bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating equations for measuring dissolved inorganic nutrient uptake in oligotrophic conditions
Authors: Stukel Michael R. 
Published: September 2020

ABSTRACTMultiple different equations have been used to quantify nutrient uptake rates from stable isotope tracer label incorporation experiments. Each of these equations implicitly assumes an underlying model for phytoplankton nutrient uptake behavior within the incubation bottle and/or pelagic environment. However, the applicability of different equations remains in question and uncertainty arising from subjective choices of which equation to use is never reported. In this study, I use two approaches to investigate the conditions under which different nutrient uptake equations should be used. First, I utilized a moderate-complexity pelagic ecosystem model that explicitly models the δ15N values of all model compartments (NEMURO+15N) to conduct simulated nitrate uptake and ammonium uptake incubations and quantify the accuracy of different nutrient uptake equations. Second, I used results of deckboard diel nutrient uptake experiments to quantify the biases of 24-h incubations relative to six consecutive 4-h incubations. Using both approaches, I found that equations that account for nutrient regeneration (i.e., isotope dilution) are more accurate than equations that do not, particularly when nutrient concentrations are low but uptake is relatively high. Furthermore, I find that if the goal is to estimatein situuptake rates it is appropriate to use anin situcorrection to standard equations. I also present complete equations for quantifying uncertainty in nutrient uptake experiments using each nutrient uptake equation and make all of these calculations available as Excel spreadsheets and Matlab scripts.
Transcription factor-target relationships complicated by knockout analysis
Authors: Dai Zhiming 
Published: September 2020

AbstractKnockout analysis is a common tool to reveal transcription factor (TF) functions. However, such a reverse genetic analysis based on observed phenotype changes in mutant cell may lead to a misunderstanding of TF wild-type functions. Here, a model was proposed, in which the knockout-observed TF-target regulatory relationships might only occur in mutant cell, and they do not reflect TF normal functions in wild-type cell. Actually, the knockout of one TF might release another TF which is the protein-protein interaction partner of the deleted TF. The free TF could bind its new target genes and cause their significant expression changes. These seemingly TF knockout affected genes are thus not directly regulated by the deleted TF, but are gain-of-regulated genes of the latter TF in mutant cell. Based on this model, multiple sources of genome-wide data were used to identify 20 such TF pairs, and one pair was validated using other independent data. TF wild-type regulatory genes are not associated with their gain-of-regulated genes. My findings revealed TF-target relationships complicated by TF knockout analysis.
ZNF410 represses fetal globin by devoted control of CHD4/NuRD
Authors: Vinjamur Divya S. , Yao Qiuming , Cole Mitchel A. , McGuckin Connor , Ren Chunyan , Zeng Jing , Hossain Mir , Luk Kevin , Wolfe Scot A. , Pinello Luca , Bauer Daniel E. 
Published: September 2020

AbstractMajor effectors of adult-stage fetal globin silencing include the transcription factors (TFs) BCL11A and ZBTB7A/LRF and the NuRD chromatin complex, although each has potential on-target liabilities for rationalβ-hemoglobinopathy therapeutic inhibition. Here through CRISPR screening we discover ZNF410 to be a novel fetal hemoglobin (HbF) repressing TF. ZNF410 does not bind directly to theγ-globin genes but rather its chromatin occupancy is solely concentrated atCHD4, encoding the NuRD nucleosome remodeler, itself required for HbF repression.CHD4has two ZNF410-bound regulatory elements with 27 combined ZNF410 binding motifs constituting unparalleled genomic clusters. These elements completely account for ZNF410’s effects onγ-globin repression. Knockout of ZNF410 reduces CHD4 by 60%, enough to substantially de-repress HbF while avoiding the cellular toxicity of complete CHD4 loss. Mice with constitutive deficiency of the homolog Zfp410 are born at expected Mendelian ratios with unremarkable hematology. ZNF410 is dispensable for human hematopoietic engraftment potential and erythroid maturation unlike known HbF repressors. These studies identify a new rational target for HbF induction for theβ-hemoglobin disorders with a wide therapeutic index. More broadly, ZNF410 represents a special class of gene regulator, a conserved transcription factor with singular devotion to regulation of a chromatin subcomplex.
Singing-related reorganization of the song motor circuit is accompanied by a shift in hormonal modulation of song
Authors: Rocha Mariana D. , Dreier Jes , Brewer Jonathan , Gahr Manfred , Vellema Michiel 
Published: September 2020

