bluuebunny/crossref_metadata_2025 huggingface dataset:
A Photonic Biosensor-Integrated Tissue Chip Platform for Real-Time Sensing of Lung Epithelial Inflammatory Markers
Authors: Cognetti John S. , Moen Matthew T. , Brewer Matthew G. , Bryan Michael R. , Tice Joshua D. , McGrath James L. , Miller Benjamin L.
Published: June 2022

Tissue chip (TC) devices seek to mimic human physiology on a small scale. They are intended to improve upon animal models in terms of reproducibility and human relevance, at a lower monetary and ethical cost. Virtually all TC systems are analyzed at an endpoint, leading to widespread recognition that new methods are needed to enable sensing of specific biomolecules in real time, as they are being produced by the TC. To address this need, we incorporated photonic biosensors for inflammatory cytokines into a model TC. Human bronchial epithelial cells seeded in a microfluidic device were stimulated with lipopolysaccharide, and the cytokines secreted in response sensed in real time. Sensing analyte transport through the TC in response to disruption of tissue barrier was also demonstrated. This work demonstrates the first application of photonic sensors to a human TC device, and will enable new applications in drug development and disease modeling.
Compensatory aortic remodeling in Marfan syndrome protects against sexually dimorphic rupture during a BAPN challenge
Authors: Weiss D. , Rego B.V. , Cavinato C. , Li D.S. , Kawamura Y. , Emuna N. , Humphrey J.D.
Published: June 2022

Transmural rupture of the aorta is responsible for significant morbidity and mortality; it occurs when wall stress exceeds local wall strength. Amongst other conditions, the aortic root and ascending aorta become vulnerable to dissection and rupture in Marfan syndrome, a connective tissue disorder that results in a progressive fragmentation and degradation of the elastic fibers of the aortic wall. Whereas competent elastic fibers are critical for aortic functionality, cross-linked collagen fibers endow the aorta with its stiffness and strength. In this paper, we contrast progressive degeneration of the ascending aorta in male and female Marfan and wild-type mice, with and without chronic exposure to a potent inhibitor of lysyl oxidase (β-aminopropionitrile, or BAPN), to examine effects of extracellular matrix cross-linking in aortic dilatation and rupture. We found a strong sexual dimorphism in aortic dilatation in Marfan mice and aortic rupture in wild-type mice, but also a compensatory remodeling of the aorta that protected the Marfan aorta against lethal rupture despite a strong BAPN challenge. This compensation appears to be mediated via increased lysyl oxidase in the female and especially male Marfan aorta, resulting in improved collagen fiber stability and integrity, particularly of fibril bundles in the adventitia.
EHD2 overexpression promotes tumorigenesis and metastasis in triple-negative breast cancer by regulating store-operated calcium entry
Authors: Luan Haitao , Bielecki Timothy A. , Mohapatra Bhopal C. , Islam Namista , Mushtaq Insha , Bhat Aaqib M. , Mirza Sameer , Chakraborty Sukanya , Raza Mohsin , Storck Matthew D. , Toss Michael S. , Meza Jane L. , Thoreson Wallace B. , Coulter Donald W. , Rakha Emad A. , Band Vimla , Band Hamid
Published: June 2022

