bluuebunny/crossref_metadata_2025 huggingface dataset:
Platelet TSP-1 Controls Prostate Cancer-Induced Osteoclast Differentiation and Bone Marrow-Derived Cell Mobilization through TGFβ-1
Authors: Kerr Bethany A. , Harris Koran S. , Shi Lihong , Willey Jeffrey S. , Soto-Pantoja David R. , Byzova Tatiana V.
Published: February 2020

The development of distant metastasis is the main cause of prostate cancer (CaP)-related death with the skeleton being the primary site of metastasis. While the progression of primary tumors and the growth of bone metastatic tumors are well described, the mechanisms controlling pre-metastatic niche formation and homing of CaP to bone remain unclear. Through prior studies, we demonstrated that platelet secretion was required for ongoing tumor growth and pre-metastatic tumor-induce bone formation and bone marrow-derived cell mobilization to cancers supporting angiogenesis. We hypothesized that proteins released by the platelet α granules were responsible for inducing changes in the pre-metastatic bone niche. We found that the classically anti-angiogenic protein thrombospondin (TSP)-1 was significantly increased in the platelets of mice bearing tumors. To determine the role of increased TSP-1, we implanted tumors in TSP-1 null animals and assessed changes in tumor growth and pre-metastatic niche formation. TSP-1 loss resulted in increased tumor size and enhanced angiogenesis but reduced bone marrow-derived cell mobilization and tumor-induced bone formation with enhanced osteoclast formation. We hypothesized that these changes in the pre-metastatic niche were due to the retention of TGF-β1 in the platelets of mice with TSP-1 deleted. To assess the importance of platelet-derived TGF-β1, we implanted CaP tumors in mice with platelet-specific deletion of TGF-β1. Similar to TSP-1 deletion, loss of platelet TGF-β1 resulted in increased angiogenesis with a milder effect on tumor size and BMDC release. Within the bone microenvironment, platelet TGF-β1 deletion prevented tumor-induced bone formation due to increased osteoclastogenesis. Thus, we demonstrate that the TSP-1/TGF-β1 axis regulates pre-metastatic niche formation and tumor-induced bone turnover. Targeting the platelet release of TSP-1 or TGF-β1 represents a potential method to interfere with the process of CaP metastasis to bone.
Investigating the Conformational Ensembles of Intrinsically-Disordered Proteins with a Simple Physics-Based Model
Authors: Zhao Yani , Cortes-Huerto Robinson , Kremer Kurt , Rudzinski Joseph F.
Published: February 2020

Intrinsically disordered proteins (IDPs) play an important role in an array of biological processes but present a number of fundamental challenges for computational modeling. Recently, simple polymer models have re-gained popularity for interpreting the experimental characterization of IDPs. Homopolymer theory provides a strong foundation for understanding generic features of phenomena ranging from single-chain conformational dynamics to the properties of entangled polymer melts, but is difficult to extend to the copolymer context. This challenge is magnified for proteins due to the variety of competing interactions and large deviations in side-chain properties. In this work, we apply a simple physics-based coarse-grained model for describing largely disordered conformational ensembles of peptides, based on the premise that sampling sterically-forbidden conformations can compromise the faithful description of both static and dynamical properties. The Hamiltonian of the employed model can be easily adjusted to investigate the impact of distinct interactions and sequence specificity on the randomness of the resulting conformational ensemble. In particular, starting with a bead-spring-like model and then adding more detailed interactions one by one, we construct a hierarchical set of models and perform a detailed comparison of their properties. Our analysis clarifies the role of generic attractions, electrostatics and side-chain sterics, while providing a foundation for developing efficient models for IDPs that retain an accurate description of the hierarchy of conformational dynamics, which is nontrivially influenced by interactions with surrounding proteins and solvent molecules.
Replication protein A binds RNA and promotes R-loop formation
Authors: Mazina Olga M. , Somarowthu Srinivas , Kadyrova Lyudmila Y. , Baranovskiy Andrey G. , Tahirov Tahir H. , Kadyrov Farid A. , Mazin Alexander V.
Published: February 2020

Replication protein A (RPA), a major eukaryotic ssDNA-binding protein, is essential for all metabolic processes that involve ssDNA including DNA replication, repair, and damage signaling. Surprisingly, we found here that RPA binds RNAin vitrowith high affinity. Using native RIP method, we isolated RNA-RPA complexes from human cells. Furthermore, RPA promotes R-loop formation between RNA and homologous dsDNA. R-loops, the three-stranded nucleic acid structure consisting of an RNA-DNA hybrid and the displaced ssDNA strand, are common in human genome. R-loops may play an important role in transcription-coupled homologous recombination and DNA replication restart. We reconstituted the process of replication restartin vitrousing RPA-generated R-loops and human DNA polymerases. These findings indicate that RPA may play a role in RNA metabolism and suggest a mechanism of genome maintenance that depends on RPA and RNA.
Mechanical heterogeneity along single cell-cell junctions is driven by lateral clustering of cadherins during vertebrate axis elongation
Authors: Huebner Robert J. , Malmi-Kakkada Abdul Naseer , Sarikaya Sena , Weng Shinuo , Thirumalai D. , Wallingford John B.
Published: February 2020

