bluuebunny/crossref_metadata_2025 huggingface dataset:
The ultrasonic vocalization (USV) syllable profile during neonatal opioid withdrawal and a kappa opioid receptor component to increased USV emissions in female mice
Authors: Wingfield Kelly K. , Misic Teodora , Jain Kaahini , McDermott Carly S. , Abney Nalia M. , Richardson Kayla T. , Rubman Mia B. , Beierle Jacob A. , Miracle Sophia A. , Sandago Emma J. , Baskin Britahny M. , Lynch William B. , Borrelli Kristyn N. , Yao Emily J. , Wachman Elisha M. , Bryant Camron D.
Published: July 2024

Rationale

Opioid use during pregnancy can lead to negative infant health outcomes, including neonatal opioid withdrawal syndrome (NOWS). NOWS comprises gastrointestinal, autonomic nervous system, and neurological dysfunction that manifest during spontaneous withdrawal. Variability in NOWS severity necessitates a more individualized treatment approach. Ultrasonic vocalizations (USVs) in neonatal mice are emitted in isolation as a stress response and are increased during opioid withdrawal, thus modeling a negative affective state that can be utilized to test new treatments.

Objectives

We sought to identify the behavioral and USV profile, brainstem transcriptomic adaptations, and role of kappa opioid receptors in USVs during neonatal opioid withdrawal.

Methods

We employed a third trimester-approximate opioid exposure model, where neonatal inbred FVB/NJ pups were injected twice-daily with morphine (10mg/kg, s.c.) or saline (0.9%, 20 ul/g, s.c.) from postnatal day(P) 1 to P14. This protocol induces reduced weight gain, hypothermia, thermal hyperalgesia, and increased USVs during spontaneous morphine withdrawal.

Results

On P14, there were increased USV emissions and altered USV syllables during withdrawal, including an increase in Complex 3 syllables in FVB/NJ females (but not males). Brainstem bulk mRNA sequencing revealed an upregulation of the kappa opioid receptor (Oprk1), which contributes to withdrawal-induced dysphoria. The kappa opioid receptor (KOR) antagonist, nor-BNI (30 mg/kg, s.c.), significantly reduced USVs in FVB/NJ females, but not males during spontaneous morphine withdrawal. Furthermore, the KOR agonist, U50,488h (0.625 mg/kg, s.c.), was sufficient to increase USVs on P10 (both sexes) and P14 (females only) in FVB/NJ mice.

Conclusions

We identified an elevated USV syllable, Complex 3, and a female-specific recruitment of the dynorphin/KOR system in increased USVs associated with neonatal opioid withdrawal severity.
Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations
Authors: Zhou Sihang , Lizarazo Simon , Mouli Leela , Chorghade Sandip , Cheng Ruiying , Rajendra K C , Kalsotra Auinash , Van Bortle Kevin
Published: July 2024

RNA polymerase III (Pol III) activity in cancer is linked to the production of small noncoding (nc)RNAs that are otherwise silent in most tissues. snaR-A (small NF90-associated RNA isoform A) - a hominid-specific ncRNA shown to enhance cell proliferation, migration, and invasion - is a cancer-emergent Pol III product that remains largely uncharacterized despite promoting growth phenotypes. Here, we applied a combination of genomic and biochemical approaches to study the biogenesis and subsequent protein interactions of snaR-A and to better understand its role as a putative driver of cancer progression. By profiling the chromatin landscapes across a multitude of primary tumor types, we show that predicted snaR-A upregulation is broadly linked with unfavorable outcomes among cancer patients. At the molecular level, we unexpectedly discover widespread interactions between snaR-A and mRNA splicing factors, including SF3B2 - a core component of the U2 small nuclear ribonucleoprotein (snRNP). We find that SF3B2 levels are sensitive to high snaR-A abundance and that depletion of snaR-A alone is sufficient to decrease intron retention levels across subpopulations of mRNA enriched for U2 snRNP occupancy. snaR-A sensitive genes are characterized by high GC content, close spatial proximity to nuclear bodies concentrated in pre-mRNA splicing factors, and functional enrichment for proteins involved in deacetylation and autophagy. We highlight examples of splicing misregulation and increased protein levels following snaR-A depletion for a wide-ranging set of factors, suggesting snaR-A-driven splicing defects may have far-reaching effects that re-shape the cellular proteome. These findings clarify the molecular activities and consequences of snaR-A in cancer, and altogether establish a novel mechanism through which Pol III overactivity may promote tumorigenesis.
Mutations in theStaphylococcus aureusGlobal Regulator CodY Confer Tolerance to an Interspecies Redox-Active Antimicrobial
Authors: Martini Anthony M. , Alexander Sara A. , Khare Anupama
Published: July 2024

