bluuebunny/crossref_metadata_2025 huggingface dataset:
Listeners with congenital amusia are sensitive to context uncertainty in melodic sequences
Authors: Quiroga-Martinez D. R. , Tillmann B. , Brattico E. , Cholvy F. , Fornoni L. , Vuust P. , Caclin A.
Published: July 2020

In typical listeners, the perceptual salience of a surprising auditory event depends on the uncertainty of its context. For example, in melodies, pitch deviants are more easily detected and generate larger neural responses when the context is highly predictable than when it is less so. However, it is not known whether amusic listeners with abnormal pitch processing are sensitive to the degree of uncertainty of pitch sequences and, if so, whether they are to a different extent than typical non-musician listeners. To answer this question, we manipulated the uncertainty of short melodies while participants with and without congenital amusia underwent EEG recordings in a passive listening task. Uncertainty was manipulated by presenting melodies with different levels of complexity and familiarity, under the assumption that simpler and more familiar patterns would enhance pitch predictability. We recorded mismatch negativity (MMN) responses to pitch, intensity, timbre, location, and rhythm deviants as a measure of auditory surprise. In both participant groups, we observed reduced MMN amplitudes and longer peak latencies for all sound features with increasing levels of complexity, and putative familiarity effects only for intensity deviants. No significant group-by-complexity or group-by-familiarity interactions were detected. However, in contrast to previous studies, pitch MMN responses in amusics were disrupted in high complexity and unfamiliar melodies. The present results thus indicate that amusics are sensitive to the uncertainty of melodic sequences and that preattentive auditory change detection is greatly spared in this population across sound features and levels of predictability. However, our findings also hint at pitch-specific impairments in this population when uncertainty is high, thus suggesting that pitch processing under high uncertainty conditions requires an intact frontotemporal loop.
A developmental stretch-and-fill process that optimises dendritic wiring
Authors: Baltruschat Lothar , Tavosanis Gaia , Cuntz Hermann
Published: July 2020

The way in which dendrites spread within neural tissue determines the resulting circuit connectivity and computation. However, a general theory describing the dynamics of this growth process does not exist. Here we obtain the first time-lapse reconstructions of neurons in living fly larvae over the entirety of their developmental stages. We show that these neurons expand in a remarkably regular stretching process that conserves their shape. Newly available space is filled optimally, a direct consequence of constraining the total amount of dendritic cable. We derive a mathematical model that predicts one time point from the previous and use this model to predict dendrite morphology of other cell types and species. In summary, we formulate a novel theory of dendrite growth based on detailed developmental experimental data that optimises wiring and space filling and serves as a basis to better understand aspects of coverage and connectivity for neural circuit formation.

In brief

We derive a detailed mathematical model that describes long-term time-lapse data of growing dendrites; it optimises total wiring and space-filling.

Highlights

Dendrite growth iterations guarantee optimal wiring at each iteration.

Optimal wiring guarantees optimal space filling.

The growth rule from fly predicts dendrites of other cell types and species.

Fly neurons stretch-and-fill target area with precise scaling relations.

Phase transition of growth process between fly embryo and larval stages.
Glycolytic pyruvate kinase moonlighting activities in DNA replication initiation and elongation
Authors: Horemans Steff , Pitoulias Matthaios , Holland Alexandria , Soultanas Panos , Janniere Laurent
Published: July 2020

Cells have evolved a metabolic control of DNA replication to respond to a wide range of nutritional conditions. Accumulating data suggest that this poorly understood control depends, at least in part, on Central Carbon Metabolism (CCM). InBacillus subtilis, the glycolytic pyruvate kinase (PykA) is intricately linked to replication. This 585 amino-acid-long enzyme comprises a catalytic (Cat) domain that binds to phosphoenolpyruvate (PEP) and ADP to produce pyruvate and ATP, and a C-terminal domain of unknown function. Interestingly, the C-terminal domain termed PEPut interacts with Cat and is homologous a domain that, in other metabolic enzymes, are phosphorylated at a conserved TSH motif at the expense of PEP and ATP to drive sugar import and catalytic or regulatory activities. To gain insights into the role of PykA in replication, DNA synthesis was analyzed in various Cat and PEPut mutants grown in a medium where the metabolic activity of PykA is dispensable for growth. Measurements of replication parameters (ori/terratio, C period and fork speed) and of the pyruvate kinase activity showed that PykA mutants exhibit replication defects resulting from side chain modifications in the PykA protein rather than from a reduction of its metabolic activity. Interestingly, Cat and PEPut have distinct commitments in replication: while Cat impacts positively and negatively replication fork speed, PEPut stimulates initiation through a process depending on Cat-PEPut interaction and growth conditions. Residues binding to PEP and ADP in Cat, stabilizing the Cat-PEPut interaction and belonging to the TSH motif of PEPut were found important for the commitment of PykA in replication.In vitro, PykA affects the activities of replication enzymes (the polymerase DnaE, helicase DnaC and primase DnaG) essential for initiation and elongation and genetically linked topykA. Our results thus connect replication initiation and elongation to CCM metabolites (PEP, ATP and ADP), critical Cat and PEPut residues and to multiple links between PykA and the replication enzymes DnaE, DnaC and DnaG. We propose that PykA is endowed with a moonlighting activity that senses the concentration of signaling metabolites and interacts with replication enzymes to convey information on the cellular metabolic state to the replication machinery and adjust replication initiation and elongation to metabolism. This defines a new type of replication regulator proposed to be part of the metabolic control that gates replication in the cell cycle.
FIP200 organizes the autophagy machinery at p62-ubiquitin condensates beyond activation of the ULK1 kinase
Authors: Turco Eleonora , Fischer Irmgard , Martens Sascha
Published: July 2020

