bluuebunny/crossref_metadata_2025 huggingface dataset:
Is maternal thyroid hormone deposition subject to a trade-off between self and egg because of iodine? An experimental study in rock pigeon
Authors: Sarraude Tom , Hsu Bin-Yan , Ruuskanen Suvi , Groothuis Ton
Published: January 2021

Maternal hormones constitute a key signalling pathway for mothers to shape offspring phenotype and fitness. Thyroid hormones (THs; triiodothyronine, T3and thyroxine, T4) are metabolic hormones known to play crucial roles in embryonic development and survival in all vertebrates. During early developmental stages, embryos exclusively rely on the exposure to maternal THs, and maternal hypothyroidism can cause severe embryonic maldevelopment. The TH molecule includes iodine, an element that cannot be synthesised by the organism. Therefore, TH production may become costly when environmental iodine availability is low. This may yield a trade-off for breeding females between allocating the hormones to self or to their eggs, potentially to the extent that it even influences the number of laid eggs. In this study, we investigated whether low dietary iodine may limit TH production and transfer to the eggs in a captive population of Rock pigeons(Columba livia).We provided breeding females with an iodine-restricted (I- diet) or iodine-supplemented diet (I+ diet) and measured the resulting circulating and yolk iodine and TH concentrations and the number of eggs laid. Our iodine-restricted diet successfully decreased both circulating and yolk iodine concentrations compared to the supplemented diet, but not circulating or yolk THs. This indicates that mothers may not be able to independently regulate hormone exposure for self and their embryos. However, egg production was clearly reduced in the I- group, with fewer females laying eggs. This result shows that restricted availability of iodine does induce a cost in terms of egg production. Whether females reduced egg production to preserve THs for themselves or to prevent embryos from exposure to low iodine and/or THs is as yet unclear.
Lithium ions display weak interaction with amyloid-beta (Aβ) peptides and have minor effects on their aggregation
Authors: Berntsson Elina , Paul Suman , Vosough Faraz , Sholts Sabrina B. , Jarvet Jüri , Roos Per M. , Barth Andreas , Gräslund Astrid , Wärmländer Sebastian K. T. S.
Published: January 2021

Alzheimer’s disease (AD) is an incurable disease and the main cause of age-related dementia worldwide, despite decades of research. Treatment of AD with lithium (Li) has showed promising results, but the underlying mechanism is unclear. The pathological hallmark of AD brains is deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils. The plaques contain also metal ions of e.g. Cu, Fe, and Zn, and such ions are known to interact with Aβ peptides and modulate their aggregation and toxicity. The interactions between Aβ peptides and Li+ions have however not been well investigated. Here, we use a range of biophysical techniques to characterizein vitrointeractions between Aβ peptides and Li+ions. We show that Li+ions display weak and non-specific interactions with Aβ peptides, and have minor effects on Aβ aggregation. These results indicate that possible beneficial effects of Li on AD pathology are not likely caused by direct interactions between Aβ peptides and Li+ions.
High quality mapping of chromatin at or near the nuclear lamina for small numbers of cells
Authors: Tran Joseph R. , Zheng Xiaobin , Adam Stephen A. , Goldman Robert D. , Zheng Yixian
Published: January 2021

The chromatin associated with the nuclear lamina (NL) is referred to as Lamina-Associated Domains (LADs). While mapping of this feature has been done using various technologies, technical limitations exist for each of the methods. Here, we present an adaptation of the Tyramide-Signal Amplification sequencing (TSA-seq) protocol, which we call chromatin pull down-based TSA-seq (cTSA-seq), that can be used to map chromatin regions at or near the NL from as little as 50,000 cells without using carriers. The cTSA-seq mapped regions are composed of LADs and smaller chromatin regions that fall within the chromatin B-compartment known to be enriched for heterochromatin and be present at the nuclear periphery. As a proof of principle, we used cTSA-seq to map chromatin at or near the assembling NL as cells exit mitosis and progress through early and later G1. Consistent with previous reports, lamin-B1 based cTSA-seq revealed that regions toward the distal ends of chromosomes are near or at the reassembling NL during early G1. The cTSA-seq mapping and analyses revealed similarity between the early G1 chromatin and oncogene-induced senescent cell populations. The cTSA-seq reported here represents a useful method for analyzing chromatin at or near the NL from small numbers of cells.
Rab10-positive tubular structures represent a novel endocytic pathway that diverges from canonical macropinocytosis in RAW264 macrophages
Authors: Kawai Katsuhisa , Nishigaki Arata , Moriya Seiji , Egami Youhei , Araki Nobukazu
Published: January 2021