Morphogenesis is governed by the interplay of molecular signals and mechanical forces across multiple length scales. The last decade has seen tremendous advances in our understanding of the dynamics of protein localization and turnover at sub-cellular length scales, and at the other end of the spectrum, of mechanics at tissue-level length scales. Integrating the two remains a challenge, however, because we lack a detailed understanding of the subcellular patterns of mechanical properties of cells within tissues. Here, in the context of the elongating body axis of a vertebrate embryo, we combine tools from cell biology and physics to demonstrate that individual cell-cell junctions display finely-patterned local mechanical heterogeneity along their length. We show that such local mechanical patterning is essential for the cell movements of convergent extension and is imparted by locally patterned clustering of a classical cadherin. Finally, the patterning of cadherins and thus local mechanics along cell-cell junctions are controlled by Planar Cell Polarity signaling, a key genetic module for CE that is mutated in diverse human birth defects.
Small-molecule inhibition of Lats kinases promotes Yap-dependent proliferation in postmitotic mammalian tissues
Authors: Kastan Nathaniel , Gnedeva Ksenia , Alisch Theresa , Petelski Aleksandra A. , Huggins David J. , Chiaravalli Jeanne , Aharanov Alla , Shakked Avraham , Tzahor Eldad , Nagiel Aaron , Segil Neil , Hudspeth A. J.
Published: February 2020

Hippo signaling is an evolutionarily conserved pathway that restricts organ growth during development and suppresses regeneration in mature organs1–3. Using a high-throughput phenotypic screen, we have identified a potent, non-toxic, and reversible inhibitor of Hippo signaling. An ATP-competitive inhibitor of Lats kinases, the compound causes Yap-dependent proliferation of murine supporting cells in the inner ear, murine cardiomyocytes, and human Müller glia in retinal organoids. RNA sequencing indicates that the substance fosters both the G1-S and G2-M checkpoint transitions and yields supporting cells capable of transdifferentiation. Upon withdrawal of the compound, a subset of supporting cells move their nuclei into the hair-cell layer and express genes characteristic of hair cells. Viral transfection of Atoh1 induces the expression of hair cellspecific proteins in progeny. The compound promotes the initial stages of the proliferative regeneration of hair cells, a process thought to be permanently suppressed in the adult mammalian inner ear.
The chloroplast ribonucleoprotein CP33B quantitatively binds thepsbAmRNA
Authors: Teubner Marlene , Lenzen Benjamin , Espenberger Lucas Bernal , Fuss Janina , Nickelsen Jörg , Krause Kirsten , Ruwe Hannes , Schmitz-Linneweber Christian
Published: February 2020

Chloroplast RNAs are stabilized and processed by a multitude of nuclear-encoded RNA binding proteins, often in response to external stimuli like light and temperature. A particularly interesting RNA based regulation occurs with thepsbAmRNA, which shows light-dependent translation. Recently, the chloroplast ribonucleoprotein CP33B was identified as a ligand of thepsbAmRNA. We here characterized the interaction of CP33B with chloroplast RNAs in greater detail using a combination of RIP-chip, quantitative dot-blot, and RNA-Bind-n-Seq experiments. We demonstrate that CP33B preferspsbAover all other chloroplast RNAs and associates with vast majority of thepsbAtranscript pool. The RNA sequence target motif determinedin vitrodoes not fully explain CP33B’s preference forpsbA, suggesting that there are other determinants of specificityin vivo.
The evolution of sex is tempered by costly hybridization inBoechera(rock cress)
Authors: Rushworth Catherine A. , Mitchell-Olds Tom
Published: February 2020

Even after decades of research, the evolution of sex remains an enigma in evolutionary biology. Typically, research addresses the costs of sex and asexuality to characterize the circumstances in which one reproductive system is more favorable. Yet surprisingly few studies address the influence of common traits that are obligately correlated with asexuality, including hybridization and polyploidy; even though these traits have substantial impacts on selective patterns. In particular, hybridization is well-known to alter trait expression; these alterations may themselves represent a cost of sex. We examined the role of reproductive isolation in the formation of de novo hybrid lineages between two widespread species in the ecological model systemBoechera. Of 664 crosses betweenBoechera strictaandBoechera retrofracta, 17% of crosses produced F1 fruits. This suggests that postmating prezygotic barriers, i.e. pollen-pistil interactions, form the major barrier to hybrid success in this system. These interactions are asymmetrical, with 110 F1 fruits produced whenB. strictawas the maternal parent. This asymmetry was confirmed using a chloroplast phylogeny of wild-collectedB. stricta,B. retrofracta, and hybrids, which showed that most hybrids have aB. strictachloroplast haplotype. We next compared fitness of F2 hybrids and selfed parentalB. strictalines, finding that F2 fitness was reduced by substantial hybrid sterility. Our results suggest that multiple reproductively isolating barriers likely influence the formation and fitness of hybrid lineages in the wild, and that these costs of hybridization likely have profound impacts on the costs of sex in the natural environment.
Cryopreservation of midbrain dopaminergic neural cells differentiated from human embryonic stem cells
Authors: Drummond Nicola J. , Dolt Karamjit Singh , Canham Maurice A. , Kilbride Peter , Morris G. John , Kunath Tilo
Published: February 2020

