bluuebunny/crossref_metadata_2025 huggingface dataset:
Trabecular bone remodeling in the ageing mouse: a micro-multiphysics agent-basedin silicomodel using single-cell mechanomics
Authors: Boaretti Daniele , Marques Francisco C. , Ledoux Charles , Singh Amit , Kendall Jack J. , Wehrle Esther , Kuhn Gisela A. , Bansod Yogesh D. , Schulte Friederike A. , Müller Ralph
Published: November 2022

Bone remodeling is regulated by the interaction between different cells and tissues across many spatial and temporal scales. Notably,in silicomodels are regarded as powerful tools to further understand the signaling pathways that regulate this intricate spatial cellular interplay. To this end, we have established a 3D multiscale micro-multiphysics agent-based (micro-MPA)in silicomodel of trabecular bone remodeling using longitudinalin vivodata from the sixth caudal vertebra (CV6) of PolgA(D257A/D257A)mice, a mouse model of premature aging. Our model includes a variety of cells as single agents and receptor-ligand kinetics, mechanomics, diffusion and decay of cytokines which regulate the cells’ behavior. We highlighted its capabilities by simulating trabecular bone remodeling in the CV6 of 5 mice over 4 weeks and we evaluated the static and dynamic morphometry of the trabecular bone microarchitecture. Based on the progression of the average trabecular bone volume fraction (BV/TV), we identified a configuration of the model parameters to simulate homeostatic trabecular bone remodeling, here named basal. Crucially, we also produced anabolic, anti-anabolic, catabolic and anti-catabolic responses with an increase or decrease by one standard deviation in the levels of osteoprotegerin (OPG), receptor activator of nuclear factor kB ligand (RANKL), and sclerostin (Scl) produced by the osteocytes. Our results showed that changes in the levels of OPG and RANKL were positively and negatively correlated with the BV/TV values after 4 weeks in comparison to basal levels, respectively. Conversely, changes in Scl levels produced small fluctuations in BV/TV in comparison to the basal state. From these results, Scl was deemed to be the main driver of equilibrium while RANKL and OPG were shown to be involved in changes in bone volume fraction with potential relevance for age-related bone features. Ultimately, this micro-MPA model provides valuable insights into how cells respond to their local mechanical environment and can help to identify critical pathways affected by degenerative conditions and ageing.
Cooperative action of separate interaction domains promotes high-affinity DNA binding ofArabidopsis thalianaARF transcription factors
Authors: Fontana Mattia , Roosjen Mark , Crespo García Isidro , van den Berg Willy , Malfois Marc , Boer Roeland , Weijers Dolf , Hohlbein Johannes
Published: November 2022

The signaling molecule auxin is pivotal in coordinating many growth and development processes in plants mainly through the modulation of gene expression. The transcriptional response to auxin is mediated by the family of auxin response factors (ARF). Monomers of this family recognize a DNA motif (TGTC[TC]/[GG]) called the auxin-response element (AuxRE). ARFs can homodimerize through their DNA binding domains (DBD) thereby enabling cooperative binding for a bipartite inverted AuxRE (IR7). In addition to the DBD, most ARFs contain a C-terminal Phox and Bem1p (PB1) domain both capable of homotypic interactions, and mediating interactions with Aux/IAA repressors. Given the dual role of the PB1 domain, and the ability of both DBD and PB1 domain to mediate dimerization, a key question is how each of these domains contributes to conferring DNA-binding specificity and affinity. So far, ARF-ARF and ARF-DNA interactions have mostly been approached using qualitative methods that do not provide a quantitative and dynamic view on the binding equilibria. Here, we utilize a DNA binding assay based on single-molecule Förster resonance energy transfer (smFRET) to study the affinity and kinetics of the interaction of severalArabidopsis thalianaARFs with an IR7 AuxRE. We show that both DBD and PB1 domains of AtARF2 contribute toward DNA binding, and we identify ARF dimer stability as a key parameter in defining affinity and kinetics seen for the DBDs of different AtARFs. Lastly, we derived an analytical solution for a four-state cyclic model that explains both the kinetics and the affinity of the interaction between AtARF2 and IR7. Our work demonstrates that the affinity of ARFs towards composite DNA response elements can be tuned by small changes of their dimerization equilibrium suggesting that this effect has major implications for ARF-mediated transcriptional activity.
Analysis of cancer genomic amplifications identifies druggable collateral dependencies within the amplicon
Authors: Pons G , Gallo-Oller G , Navarro N , Zarzosa P , Sansa-Girona J , García-Gilabert L , Magdaleno A , Segura MF , Sánchez de Toledo J , Gallego S , Moreno L , Roma J
Published: November 2022

