bluuebunny/crossref_metadata_2025 huggingface dataset:
Fgf23 expression increases atherosclerotic plaque burden in maleApoEdeficient mice
Authors: Lindberg Karolina , Ovchinnikova Olga , Moor Matthias B. , Pirault John , Ketelhuth Daniel FJ , Olauson Hannes , Hansson Göran K. , Larsson Tobias E.
Published: July 2024

Introduction

Components of both the innate and adaptive immune system impact on arterial walls in atherosclerosis. Fibroblast growth factor-23 (FGF23) is a phosphate regulating hormone linked to cardiovascular disease (CVD) in patients with and without chronic renal disease. However, it remains controversial whether FGF23 is merely a biomarker or contributes to CVD. Here, we overexpressed FGF23 inApoE-/-mice to delineate the role of FGF23 in atherogenesis.

Methods and Results

10-week oldApoE-/-mice received a hydrodynamic tail vein with a plasmid encoding for Fgf23, and were sacrificed 10 weeks later. Fgf23 concentrations increased more than 400-fold in the Fgf23 treated group, remaining high throughout the experiment. Mice in the Fgf23 group developed hypophosphatemia, secondary hyperparathyroidism and a moderate increase in plasma creatinine concentrations. MaleApoE-/-mice exposed to high Fgf23 developed larger atherosclerotic lesions compared to controls, in two different locations of aorta, whereas no differences in plaque burden were seen between femaleApoE-/-mice and controls. Serum IL-6 concentrations were increased in the Fgf23 group, associated with a vascular inflammatory response of recruited macrophages and neutrophils, and with a shift of CD4+ T effector cells from Th1 to Th17 and migration of lymphocytes to the spleen.

Conclusion

Fgf23 increases the atherosclerotic burden in maleApoE-/-mice and alters both the innate immune system and T cell subpopulations, generating an inflammatory environment that may promote adverse clinical outcomes associated with Fgf23 excess.
Distinct Mechanisms of Type 3 Secretion System Recognition Control LTB4Synthesis in Neutrophils versus Macrophages
Authors: Brady Amanda , Mora-Martinez Leonardo C. , Hammond Benjamin , Haribabu Bodduluri , Uriarte Silvia M. , Lawrenz Matthew B.
Published: July 2024

Leukotriene B4 (LTB4) is critical for initiating the inflammatory cascade in response to infection. However,Yersinia pestiscolonizes the host by inhibiting the timely synthesis of LTB4and inflammation. Here, we show that the bacterial type 3 secretion system (T3SS) is the primary pathogen associated molecular pattern (PAMP) responsible for LTB4production by leukocytes in response toYersiniaandSalmonella, but synthesis is inhibited by the Yop effectors duringYersiniainteractions. Moreover, we unexpectedly discovered that T3SS-mediated LTB4synthesis by neutrophils and macrophages require two distinct host signaling pathways. We show that the SKAP2/PLC signaling pathway is essential for LTB4production by neutrophils but not macrophages. Instead, phagocytosis and the NLRP3/CASP1 inflammasome are needed for LTB4synthesis by macrophages. Finally, while recognition of the T3SS is required for LTB4production, we also discovered a second unrelated PAMP-mediated signal independently activates the MAP kinase pathway needed for LTB4synthesis. Together, these data demonstrate significant differences in the signaling pathways required by macrophages and neutrophils to quickly respond to bacterial infections.

Significance

The production of inflammatory lipid mediators by the host is essential for timely inflammation in response to invasion by bacterial pathogens. Therefore, defining how immune cells recognize pathogens and rapidly produce these lipids is essential for us to understand how our immune system effectively controls infection. In this study, we discovered that the host signaling pathways required for leukotriene B4 (LTB4) synthesis differ between neutrophils and macrophages, highlighting important differences in how immune cells respond to infection. Together, these data represent a significant improvement in our understanding of how neutrophils and macrophages rapidly react to bacteria and provide new insights into howYersinia pestismanipulates leukocytes to evade immune recognition to cause disease.
Kingdom-specific lipid unsaturation shapes up sequence evolution in membrane arm subunits of eukaryotic respiratory complexes
Authors: Gupta Pooja , Chakroborty Sristi , Rathod Arun K. , Bhat Shreya , Ghosh Suparna , Rao T Pallavi , Nagaraj R , Manna Moutusi , Raychaudhuri Swasti
Published: July 2024

Sequence evolution of protein complexes (PCs) is constrained by protein-protein interactions (PPIs). PPI-interfaces are predominantly conserved and hotspots for disease-related mutations. How lipid-protein interactions (LPIs) constrain sequence evolution of membrane- PCs? We explore Respiratory Complexes (RCs) as a case study as these allow to compare sequence evolution in subunits exposed to both lipid-rich inner-mitochondrial membrane (IMM) and aqueous matrix. We find that lipid-exposed surfaces of the IMM-subunits but not of the matrix subunits are populated with non-PPI disease-causing mutations signifying LPIs in stabilizing RCs. Further, IMM-subunits including their exposed surfaces show high intra- kingdom sequence conservation but remarkably diverge beyond. Molecular Dynamics simulation suggests contrasting LPIs of structurally superimposable but sequence-wise diverged IMM-exposed helices of Complex I (CI) subunit Ndufa1 from human andArabidopsisdepending on kingdom-specific unsaturation of cardiolipin fatty acyl chains.in celluloassays consolidate inter-kingdom incompatibility of Ndufa1-helices due to the lipid- exposed amino acids. Plant-specific unsaturated fatty acids in human cells also trigger CI- instability. Taken together, we posit that altered LPIs calibrate sequence evolution at the IMM-arms of eukaryotic RCs.
DNA methylation database for gynecological cancer detection, classification and assay development
Authors: Boers Joachim , Boers Ruben , Sakoltchik Jan , Dasgupta Shatavisha , Martens Lotte , Tadema Kirke C.D. , Prevoo Frederique , van IJcken Wilfred F.J. , van den Munckhof Henk , Quint Wim , van Beekhuizen Heleen J. , Quint Wim H. , van Kemenade Folkert J. , Gribnau Joost
Published: July 2024

