bluuebunny/crossref_metadata_2025 huggingface dataset:
TDP-43 safeguards the embryo genome from L1 retrotransposition
Authors: Li Ten D. , Murano Kensaku , Kitano Tomohiro , Guo Youjia , Negishi Lumi , Siomi Haruhiko
Published: September 2022

Transposable elements (TEs) are genomic parasites that propagate within the host genome and introduce mutations. Long interspersed nuclear element-1 (LINE-1 or L1) is the major TE class, which occupies nearly 20% of the mouse genome. L1 is highly active in mammalian preimplantation embryos, posing a major threat to genome integrity, but the mechanism of stage-specific protection against L1 retrotransposition is unknown. Here, we show that TAR DNA binding protein 43 (TDP-43), mutations in which constitute a major risk factor for amyotrophic lateral sclerosis (ALS), inhibits L1 retrotransposition in mouse embryonic stem cells (mESCs) and preimplantation embryos. Knock-down of TDP-43 resulted in massive genomic L1 expansion and impaired cell growth in preimplantation embryos and ESCs. Functional analysis demonstrated that TDP-43 interacts with L1 open reading frame 1 protein (L1 ORF1p) to mediate genomic protection, and loss of this interaction led to de-repression of L1 retrotransposition. Our results identify TDP-43 as a guardian of the embryonic genome.

Teaser

Knocking-down of TDP-43 causes massive L1 retrotransposition in preimplantation embryos.
Viridiplantae-specific GLXI and GLXII isoforms co-evolved and detoxify glucosonein planta
Authors: Balparda Manuel , Schmitz Jessica , Duemmel Martin , Wuthenow Isabell C. , Schmidt Marc , Alseekh Saleh , Fernie Alisdair R. , Lercher Martin J. , Maurino Veronica G.
Published: September 2022

Reactive carbonyl species (RCS) such as methylglyoxal (MGO) and glyoxal (GO) are highly reactive, unwanted side-products of cellular metabolism maintained at harmless intracellular levels by specific scavenging mechanisms. MGO and GO are metabolized through the glyoxalase (GLX) system, which consists of two enzymes acting in sequence, GLXI and GLXII. While plant genomes encode a large number of different GLX isoforms, it is unclear what their specific functions are and how these arose in evolution. Here, we show that plants possess two GLX systems of different evolutionary origins and with distinct structural and functional properties. The first system is shared by all eukaryotes, scavenges MGO and GO especially during seedling establishment, and features Zn2+-type GLXI, a metal co-factor preference that arose already in the last eukaryotic common ancestor. The GLXI and GLXII of the second system can together metabolize KDG, a glucose-derived RCS, and were acquired by the last common ancestor of viridiplantae through horizontal gene transfer from proteobacteria. In contrast to bacterial GLXI homologs, which are active as dimers, plant Ni2+-type GLXI contain a domain duplication, are active as monomers, and have modified their second active site. The acquisition and neofunctionalization of a structurally, biochemically, and functionally distinct GLX systems indicate that viridiplantae are under strong selection to detoxify a diversity of RCS.
„APP family member dimeric complexes are formed predominantly in synaptic compartments“
Authors: Schilling S. , August A. , Meleux M. , Conradt C. , Tremmel L. , Teigler S. , Adam V. , Koo E.H. , Kins S. , Eggert S.
Published: September 2022

The amyloid precursor protein (APP), a key player in Alzheime’s disease (AD), is part of a larger gene family, including the APP like proteins APLP1 and APLP2. They share similar structures, form homo- and heterotypic dimers and exhibit overlapping functions. We investigated complex formation of the APP family members via two inducible dimerization systems, the FKBP-rapamycin based dimerization as well as cysteine induced dimerization, combined with coimmunoprecipitations and Blue Native (BN) gel analyses. Within the APP family, APLP1 shows the highest degree of dimerization and high molecular weight (HMW) complex formation. Interestingly, about 20% of APP is dimerized in cultured cells while about 50% of APP is dimerized in mouse brains, independent of age and splice forms. Furthermore, we could show that dimerized APP originates mostly from neurons and is enriched in synaptosomes. Finally, BN gel analysis of human cortex samples shows a significant decrease of APP dimers in AD patients compared to controls, suggesting that loss of dimers of full-length APP might correlate with loss of synapses in the process of AD.
No need for extensive artifact rejection for ICA - A multi-study evaluation on stationary and mobile EEG datasets
Authors: Klug M. , Berg T. , Gramann K.
Published: September 2022

Objective

Electroencephalography (EEG) studies increasingly make use of more ecologically valid experimental protocols involving mobile participants who actively engage with their environment (MoBI; Gramann et al., 2011). These mobile paradigms lead to increased artifacts in the recorded data that are often treated using Independent Component Analysis (ICA). When analyzing EEG data, especially in a mobile context, removing samples regarded as artifactual is a common approach before computing ICA. Automatic tools for this exist, such as the automatic sample rejection of the AMICA algorithm (Palmer et al., 2011), but the impact of the two factors movement intensity and the automatic sample rejection has not been systematically evaluated yet.

Approach

We computed AMICA decompositions on eight datasets from six open-access studies with varying degrees of movement intensities using increasingly conservative sample rejection criteria. We evaluated the subsequent decomposition quality in terms of the component mutual information, the amount of brain, muscle, and “other” components, the residual variance of the brain components, and an exemplary signal-to-noise ratio.