With nearly all cancer deaths a result of metastasis, elucidating novel pro-metastatic cellular adaptations could provide new therapeutic targets. Here, we show that overexpression of the EPS15-Homology Domain-containing 2 (EHD2) protein in a large subset of breast cancers (BCs), especially the triple-negative (TNBC) and HER2+ subtypes, correlates with shorter patient survival. The mRNAs for EHD2 and Caveolin-1/2, structural components of caveolae, show co-overexpression across breast tumors, predicting shorter survival in basal-like BC. EHD2 shRNA knockdown and CRISPR-Cas9 knockoutof EHD2, togetherwith mouse EHD2 rescue, in TNBC cell line models demonstrate a major positive role of EHD2 in promoting tumorigenesis and metastasis. Mechanistically, we link these roles of EHD2 to store-operated calcium entry (SOCE), with EHD2-dependent stabilization of plasma membrane caveolae ensuring high cell surface expression of the SOCE-linked calcium channel Orai1. The novel EHD2-SOCE oncogenic axis represents a potential therapeutic target in EHD2 and CAV1/2-overexpressing BC.
White matter and literacy: a dynamic system in flux
Authors: Roy Ethan , Richie-Halford Adam , Kruper John , Narayan Manjari , Bloom David , Nedelec Pierre , Sugrue Leo P. , Rauschecker Andreas , Brown Timothy T. , Jernigan Terry L. , McCandliss Bruce D. , Rokem Ariel , Yeatman Jason D.
Published: June 2022

Cross-sectional studies have linked differences in white matter tissue properties to reading skills. However, past studies have reported a range of, sometimes conflicting, results. Some studies suggest that white matter properties act as individual-level traits predictive of reading skill, whereas others suggest that reading skill and white matter develop as a function of an individual’s educational experience. In the present study, we tested two hypotheses: a) that diffusion properties of the white matter reflect stable brain characteristics that relate to reading skills over development or b) that white matter is a dynamic system, linked with learning over time. To answer these questions, we examined the relationship between white matter and reading in a five-year longitudinal dataset and a series of large-scale, single-observation, cross-sectional datasets (N=14,249 total participants). We find that gains in reading skill correspond to longitudinal changes in the white matter. However, in the single-observation datasets, we find no evidence for the hypothesis that individual differences in white matter predict reading skill. These findings highlight the link between dynamic processes in the white matter and learning.
Modeling the rarest of the rare: A comparison between joint species distribution models, ensembles of small models, and single-species models at extremely low sample sizes
Authors: Erickson Kelley D. , Smith Adam B.
Published: June 2022

Determining the distribution and environmental preferences of rare species threatened by global change has long been a focus of conservation. Typical minimum suggested number of occurrences ranges from ∼5 to 30, but many species are represented by even fewer occurrences. However, several newer methods may be able to accommodate such low samples sizes. These include Bayesian joint species distribution models (JSDMs) which allow rare species to statistically “borrow strength” from more common species with similar niches, and ensembles of small models (ESMs), which reduce the number of parameters by averaging smaller models. Here we explore how niche breadth and niche position relative to other species influence model performance at low sample sizes (N=2, 4, 8, 16, 32, 64) using virtual species within a community of real species. ESMs were better at discrimination tasks for most species, and yielded better-than-random accuracy even for N=2. In contrast, “traditional” single species or JSDMs were better able to estimate the underlying response curves of variables that influenced the niche, but at low sample sizes also were more likely to incorrectly identify unimportant factors as influential. Species with niches that were narrow and peripheral to the available environmental space yielded models with better discrimination capacity than species with broad niches or niches that were similar to those of other species, regardless of whether the modeling algorithm allowed for borrowing of strength. Our study suggests that some rare species may be able to be modeled reliably at very low sample sizes, although the best algorithm depends on number of occurrences and whether the niche or distribution is the focus.
Wildebeest Herds on Rolling Hills: Flocking on Arbitrary Curved Surfaces
Authors: Hueschen Christina L. , Dunn Alexander R. , Phillips Rob
Published: June 2022