The identification of novel therapeutic targets for specific cancer molecular subtypes is crucial for the development of precision oncology. In the last years, CRISPR/Cas9 screens have accelerated the discovery and validation of new targets associated with different tumor types, mutations or fusions. However, there are still many cancer vulnerabilities associated with specific molecular features that remain to be explored. Here we used data from CRISPR/Cas9 screens in 954 cancer cell lines to identify gene dependencies associated with 16 common cancer genomic amplifications. We found that high-copy number genomic amplifications generate multiple collateral dependencies within the amplified region in 94% of cases. Further, to prioritize candidate targets for each chromosomal region amplified, we integrated gene dependency parameters with both druggability data and subcellular location. Finally, analysis of the relationship between gene expression and gene dependency leads to the identification of genes, the expression of which may constitute predictive biomarkers of dependency.
Ventral Tegmental Area dopamine projections to the hippocampus trigger long-term potentiation and contextual learning
Authors: Sayegh Fares , Macri Catherine , Macedo Juliana Pi , Lejards Camille , Rampon Claire , Verret Laure , Dahan Lionel
Published: November 2022

In most models, dopamine is not involved in the initiation but only in the long-term maintenance of LTP and memory. Conversely, we discovered that repeatedly stimulating Schaffer collaterals in concomitance with midbrain dopamine afferents to CA1 triggers hippocampal LTP. Moreover, we show that this dopamine pathway is involved in contextual learning. Thus, midbrain dopamine can play the role of a teaching signal triggering non-Hebbian LTP and allowing supervised learning.
Cassava Detection from UAV Images Using YOLOv5 Object Detection Model: Towards Weed Control in a Cassava Farm
Authors: Nnadozie Emmanuel C. , Iloanusi Ogechukwu , Ani Ozoemena , Yu Kang
Published: November 2022

Most deep learning-based weed detection methods either yield high accuracy, but are slow for real-time applications or too computationally intensive for implementation on smaller devices usable on resource-constrained platforms like UAVs; on the other hand, most of the faster methods lack good accuracy. In this work, two versions of the deep learning-based YOLOv5 object detection model – YOLOv5n and YOLOv5s - were evaluated for cassava detection as a step towards real-time weed detection. The performance of the models were compared when trained with different image resolutions. The robustness of the models were also evaluated under varying field conditions like illumination, weed density, and crop growth stages. YOLOv5s showed the best accuracy whereas YOLOv5n had the best inference speed. For similar image resolutions, YOLOv5s performed better, however, training YOLOv5n with higher image resolutions could yield better performance than training YOLOv5s with lower image resolutions. Both models were robust to variations in field conditions. The speed vs accuracy plot highlighted a range of possible speed/accuracy trade-offs to guide real-time deployment of the object detection models for cassava detection.
Fish Aggregating Devices could enhance the effectiveness of blue water MPAs
Authors: Bode Michael , Game Edward T , Wegmann Alex , Pollock Kydd
Published: November 2022

In the past two decades, drifting fish aggregation devices (FADs) have revolutionised pelagic fisheries, and are now responsible for the majority of tuna purse seine catches. Here, we argue that by taking advantage of the same proven aggregative properties, FADs could be used to enhance the benefits provided by blue water Marine Protected Areas (MPAs). Using models of commercially-targeted fish populations, we explore the potential benefits that could be achieved if unfished conservation FADs were positioned within blue water MPAs. Our results suggest that conservation FADs could deliver benefits, both to target species and the broader ecosystem. By increasing the residence time of exploited species, conservation FADs will reduce average mortality rates inside MPAs. By increasing the local density of species whose populations are depressed by exploitation, FADs can also improve the function of ecosystems in blue water MPAs. Conservation FADs could therefore amplify the benefits of blue water MPAs. We find this amplification is largest in those contexts where blue water MPAs have attracted the most criticism - when their area is small compared to both the open ocean and the distribution of fish stocks that move through them.
Auditory prediction hierarchy in the human hippocampus and amygdala
Authors: Tzovara Athina , Fedele Tommaso , Sarnthein Johannes , Ledergerber Debora , Lin Jack J. , Knight Robert T.
Published: November 2022

Our brains can extract structure from the environment and form predictions given past sensory experience. Predictive circuits have been identified in wide-spread cortical regions. However, the contribution of subcortical areas, such as the hippocampus and amygdala in the formation of predictions remains under-explored. Here, we hypothesized that the hippocampus would be sensitive to predictability in sound sequences, while the amygdala would be sensitive to unexpected violations of auditory rules. We presented epileptic patients undergoing presurgical monitoring with standard and deviant sounds, in a predictable or unpredictable context. Onsets of auditory responses and unpredictable deviance effects were detected at earlier latencies in the temporal cortex compared to the amygdala and hippocampus. Deviance effects in 1-20 Hz local field potentials were detected in the lateral temporal cortex, irrespective of predictability. The amygdala showed stronger deviance responses in the unpredictable context. Additionally, low frequency deviance responses in the hippocampus (1-8 Hz) were observed in the predictable but not in the unpredictable context. Our results reveal a distributed cortical-subcortical network underlying the generation of auditory predictions, comprising temporal cortex and the hippocampus and amygdala, and suggest that the neural basis of sensory predictions and prediction error signals needs to be extended to subcortical regions.
Rapid adaptation of recombining populations on tunable fitness landscapes
Authors: Li Juan , Amado André , Bank Claudia
Published: November 2022