AbstractSex hormones are essential modulators of birdsong. Testosterone, and its active androgenic and estrogenic metabolites, 5α-dihydrotestosterone (DHT) and estradiol, can re-shape the brain circuits responsible for song learning and production. The differential mechanisms of action of these different hormones during song development and song maintenance are, nonetheless, not fully understood. Here we demonstrate that unlike testosterone, DHT treatment does not induce singing behavior in naïve adult female canaries that have never previously produced song. However, in birds with previous testosterone-induced singing experience, DHT alone is enough to promote the re-acquisition of high quality songs, even after months of silence. In addition, we show that the synaptic reorganization that accompanies vocal motor skill development requires more than DHT-induced androgen receptor activation. These results indicate that vocal motor practice will persistently modify the hormone-sensitive brain circuit responsible for song production, suggesting a mechanistic differentiation in the hormone-dependent regulation of the initial vocal motor skill acquisition and later re-acquisition.
UHRF1 suppresses viral mimicry through both DNA methylation-dependent and -independent mechanisms
Authors: Irwin RE , Scullion CA , Thursby SJ , Sun ML , Thakur A , Rothbart SB , Xu GL , Walsh CP 
Published: September 2020

AbstractSome chemotherapeutic agents which cause loss of DNA methylation have been recently shown to induce a state of “viral mimicry” involving upregulation of endogenous retroviruses (ERV) and a subsequent innate immune response. This approach may be useful in combination with immune checkpoint cancer therapies, but relatively little is known about normal cellular control of ERV suppression. The UHRF1 protein can interact with the maintenance methylation protein DNMT1 and is known to play an important role in epigenetic control in the cell. To examine potential roles of this protein in differentiated cells, we first established stable knockdowns in normal human lung fibroblasts. While these knockdown cells showed the expected loss of DNA methylation genome-wide, transcriptional changes were instead dominated by a single response, namely activation of innate immune signalling, consistent with viral mimicry. We confirmed using mechanistic approaches that activation of interferons and interferon-stimulated genes involved in double-stranded RNA detection was crucial to the response. ERVs were demethylated and transcriptionally activated in UHRF1 knockdown cells. As in these normal cell lines, ERV activation and interferon response also occurred following the transient loss of UHRF1 in both melanoma and colon cancer cell lines. Restoring UHRF1 in either transient- or stable knockdown systems abrogated ERV reactivation and interferon response, but without substantial restoration of DNA methylation. Rescued cell lines were hypersensitive to depletion of SETDB1, implicating H3K9me3 as crucial to UHRF1-mediated repression in the absence of DNA methylation. Confirming this, cells rescued with UHRF1 containing point mutations affecting H3K9me3 binding could not mediate silencing of ERV transcription or the innate immune response. Finally, by introducing similar point mutations in the mouse homologue, we could show that this pathway is conserved in mice. Our results therefore implicate UHRF1 as a key regulator of ERV suppression and strengthen the basis for cancer cell hypomethylation therapy.
Differential pathogenesis of Usutu virus isolates in mice
Authors: Kuchinsky Sarah C. , Hawks Seth A. , Mossel Eric , Coutermarsh-Ott Sheryl , Duggal Nisha K. 
Published: September 2020