Bacteria often exist in multispecies communities where interactions among different species can modify individual fitness and behavior. Although many competitive interactions have been characterized, molecular adaptations that can counter this antagonism and preserve or increase fitness remain underexplored. Here, we characterize the adaptation ofStaphylococcus aureusto pyocyanin, a redox-active interspecies antimicrobial produced byPseudomonas aeruginosa, a co-infecting pathogen frequently isolated from wound and chronic lung infections withS. aureus. Using experimental evolution, we identified mutations in a conserved global transcriptional regulator, CodY, that confer tolerance to pyocyanin and thereby enhance survival ofS. aureus. The transcriptional response of a pyocyanin tolerant CodY mutant to pyocyanin indicated a two-pronged defensive response compared to the wild type. Firstly, the CodY mutant strongly suppressed metabolism, by downregulating pathways associated with core metabolism, especially translation-associated genes, upon exposure to pyocyanin. Metabolic suppression via ATP depletion was sufficient to provide comparable protection against pyocyanin to the wild-type strain. Secondly, while both the wild-type and CodY mutant strains upregulated oxidative stress response pathways, the CodY mutant overexpressed multiple stress response genes compared to the wild type. We determined that catalase overexpression was critical to pyocyanin tolerance as its absence eliminated tolerance in the CodY mutant and overexpression of catalase was sufficient to impart tolerance to the wild-type strain. Together, these results suggest that both transcriptional responses likely contribute to pyocyanin tolerance in the CodY mutant. Our data thus provide new mechanistic insight into adaptation toward interbacterial antagonism via altered regulation that facilitates multifaceted protective cellular responses.
Induction of ectopic external gills and tetrapodomorph-like skeletal elements through homeotic transformations in the salamander branchial region
Authors: Vintr Jan , Soukup Vladimír
Published: July 2024

Homeotic transformations are morphological changes associated with alterations of identities of segments in serially repeated systems and these changes may be a source of modifications in body plan evolution. Retinoic acid (RA) signaling has previously been shown to induce homeotic transformations in the vertebral column, although its role in other vertebrate segmented systems remains unexplored.

Here, we use pharmacological inhibition of RA receptors to study homeotic transformations in the larval salamander branchial region. This region normally contains three pairs of external gills supported by the underlying skeleton, however upon treatments we observe induction of ectopic outgrowths in the posterior portion of the apparatus. We characterize these outgrowths as ectopically induced fourth external gills on the position of the otherwise gill-free segment. This induction is further associated with transformations and appearance of cartilaginous elements that phenocopy similar elements in fossil stem amphibians and tetrapodomorphs.

These experimentally instigated morphological changes qualify as homeotic transformations in the branchial region and present re-emergence of features that were lost prior to the origin of modern tetrapods. More broadly, our results point to RA signaling as a potent driver regulating the number and composition of pharyngeal segments and thus controlling the evolution of the vertebrate pharyngeal apparatus.
Memantine Inhibits Calcium-Permeable AMPA Receptors
Authors: Carrillo Elisa , Romero Alejandra Montaño , Gonzalez Cuauhtemoc U. , Turcu Andreea L. , Chen Shao-Rui , Chen Hong , Pan Hui-Lin , Vázquez Santiago , Twomey Edward C. , Jayaraman Vasanthi
Published: July 2024

Memantine is an US Food and Drug Administration (FDA) approved drug that selectively inhibits NMDA-subtype ionotropic glutamate receptors (NMDARs) for treatment of dementia and Alzheimer’s. NMDARs enable calcium influx into neurons and are critical for normal brain function. However, increasing evidence shows that calcium influx in neurological diseases is augmented by calcium-permeable AMPA-subtype ionotropic glutamate receptors (AMPARs). Here, we demonstrate that these calcium-permeable AMPARs (CP-AMPARs) are inhibited by memantine. Electrophysiology unveils that memantine inhibition of CP-AMPARs is dependent on their calcium permeability and the presence of their neuronal auxiliary subunit transmembrane AMPAR regulatory proteins (TARPs). Through cryo-electron microscopy we elucidate that memantine blocks CP-AMPAR ion channels in a unique mechanism of action from NMDARs. Furthermore, we demonstrate that memantine reverses a gain of function AMPAR mutation found in a patient with a neurodevelopmental disorder and inhibits CP-AMPARs in nerve injury. Our findings alter the paradigm for the memantine mechanism of action and provide a blueprint for therapeutic approaches targeting CP-AMPARs.
LinkR: an open source, low-code and collaborative data science platform for healthcare data analysis and visualization
Authors: Delange Boris , Popoff Benjamin , Séité Thibault , Lamer Antoine , Parrot Adrien
Published: July 2024

Background

The development of Clinical Data Warehouses (CDWs) has greatly increased access to big data in medical research. However, the lack of standardization among different data models hampers interoperability and, consequently, the research potential of these vast data resources. Moreover, data manipulation and analysis require advanced programming skills, a skill set that healthcare professionals often lack.

Methods

To address these issues, we created an open source, low-code and collaborative data science platform for manipulating, visualizing and analyzing healthcare data using graphical tools alongside an advanced programming interface. The software is based on the OMOP common data model.

Results

LinkR enables users to generate studies using data imported from multiple sources. The software organizes the studies into two main sections: individual and population data sections. In theindividual data section, user-friendly graphical tools allow users to customize data presentation, recreating the equivalent of a medical record, according to the needs of their study. Thepopulation data sectionis designed for conducting statistical analyses through both graphical and programming interfaces. The application also incorporates collaborative features, such as a messaging page and an integrated Git module. These features facilitate efficient collaboration and shared data analysis efforts across different research centers.

