bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic priming of embryonic enhancer elements coordinates developmental gene networks
Authors: Todd Christopher D , Ijaz Jannat , Torabi Fereshteh , Dovgusha Oleksandr , Bevan Stephen , Cracknell Olivia , Lohoff Tim , Clark Stephen , Argelaguet Ricard , Pearce Juliette , Kafetzopoulos Ioannis , Santambrogio Alice , Nichols Jennifer , von Meyenn Ferdinand , Guenesdogan Ufuk , Schoenfelder Stefan , Reik Wolf 
Published: September 2024

AbstractEmbryonic development requires the accurate spatiotemporal execution of cell lineage-specific gene expression programs, which are controlled by transcriptional enhancers. Developmental enhancers adopt a primed chromatin state prior to their activation; however how this primed enhancer state is established, maintained, and how it affects the regulation of developmental gene networks remains poorly understood. Here, we use comparative multi-omic analyses of human and mouse early embryonic development to identify subsets of post-gastrulation lineage-specific enhancers which are epigenetically primed ahead of their activation, marked by the histone modification H3K4me1 within the epiblast. We show that epigenetic priming occurs at lineage-specific enhancers for all three germ layers, and that epigenetic priming of enhancers confers lineage-specific regulation of key developmental gene networks. Surprisingly in some cases, lineage-specific enhancers are epigenetically marked already in the zygote, weeks before their activation during lineage specification. Moreover, we outline a generalisable strategy to use naturally occurring human genetic variation to delineate important sequence determinants of primed enhancer function. Our findings identify an evolutionarily conserved program of enhancer priming and begin to dissect the temporal dynamics and mechanisms of its establishment and maintenance during early mammalian development.
Membrane-tethered cadherin substrates reveal actin architecture at adherens junctions
Authors: Ghosh Sayantika , James John , Ummat Badeer Hassan , Köster Darius 
Published: September 2024

AbstractAdherens junctions (AJ) are E-cadherin-based adhesions at cell-cell contacts that connect the actin cytoskeleton of epithelial cells. The formation and maturation of these junctions is important in development, e.g. for the generation of epithelial tissues, and loss of adherens junctions is linked to metastasis in cancer. It is well established that AJ is a mechano-sensitive process involving the clustering of E-cadherins within the plasma membrane of cells and across adjacent cells, and the mechanical activation of α-catenins that connect E-cadherins with the actin cytoskeleton. However, how membrane mobility of E-cadherins and their organisation in time and space influence this process is less well understood, partly due to limitations to control the physical properties of cell membranes and perform high resolution in model organisms or cell monolayers. Here we place MCF7 cells labelled with fluorescent actin, e-cadherin, and α-catenin, on fluid-supported lipid bilayers containing the extracellular domain of cadherin as a biomimetic system to enable super resolution TIRF-SIM imaging of AJ. We found that MCF7 cells were able to attach and spread on these substrates, recruiting E-cadherin and α-catenin to form AJs that can mature and are mobile. Interestingly, we found that, depending on the mobility of E-cadherin within the SLB, distinct types of actin architecture emerge over time. Low mobility substrates support formin-based linear polymerisation while high mobility substrates support Arp2/3 -based branched actin polymerisation. These regions are spatially delimited within the cell and can change over time, giving rise to a mature state containing regions of both branched and linear actin.
Pseudomonas aeruginosafaces a fitness trade-off between mucosal colonization and antibiotic tolerance during airway infections
Authors: Meirelles Lucas A. , Vayena Evangelia , Debache Auriane , Schmidt Eric , Rossy Tamara , Distler Tania , Hatzimanikatis Vassily , Persat Alexandre 
Published: September 2024

