bluuebunny/crossref_metadata_2025 huggingface dataset:
Integration of the Drug-Gene Interaction Database (DGIdb) with open crowdsource efforts
Authors: Freshour Sharon , Kiwala Susanna , Cotto Kelsy C. , Coffman Adam C. , McMichael Joshua F. , Song Jonathan , Griffith Malachi , Griffith Obi L. , Wagner Alex H.
Published: September 2020

The Drug-Gene Interaction Database (DGIdb,www.dgidb.org) is a web resource that provides information on drug-gene interactions and druggable genes from various sources including publications, databases, and other web-based sources in one resource. These drug, gene, and interaction claims are normalized and grouped to identify aliases, merge concepts, and reduce redundancy. The information contained in this resource is available to users through a straightforward search interface, an application programming interface (API), and TSV data downloads. DGIdb 4.0 is the latest major update of this database. Seven new sources have been added, bringing the total number of sources included to 41. Of the previously aggregated sources, 15 have been updated. DGIdb 4.0 also includes improvements to the process of drug normalization and grouping of imported sources. Other notable updates include further development of automatic jobs for routine data updates, more sophisticated query scores for interaction search results, extensive manual curation of interaction source link outs, and the inclusion of interaction directionality. A major focus of this update was integration with crowd-sourced efforts, including leveraging the curation activities of Drug Target Commons, using Wikidata to facilitate term normalization, and integrating into NDEx for producing network representations.
Multiscale model of heart growth during pregnancy: Integrating mechanical and hormonal signaling
Authors: Yoshida Kyoko , Saucerman Jeffrey J. , Holmes Jeffrey W.
Published: September 2020

Pregnancy stands at the interface of mechanics and biology. The growing fetus continuously loads the maternal organs as circulating hormone levels surge, leading to significant changes in mechanical and hormonal cues during pregnancy. In response, maternal soft tissues undergo remarkable growth and remodeling to support the mother and baby for a healthy pregnancy. We focus on the maternal left ventricle, which increases its cardiac output and mass during pregnancy. This study develops a multiscale cardiac growth model for pregnancy to understand how mechanical and hormonal cues interact to drive this growth process. We coupled a cell signaling network model that predicts cell-level hypertrophy in response to hormones and stretch to a compartmental model of the rat heart and circulation that predicts organ-level growth in response to hemodynamic changes. We calibrated this multiscale model to data from experimental volume overload (VO) and hormonal infusions of angiotensin 2 (AngII), estrogen (E2), and progesterone (P4). We then validated the model’s ability to capture interactions between inputs by comparing model predictions against published observations for the combinations of VO+E2 and AngII+E2. Finally, we simulated pregnancy-induced changes in hormones and hemodynamics to predict heart growth during pregnancy. Our model produced growth consistent with experimental data. Overall, our analysis suggests that the rise in P4 during the first half of gestation is an important contributor to heart growth during pregnancy. We conclude with suggestions for future experimental studies that will provide a better understanding of how hormonal and mechanical cues interact to drive pregnancy-induced heart growth.
Live imaging of breast tumors shows macrophage-dependent induction and TMEM-mediated enrichment of cancer stem cells during metastatic dissemination
Authors: Sharma Ved P , Tang Binwu , Wang Yarong , Karagiannis George S , Xue Emily A , Entenberg David , Borriello Lucia , Coste Anouchka , Duran Camille L , Eddy Robert J , Kim Gina , Ye Xianjun , Jones Joan G , Grunblatt Eli , Agi Nathan , Roy Sweta , Bandyopadhyaya Gargi , Adler Esther , Surve Chinmay R , Esposito Dominic , Goswami Sumanta , Guo Wenjun , Condeelis John S , Wakefield Lalage M. , Oktay Maja H
Published: September 2020

Cancer stem cells (CSCs) play an important role during metastasis, but the dynamic behavior and induction mechanisms of CSCs are not well understood. We employed high-resolution intravital microscopy using a CSC biosensor to directly observe CSCs in live mice with mammary tumors. CSCs display the slow-migratory, invadopod-rich phenotype that is the hallmark of disseminating tumor cells. CSCs are enriched near macrophages, particularly near macrophage-containing intravasation sites called Tumor Microenvironment of Metastasis (TMEM) doorways. A dramatic enrichment of CSCs occurs on association with TMEM doorways, contributing to the finding that CSCs represent ∼>60% of circulating tumor cells. Mechanistically, stemness is induced in non-stem cancer cells upon their direct contact with macrophages via Notch signaling. In breast cancers from patients, the density of TMEM doorways correlates strongly with the proportion of cancer cells expressing stem cell markers, indicating that in human breast cancer TMEM doorways are not only cancer cell intravasation portals but also CSC programming sites.

One Sentence Summary

Intravital imaging reveals macrophage-mediated induction of cancer stem cells in vivo and their dramatic enrichment on dissemination through TMEM doorways.
Seed morphological traits as a tool to quantify variation maintained inex situcollections: a case study inPinus torreyana(Parry)
Authors: Di Santo Lionel N , Polgar Monica , Nies Storm , Hodgkiss Paul , Canning Courtney A , Wright Jessica W , Hamilton Jill A
Published: September 2020

Background

Understanding the within- and among-population distribution of trait variation within seed collections may provide a means to approximate standing genetic variation and inform plant conservation.