Conclusion

LinkR is a low-code data science platform that democratizes access, manipulation, and analysis of data from clinical data warehouses and facilitates collaborative work on healthcare data, using an open science approach.
"Stroke Patient and Stakeholder Engagement (SPSE): Concepts, Definitions, Models, Implementation Strategies, Indicators, and Frameworks - A Systematic Scoping Review"
Authors: Khankeh Hamidreza , Guyatt Gordon , Shirozhan Shima , Roudini Juliet , Rackoll Torsten , Dirnagl Ulrich
Published: July 2024

Background

Involving stroke patients in clinical research through patient engagement aims to ensure that studies are patient-centered, and may help ensure they are feasible, ethical, and credible, ultimately leading to enhanced trust and communication between researchers and the patient community. In this study, we have conducted a scoping review to identify existing evidence and gaps in SPSE.

Methods

The five-step approach outlined by Arksey and O’Malley, in conjunction with the Preferred Reporting Items for Scoping Reviews (PRISMA-ScR) guidelines, provided the structure for this review. To find relevant articles, we searched PubMed, Web of Science, and Embase databases up to February 2024. Additionally, the review team conducted a hand search using Google Scholar, key journals, and references of highly relevant articles. Reviewers conducted primary and secondary screening, ultimately selecting English-language articles with available full texts that met the eligibility criteria. Reviewers extracted data from these articles into a table designed and tested by the research team.

Results

Of 1,002 articles initially identified, 21 proved eligible. Stakeholder engagement primarily occurred during the design phase of studies and within the studies using qualitative methodologies. Although the engagement of stakeholders in the research process is increasing, practice regarding terminology and principles of implementation remains variable. Researchers have recognized the benefits of stakeholder engagement, but have also faced numerous challenges that often arise during the research process.

Conclusion

The current study identifies stakeholder groups and the benefits and challenges researchers face in implementing their engagement. Given existing challenges and limited specific models or frameworks, it is recommended to explore applied recommendations for stakeholder engagement in future studies, that may enhance stakeholder engagement, overcome obstacles, and unify researchers’ understanding of engagement and implementation.
Contrastive Self-supervised Learning for Neurodegenerative Disorder Classification
Authors: Gryshchuk Vadym , Singh Devesh , Teipel Stefan , Dyrba Martin ,   ADNI, AIBL, FTLDNI study groups
Published: July 2024

Neurodegenerative diseases such as Alzheimer’s disease (AD) or frontotemporal lobar degeneration (FTLD) involve specific loss of brain volume, detectable in vivo using T1-weighted MRI scans. Supervised machine learning approaches classifying neurodegenerative diseases require diagnostic-labels for each sample. However, it can be difficult to obtain expert labels for a large amount of data. Self-supervised learning (SSL) offers an alternative for training machine learning models without data-labels. We investigated if the SSL models can applied to distinguish between different neurodegenerative disorders in an interpretable manner. Our method comprises a feature extractor and a downstream classification head. A deep convolutional neural network trained in a contrastive self-supervised way serves as the feature extractor, learning latent representation, while the classifier head is a single-layer perceptron. We used N=2694 T1-weighted MRI scans from four data cohorts: two ADNI datasets, AIBL and FTLDNI, including cognitively normal controls (CN), cases with prodromal and clinical AD, as well as FTLD cases differentiated into its sub-types. Our results showed that the feature extractor trained in a self-supervised way provides generalizable and robust representations for the downstream classification. For AD vs. CN, our model achieves 82% balanced accuracy on the test subset and 80% on an independent holdout dataset. Similarly, the Behavioral variant of frontotemporal dementia (BV) vs. CN model attains an 88% balanced accuracy on the test subset. The average feature attribution heatmaps obtained by the Integrated Gradient method highlighted hallmark regions, i.e., temporal gray matter atrophy for AD, and insular atrophy for BV. In conclusion, our models perform comparably to state-of-the-art supervised deep learning approaches. This suggests that the SSL methodology can successfully make use of unannotated neuroimaging datasets as training data while remaining robust and interpretable.
Relative risks, the probability of necessity, and attributable fractions
Authors: Webster Anthony J.
Published: July 2024

Epidemiologists are careful to describe their findings as “associations”, and to avoid any causal language or claims. Arguably, this attempt to avoid reference to causal processes has become counterproductive. Explicitly stated or not, assumptions about causal processes are inherent in the formulation and interpretation of any statistical study. This article offers a bridge between established, extensively developed proportional hazard methods that are used to study longitudinal observational cohort data, and results for causal inference. In particular, it considers the burden of disease that would not have occurred, but for an exposure such as smoking. It shows how this “probability of necessity”, relates to population attributable fractions, and how these quantities along with their confidence intervals, can be estimated using conventional proportional hazard estimates. The example may often apply to cohort studies that consider disease-risk in the absence of prior disease. More generally, equivalent estimates can often be constructed when there is sufficient understanding to postulate a model for the causal relationship between exposures, confounders, and disease-risk, as summarised in a directed acyclic graph (DAG).
RNA mis-splicing in children with myotonic dystrophy is associated with physical function
Authors: Hartman Julia M. , Ikegami Kobe , Provenzano Marina , Bates Kameron , Butler Amanda , Jones Aileen S. , Berggren Kiera N. , Dekdebrun Jeanne , McKay Marnee J. , Baldwin Jennifer N. , Cornett Kayla M.D. , Burns Joshua , Kiefer Michael , Johnson Nicholas E. , Hale Melissa A.
Published: July 2024