Main results

We found that increasing movements of participants led to decreasing decomposition quality for individual datasets but not as a general trend across all movement intensities. The cleaning strength had less impact on decomposition results than anticipated, and moderate cleaning of the data resulted in the best decompositions.

Significance

Our results indicate that the AMICA algorithm is very robust even with limited data cleaning. Moderate amounts of cleaning such as 5 to 10 iterations of the AMICA sample rejection with 3 standard deviations as the threshold will likely improve the decomposition of most datasets, irrespective of the movement intensity.
Involvement of an IgE/Mast cell/B cell amplification loop in abdominal aortic aneurysm progression
Authors: Loste Alexia , Clément Marc , Delbosc Sandrine , Guedj Kevin , Sénémaud Jean , Gaston Anh-Thu , Morvan Marion , Even Guillaume , Gautier Grégory , Eggel Alexander , Arock Michel , Procopio Emanuele , Deschildre Catherine , Louedec Liliane , Michel Jean-Baptiste , Deschamps Lydia , Castier Yves , Coscas Raphaël , Alsac Jean-Marc , Launay Pierre , Caligiuri Giuseppina , Nicoletti Antonino , Borgne Marie Le
Published: September 2022

Aims

IgE type immunoglobulins and their specific effector cells, mast cells (MCs), are associated with abdominal aortic aneurysm (AAA) progression. In parallel, immunoglobulin-producing B cells, organised in tertiary lymphoid organs (TLOs) within the aortic wall, have also been linked to aneurysmal progression. We aimed at investigating the potential role and mechanism linking local MCs, TLO B cells, and IgE production in aneurysmal progression.

Methods and Results

Through histological assays conducted on human surgical samples from AAA patients, we uncovered that activated MCs were enriched at sites of unhealed haematomas, due to subclinical aortic wall fissuring, in close proximity to adventitial IgE+ TLO B cells. Remarkably,in vitrothe IgEs deriving from these samples enhanced MC production of IL-4, a cytokine which favors IgE class-switching and production by B cells. Finally, the role of MCs in aneurysmal progression was further analysedin vivoin ApoE-/-mice subjected to angiotensin II infusion aneurysm model, through MC-specific depletion after the establishment of dissecting aneurysms. MC-specific depletion improved intramural haematoma healing and reduced aneurysmal progression.

Conclusions

Our data suggest that MC located close to aortic wall fissures are activated by adventitial TLO B cell-produced IgEs and participate to their own activation by providing support for further IgE synthesis through IL-4 production. By preventing prompt repair of aortic subclinical fissures, such a runaway MC activation loop could precipitate aneurysmal progression, suggesting that MC-targeting treatments may represent an interesting adjunctive therapy for reducing AAA progression.
Deep6: Classification of Metatranscriptomic Sequences into Cellular Empires and Viral Realms Using Deep Learning Models
Authors: Finke Jan F. , Kellogg Colleen , Suttle Curtis A.
Published: September 2022

Metatranscriptomic data is increasingly used to study viral diversity and activity; yet, identifying and taxonomically assigning viral sequences is still challenging. Deep6 is a deep-learning model that classifies metatranscriptomic sequences into six groups: prokaryotes, eukaryotes, or one of the four viral realms. Deep6 is trained on reference coding sequences, but classification of query sequences is done reference-independent and alignment-free. The provided model is optimized for marine samples and can process sequences as short as 250 nucleotides. Average accuracies range from 0.87 to 0.97 depending on sequence length. Additionally, Deep6 includes scripts to easily encode and train custom models for other environments.
Regenerative MRL/MpJ Tendon Cells Exhibit Sex Differences in Morphology, Proliferation, Mechanosensitivity, and Cell-Matrix Remodeling
Authors: Marvin Jason C. , Brakewood Molly E. , Poon Mong Lung Steve , Andarawis-Puri Nelly
Published: September 2022

Clinical and animal studies have reported the influence of sex on the incidence and progression of tendinopathy, which results in disparate structural and biomechanical outcomes. However, there remains a paucity in our understanding of the sex-specific biological mechanisms underlying effective tendon healing. To overcome this hurdle, our group has investigated the impact of sex on tendon regeneration using the super-healer Murphy Roths Large (MRL/MpJ) mouse strain. Despite a shared scarless healing capacity, we have shown that MRL/MpJ patellar tendons exhibit sexually dimorphic regulation of gene expression for pathways involved in fibrosis, cell migration, and extracellular matrix (ECM) remodeling following an acute midsubstance injury. Moreover, we previously found decreased matrix metalloproteinase-2 (MMP-2) activity in female MRL/MpJ tendons after injury. Thus, we hypothesized that MRL/MpJ scarless tendon healing is mediated by sex-specific and temporally distinct orchestration of cell-ECM interactions. Accordingly, the present study comparatively evaluated MRL/MpJ tendon cells under two-dimensional (glass) and three-dimensional (nanofiber scaffolds) culture platforms to examine cell behavior under biochemical and biophysical cues associated with tendon homeostasis and healing. Female MRL/MpJ cells showed reduced 2D migration and spreading area accompanied with enhanced mechanosensing, 2D ECM alignment, and fibronectin-dependent cell proliferation. Interestingly, female MRL/MpJ cells cultured on 3D isotropic scaffolds showed diminished ECM deposition and alignment. Regardless of culture condition and sex, MRL/MpJ cells outperformed B6 cells and elicited a universal regenerative cellular phenotype. These results illustrate the utility of these in vitro systems for elucidating regenerative tendon cell biology, which will facilitate the long-term development of more equitable therapeutics.
Evolutionary crowdsourcing: alignment of fitness landscapes allows cross-species adaptation of a horizontally transferred gene
Authors: Kosterlitz Olivia , Grassi Nathan , Werner Bailey , McGee Ryan Seamus , Top Eva M. , Kerr Benjamin
Published: September 2022