Aims

This study aimed to estimate population- and family-level seed trait variability for existing seed collections of Torrey pine (Pinus torreyana), and to use these data to guide sampling of future collections.

Methods

We quantified variation in 14 seed morphological traits and seedling emergence within and among Torrey pine populations. Using a simulation-based approach, we used estimates of within-population variance to assess the number of maternal families required to capture 95% of trait variation within each existing seed collection.

Results

Substantial structure was observed both within and among Torrey pine populations, with island and mainland seeds varying in seed size and seed coat thickness. Despite morphological differences, seedling emergence was similar across populations. Simulations revealed that 83% and 71% of all maternal families within island and mainland seed collections respectively needed to be resampled to capture 95% of seed trait variation within existing collections.

Conclusions

From a conservation perspective, our results indicate that to optimize genetic diversity captured in Torrey pine seed collections, maximizing the number of maternal families sampled within each population will be necessary.
Tracking single molecule dynamics in the anesthetizedDrosophilabrain
Authors: Hines Adam D. , van Swinderen Bruno
Published: September 2020

Super-resolution microscopy provides valuable insight for understanding the nanoscale organization within living tissue, although this method is typically restricted to cultured or dissociated cells. Here, we develop a method to track the mobility of individual proteins inex vivoadultDrosophila melanogasterbrains, focusing on a key component of the presynaptic release machinery, syntaxin1A. We show that individual syntaxin1A dynamics can be reliably tracked within neurons in the whole fly brain, and that the mobility of syntaxin1A molecules increases following conditional neural stimulation. We then apply this preparation to the problem of general anesthesia, to address how different anesthetics might affect single molecule dynamics in intact brain synapses. We find that propofol, etomidate, and isoflurane significantly impair syntaxin1A mobility, while ketamine and sevoflurane have little effect. Resolving single molecule dynamics in intact fly brains provides a novel approach to link localized molecular effects with systems-level phenomena such as general anesthesia.

Impact statement

A new approach to track the mobility of individual molecules using intact fly brains reveals a common presynaptic effect for different intravenous and volatile general anesthetics.
Evolutionary and Structural Constraints Influencing Apolipoprotein A-I Amyloid Behaviour
Authors: Gisonno RA , Masson T , Ramella N , Barrera EE , Romanowski V , Tricerri MA
Published: September 2020

Apolipoprotein A-I (apoA-I) has a key function in the reverse cholesterol transport mediated by the high density lipoprotein (HDL) particles. However, aggregation of apoA-I single point mutants can lead to hereditary amyloid pathology. Although several studies have tackled the biophysical and structural impacts introduced by these mutations, there is little information addressing the relationship between the evolutionary and structural features that contribute to the amyloid behavior of apoA-I. We combined evolutionary studies, in silico mutagenesis and molecular dynamics (MD) simulations to provide a comprehensive analysis of the conservation and pathogenic role of the aggregation-prone regions (APRs) present in apoA-I. Sequence analysis demonstrated that among the four amyloidogenic regions described for human apoA-I, only two (APR1 and APR4) are evolutionary conserved across different species of Sarcopterygii. Moreover, stability analysis carried out with the FoldX engine showed that APR1 contributes to the marginal stability of apoA-I. Structural properties of the full-length apoA-I model suggest that aggregation is avoided by placing APRs into highly packed and rigid portions of its native fold. Following we set up to study the effect of natural mutations on protein conformation and stability. Compared to natural silent variants extracted from the gnomAD database, the thermodynamic and pathogenic impact of apoA-I amyloid mutations showed evidence of a higher destabilizing effect. MD simulations of the amyloid variant G26R evidenced the partial unfolding of the alpha-helix bundle with the concomitant exposure of APR1 to the solvent and the formation of beta-sheet segments at the C-terminus of apoA-I, giving a possible hint about the early steps involved in its aggregation. Our findings highlight APR1 as a relevant component for apoA-I structural integrity and emphasize a destabilizing effect of amyloid variants that leads to the exposure of this region. This information contributes to our understanding of how apoA-I, with its high degree of structural flexibility, maintains a delicate equilibrium between its monomeric native structure and intrinsic tendency to form amyloid aggregates. In addition, our stability measurements could be used as a proxy to interpret the structural impact of new mutations.
The Dual Mechanisms of Cognitive Control (DMCC) Project
Authors: Braver Todd S. , Kizhner Alexander , Tang Rongxiang , Freund Michael C. , Etzel Joset A.
Published: September 2020