Macroautophagy is a conserved degradation pathway, which mediates cellular homeostasis by the delivery of harmful substances into lysosomes. This is achieved by the sequestration of these substances referred to as cargo within double membrane vesicles, the autophagosomes, which formde novo. Among the many cargoes that are targeted by autophagy are condensates containing p62 and ubiquitinated proteins. p62 recruits the FIP200 protein to initiate autophagosome formation at the condensates. How FIP200 in turn organizes the autophagy machinery is unclear. Here we show that FIP200 is dispensable for the recruitment of the upstream autophagy machinery to the condensates, but it is necessary for phosphatidylinositol 3-phosphate formation and WIPI2 recruitment. We further find that FIP200 is required for the activation of the ULK1 kinase. Surprisingly, ULK1 kinase activity is not strictly required for autophagosome formation at p62 condensates. Super-resolution microscopy of p62 condensates revealed that FIP200 surrounds the condensates where it spatially organizes ATG13 and ATG9A for productive autophagosome formation. Our data provide a mechanistic insight into how FIP200 orchestrates autophagosome initiation at the cargo.
CUT&RUN detects distinct DNA footprints of RNA polymerase II near the transcription start sites
Authors: Miura Michi , Chen Honglin
Published: July 2020

CUT&RUN is a powerful tool to study protein-DNA interactionsin vivo. DNA fragments cleaved by the targeted micrococcal nuclease identify the footprints of DNA-binding proteins on the chromatin. We performed CUT&RUN on human lung carcinoma cell line A549 maintained in a multi-well cell culture plate to profile RNA polymerase II. Long (>270 bp) DNA fragments released by CUT&RUN corresponded to the bimodal peak around the transcription start sites, as previously seen with chromatin immunoprecipitation. However, we found that short (<120 bp) fragments identify a well-defined peak localised at the transcription start sites. This distinct DNA footprint of short fragments, which constituted only about 5% of the total reads, suggests the transient positioning of RNA polymerase II before promoter-proximal pausing, which has not been detected in the physiological settings by standard chromatin immunoprecipitation. We showed that the positioning of the large-size-class DNA footprints around the short-fragment peak was associated with the directionality of transcription, demonstrating the biological significance of distinct CUT&RUN footprints of RNA polymerase II.
Multiple dimensions of social motivation in adult female degus
Authors: Lidhar Navdeep K. , Thakur Ayushi , David Anna-Julia , Takehara-Nishiuchi Kaori , Insel Nathan
Published: July 2020

Many animals become more motivated to interact after a period of isolation. This phenomenon may involve general drives, e.g. for social touch or companionship, as well as drives that are specific to particular peers, and which ultimately serve to reestablish relationships between the individuals. Female degus are known to be affiliative with multiple other individuals, including unrelated and unfamiliar conspecifics, offering an opportunity to study social motivation independent from exclusive pair-bonds or overt, same-sex competition. We attempted to disentangle factors driving peer interaction by examining reunion behavior across several social isolation and separation manipulations. High levels of interaction were observed between adult females who had been separated even without isolation, revealing a drive to re-establish relationships with specific peers. The content of separation-only reunions differed from isolation, with the latter involving more early-session interaction, higher levels of allogrooming before rear-sniffing, and a higher ratio of chitter vocalizations. To assess whether post-isolation behavior was related to stress, we examined reunions following a non-social (footshock) stressor. Like isolation, footshock increased early-session interactions, but did not increase allogrooming before rear-sniffing or chittering, as compared with controls. To test whether separation-only reunion behavior shared qualities with relationship formation, we also examined reunions of new (stranger) dyads. Strangers exhibited higher levels of interaction than cagemates, with particularly high levels of late-session rear-sniffing. Like separation-only reunions, strangers showed more non-chitter vocalizations and lower levels of allogrooming before rear-sniffing. Across experiments, an exploratory clustering method was used to identify vocalizations that differed between conditions. This yielded promising leads for future investigation, including a chaff-type syllable that may have been more common during relationship renewal. Overall, results are consistent with the hypothesis that female degu reunions are supported by both general and peer-stimulus specific drives, expressed through the structure of physical and vocal interactions over time.
Modulation of neural oscillations during working memory update, maintenance, and readout: an hdEEG study
Authors: Semprini Marianna , Bonassi Gaia , Barban Federico , Pelosin Elisa , Iandolo Riccardo , Chiappalone Michela , Mantini Dante , Avanzino Laura
Published: July 2020

Working memory (WM) performance is very often measured using the n-back task, in which the participant is presented with a sequence of stimuli, and required to indicate whether the current stimulus matches the one presented n steps earlier. In this study, we used high-density electroencephalography (hdEEG) coupled to source localization to obtain information on spatial distribution and temporal dynamics of neural oscillations associated with WM update, maintenance and readout. Specifically, we a priori selected regions from a large fronto-parietal network, including also the insula and the cerebellum, and we analyzed modulation of neural oscillations by event-related desynchronization and synchronization (ERD/ERS).

