bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell cycle-driven transcriptome maturation confers multilineage competence to cardiopharyngeal progenitors
Authors: Bernadskaya Yelena Y. , Kuan Ariel , Tjärnberg Andreas , Brandenburg Jonas , Zheng Ping , Wiechecki Keira , Kaplan Nicole , Failla Margaux , Bikou Maria , Madilian Oliver , Wang Wei , Christiaen Lionel
Published: July 2024

During development, stem and progenitor cells divide and transition through germ layer- and lineage-specific multipotent states to generate the diverse cell types that compose an animal. Defined changes in biomolecular composition underlie the progressive loss of potency and acquisition of lineage-specific characteristics. For example, multipotent cardiopharyngeal progenitors display multilineage transcriptional priming, whereby both the cardiac and pharyngeal muscle programs are partially active and coexist in the same progenitor cells, while their daughter cells engage in a cardiac or pharyngeal muscle differentiation path only after cell division. Here, using the tunicate Ciona, we studied the acquisition of multilineage competence and the coupling between fate decisions and cell cycle progression. We showed that multipotent cardiopharyngeal progenitors acquire the competence to produce distinctTbx1/10(+) and (−) daughter cells shortly before mitosis, which is necessary forTbx1/10activation. By combining transgene-based sample barcoding with single cell RNA-seq (scRNA-seq), we uncovered transcriptome-wide dynamics in migrating cardiopharyngeal progenitors as cells progress through G1, S and G2 phases. We termed this process “transcriptome maturation”, and identified candidate “mature genes”, including the Rho GAP-coding geneDepdc1, which peak in late G2. Functional assays indicated that transcriptome maturation fosters cardiopharyngeal competence, in part through multilineage priming and proper oriented and asymmetric division that influences subsequent fate decisions, illustrating the concept of “behavioral competence”. Both classic feedforward circuits and coupling with cell cycle progression drive transcriptome maturation, uncovering distinct levels of coupling between cell cycle progression and fateful molecular transitions. We propose that coupling competence and fate decision with the G2 and G1 phases, respectively, ensures the timely deployment of lineage-specific programs.
Sleep Fragmentation Modulates the Neurophysiological Correlates of Cognitive Fatigue
Authors: Benkirane Oumaïma , Simor Peter , Mairesse Olivier , Peigneux Philippe
Published: July 2024

Cognitive fatigue (CF) is a critical factor affecting performance and well-being. It can be altered in suboptimal sleep quality conditions, e.g., in patients suffering from obstructive sleep apnea who experience both intermittent hypoxia and sleep fragmentation (SF). Understanding the neurophysiological basis of SF in healthy individuals can provide insights to improve cognitive functioning in disrupted sleep conditions. In this electroencephalographical (EEG) study, we investigated in 16 healthy young participants the impact of experimentally induced SF on the neurophysiological correlates of CF measured before, during, and after practice on the TloadDback, a working memory task tailored to each individual’s maximal cognitive resources. Participants spent two times three consecutive nights in the laboratory, once in an undisrupted sleep (UdS) condition and once in a SF condition induced by non-awakening auditory stimulations, counterbalanced, and performed the TloadDback task both in a high (HCL) and a low (LCL) cognitive load condition. EEG activity was recorded during wakefulness in the 5-minutes resting state immediately before and after, as well as during the 16-minutes of the TloadDback task practice. In the high cognitive load under sleep fragmentation (HCL/SF) condition, high beta power increased during the TloadDback indicating heightened cognitive effort, and beta and alpha power increased in the post- vs. pre task resting state, suggesting a relaxation rebound. In the low cognitive load/undisturbed sleep (LCL/UdS) condition, low beta activity increased suggesting a relaxed focus, as well as mid beta activity associated with active thinking. These findings highlight the dynamic impact of SF on the neurophysiological correlates of CF and underscore the importance of sleep quality and continuity to maintain optimal cognitive functioning.
Solvatochromic reporter to image plasma membrane order leaflet by leaflet reveals a highly asymmetric bilayer locally modulated by transbilayer interactions
Authors: Patra Chandrima , Samad Muzamil , van Zanten Thomas , Singh Maninder , Vishwakarma Ram A , Singh Parvinder Pal , Mayor Satyajit
Published: July 2024

The plasma membrane (PM) of cells is an asymmetric bilayer composed of a complex mixture of lipids and proteins. The emergent biophysical properties of its leaflets and their consequence on cellular function remain unexplored owing to the limitation in available probes. In this manuscript, we report on the design and characterisation of a PM-localised solvatochromic probe, C3L, based on the established reporter Laurdan. C3L is retained at the inner-leaflet due to flippase and scramblase activity, as determined by Bovine Serum Albumin-based back exchange experiments. By measuring the Generalized Polarization of C3L we are able to determine membrane order, leaflet-by-leaflet at the PM. Our results reveal that the PM is made of a tightly-packed outer/exofacial-leaflet in contrast to a disordered inner/cytoplasmic-leaflet. This differential packing is established by the maintenance of lipid asymmetry, the presence of specific lipids, Sphingomyelin in the outer-leaflet and Phosphatidylserine at the inner-leaflet, and exaggerated during mesenchymal to epithelial transition. We find spatial signatures of local modulation of the inner leaflet by protein scaffolds which promote trans-bilayer coupling of lipids. C3L thus informs on steady state lipid organisation at the asymmetric membrane while allowing further exploration of spatial regulation of lateral heterogeneity at each leaflet.
Parabrachial CGRP neurons modulates conditioned active defensive behavior under a naturalistic threat
Authors: Pyeon Gyeong Hee , Cho Hyewon , Chung Byung Min , Choi June-Seek , Jo Yong Sang
Published: July 2024