Recent advancements in protocols to differentiate human pluripotent stem cells into midbrain dopaminergic (mDA) neurons has improved the ability to model Parkinson’s disease (PD) in a dish, and has provided a scalable source of donor cells for emerging PD cell replacement therapy (CRT). However, to facilitate reproducibility, collaboration, and clinical trials it would be highly beneficial to cryopreserve committed mDA neural precursors cells in a ready-to-use format. In terms of cell manufacturing for PD CRT trials, a cryopreserved transplantation-ready mDA cell product would provide a critical opportunity for quality control, efficacy testing, and safety assessments. To address this challenge, we have compared six (6) different clinical-grade cryopreservation media and different freezing conditions for mDA neural precursor cells differentiated from two human embryonic stem cell (ESC) lines, MasterShef7 and RC17. Significant differences in cell viability were observed at 24h post-thawing, but no differences were observed immediately upon thawing. This highlights the need to check cell viability over the first 24h after thawing, and that viability of freshly thawed cells is insufficient to gauge the success of a cryopreservation protocol. Considerable apoptosis occurs in the first 24h post-thawing, and significant differences between cryopreservation procedures were only revealed during this time period. The presence of ROCK inhibitors improved cell viability at 24h for all conditions tested. A faster cooling rate of 1-2°C/min was significantly better than 0.5°C/min for all conditions tested, while rapid thawing at 37°C was not always superior to slow thawing at 4°C. Indeed, the optimal cryopreservation and thawing conditions in this study, as determined by 24h post-thaw viability, were cells frozen in PSC Cryopreservation medium at a cooling rate of 1°C/min and slow thawing at 4°C. These conditions permitted recovery of 60%-70% live cells at 24h with respect to the starting number of cryopreserved cells. Importantly, cryopreservation of mDA neural precursor cells did not alter their potential to resume differentiation into mDA neurons.

Highlights

First systematic comparison of multiple clinical-grade cryopreservation media for human ESC-derived mDA neural precursor cells

Differences in cell viability were observed at 24h after thawing, but not immediately upon thawing

Cooling rates of 1°C/min or 2°C/min were significantly better than 0.5°C/min for all cryopreservation conditions tested

A slow thawing condition at 4°C was significantly better than quick thawing at 37°C for cells frozen in PSC Cryopreservation medium

Cryopreservation of mDA cells does not significantly alter their potential to differentiate into mDA neurons
Increasing ChlorophyllaAmid Stable Nutrient Concentrations in Rhode Island Lakes and Reservoirs
Authors: Hollister J. W. , Kellogg D. Q. , Kreakie B. J. , Shivers S. , Milstead W. B. , Herron E. , Green L. , Gold A.
Published: February 2020

Addressing anthropogenic impacts on aquatic ecosystems is a focus of lake management. Controlling phosphorus and nitrogen can mitigate these impacts, but determining management effectiveness requires long-term datasets. Recent analysis of the LAke multi-scaled GeOSpatial and temporal database for the Northeast (LAGOSNE) United States found stable water quality in the northeastern and midwestern United States, however, sub-regional trends may be obscured. We analyze a sub-regional (i.e., 3000 km2) trend with the University of Rhode Island’s Watershed Watch Volunteer Monitoring Program (URIWW) dataset. URIWW has collected water quality data on Rhode Island lakes and reservoirs for over 25 years. The LAGOSNE and URIWW datasets allow for comparison of water quality trends at regional and sub-regional extents, respectively. We assess regional (LAGOSNE) and state (URIWW) trends with yearly mean anomalies calculated on a per-station basis. Sub-regionally, temperature and chlorophyllaincreased from 1993 to 2016. Total nitrogen shows a weak increase driven by low years in the early 1990s. Total phosphorus and the nitrogen:phosphorus ratio (N:P) were stable. At the regional scale, the LAGOSNE dataset shows similar trends to prior studies of the LAGOSNE with chlorophylla, total nitrogen, total phosphorus, and N:P all stable over time. In short, algal biomass, as measured by chlorophyllain Rhode Island lakes and reservoirs is increasing, despite stability in total nitrogen, total phosphorus, and the nitrogen to phosphorus ratio. This analysis suggests an association between lake temperature and primary production. Additionally, we demonstrate both the value of long-term monitoring programs, like URIWW, for identifying trends in environmental condition, and the utility of site-specific anomalies for analyzing for long-term water quality trends.
Transcriptional profiling of Multiple System Atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease
Authors: Piras Ignazio S. , Bleul Christiane , Schrauwen Isabelle , Talboom Joshua , Llaci Lorida , De Both Matthew D. , Naymik Marcus A. , Halliday Glenda , Bettencourt Conceicao , Holton Janice L. , Serrano Geidy E. , Sue Lucia I. , Beach Thomas G. , Stefanova Nadia , Huentelman Matthew J.
Published: February 2020

Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n=66) and healthy controls (HC;n=66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical sub-type.