How does standing genetic variation affect polygenic adaptation in recombining populations? Despite a large body of work in quantitative genetics, epistatic and weak additive fitness effects among simultaneously segregating genetic variants are difficult to capture experimentally or to predict theoretically. In this study, we simulated adaptation on fitness landscapes with tunable ruggedness driven by standing genetic variation in recombining populations. We confirmed that recombination hinders the movement of a population through a rugged fitness landscape. When surveying the effect of epistasis on the fixation of alleles, we found that the combined effects of high ruggedness and high recombination probabilities lead to preferential fixation of alleles that had a high initial frequency. This indicates that positively epistatic alleles escape from being broken down by recombination when they start at high frequency. We further extract direct selection coefficients and pairwise epistasis along the adaptive path. When taking the final fixed genotype as the reference genetic background, we observe that, along the adaptive path, beneficial direct selection appears stronger and pairwise epistasis weaker than in the underlying fitness landscape. Quantitatively, the ratio of epistasis and direct selection is smaller along the adaptive path (≈1) than expected. Thus, adaptation on a rugged fitness landscape may lead to spurious signals of direct selection generated through epistasis. Our study highlights how the interplay of epistasis and recombination constrains the adaptation of a diverse population to a new environment.
Allele-specific gene editing approach for vision loss restoration inRHO-associated Retinitis Pigmentosa
Authors: Liu Xiaozhen , Qiao Jing , Jia Ruixuan , Zhang Fan , Meng Xiang , Li Yang , Yang Liping
Published: November 2022

MutantRHOis the most frequent genetic cause of autosomal dominant retinitis pigmentosa. Here, we developed an allele-specific gene editing therapeutic drug to selectively target the human T17MRHOmutant allele while leaving the wild-typeRHOallele intact for the first time. We identified aStaphylococcus aureusCas9 (SaCas9) guide RNA that was highly active and specific to the human T17MRHOallele.In vitroexperiments using HEK293T cells and patient-specific induced pluripotent stem cells (iPSCs) demonstrated active nuclease activity and high specificity. Subretinal delivery of a single adeno-associated virus serotype 2/8 packaging SaCas9 and sgRNA to the retinas of theRHOhumanized mice showed that this therapeutic drug targeted the mutant allele selectively, thereby downregulating the mutantRHOmRNA expression. Administration of this therapeutic drug resulted in a long-term (up to 11 months after treatment) improvement of retinal function and preservation of photoreceptors in the mutant humanized heterozygous mice. Our study demonstrated a dose-dependent therapeutic effectin vivo.Unwanted off-target effects were not observed at the whole-genome sequencing level. Our study provides strong support for the further development of this effective therapeutic drug to treatRHO-T17M associated autosomal dominant retinitis pigmentosa (adRP), also offers a generalizable framework for developing gene editing medicine. Furthermore, our success in retoring the vision loss in the sufferingRHOhumanized mice verifies the feasibility of allele-specific CRISPR/Cas9-based medicines for other autosomal dominant inherited retinal dystrophies.
ALegionella pneumophilaeffector impedes host gene silencing to promote virulence
Authors: Toinon Justine , Rolando Monica , Charvin Magali , Filopon Didier , Schiavolin Lionel , Sy Khadeeja Adam , Vu Hai-Chi , Gallois-Montbrun Sarah , Alam Antoine , Barraud Pierre , Rusniok Christophe , Lombard Bérangère , Loew Damarys , Buchrieser Carmen , Navarro Lionel
Published: November 2022

RNA silencing is a gene silencing mechanism directed by small RNAs. Human miRNAs act as central regulators of host-bacteria interactions. However, it is unknown whether human pathogenic bacteria could impede RNA silencing to promote virulence. Here, we show that theLegionella pneumophilatype IV-secreted effector LegK1 efficiently suppresses siRNA and miRNA activities in human cells. This effect depends on its known kinase activity, but also on its novel capacity, found here, to bind Argonaute (Ago) proteins. We further demonstrate that the ability of LegK1 to activate NF-κB signaling is required for RNA silencing suppression, establishing a link between effector-mediated NF-κB signaling and RNA silencing suppression. LegK1 also promotesL. pneumophilagrowth in both amoeba and human macrophages, supporting a role for this effector in virulence. Finally, we show that, in infected-macrophages, the latter activity relies, in part, on the genetic targeting of human Ago4. These findings indicate that aL. pneumophilaeffector has evolved to suppress RNA silencing to promote virulence.

