bluuebunny/crossref_metadata_2025 huggingface dataset:
A unique conformational escape reaction of HIV-1 against an allosteric integrase inhibitor
Authors: Nakamura Tomofumi , Nakamura Teruya , Amano Masayuki , Miyakawa Toshikazu , Yamagata Yuriko , Matsuoka Masao , Nakata Hirotomo
Published: November 2019

HIV-1 integrase (IN) contributes to HIV-1 RNA binding, which is required for viral maturation. Non-catalytic site integrase inhibitors (NCINIs) have been developed as allosteric IN inhibitors, which perform anti-HIV-1 activity by disrupting IN multimerization. Here, we show that IN undergoes a novel conformational alteration to escape from NCINIs. We observed that NCINI-resistant HIV-1 variants have accumulated amino acid (AA) mutations in the IN-encoding region. We employed HPLC and thermal stability assays to show that the AA mutations affect the folding and dimerization interface of the IN catalytic core domains, resulting in severely decreased multimerization of full-length IN proteins (IN under-multimerization). The under-multimerization of IN was finally restored by HIV-1 RNA in the viral particles. Our study demonstrates that HIV-1 countervails NCINIs by IN under-multimerization as a novel escape mechanism. Our findings provide information on the understanding of IN multimerization and influence the development of unique anti-HIV-1 strategies.
The efficacy of obesity polygenic risk scores in an autistic population
Authors: Zhang David Y. , Palmer Nathan P. , Hong Chuan , Zhang Luwan , Finlayson Samuel G. , Avillach Paul , Kohane Isaac S.
Published: November 2019

Polygenic risk scores (PRS) bear great promise in understanding complex diseases and improving clinical diagnoses, but the competency of these risk scores in different populations is known to vary significantly, especially between those of European ancestry and those of other ethnic ancestries. Additionally, the applicability of these risk scores across populations different by disease, instead of ethnicity, is poorly understood. A current and largely unexplored population for the accuracy of PRS is that of individuals with autism. Combined with the increased prevalence of obesity in autistic populations, we seek to evaluate the difference in efficacy of PRS for obesity in autistic versus non-autistic populations. We show that genetic variants strongly associated with obesity in non-autistic populations are significantly less representative of the disease in autistic populations. Rather, these cases of obesity phenocopies in patients with autism may follow a different and non-conventional mechanism of action involving the regulation of oxytocin in the brain among other potential behavioral factors. Our findings elucidate the limits of PRS across populations contrasting by disease and suggest that obesity may be regulated differently in individuals with autism as compared to those without autism.
A novel dynamic network imaging analysis method reveals aging-related fragmentation of cortical networks in mouse
Authors: Llano Daniel A , Ma Chihua , Di Fabrizio Umberto , Taheri Aynaz , Stebbings Kevin A. , Yudintsev Georgiy , Xiao Gang , Kenyon Robert V. , Berger-Wolf Tanya Y.
Published: November 2019

Network analysis of large-scale neuroimaging data has proven to be a particularly challenging computational problem. In this study, we adapt a novel analytical tool, known as the community dynamic inference method (CommDy), which was inspired by social network theory, for the study of brain imaging data from an aging mouse model. CommDy has been successfully used in other domains in biology; this report represents its first use in neuroscience. We used CommDy to investigate aging-related changes in network parameters in the auditory and motor cortices using flavoprotein autofluorescence imaging in brain slices andin vivo. Analysis of spontaneous activations in the auditory cortex of slices taken from young and aged animals demonstrated that cortical networks in aged brains were highly fragmented compared to networks observed in young animals. Specifically, the degree of connectivity of each activated node in the aged brains was significantly lower than those seen in the young brain, and multivariate analyses of all derived network metrics showed distinct clusters of these metrics in young vs. aged brains. CommDy network metrics were then used to build a random-forests classifier based on NMDA-receptor blockade data, which successfully recapitulated the aging findings, suggesting that the excitatory synaptic substructure of the auditory cortex may be altered during aging. A similar aging-related decline in network connectivity was also observed in spontaneous activity obtained from the awake motor cortex, suggesting that the findings in the auditory cortex are reflections of general mechanisms that occur during aging. Therefore, CommDy therefore provides a new dynamic network analytical tool to study the brain and provides links between network-level and synaptic-level dysfunction in the aging brain.
Integrative nascent RNA methods to reveal cell-type specific transcription programs in peripheral blood and its derivative cells
Authors: Kim Samantha Sae-Young , Kim Eunyoo , Kimm Aileen Kang , Kwak Hojoong
Published: November 2019

