bluuebunny/crossref_metadata_2025 huggingface dataset:
Measuring what matters: context-specific indicators for assessing immunisation performance in Pacific Island Countries and Areas
Authors: Patel Cyra , Sargent Ginny M , Tinessia Adeline , Mayfield Helen , Chateau Dan , Ali Akeem , Tuibeqa Ilisapeci , Sheel Meru
Published: March 2024

Increasing countries’ access to data can improve immunisation coverage through evidence-based decision-making. However, data collection and reporting is resource-intensive, so needs to be pragmatic, especially in low-and-middle-income countries. We aimed to identify which indicators are most important for measuring, and improving, national immunisation performance in Pacific Island Countries (PICs). We conducted an expert elicitation study, asking 13 experts involved in delivering immunisation programs, decision-makers, health information specialists, and global development partners across PICs to rate 41 indicators based on their knowledge of the feasibility and relevance of each indicator. We also asked experts their preferences for indicators to be retained or removed from a list of indicators for PICs. Experts participated in two rating rounds, with a discussion on the reasons for ratings before the second round. We calculated mean scores for feasibility and relevance, and ranked indicators based on experts’ preferences and mean scores. We used framework analysis to identify reasons for selecting indicators. Experts agreed that certain indicators were essential to measure (e.g. data use in program planning and measles vaccination coverage), but preferences varied for most indicators. Preferences to include indicators in a set of indicators for PICs moderately correlated with scores for relevance (r=0.68) and feasibility (r=0.56). In discussions, experts highlighted usefulness for decision-making and ease of data collection, reporting and interpretation as the main reasons driving indicator selection. Country-specific factors such as health system factors, roles and influence of various immunisation actors, and macro-level factors (namely population size, distribution and mobility) affected relevance and feasibility, leading us to conclude that a single set of indicators for all PICs is inappropriate. Rather than having a strict set of indicators that all countries must measure and report against, performance indicators should be flexible, country-specific, and selected in consultation with stakeholders who collect and use the data.
Effects of Systemic Lupus Erythematosus on the Brain: A Systematic Review of Structural MRI Findings and their Relationships with Cognitive Dysfunction
Authors: Valdés Cabrera Diana , El Tal Tala , Mohamed Ibrahim , Arciniegas Santiago Eduardo , Fevrier Stephanie , Ledochowski Justine , Knight Andrea
Published: March 2024

Background

Cognitive dysfunction (CD) is highly prevalent in systemic lupus erythematosus (SLE), yet the underlying mechanisms are poorly understood. Neuroimaging utilizing advanced magnetic resonance imaging (MRI) metrics may yield mechanistic insights. We conducted a systematic review of neuroimaging studies to investigate the relationship between structural and diffusion MRI metrics and CD in SLE.

Methods

We systematically searched several databases between January 2000 and October 2023 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Retrospective, and prospective studies were screened for search criteria keywords (including structural or diffusion MRI, cognitive function, and SLE) to identify peer-reviewed articles reporting advanced structural MRI metrics and evaluating CD in human patients with SLE.

Results

Eighteen studies (8 structural MRI, 9 diffusion MRI, and 1 with both modalities) were included; sample sizes ranged from 11 to 120 participants with SLE. Neurocognitive assessments and neuroimaging techniques, parameters, and processing differed across articles. The most frequently affected cognitive domains were memory, psychomotor speed, and attention; while abnormal structural and/or diffusion MRI metrics were found more consistently in the hippocampus, corpus callosum, and frontal cortex of patients with SLE, with and without clinically diagnosed CNS involvement.

Conclusion

Advanced structural MRI analysis can identify total and regional brain abnormalities associated with CD in patients with SLE, with potential to enhance clinical assessment. Future collaborative, longitudinal studies of neuroimaging in SLE are needed to better characterize CD, with focus on harmonized neurocognitive assessments, neuroimaging acquisitions and post-processing analyses, and improved clinical characterization of SLE cohorts.
Preclinical Results: Canine Phase I Safety Study of CM-101, a Tumor Capillary Specific Streptococcal Polysaccharide Toxin, for application in Spontaneous Canine Cancer
Authors: Stout Rhett W , Boudreaux Bonnie , Inegulescu I Horia , Laine Roger A
Published: March 2024

Background

The study purpose was to evaluate canine safety of CM101, a polysaccharide Group BStreptococcus agalactiaetumor hemorrhagic toxin therapeutic.

Hypothesis

CM101 specifically targets tumor vasculature as published in a human Phase 1 safety study that showed a wide therapeutic window. The hypothesis is that dogs should display a similar safety profile with low side-effects for CM101 canine cancer therapeutics.

Animals

Considering the previous human safety trial, and in the interest of conserving purpose-bred dogs, on advice of USDA staff, we only used two healthy males, ∼20 months old.

Methods

USDA advice was to administer 10x the unit dose of 7.5µg/kg to 2 dogs and if no side effects, proceed to a pilot phase II. Given the dose was 10X the effective unit dose in humans, a further dose escalation was not considered necessary. Dogs were given 10 units (75 µg/kg) CM101 in normal saline over 22 minutes intravenously. Blood and Urine were collected before infusion, intervals post infusion, and 2 weeks after. Under anesthesia through recovery, rectal temperature, heart rate and indwelling arterial blood pressure vital signs were monitored electronically. Clinical observations recorded through two weeks after infusion.