Significance Statement

It is now well established that mammalian viruses suppress RNAi to promote their replication in host cells. However, whether mammalian pathogenic bacteria use a similar virulence strategy remains unknown. Here, we show that the LegK1 effector fromLegionella pneumophia, the causal agent of Legionnaires’ disease, efficiently suppresses RNAi in human cells. This effect depends on its ability to interact with Argonaute (Ago) proteins and to activate NF-κB signaling. In addition, LegK1 promotes virulence in infected-macrophages through the genetic targeting of human Ago4. Based on the lack of NF-κB-related factors in amoebae, and on the presence of canonical Ago proteins in these naturalL. pneumophilahosts, we propose that the RNAi suppression activity of LegK1 represents its primary virulence function.
Rewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication
Authors: Chakraborty Chaitali , Nissen Itzel , Vincent Craig A. , Hägglund Anna-Carin , Hörnblad Andreas , Remeseiro Silvia
Published: November 2022

Chromatin organization controls transcription by modulating 3D-interactions between enhancers and promoters in the nucleus. Alterations in epigenetic states and 3D-chromatin organization result in gene expression changes contributing to cancer pathogenesis. Here, we mapped the promoter-enhancer interactome and regulatory landscape of glioblastoma, the most aggressive primary brain tumour. Our data reveals profound rewiring of promoter-enhancer interactions, chromatin accessibility and redistribution of histone marks across the four glioblastoma subtypes. This leads to loss of long-range regulatory interactions and overall activation of promoters, which orchestrate changes in the expression of genes associated to glutamatergic synapses, axon guidance, axonogenesis and chromatin remodeling. SMAD3 and PITX1 emerge as the major transcription factors controlling genes related to synapse organization and axon guidance. Inhibition of SMAD3 and neuronal activity stimulation cooperate to promote cell proliferation of glioblastoma cells in co-culture with glutamatergic neurons. Our findings provide mechanistic insight into the regulatory networks that mediate neurogliomal synaptic communication.
Inhibition of Centrosome Clustering Reduces Cystogenesis and Improves Kidney Function in Autosomal Dominant Polycystic Kidney Disease
Authors: Cheng Tao , Mariappan Aruljothi , Langner Ewa , Shim Kyuhwan , Gopalakrishnan Jay , Mahjoub Moe R.
Published: November 2022

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is an inherited monogenic disorder accounting for ∼5% of patients with renal failure. Yet, therapeutics for the treatment of ADPKD remain limited. ADPKD tissues display defects in the biogenesis of the centrosome which causes genome instability, aberrant ciliary signaling, and secretion of pro-inflammatory factors that drive cyst growth and fibrosis. Cystic cells form excess centrosomes via a process termed centrosome amplification (CA), which often causes abnormal multipolar spindle configurations, mitotic catastrophe, and reduced cell viability. However, cells with CA can suppress multipolarity via “centrosome clustering”, a key mechanism by which cells circumvent apoptosis. Here, we demonstrate that inhibiting centrosome clustering can counteract the proliferation of renal cystic cells with high incidences of CA. Using ADPKD human cells and mouse models, we show that blocking centrosome clustering with two inhibitors, CCB02 and PJ34, blocks cyst initiation and growthin vitroandin vivo. Inhibition of centrosome clustering activates a p53-mediated mitotic surveillance mechanism leading to apoptosis, reduced cyst expansion, interstitial fibrosis, and improved kidney function. Transcriptional analysis of kidneys from treated mice identified pro-inflammatory signaling pathways implicated in CA-mediated cystogenesis and fibrosis. Our results provide the first evidence that centrosome clustering is a cyst-selective target for the improvement of renal morphology and function in ADPKD.
Formamide significantly enhances the efficiency of chemical adenylation of RNA sequencing ligation adaptors
Authors: Hildebrand Samuel R. , Hedger Adam K. , Watts Jonathan K. , Khvorova Anastasia
Published: November 2022

Pre-adenylated single-stranded DNA ligation adaptors are essential reagents in many next generation RNA sequencing library preparation protocols. These oligonucleotides can be adenylated enzymatically or chemically. Enzymatic adenylation reactions have high yield but are not amendable to scale up. In chemical adenylation, Adenosine 5□-phosphorimidazolide (ImpA) reacts with 5′ phosphorylated DNA. It is easily scalable but gives poor yields, requiring labor-intensive cleanup steps. Here, we describe an improved chemical adenylation method using 95% formamide as the solvent, which results in the adenylation of oligonucleotides with >90% yield. In standard conditions, with water as the solvent, hydrolysis of the starting material to adenosine monophosphate limits the yields. To our surprise, we find that rather than increasing adenylation yields by decreasing the rate of ImpA hydrolysis, formamide does so by increasing the reaction rate between ImpA and 5′-phosphorylated DNA by ∼10 fold. The method described here enables straightforward preparation of chemically adenylated adapters with higher than 90% yield, simplifying reagent preparation for NGS.
Examining Anxiety and Risk-taking in Healthy Male and Female Wistar Rats using Spatial and Temporal Analysis of Elevated Plus Maze
Authors: Sharma Sakshi , Pandey Jyotsna , Jain Suman , Singh Varsha
Published: November 2022