Recent studies suggest that calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) represent aversive information and signal a general alarm to the forebrain. If CGRP neurons serve as a true general alarm, activation of CGRP neurons can trigger either freezing or fleeing defensive behavior, depending on the circumstances. However, the majority of previous findings have reported that CGRP neurons modulate only freezing behavior. Thus, the present study examined the role of CGRP neurons in active defensive behavior, using a predator-like robot programmed to chase mice in fear conditioning. Our electrophysiological results showed that CGRP neurons encoded the intensity of various unconditioned stimuli (US) through different firing durations and amplitudes. Optogenetic and behavioral results revealed that activation of CGRP neurons in the presence of the chasing robot intensified fear memory and significantly elevated conditioned fleeing behavior during recall of an aversive memory. Animals with inactivated CGRP neurons exhibited significantly low levels of fleeing behavior even when the robot was set to be more threatening during conditioning. Our findings expand the known role of CGRP neurons in the PBN as a crucial part of the brain’s alarm system, showing they can regulate not only passive but also active defensive behaviors.
Rapid and memory-efficient analysis and quality control of large spatial transcriptomics datasets
Authors: Kӧvér Bence , Vigilante Alessandra
Published: July 2024

The 10x Visium spatial transcriptomics platform has been widely adopted due to its established analysis pipelines, robust community support, and manageable data output. However, technologies like 10x Visium have the limitation of being low-resolution, and recently spatial transcriptomics platforms with subcellular resolution have proliferated. Such high-resolution datasets pose significant computational challenges for data analysis, with regards to memory requirement and processing speed. Here, we introduce Pseudovisium, a Python-based framework designed to facilitate the rapid and memory-efficient analysis, quality control and interoperability of high-resolution spatial transcriptomics data. This is achieved by mimicking the structure of 10x Visium through hexagonal binning of transcripts. Analysis of 47 publicly available datasets concluded that Pseudovisium increased data processing speed and reduced dataset size by more than an order of magnitude. At the same time, it preserved key biological signatures, such as spatially variable genes, enriched gene sets, cell populations, and gene-gene correlations. The Pseudovisium framework allows accurate simulation of Visium experiments, facilitating comparisons between technologies and guiding experimental design. Specifically, we found high concordance between Pseudovisium (derived from Xenium or CosMx) and Visium data from consecutive tissue slices. We further demonstrate Pseudovisium’s utility by performing rapid quality control on large-scale datasets from Xenium, CosMx, and MERSCOPE platforms, identifying similar replicates, as well as potentially low-quality samples and probes. The common data format provided by Pseudovisium also enabled direct comparison of metrics across 6 spatial transcriptomics platforms and 59 datasets, revealing differences in transcript capture efficiency and quality. Lastly, Pseudovisium allows merging of datasets for joint analysis, as demonstrated by the identification of shared cell clusters and enriched gene sets in the mouse brain using data from multiple spatial platforms. By lowering the computational requirements and enhancing interoperability and reusability of spatial transcriptomics data, Pseudovisium democratizes analysis for wet-lab scientists and enables novel biological insights.
Virus-induced paraspeckle-like condensates are essential hubs for gene expression and their formation drives genomic instability
Authors: Harper Katherine L. , Harrington Elena , Hayward Connor , Wongwiwat Wiyada , White Robert E , Whitehouse Adrian
Published: July 2024

The nucleus is a highly structured environment containing multiple membrane-less bodies formed through liquid-liquid phase separation. These provide spatial separation and concentration of specific biomolecules enabling efficient and discrete processes to occur which regulate gene expression. One such nuclear body, paraspeckles, are comprised of multiple paraspeckle proteins (PSPs) built around the architectural RNA,NEAT1_2. Paraspeckle function is yet to be fully elucidated but has been implicated in a variety of developmental and disease scenarios. We demonstrate that Kaposi’s sarcoma-associated herpesvirus (KSHV) drives formation of structurally distinct paraspeckles with a dramatically increased size and altered protein composition that are essential for productive lytic replication. We highlight these virus-induced paraspeckle-like structures form adjacent to virus replication centres, functioning as RNA processing hubs for both viral and cellular transcripts during infection. Notably, we reveal that PSP sequestration into virus-induced paraspeckle-like structures results in increased genome instability during both KSHV and Epstein Barr virus (EBV) infection, implicating their formation in virus-mediated tumorigenesis.
What scRNA sequencing taught us about MGMT expression in glioblastoma
Authors: Alnahhas Iyad , Khan Mehak , Shi Wenyin
Published: July 2024

Introduction

The promoter methylation status of O-6-methylguanine-DNA methyltransferase (MGMTp) is an established predictive and prognostic marker in GBM. Previous studies showed that the expression of MGMT based on immunohistochemistry was variable and lacked association with survival. This in part is because non-tumor cells including endothelial cells and macrophages express MGMT. Advanced technologies such as single-cell RNA (scRNA) sequencing have helped to elucidate the cellular composition of cancer and its microenvironment. scRNA sequencing allows to assess gene expression level in tumor cells specifically.