We detected the highest number of DEGs in the MSA-C group (n= 747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis of MSA-C showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for theQKIgene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and an enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for β-amyloid related functional classes, including the known Alzheimer’s disease (AD) genes,APPandPSEN1.

This is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregulation between MSA and AD-related genes despite the clinical and neuropathological distinctions between the two diseases.
The Landscape of Mutational Mosaicism in Autistic and Normal Human Cerebral Cortex
Authors: Rodin Rachel E. , Dou Yanmei , Kwon Minseok , Sherman Maxwell A. , D’Gama Alissa M. , Doan Ryan N. , Rento Lariza M. , Girskis Kelly M. , Bohrson Craig L. , Kim Sonia N. , Luquette Lovelace J. , Gulhan Doga C. ,   Brain Somatic Mosaicism Network, Park Peter J. , Walsh Christopher A.
Published: February 2020

Although somatic mutations have well-established roles in cancer and certain focal epilepsies, the extent to which mutational mosaicism shapes the developing human brain is poorly understood. Here we characterize the landscape of somatic mutations in the human brain using ultra-deep (~250×) whole-genome sequencing of brains from 59 autism spectrum disorder (ASD) cases and 15 controls. We observe a mean of 26 (±10, range 10-60) somatic single nucleotide variants (sSNVs) per brain present in ≥4% of cells, with enrichment of mutations in coding and putative regulatory regions. Our analysis reveals that the first cell division after fertilization produces ~3.4 mutations, followed by 2-3 mutations in subsequent generations. This rate suggests that a typical individual possesses ~80 sSNVs present in ≥2% of cells—comparable to the number ofde novogermline mutations per generation—with about half of individuals having at least one potentially function-altering somatic mutation somewhere in the cortex. Although limited by sample size, ASD brains show an excess of somatic mutations in neural enhancer sequences compared to controls, suggesting that mosaic enhancer mutations may contribute to ASD risk.
Varying thermal exposure, host-plant traits and oviposition behaviour across vegetation ecotones
Authors: Vives-Ingla Maria , Sala-Garcia Javier , Stefanescu Constantí , Peñuelas Josep , Carnicer Jofre
Published: February 2020

Vegetation cover generates local microclimatic gradients in the understorey, being especially pronounced at narrow ecotones linking open and forested habitats (open–closed ecotones). They provide key habitats for multiple insect communities and may largely determine the exposure of herbivorous insects to the increasing impacts of climate change. We report parallel measurements of microclimatic variables, multiple host-plant traits, and oviposition behaviour in Mediterranean populations of twoPierisbutterflies across ecotones of vegetation cover. Open microhabitats were significantly warmer, drier, and more exposed to thermal amplification, which increased temperatures to values affecting insect larval survival. Host plants advanced their reproductive phenology and were shorter. Open microhabitats also inhibited the development of shade-adapted plants (e.g.Alliaria petiolata), decreasing fruit production. In contrast, the reproduction of sun-adapted host plants (e.g.Lepidium draba) was vigorous in the open microhabitats and completely inhibited in closed microhabitats, which were exclusively inhabited by non-reproductive ramets. Key plant traits for the selection of oviposition sites by butterflies, such as foliar water and chlorophyll contents, varied significantly across the open– closed ecotones. Foliar water content was always lower in the open microhabitats, whereas foliar chlorophyll gradients differed between sun- and shade-adapted plants. The oviposition behavior ofPierisbutterflies across the ecotones differed significantly between the thermotolerant species (P. rapae, preferentially selecting open microhabitats) and the thermosensitive species (P. napi, selecting microhabitats protected by vegetation cover), matching the values of thermal susceptibility estimated from parallel heat tolerance assays of the populations. The larvae of the thermotolerantPierisspecies grew under completely different thermal conditions due to differential microhabitat selection, indicating marked interspecific differences in thermal exposure (5–10 °C). These results suggest that the impacts of global warming in these communities will likely be mediated by open–closed ecotones, which determine pronounced local variability in thermal exposure, oviposition placement, and host-plant traits affecting larval performance in summer.
A Casz1 - NuRD complex regulates temporal identity transitions in neural progenitors
Authors: Mattar Pierre , Jolicoeur Christine , Shah Sujay , Cayouette Michel
Published: February 2020

Neural progenitor cells alter their output over developmental time to generate different types of neurons and glia in the correct sequences and proportions. A number of ‘temporal identity factors’ that control transitions in progenitor competence have been identified, but the molecular mechanisms underlying their function remain unclear. Here, we asked how the transcription factorCasz1, the mammalian orthologue ofDrosophila castor,regulates competence during retinal neurogenesis. We show thatCasz1is required to control the transition between neurogenesis and gliogenesis. Using BioID proteomics, we reveal that Casz1 interacts with the nucleosome remodeling and deacetylase (NuRD) complex in retinal cells. Finally, we show that both the NuRD and the polycomb repressor complexes are required for Casz1 to promote the rod fate and suppress gliogenesis. As other temporal identity factors have been found to interact with the NuRD complex in other contexts, we propose that these factors might act through a common biochemical process to regulate neurogenesis.
Harnessing tumor immune ecosystem dynamics to personalize radiotherapy
Authors: Daniel Grass G. , Alfonso Juan C.L. , Welsh Eric , Ahmed Kamran A. , Teer Jamie K. , Harrison Louis B. , Cleveland John L. , Mulé James J. , Eschrich Steven A. , Enderling Heiko , Torres-Roca Javier F.
Published: February 2020