The Elevated Plus Maze (EPM) offers a standard set up for understanding anxiety, unconditioned risk-avoidance in rodents. The animal shows a preference for enclosed safe arms and avoids risky, open arms that evoke anxiety due to elevated platform (unconditioned response to elevation). A few rodent studies aiming to understand sex-skewed representation in anxiety disorders use the maze and report that more females compared to males show high levels of anxiety and risk-avoidance on an elevated platform. Ethograms derived from examining animal behaviour in the EPM provide precise measures of behaviour of interest, enabling objective assessment of anxiety and risk behaviour. We report two new parameters that might be critical for quantitative analysis of EPM task as a measure of anxiety with reference to sex-differences in risk-taking: (a) spatial preference for arms (open & closed) (b) temporal shift in arm preference in task trials. We first report results from the conventionally derived measures confirming that males spent more time in the open arms indicating low anxiety and higher risk-taking. Preferences for the two open and two closed arms were non-uniform for males and females; male showed stronger preference for one of the two risky open arms, and females showed a stronger preference for one of the two safe closed arms. Temporal analyses indicated that males spent more time in open arms in 3 out of 6 time bins (time blocks), and females spent more time in the closed arms in 5 out of 6 time bins (time blocks), however, counter-intuitively, females showed larger increase in time spent in open arms in the last phase potentially indicating greater regulation of anxiety and increased risk-taking. Inclusion of spatial and temporal parameters in EPM studies might improve our understanding of cognitive and biological sex-differences pertaining to anxiety, and risky behaviour.
Predicting Antimicrobial Activity for Untested Peptide-Based Drugs Using Collaborative Filtering and Link Prediction
Authors: Medvedeva Angela , Teimouri Hamid , Kolomeisky Anatoly B.
Published: November 2022

The increase of bacterial resistance to currently available antibiotics has underlined the urgent need to develop new antibiotic drugs. Antimicrobial peptides (AMPs), alone or in combination with other peptides and/or existing antibiotics, have emerged as promising candidates for this task. However, given that there are thousands of known AMPs and an even larger number can be synthesized, it is inefficient to comprehensively test all of them using standard wet lab experimental methods. These observations stimulated an application of machine-learning methods to identify promising AMPs. Currently, machine learning studies frequently combine very different bacteria without considering bacteria-specific features or interactions with AMPs. In addition, the sparsity of current AMP data sets of antimicrobial activity disqualifies the application of traditional machine-learning methods or renders the results unreliable. Here we present a new approach, featuring neighborhood-based collaborative filtering, to predict with high accuracy a given bacteria’s response to untested AMPs, AMP-AMP combinations, and AMP-antibiotic combinations based on similarities between bacterial responses. Furthermore, we also developed a complementary bacteria-specific link approach that can be used to visualize networks of AMP-antibiotic combinations, enabling us to suggest new combinations that are likely to be effective. Our theoretical analysis of AMP physico-chemical features suggests that there is an optimal similarity between two different AMPs that exhibit strong synergistic behavior. This principle, alongside with our specific results, can be applied to find or design effective AMP-AMP combinations that are target-specific.

Author summary

It is well known that combinations of different antimicrobial peptides (AMPs), in comparison to single AMP species, can lead to more efficient antimicrobial activity, but the large number of possible combinations requires the application of efficient machine-learning methods. We developed a new approach consisting of collaborative filtering, link prediction, and AMP feature analysis to predict previously-unknown, bacteria-specific activity of AMP combinations, suggest novel synergistic AMP-antibiotic combinations, and guide future design of effective AMP-AMP combinations.
Variation in diet and microbial exposure shape the performance of the Asian tiger mosquito,Aedes albopictus
Authors: Raquin Vincent , Martin Edwige , Minard Guillaume , Moro Claire Valiente
Published: November 2022

Along their life cycle, mosquitoes colonize different ecological niches with various microorganisms and diet sources that likely modulate their performance(i.e.a set of mosquito fitness-related traits). However, which ecological parameters and how their variations modulate mosquito performance is not completely understood. In this study, we usedAe. albopictussurface-sterilized eggs re-associated or not to conventional bacterial microbiota upon a range of diet concentrations and addressed the impact of microbial inoculum and diet concentration variation on several mosquito performance traits. Results showed that mosquito juvenile survival depends on the interaction between bacterial inoculum load and diet concentration in the breeding water. Exposure to bacteria in rearing water shorten larval development time although it impacted larvae survival in an inoculum and diet concentration-dependent manner. Bacterial composition of larval rearing water was mainly structured by the bacterial inoculum concentration, with some Operational Taxonomic Units abundances correlating with larval traits.Ae. albopictussurvival, development and bacterial community patterns upon gradients of diet and bacterial inoculum illustrated the complex impact of diet-microbiota interaction on mosquito performance. These findings argue the importance of deciphering host-microbe-environment interactions and open promising perspectives to improveAe. albopictuscontrol measures in the field.

IMPORTANCE

Microbiota is increasingly recognized as a driving force of metazoan biology, impacting diverse traits including nutrition, behaviour or reproduction. The microbial impact on host nutrition is among the most studied host-microbe interactions although it remains poorly understood in arthropod vectors like mosquitoes. Here, we manipulated mosquito microbiota using gnotobiology to decipher the impact of bacteria and diet on the Asian tiger mosquito,Ae. albopictus.These results are key to understand the link between diet and bacteria concentration on juvenile mosquitoes as well as carry-over effects in adults. They unveil some specific aspects of mosquito-bacteria interactions while opening interesting avenues for vector management of this vector of arboviruses.
Major revisions in pancrustacean phylogeny with recommendations for resolving challenging nodes
Authors: Bernot James P. , Owen Christopher L. , Wolfe Joanna M. , Meland Kenneth , Olesen Jørgen , Crandall Keith A.
Published: November 2022