Nascent RNA sequencing is a powerful method to measure transcription with high resolution, sensitivity, and directional information, which gives distinctive information about transcription from other methods such as chromatin immunoprecipitation or mRNA sequencing. We present an integrated package of nascent RNA-seq methods - ultrafast Precision Run On (uPRO) combined with computational procedures to discover cell type specific enhancers, promoters, and transcription factor networks. uPRO is composed of adaptor ligation and reverse transcription reactions, which is reduced to a one-day procedure and makes nascent RNA-seq more feasible and flexible for a widespread use. We generated genome-wide profiles of nascent transcription in human blood derived cell lines and clinical samples of ~1 ml of untreated whole blood. We integrated these data into deep learning and hierarchical network analysis to detect enhancers, promoters, and co-expression networks to define cell-type specific transcription programs. We found conservation of position but variation of expression in cell type specific enhancers and transcription start sites. Transcription factors (TFs) such as TCF-3 and OCT1 were pivotally associated with TF-enhancer-gene networks across cell types. Intriguingly, we also discovered that TFs related to cell stress and inflammation - such as SRF, ATF, CHOP, and NF-kB - are associated with inter-individual variation of leukocyte transcription in whole blood. Our integration of experimental and computational nascent RNA methods will provide an efficient strategy to identify specific transcriptional programs, both in cell-type and patient/disease-associated, with minimal sample requirements.
Six new reference-quality bat genomes illuminate the molecular basis and evolution of bat adaptations
Authors: Jebb David , Huang Zixia , Pippel Martin , Hughes Graham M. , Lavrichenko Ksenia , Devanna Paolo , Winkler Sylke , Jermiin Lars S. , Skirmuntt Emilia C. , Katzourakis Aris , Burkitt-Gray Lucy , Ray David A. , Sullivan Kevin A. M. , Roscito Juliana G. , Kirilenko Bogdan M. , Dávalos Liliana M. , Corthals Angelique P. , Power Megan L. , Jones Gareth , Ransome Roger D. , Dechmann Dina , Locatelli Andrea G. , Puechmaille Sebastien J. , Fedrigo Olivier , Jarvis Erich D. , Springer Mark S. , Hiller Michael , Vernes Sonja C. , Myers Eugene W. , Teeling Emma C.
Published: November 2019

Bats account for ~20% of all extant mammal species and are considered exceptional given their extraordinary adaptations, including biosonar, true flight, extreme longevity, and unparalleled immune systems. To understand these adaptations, we generated reference-quality genomes of six species representing the key divergent lineages. We assembled these genomes with a novel pipeline incorporating state-of-the-art long-read and long-range sequencing and assembly techniques. The genomes were annotated using a maximal evidence approach, de novo predictions, protein/mRNA alignments, Iso-seq long read and RNA-seq short read transcripts, and gene projections from our new TOGA pipeline, retrieving virtually all (>99%) mammalian BUSCO genes. Phylogenetic analyses of 12,931 protein coding-genes and 10,857 conserved non-coding elements identified across 48 mammalian genomes helped to resolve bats’ closest extant relatives within Laurasiatheria, supporting a basal position for bats within Scrotifera. Genome-wide screens along the bat ancestral branch revealed (a) selection on hearing-involved genes (e.g LRP2, SERPINB6, TJP2), which suggest that laryngeal echolocation is a shared ancestral trait of bats; (b) selection (e.g INAVA, CXCL13, NPSR1) and loss of immunity related proteins (e.g. LRRC70, IL36G), including pro-inflammatory NF-kB signalling; and (c) expansion of the APOBEC family, associated with restricting viral infection, transposon activity and interferon signalling. We also identified unique integrated viruses, indicating that bats have a history of tolerating viral pathogens, lethal to other mammal species. Non-coding RNA analyses identified variant and novel microRNAs, revealing regulatory relationships that may contribute to phenotypic diversity in bats. Together, our reference-quality genomes, high-quality annotations, genome-wide screens and in-vitro tests revealed previously unknown genomic adaptations in bats that may explain their extraordinary traits.
Complete genome assembly of theWolbachiaendosymbiont of the horn flyHaematobia irritans irritans:a supergroup A strain with multiple horizontally acquired cytoplasmic incompatibility genes
Authors: Madhav Mukund , Parry Rhys , Morgan Jess A.T. , James Peter , Asgari Sassan
Published: November 2019

The horn fly,Haematobia irritans irritans, is a hematophagous parasite of livestock distributed throughout Europe, Africa, Asia, and the Americas. Welfare losses on livestock due to horn fly infestation are estimated to cost between USD 1-2.5 billion annually in North America and Brazil. The endosymbiotic bacteriumWolbachia pipientisis a maternally inherited manipulator of reproductive biology in arthropods and naturally infects laboratory colonies of horn flies from Kerrville, USA and Alberta, Canada, but has also been identified in wild-caught samples from Canada, USA, Mexico and Hungary. Reassembly of PacBio long-read and Illumina genomic DNA libraries from the KerrvilleH. i. irritansgenome project allowed for a complete and circularised 1.3 MbWolbachiagenome (wHae). Annotation ofwHae yielded 1249 coding genes, 34 tRNAs, three rRNAs, and five prophage regions. Comparative genomics and whole genome Bayesian evolutionary analysis ofwHae compared to publishedWolbachiagenomes suggests thatwHae is most closely related to and diverged fromWolbachiasupergroup A strains known to infectDrosophilaspp. Whole-genome synteny analyses betweenwHae and closely related genomes indicates thatwHae has undergone convoluted genome rearrangements while maintaining high nucleotide identity. Comparative analysis of the cytoplasmic incompatibility (CI) genes ofwHae suggests two phylogenetically distinct CI loci and acquisition of anotherCifBhomolog from phylogenetically distant supergroup AWolbachiastrains suggesting horizontal acquisition of these loci. ThewHae genome provides a resource for future examination of the impactWolbachiamay have in both biocontrol and potential insecticide resistance of horn flies.