Methods

We used publicly available data from two recent GBM scRNA studies that included MGMTp methylation status data for patients to explore and uncover details about MGMT expression at the single-cell level: CPTAC (13 primary samples) and Neftel (20 primary samples).

Results

In the CPTAC study, MGMT expression ranged from 0.19%-1.43% in the MGMTp methylated group (median 0.82%), and from 2.17%-28.36% in the MGMTp unmethylated group (median 5.7%). It therefore appears that 2% is a reasonable expression cutoff to predict the MGMTp methylation status based on scRNA data. In the Neftel study, MGMT expression ranged from 0-1.26% in the MGMTp methylated group (median 0.59%), and from 0.3-27.67% in the MGMTp unmethylated group (median 12.44%). Three unmethylated samples (out of 16) did not follow the 2% rule. It remains unclear if this is due to technical inaccuracies as the Neftel paper did not specify the method used to detect MGMTp methylation or even mere typos. Alternatively, could it be that truly MGMTp unmethylated samples can have low MGMT expression? Could this explain why some unmethylated MGMTp GBM patients surpass the expected survival? Interestingly, gene set enrichment analysis shows that MGMT expressing cells are enriched with mesenchymal genes, whereas MGMT negative cells are enriched with proneural genes.

Conclusion

Fewer than 2% of GBM cells express MGMT when MGMTp is methylated.
RORγt-dependent antigen-presenting cells direct regulatory T cell-mediated tolerance to food antigen
Authors: Fu Liuhui , Upadhyay Rabi , Pokrovskii Maria , Romero-Meza Gabriela , Griesemer Adam , Littman Dan R.
Published: July 2024

The gastrointestinal tract is continuously exposed to foreign antigens in food and commensal microbes with potential to induce adaptive immune responses. Peripherally induced T regulatory (pTreg) cells are essential for mitigating inflammatory responses to these agents1–4. While RORγt+antigen-presenting cells (RORγt-APCs) were shown to program gut microbiota-specific pTregs5–7, understanding of their characteristics remains incomplete, and the APC subset responsible for food tolerance has remained elusive. Here, we demonstrate that RORγt-APCs are similarly required for differentiation of food antigen-specific pTregs and establishment of oral tolerance. The ability of these cells to direct both food and microbiota-specific pTreg cell differentiation is contingent on expression of RORγt and on a unique cis-regulatory element within theRorcgene locus (Rorc(t)+7kb). Absent this +7kb element, there was a notable increase in food antigen-specific T helper 2 (Th2) cells in lieu of pTregs, leading to compromised tolerance in a mouse asthma model. By employing single-cell analyses across these models, as well as freshly resected mesenteric lymph nodes from a human organ donor, we identified a rare subset of evolutionarily conserved APCs that are dependent on RORγt, uniquely express the Prdm16 transcription factor, and are endowed with essential mediators for inducing pTreg cell differentiation. Our findings suggest that a better understanding of how RORγt-APCs develop and how they regulate T cell responses to food and microbial antigens could offer new insights into developing therapeutic strategies for autoimmune and allergic diseases as well as organ transplant tolerance.
Preventing plasmid multimer formation in commonly used synthetic biology plasmids
Authors: Vaisbourd Elizabeth , Bren Anat , Alon Uri , Glass David S.
Published: July 2024

Plasmids are an essential tool for basic research and biotechnology applications. To optimize plasmid-based circuits, it is crucial to control plasmid integrity, including the formation of plasmid multimers. Multimers are tandem repeats of entire plasmids formed during replication by failed dimer resolution. Multimers can affect the behavior of synthetic circuits, especially ones that include DNA-editing enzymes. However, occurrence of multimers is not commonly assayed. Here we survey four commonly used plasmid backbones for occurrence of multimers in cloning (JM109) and wild-type (MG1655) strains. We find that multimers occur appreciably only in MG1655, with the fraction of plasmids existing as multimers increasing with both plasmid copy number and culture passaging. In contrast, introduction of multimers into JM109 can produce strains containing only multimers. We present an MG1655ΔrecAsingle-locus knockout that avoids multimer production. These results can aid synthetic biologists in improving design and reliability of plasmid-based circuits.
Linking metastatic potential and viscoelastic properties of breast cancer spheroids via dynamic compression and relaxation in microfluidics
Authors: Tavasso Margherita , Bordoloi Ankur D. , Tanré Elsa , Dekker Sanne A. H. , Garbin Valeria , Boukany Pouyan E.
Published: July 2024

