bluuebunny/crossref_metadata_2025 huggingface dataset:
Abnormal antibodies to self-carbohydrates in SARS-CoV-2 infected patients
Authors: Butler Dorothy L. , Gildersleeve Jeffrey C.
Published: October 2020

SARS-CoV-2 is a deadly virus that is causing the global pandemic coronavirus disease 2019 (COVID-19). Our immune system plays a critical role in preventing, clearing, and treating the virus, but aberrant immune responses can contribute to deleterious symptoms and mortality. Many aspects of immune responses to SARS-CoV-2 are being investigated, but little is known about immune responses to carbohydrates. Since the surface of the virus is heavily glycosylated, pre-existing antibodies to glycans could potentially recognize the virus and influence disease progression. Furthermore, antibody responses to carbohydrates could be induced, affecting disease severity and clinical outcome. In this study, we used a carbohydrate antigen microarray with over 800 individual components to profile serum anti-glycan antibodies in COVID-19 patients and healthy control subjects. In COVID-19 patients, we observed abnormally high IgG and IgM antibodies to numerous self-glycans, including gangliosides,N-linked glycans, LacNAc-containing glycans, blood group H, and sialyl Lewis X. Some of these anti-glycan antibodies are known to play roles in autoimmune diseases and neurological disorders, which may help explain some of the unusual and prolonged symptoms observed in COVID-19 patients. The detection of antibodies to self-glycans has important implications for using convalescent serum to treat patients, developing safe and effective SARS-CoV-2 vaccines, and understanding the risks of infection. In addition, this study provides new insight into the immune responses to SARS-CoV-2 and illustrates the importance of including host and viral carbohydrate antigens when studying immune responses to viruses.
Biofilm Formation and Virulence ofShigella flexneriis Modulated by pH of Gastrointestinal Tract
Authors: Chiang I-Ling , Wang Yi , Fujii Satoru , Muegge Brian D. , Lu Qiuhe , Stappenbeck Thaddeus
Published: October 2020

Shigellainfections remain a major public health issue in developing countries. One model ofShigellapathogenesis suggests that the microfold epithelial cells in the small intestine are the preferred initial site of infection. However, a growing body of evidence supports an alternative model wherebyShigellaprimarily infects a much wider range of epithelial cells that reside primarily within the colon. Here, we investigated whether the luminal pH difference between the small intestine and colon could provide evidence in support of either model ofShigella flexneripathogenesis. As virulence factors leading to cellular invasion are linked to biofilms inS. flexneri, we examined the effect of pH onS. flexneri’s ability to form and maintain adherent biofilms when induced by deoxycholate. We showed that a basic pH inhibited formation and dispersed pre-assembled mature biofilms while an acidic pH (similar to the colonic environment) did not have either of these effects. To further elucidate this phenomenon at the molecular level, we probed the transcriptomes of biofilms andS. flexnerigrown in different pH conditions. We identified specific amino acid metabolic pathways (cysteine and arginine) that were enriched in the bacteria that formed the biofilms, but decreased upon pH increase. We then utilized a type III secretion system reporter strain to show that increasing pH reduced deoxycholate-induced virulence ofS. flexneriin a dose dependent manner. Taken together, these experiments support a model wherebyShigellainfection is favored in the colon because of the local pH differences in these organs.
Psychological Well-being and Demographic Factors can Mediate Soundscape Pleasantness and Eventfulness: A large sample study
Authors: Erfanian Mercede , Mitchell Andrew , Aletta Francesco , Kang Jian
Published: October 2020

Soundscape studies aim to consider the holistic human perception of a sound environment, including both the physical phenomena and how these are mediated by internal factors: the mechanisms underpinning the interactions between these two aspects are not well understood. This study aims to assess the influence of psychological well-being and demographic factors including age, gender, occupation status, and education levels on the dimensions of the soundscape circumplex, i.e., Pleasantness and Eventfulness. Data was collected in eleven urban locations in London through a large-scale (N=1134) soundscape survey according to the ISO 12913-2 technical specifications and incorporating the WHO-5 well-being index. Linear mixed-effects modelling applying backwards-step feature selection was used to model the interactions between internal factors including psychological well-being, age, gender, occupation status, education levels and the soundscape Pleasantness and Eventfulness, while accounting for the random effects of the survey location. The findings suggest that internal factors account for approximately 1.4% of the variance for Pleasantness and 3.9% for Eventfulness, while the influence of the locations accounted for approximately 34% and 14%, respectively. Psychological well-being is positively associated with perceived Pleasantness, while there is a negative association with Eventfulness only for males. Occupation status, in particular retirement as a proxy of age and gender, was identified as a significant factor for both dimensions. These findings offer empirical grounds for developing theories of the interaction between internal factors and soundscape formation whilst highlighting the importance of the location, namely: the context.
Chronic exposure of ErbB TKIs inhibits DRA expression and activity through an ERK/Elk-1/CREB/AP-1 dependent pathway
Authors: Yang Hong , Lin Ru-Xian , Sarker Rafiquel , Donowitz Mark
Published: October 2020