Importance

Horn flies,Haematobia irritans, are obligate hematophagous parasites of cattle having significant effects on production and animal welfare. Control of horn flies mainly relies on the use of insecticides, but issues with resistance have increased interest in development of alternative means of control.Wolbachia pipientisis an endosymbiont bacterium known to have a range of effects on host reproduction such as induction of cytoplasmic incompatibility, feminization, male killing, and also impacts on vector transmission. These characteristics ofWolbachiahave been exploited in biological control approaches for a range of insect pests. Here we report the assembly and annotation of the circular genome of theWolbachiastrain of the Kerrickville, USA horn fly (wHae). Annotation ofwHae suggests its unique features including the horizontal acquisition of additional transcriptionally active cytoplasmic incompatibility loci. This study will provide the foundation for futureWolbachia-induced biological effect studies for control of horn flies.
Brain Antibody Sequence Evaluation (BASE): an easy-to-use software for complete data analysis in single cell immunoglobulin cloning
Authors: Reincke S. Momsen , Prüss Harald , Kreye Jakob
Published: November 2019

Background

Repertoire analysis of patient-derived recombinant monoclonal antibodies is an important tool to study the role of B cells in autoimmune diseases of the human brain and beyond. Current protocols for generation of patient-derived recombinant monoclonal antibody libraries are time-consuming and contain repetitive steps, some of which can be assisted with the help of software automation.

Results

We developed BASE, an easy-to-use software for complete data analysis in single cell immunoglobulin cloning. BASE consists of two modules: aBASE for immunological annotations and cloning primer lookup, and cBASE for plasmid sequence identity confirmation before expression. Comparing automated BASE analysis with manual analysis we confirmed the validity of BASE output: identity between manual and automated aBASE analysis was 100% for all outputs, except for immunoglobulin isotype determination. In this case, aBASE yielded correct results in 96% of cases, whereas 4% of cases required manual confirmation. cBASE automatically concluded expression recommendations in 89.8% of cases, 91.8% of which were identical to manually derived results and none of them were false-positive.

Conclusions

BASE offers an easy-to-use software solution suitable for complete Ig sequence data analysis and tracking during recombinant mcAB cloning from single cells. Plasmid sequence identity confirmation by cBASE offers functionality not provided by existing software solutions in the field and will help to reduce time-consuming steps of the monoclonal antibody generation workflow.
Spotlight on the monitoring of the invasion of a carabid beetle on an oceanic islandover a 100 year period
Authors: Lebouvier M. , Lambret P. , Garnier A. , Frenot Y. , Vernon P. , Renault D.
Published: November 2019

The flightless beetleMerizodus soledadinus, originating from the Falkland Islands, was introduced to the sub-Antarctic Kerguelen Islands. We compiled the existing information on ship visits and landings on these islands to confirm the introduction date ofM. soledadinus. Using data available in the literature, in addition to collecting more than 2000 presence/absence records ofM. soledadinusover the 1991-2018 period, we tracked changes of its abundance and geographical distribution. The range expansion of this nonflying insect was initially slow, but has accelerated over the past two decades in parallel to local increased abundances of the insect’s populations. Human activities may have facilitated colonization of some localities byM. soledadinuswhich is now widely present in the eastern part of the Kerguelen archipelago. This predatory insect represents a major threat for the native invertebrate fauna; in particular, the wingless fliesAnatalanta apteraandCalycopteryx moseleyiwhich are locally displaced and/or eliminated by the beetle. If no control measures, let alone eradication, are practicable, it is essential to limit the transport of this invasive insect along with human activities. Since 2006, the Kerguelen Islands have had the status of a nature reserve, making these results of significant interests for the management of this archipelago, and more generally, emphasizing the importance of long-term biomonitoring programmes for assessing and predicting changes in the distribution of invasive organisms. Strict biosecurity measures have now been established at the Kerguelen Islands, with even greater attention paid to visits to remote sites not yet colonized byM. soledadinus.
Sex-specific genetic effects across biomarkers
Authors: Flynn Emily , Tanigawa Yosuke , Rodriguez Fatima , Altman Russ B. , Sinnott-Armstrong Nasa , Rivas Manuel A.
Published: November 2019

Sex differences have been shown in laboratory biomarkers; however, the extent to which this is due to genetics is unknown. In this study, we infer sex-specific genetic parameters (heritability and genetic correlation) across 33 quantitative biomarker traits in 181,064 females and 156,135 males from the UK Biobank study. We apply a Bayesian mixture model, Sex Effects Mixture Model, to Genome-wide Association Study summary statistics in order to (1) estimate the contributions of sex to the genetic variance of these biomarkers and (2) identify variants whose statistical association with these traits is sex-specific. We find that the genetics of most biomarker traits are shared between males and females, with the notable exception of testosterone, where we identify 119 female and 444 male-specific variants. These include protein-altering variants in steroid hormone production genes (POR, CYP3A43, UGT2B7). Using the sex-specific variants as genetic instruments for Mendelian Randomization, we find evidence for causal links between testosterone levels and height, body mass index, waist circumference, and type 2 diabetes. We also show that sex-specific polygenic risk score models for testosterone outperform a combined model. Overall, these results demonstrate that while sex has a limited role in the genetics of most biomarker traits, sex plays an important role in testosterone genetics.
Selection of HIV-1 for Resistance to Fifth Generation Protease Inhibitors Reveals Two Independent Pathways to High-Level Resistance
Authors: Spielvogel Ean , Lee Sook-Kyung , Zhou Shuntai , Lockbaum Gordon J. , Henes Mina , Sondegroth Amy , Kosovrasti Klajdi , Nalivaika Ellen A. , Ali Akbar , Yilmaz Nese Kurt , Schiffer Celia A. , Swanstrom Ronald
Published: November 2019