The Dual Mechanisms of Cognitive Control (DMCC) project provides an ambitious and rigorous empirical test of a theoretical framework that posits two key cognitive control modes: proactive and reactive. The framework’s central tenets are that proactive and reactive control reflect domain-general dimensions of individual variation, with distinctive neural signatures, involving lateral prefrontal cortex (PFC) in interactions with other brain networks and circuits (e.g., frontoparietal, cingulo-opercular). In the DMCC project, each participant is scanned while performing theoretically-targeted variants of multiple well-established cognitive control tasks (Stroop, Cued Task-Switching, AX-CPT, Sternberg Working Memory) in three separate imaging sessions, that each encourage utilization of different control modes, plus also completes an extensive out-of-scanner individual differences battery. Additional key features of the project include a high spatio-temporal resolution (multiband) acquisition protocol, and a sample that includes a substantial subset of monozygotic twin pairs and participants recruited from the Human Connectome Project. Although data collection is still continuing (target N=200), we provide an overview of the study design and protocol, planned analytic approaches and methodological development, along with initial results (N=80) revealing novel evidence of a domain-general neural signature of reactive control. In the interests of scientific community building, the dataset will be made public at project completion, so it can serve as a valuable resource.
Understanding and Improving Word Embeddings through a Neuroscientific Lens
Authors: Fereidooni Sam , Mocz Viola , Radev Dragomir , Chun Marvin
Published: September 2020

Despite the success of models making use of word embeddings on many natural language tasks, these models often perform significantly worse than humans on several natural language understanding tasks. This difference in performance motivates us to ask: (1) if existing word vector representations have any basis in the brain’s representational structure for individual words, and (2) whether features from the brain can be used to improve word embedding model performance, defined as their correlation with human semantic judgements. To answer the first question, we compare the representational spaces of existing word embedding models with that of brain imaging data through representational similarity analysis. We answer the second question by using regression-based learning to constrain word vectors to the features of the brain imaging data, thereby determining if these modified word vectors exhibit increased performance over their unmodified counterparts. To collect semantic judgements as a measure of performance, we employed a novel multi-arrangement method. Our results show that there is variance in the representational space of the brain imaging data that remains uncaptured by word embedding models, and that brain imaging data can be used to increase their coherence with human performance.
SERUM ANTIBODY RESPONSES AGAINST CARBAPENEM-RESISTANTKLEBSIELLA PNEUMONIAEIN INFECTED PATIENTS
Authors: Banerjee Kasturi , Motley Michael P. , Diago-Navarro Elizabeth , Fries Bettina C.
Published: September 2020

Background

Capsular polysaccharide (CPS) heterogeneity within carbapenem-resistantKlebsiella pneumoniae(CR-Kp) strain ST258 must be considered when developing CPS-based vaccines. We sought to characterize CPS-specific antibody responses elicited by CR-Kpinfected patients.

Method

Plasma and bacterial isolates were collected from 33 hospital patients with positive CR-Kpculture. Isolates capsule were typed bywzisequencing. Reactivity and measures of efficacy of patient antibodies were studied against 3 prevalent CR-KpCPS types (wzi29, 154and50).

Results

High IgG titers againstwzi154andwzi50CPS were documented in 79% of infected patients. Patient-derived (PD) IgGs agglutinated CR-Kpand limited growth better than naïve IgG, and promoted phagocytosis of strains across the serotype isolated from their donors. Additionally, poly-IgG fromwzi50 and wzi154patients promoted phagocytosis of non-concordant CR-Kp serotypes. Such effects were lost when poly-IgG was depleted of CPS-specific IgG. Additionally, mice infected withwzi50, wzi154, and wzi29CR-Kpstrains pre-opsonized withwzi50patient-derived IgG exhibited lower lung CFU than controls. Depletion ofwzi50Abs reversed this effect inwzi50 and wzi154infections, whereas wzi154 Ab depletion reduced Poly-IgG efficacy againstwzi29CR-Kp.

Conclusions

We are first to report cross-reactive properties of CPS-specific Abs from CR-Kppatients through bothin-vitroandin-vivomodels.

Importance

Carbapenem-resistantKlebsiella pneumoniaeis a rapidly emerging public health threat that can cause fatal infections in ~40-50% of immunocompromised patients. Due to its resistance to nearly all antimicrobials, development of alternate therapies like antibodies and vaccines are urgently needed. Capsular polysaccharides are emerging as important immunotargets as they are a crucial forKlebsiella pneumoniaepathogenesis. Studying how host’s immune system protect against specific bacteria such asKlebsiella pneumoiniae, with respect to their specific capsule-type is crucial to develop effective anti-CPS immunotherapies. In this manuscript, we are the first to characterize humoral responses developed in infected patients against carbapenem-resistantKlebsiella pneumoniaeexpressing differentwzi-capsule types. This study is the first to report efficacy of cross-reactive properties of CPS-specific Abs in bothin-vitroandin-vivomodels.
A digital 3D reference atlas reveals cellular growth patterns shaping the Arabidopsis ovule
Authors: Vijayan Athul , Tofanelli Rachele , Strauss Soeren , Cerrone Lorenzo , Wolny Adrian , Strohmeier Joanna , Kreshuk Anna , Hamprecht Fred A. , Smith Richard S. , Schneitz Kay
Published: September 2020