The growth and invasion of solid tumors are associated with changes in their viscoelastic properties, influenced by both internal cellular factors and physical forces in the tumor microenvironment. Due to the lack of a comprehensive investigation of tumor tissue viscoelasticity, the relationship between such physical properties and cancer malignancy remains poorly understood. Here, the viscoelastic properties of breast cancer spheroids, 3D (in vitro) tumor models, are studied in relation to their metastatic potentials by imposing controlled, dynamic compression within a microfluidic constriction, and subsequently monitoring the relaxation of the imposed deformation. By adopting a modified Maxwell model to extract viscoelastic properties from the compression data, the benign (MCF-10A) spheroids are found to have higher bulk elastic modulus and viscosity compared to malignant spheroids (MCF-7 and MDA-MB-231). The relaxation is characterized by two timescales, captured by a double exponential fitting function, which reveals a similar fast rebound for MCF-7 and MCF-10A. Both the malignant spheroids exhibit similar long-term relaxation and display residual deformation. However, they differ significantly in morphology, particularly in intercellular movements. These differences between malignant spheroids are demonstrated to be linked to their cytoskeletal organization, by microscopic imaging of F-actin within the spheroids, together with cell-cell adhesion strength.
Cell-Surface RNA Associates with Heparan Sulfate and RNA-Binding Proteins to Modulate Receptor-Ligand Interactions
Authors: Li Zeshi , Joshi Bhagyashree S. , Wijdeven Ruud H. , Santos-Barriopedro Irene , Shademan Milad , Bos Eric , Tanenbaum Marvin , Boons Geert-Jan , Sharp Thomas , Vermeulen Michiel , Raz Vered , Joo Chirlmin
Published: July 2024

Recent discoveries have shown the presence of RNA molecules on the cell surface, defying the traditional view that RNA only functions intracellularly. However, it is not well understood how cell-surface RNA (csRNA) is stably present on the plasma membrane and what functions it performs on the cell surface. By exploiting the RNA-sensing ability of TLR7 as a specific recombinant probe to detect csRNA and coupling it with a genome-wide CRISPR-Cas9-knockout screening to identify genes essential for csRNA presentation on cells, we identified heparan sulfate (HS) as a crucial factor for RNA presentation on cells. Using the TLR7 binding probe, cell surface proximity labelling revealed that csRNA associates mechanistically with a plethora of RNA-binding proteins, and these interactions are crucial for csRNA presentation. Moreover, csRNA modulates receptor-ligand interactions between poliovirus receptor (PVR) and killer cell immunoglobulin-like receptor 2DL5 (KIR2DL5) by acting as a co-binder, recruiting the latter to cell surface. We provide a mechanistic understanding of csRNA presentation and unveil a new layer of complexity in the csRNA-dictated regulation of cell surface receptor-ligand interactions.
Two new species ofMylochromisspecies (Cichlidae) from Lake Malawi, Africa
Authors: Turner George F.
Published: July 2024

Two new species ofMylochromisRegan 1920 are described from specimens collected on shallow rocky habitats on the northwestern coast of Lake Malawi. The generic designation is based on their prominent oblique striped pattern and lack of any of the unique features of other Malawi cichlid genera with this pattern.Mylochromis rotundussp. nov. is distinguished from most congeneric species by its relatively deep, rounded body and lack of enlarged pharyngeal teeth. It is further distinguished fromM. semipalatusandM. melanonotus(if they are different species) by its relatively shorter snout.Mylochromis durophagussp. nov. is distinguished from most congeneric species by its strongly molarised pharyngeal dentition. It differs fromMylochromis molain having a shorter snout, less acutely pointed head profile, deeper body and in having a more continuous oblique stripe.Mylochromis durophagushas a much less steep head profile thanMylochromis anaphyrmusorMylochromis sphaerodon. It is suggested thatMylochromis rotunduswas previously identified informally asMylochromis sp. ‘mollis north’, andM. durophagusasM. sp. ‘mollis chitande’. Lectotypes are designated for comparator speciesMylochromis sphaerodonandMylochromis subocularis.
Genetic Architecture and Analysis Practices of Circulating Metabolites in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program
Authors: Wang Nannan , Ockerman Franklin P. , Zhou Laura Y. , Grove Megan L. , Alkis Taryn , Barnard John , Bowler Russell P. , Clish Clary B. , Chung Shinhye , Drzymalla Emily , Evans Anne M. , Franceschini Nora , Gerszten Robert E. , Gillman Madeline G. , Hutton Scott R. , Kelly Rachel S. , Kooperberg Charles , Larson Martin G. , Lasky-Su Jessica , Meyers Deborah A. , Woodruff Prescott G. , Reiner Alexander P. , Rich Stephen S. , Rotter Jerome I. , Silverman Edwin K. , Ramachandran Vasan S. , Weiss Scott T. , Wong Kari E. , Wood Alexis C. , Wu Lang ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Yarden Ronit , Blackwell Thomas W. , Smith Albert V. , Chen Han , Raffield Laura M. , Yu Bing
Published: July 2024