Genes that undergo horizontal gene transfer (HGT) evolve in different genomic backgrounds as they move between hosts, in contrast to genes that evolve under strict vertical inheritance. Despite the ubiquity of HGT in microbial communities, the effects of host-switching on gene evolution have been understudied. Here, we present a novel framework to examine the consequences of host-switching on gene evolution by probing the existence and form of host-dependent mutational effects. We started exploring the effects of HGT on gene evolution by focusing on an antibiotic resistance gene (encoding a beta-lactamase) commonly found on conjugative plasmids in Enterobacteriaceae pathogens. By reconstructing the resistance landscape for a small set of mutationally connected alleles in three enteric species (Escherichia coli, Salmonella enterica, and Klebsiella pneumoniae), we uncovered that the landscape topographies were largely aligned with very low levels of host-dependent mutational effects. By simulating gene evolution with and without HGT using the species-specific empirical landscapes, we found that evolutionary outcomes were similar despite HGT. These findings suggest that the adaptive evolution of a mobile gene in one species can translate to adaptation in another species. In such a case, vehicles of cross-species HGT such as plasmids enable a distributed form of genetic evolution across a bacterial community, where species can ‘crowdsource’ adaptation from other community members. The role of evolutionary crowdsourcing on the evolution of bacteria merits further investigation.
Meteorin alleviates Paclitaxel-induced peripheral neuropathy in mice
Authors: Sankaranarayanan Ishwarya , Tavares-Ferreira Diana , He Lucy , Kume Moeno , Mwirigi Juliet , Madsen Torsten M. , Petersen Kenneth A. , Munro Gordon , Price Theodore J.
Published: September 2022

Chemotherapy-induced peripheral neuropathy (CIPN) is a challenging condition to treat, and arises due to severe, dose-limiting toxicity of chemotherapeutic drugs such as paclitaxel. This often results in debilitating sensory and motor deficits that are not effectively prevented or alleviated by existing therapeutic interventions. Recent studies have demonstrated the therapeutic effects of Meteorin, a neurotrophic factor, in reversing neuropathic pain in rodent models of peripheral nerve injury induced by physical trauma. Here, we sought to investigate the potential antinociceptive effects of recombinant mouse Meteorin (rmMeteorin) using a paclitaxel-induced peripheral neuropathy model in male and female mice. Paclitaxel treatment (4 x 4mg/kg, i.p.) induced hind paw mechanical hypersensitivity by day 8 after treatment. Thereafter, in a reversal dosing paradigm, five repeated injections of rmMeteorin (0.5 and 1.8mg/kg s.c. respectively) administered over 9 days produced a significant and long-lasting attenuation of mechanical hypersensitivity in both sexes. Additionally, administration of rmMeteorin (0.5 and 1.8mg/kg), initiated before and during paclitaxel treatment (prevention dosing paradigm), blocked the establishment of hind paw mechanical hypersensitivity. Repeated systemic administration of rmMeteorin in both dosing paradigms decreased histochemical signs of satellite glial cell reactivity as measured by glutamine synthetase and connexin43 protein expression in the DRG. Additionally, in the prevention administration paradigm rmMeteorin had a protective effect against paclitaxel-induced loss of intraepidermal nerve fibers. Our findings indicate that rmMeteorin has a robust and sustained antinociceptive effect in the paclitaxel-induced peripheral neuropathy model and the development of recombinant human Meteorin could be a novel and effective therapeutic for CIPN treatment.

Highlights

Meteorin produces an antinociceptive effect in both male and female mice treated with paclitaxel.

Satellite glial cell reactivity induced by paclitaxel treatment is reversed by Meteorin.

Retraction of intraepidermal nerve fibre (IENF) is blocked by Meteorin treatment in paclitaxel treated mice.

Findings suggest a disease modifying effect of Meteorin in the mouse model of paclitaxel-induced peripheral neuropathy.
Mobility of the human foot’s medial arch enables upright bipedal locomotion
Authors: Welte Lauren , Holowka Nicholas B , Kelly Luke A , Arndt Toni , Rainbow Michael J
Published: September 2022

Developing the ability to habitually walk and run upright on two feet is one of the most significant transformations to have occurred in human evolution. Many musculoskeletal adaptations enabled bipedal locomotion, including dramatic structural changes to the foot and, in particular, the evolution of an elevated medial arch (H. Elftman and Manter, 1935). The foot’s arched structure has previously been assumed to play a central role in directly propelling the centre of mass forward and upward through leverage about the toes (Herbert Elftman and Manter, 1935) and a spring-like energy recoil (Hicks, 1955). Paradoxically, these roles seemingly require either arch rigidity (for the former) or mobility (for the latter). However, it is unclear whether or how the mobility and height of the medial arch support its propulsive lever function. Here we show, using high-speed biplanar x-ray, that regardless of intraspecific differences in medial arch height, arch recoil enables a longer contact time and favourable propulsive conditions for walking upright on an extended leg. This mechanism presumably helped drive the evolution of the longitudinal arch after our last common ancestor with chimpanzees, who lack this mobility during push-off. We discovered that the previously overlooked navicular-medial cuneiform joint is primarily responsible for this mobility in human arches, suggesting that future morphological investigations of this joint will provide new interpretations of the fossil record. Our work further suggests that enabling the mobility of the longitudinal arch in footwear and surgical interventions is critical for maintaining the ankle’s natural propulsive ability.
Unbalanced response to growth variations reshapes the cell fate decision landscape
Authors: Zhu Jingwen , Chu Pan , Fu Xiongfei
Published: September 2022