A fundamental question in biology is how morphogenesis integrates the multitude of distinct processes that act at different scales, ranging from the molecular control of gene expression to cellular coordination in a tissue. Investigating morphogenesis of complex organs strongly benefits from three-dimensional representations of the organ under study. Here, we present a digital analysis of ovule development fromArabidopsis thalianaas a paradigm for a complex morphogenetic process. Using machine-learning-based image analysis we generated a three-dimensional atlas of ovule development with cellular resolution. It allows quantitative stage- and tissue-specific analysis of cellular patterns. Exploiting a fluorescent reporter enabled precise spatial determination of gene expression patterns, revealing subepidermal expression ofWUSCHEL. Underlying the power of our approach, we found that primordium outgrowth progresses evenly, discovered a novel mode of forming a new cell layer, and detected a new function ofINNER NO OUTERin restricting cell proliferation in the nucellus. Moreover, we identified two distinct subepidermal cell populations that make crucial contributions to ovule curvature. Our work demonstrates the expedience of a three-dimensional digital representation when studying the morphogenesis of an organ of complex cellular architecture and shape that eventually consists of 1,900 cells.
ADe NovoGenome Assembly, Gene Annotation, And Expression Atlas For The Monarch ButterflyDanaus plexippus
Authors: Ranz José M. , González Pablo M. , Clifton Bryan D. , Nazario Nestor O. , Hernández-Cervantes Pablo L. , Palma-Martínez María J. , Valdivia Dulce I. , Jiménez-Kaufman Andrés , Lu Megan M. , Markow Therese A. , Abreu-Goodger Cei
Published: September 2020

The monarch butterfly epitomizes insect biodiversity decline. Understanding the genetic basis of the adaptation of the monarch to a changing environment requires genomic and transcriptomic resources that better reflect its genetic diversity while being informative about gene functionality during life cycle. We report a reference-quality genome assembly from an individual resident at a nonmigratory colony in Mexico, and a new gene annotation and expression atlas for 14,865 genes, including 492 unreported long noncoding RNA (lncRNA) genes, based on RNA-seq data from 14 larval and pupal stages, plus adult morphological sections. Two thirds of the genes show significant expression changes associated with a life stage or section, with lncRNAs being more finely regulated during adulthood than protein-coding genes, and male-biased expression being four times more common than female-biased. The two portions of the heterochromosomeZdisplay distinct patterns of differential expression between the sexes, reflecting that dosage compensation is either absent or incomplete –depending on the sample– in the ancestral but not in the novel portion of theZ. This study represents a major advance in the genomic and transcriptome resources available forD. plexippuswhile providing the first systematic analysis of its transcriptional program across most of its life cycle.
Gonadotropin-releasing hormone increases the release of extracellular vesicles from gonadotropes
Authors: Fungbun Numfa , Sugiyama Makoto , Terashima Ryota , Kurusu Shiro , Kawaminami Mitsumori
Published: September 2020

While extracellular vesicles play a role in intercellular communication, it is not known how their release is regulated. We show here that hypothalamic gonadotropin-releasing hormone (GnRH) stimulates extracellular vesicle (EV) formation associated with annexin A5 (ANXA5) from pituitary gonadotropes. The results show that 1) membrane blebs containing ANXA5 are produced after GnRH agonist (GnRHa) stimulation of gonadotropes and that this is observedin situas a loss of distinction at cell-cell boundaries, 2) EV containing ANXA5 are increased by GnRHa, 3) a gonadotrope-derived EV fraction stimulates LH release from other gonadotropes, and 4) an increase in ANXA5-loaded EV occurs in the plasma of ovariectomized rats. Finally, we also showed that 5) GnRHa stimulation of blebbing and EV-ANXA5 were suppressed by a protein kinase A inhibitor. These present results demonstrate a novel autocrine/paracrine mechanism mediated through the production of EV containing ANXA5. A hormonal regulation mechanism of cell-cell communication by means of EV is suggested.
Predicting range shifts of three endangered endemic plants of the Khorassan-Kopet Dagh floristic province under global change
Authors: Erfanian Mohammad Bagher , Sagharyan Mostafa , Memariani Farshid , Ejtehadi Hamid
Published: September 2020

Khorassan-Kopet Dagh (KK) floristic province is an ecoregion that has rarely been studied. A total number of 2576 (356 endemic) vascular plants have been recorded from this area. Most of the endemic species of KK are rare and range-restricted. To assess the vulnerability of plant species under a rapidly changing climate, we can use species distribution modelling (SDM) to predict their potential present and future distribution. We used SDM to evaluate range size changes for three (critically) endangered endemic species to KK, namelyNepeta binaloudensis, Phlomoides binaludensis, andEuphorbia ferdowsiana. These plants represent KK endemic species that grow in the different elevation ranges of KK mountains. Using the HadGEM2-ES general circulation model and two Representative Concentration Pathways Scenarios (RCP), including RCP 2.6 (most optimistic) and RCP 8.5 (most pessimistic), we predicted the potential present and future (i.e., 2050 and 2070) distribution for each species. The ensemble model of nine different methods was used for this prediction. Our results showed that, except forP. binaludensisthat will face range contraction, the other species would benefit from potential range expansion in the future.Euphorbia ferdowsianawill remain limited to a narrow range of KK. However, the other two plants will have suitable habitats in various mountains of KK. To conserve flora of KK, we urge using management efforts with a focus on providing elevational migration routes at the local scales in KK mountains. Additionally, assisted migration among different mountains of this region will be beneficial to conserve its endemic plants. ForE. ferdowsianagenetic diversity storage employing seed banks and botanical garden preservation should be considered.
Si-C: method to infer biologically valid super-resolution intact genome structure from single-cell Hi-C data
Authors: Meng Luming , Wang Chenxi , Yi Shi , Luo Qiong
Published: September 2020