During update and readout, we found larger θ ERS and smaller β ERS respect to maintenance in all the selected areas. γLOWand γHIGHbands oscillations decreased in the frontal and insular cortices of the left hemisphere. In the maintenance phase we observed focally decreased θ oscillations and increased β oscillations (ERS) in most of the selected posterior areas and focally increased oscillations in γLOWand γHIGHbands in the frontal and insular cortices of the left hemisphere. Finally, during WM readout, we also found a focal modulation of the γLOWband in the left fusiform cortex and cerebellum, depending on the response trial type (true positive vs. true negative).

Overall, our study demonstrated specific spectral signatures associated with updating of memory information, WM maintenance and readout, with relatively high spatial resolution.
Disease associated mutations in mitochondrial precursor tRNAs affect binding, m1R9 methylation and tRNA processing by mtRNase P
Authors: Karasik Agnes , Fierke Carol A. , Koutmos Markos
Published: July 2020

Mitochondrial diseases linked to mutations in mitochondrial(mt) tRNA sequences are abundant. However, the contributions of these tRNA mutations to the development of diseases is mostly unknown. Mutations may affect interactions with (mt)tRNA maturation enzymes or protein synthesis machinery leading to mitochondrial dysfunction. In human mitochondria, the first step of tRNA processing is the removal of the 5’end of precursor tRNAs (pre-tRNA) catalyzed by the three-component enzyme, mtRNase P. Additionally, one sub-component of mtRNase P, mitochondrial RNase P protein 1 (MRPP1) catalyzes methylation of the R9 base in pre-tRNAs. Despite the central role of 5’ end processing in mitochondrial tRNA maturation, the link between mtRNase P and diseases is mostly unexplored. Here we investigate how 11 different human disease-linked mutations in (mt)pre-tRNAs affect the activities of mtRNase P. We find that several mutations weaken the pre-tRNA binding affinity, while the majority of mutations decrease 5’ end processing and methylation activity catalyzed by mtRNase P. Furthermore, all of the investigated mutations in (mt)pre-tRNALeu(UUR)alter the tRNA fold which contributes to the partial loss of function of mtRNase P. Overall, these results reveal an etiological link between early steps of (mt)tRNA-substrate processing and mitochondrial disease.
The developing relations between networks of cortical myelin and neurophysiological connectivity
Authors: Vandewouw Marlee M. , Hunt Benjamin A.E. , Ziolkowski Justine , Taylor Margot J.
Published: July 2020

Recent work identified that patterns of distributed brain regions sharing similar myeloarchitecture are related to underlying functional connectivity, demonstrating cortical myelin’s plasticity to changes in functional demand. However, the changing relation between functional connectivity and structural architecture throughout child and adulthood is poorly understood. We show that structural covariance connectivity measured using T1-weighted/T2-weighted ratio and functional connectivity measured using magnetoencephalography exhibit nonlinear developmental changes. We then show significant relations between structural and functional connectivity, which have both shared and distinct characteristics dependent on the neural oscillatory frequency. Increases in structure-function coupling are visible during the protracted myelination observed throughout childhood and adolescence, and are followed by decreases near the onset of adulthood to potentially support increasing cognitive flexibility and functional specialization in adulthood. Our work lays the foundation for understanding the mechanisms by which myeloarchitecture supports brain function, enabling future investigations into how clinical populations may deviate from normative patterns.
Spike protein fusion loop controls SARS-CoV-2 fusogenicity and infectivity
Authors: Pal Debnath
Published: July 2020

Compared to the other human coronaviruses, SARS-CoV-2 has a higher reproductive number that is driving the COVID-19 pandemic. The high transmission of SARS-CoV-2 has been attributed to environmental, immunological, and molecular factors. The Spike protein is the foremost molecular factor responsible for virus fusion, entry and spread in the host, and thus holds clues for the rapid viral spread. The dense glycosylation of Spike, its high affinity of binding to the human ACE2 receptor, and the efficient priming by cleavage have already been proposed for driving efficient virus-host entry, but these do not explain its unusually high transmission rate. I have investigated the Spike from six β-coronaviruses, including the SARS-CoV-2, and find that their surface-exposed fusion peptides constituting the defined fusion loop are spatially organized contiguous to each other to work synergistically for triggering the virus-host membrane fusion process. The architecture of the Spike quaternary structure ensures the participation of the fusion peptides in the initiation of the host membrane contact for the virus fusion process. The SARS-CoV-2 fusion peptides have unique physicochemical properties, accrued in part from the presence of consecutive prolines that impart backbone rigidity which aids the virus fusogenicity. The specific contribution of these prolines shows significantly diminished fusogenicityin vitroand associated pathogenesisin vivo,inferred from comparative studies of their deletion-mutant in a fellow murine β-coronavirus MHV-A59. The priming of the Spike by its cleavage and subsequent fusogenic conformational transition steered by the fusion loop may be critical for the SARS-CoV-2 spread.