Objectives

Dysregulated RNA alternative splicing is the hallmark of myotonic dystrophy type 1 (DM1). However, the association between RNA mis-splicing and physical function in children with the most severe form of disease, congenital myotonic dystrophy (CDM), is unknown.

Methods

82 participants (42 DM1 adults & 40 CDM children) with muscle biopsies and measures of myotonia, motor function, and strength were combined from five observational studies. Data were normalized and correlated with an aggregate measure of alternative splicing dysregulation, [MBNL]inferredin skeletal muscle biopsies. Multiple linear regression analysis was performed to predict [MBNL]inferredusing clinical outcome measures alone. Similar analyses were performed to predict 12-month physical function using baseline metrics.

Results

Myotonia (measured via vHOT) was significantly correlated with RNA mis-splicing in our cross-sectional population of all DM1 individuals; CDM participants alone displayed no myotonia despite a similar range of RNA mis-splicing. Measures of motor performance and muscle strength were significantly associated with [MBNL]inferredin our cohort of all DM1 individuals and when assessing CDM children independently. Multiple linear regression analyses yielded two models capable of predicting [MBNL]inferredfrom select clinical outcome assessments alone in all subjects (adjusted R2= 0.6723) or exclusively in CDM children (adjusted R2= 0.5875).

Interpretation

Our findings establish significant correlations between skeletal muscle performance and a composite measure of alternative splicing dysregulation, [MBNL]inferred,in DM1. The strength of these correlations and the development of the predictive models will assist in designing efficacious clinical trials for individuals with DM1, particularly CDM.
Ambivalent partnership of the Drosophila posterior class Hox protein Abdominal-B with the Extradenticle and Homothorax cofactors
Authors: Curt Jesús R. , Martín Paloma , Foronda David , Hudry Bruno , Kannan Ramakrishnan , Shetty Srividya , Merabet Samir , Saurin Andrew , Graba Yacine , Herrero Ernesto Sanchez
Published: July 2024

Hox proteins, a sub-group of the homeodomain (HD) transcription factor family, provide positional information for axial patterning in development and evolution. Hox protein functional specificity is reached, at least in part, through Pbc (Extradenticle (Exd) in Drosophila) and Meis/Prep (Homothorax (Hth) in Drosophila) cofactor interactions. Most of our current knowledge of Hox protein specificity stems from the study of anterior and central Hox proteins, identifying the molecular and structural bases for Hox/Pbc/Meis-Prep cooperative action. Posterior Hox class proteins, Abd-B in Drosophila and Hox9-13 in vertebrates, have been comparatively less studied. They strongly diverge from anterior and central class Hox proteins, with a low degree of HD sequence conservation and the absence of a core canonical Pbc interaction motif. Here we explore how Abd-B function interface with that of Exd/Hth using several developmental contexts, studying mutual expression control, functional dependency and intrinsic protein requirements. Results identify cross regulatory interactions setting relative expression and activity levels required for proper development. They also reveal organ-specific requirement and a binary functional interplay with Exd and Hth, either synergistic or antagonistic. This highlights context specific use of Exd/Hth cofactors, and a similar context specific use of Abd-B protein intrinsic protein requirements.
A flexible framework for minimal biomarker signature discovery from clinical omics studies without library size normalisation
Authors: Rawlinson Daniel , Zhou Chenxi , Lê Cao Kim-Anh , Coin Lachlan J.M.
Published: July 2024

Application of transcriptomics, proteomics and metabolomics technologies to clinical cohorts has uncovered a variety of signatures for predicting disease. Many of these signatures require the full ‘omics data for evaluation on unseen samples, either explicitly or implicitly through library size normalisation. Translation to low-cost point-of-care tests requires development of signatures which measure as few analytes as possible without relying on direct measurement of library size.

To achieve this, we have developed a feature selection method (Forward Selection-Partial Least Squares) which generates minimal disease signatures from high-dimensional omics datasets with applicability to continuous, binary or multi-class outcomes. Through extensive benchmarking, we show that FS-PLS has comparable performance to commonly used signature discovery methods while delivering signatures which are an order of magnitude smaller. We show that FS-PLS can be used to select features predictive of library size, and that these features can be used to normalize unseen samples, meaning that the features in the complete model can be measured in isolation for making new predictions.