Changes in the genome wide DNA methylation landscape are hallmarks of cancer cells and precursor lesions of cancers. To capitalize on utilizing DNA methylation for detection and classification of cancer, we generated a DNA methylation database of gynecological cancers and associated healthy tissues using Methylated DNA sequencing (MeD-seq). We show that target cell enrichment to generate the database is crucial for marker discovery and report a wide range of novel biomarkers for classification and tissue of origin determination of gynecological cancers. We developed a subset of these novel biomarkers, both intragenic and intergenic, into a qMSP assays that detect all gynecological cancers at once or specific gynecological cancer subtypes, as well as cancers that are not part of our database. The database generated in this study not only provides the foundation for cancer detection, classification and biomarker discovery, but also for treatment monitoring of cancers using MeD-seq on liquid biopsies.
1.94 Å structure of synthetic α-synuclein fibrils seeding MSA neuropathology
Authors: Burger Domenic , Kashyrina Marianna , Lewis Amanda J. , De Nuccio Francesco , Mohammed Inayathulla , de La Seiglière Hortense , van den Heuvel Lukas , Verchère Jérémy , Feuillie Cécile , Berbon Mélanie , Arotçarena Marie-Laure , Retailleau Aude , Bezard Erwan , Laferrière Florent , Loquet Antoine , Bousset Luc , Baron Thierry , Lofrumento Dario Domenico , De Giorgi Francesca , Stahlberg Henning , Ichas François
Published: July 2024

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease of unknown etiology, typically affecting individuals aged 50-60 and leading to patient death within a decade1–3. Characterized by the presence of oligodendroglial intracellular aggregates (GCIs) primarily composed of fibrillar alpha-synuclein (aSyn)4–8, formation of MSA neuropathology presents similarities to prion propagation9,10. While previous investigations have scrutinized fibrils extracted from MSA brains11, their “protein-only” replication was questioned12and their capacity to induce GCIs in animal models was not explored. Conversely, the synthetic fibril strain 1B13,14assembled from recombinant human aSyn self-replicates autonomouslyin vitroand induces GCIs in mice15, suggesting relevance to MSA. Here we report the high-resolution structural analysis of the 1B fibrils revealing similarities with human brain extracted MSA aSyn filaments, particularly the lack of a specific Thioflavin T (ThT) binding pocket16. In addition, 1B causes sustained intracerebral GCI spread over the years, prompt lethality in transgenic mice, and transmission of inclusion pathology to wild-type animals after crude brain homogenate inoculation. This points to an underlying prion-like seeding process which we demonstratein situusing correlative light-electron microscopy. Our findings underscore structural features of aSyn fibrils pivotal for MSA pathogenesis and provide insights for therapeutic development.
CRISPR targeting of FOXL2 c.402C>G mutation reduces malignant phenotype in granulosa tumor cells and identifies anti-tumoral compounds
Authors: Amarilla-Quintana Sandra , Navarro Paloma , Ramos Alejandra , Montero-Calle Ana , Cabezas-Sainz Pablo , Barrero Maria J , Megías Diego , Vilaplana-Martí Borja , Epifano Carolina , Gómez-Domínguez Déborah , Hernández Iván , Monzón Sara , Cuesta Isabel , Sánchez Laura , Barderas Rodrigo , García-Donas Jesús , Martín Alberto , Pérez de Castro Ignacio
Published: July 2024

FOXL2 is a transcription factor essential for sex determination and ovary development and maintenance. Mutations in this gene are implicated in syndromes involving premature ovarian failure and granulosa cell tumors (GCTs). This rare cancer accounts for less than 5% of diagnosed ovarian cancers and is causally associated with the FOXL2 c.402C>G, p.C134W mutation in 97% of the adult cases (AGCTs). In this study, we employed CRISPR technology to specifically eliminate the FOXL2 c.402C>G mutation in granulosa tumor cells. Our results show that this Cas9-mediated strategy selectively targets the mutation without affecting the wild-type allele. Granulosa cells lacking the FOXL2 c.402C>G exhibit a reduced malignant phenotype, with significant changes in cell proliferation, invasion, and cell death. Furthermore, these modified cells are more susceptible to Dasatinib and Ketoconazole. Transcriptomic and proteomic analyses reveal that CRISPR-modified granulosa tumor cells shift their expression profiles towards a wild-type like phenotype. Additionally, this altered expression signature has led to the identification of new compounds with antiproliferative and pro-apoptotic effects on granulosa tumor cells. Our findings demonstrate the potential of CRISPR technology for the specific targeting and elimination of a mutation causing granulosa cell tumors, highlighting its therapeutic promise for treating this rare ovarian cancer.

