bluuebunny/crossref_metadata_2025 huggingface dataset:
Unveiling the potential of neuron-targeted dendriplexes for siRNA delivery using a PNS-CNS-on-Chip
Authors: Spencer Ana P. , Xavier Miguel , Guimarães Sofia C. , Vilaça Adriana , Ionescu Ariel , Santos Rafael , Lázaro María , Perlson Eran , Leiro Victoria , Maoz Ben M. , Pêgo Ana P.
Published: September 2024

Neurological disorders, a leading global cause of death, encompass conditions affecting the peripheral and central nervous systems (PNS and CNS, respectively). Limited axon regeneration is a significant challenge in these disorders, and it is linked to proteins like PTEN. RNA-based therapeutics, particularly siRNAs, hold potential for silencing these inhibitory pathways, but their clinical application is hindered by poor stability and cellular uptake. Our study addressed this challenge with the development of novel, fully biodegradable dendritic nanoparticles designed specifically for neuron targeting. These nanoparticles were functionalized with the neurotropic binding domain of tetanus toxin, enhancing selective neuronal targeting and cellular internalization. We demonstrated that these dendriplexes not only maintain biocompatibility and efficient siRNA delivery in neuronal cultures but also significantly enhance axonal growth, as shown in microfluidic models. In a groundbreaking PNS-CNS-on-Chip, dendriplexes exhibited effective migration from PNS to CNS neurons, highlighting their potential for targeted therapeutic delivery. This study pioneers the application of microfluidics to demonstrate the CNS targeting of dendriplexes, paving the way for innovative treatments in the field of nanomedicine.
Harmonization of Structural Brain Connectivity through Distribution Matching
Authors: Zhou Zhen , Fischl Bruce , Aganj Iman
Published: September 2024

The increasing prevalence of multi-site diffusion-weighted magnetic resonance imaging (dMRI) studies potentially offers enhanced statistical power for investigating brain structure. However, these studies face challenges due to variations in scanner hardware and acquisition protocols. While several methods exist for dMRI data harmonization, few specifically address structural brain connectivity. We introduce a new distribution-matching approach to harmonizing structural brain connectivity across different sites and scanners. We evaluate our method using structural brain connectivity data from two distinct datasets of OASIS-3 and ADNI-2, comparing its performance to the widely used ComBat method. Our approach is meant to align the statistical properties of connectivity data from these two datasets. We examine the impact of harmonization on the correlation of brain connectivity with the Mini-Mental State Examination score and age. Our results demonstrate that our distribution-matching technique more effectively harmonizes structural brain connectivity, often producing stronger and more significant correlations compared to ComBat. Qualitative assessments illustrate the desired distributional alignment of ADNI-2 with OASIS-3, while quantitative evaluations confirm robust performance. This work contributes to the growing field of dMRI harmonization, potentially improving the reliability and comparability of structural connectivity studies that combine data from different sources in neuroscientific and clinical research.
Imputed DNA methylation outperforms measured loci associations with smoking and chronological age
Authors: Richmond Anne , Mur Jure , Harris Sarah E , Corley Janie , Elliott Hannah R , Foley Christopher N , Hannon Eilis , Kuncheva Zhana , Min Josine L , Moqri Mahdi , Ndiaye Magatte , Sun Benjamin B , Vallejos Catalina A , Ying Kejun , Gladyshev Vadim N , Cox Simon R , McCartney Daniel L , Marioni Riccardo E
Published: September 2024

Multi-locus signatures of blood-based DNA methylation are well-established biomarkers for lifestyle and health outcomes. Here, we focus on two CpGs that are strongly associated with age and smoking behaviour. Imputing these loci via epigenome-wide CpGs results in stronger associations with outcomes in external datasets compared to directly measured CpGs. If extended epigenome-wide, CpG imputation could augment historic arrays and recently-released, inexpensive but lower-content arrays, thereby yielding better-powered association studies.
Synthetic metabolic pathways for ethylene glycol assimilation outperform natural counterparts
Authors: Feigis Michelle , Mahadevan Radhakrishnan
Published: September 2024