Darunavir (DRV) is exceptional among potent HIV-1 protease inhibitors (PIs) in the high drug concentrations that are achived in vivo. Little is known about the de novo resistance pathway for DRV. We have selected for resistance to high drug concentrations against ten PIs and their structural precursor DRV. Mutations accumulated through two pathways (anchored by protease mutations I50V or I84V). Small chemical changes in the inhibitor P1’ side chain led to preferential use of one pathway over the other. Changes in the inhbitor P2’ side chain determined differences in potency that were retained in the resistant viruses. Viral variants from the two pathways showed differential selection of compensatory mutations in Gag cleavage sites. These results reveal the high level of selective pressure that is attainable with fourth generation PIs, and how features of the inhibitor affect both the resistance pathway and the residual potency in the face of resistance.
Characterizing the allele- and haplotype-specific copy number landscape of cancer genomes at single-cell resolution with CHISEL
Authors: Zaccaria Simone , Raphael Benjamin J.
Published: November 2019

Single-cell barcoding technologies have recently been used to perform whole-genome sequencing of thousands of individual cells in parallel. These technologies provide the opportunity to characterize genomic heterogeneity at single-cell resolution, but their extremely low sequencing coverage (<0.05X per cell) has thus far restricted their use to identification of the total copy number of large multi-megabase segments in individual cells. However, total copy numbers do not distinguish between the two homologous chromosomes in humans, and thus provide a limited view of tumor heterogeneity and evolution missing important events such as copy-neutral loss-of-heterozygosity (LOH). We introduce CHISEL, the first method to infer allele- and haplotype-specific copy numbers in single cells and subpopulations of cells by aggregating sparse signal across thousands of individual cells. We applied CHISEL to 10 single-cell sequencing datasets from 2 breast cancer patients, each dataset containing ≈2000 cells. We identified extensive allele-specific copy-number aberrations (CNAs) in these samples including copy-neutral LOH, whole-genome duplications (WGDs), and mirrored-subclonal CNAs in subpopulations of cells. These allele-specific CNAs alter the copy number of genomic regions containing well-known breast cancer genes including TP53, BRCA2, and PTEN but are invisible to total copy number analysis. We utilized CHISEL’s allele- and haplotype-specific copy numbers to derive a more refined reconstruction of tumor evolution: timing allele-specific CNAs before and after WGDs, identifying low-frequency subclones distinguished by unique CNAs, and uncovering evidence of convergent evolution. This reconstruction is supported by orthogonal analysis of somatic single-nucleotide variants (SNVs) obtained by pooling barcoded reads across clones defined by CHISEL.
Physico-biochemical and molecular responses of Acacia auriculiformis to salinity stress
Authors: Gupta Deepak B. , Banerjee Joydeep , Pramanik Krishnendu , Das Arpita , Pal Srikumar
Published: November 2019

Salinity limits the growth and yield of many crops across the globe and is considered as major threat to agriculture. Acacia auriculiformis, an important salt tolerant crop, is growing abundantly in the salt-affected mangrove areas of Sunderban, West Bengal, India. In the present study, we have reported the physiological, molecular and antioxidant response of this crop to a gradient of salt treatments ranging between 0 and 800 mM NaCl. As a stress response, the antioxidant enzymes viz. superoxide dismutase (SOD), catalase (CAT) and guaiacol peroxidase (GPX) were highly activated at 200, 400 and 800 mM NaCl respectively. Antioxidant metabolites such as phenols and thiols elevated with increasing salt treatments thus augmenting antioxidant activity with significant positive relationship with phenol content. Similarly, phenylalanine ammonia lyase (PAL) activity was up-regulated in a dose dependent manner with significant relationship with phenol content. This study also reported the phenolic profile for the first time in A. auriculiformis with the abundance of flavonoids. In addition, transcriptional up-regulation of Na+/H+ antiporter gene (NHX1) and the development of robust vascular tissues was noticed at 400 mM NaCl stress compared to control, while further stress at 800 mM NaCl induced poor vascular tissue growth but with higher PAL activity and consequent higher phenol content. Based on this observation, a model for salt tolerance mechanism of A. auriculiformis has been proposed.
The flow of sickle blood through glass capillaries: a point of care application
Authors: Brown Christopher D. , Aprelev Alexey M. , Ferrone Frank A.
Published: November 2019