Significance Statement

The three proximal fusion peptides constituting the fusion loop in Spike protein are the membranotropic segments most suitable for engaging the host membrane surface for its disruption. Spike’s unique quaternary structure architecture drives the fusion peptides to initiate the protein host membrane contact. The SARS-CoV-2 Spike trimer surface is relatively more hydrophobic among other human coronavirus Spikes, including the fusion peptides that are structurally more rigid owing to the presence of consecutive prolines, aromatic/hydrophobic clusters, a stretch of consecutive β-branched amino acids, and the hydrogen bonds. The synergy accrued from the location of the fusion peptides, their physicochemical features, and the fusogenic conformational transition appears to drive the virus fusion process and may explain the high spread of the SARS-CoV-2.
A Fluorescence-based High Throughput-Screening assay for the SARS-CoV RNA synthesis complex
Authors: Eydoux Cecilia , Fattorini Veronique , Shannon Ashleigh , Le Thi-Tuyet-Nhung , Didier Bruno , Canard Bruno , Guillemot Jean-Claude
Published: July 2020

The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) emergence in 2003 introduced the first serious human coronavirus pathogen to an unprepared world. To control emerging viruses, existing successful anti(retro)viral therapies can inspire antiviral strategies, as conserved viral enzymes (eg., viral proteases and RNA-dependent RNA polymerases) represent targets of choice. Since 2003, much effort has been expended in the characterization of the SARS-CoV replication/transcription machinery. Until recently, a pure and highly active preparation of SARS-CoV recombinant RNA synthesis machinery was not available, impeding target-based high throughput screening of drug candidates against this viral family. The current Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic revealed a new pathogen whose RNA synthesis machinery is highly (>96% aa identity) homologous to SARS-CoV. This phylogenetic relatedness highlights the potential use of conserved replication enzymes to discover inhibitors against this significant pathogen, which in turn, contributes to scientific preparedness against emerging viruses. Here, we report the use of a purified and highly active SARS-CoV replication/transcription complex (RTC) to set-up a high-throughput screening of Coronavirus RNA synthesis inhibitors. The screening of a small (1,520 compounds) chemical library of FDA-approved drugs demonstrates the robustness of our assay and will allow to speed-up drug repositioning or novel drug discovery against the SARS-CoV-2.

Principle of SARS-CoV RNA synthesis detection by a fluorescence-based high throughput screening assay

Highlights

- A new SARS-CoV non radioactive RNA polymerase assay is described

- The robotized assay is suitable to identify RdRp inhibitors based on HTS
Structural and molecular dynamics ofMycobacterium tuberculosismalic enzyme, a potential anti-TB drug target
Authors: Burley Kalistyn H. , Cuthbert Bonnie J. , Basu Piyali , Newcombe Jane , Irimpan Ervin M. , Quechol Robert , Foik Ilona P. , Mobley David L. , Beste Dany J.V. , Goulding Celia W.
Published: July 2020

Tuberculosis (TB) is the most lethal bacterial infectious disease worldwide. It is notoriously difficult to treat, requiring a cocktail of antibiotics administered over many months. The dense, waxy outer membrane of the TB-causing agent,Mycobacterium tuberculosis(Mtb), acts as a formidable barrier against uptake of antibiotics. Subsequently, enzymes involved in maintaining the integrity of the Mtb cell wall are promising drug targets. Recently, we demonstrated that Mtb lacking malic enzyme (MEZ) has altered cell wall lipid composition and attenuated uptake by macrophages. These results suggest that MEZ provides the required reducing power for lipid biosynthesis. Here, we present the X-ray crystal structure of MEZ to 3.6 Å resolution and compare it with known structures of prokaryotic and eukaryotic malic enzymes. We use biochemical assays to determine its oligomeric state and to evaluate the effects of pH and allosteric regulators on its kinetics and thermal stability. To assess the interactions between MEZ and its substrate malate and cofactors, Mn2+and NAD(P)+, we ran a series of molecular dynamics (MD) simulations. First, the MD analysis corroborates our empirical observations that MEZ is unusually disordered, which persists even with the addition of substrate and cofactors. Second, the MD simulations reveal that MEZ subunits alternate between open and closed states and that MEZ can stably bind its NAD(P)+cofactor in multiple conformations, including an inactive, compact NAD+form. Together the structure of MEZ and insights from its dynamics can be harnessed to inform the design of MEZ inhibitors that target Mtb.
A rapidly adaptable biomaterial vaccine for SARS-CoV-2
Authors: Langellotto Fernanda , Seiler Benjamin T. , Yu Jingyou , Cartwright Mark J. , White Des , Yeager Chyenne , Super Michael , Doherty Edward J. , Barouch Dan H. , Mooney David J.
Published: July 2020