Simple Summary

Adult granulosa cell tumors (AGCTs), characterized by a specific point mutation (C134W) in the gene FOXL2, are less than 5% of all the diagnosed ovarian cancers. Surgery is the cornerstone treatment for AGCT even at relapse, with systemic therapy showing poor results. The aim of our study is to explore the potential therapeutic effect of the elimination of the C134W mutation. To achieve our goal, we have eliminated the mutant allele using CRISPR technology. Our results demonstrate that CRISPR-mediated elimination of FOXL2-C134W reduces the malignant phenotype of granulosa tumor cells, which change their transcriptional, proteomic, and cellular phenotype to a wild type like, granulosa type. Moreover, the induced changes allowed us to find new compounds with antitumoral activity. This work highlights the therapeutic potential of CRISPR mediated technology for the treatment of AGCT.
PhoPQ-mediated lipopolysaccharide modification regulates intrinsic resistance to tetracycline and glycylcycline antibiotics inEscherichia coli
Authors: Choi Byoung Jun , Choi Umji , Ryu Dae-Beom , Lee Chang-Ro
Published: July 2024

Tetracyclines and glycylcycline are among the last-resort antibiotics used to combat infections caused by multidrug-resistant Gram-negative pathogens. Despite the clinical importance of these antibiotics, their mechanisms of resistance remain unclear. In this study, we elucidated a novel mechanism of resistance to tetracycline and glycylcycline antibiotics via lipopolysaccharide (LPS) modification. Disruption of theEscherichia coliPhoPQ two-component system, which regulates the transcription of various genes involved in magnesium transport and LPS modification, leads to increased susceptibility to tetracycline, minocycline, doxycycline, and tigecycline. These phenotypes are caused by enhanced expression of phosphoethanolamine transferase EptB, which catalyzes the modification of the inner core sugar of LPS. PhoPQ-mediated regulation of EptB expression appears to affect the intracellular transportation of doxycycline. Disruption of EptB increases resistance to tetracycline and glycylcycline antibiotics, whereas the other two phosphoethanolamine transferases, EptA and EptC, that participate in the modification of other LPS residues, are not associated with resistance to tetracyclines and glycylcycline. Overall, our results demonstrated that PhoPQ-mediated modification of a specific residue of LPS by phosphoethanolamine transferase EptB regulates resistance to tetracycline and glycylcycline antibiotics.

Importance

Elucidating the resistance mechanisms of clinically important antibiotics helps in maintaining the clinical efficacy of antibiotics and in the prescription of adequate antibiotic therapy. Although tetracycline and glycylcycline antibiotics are clinically important in combating multidrug-resistant Gram-negative bacterial infections, their mechanisms of resistance are not fully understood. Our research demonstrates that theEscherichia colitwo-component system PhoPQ regulates resistance to tetracycline and glycylcycline antibiotics by controlling the expression of phosphoethanolamine transferase EptB, which catalyzes the modification of the inner core residue of lipopolysaccharide (LPS). Therefore, our findings highlight a novel resistance mechanism to tetracycline and glycylcycline antibiotics and the physiological significance of LPS core modification inE. coli.

One sentence summary

Lipopolysaccharide modification-mediated tigecycline resistance
Bridging the Gap in Health Literacy: Harnessing the Power of Large Language Models to Generate Plain Language Summaries from Biomedical Texts
Authors: Salazar-Lara Carolina , Arias Russi Andrés Felipe , Manrique Rubén
Published: July 2024

Health literacy is essential for individuals to navigate the healthcare system and make informed decisions about their health. Low health literacy levels have been associated with negative health outcomes, particularly among older populations and those financially restricted or with lower educational attainment. Plain language summaries (PLS) are an effective tool to bridge the gap in health literacy by simplifying content found in biomedical and clinical documents, in turn, allowing the general audience to truly understand health-related documentation. However, translating biomedical texts to PLS is time-consuming and challenging, for which they are rarely accessible by those who need them. We assessed the performance of Natural Language Processing (NLP) for systematizing plain language identification and Large Language Models (LLMs), Generative Pre-trained Transformer (GPT) 3.5 and GPT 4, for automating PLS generation from biomedical texts. The classification model achieved high precision (97·2%) in identifying if a text is written in plain language. GPT 4, a state-of-the-art LLM, successfully generated PLS that were semantically equivalent to those generated by domain experts and which were rated high in accuracy, readability, completeness, and usefulness. Our findings demonstrate the value of using LLMs and NLP to translate biomedical texts into plain language summaries, and their potential to be used as a supporting tool for healthcare stakeholders to empower patients and the general audience to understand healthcare information and make informed healthcare decisions.
Epilepsy Socioeconomic Impact in a Tertiary Center in Brazil From the Patient Perspective
Authors: Romão Tayla , da Silva Everton Nunes , Kayo Monica , Mansilla Raíssa , Ferraz Lucas , D’Andrea Isabella
Published: July 2024

Background

This study aimed to evaluate the direct and indirect annual costs of epilepsy from the perspective of patients with epilepsy treated at a public tertiary center situated in Rio de Janeiro, Brazil.

Methods

A cross-sectional cost-of-illness study was conducted, using a bottom-up approach based on interviews and records of 166 outpatients with confirmed diagnoses of epilepsy. Direct costs included expenses related to treatment, and transportation, while indirect costs encompassed productivity losses due to morbidity and mortality, assessed through the human capital approach and caregivers.