By enabling discovery of small, high-performance signatures, FS-PLS addresses an important impediment for the further development of precision medical care.
Tsa1 is the dominant peroxide scavenger and a source of H2O2-dependent GSSG production in yeast
Authors: Zimmermann Jannik , Lang Lukas , Calabrese Gaetano , Laporte Hugo , Amponsah Prince S , Michalk Christoph , Sukmann Tobias , Oestreicher Julian , Tursch Anja , Peker Esra , Owusu Theresa N E , Weith Matthias , Roma Leticia Prates , Deponte Marcel , Riemer Jan , Morgan Bruce
Published: July 2024

Hydrogen peroxide (H2O2) is an important biological molecule, functioning both as a second messenger in cell signaling and, especially at higher concentrations, as a cause of cell damage. Cells harbor multiple enzymes that have peroxide reducing activityin vitro. However, the contribution of each of these enzymes towards peroxide scavengingin vivois less clear. Therefore, to directly investigatein vivoperoxide scavenging, we used the genetically encoded peroxide sensors, roGFP2-Tsa2ΔCRand HyPer7, to systematically screen the peroxide scavenging capacity of yeast thiol and heme peroxidase mutants. We show that the 2-Cys peroxiredoxin Tsa1 alone is responsible for almost all exogenous H2O2andtert-butyl hydroperoxide scavenging. The two catalases and cytochromecperoxidase only produce observable scavenging defects at higher H2O2concentrations when these three heme peroxidases are deleted in combination. We also analyzed the reduction of Tsa1in vitro, revealing that the enzyme is efficiently reduced by thioredoxin 1 with a rate constant of 2.8×106M−1s−1. When thioredoxins are oxidized, Tsa1 can become an important source of H2O2-dependent cytosolic glutathione disulfide production in yeast. Our findings clarify the importance of the various thiol and heme peroxidases for peroxide removal and suggest that most thiol peroxidases have alternative or specialized functions in specific subcellular compartments.
Developing, characterizing and modeling CRISPR-based point-of-use pathogen diagnostics
Authors: Jung Jaeyoung K. , Dreyer Kathleen S. , Dray Kate E. , Muldoon Joseph J. , George Jithin , Shirman Sasha , Cabezas Maria D. , D’Aquino Anne E. , Verosloff Matthew S. , Seki Kosuke , Rybnicky Grant A. , Alam Khalid K. , Bagheri Neda , Jewett Michael C. , Leonard Joshua N. , Mangan Niall M. , Lucks Julius B.
Published: July 2024

Recent years have seen intense interest in the development of point-of-care nucleic acid diagnostic technologies to address the scaling limitations of laboratory-based approaches. Chief among these are combinations of isothermal amplification approaches with CRISPR-based detection and readouts of target products. Here, we contribute to the growing body of rapid, programmable point-of-care pathogen tests by developing and optimizing a one-pot NASBA-Cas13a nucleic acid detection assay. This test uses the isothermal amplification technique NASBA to amplify target viral nucleic acids, followed by Cas13a-based detection of amplified sequences. We first demonstrate an in-house formulation of NASBA that enables optimization of individual NASBA components. We then present design rules for NASBA primer sets and LbuCas13a guide RNAs for fast and sensitive detection of SARS-CoV-2 viral RNA fragments, resulting in 20 – 200 aM sensitivity without any specialized equipment. Finally, we explore the combination of high-throughput assay condition screening with mechanistic ordinary differential equation modeling of the reaction scheme to gain a deeper understanding of the NASBA-Cas13a system. This work presents a framework for developing a mechanistic understanding of reaction performance and optimization that uses both experiments and modeling, which we anticipate will be useful in developing future nucleic acid detection technologies.
A novel infective endocarditis virulence factor related to multiple functions for bacterial survival in blood was discovered inStreptococcus sanguinis
Authors: Anandan Vysakh , Bao Liang , Zhu Zan , Bradley Jennifer , Assi Valery-Francine , Chavda Henna , Kitten Todd , Xu Ping
Published: July 2024

We identified the role of a conserved hypothetical protein (SSA_0451) inS. sanguinisthat is involved in the virulence of infective endocarditis. Anin vitrowhole blood killing assay and rabbit endocarditis model studies revealed that the SSA_0451 mutant (ΔSSA_0451) was significantly less virulent than the wild-type (SK36) and its complementation mutant (ΔSSA_0451C). The mechanism underlying the SSA_0451 mutant’s reduced virulence in infective endocarditis was evidentially linked to oxidative stress and environmental stress. The genes related to the survival ofS. sanguinisin an oxidative stress environment were downregulated in ΔSSA_0451, which affected its survival in blood. Our findings suggest that SSA_0451 is a novel IE virulence factor and a new target for drug discovery against IE.