The clade Pancrustacea, comprising crustaceans and hexapods, is the most diverse group of animals on earth, containing over 80% of animal species. It has been the subject of several recent phylogenomic analyses, but despite analyzing hundreds of genes, relationships within Pancrustacea show a notable lack of stability. Here, the phylogeny is estimated with expanded taxon sampling, particularly of malacostracans, using a precise tree-based approach to infer orthology. Our results show that small changes in taxon sampling have a large impact on phylogenetic estimation. By analyzing only shared orthologs between two slightly different taxon sets, we show that the differences in the resulting topologies are due to the effects of taxon sampling on the phylogenetic reconstruction method, not on ortholog identification. We compare trees resulting from our phylogenomic analyses with those from the literature to explore the large tree space of pancrustacean phylogenetic hypotheses and find that statistical topology tests reject the previously published trees in favor of the ML trees produced here. Our results reject several clades including Caridoida, Eucarida, Multicrustacea, Vericrustacea, and Syncarida. We recover a novel relationship between decapods, euphausiids, and syncarids that we refer to as the Syneucarida. With denser taxon sampling, we find Stomatopoda sister to this clade, which we name Stomatocaridea, dividing Malacostraca into three clades: Leptostraca, Peracarida, and Stomatocaridea. A new Bayesian divergence time estimation is conducted using 13 vetted fossils. We review our results in the context of other pancrustacean phylogenetic hypotheses and highlight the key taxa to sample in future studies.
Quality control for the target decoy approach for peptide identification
Authors: Debrie Elke , Malfait Milan , Gabriels Ralf , Declerq Arthur , Sticker Adriaan , Martens Lennart , Clement Lieven
Published: November 2022

Reliable peptide identification is key in mass spectrometry (MS) based proteomics. To this end, the target-decoy approach (TDA) has become the cornerstone for extracting a set of reliable peptide-to-spectrum matches (PSMs) that will be used in downstream analysis. Indeed, TDA is now the default method to estimate the false discovery rate (FDR) for a given set of PSMs, and users typically view it as a universal solution for assessing the FDR in the peptide identification step. However, the TDA also relies on a minimal set of assumptions, which are typically never verified in practice. We argue that a violation of these assumptions can lead to poor FDR control, which can be detrimental to any downstream data analysis. We here therefore first clearly spell out these TDA assumptions, and introduce TargetDecoy, a Bioconductor package with all the necessary functionality to control the TDA quality and its underlying assumptions for a given set of PSMs.

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Buffering of genetic dominance by allele-specific protein complex assembly
Authors: Badonyi Mihaly , Marsh Joseph A
Published: November 2022

Protein complex assembly often begins while at least one of the subunits is still in the process of being translated. When such cotranslational assembly occurs for homomeric complexes, made up of multiple copies of the same subunit, this will result in complexes whose subunits were translated off of the same mRNA in an allele-specific manner. It has therefore been hypothesised that cotranslational assembly may be able to counter the assembly-mediated dominant-negative effect, whereby the co-assembly of mutant and wild-type subunits “poison” the activity of a protein complex. Here, we address this, showing first that subunits that undergo cotranslational assembly are much less likely to be associated with autosomal dominant relative to recessive disorders. Moreover, we observe that subunits with dominant-negative disease mutations are significantly depleted in cotranslational assembly compared to those associated with loss-of-function mutations. Consistent with this, we also find that complexes with known dominant-negative effects tend to expose their interfaces late during translation, lessening the likelihood of cotranslational assembly. Finally, by combining protein complex properties with other protein-level features, we trained a computational model for predicting proteins likely to be associated with dominant-negative or gain-of-function molecular mechanisms, which we believe will be of considerable utility for protein variant interpretation.
All-or-None Evaluation of Prediction Certainty in Autism
Authors: Reisli Seydanur , Crosse Michael J. , Molholm Sophie
Published: November 2022

The brain generates predictions to prepare for upcoming events. As life is not always 100% predictable, it also estimates a level of certainty for these predictions. Given that autistic individuals resist even small changes in everyday life, we hypothesized impaired tuning of prediction certainty in autism. To study this, EEG was recorded from adolescents and young adults with autism while they performed a probabilistic prediction task in which cue validity was parametrically manipulated. A fully predictable condition (100% cue validity) was contrasted with less predictable conditions (84, 67 and 33% cue validity). Well characterized brain potentials were examined to assess the influence of cue validity on target anticipation (contingent negative variation; CNV), the evaluation of target statistics (P3), and prediction model updating (slow wave; SW). As expected, cue validity systematically influenced the amplitudes of the CNV, P3 and SW in controls. In contrast, cue-validity effects on CNV and SW were substantially reduced in autism. This suggests that although target statistics are accurately registered in autism, as indicated by intact modulation of the P3, they are not effectively applied to generate expectations for upcoming input or model updating. Contrasting the fully predictable with the less predictable conditions, our data suggest that autistic individuals adopted an all-or-none evaluation of certainty of their environment, rather than adjusting certainty of predictions to different levels of environmental statistics. Social responsiveness scores were associated with flexibility in representing prediction certainty, suggesting that impaired representation and updating of prediction certainty may contribute to social difficulties in autism.