The collective behavior of active agents, whether herds of wildebeest or microscopic actin filaments propelled by molecular motors, is an exciting frontier in biological and soft matter physics. Almost three decades ago, Toner and Tu developed a hydrodynamic theory of the collective action of flocks, or herds, that helped launch the modern field of active matter. One challenge faced when applying continuum active matter theories to living phenomena is the complex geometric structure of biological environments. Both macroscopic and microscopic herds move on asymmetric curved surfaces, like undulating grass plains or the surface layers of cells or embryos, which can render problems analytically intractable. In this work, we present a formulation of the Toner-Tu flocking theory that uses the finite element method to solve the governing equations on arbitrary curved surfaces. First, we test the developed formalism and its numerical implementation in channel flow with scattering obstacles and on cylindrical and spherical surfaces, comparing our results to analytical solutions. We then progress to surfaces with arbitrary curvature, moving beyond previously accessible problems to explore herding behavior on a variety of landscapes. Our approach allows the investigation of transients and dynamic solutions not revealed by analytic methods. It also enables versatile incorporation of new geometries and boundary conditions and efficient sweeps of parameter space. Looking forward, the work presented here lays the groundwork for a dialogue between Toner-Tu theory and data on collective motion in biologically-relevant geometries, from drone footage of migrating animal herds to movies of microscopic cytoskeletal flows within cells.
Intratumoral mregDC and CXCL13 T helper niches enable local differentiation of CD8 T cells following PD-1 blockade
Authors: Magen Assaf , Hamon Pauline , Fiaschi Nathalie , Troncoso Leanna , Humblin Etienne , D’souza Darwin , Dawson Travis , Park Matthew D. , Kim Joel , Hamel Steven , Buckup Mark , Chang Christie , Tabachnikova Alexandra , Schwartz Hara , Malissen Nausicaa , Lavin Yonit , Soares-Schanoski Alessandra , Giotti Bruno , Hegde Samarth , Mattiuz Raphaël , Hennequin Clotilde , Berichel Jessica Le , Zhao Zhen , Ward Stephen , Fiel Isabel , Price Colles , Fernandez Nicolas , He Jiang , Kou Baijun , Dobosz Michael , Li Lianjie , Adler Christina , Ni Min , Wei Yi , Wang Wei , Gupta Namita T. , Kundu Kunal , Cygan Kamil , Deering Raquel P. , Tsankov Alex , Kim-Schulze Seunghee , Gnjatic Sacha , Kenigsberg Ephraim , Schwartz Myron , Marron Thomas U. , Thurston Gavin , Kamphorst Alice O. , Merad Miriam
Published: June 2022

Here, we leveraged a large neoadjuvant PD-1 blockade trial in patients with hepatocellular carcinoma (HCC) to search for correlates of response to immune checkpoint blockade (ICB) within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13+ CH25H+ IL-21+ PD-1+ CD4 T helper cells (CXCL13+ Th) and Granzyme K+ PD-1+ effector-like CD8 T cells, whereas terminally exhausted CD39hi TOXhi PD-1hi CD8 T cells dominated in non-responders. Strikingly, most T cell receptor (TCR) clones that expanded post-treatment were found in pre-treatment biopsies. Notably, PD-1+ TCF-1+ progenitor-like CD8 T cells were present in tumors of responders and non-responders and shared clones mainly with effector-like cells in responders or terminally differentiated cells in non-responders, suggesting that local CD8 T cell differentiation occurs upon ICB. We found that these progenitor CD8 T cells interact with CXCL13+ Th cells within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or “mregDC”. Receptor-ligand analysis revealed unique interactions within these triads that may promote the differentiation of progenitor CD8 T cells into effector-like cells upon ICB. These results suggest that discrete intratumoral niches that include mregDC and CXCL13+ Th cells control the differentiation of tumor-specific progenitor CD8 T cell clones in patients treated with ICB.
A spatially anchored transcriptomic atlas of the human kidney papilla identifies significant immune injury and matrix remodeling in patients with stone disease
Authors: Canela Victor Hugo , Bowen William S. , Ferreira Ricardo Melo , Lingeman James E. , Sabo Angela R. , Barwinska Daria , Winfree Seth , Lake Blue , Cheng Ying-Hua , LaFavers Kaice A. , Zhang Kun , Coe Fredric L. , Worcester Elaine , Jain Sanjay , Eadon Michael T. , Williams James C. , El-Achkar Tarek M. ,   the Kidney Precision Medicine Project
Published: June 2022