Results

The majority of patients in the sample had refractory epilepsy (68.1%) and were on polytherapy (43.98%). The average per capita income of the sample was USD 434,90 per month, and 28.3% of the individuals were unemployed. The total costs amounted to USD 8,243.10 per patient per year, with 76.95% attributed to indirect costs, 23.05% to direct medical costs, and 2.31% to non-medical costs. The primary cost contributors included unemployment (30.42%), caregiver expenses (22.41%), and antiseizure medications (20.30%). The majority of patients reported purchasing all their medications (62.43%). The total out-of-pocket health expenses amounted to USD 2,090.10 per patient per year, with medications accounting for 90.89% of the expenses and transportation for 9.11%.

Conclusions

In addition to unemployment as the main cost driver, the patients incurred catastrophic spending on medications. Even though treated in a public service, out-of- pocket health expenses made up 40.04% of the average per capita income of the sample and 12.85% of the Brazilian GDP per capita in 2021. The significant patient expenditures may contribute to poor adherence to epilepsy treatment, which can exacerbate the disease and lead to increased seizure frequency. This, in turn, reduces their ability to earn income, contributing to the rise in indirect and intangible costs.
Polyamines regulate cell fate by altering the activity of histone-modifying enzymes
Authors: Emmons-Bell Maya , Forsyth Grace , Sundquist Abby , Oldeman Sylvie , Gardikioti Angeliki , de Souza Roshni , Coene Jonathan , Kamel Maryam H. , Ayyapan Shine , Fuchs Harrison A. , Verhelst Steven , Smeeton Joanna , Musselman Catherine A. , Schvartzman Juan-Manuel
Published: July 2024

Polyamines are polycationic alkyl-amines abundant in proliferating stem and cancer cells. How these metabolites influence numerous cellular functions remains unclear. Here we show that polyamine levels decrease during differentiation and that inhibiting polyamine synthesis leads to a differentiated-like cell state. Polyamines concentrate in the nucleus and are further enriched in the nucleoli of cells in culture andin vivo. Loss of polyamines drives changes in chromatin accessibility that correlate with altered histone post-translational modifications. Polyamines interact electrostatically with DNA on the nucleosome core, stabilizing histone tails in conformations accessible to modifying enzymes. These data reveal a mechanism by which an abundant metabolite influences chromatin structure and function in a non-sequence specific manner, facilitating chromatin remodeling during reprogramming and limiting it during fate commitment.
Delineation of a thrombin receptor-stimulated vascular smooth muscle cell transition generating cells in the plaque-stabilising fibrous cap
Authors: Taylor James CK , Worssam Matthew D , Oc Sebnem , Lambert Jordi , Mahbubani Krishnaa T , Foote Kirsty , Finigan Allie , Chan Yee-Hung , Figg Nichola , Clarke Murray C H , Bennett Martin R , Jørgensen Helle F
Published: July 2024

Aims

Vascular smooth muscle cells (VSMCs) accumulate in atherosclerotic plaques and exhibit remarkable phenotypic plasticity, contributing to both plaque growth and stability. The plaque-stabilising fibrous cap is rich in VSMC-derived cells, yet the cellular transitions and regulatory mechanisms governing fibrous cap formation remain unclear. We aimed to delineate the VSMC phenotypic transitions associated with this critical process.

Methods and Results

Mapping of lineage-traced VSMCs during plaque development revealed investment of VSMCs prior to fibrous cap formation. Using single-cell RNA-sequencing (scRNA-seq) profiles of lineage-traced VSMCs from atherosclerotic and acutely injured mouse arteries, we identified a disease-specific VSMC state co-expressing contractile genes with extracellular matrix (ECM) components (including fibrillar collagens and elastin) and NOTCH3, which are associated with fibrous cap formation. Computational trajectory analysis predicted that this proposed fibrous cap-related VSMC (fcVSMC) state arises from a previously described plastic, intermediate VSMC population expressing SCA1 and VCAM1. Clonal analysis further showed that NOTCH3+fcVSMCs derive from intermediate VSMCs in both atherosclerosis and an acute vascular injury model, suggesting a conserved disease-relevant mechanism. The fcVSMCs were enriched in plaque fibrous caps compared to lesion cores, consistent with a role in fibrous cap formation. By combining scRNA-seq trajectory analysis and spatial transcriptomics of human atherosclerotic plaques, we identified protease-activated receptor-1 (PAR1) as a candidate regulator of fcVSMC generation. PAR1 was expressed by VSMCs in human plaque fibrous caps and, PAR1 activation by thrombin induced expression of contractile genes and ECM components associated with the fcVSMC state in human VSMCs.

Conclusions

Our findings identify a VSMC transition linked to fibrous cap formation in atherosclerosis and show this is modelled by vascular injury. We identify VSMC-expressed PAR1 as a potential therapeutic target for promoting plaque stability by driving the transition to the matrix-producing, fibrous cap-associated VSMC state.
Nanoscale cluster mapping of molecular complexes with pixel-based correlations
Authors: Kiuchi Tai , Kobayashi Ryouhei , Ogawa Shuichiro , Elverston Louis L. H. , Watanabe Naoki
Published: July 2024