Radiotherapy is a pillar of cancer care and augments the response to immunotherapies. However, little is known regarding the relationships between the tumor immune ecosystem (TIES) and intrinsic radiosensitivity, and a pressing question in oncology is how to optimize radiotherapy to improve patient responses to immune therapies. To address this challenge, we profiled over 10,000 primary tumors for their metrics of radiosensitivity and immune cell infiltrate (ICI), and applied a new integrated in silico model that mimics the dynamic relationships between tumor growth, ICI flux and the response to radiation. We then validated this model with a separate cohort of 59 lung cancer patients treated with radiotherapy. These analyses explain radiation response based on its effect on the TIES and quantifies the likelihood that radiation can promote a shift to anti-tumor immunity. Dynamic modeling of the relationship between tumor radiosensitivity and the TIES may provide opportunity to personalize combined radiation and immunotherapy approaches.
Insight into motility-dependent pathogenicity of the zoonotic spirocheteLeptospira
Authors: Xu Jun , Koizumi Nobuo , Nakamura Shuichi
Published: February 2020

Bacterial motility is crucial for many pathogenic species in the process of invasion and/or dissemination. The spirochete bacteriaLeptospiraspp. cause symptoms, such as hemorrhage, jaundice, and nephritis, in diverse mammals including humans. Although loss-of-motility attenuate the spirochete, the mechanism of the motility-dependent pathogenicity is unknown. Here, focusing on thatLeptospiraspp. swim in liquid and crawl on solid surfaces, we investigated the spirochetal dynamics on the host tissues by infecting cultured kidney cells from various species with pathogenic and nonpathogenic leptospires. We found that, in the case of the pathogenic leptospires, a larger fraction of bacteria attached to the host cells and persistently traveled long distances using the crawling mechanism. Our results associate the kinetics and kinematic features of the spirochetal pathogens with their virulence.

One Sentence Summary

Adhesivity and crawling motility over host tissue surfaces are closely related to the pathogenicity of a zoonotic spirochete.
A population-level invasion by transposable elements triggers genome expansion in a fungal pathogen
Authors: Oggenfuss Ursula , Badet Thomas , Wicker Thomas , Hartmann Fanny E. , Singh Nikhil K. , Abraham Leen N. , Karisto Petteri , Vonlanthen Tiziana , Mundt Christopher C. , McDonald Bruce A. , Croll Daniel
Published: February 2020

Abstract

Genome evolution is driven by the activity of transposable elements (TEs). The spread of TEs can have deleterious effects including the destabilization of genome integrity and expansions. However, the precise triggers of genome expansions remain poorly understood because genome size evolution is typically investigated only among deeply divergent lineages. Here, we use a large population genomics dataset of 284 individuals from populations across the globe ofZymoseptoria tritici, a major fungal wheat pathogen. We built a robust map of genome-wide TE insertions and deletions to track a total of 2,456 polymorphic loci within the species. We show that purifying selection substantially depressed TE frequencies in most populations but some rare TEs have recently risen in frequency and likely confer benefits. We found that specific TE families have undergone a substantial genome-wide expansion from the pathogen’s center of origin to more recently founded populations. The most dramatic increase in TE insertions occurred between a pair of North American populations collected in the same field at an interval of 25 years. We find that both genome-wide counts of TE insertions and genome size have increased with colonization bottlenecks. Hence, the demographic history likely played a major role in shaping genome evolution within the species. We show that both the activation of specific TEs and relaxed purifying selection underpin this incipient expansion of the genome. Our study establishes a model to recapitulate TE-driven genome evolution over deeper evolutionary timescales.
General Framework for Tracking Neural Activity Over Long-Term Extracellular Recordings
Authors: Chaure Fernando Julian , Rey Hernan Gonzalo
Published: February 2020

The recent advances in the chronic implantation of electrodes have allowed the collection of extracellular activity from neurons over long periods of time. To fully take advantage of these recordings, it is necessary to track single neurons continuously, particularly when their associated waveform changes over time. Multiple spike sorting algorithms can track drifting neurons but they do not perform well in conditions like a temporary increase in the noise level and changes in the number of detectable neurons. In this work, we present Tracking_Graph, a general framework to track neurons under these conditions. Tracking_Graph can be implemented with different spike sorting algorithms, allowing the experimenter to use the algorithm best fitted for their setup. The main idea behind Tracking_Graph is the blockwise analysis of the recording and application of a classification algorithm to match spikes to templates in different segments, leading to a directional metric that can be used to link clusters across blocks. Moreover, the algorithm can detect and fix sorting errors (splits and merges) in isolated blocks. We compared an implementation of Tracking_Graph with other algorithms using long-term simulations and obtained superior performance in all the metrics.
Microtubule attachment and centromeric tension shape the protein architecture of the human kinetochore
Authors: Kukreja Alexander A. , Kavuri Sisira , Joglekar Ajit. P
Published: February 2020