Using the optogenetic photo-manipulation of photoactivatable (PA)-Rac1, remarkable cell surface ruffling and the formation of a macropinocytic cup (premacropinosome) could be induced in the region of RAW264 macrophages irradiated with blue light due to the activation of PA-Rac1. However, the completion of macropinosome formation did not occur until Rac1 was deactivated by the removal of the light stimulus. Following PA-Rac1 deactivation, some premacropinosomes closed into intracellular macropinosomes, whereas many others transformed into long Rab10-positive tubules without forming typical macropinosomes. These Rab10-positive tubules moved centripetally towards the Golgi region along microtubules. Surprisingly, these Rab10-positive tubules did not contain any endosome/lysosome compartment markers, such as Rab5, Rab7, or LAMP1, suggesting that the Rab10-positive tubules were not part of the degradation pathway for lysosomes. These Rab10-positive tubules were distinct from recycling endosomal compartments, which are labeled with Rab4, Rab11, or SNX1. These findings suggested that these Rab10-positive tubules belonged to a novel, non-degradative, endocytic pathway. The formation of Rab10-positive tubules from premacropinosomes was also observed in control and phorbol myristate acetate (PMA)-stimulated macrophages, although their frequencies were low. Interestingly, the formation of Rab10-positive premacropinosomes and tubules was not inhibited by phosphoinositide 3-kinase (PI3K) inhibitors, while the classical macropinosome formation requires PI3K activity. Thus, this study provides evidence to support the existence of Rab10-positive tubules as a novel, non-degradative, endocytic pathway that diverges from canonical macropinocytosis.
Expectancy-Value-Cost motivational theory to explore final year medical students’ research intentions and past research experience: a multicentre cross-sectional questionnaire study
Authors: Van Maele Louis , Devos Christelle , Guisset Séverine , Leconte Sophie , Macq Jean
Published: January 2021

Objectives

Conducting research during medical school is a commonly described way to strengthen the physician-scientists workforce. The aim of this study is to compare the strength of association of Expectancy, Value and Cost regarding a research activity with future research intentions, and to explore differences between students with or without research experience during medical school.

Design, setting and participants

An online questionnaire was sent to final-year medical students – who had already chosen their specialty – in three French-speaking Belgian universities with non-mandatory research programmes. Exploratory factor analysis (EFA) and multiple regression analysis were conducted.

Main measures

Research intention (outcome measure) was assessed using a 3-item scale. The motivational beliefs were assessed using a 10-item scale adapted from a validated scale based on the Expectancy-Value- Cost theory. Responses were recorded on a 6-point Likert scale.

Results

Participation rate was 28% (n=237). EFA revealed 4 factors with high internal consistency. 21.5% of students had positive research intentions (score 5 or above). Our model explained 82.8% of research intention variance (p < 0.001), of which three motivational beliefs had statistically significant coefficients: i) Value given to a research activity (β = 0.72, p < 0.001); ii) perceived Cost of a research activity (β = -0.11, p < 0.01); iii) Expectancy of success (β = 0.10, p < 0.05). Students with a positive research experience or students without research experience but who had strongly considered achieving one were 11.5 times more likely (95% CI, 5.0 – 26.2) to have positive research intentions at the end of medical school than other students.

Conclusions

Value given to a research activity is the key factor regarding students’ motivation to undertake research. Our study confirms the positive relationship between non-mandatory research and future research intentions, although some students without a research experience showed high motivation as well.
Do improved biomass cookstove interventions improve indoor air quality and blood pressure? A systematic review and meta-analysis
Authors: Kumar Nitya , Phillip Eunice , Cooper Helen , Davis Megan , Langevin Jessica , Clifford Mike , Stanistreet Debbi
Published: January 2021

Background

Household air pollution (HAP) kills 4 million annually, with access to clean cooking being a challenge for 37% of the world’s population. Whilst there have been advancements in improved biomass cookstove (ICS) technologies, reviews on the impact of these ICS on HAP are now more than three years old.

Objectives

This review and meta-analysis examines the most recent evidence on the impact of ICS on HAP and blood pressure (BP).

Methods

A literature search was conducted using scientific literature databases and grey literature. Studies were included if they were published between January 2012 and June 2020, reported impact of ICS interventions in non-pregnant adults in low/middle-income countries, and reported post-intervention results along with baseline of traditional cookstoves. Outcomes included 24- or 48-hour averages of kitchen area fine particulate matter (PM2.5), carbon monoxide (CO), mean systolic BP (SBP) and mean diastolic BP (DBP). Meta-analyses estimated weighted mean differences between baseline and post-intervention values for all outcome measures.

Results

Nine studies were included; eight contributed estimates for HAP and three for BP. Interventions lead to significant reductions in PM2.5 (−0.28 mg/m3, 95% CI: -0.46, -0.10), CO (−6.59ppm, 95%CI: - 10.73, -2.46) and SBP (−2.82mmHg, 95% CI: -5.53, -0.11); and a non-significant reduction in DBP (−0.80 mmHg, 95%CI: -2.33, 0.73), when compared to baseline of traditional cookstoves. Except for DBP, greatest reductions in all outcomes came from standard combustion ICS with a chimney, compared to ICS without a chimney and advanced combustion ICS. WHO air quality targets were met by post-intervention values for CO but not for PM2.5.

Conclusion

Our review suggests that ICS with a chimney results in the greatest reductions in HAP and BP. Further research on qualitative impact of such ICS on end-users is required to understand feasibility of adoption at scale.
T cell Homeostatic Imbalance in Placentae from Women with HIV in the absence of Vertical Transmission
Authors: Ikumi Nadia M. , Pillay Komala , Tilburgs Tamara , Malaba Thokozile R. , Dzanibe Sonwabile , Ann L Enninga Elizabeth , Chakraborty Rana , Lamorde Mohammed , Myer Landon , Khoo Saye , Jaspan Heather B , Gray Clive M. ,   for the DolPHIN-2 Study Group
Published: January 2021

Background

Implementation of universal antiretroviral therapy (ART) has significantly lowered vertical transmission rates but has also increased numbers of HIV-exposed uninfected children (HEU), who remain vulnerable to morbidities. Here, we investigated whether T cell alterations in the placenta contribute to altered immune status in HEU.