Super-resolution microscopy achieves a few nanometers resolution, but protein quantification and colocalization is limited by its labeling density. Here we present a method to map molecular complexes using the multiplexed data of IRIS super- resolution imaging. We developed antiserum-derived Fab IRIS probes for high- density labeling of endogenous targets, and image analysis, Protein Cluster coloring (PC-coloring), which employs pixel-based principal component analysis and clustering. PC-coloring was first used to map regions of distinct ratios of targets on the image. The molecular complex formation was then evaluated by correlation between all combinations of two proteins in each PC-colored region. We elucidate receptor recruitment and the complex formation in a clathrin-coated structure (CCS) which is pre-assembled prior to endocytosis. Upon EGF stimulation, EGFR-, EGFR-Grb2-complex- and Grb2-dominant regions lined up from the CCS rim. Along the interior of Grb2-dominant regions, Eps15, FCHo1/2 and intersectin-1 formed a complex with Grb2. The interior of Eps15-FCHo1/2 complexes was lined with Eps15-intersectin-1 complexes. The results reveal a laminar complex formation of EGFR, Grb2 and CCS components at the recruitment sites.
Sex-specific loss of mitochondrial membrane integrity in the auditory brainstem of a mouse model of Fragile X syndrome
Authors: Caron Claire , McCullagh Elizabeth A , Bertolin Giulia
Published: July 2024

Sound sensitivity is one of the most common sensory complaints for people with autism spectrum disorders (ASDs). How and why sounds are perceived as overwhelming by affected people is unknown. To process sound information properly, the brain requires high activity and fast processing, as seen in areas like the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem. Recent work has shown dysfunction in mitochondria, which are the primary source of energy in cells, in a genetic model of ASD, Fragile X syndrome (FXS). Whether mitochondrial functions are also altered in sound-processing neurons, has not been characterized yet. To address this question, we imaged the MNTB in a mouse model of FXS. We stained MNTB brain slices from wild-type and FXS mice with two mitochondrial markers, TOMM20 and PMPCB, located on the Outer Mitochondrial Membrane and in the matrix, respectively. These markers allow exploration of mitochondrial subcompartments. Our integrated imaging pipeline reveals significant sex-specific differences between genotypes. Colocalization analyses between TOMM20 and PMPCB reveal that the integrity of mitochondrial subcompartments is most disrupted in female FXS mice compared to female wildtype mice. We highlight a quantitative fluorescence microscopy pipeline to monitor mitochondrial functions in the MNTB from control or FXS mice and provide four complementary readouts. Our approach paves the way to understanding how cellular mechanisms important to sound encoding are altered in ASDs.
Design, infectability, and transcriptomic analysis of transregionally differentiated and scalable lung organoids derived from adult bronchial cells
Authors: Valenzuela Alicia Reyes , Turner Mark , Markarian Nathan , Lachance-Brais Christophe , Hanrahan John , Vali Hojatollah , Vidal Silvia , Mongeau Luc
Published: July 2024

The lung is a primary target for many lethal respiratory viruses, leading to significant global mortality. Current organoid models fail to completely mimic the cellular diversity and intricate tubular and branching structures of the human lung. Lung organoids derived from adult primary cells have so far only included cells from the input cell region, proximal or distal. Existing models are expensive. They often require cells from invasive deep lung tissue biopsies. The present study aimed to address these limitations. The lung organoids obtained using an original protocol exhibited transregional differentiation and were derived from relatively more accessible primary cells from the trachea/bronchi. Immortal bronchial cell lines were also used to simplify organoid fabrication and improve its scalability. The lung organoids are formed starting from bronchial cells with fibroblasts feeder cells in an alginate hydrogel coated with base membrane zone proteins. Characterizations were performed using bulk RNA sequencing and tandem mass tags. The resulting organoids express markers of different lung regions and mimic to some extent the tubular and branching morphology of the lung. The proteomic profile of organoid from primary cells and from cell lines was found to evolve towards that of mature lung tissue. Upregulated genes were mostly related to the respiratory system, tube development, and various aspects of respiratory viral infections. Infection with SARS-CoV-2 and influenza H1N1 was successful and did not require organoid disassembly. The organoids matured within 21 days and did not require complex or expensive culture methods. Transregionally differentiated lung organoid may find applications for the study of emerging or re-emerging viral infections and fostering the development of novel in-vitro therapeutic strategies.
Sensorimotor awareness requires intention: Evidence from minuscule eye movements
Authors: Klanke Jan-Nikolas , Ohl Sven , Rolfs Martin
Published: July 2024

Microsaccades are tiny eye movements that are thought to occur spontaneously and without awareness but can also be intentionally controlled with high precision. We used these tiny visual actions to investigate how intention modulates sensorimotor awareness by directly comparing intended, unintended, and spontaneous microsaccades. In addition, we dissociated the effects of action intention and the actions’ visual consequences on awareness. In 80% of all trials, we presented a stimulus at high temporal frequency rendering it invisible during stable fixation. Critically, the stimulus became visible when a microsaccade in the same direction caused it to slow down on the retina (generated microsaccade condition; 40% of trials) or when the microsaccades’ visual consequence was replayed (replayed microsaccade condition; 40% of trials). Participants reported whether they perceived the stimulus (visual sensitivity), whether they believed they had made a microsaccade (microsaccade sensitivity), and their level of confidence that their eye movement behavior was linked to their perception (causality assignment). Visual sensitivity was high for both, generated and replayed microsaccades and comparable for intended, unintended, and spontaneous eye movements. Microsaccade sensitivity, however, was low for spontaneous microsaccades, but heightened for both intended and unintended eye movements, showing that the intention to saccade or fixate enhances awareness of otherwise undetected eye movements. Visual consequences failed to aid eye movement awareness, and confidence ratings revealed a poor understanding of a causal relationship between eye movement and sensory consequence. These findings highlight the functional relevance of intention in sensorimotor awareness at the smallest scale of visual actions.