The nanoscale protein architecture of the kinetochore, a complex protein machine, plays an integral role in the molecular mechanisms underlying its functions in chromosome segregation. However, defining this architecture in human cells remains challenging because of the large size and compositional complexity of the kinetochore. Here, we use Förster Resonance Energy Transfer to reveal the architecture of individual kinetochore-microtubule attachments in human cells. We find that the microtubule-binding domains of the Ndc80 complex cluster at the microtubule plus-end. This clustering occurs only after microtubule attachment, and it increases proportionally with centromeric tension. Surprisingly, this clustering is independent of the organization and number of centromeric receptors for Ndc80. Moreover, Ndc80 clustering is similar in yeast and human kinetochores despite significant differences in their centromeric organizations. These and other data suggest that the microtubule-binding interface of the human kinetochore behaves like a flexible “lawn” despite being nucleated by repeating biochemical subunits.
A Generalized Discrete Dynamic Model for Human Epidemics
Authors: Zhang Wenjun , Chen Zeliang , Lu Yi , Guo Zhongmin , Qi Yanhong , Wang Guoling , Lu Jiahai
Published: February 2020

A discrete dynamic model for human epidemics was developed in present study. The model included major parameters as transmission strength and its decline parameters, mean incubation period, hospitalization time, non-hospitalization daily mortality, non-hospitalization daily recovery rate, and hospitalization proportion, etc. Sensitivity analysis of the model indicated the total cumulative cases significantly increased with initial transmission strength, hospitalization time. The total cumulative cases significantly decreased with transmission strength’s decline and hospitalization proportion, and linearly decreased with non-hospitalization daily mortality and non-hospitalization daily recovery rate. In a certain range, the total cumulative cases significantly increased with mean incubation period. Sensitivity analysis demonstrated that dynamic change of transmission strength is one of the most important and controllable factors. In addition, reducing the delay for hospitalization is much effective in weakening disease epidemic. Non-hospitalization recovery rate is of importance for enhancing immunity to recover from the disease.
Duplex real-time PCR assay for the simultaneous detection ofAchromobacter xylosoxidansandAchromobacterspp
Authors: Price Erin P. , Soler Arango Valentina , Kidd Timothy J. , Fraser Tamieka A. , Nguyen Thuy-Khanh , Bell Scott C. , Sarovich Derek S.
Published: February 2020

Several members of the Gram-negative environmental bacterial genus,Achromobacter, are associated with serious infections in immunocompromised individuals, of whichAchromobacter xylosoxidansis the most common. Despite their pathogenic potential, comparatively little is understood about these intrinsically drug-resistant bacteria and their role in disease, leading to suboptimal diagnosis and management ofAchromobacterinfections. Here, we performed comparative genomics of 158Achromobacterspp. genomes to robustly identify species boundaries, to reassign several incorrectly speciated taxa, and to identify genetic sequences specific for theAchromobactergenus and forA. xylosoxidans. Next, we developed a Black Hole Quencher probe-based duplex real-time PCR assay, Ac-Ax, for the rapid and simultaneous detection ofAchromobacterspp. andA. xylosoxidansfrom both purified colonies and polymicrobial clinical specimens. Ac-Ax was tested on 119 isolates identified asAchromobacterspp. using phenotypic or genotypic methods. In comparison to these routine diagnostic methods, the duplex assay showed superior identification ofAchromobacterspp. andA. xylosoxidans, with fiveAchromobacterisolates failing to amplify with Ac-Ax confirmed to be different genera according to 16S rRNA gene sequencing. Ac-Ax quantified bothAchromobacterspp. andA. xylosoxidansdown to ∼110 genome equivalents, and detected down to ∼12 and ∼1 genome equivalent/s, respectively.In silicoanalysis, and laboratory testing of 34 non-Achromobacterisolates and 38 adult CF sputa, confirmed duplex assay specificity and sensitivity. We demonstrate that the Ac-Ax duplex assay provides a robust, sensitive, and cost-effective method for the simultaneous detection of allAchromobacterspp. andA. xylosoxidans, and will facilitate the rapid and accurate diagnosis of this important group of pathogens.
Association Study of Over 200,000 Subjects Detects Novel Rare Variants, Functional Elements, and Polygenic Architecture of Prostate Cancer Susceptibility
Authors: Emami Nima C. , Cavazos Taylor B. , Rashkin Sara R. , Cario Clinton L. , Graff Rebecca E. , Tai Caroline G. , Mefford Joel A. , Kachuri Linda , Wan Eunice , Wong Simon , Aaronson David S. , Presti Joseph , Habel Laurel A. , Shan Jun , Ranatunga Dilrini K. , Chao Chun R. , Ghai Nirupa R. , Jorgenson Eric , Sakoda Lori C. , Kvale Mark N. , Kwok Pui-Yan , Schaefer Catherine , Risch Neil , Hoffmann Thomas J. , Eeden Stephen K. Van Den , Witte John S.
Published: February 2020