Methods

We analyzed T cells from term placentae decidua and villous tissue and paired cord blood from pregnant women with HIV (PWH) who initiated ART late in pregnancy (n=21) with pregnant women not living with HIV (PWNH) (n=9).

Results

Placentae from PWH showed inverted CD4:CD8 ratios and higher proportions of tissue resident CD8+ T cells in villous tissue relative to control placentae. CD8+ T cells in the fetal capillaries, which were of fetal origin, positively correlated with maternal plasma viraemia prior to ART initiation, implying that imbalanced T cells persisted throughout pregnancy. Additionally, the expanded memory differentiation of CD8+ T cells was confined to the fetal placental compartment and cord blood but was not observed in the maternal decidua.

Conclusions

T cell homeostatic imbalance in the blood circulation of PWH is reflected in the placenta. The placenta may be a causal link between HIV-induced maternal immune changes during gestation and altered immunity in newborn infants in the absence of vertical transmission.

Lay Summary

The effective prevention of HIV transmission during pregnancy with the rollout of antiretroviral therapy (ART) has resulted in increased numbers of HIV-exposed uninfected children (HEU). These children are vulnerable to infections and health problems and have distorted cellular immune systems at birth. We investigated whether these immune alterations originate in the placenta, as this fetal organ maintains life during pregnancy. After collecting placentae at term from pregnant women living with HIV (PWH), who started ART in the third trimester (n=21) and from pregnant women not living with HIV (PWNH) (n=9), we isolated T cells from dissected placental tissue and matching cord blood. Placentae from PWH showed inverted CD4:CD8 ratios in the placenta and cord blood with higher numbers of CD8+ T cells in the fetal part of the placenta. These CD8+ T cells mirrored events in the blood circulation of the mother and the altered balance of T cell immunity in the PWH was reflected in the placenta. Accordingly, the placenta may be a pivotal link between HIV-induced maternal immune changes and altered immunity in newborn infants in the absence of vertical transmission.
Locomotion-induced ocular motor behavior in larvalXenopusis developmentally tuned by visuo-vestibular reflexes
Authors: Bacqué-Cazenave Julien , Courtand Gilles , Beraneck Mathieu , Straka Hans , Combes Denis , Lambert François M.
Published: January 2021

Locomotion requires neural computations to maintain stable perception of the world despite disturbing consequences of the motor behavior on sensory stability. The developmental establishment of locomotor proficiency is therefore accompanied by a concurrent maturation of gaze-stabilizing motor behaviors. Using developing larvalXenopus, we demonstrate mutual plasticity of predictive spinal locomotor efference copies and multi-sensory motion signals with the aim to constantly ensure dynamically adequate eye movements during swimming. Following simultaneous ontogenetic onsets of locomotion, spino-ocular, optokinetic and otolith-ocular motor behaviors, locomotor efference copy-driven eye movements improve through gradually augmenting influences of semicircular canal signals. Accordingly, neuronal computations change from a predominating cancelation of angular vestibulo-ocular reflexes by locomotor efference copies in young larvae to a summation of these signals in older larvae. The developmental switch occurs in synchrony with a reduced efficacy of the tail-undulatory locomotor pattern generator causing gradually decaying influences on the ocular motor output.
FAM134B-RHD Protein Clustering Drives Spontaneous Budding of Asymmetric Membranes
Authors: Siggel Marc , Bhaskara Ramachandra M. , Moesser Melanie K. , Đikić Ivan , Hummer Gerhard
Published: January 2021

Living cells constantly remodel the shape of their lipid membranes. In the endo-plasmic reticulum (ER), the reticulon homology domain (RHD) of the reticulophagy regulator 1 (RETR1/FAM134B) forms dense autophagic puncta that are associated with membrane removal by ER-phagy. In molecular dynamics (MD) simulations, we find that FAM134B-RHD spontaneously forms clusters, driven in part by curvature-mediated attraction. At a critical size, the FAM134B-RHD clusters induce the formation of membrane buds. The kinetics of budding depends sensitively on protein concentration and bilayer asymmetry. Our MD simulations shed light on the role of FAM134B-RHD in ER-phagy and show that membrane asymmetry can be used to modulate the kinetics barrier for membrane remodeling.