The global COVID-19 pandemic motivates accelerated research to develop safe and efficacious vaccines. To address this need, we leveraged a biomaterial vaccine technology that consists of mesoporous silica rods (MSRs) that provide a sustained release of granulocyte-macrophage colony-stimulating factor (GM-CSF) and adjuvants to concentrate and mature antigen-presenting cells at the vaccine site. Here we explored the humoral responses resulting from the use of monophosphoryl lipid A (MPLA) as the adjuvant and SARS-CoV-2 spike proteins S1, S2, the nucleocapsid (N) protein, and receptor binding domain (RBD) as the target antigens. The dose of antigen and impact of pre-manufacturing of vaccines as versus loading antigen just-in-time was explored in these studies. Single shot MSR vaccines induced rapid and robust antibody titers to the presented antigens, even without the use of a boost, and sera from vaccinated animals demonstrated neutralizing activity against a SARS-CoV-2 pseudovirus. Overall, these results suggest the MSR vaccine system may provide potent protective immunity when utilized to present SARS-CoV-2 antigens.
Genome-wide assessment of REST binding profiles reveals distinctions between human and mouse hippocampus
Authors: McGann James C. , Spinner Michael , Garg Saurabh K. , Mullendorf Karin , Woltjer Randall L. , Mandel Gail
Published: July 2020

Background

The transcriptional repressor, RE1 Silencing Transcription Factor (REST), recognized historically as a master regulator of neuronal gene expression during mouse development, has recently been ascribed roles in human aging and neurodegenerative disorders. However, REST’s role in healthy adult human brain, and how faithfully mouse models reproduce REST function in human brain, is not known.

Results

Here, we present the first genome-wide binding profile for REST in both mouse and human postnatal hippocampus. We find the majority of REST-bound sites in human hippocampus are unique compared to both mouse hippocampus and to all other reported human ENCODE cell types. Genes associated with unique REST-bound sites include previously unidentified categories related to innate immunity and inflammation signaling, suggesting species specific roles for REST in protecting human brain health.

Conclusions

Our results suggest newly evolved functions for REST in maintaining human brain health.
PCB126-mediated effects on adipocyte energy metabolism and adipokine secretion may result in abnormal glucose uptake in muscle cells
Authors: Caron Audrey , Ahmed Fozia , Peshdary Vian , Garneau Léa , Atlas Ella , Aguer Céline
Published: July 2020

Background

Exposure to coplanar polychlorinated biphenyls (PCBs) is linked to the development of insulin resistance. Previous studies suggested that PCB126 alters muscle mitochondrial function through an indirect mechanism. Since PCBs are stored in fat, we hypothesized that PCB126 alters adipokine secretion, which in turn affects muscle metabolism.

Objectives

The objectives of this study were: 1) To study the impacts of PCB126 exposure on adipocyte cytokine/adipokine secretion; 2) To determine whether adipocyte-derived factors alter glucose metabolism and mitochondrial function in myotubes when exposed to PCB126; 3) To determine whether pre-established insulin resistance alters the metabolic responses of adipocytes exposed to PCB126 and the communication between adipocytes and myotubes.

Method

3T3-L1 adipocytes were exposed to PCB126 (1-100 nM) in two insulin sensitivity conditions (insulin sensitive (IS) and insulin resistant (IR) adipocytes), followed by the measurement of secreted adipokines, mitochondrial function and insulin-stimulated glucose uptake. Communication between adipocytes and myotubes was reproduced by exposing C2C12 or mouse primary myotubes to conditioned medium (CM) derived from IS or IR 3T3-L1 adipocytes exposed to PCB126. Mitochondrial function and insulin-stimulated glucose uptake were then determined in myotubes.

Results

PCB126 significantly increased adipokine (adiponectin, IL-6, MCP-1, TNF-α) secretion and decreased mitochondrial function, glucose uptake and glycolysis in IR but not in IS 3T3-L1 adipocytes. Altered energy metabolism in IR 3T3-L1 adipocytes was linked to decreased phosphorylation of AMP-activated protein kinase (p-AMPK) and increased superoxide dismutase 2 levels, an enzyme involved in reactive oxygen species detoxification. Exposure of myotubes to CM from PCB126-treated IR adipocytes decreased glucose uptake, without altering glycolysis or mitochondrial function. Interestingly, p-AMPK levels were increased rather than decreased in myotubes exposed to the CM of PCB126-treated IR adipocytes.

Conclusion

Taken together, these data suggest that increased adipokine secretion from IR adipocytes exposed to PCB126 may explain impaired glucose uptake in myotubes.
Metabolic fate of human immunoactive sterols inMycobacterium tuberculosis
Authors: Varaksa Tatsiana , Bukhdruker Sergey , Grabovec Irina , Marin Egor , Kavaleuski Anton , Gusach Anastasiia , Kovalev Kirill , Maslov Ivan , Luginina Aleksandra , Zabelskiy Dmitry , Astashkin Roman , Shevtsov Mikhail , Smolskaya Sviatlana , Kavaleuskaya Anna , Shabunya Polina , Baranovsky Alexander , Dolgopalets Vladimir , Charnou Yury , Savachka Aleh , Litvinovskaya Raisa , Hurski Alakseij , Shevchenko Evgeny , Rogachev Andrey , Mishin Alexey , Gordeliy Valentin , Gabrielian Andrei , Hurt Darrell E. , Nikonenko Boris , Majorov Konstantin , Apt Alexander , Rosenthal Alex , Gilep Andrei , Borshchevskiy Valentin , Strushkevich Natallia
Published: July 2020