SIGNIFICANCE STATEMENT

The ability to make predictions is integral to everyday life. Yet, as life is not always 100% predictable and it is also essential to adjust the certainty of these predictions based on the current context. This study reveals that individuals with autism are less efficient in adjusting the certainty of their predictions to the level of predictability of events. Instead, they may adopt an all-or-none evaluation of certainty. Our findings reveal novel insights into the processes underlying impaired predictive processing in autism, which may open the door to developing targeted behavioral interventions and/or non-invasive brain stimulation therapies that help autistic individuals make more accurate predictions to ease social- and rigidity-based symptoms.
Germline mosaicism in a family withMBD5haploinsufficiency
Authors: Bhatia Mehak , Cavalleri Gianpiero L. , White Máire , Delanty Norman , Sweeney Brian J. , Costello Daniel J. , Greally Marie T. , Benson Katherine A.
Published: November 2022

Haploinsufficiency of the methyl-CpG-binding domain protein 5 (MBD5) gene causes a neurodevelopmental disorder that includes intellectual disability, developmental delay, speech impairment, seizures, sleep disturbances, and behavioral difficulties. Microdeletion of 2q23.1 is the most common cause of haploinsufficiency, althoughMBD5haploinsufficiency may also cause this genetic disorder. We report a family harboring a heterozygous loss-of-function variant inMBD5(NM_018328.5:c.728delC; p.Pro243Hisfs*26), which includes three affected siblings with varying phenotypic features. Both parents were phenotypically normal but deep coverage sequencing of the parents showed germline mosaicism in the mother.
Career-washing? Unpacking employer brand promises on social media platforms
Authors: Marcet Alonso Julia , Parsons Elizabeth , Pirani Daniela
Published: November 2022

Purpose

This paper aims to explore how a global fashion retailer uses a social media platform to build an appeal via a process of online employer branding.

Design/methodology/approach

The study involved a narrative and thematic analysis of posts of a global fashion retailer on LinkedIn. The authors sampled organisational posts and the responses they received over a six-month period.

Findings

The organisation uses carefully curated success stories of “ideal” existing employees to build an appeal based on the values of growth and belonging. While varied, the responses of platform users tend to be limited to brief contributions, questioning the success of the organisation’s attempts at creating an appeal.

Research limitations/implications

The authors argue that employer branding literature needs a new conceptual toolbox, which better reflects the mediated, affective and networked nature of platforms.

Practical implications

To avoid career-washing, employer brands should engage with the networked nature of platforms, fostering authentic conversations with users rather than using platforms merely as a billboard to post content.

Originality/value

The authors theorise the appeal of the employer brand through the concept of the “employer brand promise”. Furthermore, they show how, on social networks, this promise attempts to create value through meaningful engagement. They also conclude by observing how the employer brand promise can act as a form of career-washing, where there is a significant dis-connect between the promise offered and the reality of retail work on the ground.
Knowledge storage and accessibility in an interorganizational project: empirical evidence from the Orange Line metro train
Authors: Iftikhar Rehab , Mawra Khadija
Published: November 2022

Purpose

This paper focuses on knowledge storage, knowledge accessibility and the associated challenges with these processes in an interorganizational project. For this purpose, the context of the Orange Line (OL) metro train project in Pakistan is examined, where multiple organizations were involved.

Design/methodology/approach

This study adopts an exploratory single case study approach. The empirical data comprise semi-structured interviews and archival documents. Thematic analysis is used for analyzing the data.

Findings

The distinct findings include (1) the use of knowledge storage systems, such as manual storage systems, electronic storage systems and assigning a dedicated resource; (2) that knowledge accessibility occurs at different levels within the organization (including intradepartmental and interdepartmental levels) as well as at interorganizational levels and (3) the challenges, such as misuse of knowledge, time pressures, confidentiality of sensitive knowledge, government regulations and the reliance on human memory, which are associated with knowledge storage and knowledge accessibility. Based on the findings, an integrative framework of the interplay between knowledge storage, knowledge accessibility and challenges is proposed.

Originality/value

This paper contributes to the literature on resource-based theory by examining knowledge storage and accessibility in an interorganizational project.
The effects of tie strength and data integration with supply base on supply disruption ambiguity and its impact on inventory turnover
Authors: Pandey Rahul , Chatterjee Dipanjan , Rungtusanatham Manus
Published: November 2022

Purpose

In this paper, the authors introduce supply disruption ambiguity as the inability of a sourcing firm to attach probability point estimates to the occurrence of and to the magnitude of loss from supply disruptions. The authors drew on the “ambiguity in decision-making” literature to define this concept formally, connected it to relevant supply disruption information deficit, positioned it relative to supply chain risk assessment and hypothesized and tested its negative associations with both supply base ties and inventory turnover.