Diarrhea is the major side effect of first- and second-generation ErbB tyrosine kinase inhibitors (TKI), the mechanism of which remains incompletely understood. The current studies were carried out over the time frame that ErbB TKIs usually initiate diarrhea. We report in Caco-2/bbe cells that exposure of ErbB TKIs, but not non-ErbB TKIs for six days at clinically-relevant concentrations significantly reduced the expression of DRA and inhibited apical Cl-/HCO3-exchange activity. The ErbB TKIs decreased DRA expression through an ERK/Elk-1/CREB/AP-1 dependent pathway. The blockade of ERK phosphorylation by ErbB TKIs decreased the phosphorylation of Elk-1 and the amount of total and p-CREB, and reduced the expression of C-Fos, which is part of the AP-1 complex that maintain DRA expression. Altogether, our studies demonstrate that ErbB TKIs decrease expression and activity of DRA, which occurs over the time frame that these drugs clinically cause diarrhea, and since DRA is part of the intestinal neutral NaCl absorptive process, the reduced absorption is likely to represent a major contributor to the ErbB TKI-associated diarrhea.
Non-rodent mammalian zygotes assemble dual spindles despite the presence of paternal centrosomes
Authors: Schneider Isabell , de Ruijter-Villani Marta , Hossain M. Julius , Stout Tom A. E. , Ellenberg Jan
Published: October 2020

The first mitosis of the mammalian embryo must partition the parental genomes contained in two pronuclei. In rodent zygotes, sperm centrosomes are degraded and, instead, acentriolar microtubule organizing centers and microtubule self-organization guide the assembly of two separate spindles around the genomes. In non-rodent mammals, including human or bovine, centrosomes are inherited from the sperm and have been widely assumed to be active. Whether non-rodent zygotes assemble a single centrosomal spindle around both genomes, or follow the dual spindle self-assembly pathway is unclear. To address this, we investigated spindle assembly in bovine zygotes by systematic immunofluorescence and real-time light-sheet microscopy. We show that two independent spindles form around the parental genomes despite the presence of centrosomes, which had little effect on spindle structure and were only loosely connected to the two spindles. We conclude that the dual spindle assembly pathway is conserved in non-rodent mammals. This could explain whole parental genome loss frequently observed in blastomeres of human IVF embryos.

This study investigates spindle assembly during the first embryonic division in bovine zygotes that, like human, inherit centrosomes from the sperm. It shows that two independent microtubule arrays form by self-organization around parental genomes with only loosely connected centrosomes.
Beyond broadband: towards a spectral decomposition of EEG microstates
Authors: Férat Victor , Seeber Martin , Michel Christoph M. , Ros Tomas
Published: October 2020

Originally applied to alpha oscillations in the 1970s, MS analysis has since been used to decompose mainly broadband EEG signals (e.g. 1-40 Hz). We hypothesized that MS decomposition within separate, narrow frequency bands could provide more fine-grained information for capturing the spatio-temporal complexity of multichannel EEG. In this study using a large open-access dataset (n=203), we decomposed EEG recordings into 4 classical frequency bands (delta, theta, alpha, beta) in order to compare their individual MS segmentations using mutual information as well as traditional MS measures (e.g. mean duration, time coverage). Firstly, we confirmed that MS topographies were spatially equivalent across all frequencies, matching the canonical broadband maps (A, B, C, D). Interestingly however, we observed strong informational independence of MS temporal sequences between spectral bands, together with significant divergence in traditional MS measures. For example, relative to broadband, alpha/beta band dynamics displayed greater time coverage of maps A & B, while map D was more prevalent in delta/theta bands. Moreover, by using a frequency-specificMS taxonomy (e.g. θA, αC), we were able to predict the eyes-open vs closed-behavioural state significantly better using alpha-band MS features compared with broadband ones (80% vs 73% accuracy). Overall, our findings demonstrate the value and validity of spectrally-specific MS analyses, which may prove useful for identifying new neural mechanisms in fundamental research and/or for biomarker discovery in clinical populations.
Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS-CoV-2 infection in vitro
Authors: Schloer Sebastian , Brunotte Linda , Mecate-Zambrano Angeles , Zheng Shuyu , Tang Jing , Ludwig Stephan , Rescher Ursula
Published: October 2020

The SARS-COV-2 pandemic and the global spread of coronavirus disease 2019 (COVID-19) urgently calls for efficient and safe antiviral treatment strategies. A straightforward approach to speed up drug development at lower costs is drug repurposing. Here we investigated the therapeutic potential of targeting the host- SARS-CoV-2 interface via repurposing of clinically licensed drugs and evaluated their use in combinatory treatments with virus- and host-directed drugs. We tested the antiviral potential of repurposing the antifungal itraconazole and the antidepressant fluoxetine on the production of infectious SARS-CoV-2 particles in the polarized Calu-3 cell culture model and evaluated the added benefit of a combinatory use of these host-directed drugs with remdesivir, an inhibitor of viral RNA polymerase. Drug treatments were well-tolerated and potent impaired viral replication was observed with all drug treatments. Importantly, both itraconazole-remdesivir and fluoxetine-remdesivir combinations inhibited the production of infectious SARS-CoV-2 particles > 90% and displayed synergistic effects in commonly used reference models for drug interaction. Itraconazole-Remdesivir and Fluoxetine-Remdesivir combinations are promising therapeutic options to control SARS-CoV-2 infection and severe progression of COVID-19.
The JAK2-STAT pathway epigenetically regulates tolerized genes during the first encounter with bacterial antigens
Authors: Lorente-Sorolla Clara , Morante-Palacios Octavio , Garcia-Gomez Antonio , Ciudad Laura , Català-Moll Francesc , Ruiz-Sanmartín Adolfo , Martínez-Gallo Mónica , Ferrer-Roca Ricard , Ruiz-Rodriguez Juan Carlos , Álvarez-Errico Damiana , Ballestar Esteban
Published: October 2020