Results

Total WBC (white blood cell) counts dropped below normal range two hours post-infusion, after 6-11 hours rising above the normal range, returning to baseline at 52 hours post-infusion. Creatinine kinase was elevated two hours post infusion returning to baseline in 6-72 hours. Urinalysis remained within normal limits.

Conclusions and clinical importance

No adverse effects were observed when healthy dogs were given 10 units CM101. These finding suggest a wide therapeutic window for investigation in canine cancer.
Sequence-defined oligophosphoesters for selective inhibition of the KRAS G12D/RAF1 interaction
Authors: Claringbold Bini , Vance Steven , Paul Alexandra R. , Garrett Michelle D. , Serpell Christopher J.
Published: March 2024

Rat Sarcoma (RAS) genes are the most frequently mutated genes in cancer, with KRAS being the most predominant oncogene, yet they have proved extremely difficult to drug because they operate primarily through protein-protein interactions (PPIs) which lack an obvious pocket for small molecules. Sequence-defined synthetic oligomers could combine the precision and customisability of synthetic molecules with the size requirements to address entire protein-protein interaction surfaces. We have adapted the phosphoramidite chemistry of oligonucleotide synthesis to produce a library of nearly one million non-nucleosidic oligophosphoester sequences – phosphoestamers - and used a fluorescent-activated bead sorting (FABS) process to select oligomers that inhibit the interaction between KRASG12D(the most prevalent, and undrugged, mutant) and RAF, a downstream effector of RAS whose activation results in cell proliferation. Hits were identified using tandem mass spectrometry, and validation showed effective inhibition with IC50values as low as 25 nM, and excellent selectivity for the mutant over the wild type form. These findings could lead to new drugs against cancers driven by mutant RAS, and provided proof-of-principle for the phosphoestamer platform against PPIs in general.
Differential expression and co-expression reveal cell types relevant to rare disease phenotypes
Authors: Alías-Segura Sergio , Pazos Florencio , Chagoyen Monica
Published: March 2024

Disease phenotypes, serving as valuable descriptors for delineating the spectrum of human pathologies, play a critical role in understanding disease mechanisms. Integration of these phenotypes with single-cell RNA sequencing (scRNA-seq) data facilitates the elucidation of potential associations between phenotypes and specific cell types underlying them, which sheds light on the underlying physiological processes related to these phenotypes. In this study, we utilized scRNA-seq data to infer potential associations between rare disease phenotypes and cell types. Differential expression and co-expression analyses of genes linked to abnormal phenotypes were employed as metrics to identify the involved cell types. Comparative assessments were made against existing phenotype-cell type associations documented in the literature. Our findings underscore the utility of differential expression and co-expression analyses in identifying significant relationships. Moreover, co-expression analysis unveils cell types potentially linked to abnormal phenotypes not extensively characterized in prior studies.

Key points

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Cell types underling rare disease phenotypes remain largely unknown

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Single-cell RNA-seq data from healthy tissues can be analyzed to reveal these cell types

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We employed differential expression and co-expression analysis to identify cell types associated with rare disease phenotypes

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We validated our results with known relations described in the literature
The evolutionary history of the ancient weevil family Belidae (Coleoptera: Curculionoidea) reveals the marks of Gondwana breakup and major floristic turnovers, including the rise of angiosperms
Authors: Li Xuankun , Marvaldi Adriana E. , Oberprieler Rolf G. , Clarke Dave , Farrell Brian D. , Sequeira Andrea , Ferrer M. Silvia , O'Brien Charles , Salzman Shayla , Shin Seunggwan , Tang William , McKenna Duane D.
Published: March 2024

The rise of angiosperms to ecological dominance and the breakup of Gondwana during the Mesozoic marked major transitions in the evolutionary history of insect-plant interactions. To elucidate how contemporary trophic interactions were influenced by host plant shifts and palaeogeographical events, we integrated molecular data with information from the fossil record to construct a timetree for ancient phytophagous weevils of the beetle family Belidae. Our analyses indicate that crown-group Belidae originated approximately 138 Ma ago in Gondwana, associated with Pinopsida (conifer) host plants, with larvae likely developing in dead/decaying branches. Belids tracked their host plants as major plate movements occurred during Gondwana’s breakup, surviving on distant, disjunct landmasses. Some belids shifted to Angiospermae and Cycadopsida when and where conifers declined, evolving new trophic interactions, including brood-pollination mutualisms with cycads and associations with achlorophyllous parasitic angiosperms. Extant radiations of belids in the genera Rhinotia (Australian region) and Proterhinus (Hawaiian Islands) have relatively recent temporal origins.
Conditional c-MYC activation in catecholaminergic cells drives distinct neuroendocrine tumors: neuroblastoma vs somatostatinoma
Authors: Wang Tingting , Liu Lingling , Fang Jie , Jin Hongjian , Natarajan Sivaraman , Sheppard Heather , Lu Meifen , Turner Gregory , Confer Thomas , Johnson Melissa , Steinberg Jeffrey , Ha Larry , Yadak Nour , Jain Richa , Picketts David J. , Ma Xiaotu , Murphy Andrew , Davidoff Andrew M. , Glazer Evan S. , Easton John , Chen Xiang , Wang Ruoning , Yang Jun
Published: March 2024