Graphical TOC Entry
Effects of chronic lithium treatment on anxious behaviors and serotonergic genes expression in the midbrain raphe nuclei in defeated male mice
Authors: Smagin Dmitry A. , Kovalenko Irina L. , Galyamina Anna G. , Belozertseva Irina V. , Tamkovich Nikolay V. , Baranov Konstantin O. , Kudryavtseva Natalia N.
Published: January 2021

There are experimental data that mixed anxiety/depression-like state induced by chronic social defeat stress is accompanied by development of anxiety and downregulation of serotonergic gene expression in the midbrain raphe nuclei of male mice. The paper aimed to study the effect of chronic lithium chloride (LiCl) on anxious behaviors and the expression of serotonergic genes (Tph2,Slc6a4,Htr1a,Htr5b) in the midbrain raphe nuclei of defeated mice. Slight anxiolytic effects of LiCl were found on the commucativeness in the partition test, and anxiogenic-like effects, estimated by the elevated plus-maze and social interactions tests. Chronic LiCl treatment induced overexpression of the serotonergic genes in the midbrain raphe nuclei of defeated mice. We can assume that effects of LiCl, rather anxiogenic, may be due to activation of serotonergic system induced by hyperexpression of serotonergic genes. Our findings will allow to understand the factors involved in the positive and side effects of lithium on anxiety and function of serotonergic genes which are involved into mechanisms of depression.
pr2-primers: an 18S rRNA primer database for protists
Authors: Vaulot Daniel , Geisen Stefan , Mahé Frédéric , Bass David
Published: January 2021

Metabarcoding of microbial eukaryotes (collectively known asprotists) has developed tremendously in the last decade, almost uniquely relying on the 18S rRNA gene. As microbial eukaryotes are extremely diverse, many primers and primer pairs have been developed. To cover a relevant and representative fraction of the protist community in a given study system, a wise primer choice is needed as no primer pair can target all protists equally well. As such, a smart primer choice is very difficult even for experts and there are very few on-line resources available to list existing primers. We built a database listing 179 primers and 76 primer pairs that have been used for eukaryotic 18S rRNA metabarcoding.In silicoperformance of primer pairs was tested against two sequence databases: PR2for eukaryotes and a subset of Silva for prokaryotes. This allowed to determine the taxonomic specificity of primer pairs, the location of mismatches as well as amplicon size. We developed a R-based web application that allows to browse the database, visualize the taxonomic distribution of the amplified sequences with the number of mismatches, and to test any user-defined primer set (https://app.pr2-primers.org). This tool will provide the basis for guided primer choices that will help a wide range of ecologists to implement protists as part of their investigations.
Microsecond resolved infrared spectroscopy on non-repetitive protein reactions by applying caged-compounds and quantum cascade laser frequency combs
Authors: Norahan Mohamad Javad , Horvath Raphael , Woitzik Nathalie , Jouy Pierre , Eigenmann Florian , Gerwert Klaus , Kötting Carsten
Published: January 2021

Infrared spectroscopy is ideally suited for the investigation of protein reactions at the atomic level. Many systems were investigated successfully by applying Fourier transform infrared (FTIR) spectroscopy. While rapid-scan FTIR spectroscopy is limited by time resolution (about10 ms with 16 cm-1resolution), step-scan FTIR spectroscopy reaches a time-resolution of about 10 ns but is limited to cyclic reactions that can be repeated hundreds of times under identical conditions. Consequently, FTIR with high time resolution was only possible with photoactivable proteins that undergo a photocycle. The huge number of non-repetitive reactions, e.g. induced by caged compounds, were limited to the ms time domain. The advent of dual comb quantum cascade laser allows now for a rapid reaction monitoring in the μs time domain. Here we investigate the potential to apply such an instrument to the huge class of G-proteins. We compare caged-compound induced reactions monitored by FTIR and dual comb spectroscopy, respectively, by applying the new technique to the α subunit of the inhibiting Giprotein and to the larger protein-protein complex of Gαiwith its cognate regulator of G-protein signaling (RGS). We observe good data quality with 4 μs time resolution with a wavelength resolution comparable to FTIR. This is more than three orders of magnitude faster than any FTIR measurement on G-proteins in the literature. This study paves the way for infrared spectroscopic studies in the so far unresolvable μs time regime for non-repetitive biological systems including all GTPases and ATPases.
Photosynthetic acclimation and sensitivity to short- and long-term environmental changes
Authors: Schönbeck Leonie , Grossiord Charlotte , Gessler Arthur , Gisler Jonas , Meusburger Katrin , D’Odorico Petra , Rigling Andreas , Salmon Yann , Stocker Benjamin D. , Zweifel Roman , Schaub Marcus
Published: January 2021

The future climate will be characterized by an increase in frequency and duration of drought and warming that exacerbates atmospheric evaporative demand. How trees acclimate to long-term soil moisture changes and whether these long-term changes alter trees’ sensitivity to short-term (day to months) variations of vapor pressure deficit (VPD) and soil moisture is largely unknown.

Leaf gas exchange measurements were performed within a long-term (17 years) irrigation experiment in a Scots pine-dominated forest in one of Switzerland’s driest areas on trees in naturally dry (control), irrigated, and‘irrigation-stop’ (after 11 years of irrigation) conditions.

Seventeen years of irrigation increased photosynthesis (A) and stomatal conductance (gs) and reduced the gssensitivity to increasing VPD but not to soil drying. Following irrigation-stop, gas exchange did not decrease immediately, but after three years, had decreased significantly in irrigation-stop trees. Vcmaxand Jmaxrecovered after five years.