AbstractUsutu virus (USUV;Flavivirus), a close phylogenetic and ecological relative of West Nile virus, is a zoonotic virus that can cause neuroinvasive disease in humans. USUV is maintained in an enzootic cycle betweenCulexmosquitoes and birds. Since the first isolation in 1959 in South Africa, USUV has spread throughout Africa and Europe. Reported human cases have increased over the last few decades, primarily in Europe, with symptoms ranging from mild febrile illness to severe neurological effects. In this study, we investigated whether USUV has become more pathogenic during emergence in Europe. Interferon α/β receptor knockout (Ifnar1-/-) mice were inoculated with recent USUV isolates from Africa and Europe, as well as the historic 1959 South African strain. The three tested African strains and one European strain from Spain caused 100% mortality in inoculated mice, with similar survival times and histopathology in tissues. Unexpectedly, a European strain from the Netherlands caused only 12% mortality and significantly less histopathology in tissues from mice compared to mice inoculated with the other strains. Viremia was highest in mice inoculated with the recent African strains and lowest in mice inoculated with the Netherlands strain. Based on phylogenetics, the USUV isolates from Spain and the Netherlands were derived from separate introductions into Europe, suggesting that disease outcomes may differ for USUV strains circulating in Europe. These results also suggest that while more human USUV disease cases have been reported in Europe recently, circulating African USUV strains are still a potential major health concern.Author SummaryUsutu virus (USUV) is an emerging mosquito-borne virus that causes severe neuroinvasive disease in humans. USUV was first detected in Africa in 1959, and cases of human disease have increased in recent years. Most USUV disease cases are now reported in Europe, where the virus currently circulating. One possibility for the increase in case numbers is that USUV strains have become more pathogenic over time during its spread from Africa into Europe. We compared the pathogenesis of five USUV isolates from Africa and Europe in a mouse model. Three isolates from Africa and one isolate from Europe caused 100% mortality in mice. Surprisingly, one isolate from Netherlands caused only 12% motality. Significantly less histopathology was observed in tissues from mice inoculated with the Netherlands strain compared to mice inoculated with the other four strains. Our results suggest that, even though more human USUV disease cases have been reported in Europe recently, African USUV strains are also highly pathogenic.
Reduction of Glut1 in retinal neurons but not the RPE alleviates polyol accumulation and normalizes early characteristics of diabetic retinopathy
Authors: Holoman Nicholas C. , Aiello Jacob J. , Trobenter Timothy D. , Tarchick Matthew J. , Kozlowski Michael R. , Makowski Emily R. , De Vivo Darryl C. , Singh Charandeep , Sears Jonathan E. , Samuels Ivy S. 
Published: September 2020

AbstractHyperglycemia is a key determinant for development of diabetic retinopathy (DR). Inadequate glycemic control exacerbates retinopathy, while normalization of glucose levels delays its progression. In hyperglycemia, hexokinase is saturated and excess glucose is metabolized to sorbitol by aldose reductase via the polyol pathway. Therapies to reduce retinal polyol accumulation for the prevention of DR have been elusive due to low sorbitol dehydrogenase levels in the retina and inadequate inhibition of aldose reductase. Using systemic and conditional genetic inactivation, we targeted the primary facilitative glucose transporter in the retina, Glut1, as a preventative therapeutic in diabetic male and female mice. Unlike wildtype diabetics, diabeticGlut1+/−mice did not display elevated Glut1 levels in the retina. Furthermore, diabeticGlut1+/−mice exhibited ameliorated ERG defects, inflammation and oxidative stress, which was correlated with a significant reduction in retinal sorbitol accumulation. RPE-specific reduction of Glut1 did not prevent an increase in retinal sorbitol content or early hallmarks of DR. However, like diabeticGlut1+/−mice, reduction of Glut1 specifically in retinal neurons mitigated polyol accumulation and completely prevented retinal dysfunction and the elevation of markers for oxidative stress and inflammation associated with diabetes. These results suggest that modulation of retinal polyol accumulation via Glut1 in photoreceptors can circumvent the difficulties in regulating systemic glucose metabolism and be exploited to prevent DR.SignificanceDiabetic retinopathy (DR) affects one third of diabetic patients and is the primary cause of vision loss in adults aged 20-74. While anti-VEGF and photocoagulation treatments for the late-stage vision threatening complications can prevent vision loss, a significant proportion of patients do not respond to anti-VEGF therapies and mechanisms to stop progression of early-stage symptoms remain elusive. Glut1 is the primary facilitative glucose transporter for the retina. We determined that a moderate reduction in Glut1 levels, specifically in retinal neurons, but not the RPE, was sufficient to prevent retinal polyol accumulation and the earliest functional defects to be identified in the diabetic retina. Our study defines modulation of Glut1 in retinal neurons as a targetable molecule for prevention of DR.
Toxoplasma gondiisecreted effectors co-opt host repressor complexes to inhibit necroptosis
Authors: Rosenberg Alex , Sibley L. David 
Published: September 2020