Mycobacterium tuberculosis(Mtb) infection is among top ten causes of death worldwide, and the number of drug-resistant strains is increasing. The direct interception of human immune signaling molecules by Mtb remains elusive, limiting drug discovery. Oxysterols and secosteroids regulate both innate and adaptive immune responses. Here we report a functional, structural, and bioinformatics study of Mtb enzymes initiating cholesterol catabolism and demonstrated their interrelation with human immunity. We show that these enzymes metabolize human immune oxysterol messengers. Rv2266 – the most potent among them – can also metabolize vitamin D3 (VD3) derivatives. High-resolution structures show common patterns of sterols binding and reveal a site for oxidative attack during catalysis. Finally, we designed a compound that binds and inhibits three studied proteins. The compound shows activity against Mtb H37Rv residing in macrophages. Our findings contribute to molecular understanding of suppression of immunity and suggest that Mtb has its own transformation system resembling the human phase I drug-metabolizing system.
Enhancer-associated H3K4 methylation safeguards in vitro germline competence
Authors: Bleckwehl Tore , Crispatzu Giuliano , Schaaf Kaitlin , Respuela Patricia , Bartusel Michaela , Benson Laura , Clark Stephen J. , Dorighi Kristel M. , Barral Antonio , Laugsch Magdalena , van IJcken Wilfred F. J. , Manzanares Miguel , Wysocka Joanna , Reik Wolf , Rada-Iglesias Álvaro
Published: July 2020

Germline specification in mammals occurs through an inductive process whereby competent cells in the post-implantation epiblast differentiate into primordial germ cells (PGC). The intrinsic factors that endow epiblast cells with the competence to respond to germline inductive signals remain unknown. Single-cell RNA sequencing across multiple stages of anin vitroPGC-like cells (PGCLC) differentiation system shows that PGCLC genes initially expressed in the naïve pluripotent stage become homogeneously dismantled in germline competent epiblast like-cells (EpiLC). In contrast, the decommissioning of enhancers associated with these germline genes is incomplete. Namely, a subset of these enhancers partly retain H3K4me1, accumulate less heterochromatic marks and remain accessible and responsive to transcriptional activators. Subsequently, asin vitrogermline competence is lost, these enhancers get further decommissioned and lose their responsiveness to transcriptional activators. Importantly, using H3K4me1 deficient cells, we show that the loss of this histone modification reduces the germline competence of EpiLC and decreases PGCLC differentiation efficiency. Our work suggests that, although H3K4me1 might not be essential for enhancer function, it can facilitate the (re)activation of enhancers and the establishment of gene expression programs during specific developmental transitions.
Immobilised collagen prevents shedding and induces sustained GPVI clustering and signalling in platelets
Authors: Pallini Chiara , Pike Jeremy A. , O’Shea Christopher , Andrews Robert K. , Gardiner Elizabeth E. , Watson Steve P. , Poulter Natalie S.
Published: July 2020

Collagen, the most thrombogenic constituent of blood vessel walls, activates platelets through glycoprotein VI (GPVI). In suspension, following platelet activation by collagen, GPVI is cleaved by A Disintegrin And Metalloproteinase (ADAM)10 and ADAM17. In this study, we use single-molecule localization microscopy and a 2-level DBSCAN-based clustering tool to show that GPVI remains clustered along immobilised collagen fibres for at least 3 hours in the absence of significant shedding. Tyrosine phosphorylation of spleen tyrosine kinase (Syk) and Linker of Activated T cells (LAT), and elevation of intracellular Ca2+, are sustained over this period. Syk, but not Src kinase-dependent signalling is required to maintain clustering of the collagen integrin α2β1, whilst neither is required for GPVI. We propose that clustering of GPVI on immobilised collagen protects GPVI from shedding in order to maintain sustained Src and Syk-kinases dependent signalling, activation of integrin α2β1 and continued adhesion.
Learning to Personalize Medicine from Aggregate Data
Authors: Colbaugh Rich , Glass Kristin
Published: July 2020

There is great interest in personalized medicine, in which treatment is tailored to the individual characteristics of patients. Achieving the objectives of precision healthcare will require clinically-grounded, evidence-based approaches, which in turn demands rigorous, scalable predictive analytics. Standard strategies for deriving prediction models for medicine involve acquiring ‘training’ data for large numbers of patients, labeling each patient according to the outcome of interest, and then using the labeled examples to learn to predict the outcome for new patients. Unfortunately, labeling individuals is time-consuming and expertise-intensive in medical applications and thus represents a major impediment to practical personalized medicine. We overcome this obstacle with a novel machine learning algorithm that enables individual-level prediction models to be induced from aggregate-level labeled data, which is readily-available in many health domains. The utility of the proposed learning methodology is demonstrated by: i.) leveraging US county-level mental health statistics to create a screening tool which detects individuals suffering from depression based upon their Twitter activity; ii.) designing a decision-support system that exploits aggregate clinical trials data on multiple sclerosis (MS) treatment to predict which therapy would work best for the presenting patient; iii.) employing group-level clinical trials data to induce a model able to find those MS patients likely to be helped by an experimental therapy.
Commentary on “being diagnosed with autism in adulthood: a personal case study”
Authors: Tromans Samuel , Chester Verity
Published: July 2020

Purpose

The purpose of this paper is to provide a commentary on “being diagnosed with autism in adulthood: a personal case study”.