Microbial challenges, such as widespread bacterial infection, induce endotoxin tolerance. This state of hyporesponsiveness to subsequent infections is mainly displayed by monocytes and macrophages. Endotoxin tolerance is generally acquired following a septic episode. In this study, we investigated DNA methylation changes during the acquisition ofin vitrotolerance. We identified a set of TET2-mediated demethylation events that are specific to toll-like receptor (TLR) 2 and TLR4 stimulation. Lipopolysaccharide (LPS)-specific demethylation occurs at genomic sites that have low accessibility in quiescent monocytes, concomitantly with the transcriptional activation of many inflammation-related genes, and they are enriched in binding motifs for several signal transducer and activator of transcription (STAT) family members. Indeed, STAT1, STAT3 and STAT5, elements of the JAK2 pathway, are phosphorylated in association with the acquisition of endotoxin tolerance. Inhibition of the JAK2 pathway impairs the activation of tolerized genes on the first encounter with LPS. This is evidence of a crucial role for this pathway in determining the initial response of these genes to bacterial antigens and provides a pharmacological target to prevent exacerbated responses, allowing regulated responses upon subsequent challenges. Finally, we assess the pathological relevance of the JAK2 pathway in monocytes from patients with sepsis.
The predator activity landscape predicts the anti-predator behavior and distribution of prey in a tundra community
Authors: Clermont Jeanne , Grenier-Potvin Alexis , Duchesne Éliane , Couchoux Charline , Dulude-de Broin Frédéric , Beardsell Andréanne , Bêty Joël , Berteaux Dominique
Published: October 2020

Predation shapes communities through consumptive and non-consumptive effects, where in the latter prey respond to perceived predation risk through risk management strategies occurring at different spatial and temporal scales. The landscape of fear concept is useful to better understand how predation risk affects prey behavioral decisions and distribution, and more generally the spatial dimension of predator-prey relationships. We assessed the effects of the predation risk landscape in a terrestrial Arctic community, where arctic fox is the main predator of ground-nesting bird species. Using high frequency GPS data, we developed a predator activity landscape resulting from fox space use patterns, and validated with an artificial prey experiment that it generated a predation risk landscape. We then investigated the effects of the fox activity landscape on multiple prey, by assessing the anti-predator behavior of a primary prey (snow goose) and the nest distribution of several incidental prey. Areas highly used by foxes were associated with a stronger level of nest defense by snow geese. We further found a lower probability of occurrence of incidental prey nests in areas highly used by foxes, but only for species nesting in habitats easily accessible to foxes. Species nesting in refuges consisting of micro-habitats limiting fox accessibility, like islets, did not respond to the fox activity landscape. Consistent with the scale of the fox activity landscape, this result reflected the capacity of refuges to allow bird nesting without regard to predation risk in the surrounding area. We demonstrated the value of using predator space use patterns to infer spatial variation in predation risk and better understand its effects on prey in landscape of fear studies. We also exposed the diversity of prey risk management strategies, hence refining our understanding of the mechanisms driving species distribution and community structure.
Force transduction creates long-ranged coupling in ribosomes stalled by arrest peptides
Authors: Zimmer Matthew H , Niesen Michiel JM , Miller Thomas F
Published: October 2020

Force-sensitive arrest peptides regulate protein biosynthesis by stalling the ribosome as they are translated. Synthesis can be resumed when the nascent arrest peptide experiences a pulling force of sufficient magnitude to break the stall. Efficient stalling is dependent on the specific identity of a large number of amino acids, including amino acids which are tens of angstroms away from the peptidyl transferase center (PTC). The mechanism of force-induced restart and the role of these essential amino acids far from the PTC is currently unknown. We use hundreds of independent molecular dynamics trajectories spanning over 120 μs in combination with kinetic analysis to characterize the barriers along the force-induced restarting pathway for the arrest peptide SecM. We find that the essential amino acids far from the PTC play a major role in controlling the transduction of applied force. In successive states along the stall-breaking pathway, the applied force propagates up the nascent chain until it reaches the C-terminus of SecM and the PTC, inducing conformational changes that allow for restart of translation. A similar mechanism of force propagation through multiple states is observed in the VemP stall-breaking pathway, but secondary structure in VemP allows for heterogeneity in the order of transitions through intermediate states. Results from both arrest peptides explain how residues that are tens of angstroms away from the catalytic center of the ribosome impact stalling efficiency by mediating the response to an applied force and shielding the amino acids responsible for maintaining the stalled state of the PTC.