AbstractPseudomonas aeruginosacauses antibiotic-resilient acute and chronic pneumonia, but the mechanisms by which it adapts to the airway environment are poorly understood. Here, we investigatedP. aeruginosapathoadaptive mechanisms in tissue-engineered human airway organoids. Using transposon sequencingin situ,we decoded howP. aeruginosasurvives on the mucosal surface during antibiotic treatment. Biofilm formation emerged as a major driver ofP. aeruginosacolonization. Mutants that extensively produce biofilms on mucus show limited exploratory behavior, which limits nutrient access, slowing down their growth. Conversely, biofilm-dwellingP. aeruginosabetter tolerate antibiotics via biophysical mechanisms. Finally, biofilms can shelter less-tolerant but more cytotoxic strains, thereby contributing to genotypic heterogeneity.P. aeruginosamust therefore adapt to conflicting physical and biological selective pressures to initiate chronic infections.
Genomic and metabolic characterization ofTrueperella pyogenesisolated from domestic and wild animals
Authors: Magossi Gabriela , Gzyl Katherine E. , Holman Devin B. , Nagaraja T. G. , Amachawadi Raghavendra , Amat Samat 
Published: September 2024

AbstractTrueperella pyogenesis an important bacterial pathogen implicated in infections such as mastitis, metritis, pneumonia, and liver abscesses in both domestic and wild animals as well as endocarditis and prosthetic joint infections in humans. Understanding the genomic and metabolic features that enableT. pyogenesto colonize different anatomical sites within a host and its inter-kingdom transmission and survival is important for the effective control of this pathogen. We employed whole genome sequencing, phenotype microarrays, and antimicrobial susceptibility testing to identify genomic, metabolic and phenotypic features as well as antimicrobial resistance (AMR) genes inT. pyogenesrecovered from different livestock, companion and wildlife animals. For comparative genomic analysis, 83T. pyogenesgenomes, including 60 isolated in the current study and 23 publicly available genomes were evaluated. These genomes representedT. pyogenesstrains originated from 16 different body sites of 11 different animal hosts (e.g. bovine, swine, ovine, cervid, bison, equine, chamois, feline). Additionally, 49T. pyogenesisolates (bovine, ovine, deer, swine and feline) were evaluated for phenotypic antimicrobial resistance using disk diffusion, and for metabolic profiling using the Biology GENIII MicroPlates. We identified thatT. pyogenesstrains are not host- or body site-specific. The presence of conserved virulence genes (ploandfimA), as well as genotypic and phenotypic AMR may contribute toT. pyogenes’sability to cause infections in livestock, wildlife, and pets. Most of the tested isolates metabolized diverse carbon sources and chemical compounds, suggesting that this metabolic versatility may contribute toT. pyogenes’ survival, competitive advantage, and pathogenic potential.ImportanceTrueperella pyogenesis an important animal pathogen with zoonotic potential, posing a significant health concern to both animals and humans due to its ability to cause infections across different animal host species and tissues. Current understanding of this pathogen’s adaptability and survival mechanisms is limited. Here, we evaluated the genomic, virulence, metabolic, and antimicrobial resistance characteristics ofT. pyogenesrecovered from 16 different body sites of 11 different animal hosts (livestock, companion, and wild animals). We identified multiple antimicrobial resistance and virulence genes that may enableT. pyogenesfor sustained infection and transmission. Additionally,T. pyogenesstrains displayed metabolic versatility which could also contribute to its ability to thrive in diverse environments. Understanding the genomic and metabolic, and antimicrobial resistance characteristics that enableT. pyogenesto colonize different anatomical sites within a host and its transmission between different animal species is important for the effective control of this pathogen.
Role of the SAF-A SAP domain in X inactivation, transcription, splicing, and cell proliferation
Authors: Sharp Judith A. , Sparago Emily , Thomas Rachael , Alimenti Kaitlyn , Wang Wei , Blower Michael D. 
Published: September 2024