Design/methodology/approach

The authors analysed survey data from 171 North American manufacturers and archival data for a subset (88 publicly listed) of these manufacturers via Ordinary Least Squares (OLS) estimation after ensuring that methodological concerns with survey research have been addressed. They used appropriate controls and employed the heteroskedasticity-based instrumental variable (HBIV) approach to ensure that inferences from our results are not unduly influenced by endogeneity.

Findings

Strong supply base ties decrease supply disruption ambiguity, which, in turn, increases inventory turnover. Moreover, strong supply base ties and data integration with the supply base have indirect and positive effects on inventory turnover. As sourcing firms strengthen ties and integrate data exchange with their supply base, their inventory turnover improves from access to information relevant to detect and diagnose supply disruptions effectively.

Originality/value

Research on supply disruption management has paid more attention to the “disruption recovery” stage than to the “disruption discovery” stage. In this paper, the authors add novel insights regarding the recognition and diagnosis aspects of the “disruption discovery” stage. These novel insights reveal how and why sourcing firms reduce their overall ambiguity associated with detecting and assessing losses from supply disruptions through establishing strong ties with their supply base and how and why reducing such ambiguity improves inventory turnover performance.
Colonial legacies on employment: comparisons between some former Anglophone and French colonies
Authors: Neifar Malika
Published: November 2022

Purpose

In this paper, the author assesses if the effect of structural policies, macroeconomic indicators and demographic factors on employment elasticities over the period 2000–2017 can distinguish the former French colonies from the Anglophone ones.

Design/methodology/approach

Using a panel of 44 countries taken from Africa and Middle East Area, elasticities are estimated in the first stage by rolling regression. Then, both static and dynamic panel models are investigated.

Findings

Results suggest big difference between the former French colonies and Anglophone ones. For the French colonies, product and labor market flexibility are found to have significant and positive impact on elasticities, while for Anglophone ones, only foreign direct investment and government size are found to have significant and positive impact. Besides, all reforms and/or economic measures need to be complemented by macroeconomic policies aimed to increase economic stability.

Originality/value

The results presented in this study highlight some of the factors that appear to drive the relationship between employment and some structural policies, macroeconomic indicators and demographic factors for two groups of former colonies. The paper provides policy conclusions based on these results for the two groups. This analysis may indeed help to inform future policy discussions, yet much additional work is needed to identify macroeconomic “best practices” for encouraging employment in the post-2019 covid crisis period.
What can philosophy contribute to ‘education to address pornography's influence’?
Authors: McGlynn Aidan
Published: November 2022

Responses to the pernicious influences of mainstream pornography on its viewers fall into two main sorts: regulation and education. Pornography has long been a core topic in analytic feminist philosophy, but it has largely focused on issues around regulation, in particular with trying to undermine arguments against regulation on the grounds that pornography should count as protected speech. Here I instead look at some ways that philosophy can contribute to an education-based approach, in particular to what has been called an ‘education to address pornography's influence’. I first argue that philosophical considerations can help to motivate this kind of overall approach to countering pornography's influence, but the main contribution of the paper is to contend that such considerations can also contribute to shaping the kind of content and messaging that such an education should have. I discuss two related issues, focusing on pornographic films. The first concerns the status of pornographic films as fiction; it is misleading and unhelpful to tell teenagers and young adults that pornography is ‘just fiction’, as is sometimes proposed, but it is not clear what more effective and accurate message might be offered instead. The second concerns the ways that pornographic films often present the people (and in particular the women) who perform in them as ideals or archetypes when it comes to what kinds of sexual acts people typically choose and enjoy, which I argue is a neglected form of objectification. I briefly evaluate some suggestive examples of proposed messaging, targeted at teens and young adults.
Young people's online communication and its association with mental well‐being: results from the 2019 student health and well‐being survey
Authors: Anthony Rebecca , Young Honor , Hewitt Gillian , Sloan Luke , Moore Graham , Murphy Simon , Cook Steven
Published: November 2022

Background

Online communication has become an integral aspect of daily life for young people internationally. Very little research has examined whether the association between social media use and well‐being depends on who young people engage with (i.e. real, or virtual friendships).

Methods

Data were drawn from a subsample of students (N = 38,736) who took part in the School Health Research Network (SHRN) 2019 Student Health and Well‐being (SHW) survey. A series of multivariable regression models were used to assess the association between who adolescents were communicating with online and well‐being, controlling for confounders: passive social media use; friendship quality; and cyberbullying. We also tested whether these associations were modified based on gender.

Results

Students are highly engaged on social networking sites, and these sites are used to communicate with existing friendship groups and develop virtual friendships. Frequent online communication with best friends (b = .340, p < .001) and bigger friendship groups (b = .397; p < .001) was associated with higher levels of well‐being. However, the frequency of online contact with virtual friends made online was negatively and significantly associated with well‐being (b = −.760; p < .001), with a larger negative association for girls than boys.

Conclusions

Online communication with virtual friendship networks were associated with lower mental well‐being, with stronger associations for girls than boys; however, frequent online communication with ‘real’ friends was associated with better well‐being. Our results indicate the importance of considering the nature of adolescent online communication, rather than just its quantity, in developing interventions to improve adolescent well‐being.