SummaryDuring infection,Toxoplasma gondiitranslocates effector proteins directly into its host cell to subvert various signaling pathways. Here we characterize a novel secreted effector that localizes to the host cell nucleus where it modulates NCoR/SMRT repressor complex levels to repress interferon regulated genes involved in cell death. Type I and type II interferons upregulate many genes including protein kinase R (PKR), inducing formation of the necrosome complex that activates Mixed Lineage Kinase Domain Like Pseudokinase (MLKL) to execute necrotic cell death. Toxoplasma NCoR/SMRT modulator (TgNSM) acts together with another secreted effector TgIST, previously shown to down-modulate IFN-γ signaling to block immune functions. Together TgNSM and TgIST block IFN driven expression of PKR and MLKL, thus preventing host cell necroptotic death. The mechanism of action of TgNSM highlights a previously unappreciated role of NCoR/SMRT in regulation of necroptosis, assuring survival of intracellular cysts, and maintenance of chronic infection.
Why quadratic log-log dependence is ubiquitous and what next
Authors: Aguilar Sean R. , Kreinovich Vladik , Pham Uyen 
Published: September 2020

Purpose
In many real-life situations ranging from financial to volcanic data, growth is described either by a power law – which is linear in log-log scale or by a quadratic dependence in the log-log scale. The purpose of this paper is to explain this empirical fact.

Design/methodology/approach
The authors use natural scale invariance requirements.

Findings
In this paper, the authors used natural scale invariance requirement to explain the ubiquity of quadratic log-log dependencies. The authors also explain what to do if quadratic log-log models turn out to be insufficiently accurate. In this case, scale-invariance requirements lead to dependencies which in the log-log scale take cubic, 4th order, etc. form.

Originality/value
To the best of authors’ knowledge, this is the first theoretical explanation of the empirical quadratic log-log dependence.
Injustice perceptions, workplace bullying and intention to leave
Authors: Reknes Iselin , Glambek Mats , Einarsen Ståle Valvatne 
Published: September 2020

PurposeIntention to leave as an outcome of exposure to workplace bullying is well documented in previous studies, yet, research on explanatory conditions for such an association is lacking.Design/methodology/approachThe present study investigates the relationship between injustice perceptions, exposure to bullying behaviors and turnover intention, employing a moderated mediation analysis based on a reanalysis and extension of data gathered among a sample of Norwegian bus drivers (N = 1, 024).FindingsAs hypothesized, injustice perceptions were indirectly related to intention to leave via workplace bullying, however, only under conditions of higher perceived injustice levels.Practical implicationsThe results underscore the importance of preventing workplace bullying and of maintaining ample levels of justice at work, where employees are treated with fairness and respect.Originality/valueThe study adds important knowledge to the bullying literature by focusing on the role of mechanisms and moderators in bullying situations, investigating how the combination of workplace bullying and injustice perceptions is reflected in employees' intention to leave the organization.
Finance-institution-growth trilogy: time-series insights from South Africa
Authors: Olaniyi Clement Olalekan , Adedokun Adebayo 
Published: September 2020