Circulating metabolite levels partly reflect the state of human health and diseases and can be impacted by genetic determinants. Hundreds of loci associated with circulating metabolites have been identified; however, most findings focus on predominantly European ancestry or single-study analyses. Leveraging the rich metabolomics resources generated by the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program, we harmonized and accessibly cataloged 1,729 circulating metabolites among 25,058 ancestrally diverse samples. We provided a set of reasonable strategies for outlier and imputation handling to process metabolite data. Following the practical analysis framework, we further performed a genome-wide association analysis on 1,135 selected metabolites using whole genome sequencing data from 16,359 individuals passing the quality control filters, and discovered 1,778 independent loci associated with 667 metabolites. Among 108 novel locus-metabolite pairs, we detected not only novel loci within previously implicated metabolite associated genes but also novel genes (such asGAB3andVSIG4located in the X chromosome) that have putative roles in metabolic regulation. In the sex-stratified analysis, we revealed 85 independent locus-metabolite pairs with evidence of sexual dimorphism, including well-known metabolic genes such asFADS2,D2HGDH,SUGP1,UTG2B17, strongly supporting the importance of exploring sex difference in the human metabolome. Taken together, our study depicted the genetic contribution to circulating metabolite levels, providing additional insight into the understanding of human health.
An ultraconserved snoRNA-like element in long noncoding RNACRNDEpromotes ribosome biogenesis and cell proliferation
Authors: Lee Jong-Sun , Dan Tu , Zhang He , Cheng Yujing , Rehfeld Frederick , Brugarolas James , Mendell Joshua T.
Published: July 2024

Cancer cells frequently upregulate ribosome production to support tumorigenesis. While small nucleolar RNAs (snoRNAs) are critical for ribosome biogenesis, the roles of other classes of noncoding RNAs in this process remain largely unknown. Here we performed CRISPRi screens to identify essential long noncoding RNAs (lncRNAs) in renal cell carcinoma (RCC) cells. This revealed that an alternatively-spliced isoform of lncRNAColorectal Neoplasia Differentially Expressedcontaining an ultraconserved element (UCE), referred to asCRNDEUCE, is required for RCC cell proliferation.CRNDEUCElocalizes to the nucleolus and promotes 60S ribosomal subunit biogenesis. The UCE ofCRNDEfunctions as an unprocessed C/D box snoRNA that directly interacts with ribosomal RNA precursors. This facilitates delivery of eIF6, a key 60S biogenesis factor, which binds toCRNDEUCEthrough a sequence element adjacent to the UCE. These findings highlight the functional versatility of snoRNA sequences and expand the known mechanisms through which noncoding RNAs orchestrate ribosome biogenesis.
Diet of Andean leaf-eared mice (Phyllotis) living at extreme elevations on Atacama volcanoes: insights from metagenomics, DNA metabarcoding, and stable isotopes
Authors: Quezada-Romegialli Claudio , Quiroga-Carmona Marcial , D’Elía Guillermo , Harrod Chris , Storz Jay F.
Published: July 2024

On the flanks of >6000 m Andean volcanoes that tower over the Atacama Desert, leaf-eared mice (Phyllotis vaccarum) live at extreme elevations that surpass known vegetation limits. What the mice eat in these barren, hyperarid environments has been the subject of much speculation. According to the arthropod fallout hypothesis, sustenance is provided by windblown insects that accumulate in snowdrifts (‘aolian deposits’). It is also possible that mice feed on saxicolous lichen or forms of cryptic vegetation that have yet to be discovered at such high elevations. We tested hypotheses about the diet of mice living at extreme elevations on Atacama volcanoes by combining metagenomic and DNA metabarcoding analyses of gut contents with stable-isotope analyses of mouse tissues. Genomic analyses of contents of the gastrointestinal tract of a live-captured mouse from the 6739 m summit of Volcán Llullaillaco revealed evidence for an opportunistic but purely herbivorous diet, including lichens. Although we found no evidence of animal DNA in gut contents of the summit mouse, stable isotope data indicate that mice native to elevations at or near vegetation limits (∼5100 m) include a larger fraction of animal prey in their diet than mice from lower elevations. Some plant species detected in the gut contents of the summit mouse are known to exist at lower elevations at the base of the volcano and in the surrounding Altiplano, suggesting that such plants may occur at higher elevations beneath the snowpack or in other cryptic microhabitats.
“They don’t know how to live with a child with these conditions, they can’t understand…”: The lived experiences of parenting a child with a genetic neurodevelopmental disorder
Authors: Low Karen J. , Treneman-Evans Georgia , Wynn Sarah L ,   GenROC Study Consortium, Ingram Jenny
Published: July 2024

Background

A genetic neurodevelopmental diagnosis (GND) impacts all aspects of a child and family’s life. GNDs are rare; most have limited natural history data. We aimed to understand parents’ experiences around data acquisition about their child’s GNDs which can help inform clinical practice.

Design and participants

This analysis is part of the UK multicentre GenROC study. We conducted 17 semi-structured interviews with parents of children with GNDs (aged 0-15 years). Data were analysed following the principles of thematic analysis.

Results

Five main themes are reported:

Impact on the family around a genetic diagnosis

Distress results from diagnosis wait, the act of receiving it, associated irreversibility (loss of hope) and family/reproductive implications.

GNDs and Uncertainty: Lack of data and rareness causes uncertainty for the future.

Relationships with health professionals

Positive where parents are empowered and feel part of the team; Negative –parents feel not heard/believed or lack of expertise/understanding.

Parent mental health

GNDs can be a significant burden to family life. Need for advocating for services is a negative impact. Isolation through rareness is a factor – this can be helped by support networks which mostly consist of gene specific Facebook groups.

Development of positive parent identities

including that of advocate, professional and educator.