The MYC proto-oncogenes (c-MYC,MYCN,MYCL) are among the most deregulated oncogenic drivers in human malignancies including high-risk neuroblastoma, 50% of which areMYCN-amplified. Genetically engineered mouse models (GEMMs) based on theMYCNtransgene have greatly expanded the understanding of neuroblastoma biology and are powerful tools for testing new therapies. However, a lack of c-MYC–driven GEMMs has hampered the ability to better understand mechanisms of neuroblastoma oncogenesis and therapy development given that c-MYC is also an important driver of many high-risk neuroblastomas. In this study, we report two transgenic murine neuroendocrine models driven by conditional c-MYC induction in tyrosine hydroxylase (Th) and dopamine β-hydroxylase (Dbh)-expressing cells. c-MYC induction in Th-expressing cells leads to a preponderance of Pdx1+somatostatinomas, a type of pancreatic neuroendocrine tumor (PNET), resembling human somatostatinoma with highly expressed gene signatures of δ cells and potassium channels. In contrast, c-MYC induction in Dbh-expressing cells leads to onset of neuroblastomas, showing a better transforming capacity than MYCN in a comparable C57BL/6 genetic background. The c-MYC murine neuroblastoma tumors recapitulate the pathologic and genetic features of human neuroblastoma, express GD2, and respond to anti-GD2 immunotherapy. This model also responds to DFMO, an FDA-approved inhibitor targeting ODC1, which is a known MYC transcriptional target. Thus, establishing c-MYC–overexpressing GEMMs resulted in different but related tumor types depending on the targeted cell and provide useful tools for testing immunotherapies and targeted therapies for these diseases.
DNA replication initiation drives focal mutagenesis and rearrangements in human cancers
Authors: Murat Pierre , Guilbaud Guillaume , Sale Julian E.
Published: March 2024

The rate and pattern of mutagenesis in cancer genomes is significantly influenced by DNA accessibility and active biological processes. Here we show that efficient sites of replication initiation drive and modulate specific mutational processes in cancer. Sites of replication initiation impede nucleotide excision repair in melanoma and are off-targets for activation-induced deaminase (AICDA) activity in lymphomas. Using ductal pancreatic adenocarcinoma as a cancer model, we demonstrate that the initiation of DNA synthesis is error-prone at G-quadruplex-forming sequences in tumours displaying markers of replication stress, resulting in a previously recognised but uncharacterised mutational signature. Finally, we demonstrate that replication origins serve as hotspots for genomic rearrangements, including structural and copy number variations. These findings reveal replication origins as functional regulators of tumour biology and demonstrate that replication initiation both passively and actively drives focal mutagenesis in cancer genomes.
PARP14 inhibits the inflammatory response of macrophages through the NF-κB pathway
Authors: Guo Xuefei , Zhao Yang
Published: March 2024

The poly-ADP-ribose polymerase (PARP) superfamily consists of 17 members, which regulate many biological processes in physiological or pathological conditions, such as DNA damage repair, anti-viral responses, and development of adaptive immune cells. Among them, PARP14 is the biggest member, containing two RNA recognition motifs at the N-terminal, three macro-domains, one WWE domain, and one PARP domain at the C-terminal, which was reported to regulate IL4/STAT6 signaling in adaptive immune cells. However, whether PARP14 participates in regulating host inflammatory response remains unclear. In a previous study, we observed that virus infection and LPS treatment induced the transcription ofParp14. By comparing the primary macrophages derived fromParp14KO and WT mice, we found that some inflammatory cytokines were significantly induced in KO macrophages. Still, the expression ofIfnb1had no significant difference compared to the WT macrophages. RNA-seq analysis showed that the KO group had a more robust inflammatory response but a weaker innate immune response upon stimulation. We validated these results by performing a knockdown ofParp14in RAW 264.7 cells. Moreover, the survival time of the KO mice was much shorter than that of the WT group upon LPS injection. Transcription factor enrichment analysis indicated that nuclear factor-kappaB1 (NF-κB1) may be the main reason for increasing the production of these inflammatory cytokines. As expected, the up-regulation was deleted upon the treatment of the inhibitor of NF-κB, JSH23. These data imply that PARP14 regulates inflammatory responses through the NF-κB pathway.
The pivotal role of Drgx in survival, wiring and identity of T4/T5 neurons
Authors: Gizler Laura , Schneider Katharina , Steigleder Sarah , Benmaamar Simon , Schneuwly Stephan , Rass Mathias
Published: March 2024