The potential association between rare germline genetic variants and prostate cancer (PrCa) susceptibility has been understudied due to challenges with assessing rare variation. Furthermore, although common risk variants for PrCa have shown limited individual effect sizes, their cumulative effect may be of similar magnitude as high penetrance mutations. To identify rare variants associated with PrCa susceptibility, and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we analyzed large population-based cohorts, custom genotyping microarrays, and imputation reference panels in an integrative study of PrCa genetic etiology. In particular, 11,649 men (6,196 PrCa cases, 5,453 controls) of European ancestry from the Kaiser Permanente Research Program on Genes, Environment and Health, ProHealth Study, and California Men’s Health Study were genotyped and meta-analyzed with 196,269 European-ancestry male subjects (7,917 PrCa cases, 188,352 controls) from the UK Biobank. Six novel loci were genome-wide significant in our meta-analysis, including two rare variants (minor allele frequency < 0.01, at 3p21.31 and 8p12). Gene-based rare variant tests implicated a previously discovered PrCa gene (HOXB13) as well as a novel candidate (ILDR1) highly expressed in prostate tissue. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants atHOXB13and other loci, reflecting their evolutionary history. Furthermore, a polygenic risk score (PRS) of 187 known, largely common PrCa variants was strongly associated with risk in non-Hispanic whites (90thvs. 10thdecile OR = 7.66,P= 1.80*10-239). Many of the 187 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a six-fold difference in log-probability of Androgen Receptor binding at the variant rs2680708 (17q22). Our finding of two novel rare variants associated with PrCa should motivate further consideration of the role of low frequency polymorphisms in PrCa, while the considerable effect of PrCa PRS profiles should prompt discussion of their role in clinical practice.
The Pebble/Rho1/Anillin pathway controls polyploidization and axonal wrapping activity in the glial cells of theDrosophilaeye
Authors: Tavares Lígia , Grácio Patrícia , Ramos Raquel , Traquete Rui , Relvas João B. , Pereira Paulo S.
Published: February 2020

During development glial cell are crucially important for the establishment of neuronal networks. Proliferation and migration of glial cells can be modulated by neurons, and in turn glial cells can differentiate to assume key roles such as axonal wrapping and targeting. To explore the roles of actin cytoskeletal rearrangements in glial cells, we studied the function of Rho1 inDrosophiladeveloping visual system. We show that the Pebble (RhoGEF)/Rho1/Anillin pathway is required for glia proliferation and to prevent the formation of large polyploid perineurial glial cells, which can still migrate into the eye disc if generated. Surprisingly, this Rho1 pathway is not necessary to establish the total glial membrane area or for the differentiation of the polyploid perineurial cells. The resulting polyploid wrapping glial cells are able to initiate wrapping of axons in the basal eye disc, however the arrangement and density of glia nuclei and membrane processes in the optic stalk are altered and the ensheathing of the photoreceptor axonal fascicles is reduced.
Experimental and computational studies on heterocyclic organic compounds as corrosion inhibitors for copper immersed in O/W emulsion medium
Authors: Xiong Sang , Si Jia , Sun Jianlin , Wu Hao , Dong Hongchen , Zhang Chao
Published: February 2020

Purpose

Corrosion inhibitors for copper immersed in emulsion were investigated by experiments and theoretical calculations, and this study aims to propose a new inhibition mechanism of the inhibitors having protective effects for copper corrosion.

Design/methodology/approach

Adsorption behavior of penta-heterocycles (thiophene, 1,2,5-oxadiazole, furan, 2 H-1,2,3-triazole, pyrrole and 1,2,5-thiadiazole) as corrosion inhibitors for copper immersed in oil-in-water (O/W) emulsions was investigated by weight loss, electrochemical tests, morphological characterization and theoretical calculations.

Findings

The orders of inhibition effect are furan < pyrrole < thiophene < 1,2,5-oxadiazole < 2H-1,2,3-triazole < 1,2,5-thiadiazole, and 1,2,5-thiadiazole at 0.5 mM has the best inhibition effect for copper immersed in emulsion. The results of scanning probe microscope, scanning electron microscope and electrochemical test show that a protective barrier can be formed on the surface of copper substrate with six corrosion inhibitors, thus effectively inhibiting the corrosion of copper mainly through chemisorption and following Langmuir’s adsorption isotherm.

Originality/value

Quantum chemical and molecular dynamic simulations demonstrate that all these compounds attached to Cu matrix with a flat-adsorption mode to prevent the emulsion corrode copper. Adsorbed inhibitors act as a barrier at Cu matrix to block corrosion and improve hydrophobicity.
DEA window analysis and Malmquist index to assess efficiency and productivity in the Spanish electricity sector
Authors: Sánchez-Ortiz Jaime , Garcia-Valderrama Teresa , Rodríguez-Cornejo Vanesa , Cabrera-Monroy Francisca
Published: February 2020

Purpose

The purpose of this paper is to demonstrate that overcapacity and tariff deficit (external constraints) negatively affect the efficiency of distribution firms in the Spanish electricity sector. To do this, the paper is based on the theory of constraints and theory of economic regulation.