There is a strong demand for the methods that can efficiently reconstruct biologically valid super-resolution intact genome 3D structures from sparse and noise single-cell Hi-C data. Here, we developed Single-Cell Chromosome Conformation Calculator (Si-C) within the Bayesian theory framework and applied this approach to reconstruct intact genome 3D structures from the single-cell Hi-C data of eight G1-phase haploid mouse ES cells. The inferred 100-kb and 10-kb structures consistently reproduce the known conserved features of chromatin organization revealed by independent imaging experiments. The analysis of the 10-kb resolution 3D structures revealed cell-to-cell varying domain structures in individual cells and hyperfine structures in domains, such as loops. An average of 0.2 contact reads per divided bin is sufficient for Si-C to obtain reliable structures. The valid super-resolution structures constructed by Si-C demonstrates the potential for visualizing and investigating interactions between all chromatin loci at genome scale in individual cells.
Thalamocortical spectral transmission relies on balanced input strengths
Authors: Saponati Matteo , Garcia-Ojalvo Jordi , Cataldo Enrico , Mazzoni Alberto
Published: September 2020

The thalamus is a key element of sensory transmission in the brain, as all sensory information is processed by the thalamus before reaching the cortex. The thalamus is known to gate and select sensory streams through a modulation of its internal activity in which spindle oscillations play a preponderant role, but the mechanism underlying this process is not completely understood. In particular, how do thalamocortical connections convey stimulus-driven information selectively over the background of thalamic internally generated activity (such as spindle oscillations)? Here we investigate this issue with a spiking network model of connectivity between thalamus and primary sensory cortex reproducing the local field potential of both areas. We found two features of the thalamocortical dynamics that filter out spindle oscillations: i) spindle oscillations are weaker in neurons projecting to the cortex, ii) the resonance dynamics of cortical networks selectively blocks frequency in the range encompassing spindle oscillations. This latter mechanism depends on the balance of the strength of thalamocortical connections toward excitatory and inhibitory neurons in the cortex. Our results pave the way toward an integrated understanding of the sensory streams traveling between the periphery and the cortex.
First report of nematodes inLutzomyia edwardsi(Diptera: Psychodidae, Phlebotominae) in cave, in the municipality of Sumidouro, State of Rio of Janeiro, Brazil
Authors: Carreira Alves João Ricardo , do Carmo Cleber Nascimento , Menezes Rodrigo Caldas , Vilela Mauricio Luís , dos Santos-Mallet Jacenir Reis
Published: September 2020

It is registered for the first time, the encounter ofLutzomyia edwardsi(Mangabeira) species of sandfly considered as a probable vector ofLeishmania(Viannia)braziliensis(Vianna), main etiological agent of American cutaneous leishmaniasis in humans, for the municipality of Sumidouro, State of Rio of Janeiro. Leishmaniasis is currently considered a neglected tropical disease in the Americas. The objective of this study was to know the phlebotomine fauna in an area of Atlantic forest, with a cave in this municipality. From the sandflies collected, in 2009 and 2010, with a light trap, type CDC it is reported in a unique way, the encounter of a femaleL. edwardsi, infected with nematodes in a cave in the locality of São Caetano, in Sumidouro, state of Rio of Janeiro, Brazil. The description of sandfly and nematodes was carried out. The presence of this species in areas of leishmaniasis cases in the municipality of Sumidouro and its surroundings, requires the adoption of relevant entomological and / or epidemiological surveillance, by the Municipal Health Department of the region, when registering this disease.
The regulatory function of the AAA4 ATPase domain of cytoplasmic dynein
Authors: Liu Xinglei , Rao Lu , Gennerich Arne
Published: September 2020

Cytoplasmic dynein is the primary motor for microtubule minus-end-directed transport and is indispensable to eukaryotic cells. Although each motor domain of dynein contains three active AAA+ ATPases (AAA1, 3, and 4), only the functions of AAA1 and 3 are known. Here, we use single-molecule fluorescence and optical tweezers studies to elucidate the role of AAA4 in dynein’s mechanochemical cycle. We demonstrate that AAA4 controls the priming stroke of the motion-generating linker, which connects the dimerizing tail of the motor to the AAA+ ring. Before ATP binds to AAA4, dynein remains incapable of generating motion. However, when AAA4 is bound to ATP, the gating of AAA1 by AAA3 prevails and dynein motion can occur. Thus, AAA1, 3, and 4 work together to regulate dynein function. Our work elucidates an essential role for AAA4 in dynein’s stepping cycle and underscores the complexity and crosstalk among the motor’s multiple AAA+ domains.
D1, not D2, dopamine receptor activation dramatically improves MPTP-induced parkinsonism unresponsive to levodopa
Authors: Mailman Richard B. , Yang Yang , Huang Xuemei
Published: September 2020