Biomanufacturing can play a pivotal role in the transition away from fossil fuel dependence for the production of chemicals and fuels. There is growing interest in alternative bioproduction feedstocks to conventional sugars that do not compete for land use with food production. Ethylene glycol, a C2 compound that can be recovered from plastic waste or derived from CO2with increasing efficiency, is gaining attention as a carbon source for microbial processes. Here we review the natural and synthetic metabolic pathways currently available for ethylene glycol assimilation. The pathways are compared in terms of their maximum theoretical yields for biomass and value-added products, thermodynamic favourability, minimum enzyme costs, and orthogonality to central carbon metabolism. We find that synthetic pathways outperform their natural counterparts in terms of higher thermodynamic driving forces, reduced enzyme costs, and higher theoretical yields for the majority of bioproducts analyzed as well as for biomass. However, natural assimilation pathways are equally or even more orthogonal to growth-associated reactions than synthetic pathways. Given these tradeoffs, the optimal EG assimilation pathway may depend on product and process choice.
Enhanced CRISPR/Cas-Based Immunoassay through Magnetic Proximity Extension and Detection
Authors: Shao Fangchi , Hu Jiumei , Zhang Pengfei , Akarapipad Patarajarin , Park Joon Soo , Lei Hanran , Hsieh Kuangwen , Wang Tza-Huei
Published: September 2024

Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas-associated systems have recently emerged as a focal point for developing next-generation molecular diagnosis, particularly for nucleic acid detection. However, the detection of proteins is equally critical across diverse applications in biology, medicine, and the food industry, especially for diagnosing and prognosing diseases like cancer, Alzheimer’s and cardiovascular conditions. Despite recent efforts to adapt CRISPR/Cas systems for protein detection with immunoassays, these methods typically achieved sensitivity only in the femtomolar to picomolar range, underscoring the need for enhanced detection capabilities. To address this, we developed CRISPR-AMPED, an innovative CRISPR/Cas-based immunoassay enhanced by magnetic proximity extension and detection. This approach combines proximity extension assay (PEA) with magnetic beads that converts protein into DNA barcodes for quantification with effective washing steps to minimize non-specific binding and hybridization, therefore reducing background noise and increasing detection sensitivity. The resulting DNA barcodes are then detected through isothermal nucleic acid amplification testing (NAAT) using recombinase polymerase amplification (RPA) coupled with the CRISPR/Cas12a system, replacing the traditional PCR. This integration eliminates the need for thermocycling and bulky equipment, reduces amplification time, and provides simultaneous target and signal amplification, thereby significantly boosting detection sensitivity. CRISPR-AMPED achieves attomolar level sensitivity, surpassing ELISA by over three orders of magnitude and outperforming existing CRISPR/Cas-based detection systems. Additionally, our smartphone-based detection device demonstrates potential for point-of-care applications, and the digital format extends dynamic range and enhances quantitation precision. We believe CRISPR-AMPED represents a significant advancement in the field of protein detection.
Residence Times and Legacy of Biogenic Carbon in Ocean Reservoirs
Authors: Visser André W.
Published: September 2024

Quantifying the sequestration potential of biologically driven carbon fluxes in the ocean depends critically on residence times – how long carbon remains stored in reservoirs before being re-exposed to the atmosphere. Simple mass balance provides estimates for many of the major ocean biogenic carbon reservoirs. For vegetated coastal ecosystems (mangroves, sea grass meadows, salt marshes) that globally store 20 to 40 PgC, this is 200 to 500 years, while for the biological carbon pump, a reservoir of about 2000 PgC, it is between 200 to 800 years. Over these time scales respective reservoirs reach equilibrium if left undisturbed. Importantly, near equilibrium of ocean reservoirs during the Holocene can be inferred from the near steady atmospheric concentrations during this period. The degradation of habitats and the over-exploitation of living marine resources particularly in the last 75 years have tipped these natural processes out of balance, to the extent where many are now net emitters of legacy carbon back to the atmosphere. The analysis exposes a conflict between how sequestration is reported in oceanographic literature and how it is understood with regards durable carbon capture and storage. Nature-based solutions can be sought to address parts of the climate crisis, by improving ecosystem health and biodiversity, but are unlikely to provide solutions to carbon management on a scale commensurate with anthropogenic emissions. The best we can do is to limit net emissions by restoring what we can, and to ensure that future practices do not further tip ocean carbon reservoirs out of balance.