The development ofDrosophila melanogaster’sT4/T5 motion-sensing neurons has been extensively studied. Despite identifying many genes, important developmental steps remain unknown. This study investigates the Paired-like homeobox transcription factor Dorsal root ganglia homeobox (Drgx) in T4/T5 neuron development.Drgxexpression initiates in T4/T5 neuroblasts and persists in mature neurons. Knockdowns using T4/T5-specific drivers yield distinct phenotypes in the optic lobe, including dendrite mistargeting and reduced lobular plate size due to apoptosis in early knockdowns. Late knockdowns exhibit only extensive mistargeting. Therefore, Drgx plays a dual role, initially inhibiting apoptosis and later on establishing T4/T5 neuron identity and circuit formation. Targeted DamID (TaDa) and RNA-sequencing (RNA-seq) identify Drgx target genes involved in apoptosis and neuron projection development. Therefore, Drgx orchestrates vital stages in T4/T5 neuron development, influencing survival, identity, and circuitry and connects to the previously identified transcription factorSox102Fas a target of Drgx.

Summary statement

The Paired-like homeobox transcription factor Drgx is essential for the correct establishment of the identity of a specific type of motion vision neurons inDrosophila.
Development of MHC Class I Blocking Peptides to Target Metabolic Dysfunction-Associated Steatohepatitis CD8+T Cell Activation
Authors: Adams Victoria , Sarma Sudeep , Hall Carol K. , Kennedy Arion
Published: March 2024

MHC class I molecules play a crucial role in the immune system by presenting peptides derived from intracellular proteins to cytotoxic T lymphocytes (CTLs). This process is essential for immune surveillance and eliminating infected or malignant cells. In some diseases, the immune system fails to recognize and eliminate abnormal cells, leading to disease progression. Under conditions of metabolic dysfunction-associated steatohepatitis (MASH), subsets of CD8+T cells have been identified as pathogenic, leading to inflammation and fibrosis. Therefore, explicitly targeting factors responsible for T cell activation may be necessary to prevent the onset of MASH and future complications such as cirrhosis or hepatocellular carcinoma. We have identified a specific MHC class I antigen that activates hepatic and splenic CD8+T cells isolated from MASH mice. To specifically target the antigen, we developed two MHC H2-Kbblocking peptides, MHCP3 and MHCP5, that competitively inhibit the Ncf2 peptide from binding to H2-Kband reduce activation and proliferation of CD8+T cells. By inhibiting the recognition of specific antigens, these blocking peptides may prevent the activation of CD8+T cells and progression of MASH.
A multi-modal image fusion workflow incorporating MALDI imaging mass spectrometry and microscopy for the study of small pharmaceutical compounds
Authors: Liang Zhongling , Guo Yingchan , Sharma Abhisheak , McCurdy Christopher R. , Prentice Boone M.
Published: March 2024

Multi-modal imaging analyses of dosed tissue samples can provide more comprehensive insight into the effects of a therapeutically active compound on a target tissue compared to single-modal imaging. For example, simultaneous spatial mapping of pharmaceutical compounds and endogenous macromolecule receptors is difficult to achieve in a single imaging experiment. Herein, we present a multi-modal workflow combining imaging mass spectrometry with immunohistochemistry (IHC) fluorescence imaging and brightfield microscopy imaging. Imaging mass spectrometry enables direct mapping of pharmaceutical compounds and metabolites, IHC fluorescence imaging can visualize large proteins, and brightfield microscopy imaging provides tissue morphology information. Single-cell resolution images are generally difficult to acquire using imaging mass spectrometry, but are readily acquired with IHC fluorescence and brightfield microscopy imaging. Spatial sharpening of mass spectrometry images would thus allow for higher fidelity co-registration with higher resolution microscopy images. Imaging mass spectrometry spatial resolution can be predicted to a finer value via a computational image fusion workflow, which models the relationship between the intensity values in the mass spectrometry image and the features of a high spatial resolution microscopy image. As a proof of concept, our multi-modal workflow was applied to brain tissue extracted from a Sprague Dawley rat dosed with a kratom alkaloid, corynantheidine. Four candidate mathematical models including linear regression, partial least squares regression (PLS), random forest regression, and two-dimensional convolutional neural network (2-D CNN), were tested. The random forest and 2-D CNN models most accurately predicted the intensity values at each pixel as well as the overall patterns of the mass spectrometry images, while also providing the best spatial resolution enhancements. Herein, image fusion enabled predicted mass spectrometry images of corynantheidine, GABA, and glutamine to approximately 2.5 μm spatial resolutions, a significant improvement compared to the original images acquired at 25 μm spatial resolution. The predicted mass spectrometry images were then co-registered with an H&E image and IHC fluorescence image of the μ- opioid receptor to assess co-localization of corynantheidine with brain cells. Our study also provides insight into the different evaluation parameters to consider when utilizing image fusion for biological applications.
SuperResNET GUI: model-free single molecule network analysis software achieves molecular resolution of Nup96
Authors: Li Y. Lydia , Khater Ismail M. , Hallgrimson Christian , Cardoen Ben , Wong Timothy H. , Hamarneh Ghassan , Nabi Ivan R.
Published: March 2024