These results suggest that long-term release of soil drought reduces the sensitivity to atmospheric evaporative demand and that atmospheric constraints may play an increasingly important role in combination with soil drought. In addition, they suggest that structural adjustments lead to an attenuation of initially strong leaf-level acclimation to strong multiple-year drought.
scRNA-seq Reveals A Macrophage Subset That Provides A Splenic Replication Niche For IntracellularSalmonella
Authors: Hoffman Dotan , Tevet Yaara , Rosenberg Gili , Vainman Leia , Solomon Aryeh , Hen-Avivi Shelly , Ben-Moshe Noa Bossel , Avraham Roi
Published: January 2021

Interactions between intracellular bacteria and mononuclear phagocytes give rise to diverse cellular phenotypes that may determine the outcome of infection. Recent advances in single cell RNA-seq (scRNA-seq) have identified multiple subsets within the mononuclear population defined by unique molecular features, but the implications to their function during infection is unknown. Here, we applied high resolution kinetic analysis using microscopy, flow cytometry and scRNA-seq to survey the mononuclear niche of intracellularSalmonellaTyphimurium (S.Tm) during early systemic infection in mice. We describe an eclipse like growth kinetics in the spleen, with a first phase of bacterial control mediated by tissue resident red pulp macrophages. A second phase involved bacterial growth mediated by intracellular replication within a macrophage population we termed CD9 macrophages, that originate from non-classical monocytes.Nr4a1e2−/−mice, specifically depleted of non-classical monocytes but not other mononuclear cells, are more resistant toS.Tm infection. Our study underscores a cell-type specific host-pathogen interaction that determines early infection growth dynamics and has implications to the infection outcome of the entire organism.
Drivers of taxonomic, functional and phylogenetic diversities in dominant ground-dwelling arthropods of coastal heathlands
Authors: Hacala Axel , Lafage Denis , Prinzing Andreas , Sawtschuk Jérôme , Pétillon Julien
Published: January 2021

Although functional and phylogenetic diversities are increasingly used in ecology for a large variety of purposes, their relationships remain unclear and likely vary presumably over taxa, yet most recent studies focused on plant communities. Different concepts predict that a community becomes functionally more diverse by adding phylogenetic lineages, subtracting lineages, adding species, reducing or increasing environmental constraints. In this study, we investigated ground-dwelling spider, ground beetle and ant assemblages in coastal heathlands (>11 000 individuals, 216 species), and their estimated functional and phylogenetic diversities as minimum spanning trees using several traits related to the morphology, feeding habits and dispersal of species, and phylogenetic trees, respectively. Correlations were overall positive and high between functional and phylogenetic diversities. Accounting for taxonomic diversities and environments made disappear this relationship in ants, but maintained them in spiders and ground beetles, where taxonomic diversity related to functional diversity only via increasing phylogenetic diversity. Environmental constraints reduced functional diversity in ants, but affected functional diversity only indirectly via phylogenetic diversity (ground beetles) and taxonomic and then phylogenetic diversity (spiders and ground beetles). Results are consistent with phylogenetic conservatism in traits in spiders and ground beetles, while in ants traits appear more neutral with any new species potentially representing a new trait state. Lineage diversities mostly increased with taxonomic diversities, possibly reflecting un-measured environmental conditions.
Metabolic engineering ofSaccharomyces cerevisiaefor efficient conversions of glycerol to ethanol
Authors: Khattab Sadat M. R. , Watanabe Takashi
Published: January 2021

Glycerol is an eco-friendly solvent enhancing plant-biomass decomposition through the glycell process to bio-based chemicals. Nonetheless, the lack of efficient conversion of glycerol by naturalSaccharomyces cerevisiaerestrains many biorefineries-scenarios. Here, we outline a comprehensive strategy for generating efficient glycerol fermentingS. cerevisiaevia rewriting the oxidation of cytosolic nicotinamide adenine dinucleotide by O2-dependent dynamic shuttle while abolishing glycerol phosphorylation and biosynthesis pathways. By following a vigorous glycerol oxidative pathway, our engineered strain demonstrated a breakthrough in conversion efficiency (CE), reaching up to 0.49g-ethanol/g-glycerol—98% of theoretical conversion—with production rate >1 gL−1h−1on rich-medium. Interestingly, the glycerol consumption and its fermentation unrepressed during the mixing by glucose until the strain produced >86 g/L of bioethanol with 92.8% of CE. Moreover, fine-tuning of O2boosted the production rate to >2 gL−1h−1with 82% of CE. Impressively, the strategy flipped the ancestral yeast even from non-growing on glycerol, on the minimal medium, to a fermenting strain with productivities 0.25-0.5 gL−1h−1and 84-78% of CE, respectively. Our findings promote utlising glycerol efficiently in several eco-friendly biorefinery approaches.

Efficient fermentation of glycerol in S. cerevisiae was established by comprehensive engineering of glycerol pathways and rewriting NADH pathway.
Bromodomain 4 inhibition leads toMYCNdownregulation in Wilms’ tumor cells
Authors: Woods Andrew D. , Berlow Noah E. , Purohit Reshma , Freier Katherine E. Tranbarger , Michalek Joel E. , Lathara Melvin , Matlock Kevin , Srivivasa Ganapati , Royer-Pokora Brigitte , Veselska Renata , Keller Charles
Published: January 2021