Conclusions

GNDs represent a major challenge for families, clinicians and service providers. Distressed parents are struggling to cope with challenges and suffer poor mental health. Psychosocial support, better signposting, and health professional education may help.

Patient contribution

PPI group contributed to topic guide development and commented on findings.
Instability of high polygenic risk classification and mitigation by integrative scoring
Authors: Misra Anika , Truong Buu , Urbut Sarah M. , Sui Yang , Fahed Akl C. , Smoller Jordan W. , Patel Aniruddh P. , Natarajan Pradeep
Published: July 2024

Polygenic risk scores (PRS) continue to improve with novel methods and expanding genome-wide association studies. Healthcare and commercial laboratories are increasingly deploying PRS reports to patients, but it is unknown how the classification of high polygenic risk changes across individual PRS. Here, we assessed association and classification performance of cataloged PRS for three complex traits. We chronologically ordered all trait-related publications (Pubn) and identified the single PRS Best(Pubn) for each Pubnthat had the strongest association with the target outcome. While each Best(Pubn) demonstrated generally consistent population-level strengths of associations, classification of individuals in the top 10% of each Best(Pubn) distribution varied widely. Using the PRSmix framework, which integrates information across several PRS to improve prediction, we generate corresponding ChronoAdd(Pubn) scores for each Pubnthat combine all polygenic scores from all publications up to and including Pubn. When compared with Best(Pubn), ChronoAdd(Pubn) scores demonstrated more consistent high-risk classification amongst themselves. This integrative scoring approach provides stable and reliable classification of high-risk individuals, and is an adaptable framework into which new scores can be incorporated as they are introduced, integrating easily with current PRS implementation strategies.
TORC1-dependent control of fission yeast cohesin
Authors: Besson Dorian , Vaur Sabine , Vazquez Stéphanie , Tournier Sylvie , Gachet Yannick , Birot Adrien , Claverol Stéphane , Marston Adèle , Damdimopoulos Anastasios , Ekwall Karl , Javerzat Jean-Paul
Published: July 2024

The Target of Rapamycin Complex 1 (TORC1) integrates cellular cues and adapts cell growth and metabolism through substrate-specific phosphorylation. A genetic screen for suppressors of a conditional mutant of the cohesin loader Mis4 identified hypomorphic mutants of TORC1. Downregulation of TORC1 enhanced the binding of cohesin and its loader to their regular sites on chromosomes. In the context of impaired cohesin loading, TORC1 downregulation rescued chromosome segregation whereas upregulation had the opposite effect, suggesting environmental cues impinge on the robustness of chromosome segregation. TORC1 co-purified with cohesin from cellular extracts and the phosphorylation level of specific residues on Mis4 and cohesin were reduced in TORC1 mutants. Cohesin mutations mimicking the non-phosphorylated state mirrored the effects of TORC1 downregulation. Challenging cells with various conditions revealed that Mis4 and TORC1 regulate a common set of genes involved in the response to environmental changes. These genes are preferentially located far from centromeres and close to telomeres. We propose that cohesin is an effector of TORC1, orchestrating alterations in chromosome structure that facilitate cellular adaptation to environmental changes.
Defensive symbiont genotype distributions are linked to parasitoid attack networks
Authors: Wu Taoping , Rodrigues Anoushka A. , Fayle Tom , Henry Lee M.
Published: July 2024

Facultative symbionts are widespread in arthropods and can provide important services such as protection from natural enemies. Yet what shapes associations with defensive symbionts in nature remains unclear. Two hypotheses suggest that either interactions with antagonists, or host plants, may explain the prevalence of symbionts through shared selective pressures and routes of horizontal transmission. Here we investigate the factors driving similarities in theHamiltonella defensasymbiosis shared among host species within field collected aphid communities. We show that,Hamiltonella’sgenotype distribution strongly aligns with sharing the same parasitoids, rather than host plants, highlighting parasitoids as a key selective agent shaping the symbiosis across host species. Our data indicates parasitoid host-specificity drives the prevalence of specific aphid-Hamiltonellaassociations, suggesting defensive symbioses are maintained by the selective pressure imposed by dominant parasitoid species. These findings underscore the importance of interactions with natural enemies in explaining patterns of defensive symbiosis in nature.
CRISPR-inhibition screen for lncRNAs linked to melanoma growth and metastasis
Authors: Petroulia Stavroula , Hockemeyer Kathryn , Tiwari Shashank , Berico Pietro , Shamloo Sama , Banijamali Seyedeh Elnaz , Vega-Saenz de Miera Eleazar , Gong Yixiao , Thandapani Palaniraja , Wang Eric , Schulz Michael , Tsirigos Aristotelis , Osman Iman , Aifantis Ioannis , Imig Jochen
Published: July 2024

Melanoma being one of the most common and deadliest skin cancers, has been rising since the past decade. Patients at advanced stages of the disease have very poor prognoses, as opposed to at the earlier stages. Nowadays the standard-of-care of advanced melanoma is resection followed by immune checkpoint inhibition based immunotherapy. However, a substantial proportion of patients either do not respond or develop resistances. This underscores a need for novel approaches and therapeutic targets as well as a better understanding of the mechanisms of melanoma pathogenesis. Long non-coding RNAs (lncRNAs) comprise a poorly characterized class of functional players and promising targets in promoting malignancy. Certain lncRNAs have been identified to play integral roles in melanoma progression and drug resistances, however systematic screens to uncover novel functional lncRNAs are scarce. Here, we profile differentially expressed lncRNAs in patient derived short-term metastatic cultures and BRAF-MEK-inhibition resistant cells. We conduct a focused growth-related CRISPR-inhibition screen of overexpressed lncRNAs, validate and functionally characterize lncRNA hits with respect to cellular growth, invasive capacities and apoptosis in vitro as well as the transcriptomic impact of our lead candidate the novel lncRNA XLOC_030781. In sum, we extend the current knowledge of ncRNAs and their potential relevance on melanoma.