We show that the characteristic time for sickled blood to traverse 100 µm-diameter glass capillaries can be used as the foundation for a useful point-of-care diagnosis for sickle cell disease. 3.2 cm long capillaries were inserted into a 5 µL drop of blood, and 1/4 µL was spontaneously drawn into the tube. The rate at which the blood traversed the capillary was significantly changed by deoxygenation only for sickle genotypes, a consequence of the increased viscosity of cells containing sickle fibers. Under these conditions, we find deoxygenation causes the time for sickle blood to traverse the capillary to increase to about 3 times its original value, in contrast to normal blood, where the times are equivalent regardless of state of oxygenation. This corresponds to readily-observed time differences of around 10 s for capillary traversal. Such changes are present for blood from homozygous sickle cell patients, as well as heterozygous patients with hemoglobin AS, SC, and Sβ+ thalassemia. Moreover, we demonstrate that this test is sensitive to sickling therapies that increase the production of fetal Hb. This viscosity-based measurement thus offers the prospect of an assay that is 10 times faster than any current test of which we are aware, at costs that rival the least expensive of any current assays.
Producing Human Amniotic Epithelial Cells-only Membrane for Transplantation
Authors: Xu Chenze , Ahmed Waqas , Xie Lili , Peng Yan , Wang Qizheng , Guo Meijin
Published: November 2019

Human amniotic epithelial cells (hAECs), as pluripotent stem cells, have characteristics of immune privilege and great clinical potential. Here, we produced hAECs membrane consisting of single-layer hAECs and basal membrane (BM) of human amniotic membrane (hAM). In conventional methods, hAECs were isolated from hAM by repeated trypsin digestion. In this study, collagenase I and cell scraper were used to remove human amniotic mesenchymal stem cells (hAMSCs) from hAM and hAECs-only membranes were produced. These hAECs on the membranes were evaluated by surface biomarkers including epithelial cell adhesion molecule (EpCAM), stage-specific embryonic antigen 4 (SSEA4) and endoglin (CD105), transcriptional level of biomarkers including POU class 5 homeobox 1 (OCT4), sex determining region Y-box 2 (SOX2), fibroblast growth factor 4 (FGF4), immunofluorescence of cytokeratin-8 (CK-8), alpha smooth muscle actin (α-SMA) and collagen type I alpha 1 chain (ColA1). Finally, the hAECs membrane were transplanted on skin-removed mice to evaluate its effect on wound healing. In comparison to the hAECs isolated by the conventional methods, the cells isolated by this proposed method had higher purity of hAECs, expressed higher in pluripotency related genes, and maintained an epithelium construction in a long-term culture. In mice application, the hAECs membrane effectively improved the skin wound healing. An efficient method was successfully established to produce hAECs membrane in this work which not only held promise to obtain hAECs in higher purity and quality, but also showed practical clinical potential.
De novo transcriptome sequence of Senna tora provides insights into anthraquinone biosynthesis
Authors: Kang Sang-Ho , Lee Woo-Haeng , Lee Chang-Muk , Sim Joon-Soo , Won So Youn , Han So-Ra , Kwon Soo-Jin , Kim Jung Sun , Kim Chang-Kug , Oh Tae-Jin
Published: November 2019

Senna tora is an annual herb with rich source of anthraquinones that have tremendous pharmacological properties. However, there is little mention of genetic information for this species, especially regarding the biosynthetic pathways of anthraquinones. To understand the key genes and regulatory mechanism of anthraquinone biosynthesis pathways, we performed spatial and temporal transcriptome sequencing of S. tora using short RNA sequencing (RNA-Seq) and long-read isoform sequencing (Iso-Seq) technologies, and generated two unigene sets composed of 118,635 and 39,364, respectively. A comprehensive functional annotation and classification with multiple public databases identified array of genes involved in major secondary metabolite biosynthesis pathways and important transcription factor (TF) families (MYB, MYB-related, AP2/ERF, C2C2-YABBY, and bHLH). Differential expression analysis indicated that the expression level of genes involved in anthraquinone biosynthetic pathway regulates differently depending on the degree of tissues and seeds development. Furthermore, we identified that the amount of anthraquinone compounds were greater in late seeds than early ones. In conclusion, these results provide a rich resource for understanding the anthraquinone metabolism in S. tora.
Self-sustained Planar Intercalations due to Mechanosignaling Feedbacks Lead to Robust Axis Extension during Morphogenesis
Authors: Anbari Samira , Buceta Javier
Published: November 2019

Tissue elongation is a necessary process in metazoans to implement their body plans that is not fully understood. Here we propose a mechanism based on the interplay between cellular mechanics and primordia patterning that results in self-sustained planar cell intercalations. Thus, we show that a location-dependent modulation of cell mechanics due to positional information leads to robust axis extension. To illustrate the plausibility of this model, we use different experimentally reported patterning mechanisms in simulations that implement mechano-signaling feedback. Our results suggest that robust elongation relies on a trade-off between cellular and tissue strains that is orchestrated via the cleavage orientation. In the particular context of axis extension in Turing-patterned primordia we report that the combination of different directional cell activities lead to synergetic effects. Altogether, our findings help to understand how the emerging phenomenon of tissue elongation emerges from the individual cell dynamics.
Semaphorin 3a reduces the side effects of radiation on BMSCs by reducing ROS
Authors: Huang Bo , Tang Haiyang , He Tao , Yang Zheng , Gong Ping
Published: November 2019

1.

Background/Aims

Radiotherapy does not only kill tumor cells but also impairs the function of adjacent tissues, especially bone metabolism by damaging bone marrow stromal stem cells (BMSCs). This study aimed to investigate the effect of semaphorin 3a (Sema3a) on BMSCs exposed to 2 Gy radiation.