Wilms’ tumor is the most common childhood kidney cancer. Two distinct histological subtypes of Wilms’ tumor have been described: tumors lacking anaplasia (the favorable subtype) and tumors displaying anaplastic features (the unfavorable subtype). Children with favorable disease generally have a very good prognosis, while those with anaplasia are oftentimes refractory to standard treatments and suffer poor outcomes.MYCNdysregulation has been associated with a number of pediatric cancers including the anaplastic subtype of Wilms’ tumor. In this context, we undertook a functional genomics approach to uncover novel therapeutic strategies for those patients with anaplastic Wilms’ tumor. Genomic analysis andin vitroexperimentation demonstrate that Wilms’ tumor cell growth can be reduced by modulatingMYCNoverexpression via BRD4 inhibition. We observed a time dependent reduction of MYCN and MYC protein levels upon BRD4 inhibition in Wilms’ tumor cell lines which led to increased cell death and suppressed proliferation. We suggest that AZD5153, a novel dual-BRD4 inhibitor, can reduce MYCN levels and should be further explored for its therapeutic potential against Wilms’ tumor.
Inhibition of Extracellular Vesicle-Associated MMP2 Abrogates Intercellular Transfer of Hepatic miR-122 to Tissue Macrophages and Curtails Liver Inflammation
Authors: Das Arnab , Basu Sudarshana , Bandyopadhyay Diptankar , Dutta Debduti , Chakrabarti Sreemoyee , Adak Moumita , Swarnakar Snehasikta , Chakrabarti Partha , Bhattacharyya Suvendra N.
Published: January 2021

microRNA-122 (miR-122), a liver specific regulatory RNA, plays an important role in controlling metabolic homeostasis in mammalian liver cells. Interestingly, miR-122 is also a proinflammatory microRNA and when exported to tissue resident macrophage induces expression of inflammatory cytokines there. We found intercellular transfer of miR-122 in lipid exposed liver plays a role in liver inflammation. Exploring the mechanism of intercellular miR-122 transfer from hepatic cells, we detected MMP2 on the membrane of extracellular vesicles derived from hepatic cells which proved to be essential for transfer of extracellular vesicles and their miRNA content from hepatic to non-hepatic cells. Matrix metalloprotease 2 or MMP2 is a metalloproteinase that plays a key role in shaping and remodelling the extracellular matrix of human tissue by targeting degradation of matrix proteins. MMP2 was found to increase the movement of the EVs along the extracellular matrix to enhance their uptake in recipient cells. Inhibition of MMP2 restricts functional transfer of hepatic miRNAs across the hepatic and non-hepatic cell boundaries. By targeting MMP2, we could reduce the innate immune response in mammalian liver by preventing intra-tissue miR-122 transfer.

Abstract Figure

Human hepatocytes on exposure to high lipid export out miRNAs including proinflammatory miR-122.

Extracellular miR-122 is taken up by tissue macrophages to get them activated to produce inflammatory cytokines.

MMP2 present on the surface of the EVs released by hepatocyte is essential for miRNA transfer to macrophage cells

Inhibition of MMP2 prevents miR-122 transfer to macrophage and stops activation of recipient macrophage.
Differential requirements for MDM2 E3 activity during embryogenesis and in adult mice
Authors: Humpton Timothy J. , Nomura Koji , Weber Julia , Magnussen Helge M. , Hock Andreas K. , Nixon Colin , Dhayade Sandeep , Stevenson David , Huang Danny T. , Strathdee Douglas , Blyth Karen , Vousden Karen H.
Published: January 2021

The p53 tumor suppressor protein is a potent activator of proliferative arrest and cell death. In normal cells, this pathway is restrained by p53 protein degradation mediated by the E3-ubiquitin ligase activity of MDM2. Oncogenic stress releases p53 from MDM2 control, so activating the p53 response. However, many tumors that retain wild-type p53 inappropriately maintain the MDM2-p53 regulatory loop in order to continuously suppress p53 activity. We have shown previously that single point mutations in the human MDM2 RING finger domain prevent the interaction of MDM2 with the E2/ubiquitin complex, resulting in the loss of MDM2's E3 activity without preventing p53 binding. Here, we show that an analogous mouse MDM2 mutant (MDM2 I438K) restrains p53 sufficiently for normal growth but exhibits an enhanced stress response in vitro. In vivo, constitutive expression of MDM2 I438K leads to embryonic lethality that is rescued by p53 deletion, suggesting MDM2 I438K is not able to adequately control p53 function through development. However, the switch to I438K expression is tolerated in adult mice, sparing normal cells but allowing for an enhanced p53 response to DNA damage. Viewed as a proof of principle model for therapeutic development, our findings support an approach that would inhibit MDM2 E3 activity without preventing MDM2/p53 binding as a promising avenue for development of compounds to activate p53 in tumors with reduced on-target toxicities.
TFs for TEs: the transcription factor repertoire of mammalian transposable elements
Authors: Hermant Clara , Torres-Padilla Maria-Elena
Published: January 2021