Significance

Previously considered as transcriptional noise, lncRNAs have emerged as novel players in regulating many cellular aspects in health and disease including melanoma. However, the number and as well as the extent of functional significance of most lncRNAs remains elusive. We provide a comprehensive strategy to identify functionally relevant lncRNAs in melanoma by combining expression profiling with CRISPR-inhibition growths screens lowering the experimental effort. We also provide a larger resource of differentially expressed lncRNAs with potential implications in melanoma growth and invasion. Our results broaden the characterized of lncRNAs as potential targets for future therapeutic applications.
Neural correlates of phonetic categorization under auditory (phoneme) and visual (grapheme) modalities
Authors: Bidelman Gavin M. , York Ashleigh , Pearson Claire
Published: July 2024

We tested whether the neural mechanisms of phonetic categorization are specific to speech sounds or generalize to graphemes (i.e., visual letters) of the same phonetic label. Given that linguistic experience shapes categorical processing, and letter-speech sound matching plays a crucial role during early reading acquisition, we hypothesized sound phoneme and visual grapheme tokens representing the same linguistic identity might recruit common neural substrates, despite originating from different sensory modalities. Behavioral and neuroelectric brain responses (ERPs) were acquired as participants categorized stimuli from sound (phoneme) and homologous letter (grapheme) continua each spanning a /da/ - /ga/ gradient. Behaviorally, listeners were faster and showed stronger categorization of phoneme compared to graphemes. At the neural level, multidimensional scaling of the EEG revealed responses self-organized in a categorial fashion such that tokens clustered within their respective modality beginning ∼150-250 ms after stimulus onset. Source-resolved ERPs further revealed modality-specific and overlapping brain regions supporting phonetic categorization. Left inferior frontal gyrus and auditory cortex showed stronger responses for sound category members compared to phonetically ambiguous tokens, whereas early visual cortices paralleled this categorical organization for graphemes. Auditory and visual categorization also recruited common visual association areas in extrastriate cortex but in opposite hemispheres (auditory = left; visual=right). Our findings reveal both auditory and visual sensory cortex supports categorical organization for phonetic labels within their respective modalities. However, a partial overlap in phoneme and grapheme processing among occipital brain areas implies the presence of an isomorphic, domain-general mapping for phonetic categories in dorsal visual system.
Intermodulation spectroscopy and the nonlinear response of two-level systems in superconducting coplanar-waveguide resonators
Authors: Biznárová Janka , Rivera Hernández J.C. , Forchheimer Daniel , Bylander Jonas , Haviland David B. , Andersson Gustav
Published: July 2024

Two-level system (TLS) loss typically limits the coherence of superconducting quantum circuits. The loss induced by TLS defects is nonlinear, resulting in quality factors with a strong dependence on the circulating microwave power. We observe frequency mixing due to this nonlinearity by applying a two-tone drive to a coplanar waveguide resonator and measuring the intermodulation products using a multifrequency lock-in technique. This intermodulation spectroscopy method provides an efficient approach to characterizing TLS loss in superconducting circuits. Using harmonic balance reconstruction, we recover the nonlinear parameters of the device-TLS interaction, which are in good agreement with the standard tunneling model for TLSs.

Published by the American Physical Society
2024
Integrate-and-fire model of disease transmission
Authors: Hussain Shahbanno A. , Meine David C. A. , Vvedensky Dimitri D.
Published: July 2024

We create an epidemiological susceptible-infected-susceptible model of disease transmission using integrate-and-fire nodes on a network, allowing memory of previous interactions and infections. Agents in the network sum infectious matter from their nearest neighbors at every time step, until they exceed their infection threshold, at which point they “fire” and become infected for as long as the recovery time. The model has memory of previous interactions by tracking the amount of infectious matter carried by agents as well as just binary infected or susceptible states, and the model has memory of previous infections by modeling immunity as increasing the infection threshold after recovery. Creating a simulation of the model on networks with a power-law degree distribution and homogeneous agent parameters, we find a single strain version of the model matches well with the England COVID-19 case data, with a root-mean-squared error of 0.014%. A simulation of a multistrain version of the model (where there is cross-strain immunity) matches well with the influenza strain A and strain B case numbers in Canada, with a root-mean-squared error of 0.002% and 0.0012%, respectively, though due to the coupling in the model, both strains peak in phase. Since the dynamics of the model successfully capture real-life transmission dynamics, we test interventions to study their effect on case numbers, with both quarantining and social gathering restrictions lowering the peak. Since the model has memory, the stricter the intervention, the higher the secondary peak when the restriction is removed, showing that interventions change only the shape of the curves and not the overall number infected in the population.