PurposeThis study examines the moderating effect of institutional quality on the finance-growth nexus in South Africa from 1986 to 2015.Design/methodology/approachThis study adopts unit root tests, cointegration test and autoregressive distributed lag (ARDL) model.FindingsThe findings reveal that institutional quality constitutes a drain to the growth benefits of financial development (FD) in South Africa in the short-run while FD and institutional quality converge to enhance growth process of the country in the long-run. Also, the threshold of institutional quality beyond which institution stimulates strong positive impact of finance on growth is estimated to be 6.42 on a 10-point scale.Practical implicationsThis study, therefore, suggests that institutional quality matters in the way FD influences economic growth in South Africa. Hence, stakeholders are encouraged to trace and block lapses and loopholes in the institutional framework guiding financial system in South Africa so as to maximize growth benefits of FD.Originality/valueThis study contributes to the extant studies by introducing a country-specific analysis into the empirical examination of how institutional quality influences the impact of FD on economic growth. Also, this study deviates from other studies by determining the threshold of institutional quality beyond which FD stimulates strong positive effect on economic growth in South Africa
Family business and sport entrepreneurship
Authors: Ratten Vanessa 
Published: September 2020

PurposeMany sport enterprises involve family members either as owners, employees or supporters, depending on the circumstances. Despite the embedded way families define and help to build sport enterprises, there is a lack of linkage in the academic literature between family business and sport entrepreneurship. The aim of this article is to understand the linkage in more detail by focusing on the way sport, family and entrepreneurship are embedded in society.Design/methodology/approachDue to the exploratory nature of the study, a qualitative approach was undertaken to understand the feelings and perceptions surrounding the process of sport entrepreneurship in family businesses.FindingsThe findings suggest that family businesses view the process of sport entrepreneurship as being context-dependent that relies on the interaction of family members for its success. This means that networking and co-creation are part of this process.Research limitations/implicationsAs the role of families in sport enterprises becomes more acknowledged, it is important that research keeps up-to-date with this trend. Thus, the findings of this article will help more family businesses with their sport-related ventures.Originality/valueThis article is the first to explicitly examine the linkage between family entrepreneurship and sport entrepreneurship, thereby paving the way for more research to examine this interesting research area.
Successor selection in family business using theory of planned behaviour and cognitive dimension of social capital theory: evidence from Ghana
Authors: Wu Mengyun , Coleman Martha , Abdul Rahaman Abdul Rashid , Edziah Bless Kofi 
Published: September 2020

PurposeSuccession of family enterprises has been an issue of concern to a number of researchers, and extensive studies have been conducted on this. Transfer of family business from one generation to next has resulted in collapse of most family business in both developed and developing economies. This study looked at succession in family enterprise in Ghana using theory of planned behaviour (Ajzen, 1991) and cognitive dimension of social capital theory to know the intention of founder/incumbent to hand over the family business to an internal successor.Design/methodology/approachOur target population for this study is family businesses run in Ghana, Western region. Ghana is not having statistical database on family businesses; therefore, the study relied on the database of registered SMEs which was gotten from Registrar General's Department, Ghana. This is the government department that is in charge of registering business in Ghana. A sample of 596 was used and received a response rate of 60%. The study used structural equation model to find out how the variables correlate to discover the intention of the founder/successor on internal succession.FindingsIt was discovered that intention of founder/incumbent to hand over to an internal successor is predominantly determined by attitude, subjective norm, perceived behavioural control and cognitive dimension of the social capital. Trust does not influence the intention of founder/incumbent but attitude; this rejects the findings of most researchers.Research limitations/implicationsMost family enterprises were not registered, which made it difficult to reach out to all family businesses. This limited the authors approach to only the registered family enterprises.Practical implicationsFamily firms are the backbone of any economy, which comprise mostly of SMEs. Therefore, the understanding of succession by incumbents/founders as well as policymakers enhances firms' value and continuity.Originality/valueThe study was conducted in Africa, Ghana in particular, owing to the limited studies in this region.