Significance Statement

Marine animals and plants maintain large pools of carbon in the ocean and coastal areas that have been laid down by generations past. This legacy carbon is continuously being recycled on time scales of 100s of years. Left undisturbed, as they were for most of the last 10000 years, these carbon pools tend to equilibrium; flux in equals flux out. Human activities such as over fishing and coastal construction, particularly in the past 75 years, have tipped these natural cycles out of balance to the extent where many pools are now net emitters of carbon. Conservation and restoration of marine habitats can bring these cycles back into balance but cannot be counted as offsetting fossil fuel emissions.
Nested inference of pairwise interactions from strain frequency data across settings and context-dependent mutual invasibilities
Authors: Le Thi Minh Thao , Madec Sten , Gjini Erida
Published: September 2024

How does coexistence of multiple species or pathogen strains arise in a system? What do coexistence patterns in time and space reveal about the epidemiology, ecology and evolution of such systems? Species abundance patterns often defy fully mechanistic explanations, especially when compositional variation and relative taxa abundances differ across settings. To link such variation to deterministic biological processes in acause-and-effectfashion requires modeling frameworks that are general in spirit, simple enough to understand and implement, and easily-applicable to multi-site data and their environmental gradients. Here, we propose a method to study variation in serotype frequencies ofStreptococcus pneumoniaebacteria across different geographic endemic settings. We use the framework of replicator dynamics, derived for a multi-strainSISmodel with co-colonization, to extract from 5 countries data fundamental parameters of inter-strain interactions, based on pairwise invasion fitnesses and their context-dependence. We integrate serotype frequency distributions and serotype identities (SAD + identities) collected from cross-sectional epidemiological surveys in Denmark, Nepal, Iran, Brazil and Mozambique. The snapshot observations are modelled under the same nested framework, by which we present a rationale for mechanistically linking and fitting multi-strain distributions across sites. Besides yielding an effective numerical estimation for more than 70% of the 92 × 92 (αij) in the pneumococcus serotype interaction matrix, this study offers a new proof-of-concept in the inference of random multi-species interactions. We show that in pneumococcus the vast majority of standardized interaction coefficients in co-colonization are concentrated near zero, with a few serotype pairs displaying extreme deviations from the mean. This statistical pattern confirms that the co-colonization coefficients in pneumococcus display a random probability distribution governed by a limited set of parameters, which are slightly modulated in each epidemiological context to shape coexistence. We also discuss key assumptions that must be carefully balanced in the estimation procedure. Our study paves the way for a deeper qualitative and quantitative understanding of the high-dimensional interaction landscape in multi-strain co-colonization systems.
Glia multitask to compensate for neighboring glial cell dysfunction
Authors: Beachum Allison N. , Salazar Gabriela , Nachbar Amelia , Krause Kevin , Klose Hannah , Meyer Kate , Maserejian Ariana , Ross Grace , Boyd Hannah , Weigel Thaddeus , Ambaye Lydia , Miller Hayes , Coutinho-Budd Jaeda
Published: September 2024

As glia mature, they undergo glial tiling to abut one another without invading each other’s boundaries. Upon the loss of the secreted neurotrophin Spätzle3 (Spz3),Drosophilacortex glia transform morphologically and lose their intricate interactions with neurons and surrounding glial subtypes. Here, we reveal that all neighboring glial cell types (astrocytes, ensheathing glia, and subperineurial glia) react by extending processes into the previous cortex glial territory to compensate for lost cortex glial function and reduce the buildup of neuronal debris. However, the loss of Spz3 alone is not sufficient for glia to cross their natural borders, as blocking CNS growth via nutrient-restriction blocks the aberrant infiltration induced by the loss of Spz3. Surprisingly, even when these neighboring glia divert their cellular resources beyond their typical borders to take on new compensatory roles, they are able to multitask to continue to preserve their own normal functions to maintain CNS homeostasis.