AbstractSAF-A is conserved throughout vertebrates and has emerged as an important factor regulating a multitude of nuclear functions, including lncRNA localization, gene expression, and splicing. SAF-A has several functional domains, including an N-terminal SAP domain that binds directly to DNA. Phosphorylation of SAP domain serines S14 and S26 are important for SAF-A localization and function during mitosis, however whether these serines are involved in interphase functions of SAF-A is not known. In this study we tested for the role of the SAP domain, and SAP domain serines S14 and S26 in X chromosome inactivation, protein dynamics, gene expression, splicing, and cell proliferation. Here we show that the SAP domain serines S14 and S26 are required to maintain XIST RNA localization and polycomb-dependent histone modifications on the inactive X chromosome in female cells. In addition, we present evidence that an Xi localization signal resides in the SAP domain. We found that that the SAP domain is not required to maintain gene expression and plays only a minor role in mRNA splicing. In contrast, the SAF-A SAP domain, in particular serines S14 and S26, are required for normal protein dynamics, and to maintain normal cell proliferation. We propose a model whereby dynamic phosphorylation of SAF-A serines S14 and S26 mediates rapid turnover of SAF-A interactions with DNA during interphase.
Phosphoinositide-focused CRISPR screen identifies novel genetic vulnerabilities in PDAC and AML cells
Authors: Lee Daniel KC , Loke Ryan , Chow Jonathan TS , Gabra Martino M , Salmena Leonardo 
Published: September 2024

AbstractPhosphoinositides (PIs) are minor but essential phospholipids that play crucial roles in cellular signaling pathways, membrane dynamics, and the regulation of various cellular processes. We developed and utilized a novel PI-focused CRISPR gRNA library to perform negative-selection and positive-selection screens in PANC-1 and OCI-AML2 cells, models of pancreatic ductal adenocarcinoma (PDAC) and acute myeloid leukemia (AML), respectively. Through these screens, we identified 28 essential genes in PANC-1, 84 essential genes in OCI-AML2, and 28 regulators of colony formation in OCI-AML2. Our results using this small and focused library uncovered false negatives and subtle effects that may be missed in genome-wide approaches, while enabling adaptation to different screening conditions. Overall, our results uncovered previously uncharacterized essential genes in PDAC and AML that can be leveraged as therapeutic targets and biomarkers. We also demonstrate that focused libraries offer a more efficient and targeted approach to uncovering critical genetic determinants of cancer progression.
The structural influence of the oncogenic driver mutation N642H in the STAT5B SH2 domain
Authors: Haas-Neill Liam , Meneksedag-Erol Deniz , Chaudhry Ayesha , Novoselova Masha , Ashraf Qirat F. , de Araujo Elvin D. , Wilson Derek J. , Rauscher Sarah 
Published: September 2024

AbstractThe point mutation N642H of the signal transducer and activator of transcription 5B (STAT5B) protein is associated with aggressive and drug-resistant forms of leukemia. This mutation is thought to promote cancer due to hyperactivation of STAT5B caused by increased stability of the active, parallel dimer state. However, the molecular mechanism leading to this stabilization is not well understood as there is currently no structure of the parallel dimer. To investigate the mutation’s mechanism of action, we conducted extensive all-atom molecular dynamics simula-tions of multiple oligomeric forms of both STAT5B and STAT5BN642H, including a model for the parallel dimer. The N642H mutation directly affects the hydrogen bonding network within the phosphotyrosine (pY)-binding pocket of the parallel dimer, enhancing the pY-binding in-teraction. The simulations indicate that apo STAT5B is highly flexible, exploring a diverse conformational space. In contrast, apo STAT5BN642Haccesses two distinct conformational states, one of which resembles the conformation of the parallel dimer. The simulation predic-tions of the effects of the mutation on structure and dynamics are supported by the results of hydrogen-deuterium exchange (HDX) mass spectrometry measurements carried out on STAT5B and STAT5BN642Hin which a phosphopeptide was used to mimic the effects of parallel dimer-ization on the SH2 domain. The molecular-level information uncovered in this work contributes to our understanding of STAT5B hyperactivation by the N642H mutation and could help pave the way for novel therapeutic strategies targeting this mutation.
Modelling the potential spread of Clade Ib MPXV in an Asia Pacific city
Authors: Jin Shihui , Gan Gregory , Endo Akira , Prem Kiesha , Tan Rayner Kay Jin , Lim Jue Tao , Ejima Keisuke , Dickens Borame L 
Published: September 2024