Significance Statement

As nascent proteins are synthesized by the ribosome, their interactions with the environment can create pulling forces on the nascent protein that can be transmitted to the ribosome’s catalytic center. These forces can affect the rate and even the outcome of translation. We use simulations to characterize the pathway of force transduction along arrest peptides and discover how secondary structure in the nascent protein and its interactions with the ribosome exit tunnel impede force propagation. This explains how amino acids in arrest peptides that are tens of angstroms away from the ribosome’s catalytic center contribute to stalling, and, more broadly, suggests how structural features in the nascent protein dictate the ribosome’s ability to functionally respond to its environment.
Evolutionary and phylogenetic insights from a nuclear genome sequence of the extinct, giant ‘subfossil’ koala lemurMegaladapis edwardsi
Authors: Marciniak Stephanie , Mughal Mehreen R. , Godfrey Laurie R. , Bankoff Richard J. , Randrianatoandro Heritiana , Crowley Brooke E. , Bergey Christina M. , Muldoon Kathleen M. , Randrianasy Jeannot , Raharivololona Brigitte M. , Schuster Stephan C. , Malhi Ripan S. , Yoder Anne D. , Louis Edward E. , Kistler Logan , Perry George
Published: October 2020

No endemic Madagascar animal with body mass >10 kg survived a relatively recent wave of extinction on the island. From morphological and isotopic analyses of skeletal ‘subfossil’ remains we can reconstruct some of the biology and behavioral ecology of giant lemurs (primates; up to ~160 kg), elephant birds (up to ~860 kg), and other extraordinary Malagasy megafauna that survived well into the past millennium. Yet much about the evolutionary biology of these now extinct species remains unknown, along with persistent phylogenetic uncertainty in some cases. Thankfully, despite the challenges of DNA preservation in tropical and sub-tropical environments, technical advances have enabled the recovery of ancient DNA from some Malagasy subfossil specimens. Here we present a nuclear genome sequence (~2X coverage) for one of the largest extinct lemurs, the koala lemurMegaladapis edwardsi(~85kg). To support the testing of key phylogenetic and evolutionary hypotheses we also generated new high-coverage complete nuclear genomes for two extant lemur species,Eulemur rufifronsandLepilemur mustelinus, and we aligned these sequences with previously published genomes for three other extant lemur species and 47 non-lemur vertebrates. Our phylogenetic results confirm thatMegaladapisis most closely related to the extant Lemuridae (typified in our analysis byE. rufifrons) to the exclusion ofL. mustelinus, which contradicts morphology-based phylogenies. Our evolutionary analyses identified significant convergent evolution betweenM. edwardsiand extant folivorous primates (colobine monkeys) and ungulate herbivores (horses) in genes encoding protein products that function in the biodegradation of plant toxins and nutrient absorption. These results suggest that koala lemurs were highly adapted to a leaf-based diet, which may also explain their convergent craniodental morphology with the small-bodied folivoreLepilemur.
“Distinct roles of dorsal and ventral subthalamic neurons in action selection and cancellation.”
Authors: Mosher Clayton P. , Mamelak Adam N. , Malekmohammadi Mahsa , Pouratian Nader , Rutishauser Ueli
Published: October 2020

The subthalamic nucleus (STN) supports action selection by inhibiting all motor programs except the desired one. Recent evidence suggests that STN can also cancel an already selected action when goals change, a key aspect of cognitive control. However, there is little neurophysiological evidence for a dissociation between selecting and cancelling actions in the human STN. We recorded single neurons in the STN of humans performing a stop-signal task. Movement-related neurons suppressed their activity during successful stopping whereas stop-signal neurons activated at low-latencies regardless of behavioral outcome. In contrast, STN and motor-cortical beta-bursting occurred only later in the stopping process. Task-related neuronal properties varied by recording location from dorsolateral movement to ventromedial stop-signal tuning. Therefore, action selection and cancellation coexist in STN but are anatomically segregated. These results show that human ventromedial STN neurons carry fast stop-related signals suitable for implementing cognitive control.
The spore of the beans: Spatially explicit models predict coffee rust spread in fragmented landscapes
Authors: Beasley E.M. , Aristizábal N. , Bueno E. , White E.R.
Published: October 2020

Landscape structure influences the spread of plant pathogens, primarily by affecting pathogen dispersal. Coffee leaf rust (Hemileia vastatrix), a fungal disease that causes heavy economic losses in the coffee industry, is likely to be affected by landscape structure via dispersal of its wind-borne spores. Previous studies have found positive associations between leaf rust incidence and the proportion of pasture cover, suggesting that deforestation may facilitate rust spore dispersal. We explored this idea by modeling the spread of rust transmission in simulated landscapes. Specifically, we modeled within-patch transmission using a probabilistic cellular automata model, and between-patch transmission using a random walk with spore movement inhibited by forest canopy cover. We used this model to understand how the spread of coffee rust is affected by: 1) clustering of coffee plants, 2) clustering of deforestation, and 3) proportion of landscape deforestation. We found that clustering of coffee plants is the primary driver of rust transmission, affecting the likelihood and severity of rust outbreak. Deforestation is important in landscapes with high clustering of coffee: rust outbreaks are more severe in landscapes with a higher proportion of deforested areas, and more variable in landscapes where deforested areas are more evenly dispersed throughout the landscape.
Replicability of spatial gene expression atlas data from the adult mouse brain
Authors: Lu Shaina , Ortiz Cantin , Fürth Daniel , Fischer Stephan , Meletis Konstantinos , Zador Anthony , Gillis Jesse
Published: October 2020