Significance statement

While eye movements are among the most frequent human actions, they are rarely perceived consciously, despite causing sweeping changes in retinal inputs. Here investigate how intention can modulate awareness of even the smallest human actions: microsaccades. We developed a novel paradigm that allowed us to dissociate the role of action intention and an action’s sensory consequence for awareness, two factors that previous research has typically confounded. Our data provide strong evidence that observers can detect small eye movements reliably and demonstrates that sensitivity towards microsaccades was neither driven by an eye movement’s motor component nor its visual consequences alone. Instead, we find that intention opens a gate to sensorimotor awareness, even for actions typically too small to be perceived.
Myoferlin is an essential component of late-stage vRNP trafficking vesicles for enveloped RNA viruses
Authors: Bonazza Stefano , Turkington Hannah L , Coutts Hannah L , Sukumar Swathi , Hawthorn Courtney , Getty Erin M P E , Touzelet Olivier , Barabas Judit , Power Ultan F , Courtney David G
Published: July 2024

The Rab11a endosomal recycling pathway is exploited by important respiratory RNA viruses such as IAV and RSV, aiding viral egress from the apical surface of polarized epithelial cells. Late in infection, Rab11a-containing vesicles specifically transport viral ribonucleoprotein (vRNP) complexes towards the cell surface before packaging and budding. Rather than employing traditional Rab11a-positive recycling endosomes, virus-infected cells generate remodelled Rab11a-containing vesicles, as observed during IAV infection. Besides Rab11a, no other conserved host co-factors have been identified among these various vRNP trafficking vesicles. Here we discovered and confirmed myoferlin’s association with IAV vRNPs in the cytoplasm and colocalisation with Rab11a during late stages of infection. We also found that this role was conserved in late-stage vRNP trafficking of other viruses, including RSV and SeV. Myoferlin likely recruits the EHD family of proteins, which are involved in endosomal biogenesis, to these unique vRNP trafficking endosomes, highlighting myoferlin’s pivotal role in viral replication.
Neural correlates of nightmares revisited: findings from large-scale fMRI cohorts
Authors: Pereira Mariana , Terpstra Noëlle , Rutiku Renate , Sandberg Kristian , Dresler Martin , Krause Florian
Published: July 2024

Study Objectives

Nightmares are linked to daytime distress and psychiatric and neurological disorders. However, knowledge about the brain regions involved in nightmare production is sparse. This study aimed to examine the relationship between nightmare frequency and the functional connectivity of the amygdala with the prefrontal cortex, which is central to emotional regulation. Additionally, the study sought to replicate previous findings on the neural correlates of nightmares using two large cohorts.

Methods

464 participants underwent functional and structural MRI recordings and answered questions assessing nightmare and dream recall frequency. A general linear model assessed the voxelwise correlation between the amygdala-prefrontal cortex connectivity with nightmare frequency. Additionally, regional homogeneity (ReHo) maps were calculated, high and low nightmare frequency and the entire nightmare frequency spectrum contrasts were determined while controlling for age, sex, and dream recall frequency.

Results

The study did not find a significant correlation between nightmare frequency and amygdala-prefrontal cortex connectivity. Previous ReHo findings of group differences between high and low nightmare frequency could not be replicated. However, parametric analysis revealed an association between nightmare frequency and ReHo differences in the cerebellum.

Conclusions

This failure to confirm hypothesized and previously reported results, especially with a larger sample size, suggests a need to reevaluate the existing knowledge of the neural correlates of nightmares and consider individual differences such as personality, trauma history, and cognitive processes. Overall, our findings highlight the complexities of interpreting neuroimaging data in sleep research.
Aging-associated Alterations in the Gene Regulatory Network Landscape Associate with Risk, Prognosis and Response to Therapy in Lung Adenocarcinoma
Authors: Saha Enakshi , Ben Guebila Marouen , Fanfani Viola , Shutta Katherine H. , DeMeo Dawn L. , Quackenbush John , Lopes-Ramos Camila M.
Published: July 2024

Aging is the primary risk factor for many individual cancer types, including lung adenocarcinoma (LUAD). To understand how aging-related alterations in the regulation of key cellular processes might affect LUAD risk and survival outcomes, we built individual (person)-specific gene regulatory networks integrating gene expression, transcription factor protein-protein interaction, and sequence motif data, using PANDA/LIONESS algorithms, for both non-cancerous lung tissue samples from the Genotype Tissue Expression (GTEx) project and LUAD samples from The Cancer Genome Atlas (TCGA). In GTEx, we found that pathways involved in cell proliferation and immune response are increasingly targeted by regulatory transcription factors with age; these aging-associated alterations are accelerated by tobacco smoking and resemble oncogenic shifts in the regulatory landscape observed in LUAD and suggests that dysregulation of aging pathways might be associated with an increased risk of LUAD. Comparing normal adjacent samples from individuals with LUAD with healthy lung tissue samples from those without LUAD, we found that aging-associated genes show greater aging-biased targeting patterns in younger individuals with LUAD compared to their healthy counterparts of similar age, a pattern suggestive of age acceleration. This implies that an accelerated aging process may be responsible for tumor incidence in younger individuals. Using drug repurposing tool CLUEreg, we found small molecule drugs with potential geroprotective effects that may alter the accelerating aging profiles we found. We also observed that, in contrast to chronological age, a network-informed aging signature was associated with survival and response to chemotherapy in LUAD.
TORC1-containing signaling endosomes source membrane from vacuoles
Authors: Muneshige Kenji , Hatakeyama Riko
Published: July 2024

Organelle biogenesis is fundamental to eukaryotic cell biology. Yeast signaling endosomes were recently identified as a signaling platform for the evolutionarily conserved Target of Rapamycin Complex 1 (TORC1) kinase complex. Despite the importance of signaling endosomes for TORC1-mediated control of cellular metabolism, how this organelle is generated has been a mystery. Here, we developed a system to induce synchronizedde novoformation of signaling endosomes, enabling real-time monitoring of their biogenesis. Using this system, we identify vacuoles as a membrane source for newly formed signaling endosomes. Membrane supply from vacuoles is mediated by the CROP membrane-cutting complex, consisting of Atg18 PROPPIN and retromer subunits. The formation of signaling endosomes requires TORC1 activity, suggestive of a tightly regulated process. This study unveiled the first mechanistic principles and molecular participants of signaling endosome biogenesis.