Author summary

This study focused on SSA_0451, a conserved hypothetical protein inS. sanguinis, to explore its potential role as a virulence factor. Throughin vitrowhole blood killing assays and rabbit IE models, it was found that the SSA_0451 mutant exhibited reduced virulence compared to the wild-type and a complemented mutant. The study linked the mutant’s diminished virulence in IE to heightened susceptibility to oxidative and environmental stresses, supported by downregulation of genes crucial for oxidative stress survival inS. sanguinis. These findings identify SSA_0451 as a novel virulence factor in IE and propose it as a promising target for future drug development against this condition.
Profiling Tel1 Signaling Reveals a Non-Canonical Motif Targeting DNA Repair and Telomere Control Machineries
Authors: Comstock Will , Sanford Ethan , Navarro Marcos , Smolka Marcus B
Published: July 2024

The stability of the genome relies on Phosphatidyl Inositol 3-Kinase-related Kinases (PIKKs) that sense DNA damage and trigger elaborate downstream signaling responses. InS. cerevisiae, the Tel1 kinase (ortholog of human ATM) is activated at DNA double strand breaks (DSBs) and short telomeres. Despite the well-established roles of Tel1 in the control of telomere maintenance, suppression of chromosomal rearrangements, activation of cell cycle checkpoints, and repair of DSBs, the substrates through which Tel1 controls these processes remain incompletely understood. Here we performed an in depth phosphoproteomic screen for Tel1-dependent phosphorylation events. To achieve maximal coverage of the phosphoproteome, we developed a scaled-up approach that accommodates large amounts of protein extracts and chromatographic fractions. Compared to previous reports, we expanded the number of detected Tel1-dependent phosphorylation events by over 10-fold. Surprisingly, in addition to the identification of phosphorylation sites featuring the canonical motif for Tel1 phosphorylation (S/T-Q), the results revealed a novel motif (D/E-S/T) highly prevalent and enriched in the set of Tel1-dependent events. This motif is unique to Tel1 signaling and not shared with the Mec1 kinase, providing clues to how Tel1 plays specialized roles in DNA repair and telomere length control. Overall, these findings define a Tel1-signaling network targeting numerous proteins involved in DNA repair, chromatin regulation, and telomere maintenance that represents a framework for dissecting the molecular mechanisms of Tel1 action.
Ecology of prophage-like elements inBacillus subtilisat global and local geographical scale
Authors: Stefanič Polonca , Stare Eva , Floccari Valentina A. , Kovac Jasna , Hertel Robert , Rocha Ulisses , Kovács Ákos T. , Mandić-Mulec Ines , Strube Mikael Lenz , Dragoš Anna
Published: July 2024

Prophages account for a substantial part of most bacterial genomes, but the impacts on hosts remain poorly understood. Here, we combined computational and laboratory experiments to explore the abundance, distribution, and activity of prophage elements inBacillus subtilis. NCBI database genome sequences and isolates from 1 cm3riverbank soil samples were analyzed to provide insights at global and local geographical scales, respectively. Most prophages in wildB. subtilisisolates were related to mobile genetic elements previously identified in laboratory strains. Some large groups of prophages were closely related to completely uncharacterized yet functional Bacillus phages, or completely unknown. As certain prophage groups were unique to local isolates, we explored factors influencing prophages within a single genome. Phylogenetic relatedness was a slightly better predictor of host prophage repertoire than geographical origin. We show that cryptic phages can play a major role in acquisition and/or maintenance of other prophage elements both via strong antagonism or by co-dependence. Laboratory experiments showed that most predicted prophages may be cryptic, since they failed to induce under DNA-damaging stress conditions. Interestingly, the magnitude of stress responses remained proportional to the total number of prophage elements predicted, suggesting their importance in host physiology. This study highlights the diversity, integration patterns, and co-occurrence of prophages inB. subtilisand their potential impact on host evolution and physiology. Understanding these dynamics provides insight into bacterial genome evolution and prophage-host interactions, laying the groundwork for future experimental studies on the roles of phages in the ecology and evolution of this bacterial species.
Promoted Read-through and Mutation Against Pseudouridine-CMC by an Evolved Reverse Transcriptase
Authors: He Zhiyong , Qiu Weiqi , Zhou Huiqing
Published: July 2024

Pseudouridine (Ψ) is an abundant RNA chemical modification that can play critical roles in the biological functions of RNA, and RNA-therapeutic applications. Current Ψ detection methods are limited in identifying Ψs at base-resolution in U-rich sequence contexts, where Ψ occurs frequently. The N-cyclohexyl N’-(2-morpholinoethyl)carbodiimide (CMC) can selectively label Ψ in RNA by forming the CMC-Ψ adduct. Here we report that an evolved reverse transcriptase (“RT-1306”) shows promoted read-through and mutation against the CMC-Ψ. The mutation signature can resolve the occurrence of Ψs within UU-containing sequences. We developed “Mut-Ψ-seq” utilizing CMC and RT-1306 for transcriptome-wide mapping of Ψ at base-resolution. The mutation signatures robustly identify reported Ψs in human rRNAs via the ROC analysis, and elongated CMC reaction duration increases the detection sensitivity of Ψ. We report a high-confidence list of Ψ sites in polyA-enriched RNAs from HEK-293T cells identified by orthogonal chemical treatments (CMC and bisulfite). The mutation signatures resolve the position of Ψ in UU-containing sequences, revealing diverse occurrence of Ψs in such sequences. This work provides new methods and datasets for biological research of Ψ, and demonstrates the potential of combining the reverse transcriptase engineering and selective chemical labeling to expand the toolkit for RNA chemical modifications studies.
Legal nature of the court’s discretionary power in business contract revocation
Authors: Khawaldeh Ahmed M.
Published: July 2024

Purpose

This paper aims to know the legal nature of the court’s discretionary power in business contract revocation.