Background

Spatial gene expression is particularly interesting in the mammalian brain, with the potential to serve as a link between many data types. However, as with any type of expression data, cross-dataset benchmarking of spatial data is a crucial first step. Here, we assess the replicability, with reference to canonical brain sub-divisions, between the Allen Institute’sin situ hybridizationdata from the adult mouse brain (ABA) and a similar dataset collected using Spatial Transcriptomics (ST). With the advent of tractable spatial techniques, for the first time we are able to benchmark the Allen Institute’s whole-brain, whole-transcriptome spatial expression dataset with a second independent dataset that similarly spans the whole brain and transcriptome.

Results

We use LASSO, linear regression, and correlation-based feature selection in a supervised learning framework to classify expression samples relative to their assayed location. We show that Allen reference atlas labels are classifiable using transcription, but that performance is higher in the ABA than ST. Further, models trained in one dataset and tested in the opposite dataset do not reproduce classification performance bi-directionally. Finally, while an identifying expression profile can be found for a given brain area, it does not generalize to the opposite dataset.

Conclusions

In general, we found that canonical brain area labels are classifiable in gene expression space within dataset and that our observed performance is not merely reflecting physical distance in the brain. However, we also show that cross-platform classification is not robust. Emerging spatial datasets from the mouse brain will allow further characterization of cross-dataset replicability.
A functional genomic screen inSaccharomyces cerevisiaereveals divergent mechanisms of resistance to different alkylphosphocholine chemotherapeutic agents
Authors: Garcia Jacquelin M. , Schwabe Michael J. , Voelker Dennis R. , Riekhof Wayne R.
Published: October 2020

The alkylphosphocholine (APC) class of antineoplastic and antiprotozoal drugs, such as edelfosine and miltefosine, are structural mimics of lyso-phosphatidylcholine (lyso-PC), and are inhibitory to the yeastSaccharomyces cerevisiaeat low micromolar concentrations. Cytotoxic effects related to inhibition of phospholipid synthesis, induction of an unfolded protein response, inhibition of oxidative phosphorylation, and disruption of lipid rafts have been attributed to members of this drug class, however the molecular mechanisms of action of these drugs remain incompletely understood. Cytostatic and cytotoxic effects of the alkylphosphocholines exhibit variability with regard to chemical structure, leading to differences in effectiveness against different organisms or cell types. We now report the comprehensive identification ofSaccharomyces cerevisiaetitratable-essential gene and haploid non-essential gene deletion mutants that are resistant to the APC drug miltefosine (hexadecyl-O-phosphocholine). 58 strains out of ~5600 tested displayed robust and reproducible resistance to miltefosine. This gene set was heavily enriched in functions associated with vesicular transport steps, especially those involving endocytosis and retrograde transport of endosome derived vesicles to the Golgi or vacuole, suggesting a role for these trafficking pathways in transport of miltefosine to potential sites of action in the endoplasmic reticulum (ER) and mitochondrion. In addition, we identified mutants with defects in phosphatidylinositol-4-phosphate synthesis (TetO::STT4) and hydrolysis (sac1Δ), an oxysterol binding protein homolog (osh2Δ), a number of ER resident proteins, and multiple components of the eisosome. These findings suggest that ER-plasma membrane contact sites and retrograde vesicle transport are involved in the interorganelle transport of lyso-PtdCho and related lyso-phospholipid-like analogs to their intracellular sites of cytotoxic activity.
Understanding the potential benefits of adaptive therapy for metastatic melanoma
Authors: Kim Eunjung , Brown Joel S. , Eroglu Zeynep , Anderson Alexander R.A.
Published: October 2020

Adaptive therapy is an evolution-based treatment approach that aims to maintain tumor volume by employing minimum effective drug doses or timed drug holidays. For successful adaptive therapy outcomes, it is critical to find the optimal timing of treatment switch points. Mathematical models are ideal tools to facilitate adaptive therapy dosing and switch time points. We developed two different mathematical models to examine interactions between drug-sensitive and resistant cells in a tumor. The first model assumes genetically fixed drug-sensitive and resistant populations that compete for limited resources. Resistant cell growth is inhibited by sensitive cells. The second model considers phenotypic switching between drug-sensitive and resistant cells. We calibrated each model to fit melanoma patient biomarker changes over time and predicted patient-specific adaptive therapy schedules. Overall, the models predict that adaptive therapy would have delayed time to progression by 6-25 months compared to continuous therapy with dose rates of 6%-74% relative to continuous therapy. We identified predictive factors driving the clinical time gained by adaptive therapy. The first model predicts 6-20 months gained from continuous therapy when the initial population of sensitive cells is large enough, and when the sensitive cells have a large competitive effect on resistant cells. The second model predicts 20-25 months gained from continuous therapy when the switching rate from resistant to sensitive cells is high and the growth rate of sensitive cells is low. This study highlights that there is a range of potential patient specific benefits of adaptive therapy, depending on the underlying mechanism of resistance, and identifies tumor specific parameters that modulate this benefit.
MGDrivE 2: A simulation framework for gene drive systems incorporating seasonality and epidemiological dynamics
Authors: Wu Sean L. , Bennett Jared B. , Sánchez C. Héctor M. , Dolgert Andrew J. , León Tomás M. , Marshall John M.
Published: October 2020