Kidney stone disease causes significant morbidity and increases health care utilization. The pathogenesis of stone disease is not completely understood, due in part to the poor characterization of the cellular and molecular makeup of the kidney papilla and its alteration with disease. We deciphered the cellular and molecular niche of the human renal papilla in patients with calcium oxalate (CaOx) stone disease compared to healthy subjects using single nuclear RNA sequencing, spatial transcriptomics and high-resolution large-scale multiplexed 3D and Co-Detection by indexing (CODEX) imaging. In addition to identifying cell types important in papillary physiology, we defined subtypes of immune, stromal and principal cells enriched in the papilla, and characterized an undifferentiated epithelial cell cluster that was more prevalent in stone patients. Despite the focal nature of mineral deposition in nephrolithiasis, we uncovered a global injury signature involving multiple cell types within the papilla, characterized by immune activation, oxidative stress and extracellular matrix remodeling. The microenvironment of mineral deposition had features of an immune synapse with antigen presenting inflammatory macrophages interacting with T cells, and an immune repertoire ranging from inflammation to fibrosis. The expression of MMP7 and MMP9 was associated with stone disease and mineral deposition, respectively. MMP7 and MMP9 were significantly increased in the urine of patients with CaOx stone disease compared to non-stone formers, and their levels correlated with disease activity in stone formers. Our results define the spatial molecular landscape and specific pathways contributing to stone-mediated injury in the human papilla, and identify potential urinary biomarkers.
Membrane curvature governs the distribution of Piezo1 in live cells
Authors: Yang Shilong , Miao Xinwen , Arnold Steven , Li Boxuan , Ly Alan T. , Wang Huan , Wang Matthew , Guo Xiangfu , Pathak Medha M. , Zhao Wenting , Cox Charles D. , Shi Zheng
Published: June 2022

Piezo1 is abona fidemechanosensitive ion channel ubiquitously expressed in mammalian cells. The distribution of Piezo1 within a cell is essential for various biological processes including cytokinesis, cell migration, and wound healing. However, the underlying principles that guide the subcellular distribution of Piezo1 remain largely unexplored. Here, we demonstrate that membrane curvature serves as a key regulator of the spatial distribution of Piezo1 in the plasma membrane of living cells. Piezo1 depletes from highly curved membrane protrusions such as filopodia and enriches to nanoscale membrane invaginations. Quantification of the curvaturedependent sorting of Piezo1 directly reveals thein situnano-geometry of the Piezo1-membrane complex. Piezo1 density on filopodia increases upon activation, independent of Ca2+, suggesting flattening of the channel upon opening. Consequently, the expression of Piezo1 inhibits filopodia formation, an effect that diminishes with channel activation.
Tumor-educated monocytes suppress T cells via adenosine and depletion of adenosine in the tumor microenvironment with adenosine deaminase enzyme promotes response to immunotherapy
Authors: Sarkar Omar S. , Donninger Howard , Rayyan Numan Al , Chew Lewis C. , Stamp Bryce , Zhang Xiang , Whitt Aaron , Li Chi , Hall Melissa , Mitchell Robert A. , Zippelius Alfred , Eaton John , Chesney Jason A. , Yaddanapudi Kavitha
Published: June 2022