Design/methodology/approach

A commentary on an individual’s personal experiences of being referred to autism assessment services and subsequently receiving a diagnosis of autism in adulthood.

Findings

Many individuals are not diagnosed with autism until their adult life, and as a result, miss the benefits of timely introduction of sources of support, such as during their schooling. Receiving an autism diagnosis can come as a relief and promote self-understanding, but availability of high-quality post-diagnostic support services and accommodating employers are both highly important.

Originality/value

A commentary on an original viewpoint is published in this special edition on gender and diversity.
Factors influencing students' reactions to ethical dilemmas in advertising'
Authors: Cheah Isaac , Shimul Anwar Sadat
Published: July 2020

Purpose

The purpose of this study is to extend existing research on ethics in advertising through investigating the key factors that influence students' reaction towards ethical dilemmas.

Design/methodology/approach

Several hypotheses are developed and tested across twenty three ethical dilemma scenarios relative to advertising and business. Using information collected from business students (1297 useable responses) at a large Western Australian university.

Findings

The results indicates significant differences amongst culture, educational background, gender, work experience and corporate culture towards students' reactions to ethical dilemmas.

Practical implications

This research suggests that providing a stronger emphasis on ethics in educational institutions will increase the likeliness for students in behaving ethically. The managerial implications of these findings are also discussed, including the development of a potential ethical work context and programmes that enhance ethical sensitivity. Managers and executives would also benefit from this study by encouraging better ethical performance through understanding employees' behaviour.

Originality/value

Extant studies on ethical dilemmas in advertising highly focus on European's and North American's ethical beliefs. Thus, this paper look at the Western Australian sample of students at a broader context through acknowledging East Asian student sample in Western Australia; Chinese, Indonesian, Malaysian and Taiwanese.
Simultaneous identification of timewise terms and free boundaries for the heat equation
Authors: Huntul Mousa , Tamsir Mohammad
Published: July 2020

Purpose

The purpose of this paper is to provide an insight and to solve numerically the identification of timewise terms and free boundaries coefficient appearing in the heat equation from over-determination conditions.

Design/methodology/approach

The formulated coefficient identification problem is inverse and ill-posed, and therefore, to obtain a stable solution, a nonlinear Tikhonov regularization least-squares approach is used. For the numerical discretization, the finite difference method combined with a regularized nonlinear minimization is performed using the MATLAB subroutine lsqnonlin.

Findings

The numerical results presented for two examples show the efficiency of the computational method and the accuracy and stability of the numerical solution even in the presence of noise in the input data.

Research limitations/implications

The mathematical formulation is restricted to identify coefficients in unknown components dependent on time, and this may be considered as a research limitation. However, there is no research implication to overcome this, as the known input data is also limited to single temperature in heat equation with Stefan conditions, and the first- and second-order heat moments measurements at a particular time location.

Practical implications

As noisy data are inverted, the study models real situations in which practical measurements are inherently contaminated with noise.

Social implications

The identification of the timewise terms and free boundaries will be of great interest in the heat transfer community and related fluid flow applications.

Originality/value

The current investigation advances previous studies, which assumed that the coefficient multiplying the lower order temperature term depends on time. The knowledge of this physical property coefficient is very important in heat transfer and fluid flow. The originality lies in the insight gained by performing for the numerical simulations of inversion to find the timewise terms and free boundaries coefficient dependent on time in the heat equation from noisy measurements.
Wealth out of Waste (WOW): a business paradox
Authors: Mathur Mini , Kothari Smita P.
Published: July 2020

Learning outcomes

Help students understand Porter’s five forces framework. Explore and analyze possible growth strategies using the Ansoff matrix.

Case overview/synopsis

This case study integrates lessons in growth strategies, Porter’s five forces and the Ansoff matrix. Vijay Kothari, Founder of Wealth out of Waste (WOW) is in a fix. In spite of functioning in an environment of abundant demand and potential, he is unable to perform in his optimum capacity because of operational and manpower-related issues. WOW, which turned nine in 2019, is a sort of monopoly in the organized business of scheduled collection of recyclable trash. WOW is operating in a 2% market with 98% being captured by traditional “pastiwalas.” From the current waiting period of up to seven days, Kothari wants to service any area in the city of Ahmedabad, Gujarat, India within 2 h. To achieve this objective, how should Kothari overcome the growth challenge in the business.

Complexity academic level

Undergraduate and postgraduate.

Supplementary materials

Teaching Notes are available for educators only.