Graphical Abstract
BayesQuantify: an R package utilized to refine the ACMG/AMP criteria according to the Bayesian framework
Authors: Liu Sihan , Feng Xiaoshu , Bu Fengxiao
Published: September 2024

Improving the precision and accuracy of variant classification in clinical genetic testing involves further specification and stratification of the ACMG/AMP criteria. The Bayesian framework proposed by ClinGen has provided a mathematical foundation for evidence refinement, successfully quantifying, and extending the evidence strengths of PS1, PS4, PM5, and PP3/BP4. However, existing software and tools designed for quantifying the evidence strength and establishing corresponding thresholds to refine the ACMG/AMP criteria are lacking. To address this gap, we have developedBayesQuantify, an R package that aims to provide users with a unified resource for quantifying the strength of evidence for ACMG/AMP criteria using a naive Bayes classifier. By analyzing publicly available data, we demonstrateBayesQuantify’s capability to offer objective and consistent refinement of the ACMG/AMP evidence. BayesQuantify is available from GitHub athttps://github.com/liusihan/BayesQuantify.
Adipocyte progenitors are primary contributors to the disrupted epithelial niche that is sustained following abrupt mammary gland involution
Authors: Nuthalapati Prashant , Maiti Dibyo , Kwende Sharon A. , Maity Subhajit , Ning Dun , Joshi Purna A.
Published: September 2024

A short duration of breastfeeding is a risk factor for the development of high-mortality, postpartum, triple-negative breast cancer. The intrinsic properties of cancer-initiating epithelial cells that persist following breastfeeding cessation and mammary gland remodeling are poorly understood. Previously, we showed that Platelet-Derived Growth Factor Receptor alpha (PDGFRα)-expressing stromal mammary adipocyte progenitors (MAPs) differentiate into epithelial luminal progenitors in the adult gland. In the current study, we demonstrate that MAP-derived luminal progenitors retain a mesenchymal transcriptomic signature. In an abrupt involution model that mimics a short breastfeeding duration, MAP-derived luminal progenitors persist and dominate luminal epithelia, undergoing transcriptomic alterations that signify a distinct ferrometabolic state linked to cancer. Concurrently, MAPs adopt an alternative interferon-mediated profibrotic and invasive stromal fate. Our work uncovers MAPs to be the primary cellular origin of a pathological stromal and epithelial microenvironment following abrupt involution, presenting a potential therapeutic target in postpartum breast cancer.
Evolution is coupled with branching across many granularities of life
Authors: Douglas Jordan , Bouckaert Remco , Harris Simon C , Carter Charles W , Wills Peter R
Published: September 2024

