority genes, we identify novel components of the FMR1 regulation program. Our results provide new insights into gene regulation by a critical neuronal RNA-BP in human neurodevelopment.
Integrated annotations and analyses of small RNA–producing loci from 47 diverse plants
Authors: Lunardon Alice , Johnson Nathan R. , Hagerott Emily , Phifer Tamia , Polydore Seth , Coruh Ceyda , Axtell Michael J.
Published: March 2020

Plant endogenous small RNAs (sRNAs) are important regulators of gene expression. There are two broad categories of plant sRNAs: microRNAs (miRNAs) and endogenous short interfering RNAs (siRNAs). MicroRNA loci are relatively well-annotated but compose only a small minority of the total sRNA pool; siRNA locus annotations have lagged far behind. Here, we used a large data set of published and newly generated sRNA sequencing data (1333 sRNA-seq libraries containing more than 20 billion reads) and a uniform bioinformatic pipeline to produce comprehensive sRNA locus annotations of 47 diverse plants, yielding more than 2.7 million sRNA loci. The two most numerous classes of siRNA loci produced mainly 24- and 21-nucleotide (nt) siRNAs, respectively. Most often, 24-nt-dominated siRNA loci occurred in intergenic regions, especially at the 5′-flanking regions of protein-coding genes. In contrast, 21-nt-dominated siRNA loci were most often derived from double-stranded RNA precursors copied from spliced mRNAs. Genic 21-nt-dominated loci were especially common from disease resistance genes, including from a large number of monocots. Individual siRNA sequences of all types showed very little conservation across species, whereas mature miRNAs were more likely to be conserved. We developed a web server where our data and several search and analysis tools are freely accessible.
Odor modulates the temporal dynamics of fear memory consolidation
Authors: Grella Stephanie L. , Fortin Amanda H. , McKissick Olivia , Leblanc Heloise , Ramirez Steve
Published: March 2020

Systems consolidation (SC) theory proposes that recent, contextually rich memories are stored in the hippocampus (HPC). As these memories become remote, they are believed to rely more heavily on cortical structures within the prefrontal cortex (PFC), where they lose much of their contextual detail and become schematized. Odor is a particularly evocative cue for intense remote memory recall and despite these memories being remote, they are highly contextual. In instances such as posttraumatic stress disorder (PTSD), intense remote memory recall can occur years after trauma, which seemingly contradicts SC. We hypothesized that odor may shift the organization of salient or fearful memories such that when paired with an odor at the time of encoding, they are delayed in the de-contextualization process that occurs across time, and retrieval may still rely on the HPC, where memories are imbued with contextually rich information, even at remote time points. We investigated this by tagging odor- and non-odor-associated fear memories in male c57BL/6 mice and assessed recall and c-Fos expression in the dorsal CA1 (dCA1) and prelimbic cortex (PL) 1 or 21 d later. In support of SC, our data showed that recent memories were more dCA1-dependent whereas remote memories were more PL-dependent. However, we also found that odor influenced this temporal dynamic, biasing the memory system from the PL to the dCA1 when odor cues were present. Behaviorally, inhibiting the dCA1 with activity-dependent DREADDs had no effect on recall at 1 d and unexpectedly caused an increase in freezing at 21 d. Together, these findings demonstrate that odor can shift the organization of fear memories at the systems level.
Sleep deprivation induces fragmented memory loss
Authors: Ashton Jennifer E. , Harrington Marcus O. , Langthorne Diane , Ngo Hong-Viet V. , Cairney Scott A.
Published: March 2020

Sleep deprivation increases rates of forgetting in episodic memory. Yet, whether an extended lack of sleep alters the qualitative nature of forgetting is unknown. We compared forgetting of episodic memories across intervals of overnight sleep, daytime wakefulness, and overnight sleep deprivation. Item-level forgetting was amplified across daytime wakefulness and overnight sleep deprivation, as compared to sleep. Importantly, however, overnight sleep deprivation led to a further deficit in associative memory that was not observed after daytime wakefulness. These findings suggest that sleep deprivation induces fragmentation among item memories and their associations, altering the qualitative nature of episodic forgetting.
Sign-tracking behavior is sensitive to outcome devaluation in a devaluation context-dependent manner: implications for analyzing habitual behavior
Authors: Amaya Kenneth A. , Stott Jeffrey J. , Smith Kyle S.
Published: March 2020