Materials

BMSCs were divided into four groups, namely, group A (0 Gy), group B (2 Gy), group C (0 Gy + Sema3a), and group D (2 Gy + Sema3a). A Cell Counting Kit-8 kit, Alizarin-Red and Oil-Red-O staining, alkaline phosphatase activity kit, and dichlorodihydro-fluoresce in diacetate were used to test cell proliferation, cell cycle, osteogenic ability, adipogenic ability, and the level of reactive oxygen species (ROS), respectively, in each group. Real-time PCR was performed to test the expression of osteogenic (osteocalcin and Runt-related transcription factor 2), adipogenic (peroxisome proliferator-activated receptor gamma), interleukin (IL)-6, and tumor necrosis factor (TNF)-α genes.

Results

BMSC proliferation, osteogenic differentiation, and the number of cells undergoing division (S+G2 phase of the cell cycle) were found to be lower in group B than in group A. and the cellular levels of ROS, adipogenic differentiation, and expression of inflammatory factors (IL-6 and TNF-α) were higher in group B than in group A. Furthermore, osteogenic differentiation ability was higher in group D than in group B, and adipogenic differentiation ability, cellular levels of ROS, and gene expression of TNF-α and IL-6 were lower in group D than in group B.

Conclusion

This study demonstrated that 2 Gy radiation could decrease the osteogenic differentiation ability of BMSCs and increase their adipogenic differentiation ability by increasing the production of ROS. However, Sema3a could reduce these side effects by decreasing the levels of ROS.
Multiplexed direct detection of barcoded protein reporters on a nanopore array
Authors: Cardozo Nicolas , Zhang Karen , Doroschak Katie , Nguyen Aerilynn , Siddiqui Zoheb , Strauss Karin , Ceze Luis , Nivala Jeff
Published: November 2019

Genetically encoded reporter proteins are a cornerstone of molecular biology. While they are widely used to measure many biological activities, the current number of uniquely addressable reporters that can be used together for one-pot multiplexed tracking is small due to overlapping detection channels such as fluorescence. To address this, we built an expanded library of orthogonally-barcoded Nanopore-addressable protein Tags Engineered as Reporters (NanoporeTERs), which can be read and demuxed by nanopore sensors at the single-molecule level. By adapting a commercially available nanopore sensor array platform typically used for real-time DNA and RNA sequencing (Oxford Nanopore Technologies’ MinION), we show direct detection of NanoporeTER expression levels from unprocessed bacterial culture with no specialized sample preparation. These results lay the foundations for a new class of reporter proteins to enable multiplexed, real-time tracking of gene expression with nascent nanopore sensor technology.
A multi-measure approach for assessing the performance of fMRI preprocessing strategies in resting-state functional connectivity
Authors: Kassinopoulos Michalis , Mitsis Georgios D.
Published: November 2019

It is well established that head motion and physiological processes (e.g. cardiac and breathing activity) should be taken into consideration when analyzing and interpreting results in fMRI studies. However, even though recent studies aimed to evaluate the performance of different preprocessing pipelines there is still no consensus on the optimal strategy. This is partly due to the fact that the quality control (QC) metrics used to evaluate differences in performance across pipelines have often yielded contradictory results. Furthermore, preprocessing techniques based on physiological recordings or data decomposition techniques (e.g. aCompCor) have not been comprehensively examined. Here, to address the aforementioned issues, we propose a framework that summarizes the scores from eight previously proposed and novel QC metrics to a reduced set of two QC metrics that reflect the signal-to-noise ratio and the reduction in motion artifacts and biases in the preprocessed fMRI data. Using this framework, we evaluate the performance of three commonly used practices on the quality of data: 1) Removal of nuisance regressors from fMRI data, 2) discarding motion-contaminated volumes (i.e., scrubbing) before regression, and 3) low-pass filtering the data and the nuisance regressors before their removal. Using resting-state fMRI data from the Human Connectome Project, we show that the scores of the examined QC metrics improve the most when the global signal (GS) and about 17% of principal components from white matter (WM) are removed from the data. Finally, we observe a small further improvement with low-pass filtering at 0.20 Hz and milder variants of WM denoising, but not with scrubbing.
Reduced Auditory Steady State Responses in Autism Spectrum Disorder
Authors: Seymour R.A , Rippon G , Gooding-Williams G , Sowman P.F. , Kessler K
Published: November 2019

Background

Auditory steady state responses (ASSRs) are elicited by clicktrains or amplitude-modulated tones, which entrain auditory cortex at their specific modulation rate. Previous research has reported reductions in ASSRs at 40Hz for autism spectrum disorder (ASD) participants and first-degree relatives of people diagnosed with ASD [1,2].

Methods

Using a 1.5s-long auditory clicktrain stimulus, designed to elicit an ASSR at 40Hz, this study attempted to replicate and extend these findings. Magnetencephalography (MEG) data were collected from 18 adolescent ASD participants and 18 typically developing controls.

Results

The ASSR localised to bilateral primary auditory regions. Regions of interest were thus defined in left and right primary auditory cortex (A1). While the transient gamma-band response (tGBR) from 0-0.1s following presentation of the clicktrain stimulus was not different between groups, for either left or right A1, the ASD group had reduced oscillatory power at 40Hz from 0.5 to 1.5s post-stimulus onset, for both left and right A1. Additionally, the ASD group had reduced inter-trial coherence (phase consistency over trials) at 40Hz from 0.64-0.82s for right A1 and 1.04-1.22s for left A1.