Abstract

Levodopa is the Parkinson’s disease standard-of-care, but continued loss of dopamine neurons with disease progression decreases its bioconversion to dopamine, leading to increased side effects and decreased efficacy. In theory, dopamine agonists could equal levodopa, but no approved oral “dopamine agonist” matches the efficacy of levodopa. Although there are consistent data in both primate models and in Parkinson’s disease showing that selective high intrinsic activity D1agonists can equal levodopa, there are no data on whether such compounds would be effective in severe disease when levodopa efficacy is lower or even absent. We compared two approved antiparkinson drugs (levodopa and the D2/3agonist bromocriptine) with the experimental selective D1full agonist dihydrexidine in two severely parkinsonian MPTP-treated non-human primates. Bromocriptine caused no discernable improvement in parkinsonian signs, whereas levodopa caused a small transient improvement in one of the two subjects. Conversely, the full D1agonist dihydrexidine caused a dramatic improvement in both subjects, decreasing parkinsonian signs by ca. 75%. No attenuation of dihydrexidine effects was observed when the two subjects were pretreated with the D2antagonist remoxipride. These data provide evidence that selective D1agonists may provide profound antiparkinson symptomatic relief even when the degree of nigrostriatal degeneration is so severe that current drugs are ineffective. Until effective disease-modifying therapies are discovered, high intrinsic activity D1agonists may offer a major therapeutic advance in improving the quality of life, and potentially the longevity, of late stage Parkinson’s patients.
Diesel2p mesoscope with dual independent scan engines for flexible capture of dynamics in distributed neural circuitry
Authors: Yu Che-Hang , Stirman Jeffrey N. , Yu Yiyi , Hira Riichiro , Smith Spencer L.
Published: September 2020

Imaging the activity of neurons that are widely distributed across brain regions deep in scattering tissue at high speed remains challenging. Here, we introduce an open-source system with Dual Independent Enhanced Scan Engines for Large Field-of-view Two-Photon imaging (Diesel2p). Combining novel optical design, adaptive optics, and temporal multiplexing, the system offers subcellular resolution over a large field-of-view (∼ 25 mm2) with independent scan engines. We demonstrate the flexibility and various use cases of this system for calcium imaging of neurons in the living brain.
Pre-determined macromolecular leakage sites with dynamic properties establish endothelial intra-vessel heterogeneity
Authors: Richards M , Venkatraman L , Claesson-Welsh L
Published: September 2020

Endothelial cells display heterogeneous properties based on location and function. How this heterogeneity influences endothelial barrier stability both between and within vessel subtypes is unexplored. We find here that endothelial cells exhibit heterogeneous barrier properties on inter-organ and intra-vessel levels. Using intravital microscopy and sequential stimulation of the ear dermis with vascular endothelial growth factor-A and/or histamine, we observe distinct, reappearing sites, common for both agonists, where leakage preferentially takes place. Further, through repetitive stimulation of the diaphragm and trachea, we find inter-organ conservation of such leakage sites. Qualitatively, pre-determined sites display distinct leakage properties and enhanced barrier breakdown compared to less susceptible regions. Mechanistically, pre-determined sites exhibit lower laminin α5 deposition, which correlates with reduced junctional vascular endothelial (VE)-Cadherin. These data thus highlight functional intra-vessel heterogeneity that defines pre-determined sites which display distinct leakage properties and which may have great impact on pathological vascular leakage and drug delivery.
MICAL2 acts through Arp3B isoform-specific Arp2/3 complexes to destabilize branched actin networks
Authors: Galloni Chiara , Carra Davide , Abella Jasmine V. G. , Kjær Svend , Singaravelu Pavithra , Barry David J , Kogata Naoko , Guérin Christophe , Blanchoin Laurent , Way Michael
Published: September 2020

The Arp2/3 complex (Arp2, Arp3 and ARPC1-5) is essential to generate branched actin filament networks for many cellular processes. Human Arp3, ARPC1 and ARPC5 exist as two isoforms but the functional properties of Arp2/3 iso-complexes is largely unexplored. Here we show that Arp3B, but not Arp3 is subject to regulation by the methionine monooxygenase MICAL2, which is recruited to branched actin networks by coronin-1C. Although Arp3 and Arp3B iso-complexes promote actin assembly equally efficiently in vitro, they have different cellular properties. Arp3B turns over significantly faster than Arp3 within the network and upon its depletion actin turnover decreases. Substitution of Arp3B Met293 by Thr, the corresponding residue in Arp3 increases actin network stability, and conversely, replacing Arp3 Thr293 with Gln to mimic Met oxidation promotes network disassembly. Thus, MICAL2 regulates a subset of Arp2/3 complexes to control branched actin network disassembly.
PRAM: a novel pooling approach for discovering intergenic transcripts from large-scale RNA sequencing experiments
Authors: Liu Peng , Soukup Alexandra A. , Bresnick Emery H. , Dewey Colin N. , Keleş Sündüz
Published: September 2020