Across many different scales of life, the rate of evolutionary change is often accelerated at the time when one lineage splits into two. The emergence of novel protein function can be facilitated by gene duplication (neofunctionalisation); rapid morphological change is often accompanied with speciation (punctuated equilibrium); and the establishment of cultural identity is frequently driven by sociopolitical division (schismogenesis). In each case, the change resists re-homogenisation; promoting assortment into distinct lineages that are susceptible to different selective pressures, leading to rapid divergence. The traditional gradualistic view of evolution struggles to detect this phenomenon. We have devised a probabilistic framework that constructs phylogenies, tests hypotheses, and improves divergence time estimation when evolutionary bursts are present. As well as assigning a clock rate of gradual evolution to each branch of a tree, this model also assigns a spike of abrupt change, and independently estimates the contributions arising from each process. We provide evidence of abrupt evolution at the time of branching for proteins (aminoacyl-tRNA synthetases), animal morphologies (cephalopods), and human languages (Indo-European). These three cases provide unique insights: for aminoacyl-tRNA synthetases, the trees are substantially different from those obtained under gradualist models; Cephalopod morphologies are found to evolve almost exclusively through abrupt shifts; and Indo-European dispersal is estimated to have started around 6000 BCE, corroborating the recently proposed hybrid explanation. This work demonstrates a robust means for detecting burst-like processes, and advances our understanding of the link between evolutionary change and branching events. Our open-source code is available under a GPL license.
Mitochondrial complex I deficiency occurs in skeletal muscle of a subgroup of individuals with Parkinson’s disease
Authors: Kverneng Simon Ulvenes , Stige Kjersti Eline , Berven Haakon , Mostafavi Sepideh , Lundervold Katarina , Brischigliaro Michele , Brakedal Brage , Skeie Geir Olve , Flønes Irene Hana , Toker Lilah , Fernandez-Vizarra Erika , Skogseth Ragnhild Eide , Haugarvoll Kristoffer , Torres Cleuren Yamila N , Dölle Christian , Nido Gonzalo S , Tzoulis Charalampos
Published: September 2024

Widespread neuronal complex I (CI) deficiency was recently reported to be a characteristic in a subgroup of individuals with idiopathic Parkinson’s disease (PD). Here, we sought to determine whether a CI deficient subgroup could be discerned using clinically accessible muscle biopsy. Vastus lateralis needle biopsies were collected from 83 individuals with PD and 29 neurologically healthy controls and analyzed by immunohistochemistry for complexes I and IV, cytochrome c oxidase/succinate dehydrogenase (COX/SDH) histochemistry, and spectrophotometric activity assays of complexes I-IV. Mitochondrial DNA (mtDNA) copy number, deletions, and point variation were analyzed in single muscle fibers and bulk biopsy samples. PD muscle exhibited reduced CI activity at the group level, with 9% of cases falling below two standard deviations of the control group. This deficiency was not associated with mtDNA abnormalities. Our findings support the existence of a PD subpopulation characterized by CI pathology and suggest that stratification by extra-neural mitochondrial dysfunction may be informative for selecting individuals for clinical trials.
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

Embryonic 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

Adherens 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

Pseudomonas 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

Trueperella 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.

Importance

Trueperella 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

SAF-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

Phosphoinositides (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

The 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

Background

The 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.

Methods

A 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.

Findings

Up 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.

Interpretation

The 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

Like 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.
de Sitter vacua in
O(d,d)
invariant cosmology
Authors: Liu Yang , Padilla Antonio , Saffin Paul M. , Smith Robert G. C.
Published: September 2024

We perform a thorough analysis of de Sitter solutions in O(d,d) invariant cosmologies. Starting with a homogeneous and isotropic framework we examine conditions for the existence of such solutions to the vacuum field equations, nonperturbative in α′ in both the string frame and the Einstein frame. We elucidate the nature of the instability in the string frame vacuum. For the Einstein frame, we demonstrate that the de Sitter solutions cannot be eternal. We then extend our analysis to include Bianchi I universes where the O(d,d) symmetry includes scale factor exchange as well as scale factor duality. We show how the theory can be extended to the anisotropic case so that it admits de Sitter solutions, noting the crucial role played by the O(d,d) symmetry in satisfying any additional constraints.

Published by the American Physical Society
2024
Entanglement Autodistillation from Particle Decays
Authors: Aguilar-Saavedra J. A. , Casas J. A.
Published: September 2024

Particle decays do not constitute a spin “measurement” in the quantum-mechanical sense but still modify the spin state, in particular, for an entangled system. We show that for a spin-entangled pair of particles the entanglement of the system can increase after the decay of one particle. This unique phenomenon has no equivalent for stable particles and could be observable in top pair production at a high-energy polarized e+e− collider.