Motivationally attractive cues can draw in behavior in a phenomenon termed incentive salience. Incentive cue attraction is an important model for animal models of drug seeking and relapse. One question of interest is the extent to which the pursuit of motivationally attractive cues is related to the value of the paired outcome or can become unrelated and habitual. We studied this question using a sign-tracking (ST) paradigm in rats, in which a lever stimulus preceding food reward comes to elicit conditioned lever-interaction behavior. We asked whether reinforcer devaluation by means of conditioned taste aversion, a classic test of habitual behavior, can modify ST to incentive cues, and whether this depends upon the manner in which reinforcer devaluation takes place. In contrast to several recent reports, we conclude that ST is indeed sensitive to reinforcer devaluation. However, this effect depends critically upon the congruence between the context in which taste aversion is learned and the context in which it is tested. When the taste aversion successfully transfers to the testing context, outcome value strongly influences ST behavior, both when the outcome is withheld (in extinction) and when animals can learn from outcome feedback (reacquisition). When taste aversion does not transfer to the testing context, ST remains high. In total, the extent to which ST persists after outcome devaluation is closely related to the extent to which that outcome is truly devalued in the task context. We believe this effect of context on devaluation can reconcile contradictory findings about the flexibility/inflexibility of ST. We discuss this literature and relate our findings to the study of habits generally.
A measurement method of free-form tube based on multi-view vision for industrial assembly
Authors: Wu Tianyi , Liu Jian Hua , Liu Shaoli , Jin Peng , Huang Hao , Liu Wei
Published: March 2020

Purpose

This paper aims to solve the problem of free-form tubes’ machining errors which are caused by their complex geometries and material properties.

Design/methodology/approach

In this paper, the authors propose a multi-view vision-based method for measuring free-form tubes. The authors apply photogrammetry theory to construct the initial model and then optimize the model using an energy function. The energy function is based on the features of the image of the tube. Solving the energy function allows to use the gray features of the images to reconstruct centerline point clouds and thus obtain the pertinent geometric parameters.

Findings

According to the experiments, the measurement process takes less than 2 min and the precision of the proposed system is 0.2 mm. The authors used simple operations to carry out the measurements, and the process is fully automatic.

Originality/value

This paper proposes a method for measuring free-form tubes based on multi-view vision, which has not been attempted to the best of authors’ knowledge. This method differs from traditional multi-view vision measurement methods, because it does not rely on the data of the design model of the tube. The application of the energy function also avoids the problem of matching corresponding points and thus simplifying the calculation and improving its stability.
Development of low glycemic index crackers from water chestnut and barley flour
Authors: Hussain Syed Zameer , Beigh Mushtaq , Qadri Tahiya , Ahmad Imtiyaz , Naseer Bazila
Published: March 2020

Purpose

The purpose of the present study was to develop low Glycemic Index (GI) crackers from water chestnut flour (WCF) and barley flour (BF).

Design/methodology/approach

Five blends were prepared by mixing WCF with BF in the proportion of 100:0, 70:30, 50:50, 30:70 and 0:100, respectively. The baking process as well as ingredients were modified for the production of low GI crackers.

Findings

BF incorporation had significant (p < 0.05) effect on physical characteristics, organoleptic attributes and glycemic response of crackers. The resistant starch content of final product was found to be higher than WCF and BF. The research confirmed that replacement of 30 percent WCF with BF is feasible for development of low GI crackers with desired sensory attributes. The inference drawn from storage studies was that the developed crackers can be stored safely (with an overall acceptability score of greater than three on a 5-point scale) in metallized polyethylene up to 35 days under refrigerated conditions and 28 days under ambient conditions.

Research limitations/implications

Although low GI crackers were developed successfully from WCF and BF in the present study. However, detailed storage studies of such crackers can be done in future so as to perform the tests of type-intensity and temporal dominance of sensation. Also, in view of their low GI, these crops need to be evaluated in future for development of other bakery products like bread, cake, muffins, etc.

Practical implications

Water chestnut and barley despite having good nutritional profile and low GI are still considered as underutilized crops. In the present study, these crops were explored for development of low GI crackers especially for people suffering from diabetes. The outcome of this study will open up a new window in the baking sector to develop low GI crackers viz-a-viz will add value to these crops which will help to provide remunerative returns to those who are directly or indirectly involved in trade of these underutilized crops.