Publicly available RNA-seq data is routinely used for retrospective analysis to elucidate new biology. Novel transcript discovery enabled by joint analysis of large collections of RNA-seq data sets has emerged as one such analysis. Current methods for transcript discovery rely on a ‘2-Step’ approach where the first step encompasses building transcripts from individual data sets, followed by the second step that merges predicted transcripts across data sets. To increase the power of transcript discovery from large collections of RNA-seq data sets, we developed a novel ‘1-Step’ approach named Pooling RNA-seq and Assembling Models (PRAM) that builds transcript models from pooled RNA-seq data sets. We demonstrate in a computational benchmark that 1-Step outperforms 2-Step approaches in predicting overall transcript structures and individual splice junctions, while performing competitively in detecting exonic nucleotides. Applying PRAM to 30 human ENCODE RNA-seq data sets identified unannotated transcripts with epigenetic and RAMPAGE signatures similar to those of recently annotated transcripts. In a case study, we discovered and experimentally validated new transcripts through the application of PRAM to mouse hematopoietic RNA-seq data sets. We uncovered new transcripts that share a differential expression pattern with a neighboring gene Pik3cg implicated in human hematopoietic phenotypes, and we provided evidence for the conservation of this relationship in human. PRAM is implemented as an R/Bioconductor package.
Price bubbles in agricultural commodity markets and contributing factors: evidence for corn and soybeans in China
Authors: Mao Qianqian , Ren Yanjun , Loy Jens-Peter
Published: September 2020

Purpose

The purpose of this paper is to detect the existence of price bubbles and examine the possible contributing factors that associate with price bubble occurrences in China agricultural commodity markets.

Design/methodology/approach

Using recently developed rolling window right-side augmented Dickey–Fuller test, we first detect the dates of price bubbles in China's two important agricultural commodity markets, namely corn and soybeans. Then, we use a penalized maximum likelihood estimation of a multinomial logistic model to estimate the contributing factors of price bubbles in both markets, respectively.

Findings

Results from the bubble detection indicate that price bubbles account for 5.48% (3.91%) of the studied periods for corn (soybeans). More importantly, we find that market liquidity and speculation have opposite effects on the occurrences of bubbles in the corn and soybeans market. World stocks-to-use and exchange rates affect the occurrences of bubbles in a different way for each commodity, as well. Price bubbles are more likely associated with strong economic activity, high interest rates and low inflation levels.

Originality/value

This is the first study considering commodity-specific features into the formation of price bubbles. Through accurately identifying the bubble dates and fixing the estimation bias of rare events models, this study enables us to obtain robust results for each commodity. The results imply that China's corn and soybeans market respond differently to the speculative activity and external shocks from international markets. Therefore, future policy regulations on commodity markets should focus on more commodity-specific factors when aiming at avoiding bubble occurrences.
A multilevel approach to competence management in innovative small and medium-sized enterprises (SMEs): literature review and research agenda
Authors: Loufrani-Fedida Sabrina , Aldebert Bénédicte
Published: September 2020

Purpose

This paper aims to improve the understanding of competence management in innovative small and medium-sized enterprises (SMEs) through a multilevel approach.

Design/methodology/approach

This paper adopts a three-part structure to propose a conceptual and theoretical framework. It first explores the full scope of multilevel approaches to human resource management research, both in theory and in practice. It then reviews the literature on competence management in innovative SMEs, before demonstrating that the topic is a multilevel phenomenon. Finally, it reflects on the research and methodology implications, identifies limitations and provides suggestions for future research.

Findings

This literature review shows that competence management in innovative SMEs is a multilevel phenomenon. It outlines the research and methodology implications, identifies limitations and suggests future research directions.

Originality/value

The overarching contribution is to offer a literature review and a research agenda for a multilevel approach to competence management in the development of innovative SMEs.
New ventures as value cocreators in digital ecosystems
Authors: Prashantham Shameen
Published: September 2020

Purpose

To stimulate further research aimed at understanding how value can be cocreated by participants in digital ecosystems, this paper draws attention to new ventures as focal actors in innovation ecosystems orchestrated by hub firms.

Design/methodology/approach

This is a conceptual article that imports the notion of network oscillation (a pattern of brokerage-closure-brokerage) from social network studies to the conversation on digital ecosystems.

Findings

One potential pattern that a new venture may pursue to increase its prospects of cocreating value in an innovation ecosystem includes: (1) brokerage to gain managerial attention from a business unit of the hub firm, (2) switching to closure to attract attention from the wider hub firm (e.g. headquarters) and (3) reverting to brokerage to pursue synergistic network expansion opportunities from the wider interfirm ecosystem.

Research limitations/implications

The exploratory ideas in this paper can help advance both entrepreneurship and information systems research.

Originality/value

This paper offers preliminary ideas on egocentric network dynamics associated with a new venture partnering with a large ecosystem hub firm. Such a perspective is appropriate since achieving value creation through active partnering requires building and strengthening ties over time across the hub firm's ecosystem.
Budgetary responses to COVID-19: the case of South Korea
Authors: Kim Bong Hwan
Published: September 2020

Purpose

This paper presents the details, circumstances and issues relating to Korea's budgetary responses to COVID-19.

Design/methodology/approach

The author analyzes the details and consequences of budget responses to COVID-19 of Korea.