Although immune checkpoint inhibitor (ICI) therapy has provided robust results in many cancer types such as melanoma and lung cancer, a large percentage of patients remain unresponsive to this therapy. Emerging evidence strongly suggests that one of the contributing factors in ICI resistance is monocytic myeloid derived suppressor cells (M-MDSCs) that accumulate in late-stage cancer patients. These M-MDSCs are a subset of innate immune cells and possess potent immunosuppressive activity against T lymphocytes. Here we provide evidence of a mechanism by which CD73-expressing M-MDSCs in the tumor microenvironment (TME) exhibit superior T cell suppressor function via adenosine. We show that tumor-derived PGE2, a prostaglandin frequently found at high levels in the TME, directly induces CD73 expression in M-MDSCs by initiating a signaling pathway that is mediated by both Stat3 and CREB. The resulting CD73 overexpression induces elevated levels of adenosine, a nucleoside with strong T cell suppressive activity, culminating in the suppression of CD8+ T cell-mediated anti-tumor responses. We also show that depletion of adenosine in the TME by the repurposed drug PEGylated Adenosine Deaminase (PEG-ADA) increases CD8+ T cell anti-tumor activity and enhances response to ICI therapy in preclinical models of cancer. Our results suggest that use of PEG-ADA is a viable therapeutic option to overcome ICI therapeutic resistance in advanced cancer patients.
A self-blinking DNA probe for 3D superresolution imaging of native chromatin
Authors: Zheng Yang , Ye Sen , Li Shumin , Liu Cuifang , Luo Shihang , Xia Ruiqin , Chen Yanqin , Li Yunsheng , Zhu Zhenni , Huang Lingyi , Deng Shan , Yuen Karen Wing Yee , Chen Ping , Zhang Yongdeng , Ji Wei , Luo Ruibang , Li Guohong , Yang Dan
Published: June 2022

Single-molecule localization microscopy is a powerful superresolution imaging technique to study biological questions by visualizing subcellular fine structures with nanometer-scale precision. However, its application in live-cell imaging studies has been impeded by the paucity of self-blinking organic fluorophores that enable high spatiotemporal resolution and labeling/localization density at a moderate laser intensity. Herein, we report a self-blinking Si-rhodamine dye6-HESiRwith a suitably increased “ON” fraction and a fluorogenic self-blinking dsDNA probe6-HoeHESiRas a powerful tool for 3D superresolution imaging of native chromatin in eukaryotes without the use of photoswitching buffer and high laser intensity. With the probe6-HoeHESiR, 3D superresolution imaging of in vitro reconstituted nucleosomal arrays and chromatin fibers yielded results consistent with EM analysis. Similar euchromatin and heterochromatin structures were visualized in fixed and live cells with high spatiotemporal resolution and labeling density, providing the first live-cell evidence for a hierarchical model of chromatin organization. 3D imaging results obtained in the presence of selective inhibitors of histone deacetylases also corroborate chromatin fiber decompaction upon hyperacetylation of histones.
Postsynaptic burst reactivation of hippocampal neurons enables associative plasticity of temporally discontiguous inputs
Authors: Fuchsberger Tanja , Clopath Claudia , Jarzebowski Przemyslaw , Brzosko Zuzanna , Wang Hongbing , Paulsen Ole
Published: June 2022

A fundamental unresolved problem in neuroscience is how the brain associates in memory events that are separated in time. Here we propose that reactivation-induced synaptic plasticity can solve this problem. Previously, we reported that the reinforcement signal dopamine converts hippocampal spike timing-dependent depression into potentiation during continued synaptic activity (Brzosko et al., 2015). Here, we report that postsynaptic bursts in the presence of dopamine produces input-specific LTP in hippocampal synapses 10 minutes after they were primed with coincident pre- and postsynaptic activity. The priming activity sets an NMDAR-dependent silent eligibility trace which, through the cAMP-PKA cascade, is rapidly converted into protein synthesis-dependent synaptic potentiation, mediated by a signaling pathway distinct from that of conventional LTP. Incorporated into a computational model, this synaptic learning rule adds specificity to reinforcement learning by controlling memory allocation and enabling both ‘instructive’ and ‘supervised’ reinforcement learning. We predicted that this mechanism would make reactivated neurons activate more strongly and carry more spatial information than non-reactivated cells, which was confirmed in freely moving mice performing a reward-based navigation task.
Effects of Livestock Grazing Exclusion on Perennial Grasses and Woody Species on the San Pedro Riparian National Conservation Area, Arizona
Authors: Radke Marcia F.
Published: June 2022