AbstractBackgroundThe ongoing 2024 mpox outbreak in several African countries, driven by the novel Clade 1b strain, has resulted in imported cases being reported in Sweden and Thailand. The Asia Pacific (APAC) region, with little exposure to previous mpox waves, is particularly vulnerable to local transmission triggered by importation. While this highlights the importance of early preparedness, current knowledge of the virus’s transmission dynamics remains too limited to effectively inform policy-making and resource planning.MethodsA compartmental model was constructed to characterise the potential mpox transmission triggered by importation in an APAC city. Outbreaks were simulated under diverse hypothetical scenarios considering transmission mechanisms, different affected subpopulations, levels of disease transmissibility, and importation frequencies. The impacts of various non-pharmaceutical interventions (NPIs) including isolation, and vaccination strategies were projected and compared.FindingsUp to 30% of the population would be infected in the scenario of high sexual and moderate non-sexual transmissibility in the general community, with minimal impact from importation frequency on outbreak size and healthcare burden. The sequential introduction of mandatory home isolation for diagnosed cases, pre-departure screening of international arrivals, and contact tracing were projected to lower the peak outbreak size by 35%, 0.04%, and 1.1%, respectively, while the reduction would be 30% with proper vaccination by prioritising the sexually active group. These measures would significantly decrease disease morbidity and mortality rates, thereby alleviating the disease’s pressure on healthcare systems.InterpretationThe potential mpox outbreak in the APAC setting could be alleviated through strong surveillance and timely response from stakeholders. NPIs are recommended over vaccination for outbreak management due to their demonstrated effectiveness and practicability.
Active EB1 surges promote tubulin influx into the growing outer segments of the bipartite olfactory cilia inDrosophila
Authors: Agarwal Riddhi Girdhar , Iyer Saishree , Barbora Ayan , Gadgil Yogesh , Jana Swadhin , Ray Krishanu 
Published: September 2024

AbstractLike a photoreceptor cilium, the sensory cilia have a complex bipartite architecture containing 9+0 connecting cilium at the base and a singlet microtubule-supported, highly membranous outer segment, essential for the receptor display. How such diverse cilia morphology and underlying microtubule cytoskeleton develops remains unclear. Here we show that individual olfactory cilium, inside the large basiconic sensilla in developingDrosophilaantenna, grows in episodic steps following several pulsatile influxes of tubulin. Each tubulin influx event is preceded by transient elevations of a microtubule-stabilising protein, the End-binding protein 1 (EB1). Additionally, EB1 is found to specifically interact with the tail domain ofDrosophilaKLP68D, an orthologue of the kinesin-2β motor subunit,in vitro. Finally, the loss of EB1 in olfactory neurons preceding the growth surges reduces the tubulin influx as well as arrests the olfactory cilia assembly and stability. These findings suggest a novel mechanism of bipartite cilia assembly.
Ground state magnetic structure and magnetic field effects in the layered honeycomb antiferromagnet YbOCl
Authors: Zhang Zheng , Cai Yanzhen , Jiao Jinlong , Kang Jing , Yu Dehong , Roessli Bertrand , Zhang Anmin , Ji Jianting , Jin Feng , Ma Jie , Zhang Qingming 
Published: September 2024

YbOCl is a representative member of the van der Waals layered honeycomb rare-earth chalcohalide RChX (R = rare earth; Ch = O, S, Se, and Te; and X = F, Cl, Br, and I) family reported recently. Its spin ground state remains to be explored experimentally. We grew high-quality single crystals of YbOCl and conducted comprehensive thermodynamic, elastic, and inelastic neutron scattering experiments down to 50 mK. The experiments reveal an antiferromagnetic phase below 1.3 K which is identified as a spin ground state with an intralayer ferromagnetic and interlayer antiferromagnetic ordering. By applying sophisticated numerical techniques to a honeycomb (nearest-neighbor)–triangle (next-nearest-neighbor) model Hamiltonian which accurately describes the highly anisotropic spin system, we are able to simulate the experiments well and determine the diagonal and off-diagonal spin-exchange interactions. The simulations give an antiferromagnetic Kitaev term comparable to the Heisenberg one. The experiments under magnetic fields allow us to establish a magnetic field–temperature phase diagram around the spin ground state. Most interestingly, a relatively small magnetic field (∼0.3 to 3 T) can significantly suppress the antiferromagnetic order, suggesting an intriguing interplay of the Kitaev interaction and magnetic fields in the spin system. The present study provides fundamental insights into the highly anisotropic spin systems and opens a window to look into Kitaev spin physics in a rare-earth-based system.