SuperResNET is an integrated machine learning-based analysis software for visualizing and quantifying 3D point cloud data acquired by single molecule localization microscopy (SMLM). The computational modules of SuperResNET include correction for multiple blinking of a single fluorophore, denoising, segmentation (clustering), and feature extraction, which are then used for cluster group identification, modularity analysis, blob retrieval and visualization in 2D and 3D. Using publicly available dSTORM data, we apply a graphical user interface (GUI) version of SuperResNET to nucleoporin Nup96 structures, that present a highly organized octagon structure comprised of eight corners. SuperResNET GUI effectively segments nuclear pores and Nup96 corners based on differential proximity threshold analysis. SuperResNET GUI quantitatively analyzes features from segmented nuclear pore structures, including complete structures with 8-fold symmetry, and from segmented corners. SuperResNET GUI modularity analysis of segmented corners distinguishes two modules at 11.1 nm distance, corresponding to two individual Nup96 molecules. SuperResNET GUI is therefore a model-free tool that can reconstruct network architecture and molecular distribution of subcellular structures without the bias of a specified prior model, attaining molecular resolution from dSTORM data. SuperResNET GUI provides flexibility to report on structural diversity in situ within the cell without model-fitting, providing opportunities for biological discovery.
Molecular signatures and associated regulators of the pea leaf response to sulfur deficiency and water deficit as revealed by multi-omics analyses
Authors: Bonnot Titouan , Henriet Charlotte , Aimé Delphine , Kreplak Jonathan , Térézol Morgane , Balliau Thierry , Ourry Alain , Zivy Michel , Vernoud Vanessa , Gallardo Karine
Published: March 2024

Sulfur availability in soils affects both yield and seed quality in major crops, and the plant capacity to tolerate environmental constraints. Under stress combination, plants often show specific responses at the molecular level. To dissect the molecular responses to sulfur deficiency in interaction or not with water deficit, a multi-omics approach was used focusing on the leaves of pea (Pisum sativum), at several days during the early reproductive phase. Using ionomics, transcriptomics, proteomics and gene network analyses, we identified a module of genes strongly driven by sulfur availability. This includes known and putative new players of plant responses to sulfur-deprived conditions. Conserved profiles between proteins and mRNAs were specifically observed within this module, suggesting transcriptional regulation. While moderate water deficit had little impact when occurring alone, it thoroughly perturbed plant growth and the leaf transcriptome and proteome when combined with sulfur deficiency. Under this stress combination, molecular responses were amplified, notably at the transcriptome level, in a time-specific manner. Genes with specific or greater responses under this condition were identified, and transcriptional regulators of the highlighted genes and pathways were predicted, which may represent interesting targets to develop crops tolerant to multi-stress conditions.
SARS-CoV-2 methyltransferase nsp10-16 in complex with natural and drug-like purine analogs for guiding structure-based drug discovery
Authors: Kremling Viviane , Falke Sven , Fernández-García Yaiza , Ehrt Christiane , Kiene Antonia , Klopprogge Bjarne , Scheer Emilie , Barthels Fabian , Middendorf Philipp , Kühn Sebastian , Günther Stephan , Rarey Matthias , Chapman Henry N. , Oberthür Dominik , Sprenger Janina
Published: March 2024

Non-structural protein 10 (nsp10) and non-structural protein 16 (nsp16) are part of the RNA synthesis complex, which is crucial for the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nsp16 exhibits 2’-O-methyltransferase activity during viral messenger RNA capping and is active in a heterodimeric complex with enzymatically inactive nsp10. It has been shown that inactivation of the nsp10-16 protein complex interferes severely with viral replication, making it a highly promising drug target. As information on ligands binding to the nsp10-16 complex (nsp10-16) is still scarce, we screened the active site for potential binding of drug-like and fragment-like compounds using X-ray crystallography. The screened set of 234 compounds consists of derivatives of the natural substrateS-adenosyl methionine (SAM) and adenine derivatives, of which some have been described previously as methyltransferase inhibitors and nsp16 binders. A docking study guided the selection of many of these compounds. Here we report structures of binders to the SAM site of nsp10-16 and for two of them, toyocamycin and sangivamycin, we present additional crystal structures in the presence of a second substrate, Cap0-analog/Cap0-RNA. The identified hits were tested for binding to nsp10-16 in solution and antiviral activity in cell culture. Our data provide important structural information on various molecules that bind to the SAM substrate site which can be used as novel starting points for selective methyltransferase inhibitor designs.
Visualizing histone H4K20me1 in knock-in mice expressing the mCherry-tagged modification-specific intracellular antibody
Authors: Sato Yuko , Takenoshita Maoko , Ueoka Miku , Ueda Jun , Yamagata Kazuo , Kimura Hiroshi
Published: March 2024