Limitations

In this study, we did not conduct a clinical autism assessment (e.g. the ADOS), and therefore it remains unclear whether ASSR power and/or ITC are associated with the clinical symptoms of ASD.

Conclusion

Overall, our results support a specific reduction in ASSR oscillatory power and inter-trial coherence in ASD, rather than a generalised deficit in gamma-band responses. We argue that this could reflect a developmentally relevant reduction in non-linear neural processing.
More evidence for a long-latency mismatch response in urethane-anaesthetised mice
Authors: O’Reilly Jamie A. , Angsuwatanakul Thanate
Published: November 2019

Prolonged electrophysiological responses to oddball stimuli have recently been observed from anaesthetised rodents. This deviant-related activity is found to extend through 200 to 700 ms post-stimulus; a window typically obstructed from analysis by the response to subsequent stimuli in the auditory sequence. A simple methodological development in terms of difference waveform computation using two adjoining evoked responses has enabled visualisation of this activity over a longer window of analysis than previously available. In the present study, the double-epoch subtraction technique was retroactively applied to data from 13 urethane-anaesthetised mice. Oddball paradigm waveforms were compared with those of a many-standards control sequence, confirming that oddball stimuli evoked long-latency potentials that did not arise from standard or control stimuli. Statistical tests were performed at every time point from 0 to 700 ms post stimuli to highlight regions of significant difference. Oddball-induced mismatch responses were found to display significantly greater long-latency potentials than identical stimuli presented in an equal-probability context. As such, it may be concluded that long-latency potentials were evoked by the oddball condition. How this feature of the anaesthetised rodent mismatch response relates to human mismatch negativity is unclear, although it may be tentatively linked to the human P3a component, which is considered to emerge downstream from mismatch negativity.
Cell-type Specific Learning of Attentional Gating in Primate Striatum
Authors: Boroujeni Kianoush Banaie , Oemisch Mariann , Hassani Seyed Alireza , Womelsdorf Thilo
Published: November 2019

Cognitive flexibility depends on a fast neural learning mechanism for enhancing momentary relevant over irrelevant information. A possible neural mechanism realizing this enhancement uses fast-spiking interneurons (FSIs) in the striatum to train striatal projection neurons to gate relevant and suppress distracting cortical inputs. We found support for such a mechanism in nonhuman primates during the flexible adjustment of visual attention. FSIs gated visual attention cues during feature-based learning. One FSI population showed stronger inhibition during learning, while another FSI subpopulation showed weaker inhibition after learning signifying post-learning disinhibition. Additionally, a smaller neural subpopulation increased activity when salient distractor events were successfully suppressed. These findings highlight that fast behavioral learning of feature relevance is accompanied by fast neural learning of cell-type specific cortico-striatal gating.
Personalized single-cell networks: a framework to predict the response of any gene to any drug for any patient
Authors: Harikumar Haripriya , Quinn Thomas P. , Rana Santu , Gupta Sunil , Venkatesh Svetha
Published: November 2019

Background

The last decade has seen a major increase in the availability of genomic data. This includes expert-curated databases that describe the biological activity of genes, as well as high-throughput assays that measure gene expression in bulk tissue and single cells. Integrating these heterogeneous data sources can generate new hypotheses about biological systems. Our primary objective is to combine population-level drug-response data with patient-level single-cell expression data to predict how any gene will respond to any drug for any patient.

Methods

We take 2 approaches to benchmarking a “dual-channel” random walk with restart (RWR) for data integration. First, we evaluate how well RWR can predict known gene functions from single-cell gene co-expression networks. Second, we evaluate how well RWR can predict known drug responses from individual cell networks. We then present two exploratory applications. In the first application, we combine the Gene Ontology database with glioblastoma single cells from 5 individual patients to identify genes whose functions differ between cancers. In the second application, we combine the LINCS drug-response database with the same glioblastoma data to identify genes that may exhibit patient-specific drug responses.

Conclusions

Our manuscript introduces two innovations to the integration of heterogeneous biological data. First, we use a “dual-channel” method to predict up-regulation and down-regulation separately. Second, we use individualized single-cell gene co-expression networks to make personalized predictions. These innovations let us predict gene function and drug response for individual patients. Taken together, our work shows promise that single-cell co-expression data could be combined in heterogeneous information networks to facilitate precision medicine.
Angiocrine factors from HUVECs amplify erythroid cells
Authors: Sugimura Ryohichi , Ohta Ryo , Mori Chihiro , Sano Emi , Sugiyama Tatsuki , Nagasawa Takashi , Niwa Akira , Torisawa Yu-suke , Saito Megumu K.
Published: November 2019