The global regulation of cell growth rate on gene expression perturbs the performance of gene networks, which would impose complex variations on the cell-fate decision landscape. Here, we utilize a simple synthetic circuit of mutual repression that allows a bistable landscape, to examine how such global regulation would affect the stability of phenotypic landscape and the accompanying dynamics of cell-fate determination. We show that the landscape experiences a growth-rate-induced bifurcation between monostability and bistability. Theoretical and experimental analyses reveal that this bifurcating deformation of landscape arises from the unbalanced response of gene expression to growth variations. The path of growth transition across the bifurcation would reshape cell-fate decisions. These results demonstrate the importance of growth regulation on cell-fate determination processes, regardless of specific molecular signalling or regulation.
Siderophore-mediated iron partition promotes dynamical coexistence between cooperators and cheaters
Authors: Shao Jiqi , Rong Nan , Wu Zhenchao , Gu Shaohua , Liu Beibei , Shen Ning , Li Zhiyuan
Published: September 2022

Microbes shape their habitats through consuming resources, as well as actively producing and secreting diverse chemicals. These chemicals serve various niche-construction functions and can be considered “public good” for the community. Most microorganisms, for instance, release small molecules known as siderophores to scavenge irons from the extracellular environment. Despite being exploitable by cheaters, biosynthetic genes producing such molecules widely exist in nature, invoking active investigation on the possible mechanisms for producers to survive cheater invasion. In this work, we utilized the chemostat-typed model to demonstrate that the division of the iron by private and public siderophores can promote stable or dynamical coexistence between the cheater and “partial cooperators”, an adaptive strategy with the production of both public and private siderophores. Further, our analysis revealed that when microbes not only consume but also produce resources, this type of “resource partition model” exhibit different stability criteria than that of the classical consumer resource model, allowing more complex systems dynamics.
Universal abundance fluctuations across microbial communities, tropical forests, and urban populations
Authors: George Ashish B. , O’Dwyer James
Published: September 2022

The growth of complex populations, such as microbial communities, forests, and cities, occurs over vastly different spatial and temporal scales. Although research in different fields has developed detailed, system-specific models to understand each individual system, a unified analysis of different complex populations is lacking; such an analysis could deepen our understanding of each system and facilitate cross-pollination of tools and insights across fields. Here, for the first time we use a shared framework to analyze time-series data of the human gut microbiome, tropical forest, and urban employment. We demonstrate that a single, three-parameter model of stochastic population dynamics can reproduce the empirical distributions of population abundances and fluctuations in all three data sets. The three parameters characterizing a species measure its mean abundance, deterministic stability, and stochasticity. Our analysis reveals that, despite the vast differences in scale, all three systems occupy a similar region of parameter space when time is measured in generations. In other words, although the fluctuations observed in these systems may appear different, this difference is primarily due to the different physical timescales associated with each system. Further, we show that the distribution of temporal abundance fluctuations is described by just two parameters and derive a two-parameter functional form for abundance fluctuations to improve risk estimation and forecasting.
Exocytotic dynamics of glucagon-like peptide-1 from enteroendocrine L cell line is regulated by actin polymerization
Authors: Harada Kazuki , Takashima Maoko , Kitaguchi Tetsuya , Tsuboi Takashi
Published: September 2022

Stimulus-secretion coupling of glucagon-like peptide-1 (GLP-1) from enteroendocrine L cells is important for glucose homeostasis. Although intracellular second messengers including Ca2+ and cAMP, and cellular structures including actin cytoskeleton play roles in induction of exocytosis of GLP-1 granules, little is known about the specific part in the process of exocytosis in which they are involved. Here we explored the role of those molecules by live-cell imaging with mouse L cell line GLUTag cells, and used two stimuli: deoxycholic acid (DCA) and high K+. DCA increased both intracellular Ca2+ and cAMP levels, while high K+ only increased Ca2+. We next monitored a single exocytosis of GLP-1 granules and found that, during the first 10 minutes of stimulation, both stimuli mainly induced the exocytosis from the predocked granules with the plasma membrane before stimulation or granules immediately fused to the plasma membrane without docking. Furthermore, inhibition of actin polymerization suppressed the proportion of exocytosis by the predocked granules. These results suggest that the exocytotic process of GLP-1 granules is determined by interaction with F-actin upon the increase of either Ca2+ or cAMP.