Membrane is supplied by vacuoles during biogenesis of yeast signaling endosomes, in a process mediated by the membrane-cutting CROP complex and promoted by TORC1 kinase activity.
Transdiagnostic Neurobiology of Social Cognition and Individual Variability as Measured by Fractional Amplitude of Low-Frequency Fluctuation in Schizophrenia and Autism Spectrum Disorders
Authors: Bagheri Soroush , Yu Ju-Chi , Gallucci Julia , Tan Vinh , Oliver Lindsay D. , Dickie Erin W. , Rashidi Ayesha G. , Foussias George , Lai Meng-Chuan , Buchanan Robert W. , Malhotra Anil K. , Voineskos Aristotle N. , Ameis Stephanie H. , Hawco Colin
Published: July 2024

Fractional amplitude of low-frequency fluctuation (fALFF) is a validated measure of resting-state spontaneous brain activity. Previous fALFF findings in autism and schizophrenia spectrum disorders (ASDs and SSDs) have been highly heterogeneous. We aimed to use fALFF in a large sample of typically developing control (TDC), ASD and SSD participants to explore group differences and relationships with inter-individual variability of fALFF maps and social cognition. fALFF from 495 participants (185 TDC, 68 ASD, and 242 SSD) was computed using functional magnetic resonance imaging as signal power within two frequency bands (i.e., slow-4 and slow-5), normalized by the power in the remaining frequency spectrum. Permutation analysis of linear models was employed to investigate the relationship of fALFF with diagnostic groups, higher-level social cognition, and lower-level social cognition. Each participant’s average distance of fALFF map to all others was defined as a variability score, with higher scores indicating less typical maps. Lower fALFF in the visual and higher fALFF in the frontal regions were found in both SSD and ASD participants compared with TDCs. Limited differences were observed between ASD and SSD participants in the cuneus regions only. Associations between slow-4 fALFF and higher-level social cognitive scores across the whole sample were observed in the lateral occipitotemporal and temporoparietal junction. Individual variability within the ASD and SSD groups was also significantly higher compared with TDC. Similar patterns of fALFF and individual variability in ASD and SSD suggest some common neurobiological deficits across these related heterogeneous conditions.
An HERV-WENVtranscription in atypical memory B cells linked to COVID-19 evolution and risk for long COVID can express the encoded protein from a ribosome readthrough of mRNA from chromosome X
Authors: Brunel Joanna , Paganini Julien , Galloux Melissa , Charvet Benjamin , Perron Hervé
Published: July 2024

The human genome comprises 8% of endogenous retroviruses (HERVs). Though HERVS contribute to physiological functions, copies retained pathogenic potential. The HERV-W ENV protein was shown expressed in patients with worse COVID-19 symptoms and post-COVID syndrome. A significant detection of the mRNA encoding HERV-W ENV from patients with COVID-19 in B cells from RNAseq reads obtained from peripheral blond mononuclear cells. This data stratified with increased COVID-19 symptoms or with post-acute sequelae of COVID-19 (long COVID) after 3 months. The HERV-WENV-U3RRNA was confirmed to display the best alignment with chromosome X ERVWE2 locus. However, a stop codon precluding its translation was re-addressed after recent understandings of ribosome readthrough mechanisms. Experimental results evidenced that this HERV gene can effectively express a full-length protein in the presence of molecules allowing translation via a readthrough mechanism at the ribosome level. Results not only confirm HERV-WENVRNA origin in these patients, but show for the first time how a defective HERV copy can be translated into a complete protein when specific factors make it possible at the ribosome level. The present proof of concept now requires further studies to identify the factors involved in this newly understood mechanism, following SARS-CoV-2 exposure.
A spatially resolved multiomic single-cell atlas of soybean development
Authors: Zhang Xuan , Luo Ziliang , Marand Alexandre P. , Yan Haidong , Jang Hosung , Bang Sohyun , Mendieta John P. , Minow Mark A.A. , Schmitz Robert J.
Published: July 2024

Cis-regulatory elements (CREs) precisely control spatiotemporal gene expression in cells. Using a spatially resolved single-cell atlas of gene expression with chromatin accessibility across ten soybean tissues, we identified 103 distinct cell types and 303,199 accessible chromatin regions (ACRs). Nearly 40% of the ACRs showed cell-type-specific patterns and were enriched for transcription factor (TF) motifs defining diverse cell identities. We identifiedde novoenriched TF motifs and explored conservation of gene regulatory networks underpinning legume symbiotic nitrogen fixation. With comprehensive developmental trajectories for endosperm and embryo, we uncovered the functional transition of the three sub-cell types of endosperm, identified 13 sucrose transporters sharing the DOF11 motif that were co-up-regulated in late peripheral endosperm and identified key embryo cell-type specification regulators during embryogenesis, including a homeobox TF that promotes cotyledon parenchyma identity. This resource provides a valuable foundation for analyzing gene regulatory programs in soybean cell types across tissues and life stages.
Molecular control of dormancy transitions throughout the year in the monoecious cork oak
Authors: Silva Helena Gomes , Sobral Rómulo , Alhinho Ana Teresa , Afonso Hugo Ricardo , Ribeiro Teresa , Silva Patrícia M. A. , Bousbaa Hassan , Morais-Cecílio Leonor , Costa Maria Manuela Ribeiro
Published: July 2024