The objective of this study was to determine the effects of livestock exclusion on native and non-native perennial grass richness and frequency, and woody species frequency on the San Pedro Riparian National Conservation Area. A significant increase in species richness of native perennial grass species was noted overall and in retired agricultural fields, supporting the hypothesis of increased species richness with grazing exclusion. There was a significant increase in the number of plots that contained an increase in bristlegrass (Setaria macrostachya Kunth and S. leucopila (Scribn. & Merr.) K. Schum.). No significant change in species richness of non-native invasive perennial grass species was observed. Lehmann lovegrass (Eragrostis lehmanniana Nees) had a significant increase in the number of plots that contained the species, supporting the hypothesis that Lehmann lovegrass expansion would occur in previously uninvaded areas even without current livestock grazing. Velvet mesquite (Prosopis velutina Wooton) exhibited a significant increase in canopy frequency, but velvet mesquite basal frequency showed no significant increase or decrease. Results indicate that past grazing was a primary factor leading to the current distribution and density of mesquite on the SPRNCA because the same basal (i.e. rooted stem) frequency existed prior to and after grazing exclusion. Management considerations include continued grazing exclusion, inventory and monitoring of pollinator plants, continued monitoring of pace frequency transects, use of prescribed fire in uplands, monitoring of soil erosion, and implementation of erosion controls.
PIEZO1 discriminates mechanical stimuli
Authors: Ozkan Alper D. , Wijerathne Tharaka D. , Gettas Tina , Lacroix Jérôme J.
Published: June 2022

PIEZO1 channels open in response to numerous mechanical stimuli, such as physical membrane deformations, which modulate the curvature of flexible domains called blades. Yet, whether different stimuli cause similar blade motions and whether these rearrangements correlate with pore opening remain unclear. Here, we scan local conformational changes along the PIEZO1 blade using fluorescent probes. We identify two distant probes, one intracellular proximal and the other extracellular distal, which independently and robustly respond to flow stimuli. Flow-induced signals from both probes exquisitely correlate with PIEZO1-dependent calcium influx and specifically increase in presence of fast-inactivating pore mutations. In contrast, both probes remain fluorimetrically silent to hypotonic shocks and indentations, two stimuli that otherwise evoke normal electrochemical responses in both engineered channels. This study reveals that flow-induced blade motions are functionally coupled to the pore and that at least two distant blade regions discriminate flow from two other stimuli, suggesting that PIEZO1 mobilizes distinct mechanisms to sense a broad range of mechanical cues.

Teaser

Fluorimetric evidence suggests that different mechanical stimuli impart distinct rearrangements in PIEZO1’s mechanosensory domains.
Rational selection and Characterisation of bile acid (BA) metabolising species of infant origin
Authors: Long Sarah L. , Joyce Susan A.
Published: June 2022

Bile acids (BAs), biological detergents for nutrient digestion, are important local and systemic signalling molecules to interact with a variety of cell receptors central to influence host responses. While BAs are synthesized in the liver, the range and diversity of bile acids available to interact with these receptors is dictated by the gut microbiota. Bile salt hydrolase (BSH) activity is one such function, it is commonly represented and highly conserved across all major bacterial phyla in the gut. Studies relating to the importance of such modifications in early life are scarce. This study highlights BA metabolism diversity by functionally isolating BA metabolizing strains and by characterizing specific classes of BSH from the formula–fed transitioning gut. Isolates were identified to species levels,in silicoandin vitrocharacterisation of their BSH genetic content, enzyme activity and substrate specificity. One of these isolates was identified asLactobacillus acidophilus, a species frequently applied as a probiotic whereas three of these four isolates were identified asEnterococcus avium. This particular species is not well characterized in the literature and to our knowledge this is the first report of BSH activity and assessment for probiotic potential within this class of microbes. This study indicates that microbial BA altering activity appears functionally reduced, in the formula fed infant gut.
Aging-related iron deposit prevents the benefits of HRT from late postmenopausal atherosclerosis
Authors: Xu Tianze , Cai Jing , Wang Lei , Xu Li , Zhao Hongting , Wang Fudi , Meyron-Holtz Esther , Missirlis Fanis , Qiao Tong , Li Kuanyu
Published: June 2022