Design/methodology/approach

Following the normative method that analyzes legislation using secondary data consisting of primary, secondary and tertiary legal materials, this research was conducted during the period November, 2023 – February, 2024. Moreover, studies that addressed the legal nature of the court’s discretionary power in business contract revocation and published since 2000 were included. The focus was made upon the business contract’s retroactive effect in relation to the Court’s discretionary power.

Findings

From the initial 312 studies reviewed, 20 met the inclusion criteria. The business contract's retroactive effect in relation to the Court’s discretionary power has been considered by the relatively small number of studies included in the review. Researchers from different countries explored the phenomenon, using different approaches to explore the topic. However, none of these researchers has examined the phenomenon in the Jordanian Context.

Research limitations/implications

This research is unique, as it examines the legal nature of the court’s discretionary power in business contract revocation, which has not been investigated in the Jordanian context. The previous researches on business contract revocation have addressed laws other than the Jordanian law.

Practical implications

This research will be a guide for the Jordanian legislation to draft a business contract law that regulates the court's interference in cases of business contract revocation and clearly specify its role in this regard.

Social implications

This research will increase the Jordanian people's awareness of the legal nature of court in cases of business contract revocation. Moreover, it will make them familiar with the current laws so that they will legally deal with cases of this kind.

Originality/value

It is very important to conduct this research to review the papers and laws related to business contract revocation in Jordan since this issue has not been investigated.
The emergence of discrimination due to miscategorization
Authors: Yasar M. Alperen
Published: July 2024

Purpose

This study explores the emergence of discrimination based on observable characteristics. In many instances, agents presume differences arising from traits such as race or gender, even when these parameters are irrelevant to the situation at hand. This paper intends to reveal an emergent behavior and a persistent culture of discrimination caused by miscategorization in strategic interactions.

Design/methodology/approach

We assume that agents occasionally engage in conflicts modeled as asymmetric hawk and dove games, where boundedly rational agents may categorize their opponents based on observable traits to make effective decisions. Three categorization strategies are considered: fine-grained, regular, and coarse-grained. Subsequently, an evolutionary agent-based model is employed to examine the performance of these strategies in a dynamic environment.

Findings

The results demonstrate that fine-grained categorization provides an advantage when the cost of fighting is low, while coarse-grained categorizers exhibit more peaceful behavior, gaining an advantage when the cost of conflict is high. Our primary finding indicates the emergence of discrimination based on non-relevant traits, manifested through consistent aggressive behavior towards individuals possessing these traits.

Originality/value

This paper is the first to investigate the emergence of discrimination without assuming prior differences between groups. Previous studies have assumed either an initial population difference or a homophily-based approach. In contrast, we demonstrate that discrimination can emerge even in the absence of such assumptions. Discrimination between two groups may arise as long as there are agents who label these categories.
The relationship between low-consumption single-use plastic awareness and behaviour: a case study of FPT University students (Ho Chi Minh Branch)
Authors: Nguyen Nhi Yen , Tran Hao Gia , Tra Dang Thanh , Le Nhung Tuyet , Nguyen Hien Thi Thuy
Published: July 2024

Purpose

This study aims to combine two theories, the Theory of Planned Behaviour (TPB) and the Norm Activation Model (NAM), to investigate the relationship between the awareness of reducing single-use plastic waste's environmental cost and the behaviour to limit the use of single-use plastic products (SUPPs) by FPT university students.

Design/methodology/approach

Quantitative research methodologies were employed on a sample of 506 university students. The survey data was then examined using SPSS, SPSS AMOS and SmartPLS software.

Findings

The overarching conclusion of the study is that awareness of reducing single-use plastic waste's environmental cost has a positive impact on FPT university students' behaviour to reduce their use of single-use plastic products. Another intriguing discovery is how socialisation of responsibility affects pro-environmental behaviour through the interplay between personal norms, subjective norms and behavioural intention.

Originality/value

This study on the relationship between SUPP low-consumption awareness and behaviour and mediating factors is a necessary foundation for future studies related to changing the behaviour of students using SUPPs. That will also be a solid foundation for practical plans to change behaviour using SUPPs through communication campaigns to increase awareness.
Sustainability in (engineering) education through reclaiming and reusing electronic components from e-waste: a last decade research review
Authors: Nikoloudakis Nikolaos , Rangoussi Maria
Published: July 2024

Purpose

This paper aims to investigate the e-waste aspect of sustainability in education, with a specific interest in engineering education. Specifically, it focuses on recycling through reclaiming electronic components from e-waste and reusing them in repairs or in the design and construction of new devices.

Design/methodology/approach

A systematic literature review is performed according to the PRISMA methodology. In total, 27 articles are analysed as to publication parameters, characteristics and evaluation of educational interventions on e-waste and evaluation results across major domains of learning (cognitive, affective and 21st century skills).