During development and differentiation, histone modifications dynamically change locally and globally, associated with transcriptional regulation, DNA replication and repair, and chromosome condensation. The level of histone H4 Lys20 monomethylation (H4K20me1) increases during the G2 to M phases of the cell cycle and is enriched in facultative heterochromatin, such as inactive X chromosomes in cycling cells. To track the dynamic changes of H4K20me1 in living cells, we have developed a genetically encoded modification-specific intracellular antibody (mintbody) probe that specifically binds to the modification. Here, we report the generation of knock-in mice in which the coding sequence of the mCherry-tagged version of the H4K20me1-mintbody is inserted into theRosa26locus. The knock-in mice, which ubiquitously expressed the H4K20me1-mintbody, developed normally and were fertile, indicating that the expression of the probe does not disturb the cell growth, development, or differentiation. Various tissues isolated from the knock-in mice exhibited nuclear fluorescence without the need for fixation. The H4K20me1-mintbody was enriched in inactive X-chromosomes in developing embryos and in XY bodies during spermatogenesis. The knock-in mice will be useful for the histochemical analysis of H4K20me1 in any cell types.
A Foxf1-Wnt-Nr2f1 cascade promotes atrial cardiomyocyte differentiation in zebrafish
Authors: Coppola Ugo , Kenney Jennifer , Waxman Joshua S.
Published: March 2024

Nr2f transcription factors (TFs) are conserved regulators of vertebrate atrial cardiomyocyte (AC) differentiation. However, little is known about the mechanisms directing Nr2f expression in ACs. Here, we identified a conserved enhancer 3’ to thenr2f1alocus, which we call3’reg1-nr2f1a(3’reg1), that can promote Nr2f1a expression in ACs. Sequence analysis of the enhancer identified putative Lef/Tcf and Foxf TF binding sites. Mutation of the Lef/Tcf sites within the3’reg1reporter, knockdown of Tcf7l1a, and manipulation of canonical Wnt signaling support that Tcf7l1a is derepressed via Wnt signaling to activate the transgenic enhancer and promote AC differentiation. Similarly, mutation of the Foxf binding sites in the3’reg1reporter, coupled with gain- and loss-of-function analysis supported that Foxf1 promotes expression of the enhancer and AC differentiation. Functionally, we find that Wnt signaling acts downstream of Foxf1 to promote expression of the3’reg1reporter within ACs and, importantly, both Foxf1 and Wnt signaling require Nr2f1a to promote a surplus of differentiated ACs. CRISPR-mediated deletion of the endogenous3’reg1abrogates the ability of Foxf1 and Wnt signaling to produce surplus ACs in zebrafish embryos. Together, our data support that downstream members of a conserved regulatory network involving Wnt signaling and Foxf1 function on anr2f1aenhancer to promote AC differentiation in the zebrafish heart.

Author Summary

Vertebrate hearts are comprised of atrial chambers, which receive blood, and ventricular chambers which expel blood, whose functions need to be coordinated for proper blood circulation. During development, different genetic programs direct the development of these chambers within the vertebrate heart. Members of a family of genes calledNr2fsare conserved regulators of atrial chamber development in vertebrates, with mutations inNr2f2of humans being associated with congenital heart defects affecting the atrium. Here, we examine how the genenr2f1a, which is required for normal atrial chamber development in the model zebrafish, is regulated. Using tools, including transgenic reporter lines and genetic mutants, we identify that factors previously shown to regulate atrial chamber development in mammals have conserved roles regulating a genetic element that promotesnr2f1aexpression within developing atrial cells. Since there is a lack of understanding regarding regulation ofNr2fgenes during vertebrate atrial cell development, our work provides insights into the conservation of genetic networks that promote heart development in vertebrates and if perturbed could underlie congenital heart defects.
ERK signaling promotes resistance to TRK kinase inhibition in NTRK fusion-driven glioma mouse models
Authors: Schmid Sebastian , Russell Zachary R , Yamashita Alex Shimura , West Madeline E , Parrish Abigail G , Walker Julia , Rudoy Dmytro , Yan James Z , Quist David C , Gessesse Betemariyam N , Alvinez Neriah , Cimino Patrick J , Kumasaka Debra K , Parchment Ralph E , Holland Eric C , Szulzewsky Frank
Published: March 2024

Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we developed a series of genetically engineered mouse models of treatment-naïve and –experienced NTRK1/2/3 fusion-driven gliomas. Both the TRK kinase domain and the N-terminal fusion partners influenced tumor histology and aggressiveness. Treatment with TRK kinase inhibitors significantly extended survival of NTRK fusion-driven glioma mice in a fusion– and inhibitor-dependent manner, but tumors ultimately recurred due to the presence of treatment-resistant persister cells. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools for preclinical testing of novel inhibitors and to study the cellular responses of NTRK fusion-driven gliomas to therapy.
Non-linear development of EEG coherence in adolescents and young adults shown by the analysis of neurophysiological trajectories and their covariance
Authors: Chorlian David B. , Kamarajan Chella , Meyers Jacquelyn L. , Pandey Ashwini K. , Zhang Jian , Kinreich Sivan , Porjesz Bernice
Published: March 2024

To contribute to the understanding of changes in the factors governing the development of neural connectivity, the developmental structure of EEG coherence in adolescents and young adults was analyzed using the means, variances, and covariances of high alpha frequency band coherence measures from a set of 27 coherence pairs obtained from a sample of 1426 participants from the COGA study with 5006 observations over ages 12 through 31. Means and covariances were calculated at 96 age centers by a LOESS method.