Findings

Korea has implemented two supplementary budgets, worth 50 tn KRW, which were approved by the National Parliament within an average of 13 days. This was an exceptionally quick approval by the Parliament. While these prompt actions help the government provide necessary measures to combat the pandemic, hasty decisions may have long-term consequences on fiscal soundness. Effective handling of COVID-19 in Korea increased the approval rating for the current administration.

Originality/value

This is consistent with the argument by Bartels (2013) who states that ordinary citizens assess politicians and policies primarily on the basis of visible evidence of success or failure. Because evaluations on government projects other than handling crisis is out of people's interests during pandemic, inefficient projects tend to be maintained. For future, it is desirable to have a fiscal rule beforehand to address a crisis.
Reflections on the Austrian COVID-19 budgetary emergency measures and their potential to reconfigure the public financial management system
Authors: Seiwald Johann , Polzer Tobias
Published: September 2020

Purpose

Crises constitute stress tests for public sectors, with public financial management (PFM) systems having to respond to emergency needs. In this study, the authors analyze (1) what elements of the Austrian PFM system have been affected by the COVID-19 pandemic and (2) what mechanisms have been applied to close identified gaps in the PFM system and to ensure alignment with budget principles. The authors then reflect on these PFM measures.

Design/methodology/approach

The research departs from the pre-crisis configuration of the Austrian PFM system. Making use of a data triangulation strategy, the paper analyses draft laws and regulations with corresponding explanatory notes and impact assessments, transcripts from debates in the federal Parliament and articles and commentaries issued by various stakeholders.

Findings

The analysis of five areas relevant to the reconfiguration of the Austrian PFM system shows that the pandemic has caused an external shock, but at the same time, the current system has not been challenged in substance and has been utilized to react to the pandemic—resulting in (ad hoc) modifications. The system has proved robust and crisis responsive; however, in a reactive pattern, emerging ad hoc elements have been integrated, with a number of defensive mechanisms ensuring compliance with budget principles. In addition, in some areas, more proactive actions have been taken for closing system gaps (e.g. risk disclosure).

Originality/value

The authors evaluate the likelihood of (proposed, decided and implemented) emerging elements or revisions to a PFM system being embedded into the existing PFM system, alongside reflecting on results and necessary further adjustments.
Citizen science versus professional data collection: Comparison of approaches to mosquito monitoring in Germany
Authors: Pernat Nadja , Kampen Helge , Jeschke Jonathan M. , Werner Doreen
Published: September 2020

Due to the recent emergence of invasive mosquito species and the outbreaks of mosquito‐borne diseases in Europe, research on the ecology and diversity of the mosquito fauna has returned to scientific agendas. Through a nationwide surveillance programme in Germany, mosquitoes have been monitored actively by systematically operated traps since 2011, and passively by the ‘Mückenatlas’ (mosquito atlas) citizen science project launched in 2012.

To assess the performance of both monitoring methods we compared the two respective datasets with regard to habitat coverage, species composition and the ability to detect invasive mosquitoes. The datasets include observations from the beginning of the project until the end of 2017.

We found significant differences in species composition caused by land use types and the participants’ recording activity. Active monitoring performed better in mapping mosquito diversity, whereas passive monitoring better detected invasive species, thereby using data from private premises scientists usually cannot access.

Synthesis and applications. Active and passive monitoring is complementary. Combining them allows for the determination of mosquito diversity, efficient detection of emerging invasive species and the initiation of rapid‐response actions against such invaders. The ‘Mückenatlas’ sets an example for the usefulness of citizen science when included in a national monitoring programme, an approach that may be worth copying for tackling the global spread of arthropod vectors of disease agents.
Mismatched spatial scales can limit the utility of citizen science data for estimating wildlife‐habitat relationships
Authors: Bauder Javan M. , Cervantes Alyson M. , Avrin Alexandra C. , Whipple Laura S. , Farmer Morgan J. , Miller Craig A. , Benson Thomas J. , Stodola Kirk W. , Allen Maximilian L.
Published: September 2020

While most carnivore populations are declining worldwide, some species are successfully living in human‐modified landscapes. For example, coyotes (Canis latrans) have expanded their range across North America and into many urban areas making it important to understand factors influencing broad‐scale patterns of occurrence. We used citizen science data in the form of coyote observations by archery deer hunters from throughout the state of Illinois to evaluate factors affecting coyote detection and occupancy. Our statewide participant‐level occupancy estimate (0.63) was 58% greater than our naïve occupancy estimate (0.40) while detection probability was <0.25, highlighting the importance of using modeling frameworks that account for imperfect detection when modeling occupancy of cryptic species with low detection rates. Time period (AM/PM) had the largest effect on detection of coyotes, with detections greater in the AM. The number of hours hunted (analogous to effort) also impacted coyote detection, with more hours hunted increasing coyote detections. In contrast, none of the landscape covariates examined had strong effects on coyote occupancy. While coyote ubiquity and generalist habitat use may at least partially explain our results, we suspect it also is because the landscape covariates were measured at the county level, as more precise participant location data were unavailable, whereas participants effectively surveyed a much smaller area. Since scale affects the strength and direction of species‐habitat relationships, this scale mismatch is likely an important limitation when using many sources of citizen scientist observations to infer species‐habitat relationships for widespread generalist species when precise participant location data are unavailable.