Interest in gene drive technology has continued to grow as promising new drive systems have been developed in the lab and discussions are moving towards implementing field trials. The prospect of field trials requires models that incorporate a significant degree of ecological detail, including parameters that change over time in response to environmental data such as temperature and rainfall, leading to seasonal patterns in mosquito population density. Epidemiological outcomes are also of growing importance, as: i) the suitability of a gene drive construct for release will depend on its expected impact on disease transmission, and ii) initial field trials are expected to have a measured entomological outcome and a modeled epidemiological outcome.

We present MGDrivE 2 (Mosquito Gene Drive Explorer 2): an extension of and development from the MGDrivE 1 simulation framework that investigates the population dynamics of a variety of gene drive architectures and their spread through spatially-explicit mosquito populations. Key strengths and improvements of the MGDrivE 2 framework are: i) the ability of parameters to vary with time and induce seasonal population dynamics, ii) an epidemiological module accommodating reciprocal pathogen transmission between humans and mosquitoes, and iii) an implementation framework based on stochastic Petri nets that enables efficient model formulation and flexible implementation.

Example MGDrivE 2 simulations are presented to demonstrate the application of the framework to a CRISPR-based homing gene drive system intended to drive a disease-refractory gene into a population, incorporating time-varying temperature and rainfall data, and predict impact on human disease incidence and prevalence. Further documentation and use examples are provided in vignettes at the project’s CRAN repository.

MGDrivE 2 is an open-source R package freely available on CRAN. We intend the package to provide a flexible tool capable of modeling gene drive constructs as they move closer to field application and to infer their expected impact on disease transmission.
Brain preparedness: The proactive role of the cortisol awakening response
Authors: Xiong Bingsen , Chen Changming , Tian Yanqiu , Zhang Shouwen , Liu Chao , Evans Tanya M. , Fernández Guillén , Wu Jianhui , Qin Shaozheng
Published: October 2020

Upon awakening from nighttime sleep, the stress hormone cortisol exhibits a burst in the morning within 30-minutes in humans. This cortisol awakening response (CAR) is thought to prepare the brain for upcoming challenges. Yet, the neurobiological mechanisms underlying the CAR-mediated ‘preparation’ function remains unknown. Using blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD-fMRI) with a dedicated prospective design and pharmacological manipulation, we investigated this proactive mechanism in humans across two fMRI studies. In Study 1, we found that a robust CAR was predictive of less hippocampal and prefrontal activity, though enhanced functional coupling between those regions and facilitated working memory performance, during a demanding task later in the afternoon. These results implicate the CAR in proactively promoting brain preparedness based on improved neural efficiency. To address the causality of this proactive effect, we conducted a second study (Study 2) in which we suppressed the CAR with a double blind, placebo controlled, randomized design usingDexamethasone. We found that pharmacological suppression of CAR mirrored the proactive effects from Study 1. Dynamic causal modeling analyses further revealed a reduction of prefrontal top-down modulation over hippocampal activity when performing a cognitively demanding task in the afternoon. These findings establish a causal link between the CAR and its proactive role in optimizing brain functional networks involved in neuroendocrine control and memory.
Overcoming resistance to immune checkpoint therapy in PTEN-null prostate cancer by sequential intermittent anti-PI3Kα/β/δ and anti-PD-1 treatment
Authors: Qi Zhi , Xu Zihan , Zhang Liuzhen , Zou Yongkang , Yan Wenyu , Li Cheng , Liu Ningshu , Wu Hong
Published: October 2020

Prostate cancers generally lack T cell infiltration and display resistance to immune checkpoint therapies (ICT). We found that intermittent but not daily dosing of PI3Kα/β/δ inhibitor BAY1082439 on aPten-null spontaneous prostate cancer model could overcome ICT resistance and unleash CD8+T cell-dependent anti-tumor immunityin vivo. Mechanistically, BAY1082439 convertsPten-null cancer cell-intrinsic immune-suppression to immune-stimulation by promoting IFNα/γ pathway activation, β2-microglubin expression and CXCL10/CCL5 secretion. Together with its preferential Treg inhibition activity, BAY1082439 promotes clonal expansion of tumor-associated CD8+T cells. Once primed, tumors remain as T cell-inflamed and become responsive to anti-PD-1 therapy. Our data suggest that intermittent PI3K inhibition can alleviatePten-null cancer cell-intrinsic immunosuppressive activity and turn “cold” tumors into T cell-inflamed ones, paving the way for successful ICT.