Published by the American Physical Society
2024
Efficient percolation simulations for lossy photonic fusion networks
Authors: Löbl Matthias C. , Paesani Stefano , Sørensen Anders S.
Published: September 2024

The study of percolation phenomena has various applications ranging from social networks or materials science to quantum information. The most common percolation models are bond or site percolation for which the Newman-Ziff algorithm enables an efficient simulation. Here, we consider several nonstandard percolation models that appear in the context of measurement-based photonic quantum computing with so-called graph states and fusion networks. The associated percolation thresholds determine the tolerance to photon loss in such systems and we develop modifications of the Newman-Ziff algorithm to efficiently perform the corresponding percolation simulations. We demonstrate our algorithms by using them to characterize exemplary fusion networks and graph states.

Published by the American Physical Society
2024
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
Machine-learning classification with additivity and diverse multifractal pathways in multiplicativity
Authors: Mangalam Madhur , Seckler Henrik , Kelty-Stephen Damian G.
Published: September 2024

Evidence of multifractal structures has spread to a wider set of physiological time series supporting the intricate interplay of biological and psychological functioning. These dynamics manifest as random multiplicative cascades, embodying nonlinear relationships characterized by recurring division, branching, and aggregation processes implicating noise across successive generations. This investigation focuses on how well the diversity of multifractal properties can be specific to the type of cascade relationship between generation (i.e., multiplicative, additive, or a mixture) as well as to the type of noise (i.e., including additive white Gaussian noise, fractional Gaussian noise, and various amalgamations) among 15 distinct types of binomial cascade processes. Cross-correlation analysis of multifractal spectral features confirms that these features capture nuanced aspects of cascading processes with minimal redundancy. Principal component analysis using 13 distinct multifractal spectral features shows that different cascade processes can manifest multifractal evidence of nonlinearity for distinct reasons. This transparency of multifractal spectral features to underlying cascade dynamics becomes less amenable to machine-learning strategies. Fully connected neural networks struggled to classify the 15 distinct types of cascade processes based on the respective multifractal spectral features (45.5% accuracy) yet demonstrated improved accuracy when addressing single categories of cross-generation relationships, that is, additive (91.6%), multiplicative (75.4%), or additomultiplicative (70.6%). While traditional principal component analysis reveals distinct loadings attributed to individual noise processes, multiplicative relationships between generations effectively make the constituent noise processes less discernible to neural networks. Neural networks may lack sufficient hierarchical depth required to effectively distinguish among nonadditive cascading processes, recommending either elaborating multifractal geometry or using alternate architectures for machine-learning classification of cascades with multiplicative relationships.

Published by the American Physical Society
2024
μ-Chlorido-bis{[1-benzyl-3-(2,4,6-trimethylphenyl)imidazol-2-ylidene-κC]silver(I)} chloride 1,2-dichloroethane hemisolvate
Authors: Malek Kotiba , Arumugam Kuppuswamy
Published: September 2024

The title compound, [Ag2(C19H20N2)4]Cl·0.5C2H4Cl2, can be readily generated by treatment of (1-benzyl-3-(2,4,6-trimethylphenyl)imidazolium chloride with sodium bis(trimethylsilyl)amide followed by silver chloride. The molecular structure of the compound was confirmed using NMR spectroscopy and single-crystal X-ray diffraction analysis. The crystal structure of the title compound at 110 K has monoclinic (P21/c) symmetry. The represented silver compound is of interest with respect to antibacterial properties and the structure displays a series of weak intermolecular hydrogen-bonding interactions with the chloride counter-anion.
“The seven principles of universal design of research”: how to increase user diversity in mainstream research
Authors: Berget Gerd , Kvikne Birgit
Published: September 2024

Purpose

User 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/approach

The 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.

Findings

Extensive 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/implications

This study contributes with methodological approaches to enhance inclusion of all types of participants in mainstream research.

Originality/value

The 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.