Summary statement

Exocytotic process of glucagon-like peptide-1 granules from a mouse enteroendocrine L cell line is regulated by actin polymerization immediately after elevation of intracellular Ca2+ or cAMP levels.
Ablation of ZC3H11A causes early embryonic lethality and dysregulation of metabolic processes
Authors: Younis Shady , Jouneau Alice , Larsson Mårten , Oudin Jean-Francois , Brochard Vincent , Andersson Leif
Published: September 2022

ZC3H11A is a stress-induced mRNA binding protein required for efficient growth of nuclear-replicating viruses, while being dispensable for the viability of cultured human cells. The cellular functions of ZC3H11A during embryo development are unknown. Here we report the generation and phenotypic characterization of Zc3h11a knock-out mice. Heterozygous null Zc3h11a mice were born at the expected frequency without distinguishable phenotypic differences compared with wild-type. In contrast, homozygous null Zc3h11a mice were missing, indicating that Zc3h11a is crucial for embryonic viability and survival. Zc3h11a−/– embryos were detected at the expected Mendelian ratios up to late preimplantation stage (E4.5). However, phenotypic characterization at E6.5 revealed degeneration of Zc3h11a−/– embryos, indicating developmental defects around the time of implantation. Transcriptomic analyses documented a dysregulation of glycolysis and fatty acid metabolic pathways in Zc3h11a−/– embryos at E4.5. Proteomic analysis indicated a tight interaction between ZC3H11A and mRNA-export proteins in embryonic stem cells. Furthermore, CLIP-seq analysis demonstrated that ZC3H11A binds a subset of mRNA transcripts that are critical for metabolic regulation of embryonic cells. Altogether, the results show that ZC3H11A is participating in export and post-transcriptional regulation of selected mRNA transcripts required to maintain metabolic processes in embryonic cells. While ZC3H11A is essential for the viability of the early mouse embryo, inactivation of Zc3h11a expression in adult tissues using a conditional knock-out did not lead to obvious phenotypic defects.
Survey of activation-induced genome architecture reveals a novel enhancer of Myc
Authors: Chan Wing Fuk , Coughlan Hannah D , Ruhle Michelle , Iannarella Nadia , Alvarado Carolina , Groom Joanna R. , Keenan Christine R , Kueh Andrew J. , Wheatley Adam K. , Smyth Gordon K , Allan Rhys S , Johanson Timothy M
Published: September 2022

The transcription factor Myc is critically important in driving cell proliferation, a function that is frequently dysregulated in cancer. To avoid this dysregulation Myc is tightly controlled by numerous layers of regulation. One such layer is the use of distal regulatory enhancers to drive Myc expression. Here, using chromosome conformation capture to examine B cells of the immune system in the first hours after their activation, we reveal a previously unidentified enhancer of myc. The interactivity of this enhancer coincides with a dramatic, but discrete, spike in Myc expression 3 hours post-activation. However, genetic deletion of this region, has little impact on Myc expression, Myc protein level or in vitro and in vivo cell proliferation. Examination of the enhancer deleted regulatory landscape suggests that enhancer redundancy likely sustains Myc expression. This work highlights not only the importance of temporally examining enhancers, but also the complexity and dynamics of the regulation of critical genes such as Myc.
SARS-CoV-2 infection of human neurons requires endosomal cell entry and can be blocked by inhibitors of host phosphoinositol-5 kinase
Authors: Kettunen Pinja , Lesnikova Angelina , Räsänen Noora , Ojha Ravi , Palmunen Leena , Laakso Markku , Lehtonen Šárka , Kuusisto Johanna , Pietiläinen Olli , Vapalahti Olli P. , Kostinaho Jari , Rolova Taisia , Balistreri Giuseppe
Published: September 2022

COVID-19 is a disease caused by coronavirus SARS-CoV-2. In addition to respiratory illness, COVID-19 patients exhibit neurological symptoms that can last from weeks to months (long COVID). It is unclear whether these neurological manifestations are due to infection of brain cells. We found that a small fraction of cortical neurons, but not astrocytes, were naturally susceptible to SARS-CoV-2. Based on the inhibitory effect of blocking antibodies, the infection seemed to depend on the receptor angiotensin-converting enzyme 2 (ACE2), which was expressed at very low levels. Although only a limited number of neurons was infectable, the infection was productive, as demonstrated by the presence of double-stranded RNA in the cytoplasm (the hallmark of viral replication), abundant synthesis of viral late genes localized throughout the neuronal cell, and an increase in viral RNA in the culture medium within the first 48 h of infection (viral release). The productive entry of SARS-CoV-2 requires the fusion of the viral and cellular membranes, which results in the delivery of viral genome into the cytoplasm of the target cell. The fusion is triggered by proteolytic cleavage of the viral surface protein spike, which can occur at the plasma membrane or from endo/lysosomes. Using specific combinations of small-molecule inhibitors, we found that SARS-CoV-2 infection of human neurons was insensitive to nafamostat and camostat, which inhibit cellular serine proteases found on the cell surface, including TMPRSS2. In contrast, the infection was blocked by apilimod, an inhibitor of phosphatidyl-inositol 5 kinase (PIK5K) that regulates endosomal maturation.