In the current study, trajectories of covariance matrices considered as individual units were determined by tensorial analysis: calculation of Riemannian geodesic (non-Euclidean) distances between matrices and application of both linear and non-linear dimension reduction techniques to these distances. Results were evaluated by bootstrap methods.

Mean coherence trajectories for males and females were very similar, showing a steady upward trend from ages 12 to 20 which diminishes gradually from 20 to 25 and reaches stability from 25 to 31. In contrast, the individual covariance trajectories of males and female differed, with the male covariance levels becoming greater than that of females during the developmental process. Tensorial determination of the distances from the initial covariance matrix of subsequent covariance matrices to age 20 had the same trajectory as the mean coherence values. Tensorial determination of the trajectories of the covariance matrices of males and females based on their all pairs geodesic distances revealed a non-linear pattern in the multi-dimensional space of each of the trajectories: A steady increase in one dimension is accompanied by deviations from it peaking at age 20 which have both transient and lasting effects. There is a precise temporal parallelism of this pattern of covariance in males and females, while there is a consistent distance between the male and female covariance structures throughout the developmental process. Between region differences (anterior-posterior) within each sex are greater than between sex differences within regions. Examining development using multiple methods provides unique insight into the developmental process.
Eedcontrols craniofacial osteoblast differentiation and mesenchymal proliferation from the neural crest
Authors: Casey-Clyde Tim , Liu S. John , Serrano Juan Antonio Camara , Teng Camilla , Jang Yoon-Gu , Vasudevan Harish N. , Bush Jeffrey O. , Raleigh David R.
Published: March 2024

The histone methyltransferase Polycomb repressive complex 2 (PRC2) is required for specification of the neural crest, and mis-regulation of neural crest development can cause severe congenital malformations. PRC2 is necessary for neural crest induction, but the embryonic, cellular, and molecular consequences of PRC2 activity after neural crest induction are incompletely understood. Here we show thatEed, a core subunit of PRC2, is required for craniofacial osteoblast differentiation and mesenchymal proliferation after induction of the neural crest. Integrating mouse genetics with single-cell RNA sequencing, our results reveal that conditional knockout ofEedafter neural crest cell induction causes severe craniofacial hypoplasia, impaired craniofacial osteogenesis, and attenuated craniofacial mesenchymal cell proliferation that is first evident in post-migratory neural crest cell populations. We show thatEeddrives mesenchymal differentiation and proliferationin vivoand in primary craniofacial cell cultures by regulating diverse transcription factor programs that are required for specification of post-migratory neural crest cells. These data enhance understanding of epigenetic mechanisms that underlie craniofacial development, and shed light on the embryonic, cellular, and molecular drivers of rare congenital syndromes in humans.
Endogenous Nodal switches Wnt interpretation from posteriorization to germ layer differentiation in geometrically constrained human pluripotent cells
Authors: Ortiz-Salazar Miguel Angel , Camacho-Aguilar Elena , Warmflash Aryeh
Published: March 2024

The Wnt pathway is essential for inducing the primitive streak, the precursor of the mesendoderm, as well as setting anterior-posterior coordinates. How Wnt coordinates these diverse activities remains incompletely understood. Here, we show that in Wnt-treated human pluripotent cells, endogenous Nodal signaling is a crucial switch between posteriorizing and primitive streak-including activities. While treatment with Wnt posteriorizes cells in standard culture, in micropatterned colonies, higher levels of endogenously induced Nodal signaling combine with exogenous Wnt to drive endoderm differentiation. Inhibition of Nodal signaling restores dose-dependent posteriorization by Wnt. In the absence of Nodal inhibition, micropatterned colonies undergo spontaneous, elaborate morphogenesis concomitant with endoderm differentiation even in the absence of added extracellular matrix proteins like Matrigel. Our study shows how Wnt and Nodal combinatorially coordinate germ layer differentiation with AP patterning and establishes a system to study a natural self-organizing morphogenetic event inin vitroculture.
Theory of x-ray absorption spectroscopy for ferrites
Authors: Sorgenfrei Felix , Alouani Mébarek , Schött Johan , Jönsson H. Johan M. , Eriksson Olle , Thunström Patrik
Published: March 2024

The theoretical calculation of the interaction of electromagnetic radiation with matter remains a challenging problem for contemporary electronic structure methods, in particular, for x-ray spectroscopies. This is not only due to the strong interaction between the core hole and the photoexcited electron, but also due to the elusive multiplet effects that arise from the Coulomb interaction among the valence electrons. In this work we report a method based on density functional theory in conjunction with multiplet ligand-field theory to investigate various core-level spectroscopies, in particular, x-ray absorption spectroscopy (XAS) and x-ray magnetic circular dichroism (XMCD). The developed computational scheme is applied to the L2,3 XAS and XMCD edges of magnetite (Fe3O4) as well as cobalt ferrite (CoFe2O4) and nickel ferrite (NiFe2O4). The results are in overall good agreement with experimental observations, both regarding the XAS L2/L3 branching ratio, the peak positions, as well as the relative intensities. The agreement between theory and experiment is equally good for XAS and the XMCD spectra, for all studied systems. The results are analyzed in terms of eg and t2g orbital contribution, and the robustness of the spectra with regard to the uncertainties of the Slater parameters is investigated. The analysis also highlights the strong effect of the 2p−3d interaction in x-ray spectroscopy.