Subject code

CSS 11: Strategy.
A systematic review of mental stressors in the construction industry
Authors: Tijani Bashir , Jin Xiaohua , Osei-kyei Robert
Published: July 2020

Purpose

Stressors emanated from construction projects are causative factors for occupational stress inherent in the construction industry. Concomitant implications of stressors ignite a burst of empirical evidence, which necessitates a systematic review to capture the state of art of the extant literature. Therefore, this paper addresses this significant gap by conducting a systematic review of mental stressors.

Design/methodology/approach

A three-stage screening and data extraction method were employed to retrieve 38 papers that met the inclusion criteria for the study.

Findings

The annual publication trends and contributions of selected journals were elucidated. Moreover, this review identified 49 stressors from 38 selected peer-reviewed journals between 1997 and 2020. The most frequently reported mental stressors include work overload, home-work conflict, poor working environment, role ambiguity and poor working relationships. The 49 stressors could be classified into five main categories, namely; organizational stressors, task stressors, personal stressors, physical stressors and gender-related stressors.

Originality/value

The findings of the study broaden the understanding of the practitioners and policymakers on the dynamics of stressors for the development of stress interventions. Future research should focus on exploration of mental stressors specific to construction projects and different occupational trades.
Identification of drivers of employee engagement in Indian power companies
Authors: Mohanty Samarendra Kumar , P Arunprasad
Published: July 2020

Purpose

The purpose of this paper is to extend the scope of social exchange theory (SET) to explore employee engagement and test its application in the context of Indian power companies. The study also attempts to explore the antecedents of employee engagement. This study includes organizational culture and three trusts, that is co-worker trust, supervisor trust and organizational trust whose presence in the organization influences employee engagement.

Design/methodology/approach

The study includes a sample of 812 executives who represent three major functions of the Indian power sector, that is power generation, power transmission and power distribution. The relationships between constructs are evaluated using structural equation modeling.

Findings

The findings of this study indicate that four resources in the organization influence employee engagement in different ways. Three constructs representing co-worker trust, supervisor trust and organizational trust partially mediate the relation between organizational culture and employee engagement. This study also compares the engagement levels of the employees from three power companies.

Research limitations/implications

This study is focused on companies operating in only the government sector.

Practical implications

Ensuring engagement from employees for the critical power sector is expected to support the development of the HR practices in this sector. Identification of sector-specific resources is expected to aid both employees and policymakers from the organization.

Social implications

This study assists the policy makers in the organization by showcasing the importance of organizational culture, interpersonal and organizational trusts and their impact on employee engagement.

Originality/value

Resource theory explains why certain resources in the workplace are exchanged for employee engagement. This study extends theories of engagement as well as SET and examines their application as employee engagement in the context of executives from Indian power companies. This understanding will aid the practitioners and researchers to further their understanding of employee engagement.
An exploration of digital ride-hailing multisided platforms' market dynamics: empirical evidence from the Uber case study
Authors: Cosenz Federico , Qorbani Davood , Yamaguchi Yokei
Published: July 2020

Purpose

The purpose of this paper is to experiment a dynamic performance management (DPM) approach to explore and assess the business dynamics of digital ride-hailing platforms with a focus on both supply and demand sides, and related interplays.

Design/methodology/approach

The research adopts the DPM framework supported by simulation-based experimentations for developing a systemic case interpretation of Uber Inc. and its specific business complexity.

Findings

The emerging scenario analysis reveals that changes in the commission percentage for drivers and cutting prices for customers (car hailers) by competitors have significant impacts on the car-hailing industry.

Originality/value

DPM and associated simulation-based analysis of the ride-hailing business may provide significant managerial decision insights and a ground base research in a relatively less-explored field within the strategic management domain.
Assessing Dutch housing cycle and near-term market prospects
Authors: Jadevicius Arvydas , van Gool Peter
Published: July 2020

Purpose

This study is a practice undertaking examining three main concerns that currently dominate Dutch housing market debate: how long is the cycle, will the current house price inflation continue and is housing market in a bubble. With national house prices reaching record highs across all major cities, future market prospects became a topic of significant debate among policymakers, investors and the populace.

Design/methodology/approach

A triangulation of well-established academic methods is used to perform investigation. The models include Hodrick-Prescott (HP) filter, volatility autoregressive conditional heteroskedasticity (ARCH approximation) and right tail augmented Dickey–Fuller (Rtadf) test (bubble screening technique).

Findings

Interestingly, over the years from 1985 to 2019 research period, filtering extracts only one Dutch national housing cycle. This is a somewhat distinct characteristic compared to other advanced Western economies (inter alia the UK and the USA) where markets tend to experience 8- to 10-year gyrations. Volatility and Rtadf test suggest that current house prices in most Dutch cities are in excess of historical averages and statistical thresholds. House price levels in Almere, Amsterdam, The Hague, Groningen, Rotterdam and Utrecht are of particular concern.

Originality/value

Retail investors should therefore be cautious as they are entering the market at the time of elevated housing values. For institutional investors, those investing in long-term, housing in key Dutch metropolitan areas, even if values decline, is still an attractive investment conduit.