Importance

COVID-19 is a disease caused by coronavirus SARS-CoV-2. Millions of patients display neurological symptoms, including headache, impairment of memory, seizures and encephalopathy, as well as anatomical abnormalities such as changes in brain morphology. Whether these symptoms are linked to brain infection is not clear. The mechanism of the virus entry into neurons has also not been characterized. Here we investigated SARS-CoV-2 infection using a human iPSC-derived neural cell model and found that a small fraction of cortical neurons was naturally susceptible to infection. The infection depended on the ACE2 receptor and was productive. We also found that the virus used the late endosomal/lysosomal pathway for cell entry and that the infection could be blocked by apilimod, an inhibitor of the cellular phosphatidyl-inositol 5 kinase.
The transcriptional and epigenetic reprogramming associated with chronic IL1β-mediated expansion and myeloid priming in TET2 deficient stem and progenitor cells
Authors: McClatchy J. , Strogantsev R. , Wolfe E. , Lin H. , Mohammadhosseini M. , Davis B.A. , Eden C. , Goldman D. , Fleming W.H. , Conley P , Wu G. , Cimmino L. , Mohammed H. , Agarwal A.
Published: September 2022

Clonal hematopoiesis (CH) increases the risk for the development of hematological malignancy and cardiovascular disease. IL1β is elevated in patients with CH and its inhibition mitigates cardiovascular risk in murine models withTet2loss-of-function. How IL1β alters population dynamics of hematopoietic cells uponTet2deletion (Tet2-KO) is not well understood. We demonstrated IL1β expandsTet2-KO monocytes/macrophages, and long-term hematopoietic stem cells. IL1β promoted myeloid bias over other lineages ofTet2-KO HSPCs coinciding with the failure to demethylate lineage-associated enhancer and transcription factor binding sites. IL1β enhanced the self-renewal ability ofTet2-KO HSPCs by upregulating genes associated with self-renewal and by resisting the demethylation of binding sites of transcription factors promoting terminal differentiation. The IL1β-mediated premalignant phenotype is suppressed by the IL1β antagonist or deletion of the IL1 receptor-1,in vivoin aged mice. Our results demonstrate that targeting IL1 signaling could be an efficient early intervention strategy in preleukemic disorders.

STATEMENT OF SIGNIFICANCE

IL1β promoted myeloid expansion and self-renewal capacity ofTET2-nullpre-leukemic cells. Lineage bias occurred early within progenitors towards pro-inflammatory macrophages. Genes specific to aging and with roles in promoting self-renewal capacity, and myeloid bias were upregulated. Hypermethylation occurred within lymphoid and erythroid lineage-specific regulatory elements. Targeting IL1R1 reduced aberrant myeloid bias and premalignant phenotype.
The filipodia-like protrusions of adjacent somatic cells shape the developmental potential of mouse oocytes
Authors: Crozet Flora , Letort Gaëlle , Da Silva Christelle , Eichmuller Adrien , Tortorelli Anna Francesca , Belle Morgane , Dumont Julien , Piolot Tristan , Dauphin Aurélien , Coulpier Fanny , Chédotal Alain , Maître Jean-Léon , Verlhac Marie-Hélène , Clarke Hugh.J , Terret Marie-Emilie
Published: September 2022

The oocyte must grow and mature before fertilization, thanks to a close dialogue with the somatic cells which surround it. Part of this communication is through filopodialike protrusions, called transzonal projections (TZPs), sent by the somatic cells to the oocyte membrane. To investigate the contribution of TZPs to oocyte quality, we impaired their structure by generating a full knockout mouse of the TZP structural component Myosin-X (MYO10). Using spinning disk and super-resolution microscopy combined with a machine learning approach to phenotype oocyte morphology, we show that the lack ofMyo10decreases TZP density during oocyte growth. Reduction in TZPs does not prevent oocyte growth but impairs oocyte-matrix integrity. Importantly, we reveal by transcriptomic analysis that gene expression is altered in TZP-deprived oocytes, and that oocyte maturation and subsequent early embryonic development are partially affected, effectively reducing mouse fertility. We propose that TZPs play a role in the structural integrity of the germline-somatic complex, which is essential for regulating gene expression in the oocyte and thus its developmental potential.
Zinc-finger protein 518 plays a crucial role in pericentromeric heterochromatin formation by linking satellite DNA to heterochromatin
Authors: Ohta Shinya , Ohzeki Jun-Ichirou , Sato Nobuko , Noma Ken-Ichi , Masumoto Hiroshi
Published: September 2022

Aneuploidy is caused by chromosomal missegregation and is frequently observed in cancers and hematological diseases. Pericentromeric heterochromatin formation is essential for proper chromosome segregation; however, it is unclear how heterochromatin is targeted to pericentromeres. In this study, we investigated the involvement of two homologous zinc-finger proteins (ZNF518A and ZNF518B) in heterochromatin formation at pericentromeres by determining the cellular localization of ZNF518, centromeric proteins such as CENP-A and CENP-B, and heterochromatin factors, including HP1 and histone H3K9 trimethylation. The results showed that various segments in ZNF518 interact with CENP-B, HP1, and G9a histone H3K9 methyltransferase. In conclusion, we identified a novel mechanism underlying pericentromeric heterochromatin formation mediated by ZNF518.
Single-cell brain organoid screening identifies developmental defects in autism
Authors: Li Chong , Fleck Jonas Simon , Martins-Costa Catarina , Burkard Thomas R. , Stuempflen Marlene , Vertesy Ábel , Peer Angela Maria , Esk Christopher , Elling Ulrich , Kasprian Gregor , Corsini Nina S. , Treutlein Barbara , Knoblich Juergen A.
Published: September 2022