Published by the American Physical Society
2024
“The seven principles of universal design of research”: how to increase user diversity in mainstream research
Authors: Berget Gerd , Kvikne Birgit 
Published: September 2024

PurposeUser diversity has been discussed in many fields of study for decades. Nevertheless, some cohorts are rarely included in mainstream research. According to the concept of universal design of research (UDR), people with disabilities should be more often included in participant pools. There is, however, a need for certain methodological considerations to achieve UDR.Design/methodology/approachThe suggested guidelines are based upon existing guidelines and research in addition to key takeaways from studies conducted by the authors over the past 15 years. Six studies are used to show how the guidelines can be applied in research involving three example cohorts, namely people with dyslexia, aphasia and intellectual disability.FindingsExtensive guidelines are needed to increase user inclusion in mainstream studies and support researchers in conducting purposeful and ethical research. The suggested guidelines should be examined for other cohorts to ensure that all types of user needs are accommodated.Research limitations/implicationsThis study contributes with methodological approaches to enhance inclusion of all types of participants in mainstream research.Originality/valueThe main contribution is The seven principles of UDR, a further development of the original principles for UDR.
Augmenting the base in an upheaval market – a case of Praajasv Foundation
Authors: Dave Chandni , Bhatt Kedar , Shaikh Nazneen Mohmedarif 
Published: September 2024

Learning outcomes
Upon completion of the case study, students will be able to assess the business environment a firm faces and develop strategies to match its strengths and weaknesses vis-à-vis opportunities and threats; formulate growth/expansion strategies for a firm; and evaluate resources of the firm to develop a competitive advantage.

Case overview/synopsis
The case describes the journey of Praajasv Foundation, an institute that provides coaching for students pursuing civil service exams in Gujarat. Established in 2019 in a rented space in Ahmedabad, Praajasv made a name for itself in the competitive market of civil service exam coaching by 2022, thanks to its expert tutors and focus on quality education. However, with the changing dynamics of the industry, Malhar Bhatt, the COO of Praajasv, must navigate the institute to strengthen its position. The increasing number of aspirants for the Class-III cadre exams and the presence of strong national competitors pose significant challenges for Malhar in terms of strategic planning. The rise of online education as an alternative to classroom teaching has also altered the competitive landscape of the industry. How do these trends impact Malhar’s plans for Praajasv? How should Malhar plan to expand the Praajasv Foundation in the coming years?

Complexity academic level
This case can be useful for students majoring in strategic management and marketing management at the master’s level

Supplementary materials
Teaching notes are available for educators only.

Subject code
CSS 8: Marketing.
Connection between urbanization and CO2 emissions in South Africa: does global uncertainty matter?
Authors: Fasanya Ismail Olaleke , Arek-Bawa Oghenefejiro 
Published: September 2024

Purpose
Given the interest in sustainable development, this study aims to assess the relationship between CO2 and urbanization as well as the role of world uncertainty in this association in a South African context.

Design/methodology/approach
This study focuses on yearly data from 1968 to 2020. To do this, the authors use the autoregressive distributed lag (ARDL) approach.

Findings
The authors find that urbanization’s effect on CO2 emissions is only significant when it is augmented with world uncertainty. Moreover, this effect is negative (referring to a reduction in CO2 emissions). Meanwhile, the authors find that GDP has a positive (that is, increasing) and significant effect on CO2 emissions. Overall, policymakers should focus on decoupling economic growth from traditional fossil fuels that produce greenhouse gas emissions.

Originality/value
The existing body of research contains numerous studies examining the relationship between urbanization and CO2 emissions. However, the dearth of research on the impact of global uncertainty on this connection is weak. Hence, this study aims to fill this gap and make a significant contribution to the field.