Erythropoiesis is regulated by microenvironmental factors from the vasculature. Enhanced erythropoiesis, which occurs under stress or during development, amplifies erythroid cells to meet the demand of red blood cells. This process uncouples cell division and differentiation, thus the accumulated erythroid cells remain undifferentiated in the vasculature. However, little is known about how vascular endothelial cells (ECs) regulate erythropoiesis. Here we identified that human umbilical vein endothelial cells (HUVECs) keep erythroid cells undifferentiated and amplify their number. We determined that HUVECs amplify erythroid cells via secreted angiocrine factors. The expression profile of these factors suggested that they resemble macrophage-crines for enhanced erythropoiesis. Molecularly, HUVECs mediate the activation of ERK signaling. These data indicate that angiocrine factors from HUVECs enhance erythropoiesis via the amplification of undifferentiated erythroid cells. Our study contributes to the ultimate goal of harnessing erythropoiesis to replace blood transfusions.
Schizophrenia patients show aberrant brain dynamics associated with gestalt-perception and corollary discharge: Reflections from ERP and fMRI findings
Authors: Sasidharan Arun , Nair Ajay Kumar , Marigowda Vrinda , Lukose Ammu , John John P , Kutty Bindu M
Published: November 2019

Background

Schizophrenia is a disorder of higher mental attributes, and is characterized by psychotic symptoms that are believed to involve a basic inability to make valid predictions about expected sensations and experiences. These have been reported separately while monitoring either externally generated environmental patterns (e.g. gestalt-perception) or self-generated sensory experiences (e.g. corollary-discharge). As the pathophysiology behind predictive dysfunction is better viewed as an aberration in brain’s functional synchrony, a whole brain assessment using electroencephalographic (EEG) event related potential (ERP) and functional magnetic resonance imaging (fMRI) techniques, would offer a wider perspective to brain network abnormalities in schizophrenia.

Method

We used our lab-developed game-based task which presents degraded two-tone images to assess gestalt-perception, and simultaneously alters the congruency between participant’s button-press response and its auditory feedback to assess corollary-discharge. In both patients with schizophrenia and age-matched healthy controls, we explored event-related changes in an EEG-ERP study (n=21 each) and whole brain functional connectivity changes in a fMRI study (patients,n=12; controls,n=16), using the same task.

Results

Patients showed reduced event-related EEG dynamics during both the error-prediction conditions (gestalt-perception and corollary-discharge), which include reduction in average waveforms (around N170 and N1-P2 complex, respectively) and altered theta dynamics (power and phase). Source-level EEG measures were clustered around the cingulo-insular network. fMRI functional connectivity analysis also found the abnormality in these brain regions, forming significantly weak connections with right insular/opercular cortex.

Conclusions

This is the first study to explore ‘thalamo-cortical dysfunction hypothesis’ in schizophrenia by integrating prediction-error-coding during perception (‘gestalt-perception’) and action (‘corollary-discharge’) using two neuroimaging modalities (EEG-ERP and fMRI). Besides adding to the knowledgebase of schizophrenia research, our novel task design and findings on theta-oscillation could benefit in the development of effective neuromodulatory therapeutic tools for patients with schizophrenia such as neurofeedback and transcranial brain stimulation.
Profitability calculations under trial of strength
Authors: Laguecir Aziza , Chapman Christopher S. , Kern Anja
Published: November 2019

Purpose

The purpose of this paper is to examine the organizational construction of profit at the responsibility-centre level, how underlying cost calculations are challenged, and the role of accountants therein.

Design/methodology/approach

This paper analyses profit calculation in a public social housing organization that experienced New Public Management (NPM). Participant observations, archives and interviews inform the study over three years, enabling access to day-to-day practices.

Findings

This study examines a trial of strength that revisited long-existing profitability and cost calculations. Accountants held competing views of how to treat labour costs. Some were anti-programme during a trial of incompatibility, while others were programme defenders. The authors also provide evidence of the stability of an established network and its resistance to the claims of an adversary spokesperson in a trial of strength. The concept of trial of incompatibility proved helpful in showing how the actor networks within OMEGA played out the tension between profit orientation and the social mission of offering affordable dwellings.

Research limitations/implications

The paper provides rare qualitative data on the significant and complex role of calculative costing choices in determining intra-organizational profitability and its interference with the inherent social mission of the organization.

Practical implications

The authors suggest that profitability calculations are influenced not only by economic context but also by different views of organizational actors regarding how to calculate profit. These calculations would benefit from a more detailed and explicit documentation of reasons for choices made, given the potential for different and, in principle, equally valid approaches. The authors provide further evidence of the complexity of the public social housing sector.

Social implications

This research points to a departure from the mission of public social housing in the face of NPM reforms and further questions the compatibility of a profit orientation with the provision of affordable dwellings.

Originality/value

The findings show intra-accounting variation regarding a specific element of profit calculation (labour costs) relating to the organization’s wider mission and status.
A study of motivation and team member selection in online games
Authors: Lou Tianyang , Zu Yuning , Zhu Ling
Published: November 2019

Purpose

The purpose of this paper is to investigate impact of playing motivation on team member selection (TMS) in online games specifically related to Massively Multiplayer Online Role-playing Game environment.

Design/methodology/approach

A self-administered questionnaire was developed and administered to an online sample of 9,335 CR3 players.

Findings

The findings of this research indicated that social and immersion motivations have a significant effect on TMS. Additionally, it was discovered that achievement motivation has a positive relationship with dispositional TMS, a negative relationship to bond-based TMS. The moderation effect of frequency and gender is also demonstrated.

Research limitations/implications

The study verified the relationships of the theoretical model of the game motivation and TMS.

Originality/value

This study provides advice to operators of online games when motivating players to work in groups.