Design/methodology/approach

Data envelopment analysis (DEA) window methodology is carried out on the constant scales (I-C) with a sample consisting of five main distribution firms during the period from 2006 to 2015. In turn, an analysis of the Malmquist index is carried out to assess whether it has had a displacement with respect to the efficiency frontier.

Findings

The results show that the overcapacity and the tariff deficit negatively affect the efficiency of the distribution firms of the Spanish electricity sector. In addition, there is an existence of external constraints that affect the activities of regulated organisations and the importance of adequate legislation in regulated sectors.

Originality/value

This study defines a model that shows how the efficiency problems associated with electricity distribution companies such as productive overcapacity or tariff deficit can be measured based on the theory of constraints and theory of economic regulation.
Complexity drivers in engineering design
Authors: Benabdellah Abla Chaouni , Benghabrit Asmaa , Bouhaddou Imane
Published: February 2020

Purpose

In the era of industry 4.0, managing the design is a challenging mission. Within a dynamic environment, several disciplines have adopted the complex adaptive system (CAS) perspective. Therefore, this paper aims to explore how we may deepen our understanding of the design process as a CAS. In this respect, the key complexity drivers of the design process are discussed and an organizational decomposition for the simulation of the design process as CAS is conducted.

Design/methodology/approach

The proposed methodology comprises three steps. First, the complexity drivers of the design process are presented and are matched with those of CAS. Second, an analysis of over 111 selected papers is presented to choose the appropriate model for the design process from the CAS theory. Third, the paper provides methodological guidelines to develop an organizational decision support system that supports the complexity of the design process.

Findings

An analysis of the key drivers of design process complexity shows the need to adopt the CAS theory. In addition to that, a comparative analysis between all the organizational methodologies developed in the literature leads the authors to conclude that agent-oriented Software Process for engineering complex System is the appropriate methodology for simulating the design process. In this respect, a system requirements phase of the decision support system is conducted.

Originality/value

The originality of this paper lies in the fact of analysing the complexity of the design process as a CAS. In doing so, all the richness of the CAS theory can be used to meet the challenges of those already existing in the theory of the design.
Why organizational loyalty programs cannot prevent switching
Authors: Mattison Thompson Frauke , Tuzovic Sven
Published: February 2020

Purpose

The purpose of this study is to investigate the extent to which loyalty programs can prevent switching, and how individual level cultural values impact this. Loyalty programs are designed to create switching costs, which reduce customers’ desire to leave. However, in practice, these programs are often misapplied; that is, most companies inadvertently treat all customers as equal. While ample research has examined the role of loyalty reward programs in facilitating customer loyalty, little is known about the extent to which individual-level cultural values moderate customer loyalty measures of trust and affective commitment and how this impacts the effectiveness of loyalty programs; that is, consumers’ intentions to “stick” with the program or to switch.

Design/methodology/approach

This study uses a quasi-experiment combined with an extensive survey to collect the data.

Findings

Based on data collected from one industrial country and four emerging countries, the results show that loyalty programs do not universally prevent switching behavior. Instead, this study finds that individual-level uncertainty avoidance and collectivist values significantly moderate the effects.

Originality/value

This study helps advance the understanding of how international retailers can increase their loyalty program effectiveness and reduce customer switching to competitors.
Impact of surface acting and deep acting techniques on teachers’ organizational commitment
Authors: Ogunsola Kazeem Olanrewaju , Fontaine Rodrique Ancelot Harvey , Jan Muhammad Tahir
Published: February 2020

Purpose

This paper aims to examine the relationship between surface acting (SA), deep acting (DA) and organizational commitment (OC).

Design/methodology/approach

Guided by affective events theory, the study adapted emotional labour scale and three components model to profile 373 teachers from 30 schools around Peninsular Malaysia. A list-based simple random sampling technique was used to select respondents. Structural equation modeling (SEM) was used to test hypotheses, and the proposed model was assessed through renowned fit indices.

Findings

OC was hypothesized as a second-order construct. SEM result indicates that both SA and DA have significant negative relationship with OC. Fit indices of the hypothesized model showed χ²/dfratio (560.069/265) = 2.113, RMSEA (0.055), and CFI (0.936). This result provides empirical support for the data collected.

Research limitations/implications

The study provides new insight on the ongoing debate about SA and DA. Therefore, it advances body of research in this regard. The implication for HR managers is that strategic polices can be institutionalized to buffer the consequences of SA and DA. This is due to the fact that SA and DA may not be abolished for service employees like teachers. The practical implication for teachers is the understanding that emotional regulation process is inevitable because teaching is profoundly an emotional activity job. Besides being a cross-sectional study, the sampled population may have limited the study’s outcomes.

Originality/value

Given existing inconsistent results on the consequences of SA and DA, this study shows that not only SA can lead to negative after-effects, DA can also cause the same. Future study can explore spiritual intelligence to examine how best SA and DA can be performed at reduced consequences on OC.