Originality/value

This was the first reported innovative attempt to develop low GI crackers from WCF and BF. For development of crackers having desired sensory characteristics, it was found feasible to blend WCF and BF in the ratio of 70:30.
Natural convection of a nanofluid-filled circular enclosure partially saturated with a porous medium using ISPH method
Authors: Aly Abdelraheem M.
Published: March 2020

Purpose

The purpose of this study is to simulate the natural convection of a heated square shape embedded in a circular enclosure filled with nanofluid using an incompressible smoothed particle hydrodynamics (ISPH) method.

Design/methodology/approach

In the ISPH method, the evaluated pressure was stabilized by using a modified source term in solving the pressure Poisson equation. The divergence of the velocity was corrected, and the dummy particles were used to treat the rigid boundary. Dummy wall particles were initially settled in outer layers of the circular enclosure for preventing particle penetration and reducing the error of truncated kernel. The circular enclosure was partially filled with a porous medium near to the outer region. The single-phase model was used for the nanofluid, and the Brinkman–Forchheimer-extended Darcy model was used for the porous medium. Dummy wall particles were initially settled in outer layers of circular enclosure for preventing particle penetration and reducing error from the truncated kernel on the boundary.

Findings

The length of the inner square shape plays an important role in enhancing the heat transfer and reducing the fluid flow inside a circular enclosure. The porous layer represents a resistance force for the fluid flow and heat transfer, and, consequently, the velocity field and temperature distributions are reduced at the outer region of the circular cylinder. Then, the radius of the inner square shape, Darcy parameter and radius of the porous layer were considered the main factors for controlling the fluid flow and heat transfer inside a circular enclosure. The average Nusselt number decreases as the inner square length, radius of the porous layer and solid volume fraction increase.

Originality/value

The stabilized ISPH method is corrected for simulating the natural convection from an inner hot square inside a nanofluid-filled circular enclosure saturated with a partial layer of a porous medium.
Does advertising really work?
Authors: Wu Keke , Yu Yan , Dong Dayong
Published: March 2020

Purpose

This paper aims to examine the direct and indirect effects of advertising on investor behavior.

Design/methodology/approach

The authors use a novel and direct measure of investor attention: the number of investors whose watch lists has the stock.

Findings

The authors find that beyond its direct effect through information dissemination, advertising has an indirect effect with regard to grabbing investor attention and the trading response. The authors further find that an increase in attention induces a positive influence on the impact of advertising on investor behavior.

Originality/value

First, it complements studies of home bias, in which investors are more likely to buy familiar stocks. Second, it also complements the literature on advertising and investor attention and on attention and capital markets. Third, with a new and unambiguous measure of investor attention. Fourth, combining the direct and indirect aspects, this study presents a detailed description of the financial market effect of advertising.
Determinants of homeownership in Europe – an empirical analysis based on SHARE
Authors: Garcia Maria Teresa Medeiros , Figueira Rafael
Published: March 2020

Purpose

The purpose of this paper is to explore the determinants of homeownership in Europe.

Design/methodology/approach

In this study, a logit model that predicts whether an individual is a homeowner or not was estimated. Wave 6 (2015) from the Survey of Health, Ageing and Retirement in Europe was used, through a sample of 46,003 respondents across all Europe and through four subsamples (Eastern, Southern, Northern and Western Europe).

Findings

The findings reveal that several factors influence homeownership, namely, geographic location, age, gender, number of children, marital status, job situation, household income, high education, years of education, political orientation and holding bonds, stocks, mutual funds, bank accounts, saving accounts, individual retirement account or life insurance. Different results were obtained when the four subsamples were considered.

Research limitations/implications

The research findings provide an attempt to disentangle the main factors influencing homeownership. However, only individuals above 50 years of age were considered because of the database characteristics.

Practical implications

This paper provided insights to consider public policies that try to increase homeownership rates.

Social implications

The results put in evidence the likelihood characteristics of a homeowner. Therefore, public policies should address those who do not fulfill those when promoting higher homeownership rates. For example, attention should be given to low and middle-income individuals.

Originality/value

The paper emphasised the characteristics of a homeowner in Europe, contributing to the discussion on this topic among policymakers, practitioners and researchers in Europe.