Published by the American Physical Society
2024
Predicting Heteropolymer Interactions: Demixing and Hypermixing of Disordered Protein Sequences
Authors: Adachi Kyosuke , Kawaguchi Kyogo
Published: July 2024

Cells contain multiple condensates which spontaneously form due to the heterotypic interactions between their components. Although the proteins and disordered region sequences that are responsible for condensate formation have been extensively studied, the rule of interactions between the components that allow demixing, i.e., the coexistence of multiple condensates, is yet to be elucidated. Here, we construct an effective theory of the interaction between heteropolymers by fitting it to the molecular dynamics simulation results obtained for more than 200 sequences sampled from the disordered regions of human proteins. We find that the sum of amino acid pair interactions across two heteropolymers predicts the Boyle temperature qualitatively well, which can be quantitatively improved by the dimer pair approximation, where we incorporate the effect of neighboring amino acids in the sequences. The improved theory, combined with the finding of a metric that captures the effective interaction strength between distinct sequences, allowed the selection of up to three disordered region sequences that demix with each other in multicomponent simulations, as well as the generation of artificial sequences that demix with a given sequence. The theory points to a generic sequence design strategy to demix or hypermix thanks to the low-dimensional nature of the space of the interactions that we identify. As a consequence of the geometric arguments in the space of interactions, we find that the number of distinct sequences that can demix with each other is strongly constrained, irrespective of the choice of the coarse-grained model. Altogether, we construct a theoretical basis for methods to estimate the effective interaction between heteropolymers, which can be utilized in predicting phase separation properties as well as rules of assignment in the localization and functions of disordered proteins.

Published by the American Physical Society
2024
Quantifying Quantum Chaos through Microcanonical Distributions of Entanglement
Authors: Rodriguez-Nieva Joaquin F. , Jonay Cheryne , Khemani Vedika
Published: July 2024

A characteristic feature of “quantum chaotic” systems is that their eigenspectra and eigenstates display universal statistical properties described by random matrix theory (RMT). However, eigenstates of local systems also encode structure beyond RMT. To capture this feature, we introduce a framework that allows us to compare the properties of eigenstates in local systems with those of pure random states. In particular, our framework defines a notion of distance between quantum state ensembles that utilizes the Kullback-Leibler divergence to compare the microcanonical distribution of entanglement entropy (EE) of eigenstates with a reference RMT distribution generated by pure random states (with appropriate constraints). This notion gives rise to a quantitative metric for quantum chaos that not only accounts for averages of the distributions but also higher moments. The differences in moments are compared on a highly resolved scale set by the standard deviation of the RMT distribution, which is exponentially small in system size. As a result, the metric can distinguish between chaotic and integrable behaviors and, in addition, quantify and compare the of chaos (in terms of proximity to RMT behavior) between two systems that are assumed to be chaotic. We implement our framework in local, minimally structured, Floquet random circuits, as well as a canonical family of many-body Hamiltonians, the mixed-field Ising model (MFIM). Importantly, for Hamiltonian systems, we find that the reference random distribution must be appropriately constrained to incorporate the effect of energy conservation in order to describe the ensemble properties of midspectrum eigenstates. The metric captures deviations from RMT across all models and parameters, including those that have been previously identified as strongly chaotic, and for which other diagnostics of chaos such as level spacing statistics look strongly thermal. In Floquet circuits, the dominant source of deviations is the second moment of the distribution, and this persists for all system sizes. For the MFIM, we find significant variation of the KL divergence in parameter space. Notably, we find a small region where deviations from RMT are minimized, suggesting that “maximally chaotic” Hamiltonians may exist in fine-tuned pockets of parameter space.

Published by the American Physical Society
2024
“Coolness” and “joy” in games: factors influencing mobile game players' willingness to make in-game purchases
Authors: Ma Yining , He Wang
Published: July 2024

Purpose

This study aims to deeply explore the factors influencing mobile game players' willingness to make in-game purchases, providing references for game developers and marketers to formulate effective strategies.

Design/methodology/approach

This research integrates the coolness factors and hedonic motivation system acceptance model to construct a comprehensive theoretical model analyzing mobile game players' willingness to make in-game purchases. The framework includes multidimensional variables such as joy, coolness, immersion, and game experience. Using data from 392 surveys collected from mobile game forums and social networks, the study employs structural equation modeling to analyze the factors and mechanisms influencing players' willingness to make in-game purchases and to verify the related research hypotheses.

Findings

The findings reveal that coolness factors have a significant positive impact on game experience and immersion, which in turn affect players' willingness to make in-game purchases. Game experience has a significant positive impact on both immersion and purchase willingness. A good game experience not only increases players' immersion but also directly enhances their willingness to make in-game purchases. Immersion plays a mediating role in the influence of coolness factors and joy on purchase willingness.

Originality/value

By integrating coolness theory with the hedonic motivation system acceptance model, this study constructs a comprehensive model to explore mobile game players' willingness to make in-game purchases. The combination of variables, including personal psychological and social psychological factors, provides a thorough analysis of the factors influencing mobile game purchase willingness, enriching existing research.