Development of the human brain involves processes that are not seen in many other species, but can contribute to neurodevelopmental disorders (1–4). Cerebral organoids can be used to investigate neurodevelopmental disorders in a human context but are limited by variability and low throughput. We have developed the CRISPR-human organoids-scRNA-seq (CHOOSE) system that utilizes verified pairs of gRNAs, inducible CRISPR/Cas9-based genetic disruption, and single-cell transcriptomics for pooled loss-of-function screening in mosaic organoids. Genetic perturbations of 36 high-risk autism spectrum disorder (ASD) genes related to transcriptional regulation allowed us to identify their effects on cell fate determination and discover developmental stages susceptible to ASD gene perturbations. We construct a developmental gene regulatory network (GRN) of cerebral organoids from single-cell multiomic data including transcriptome and chromatin modalities and identify ASD-associated and perturbation-enriched regulatory modules. We show that perturbing members of the BAF chromatin remodeling complex leads to an expanded population of ventral telencephalon progenitors. Specifically, the BAF subunit ARID1B controls the fate transitions of progenitors to oligodendrocyte precursor cells and interneurons, which we confirmed in patient-specific induced pluripotent stem cell (iPSC) derived organoids. Our study paves the way for phenotypically characterizing disease susceptibility genes in human organoid models with cell type, developmental trajectory, and gene regulatory network readouts.
Time to budbreak is not enough: cold hardiness evaluation is necessary in dormancy and spring phenology studies
Authors: North Michael G. , Kovaleski Al P.
Published: September 2022

Dormancy of buds is an important phase in the life cycle of perennial plants growing in environments where unsuitable growth conditions occur seasonally. In regions where low temperature defines these unsuitable conditions, the attainment of cold hardiness is also required to survive. The end of the dormant period culminates in budbreak and flower emergence, or spring phenology, one of the most appreciated and studied phenological events. Despite this, we have a limited physiological and molecular understanding of dormancy, which has negatively affected our ability to model budbreak. Here we highlight the importance of including cold hardiness in studies that typically only characterize time to budbreak. We show how different temperature treatments may lead to increases in cold hardiness, and by doing so also (inadvertently) increase time to budbreak. Therefore, erroneous interpretations of data may occur by not phenotyping cold hardiness. Changes in cold hardiness were very likely present in previous experiments to study dormancy, especially when those included below freezing temperature treatments. Separating the effects between chilling accumulation and cold acclimation in future studies will be essential for increasing our understanding of dormancy and spring phenology in plants.
The structure, catalytic mechanism, and inhibitor identification of phosphatidylinositol remodeling MBOAT7
Authors: Wang Kun , Lee Chia-Wei , Sui Xuewu , Kim Siyoung , Wang Shuhui , Higgs Aidan B , Baublis Aaron J , Voth Gregory A , Liao Maofu , Walther Tobias C , Farese Robert V
Published: September 2022

Cells remodel glycerophospholipid acyl chains via the Lands cycle to adjust membrane properties. Membrane-bound O-acyltransferase (MBOAT) 7 acylates lyso-phosphatidylinositol (lyso-PI) with arachidonyl-CoA. MBOAT7 mutations cause brain developmental disorders, and reduced expression is linked to fatty liver disease. Further, increased MBOAT7 expression is linked to hepatocellular and renal cancers. The mechanistic basis of MBOAT7 catalysis and substrate selectivity are unknown. Here, we report the structure and a model for the catalytic mechanism of human MBOAT7. Arachidonyl-CoA and lyso-PI access the catalytic center through a twisted tunnel from the cytosol and lumenal sides, respectively. N-Terminal residues on the ER lumenal side determine phospholipid headgroup selectivity: swapping them between MBOATs 1, 5, and 7 converts enzyme specificity for different lyso-phospholipids. Finally, the MBOAT7 structure and virtual screening enabled identification of small-molecule inhibitors that may serve as lead compounds for pharmacologic development.
HOPE-SIM, a cryo-structured illumination fluorescence microscopy system for accurately targeted cryo-electron tomography
Authors: Li Shuoguo , Jia Xing , Niu Tongxin , Zhang Xiaoyun , Qi Chen , Xu Wei , Deng Hongyu , Sun Fei , Ji Gang
Published: September 2022

Cryo-focused ion beam (cryo-FIB) milling technology has been developed for the fabrication of cryo-lamella of frozen native specimens for study by in situ cryo-electron tomography (cryo-ET). However, the precision of the target of interest is still one of the major bottlenecks limiting application. Here, we developed a new cryo-correlative light and electron microscopy (cryo-CLEM) system named HOPE-SIM by incorporating a 3D structured illumination fluorescence microscopy (SIM) system and an upgraded high-vacuum stage to achieve efficiently targeted cryo-FIB. With the 3D super resolution of cryo-SIM as well as our cryo-CLEM software, 3D-View, the correlation precision of targeting region of interest can reach to 150 nm enough for the subsequent cryo-lamella fabrication. We successfully utilized the HOPE-SIM system to prepare cryo-lamellae targeting mitochondria, centrosomes of HeLa cells and herpesvirus assembly compartment of infected BHK-21 cells, which suggests the high potency of the HOPE-SIM system for future in situ cryo-ET workflows.
Semantic and population analysis of the genetic targets related to COVID-19 and its association with genes and diseases
Authors: Papageorgiou Louis , Papakonstantinou Eleni , Diakou Io , Pierouli Katerina , Dragoumani Konstantina , Bacopoulou Flora , Chrousos George P , Eliopoulos Elias , Vlachakis Dimitrios
Published: September 2022