Bud dormancy plays a vital role in flowering regulation and fruit production, being highly regulated by endogenous and environmental cues. Deployment of epigenetic modifications and differential gene expression control bud dormancy/break cycles. Information on how these genetic and epigenetic mechanisms are regulated throughout the year is still scarce for temperate trees, such asQuercus suber. Here, the expression levels ofQsCENLandQsDYL1during different seasonal cycles of bud development suggest thatQsCENLmay be implicated in the establishment of growth cessation inQ. suberand thatQsDYL1is a good dormancy marker. Moreover, the analysis of the profiles of epigenetic marks and the expression of modifiers, in dormant versus non-dormant bud meristems, indicate that epigenetic regulation is implicated in how bud development progresses inQ. suber. The identification of bud specific mechanisms opens new possibilities to understand how trees respond to challenging environmental signals derived from climate change.
DWARF14 and KARRIKIN INSENSITIVE2 mediate signaling of the apocarotenoid zaxinone in Arabidopsis
Authors: Moreno Juan C. , Hameed Umar Shahul , Balakrishna Aparna , Ablazov Abdugaffor , Liew Kit Xi , Jamil Muhamad , Mi Jianing , Alashoor Kawthar , de Saint Germain Alexandre , Arold Stefan T. , Al-Babili Salim
Published: July 2024

The natural growth regulator zaxinone increases the levels of the phytohormones strigolactone (SL) and abscisic acid in Arabidopsis (Arabidopsis thaliana) via unknown mechanisms. We demonstrate that parts of the effects of zaxinone in Arabidopsis depend on the SL receptor DWARF14 (AtD14), the karrikin receptor KARRIKIN INSENSITIVE2 (AtKAI2), and the F-Box protein MORE AXILLARY BRANCHING2 (AtMAX2) that mediates the signaling of SLs and karrikins. Binding assays and co-crystallization revealed zaxinone as an additional ligand ofAtD14 and an SL antagonist that interrupts the interaction ofAtD14 withAtMAX2. Zaxinone also bound toAtKAI2. These findings unveil a perception mechanism for zaxinone in Arabidopsis and demonstrate the capability ofAtD14 andAtKAI2 to bind signaling molecules, other than strigolactones or karrikins, and mediate their transduction.
More on black holes perceiving the dark dimension
Authors: Anchordoqui Luis A. , Antoniadis Ignatios , Lüst Dieter
Published: July 2024

In the last two years, the dark dimension scenario has emerged as focal point of many research interests. In particular, it functions as a stepping stone to address the cosmological hierarchy problem and provides a colosseum for dark matter contenders. We reexamine the possibility that primordial black holes (PBHs) perceiving the dark dimension could constitute all of the dark matter in the Universe. We reassess limits on the abundance of PBHs as dark matter candidates from γ-ray emission resulting from Hawking evaporation. We reevaluate constraints from the diffuse γ-ray emission in the direction of the Galactic Center that offer the best and most solid upper limits on the dark matter fraction composed of PBHs. The revised mass range that allows PBHs to assemble all cosmological dark matter is estimated to be 1015≲MBH/g≲1021. We demonstrate that, due to the constraints from γ-ray emission, quantum corrections due to the speculative memory burden effect do not modify this mass range. We also investigate the main characteristics of PBHs that are localized in the bulk. We show that PBHs localized in the bulk can make all cosmological dark matter if 1011≲MBH/g≲1021. Finally, we comment on the black holes that could be produced if one advocates a space with two boundaries for the dark dimension.

Published by the American Physical Society
2024
Diffeomorphism invariant classical-quantum path integrals for Nordström gravity
Authors: Oppenheim Jonathan , Russo Andrea , Weller-Davies Zachary
Published: July 2024

When classical degrees of freedom and quantum degrees of freedom are consistently coupled, the former diffuse, while the latter undergo decoherence. Here, we construct a theory of quantum matter fields and Nordström gravity in which the space-time metric is treated classically. The dynamics is constructed via the classical-quantum path integral and is completely positive, trace preserving (CPTP) and respects the classical-quantum split. The weak-field limit of the model matches the Newtonian limit of the full covariant path integral, but it is easier to show that the theory is both diffeomorphism invariant and CPTP and has the appropriate classical limit.

Published by the American Physical Society
2024
Momentum-dependent field redefinitions in asymptotic safety
Authors: Knorr Benjamin
Published: July 2024

We discuss general momentum-dependent field redefinitions in the context of quantum-gravitational scattering amplitudes in general, and asymptotic safety in particular. Implementing such redefinitions at the lowest curvature order, we can bring the graviton propagator into tree-level form, avoiding issues of fiducial ghost poles and their associated violations of unitarity. We compute the beta function for Newton’s constant, and find an asymptotically safe fixed point whose critical exponent changes by 0.4% compared to not resolving the momentum-dependent field redefinition. This provides a strong indication that this fixed point does not feature extra degrees of freedom related to ghostly modes, and has a good chance of being related to a unitary theory.

Published by the American Physical Society
2024