Findings

The reviewed subject is under-research; publications are rare and mostly in conference proceedings. The majority of interventions take place at university level, in face-to-face mode, using a practical approach in hands-on labs. Educational methods draw from modern, learner-centred pedagogies such as collaborative learning and constructionism. Topics focus on innovative design and construction, while interventions tend to become embedded in engineering curricula/courses. Evaluation of learners’ gains across domains of learning is rare and follows informal procedures that shake the reliability of results. Domains other than the cognitive are scarcely and subjectively evaluated.

Originality/value

Contrary to other aspects of sustainability, the aspect of e-waste has not been reviewed. The applied, hands-on approach and the analytic, synthetic, collaboration and creativity skills it requires are all much valued in education. The current review, therefore, comes to inform, inspire and guide educators and researchers in planning and implementing activities on this subject.
Nonlinear dynamic analysis of water-lubricated textured journal bearings with cavitation effect
Authors: Li Xiuwei , Li XingYang , Zhang Guokun , Wang Yu , Liu Qinglei , Li Qiang
Published: July 2024

Purpose

The purpose of this paper is to investigate the effects of different surface structures, dimensional parameters and cavitation models on the lubrication characteristics of water-lubricated journal bearings.

Design/methodology/approach

In this paper, the coupling iteration method of ANSYS and MATLAB is established to calculate the journal orbits of water-lubricated bearing, and the differences between the journal orbits of the smoothed and the textured water-lubricated bearings are compared and analyzed, and the effects of different bearing materials, L/D ratios and clearance ratios on the lubrication performance of water-lubricated bearings are investigated. The effects of different cavitation models on the static equilibrium position and whirling trajectory of water-lubricated bearings are compared.

Findings

The results show that when the surface texture is distributed in the upper bearing or the bearing elastic modulus decreases, the bearing stability increases. Considering shear cavitation and noncondensing gas, the rotor journal orbits amplitude decreases at high speed with low clearance ratio. A water film test rig for water-lubricated bearings is built to measure the full-circle water film pressure of water-lubricated journal bearings, and the experimental results are compared with the simulation results, which are in good agreement.

Originality/value

The findings provide a theoretical basis for optimizing the structure of water-lubricated bearings.
Exploring authenticity meanings in the global-local continuum: semiotic insights from the Måneskin case
Authors: Corciolani Matteo
Published: July 2024

Purpose

This article explores brand positioning and authenticity within the global-local continuum, utilizing the evolution of the Italian rock band, Måneskin, as a case study.

Design/methodology/approach

Employing Greimas’s (1987) semiotic framework, I analyze social media and media articles on Måneskin’s success, unveiling consumer perceptions of global, local and intermediate brand positionings and related authenticity dimensions. I particularly uncover a narrative centered on “global” versus “local” brand positioning and their counterparts (i.e. “not global” and “not local”), forming a semiotic square.

Findings

In the “global” perception, the band is evaluated in terms of conforming to global standards, while, in the “local” understanding, the emphasis shifts to connections to local roots. In the “glocalization” perspective (global and local), the band’s activities are assessed concerning an integration between global conformity and local connections. The “glalienation” viewpoint (neither global nor local) is related to consistency, in the sense of being unique and avoiding a commitment to either global or local values. The data also highlight issues of inconsistency regarding brand positioning’s contradictions, such as the band’s incoherently merging local and non-local elements.

Originality/value

The proposed structural semiotics approach enriches previous theories by examining authenticity within global-local dynamics, offering insights into various authenticity dimensions and their interplay. It underlines shifts in authenticity perceptions and challenges binary brand positioning, advocating for strategic placement across the global-local continuum. Moreover, it emphasizes leveraging cultural elements and semiotics to effectively communicate authenticity.
Ambicultural sensitivity and relational embeddedness in fostering B2B relationship
Authors: Saragih Harriman Samuel
Published: July 2024

Purpose

This study aims to explore the interplay of ambicultural sensitivity and relational embeddedness in the quality of B2B relationships. Specifically, it examines how these factors contribute to enhancing the adaptability, collaboration and competitive advantage of multinational corporations and institutions operating within diverse cultural landscapes.

Design/methodology/approach

Using an abductive qualitative case study methodology, this study engaged professionals from three diverse multinational corporations in Indonesia − an energy services provider, a logistics services company and a not-for-profit institution. The objective was to explore the integration and implications of ambicultural sensitivity across varied cultural and industry settings.

Findings

This study demonstrates that ambicultural sensitivity − the ability to understand, appreciate and integrate diverse cultural values − enhances B2B relationships through its manifestation in individual and organizational practices. It facilitates a dynamic merging of cultural perspectives and management approaches within intercultural interactions. Furthermore, relational embeddedness is identified as crucial for successful cross-cultural collaboration and innovation. These insights highlight the strategic value of cultural integration and sensitivity in maintaining a competitive edge in the global marketplace.

Originality/value

This study adds to the B2B marketing literature by providing a nuanced understanding of how ambicultural sensitivity and relational embeddedness operate in the context of B2B relationships.