Significance

The combination of ICT and targeted therapies holds great promises for broad and long-lasting therapeutic effects for cancers. However, combining ICT with anti-PI3K inhibitors have been difficult because the multifaceted effects of PI3K on both cancer cells and immune cells within the tumor microenvironment. Here we show a carefully designed anti-PI3K treatment, both in its specificity and dosing schedule, to inhibit cancer cell growth while promoting anti-tumor immunity, is critically important for successful ICT. Since the PI3K pathway is one of the most frequently altered signaling pathways in human cancers, our work may shed light on treating those cancers with PI3K activation and overcome resistance to ICT.

Highlights

Intermittent PI3Kα/β/δ inhibitor BAY1082439 treatment overcomes ICT resistance

BAY1082439 turnsPten-null prostate cancer from “cold” to T cell-inflamed

BAY1082439 inhibits cancer cell-intrinsic immunosuppressive activity and Treg

BAY1082439 promotes clonal expansion and immunity of tumor-associated CD8+T cells
Dynamic transformation of communal and exchange schemata in multicultural relationships
Authors: Liu Leigh Anne , Chiu Chi-Yue , Zhang Zhi-Xue
Published: October 2020

Purpose

The purpose of this paper is to conceptually distinguish between communal and exchange relationship schemata and analyze their dynamic interactions and transformations in multicultural contexts.

Design/methodology/approach

Drawing on theories of social capital, social exchange, networks and relational models, the authors propose a framework to conceptualize how the communal and exchange relationship schemata can be transformed, integrated and multiplied under contextual influences, especially in culturally complex settings faced by multinational organizations.

Findings

The authors elucidate the dynamic processes of schemata interactions and transformations in relationship management at interpersonal, interorganizational and national levels in a variety of intercultural contexts, including interactions between monoculturals from different cultures and interplay of cultures within biculturals and among multiculturals. The authors explain how schemata integration and fusion can provide competitive advantages in navigating multicultural relationships.

Research limitations/implications

Systematic qualitative and quantitative studies are recommended to further test and refine the proposed ideas regarding the dynamic interactions and transformations of relationship schemata.

Practical implications

This paper presents implications for individuals, country managers and leaders who need to initiate and maintain relationships with culturally different others. The authors highlight the desirability of being aware of one's own relational schema, understanding others' schema, bridging the two schemata as well as fostering integration and fusion of the schemata.

Social implications

The 2020 global pandemic and various social upheavals around the world highlight the urgency of finding effective mental models to manage relationships. The inclusive and adaptive ways of thinking about relationships can potentially facilitate harmonious connections and conflict resolution.

Originality/value

The authors conceptually disentangle two established relationship schemata and offer a model of their dynamic synergetic transformations.
Ontology for preserving the knowledge base of traditional dances (OTD)
Authors: Kalita Deepjyoti , Deka Dipen
Published: October 2020

Purpose

Systematic organization of domain knowledge has many advantages in archiving, sharing and retrieval of information. Ontologies provide a cushion for such practices in the semantic Web environment. This study aims to develop an ontology that can preserve the knowledge base of traditional dance practices.

Design/methodology/approach

It is hypothesized that an ontology-based approach for the chosen domain might boost collaborative research prospects in the domain. A systematic methodology was developed for modeling the ontology based on the analytico-synthetic rule of library classification. Protégé 5.2 was used as an editor for the ontology using the Web ontology language combined with description logic axioms. Ontology was later implemented in a local GraphDB repository to run queries over it.

Findings

The developed ontology on traditional dances (OTD) was tested using the dances of the Rabha tribes of North East India. Rabha tribes are from an indigenous mongoloid community and have a robust presence in Southeast Asian countries, such as Myanmar, Thailand, Bangladesh, Bhutan and Nepal. The result from HermiT reasoner found the presence of no logical inconsistency in the ontology, while the OOPS! pitfall checker tool reported no major internal inconsistency. The induced knowledge base of traditional dances of the Rabha’s in the developed OTD was further validated based on some competency questions.

Research limitations/implications

In the growing trend of globalization, preservation of the cultural knowledge base of human societies is an important issue. Traditional dances reflect a strong base of the cultural heritage of human societies as they are closely related to the lifestyle, habitat, religious practices and festivals of a specific community.

Originality/value

The current study is exclusively designed, keeping in mind the variables of traditional dance domain based on a survey of the user- and domain-specific needs. The ontology finds probable uses in traditional knowledge information systems, lifestyle-based e-commerce sites and e-learning platforms.
Demographic determinants of charity donors and its implication for cashwaqfinstitutions in Malaysia
Authors: Khan Abidullah , Mohd. Shafiai Muhammad Hakimi , Shaique Muhammad , Khan Shabeer
Published: October 2020

Purpose

The purpose of this study is to identify the demographic groups that can be targeted for donations by the cashwaqfinstitutions for their marketing campaigns in Malaysia.

Design/methodology/approach

This paper uses a structured questionnaire to acquire the understanding of Malays about the existence of poverty in Malaysia and to identify the demographic groups that can be targeted for the marketing campaigns of cashwaqfinstitutions. The sample consisted of 430 Malays respondents residing in Selangor. The study used the methodology of Baron and Kenny for mediation analysis.