SARS-CoV-2 is a coronavirus responsible for one of the most serious, modern worldwide pandemics, with lasting and multi-faceted effects. By late 2021, SARS-CoV-2 has infected more than 180 million people and has killed more than 3 million. The virus gains entrance to human cells through binding to ACE2 via its surface spike protein and causes a complex disease of the respiratory system, termed COVID-19. Vaccination efforts are being made to hinder the viral spread and therapeutics are currently under development. Towards this goal, scientific attention is shifting towards variants and SNPs that affect factors of the disease such as susceptibility and severity. This genomic grammar, tightly related to the dark part of our genome, can be explored through the use of modern methods such as natural language processing. We present a semantic analysis of SARS-CoV-2 related publications, which yielded a repertoire of SNPs, genes and disease ontologies. Population data from the 100Genomes Project were subsequently integrated into the pipeline. Data mining approaches of this scale have the potential to elucidate the complex interaction between COVID-19 pathogenesis and host genetic variation; the resulting knowledge can facilitate the management of high-risk groups and aid the efforts towards precision medicine.
Strategic stances and organizational performance: Are strategic performance measurement systems the missing link?
Authors: Aljuhmani Hasan Yousef , Ababneh Bashar , Emeagwali Lawrence , Elrehail Hamzah
Published: September 2022

Purpose

Although prior researchers have consistently established a significant relationship between different strategic stances and organizational performances across different research contexts, the mechanisms underlying this link remain unclear. This study attempts to fill this gap in the literature by testing the mediating effect of the use of strategic performance measurement systems (SPMS) on the relationship between strategic stances (prospector, defender, and reactor) and organizational performance in the public sector.

Design/methodology/approach

This research is based on data collected by surveying 224 managers at public organizations in the Turkish Republic of Northern Cyprus (TRNC) and conducts an analysis using structural equation modeling (SEM).

Findings

The study findings show that prospector strategy is positively associated with organizational performance through the use of SPMS. The reactor strategy was negatively related to organizational performance through the use of SPMS. The defender strategy shows mixed results in terms of its effect on the use of SPMS and organizational performance.

Research limitations/implications

The results obtained here provide strong evidence of the vitality of the use of SPMS for efficiency and effectiveness as a mediator between prospector strategy and organizational performance. To extend this position, future researchers could incorporate other contingent variables, such as structural autonomy, or use experimental design methods during economic austerity in the aftermath of the coronavirus disease 2019 (COVID-19) global pandemic.

Originality/value

This study represents an attempt to address public administration literature' general calls for grounded research that spells out to practitioners how different strategic stances are likely to affect the use of SPMS to achieve organizational performance levels in the public sector. The present study extends the public administration literature by examining the unexplored linkage of the use of SPMS through which strategic stances influence organizational performance in major public sector organizations.
Analyzing the strength of novelty and meaningfulness in astrotourism experiences: the mediating role of hedonism
Authors: Rodrigues Áurea , Loureiro Sandra Maria Correia
Published: September 2022

Purpose

This study aims to explore the relationships among novelty, meaningfulness, hedonism and loyalty in the context of an astrotourism experience.

Design/methodology/approach

Data were collected using a convenience sample at an astrotourism event in Portugal. A self‐administered questionnaire was designed using established scales. In total, 296 usable responses were analyzed using partial least square (PLS)-structural equation modeling.

Findings

The result of the structural model shows that novelty and meaningfulness affect hedonism, which in turn influences loyalty. Novelty and meaningfulness contribute 62.8% to the variance in hedonism and 31.3% to the variability in loyalty.

Originality/value

This study deepens knowledge of the tourist behavior of astrotourists. Destinations and managers that develop astrotourism activities can also benefit from deeper knowledge about the emotional process of the astrotourism experience and its impact on behavioral loyalty.
The influence of higher learning institutions in developing the experience economy from the perspective of the urban community
Authors: Nor Azazi Noor Alyani , Shaed Maslina Mohammed , Samsurijan Mohamad Shaharudin , Ebekozien Andrew
Published: September 2022

Purpose

The development of higher learning institutions (HLIs) is considered a strategy to trigger urban space development – and it is the economy in most developing countries. HLIs can develop and maintain pace with the experience economy in the current urban economy, particularly in the services sector. This paper seeks to evaluate the influence of HLIs on elements of the experience economy in the urban services sector in Bandar Baru Bangi (BBB), a knowledge-based city.

Design/methodology/approach

The research adopted a purposive sampling technique and engaged 382 urban community respondents in BBB, Malaysia. The study used four elements (education, gastronomy, health, and the retail sectors) to assess the experience economy performance.

Findings

The results show that the local community is the “active users” of the services, and the active users have enjoyed the existence of the experience economy. Findings reveal a preference for education and health over gastronomy and retail sectors. Of these four sectors, the education sector experience had the most prominent effect, thereby showing that the higher learning institutions around this city served a major role in the sector development of urban services.

Research limitations/implications

The research used a purposive sampling method and engaged 382 respondents in BBB, Malaysia. The restriction of the study area to BBB is a limitation component. Future studies should explore a large-scale investigation to evaluate better and validate the results.

Practical implications

The research has shown that the city's higher education institutions have affected the development of the experience economy in the four sectors.

Originality/value

The study shows that the framework of the experience economy and the establishment of HLIs can stimulate the experience economy within the urban services sector.