Postmenopausal atherosclerosis has been attributed to estrogen deficiency. The beneficial effect of hormone replacement therapy (HRT), however, is lost in late postmenopausal women with atherogenesis. We asked whether aging-related iron accumulation affects estrogen receptor α (ERα) expression explaining HRT inefficacy. A negative correlation between aging-related systemic iron deposition and ERα expression in postmenopausal AS patients was established. In an ovariectomized ApoE-/- mouse model, estradiol treatment had contrasting effects on ERα expression in early versus late postmenopausal mice. ERα expression was inhibited by iron treatment in cell culture and iron-overloaded mice. Combined treatment with estradiol and iron further decreased ERα expression, mediated by iron-regulated E3 ligase Mdm2. In line with these observations, cellular cholesterol efflux was reduced and endothelial homeostasis was disrupted and, consequently, atherosclerosis was aggravated. Accordingly, systemic iron chelation attenuated estradiol-triggered progressive atherosclerosis in late postmenopausal mice. Thus, iron and estradiol together downregulate ERα through Mdm2-mediated proteolysis, explaining failures of HRT in late postmenopausal subjects with aging-related iron accumulation. HRT is recommended immediately after menopause along with appropriate iron chelation to protect from atherosclerosis.
Cerebral Organoids In Primary Progressive Multiple Sclerosis Reveal Stem Cell Disruption And Failure To Produce Oligodendrocytes
Authors: Daviaud Nicolas , Chen Eric , Edwards Tara , Sadiq Saud A
Published: June 2022

Multiple sclerosis (MS) is an auto-immune inflammatory disorder affecting the central nervous system. The cause of the disease is unknown but both genetic and environmental factors are implicated in the pathogenesis. We derived cerebral organoids from induced pluripotent stem cells (iPSC) of healthy control subjects as well as from primary progressive MS (PPMS), secondary progressive MS (SPMS) and relapsing remitting MS (RRMS) patients to better understand the pathologic basis of the varied clinical phenotypic expressions of MS. In MS organoids, most notably in PPMS, we observed a decrease of proliferation marker Ki67 and a reduction of the SOX2+ stem cell pool associated with an increased expression of neuronal markers CTIP2 and TBR1. This dysregulation of the stem cell pool is associated with a decreased expression of the cell cycle inhibitor p21. Our findings show that the genetic background of a patient can directly alter stem cell function. This study also provides new insights on the innate cellular dysregulation in MS and identifies p21 pathway as a new potential target for therapeutic strategies in MS.

Summary Statement

Using cerebral organoids derived from patients with multiple sclerosis we detected that p21 decrease may induce a disruption of the stem cell cycle leading to a defect of oligodendrocyte differentiation
Regulation of urea cycle by reversible high stoichiometry lysine succinylation
Authors: Zhang Ran , Xie Xueshu , Carrico Chris , Meyer Jesse G. , Wei Lei , Bons Joanna , Rose Jacob , Riley Rebeccah , Kwok Ryan , Kumaar Prasanna A. , He Wenjuan , Nishida Yuya , Liu Xiaojing , Locasale Jason W. , Schilling Birgit , Verdin Eric
Published: June 2022