Transposable elements (TEs) are genetic elements capable of changing position within the genome. Although their mobilization can constitute a threat to genome integrity, nearly half of modern mammalian genomes are composed of remnants of TE insertions. The first critical step for a successful transposition cycle is the generation of a full-length transcript. TEs have evolved cis-regulatory elements enabling them to recruit host-encoded factors driving their own, selfish transcription. TEs are generally transcriptionally silenced in somatic cells, and the mechanisms underlying their repression have been extensively studied. However, during germline formation, preimplantation development, and tumorigenesis, specific TE families are highly expressed. Understanding the molecular players at stake in these contexts is of utmost importance to establish the mechanisms regulating TEs, as well as the importance of their transcription to the biology of the host. Here, we review the transcription factors known to be involved in the sequence-specific recognition and transcriptional activation of specific TE families or subfamilies. We discuss the diversity of TE regulatory elements within mammalian genomes and highlight the importance of TE mobilization in the dispersal of transcription factor-binding sites over the course of evolution.
Considerations for Membrane Protein Purification
Authors: Kielkopf Clara L. , Bauer William , Urbatsch Ina L.
Published: January 2021

Isolating membrane proteins from their native cells while maintaining structural and functional integrity is challenging. Many detergents have been developed over the years that interact favorably with membrane proteins and mimic the physical properties of the lipid bilayer. Choosing the appropriate detergent is crucial for the successful extraction of a protein in its properly folded, active conformation.
An investigation of a series of layered Zn-1,4-diazabicyclo[2.2.2]octane metal–organic frameworks: local structure and adsorption properties of mixed-metal centre
Authors: Ding Chang-Chun , Chu Xiao-Hong , Zhang Meng-Jia , Fu Jia
Published: January 2021

The mixed-metal pillar-layered metal–organic frameworks of Zn(bdc)(DABCO)0.5, Zn0.5Cu0.5(bdc)(DABCO)0.5 and Cu(bdc)(DABCO)0.5 (bdc = 1,4-benzenedicarboxylate, DABCO = 1,4-diazabicyclo[2.2.2]octane) are investigated for their local structures and gas adsorption properties. According to the obtained electron paramagnetic resonance (EPR) spectra, the distorted structures around Cu2+ are proposed to be tetragonally and orthorhombically elongated [CuO4N] with the well fitted high-order perturbation formulae of the EPR parameters. Due to the doped Cu2+, the adsorption isotherms of industrially relevant gases (CO2, CO, CH4 and N2) and lower alkanes (CH4, C2H6, C3H8, C4H10 and C5H12) are different, especially at different temperatures. By combining the structural properties and adsorption isotherms, a comprehensive study suggests that the ZnDABCO series can be a controllable tool in gas storage and separation.
Experimental investigation on nozzle diameter of vortex gripper
Authors: Zhao Jianghong , Li Xin
Published: January 2021

Purpose

Vortex grippers use tangential nozzles to form vortex flow and are able to grip a workpiece without any physical contact, thus avoiding any unintentional workpiece damage. This study aims to use experimental and theoretical methods to investigate the effects of nozzle diameter on the performance.

Design/methodology/approach

First, various suction force-distance curves were developed to analyze the effects of nozzle diameter on the maximum suction force. This study determines the tangential velocity distribution on the workpiece surface by substituting the experimental pressure distribution data into simplified Navier-Stokes equations and then used these equations to analyze the effects on the flow field. Subsequent theoretical analysis of the distribution of pressure and circumferential velocity further validated the experimental results. Next, by rearranging these relationships, the study considered the effects of nozzle diameter on the inherent vortex gripper characteristics. In addition, this study developed various suction force-energy consumption curves to analyze the effects of nozzle diameter.

Findings

The results of this study indicated that the vortex gripper’s circumferential velocity and maximum suction force decrease with increasing nozzle diameter. Nozzle diameter did not significantly affect the inherent frequency of the vortex gripper-workpiece inertial system or the corresponding suspension stability of the workpiece. However, an increase in nozzle diameter did effectively increase the vortex gripper’s suspension region. Finally, as the nozzle diameter increased, the energy required to achieve the same maximum suction force decreased.

Originality/value

This study’s findings can enable optimization of nozzle design in emerging vortex gripper designs and facilitate informed selection among existing vortex grippers.
Business analytics practices and managerial implications based on the evidence from Korea
Authors: Min Hokey
Published: January 2021

Purpose

Despite a growing interest in business analytics (BA) from the business and academic communities, it is still unknown what truly motivates and hinders the adoption of BA. To have a clear picture of what will lead to the successful implementation of BA, this paper identifies contextual variables (e.g. user characteristics, organizational readiness and technology infrastructure/expertise) that significantly influence the BA adoption decision.

Design/methodology/approach

This paper conducted a series of classification, discriminant and logistics regressions analyses to analyze the differences in mail survey responses between adopters and nonadopters of BA and then determine what either motivate or inhibit the BA adoption.

Findings

Through a series of hypothesis testing, we discovered that large firms with a greater number of information technology (IT) staff and budget tended to adopt BA more than their smaller counterparts. Also, we found that BA skeptics, who did not fully recognize BA benefit potentials, were more concerned about BA implementation costs and experienced the greater organization resistance to BA adoption than the others did. Therefore, they were less likely to adopt BA.