Published by the American Physical Society
2024
First Measurement of Discrimination between Helium and Electron Recoils in Liquid Xenon for Low-Mass Dark Matter Searches
Authors: Haselschwardt S. J. , Gibbons R. , Chen H. , Kravitz S. , Manalaysay A. , Xia Q. , Lippincott W. H. , Sorensen P.
Published: March 2024

We report the first measurement of discrimination between low-energy helium recoils and electron recoils in liquid xenon. This result is relevant to proposed low-mass dark matter searches which seek to dissolve light target nuclei in the active volume of liquid-xenon time projection chambers. Low-energy helium recoils were produced by degrading α particles from Po210 with a gold foil situated on the cathode of a liquid xenon time-projection chamber. The resulting population of helium recoil events is well separated from electron recoils and is also offset from the expected position of xenon nuclear recoil events.

Published by the American Physical Society
2024
Expected idiosyncratic entropy
Authors: Tavakoli Baghdadabad Mohammadreza
Published: March 2024

Purpose

We propose a risk factor for idiosyncratic entropy and explore the relationship between this factor and expected stock returns.

Design/methodology/approach

We estimate a cross-sectional model of expected entropy that uses several common risk factors to predict idiosyncratic entropy.

Findings

We find a negative relationship between expected idiosyncratic entropy and returns. Specifically, the Carhart alpha of a low expected entropy portfolio exceeds the alpha of a high expected entropy portfolio by −2.37% per month. We also find a negative and significant price of expected idiosyncratic entropy risk using the Fama-MacBeth cross-sectional regressions. Interestingly, expected entropy helps us explain the idiosyncratic volatility puzzle that stocks with high idiosyncratic volatility earn low expected returns.

Originality/value

We propose a risk factor of idiosyncratic entropy and explore the relationship between this factor and expected stock returns. Interestingly, expected entropy helps us explain the idiosyncratic volatility puzzle that stocks with high idiosyncratic volatility earn low expected returns.
Examining knowledge and skills acquisition from youth leadership programs in Brunei: is self-esteem the missing link in training transfer?
Authors: Hisa Adilah , Ishak Nurul Amirah , Islam Md Zahidul
Published: March 2024

Purpose

This study aims to examine the impact of knowledge and skills acquisition from youth leadership programs on the extent of training transfer. Additionally, it explores the role of self-esteem as a potential intervening mechanism in linking the acquired knowledge and skills to the transfer of training.

Design/methodology/approach

Using a non-probability purposive sampling, data were gathered from participants of youth leadership programs in Brunei. The study hypotheses were validated using multiple linear regression analysis and Hayes PROCESS macro.

Findings

The findings revealed that knowledge and skills acquisition positively affect the extent of training transfer among youth leadership program participants. Moreover, self-esteem is found to be a crucial mediator in the relationship between knowledge and skills acquired from youth leadership programs and the extent of training transfer.

Practical implications

The study suggests that to optimize the transfer of training in the youth leadership programs, relevant stakeholders – training providers, and practitioners – must prioritize not only the knowledge and skills acquisition but also the cultivation of participants’ self-esteem. To achieve this, a primary focus should be placed on the criticality of designing such programs to address these factors. Policymakers, particularly in Brunei, can enhance the leadership pipeline among the youth population and expedite progress toward achieving the national vision by aligning leadership development initiatives with the broader national development agenda.

Originality/value

Collectively, this study enhances understanding of training transfer in youth leadership development, an often-overlooked area in the literature.
Project managers: old, grumpy and suspicious or just “once bitten, twice shy?”
Authors: Prater James , Kirytopoulos Konstantinos
Published: March 2024

Purpose

This research aspires to contribute in the area of exploration of the psychological traits evolving by practitioners within the project management profession. Specifically, it investigates whether there is any difference in optimism levels among experienced project management practitioners and newcomers in the profession.

Design/methodology/approach

The research used the life orientation test-revised (LOTR) (Scheier et al., 1994) to calculate respondents’ optimism scores. With these scores at hand, the researchers could then apply inferential statistics in order to deduce any differences observed among optimism score and the respondents’ characteristics (age, years of experience etc.).

Findings

Based on the results of this research, several demographic variables were shown to be statistically significant with optimism. These were (1) the number of years of experience the respondent had in managing projects, (2) working in a government organisation and (3) possessing specific project management certifications, all of which were found to adversely affect the respondent’s optimism score.

Originality/value

This research was unique in applying a well-known psychological test instrument (LOTR) to provide insight into the psychological impacts of a career as an information technology (IT) project manager. It is also highly likely that this correlation between the length of time working as a project manager and the adverse impact on their optimism would also apply to not just IT project managers but all experienced project managers.