Findings

The finding indicates that Malays do hold sympathies towards the poor. Further investigation shows that high-income class and female are the two demographic groups that are more sympathetic towards the poor because of their strong belief in charity.

Research limitations/implications

The data collection is limited to Selangor only. However, it provides enough information about the demographic groups which is worth exploring for the future researchers in order to come up with marketing strategies related to cash waqf collections.

Practical implications

On the basis of findings, cash waqf institutions in Malaysia can come up with marketing strategies to attract high-income class and females as their potential donors.

Originality/value

The charity institution specifically cashwaqfinstitutions in Malaysia are struggling to identify the right target groups for their marketing campaigns. This study used attribution theory to identify the target groups which is overshadowed by the previous research studies in the context of Malaysia.
Similarities and differences in managing the Covid-19 crisis and climate change risk
Authors: Ruiu Maria Laura , Ragnedda Massimo , Ruiu Gabriele
Published: October 2020

Purpose

This paper investigates both similarities and differences between two global threats represented by climate change (CC) and Covid-19 (CV). This will help understand the reasons behind the recognition of the CV as a pandemic that requires global efforts, whereas efforts to tackle climate change still lack such urgency. This paper aims to answer to the following questions: What are the elements that make CV restrictions acceptable by both the public and policymakers? and What are the elements that make CC restrictions not acceptable?

Design/methodology/approach

This paper analyses the situation reports released by the World Health Organisation between the 11th of March (declaration of pandemic) and the 22nd of April, and their associated documents such as the Strategic Preparedness and Response Plan (WHO), the Risk Communication and Community Engagement Action Plan (WHO) and its updated version (WHO) and the Handbook for public health capacity-building (WHO). The analysis ends one week after President Trump’s announcement to suspend US funding to WHO (Fedor and Manson, 2020) and his support to public demonstrations against restrictions.

Findings

The application of the second stage of the “Crisis and Emergency Risk Communication” model identifies five lessons that can be learned from this comparison. These relate to the necessity to simultaneously warn (about the severity of a threat) and reassure (by suggesting specific courses of action) the public; the need for multilevel collaboration that integrates collective and individual actions; the capacity to present cohesive messages to the public; the risk of politicisation and commodification of the issue that might undermine global efforts to tackle the threat; and the capacity to trigger individual responses through the promotion of self-efficacy.

Originality/value

This paper identifies both similarities and differences between CC and CV managements to understand why the two threats are perceived and tackled in different ways. The analysis of official documents released by both the World Health Organisation and the Intergovernmental Panel on Climate CV outbreak as a crisis, whereas climate change is still anchored to the status of a future-oriented risk.
A multilevel model of job insecurity and engagement
Authors: Pap Zselyke , Vîrgă Delia , Notelaers Guy , Maricuțoiu Laurențiu
Published: October 2020

Purpose

The purpose of this current study was to investigate the moderating effect of autonomy (individual-level job resource) and social supportive climate (group-level job resource) on the negative relationship between job insecurity and work engagement.

Design/methodology/approach

Cross-sectional data were gathered and analyzed using hierarchical linear modeling from 3,812 participants nested in 116 work units.

Findings

A significant interaction between job insecurity and autonomy offered support for the buffering hypothesis of autonomy. Hypotheses regarding both the direct and the buffering effect of social supportive climate were also supported, suggesting that shared perceptions of a supportive environment can reduce the negative impact of job insecurity on work engagement.

Practical implications

Focus on unit climate can aid practitioners in designing interventions that take into account the effects, and make use of resources that are shared in the work-group.

Originality/value

This study extends the job demands-resources theory, showing that resources exist not only at the level of the individual but also a group-level phenomenon, and interact with demands across levels.
Predictors of information literacy self-efficacy among medical students: PLS-SEM analysis
Authors: Soroya Saira Hanif , Iqbal Malik Muhammad Yasir , Soroya Muhammad Shahid , Mahmood Khalid
Published: October 2020

Purpose

The study was designed to examine the predictors of information literacy self-efficacy skills (IL skills) of medical students.

Design/methodology/approach

The study was quantitative in nature and was carried out by using survey research method. Wong and Law Emotional Intelligence Scale (WLEIS) and Information Literacy Self-Efficacy Scale for medical students (ILSES-M) were used to collect the data. Data was collected randomly from 223 out of 526 undergraduate medical students on proportionally random basis according to the number of students available in each year. PLS-SEM analysis was run with the help of SmartPLS 3.2.

Findings

The findings of the study revealed that three subconstructs for emotional intelligence (EI), that is, self-emotions appraisal, others-emotion appraisal, use of emotions, had a statistically significant positive impact (p < 0.05) on information literacy (IL) self-efficacy of the medical students. The findings further confirm that English language proficiency and frequency of attended IL instruction sessions also have a significant positive impact on IL self-efficacy of medical students.

Originality/value

The exploration of EI in relation to IL is comparatively a novel area. The study observed the influence of EI level on IL self-efficacy of medical students. The study will be a significant contribution to the IL literature. The results may help the information professionals/librarians, particularly those who are engaged in teaching and designing IL programs.