Originality/value

In the era of knowledge-based economy, the firm's ability to derive actionable insights from big data can be a game changer. Such ability can be developed and nurtured by utilizing BA which is designed to help business executives and policymakers make well-thought and informed decisions. This paper is one of the first attempts to develop practical guidelines for the successful implementation of BA based on the exploratory study of BA practices among the Korean firms.
Putting family first as a boundary management tactic
Authors: Thompson Merideth , Carlson Dawn S. , Kacmar K. Michele
Published: January 2021

Purpose

The authors examine a boundary management tactic for managing the work–family interface: putting family first (PFF). PFF is a boundary management tactic defined as the voluntary behavior of intentionally putting family obligations ahead of work obligations in a way that violates organizational norms

Design/methodology/approach

In Study 1, The authors develop a theoretically derived measure of PFF and distinguish it theoretically and empirically from similar existing constructs, examining convergent and discriminate validity to demonstrate its uniqueness. In Study 2, the authors demonstrate PFF's predictive validity beyond the job incumbent using a three-way matched sample of 226 individuals, including the job incumbent's coworker and spouse.

Findings

The authors established and validated a measure of PFF, developing and replicating the nomological network. PFF crossed over to positively relate to coworker role overload, job frustration and work–family conflict and to spousal stress transmission and relationship tension. Similarly, PFF related negatively to spousal family satisfaction and organizational commitment.

Originality/value

The authors extend the work–family and boundary management literatures by proposing a new form of boundary management, PFF, which is a tactic for managing the work–family interface, and explore how its use influences not only the job incumbent but also the coworker and the spouse.
Machiavellianism, locus of control, moral identity, and ethical leadership among public service leaders in Malaysia: the moderating effect of ethical role modelling
Authors: Zainun Nor Farah Hanis , Johari Johanim , Adnan Zurina
Published: January 2021

Purpose

The objective of this study is to examine the predicting role of Machiavellianism, locus of control and moral identity on ethical leadership. This study also assessed the moderating role of ethical role modelling in the linkage between Machiavellianism, locus of control, moral identity and ethical leadership.

Design/methodology/approach

A total of 202 public service leaders in Malaysia participated in the study. A quantitative study was conducted and structural equation modelling was used to test the hypotheses.

Findings

Moral identity poses a substantial influence on ethical leadership. Ethical role modelling is a significant moderator in the association between moral identity and ethical leadership.

Research limitations/implications

This study contributes to the social learning theory by assessing Machiavellianism, locus of control and moral identity as the predictors of ethical leadership among public service leaders in Malaysia. Future study can be further extended to both managerial and support staff to understand the ethical phenomenon in Malaysian public sector.

Practical implications

The study highlights the need for public sector to give considerable attention to moral identity in boosting ethical leadership among public service leaders in Malaysia's public sector. Furthermore, the element of ethical role modelling should not be neglected as this factor is a valid moderator in nurturing ethical leadership among public service leaders.

Originality/value

The study deepens the knowledge on the importance of ethical role modelling as a moderator in assessing the influence of the predictors on ethical leadership. Further, this study demonstrates that public service leaders who reported high moral identity would have higher ethical leadership if they experienced good ethical role modelling.
Effect of changing geometrical characteristics for different shapes of a single ridge passing through elastohydrodynamic of point contacts
Authors: Abd Alsamieh Mohamed
Published: January 2021

Purpose

The purpose of this paper is to study the behavior of a single ridge passing through elastohydrodynamic lubrication of point contacts problem for different ridge shapes and sizes, including flat-top, triangular and cosine wave pattern to get an optimal ridge profile.

Design/methodology/approach

The time-dependent Reynolds’ equation is solved using Newton–Raphson technique. Several shapes of surface feature are simulated and the film thickness and pressure distribution are obtained at every time step by simultaneous solution of the Reynolds’ equation and film thickness equation, including elastic deformation. Film thickness and pressure distribution are chosen to be the criteria in the comparisons.

Findings

The geometrical characteristics of the ridge play an important role in the formation of lubricant film thickness profile and the pressure distribution through the contact zone. To minimize wear, friction and fatigue life, an optimal ridge profile should have smooth shape with small ridge size. Obtained results are compared with other published numerical results and show a good agreement.

Originality/value

The study evaluates the performance of different surface features of a single ridge with different shapes and sizes passing through elastohydrodynamic of point contact problem in relation to film thickness and pressure profile.
An improved degraded adhesion model for wheel–rail under braking conditions
Authors: Zhu Wenliang , Zhu Wenjian , Zheng Shubin , Wu Na
Published: January 2021

Purpose

The purpose of this paper is to develop an improved adhesion model to better reproduce the low adhesion condition of the anti-skid control for rail vehicles under braking condition.

Design/methodology/approach

In view of the low adhesion characteristics for rail vehicles under braking conditions, the Polach adhesion model was improved based on the sliding power and sliding energy. The wheel–rail low adhesion model suitable for braking condition was given. The analysis of braking anti-skid control under emergency braking condition was carried out through the co-simulation, and compared with the test data; the effectiveness and practicability of the improved low adhesion model were verified.

Findings

The results showed that the improved adhesion model is simple and efficient and the parameters involved are less, and it can be directly applied to the real-time simulation of anti-skid control in the process of train braking.

Originality/value

This paper can provide a theoretical reference for the reasons of change and improvement of adhesion between wheel and rail caused by the adjustment of braking force under anti-skid control, which can fulfill a need to the study of sliding energy on the contact surface, the removal effect of pollutants on the wheel–rail surface and the improvement and recovery of adhesion caused.

Peer review

The peer review history for this article is available at: https://publons.com/publon/10.1108/ILT-07-2020-0244/