The post-translational modification, lysine succinylation is implicated in the regulation of various metabolic pathways. However, its biological relevance remains uncertain due to methodological difficulties in determining high-impact succinylation sites. In the present study, using stable isotope labeling and data-independent acquisition mass spectrometry, we quantified lysine succinylation stoichiometries in mouse livers. Despite the low overall stoichiometry of lysine succinylation, several high stoichiometry sites were identified, especially upon deletion of the desuccinylase SIRT5. In particular, multiple high stoichiometry lysine sites identified in argininosuccinate synthase (ASS1), a key enzyme in urea cycle, are regulated by SIRT5. Mutation of the high stoichiometry lysine in ASS1 to succinyl-mimetic glutamic acid significantly decreased its enzymatic activity. Metabolomics profiling confirms that SIRT5 deficiency decreases urea cycle activity in liver. Importantly, SIRT5 deficiency compromises ammonia tolerance and reduces locomotor and exploratory activity in male mice upon high-ammonium diet feeding. Therefore, lysine succinylation is functionally important in ammonia metabolism.
Experimental support for human papillomavirus genome amplification early after infectious delivery
Authors: Zwolinska Katarzyna , Bienkowska-Haba Malgorzata , Scott Rona S. , Sapp Martin
Published: June 2022

Even though replication and transcription of human papillomavirus type 16 (HPV16) has been intensively studied, little is known about immediate early events of the viral life cycle due to the lack of an efficient infection model allowing genetic dissection of viral factors. We employed the recently developed infection model (Bienkowska-Haba et al. PLOS Pathogen 2018) to investigate genome amplification and transcription immediately after infectious delivery of viral genome to nuclei of primary keratinocytes. Using EdU pulse labeling and highly sensitive fluorescencein situhybridization, we observed that the HPV16 genome is replicated and amplified in an E1 and E2 dependent manner. Knockout of E1 resulted in failure of the viral genome to replicate and amplify. In contrast, knockout of the E8^E2 repressor led to increased viral genome copy number confirming previous reports. Genome copy control by E8^E2 was confirmed for differentiation-induced genome amplification. Lack of functional E1 had no effect on transcription from the early promoter, suggesting that viral genome replication is not required for p97 promoter activity. However, infection with an HPV16 mutant virus defective for E2 transcriptional function revealed a requirement of E2 for efficient transcription from the early promoter. In absence of the E8^E2 protein, early transcript levels are unaltered and even decreased when normalized to genome copy number. Surprisingly, lack of functional E8^E2 repressor did not affect E8^E2 transcript levels when normalized to genome copy number. These data suggest that the main function of E8^E2 in the viral life cycle is to control genome copy number.

IMPORTANCE

It is being assumed that HPV utilizes three different modes of replication during its lifecycle: initial amplification during the establishment phase, genome maintenance and differentiation-induced amplification. However, HPV16 initial amplification was never formally proven due to a lack of an infection model. Using our recently established infection model (Bienkowska-Haba et al. PLOS Pathogen 2018), we demonstrate herein that viral genome is indeed amplified in an E1 and E2 dependent manner. Furthermore, we find that the main function of the viral repressor E8^E2 is to control viral genome copy number. We did not find evidence that it regulates its own promoter in a negative feedback loop. Our data also suggest that the E2 transactivator function is required for stimulation of early promoter activity, which has been debated in the literature. Overall, this report confirms the usefulness of the infection model for studying early events of the HPV lifecycle using mutational approaches.
Human Papillomavirus Genome Copy Number Is Maintained by S Phase Amplification, Leakage to the Cytosol during Mitosis and Lysosomal Degradation in G1 Phase
Authors: Bienkowska-Haba Malgorzata , Zwolinska Katarzyna , Keiffer Timothy , Sapp Martin
Published: June 2022

The current model for human papillomavirus (HPV) replication is comprised of three modes of replication. Following infectious delivery, the viral genome is amplified during the establishment phase to reach up to some hundred copies per cell. HPV genome copy number remains constant during the maintenance stage. Differentiation of infected cells induces HPV genome amplification. Using highly sensitive in situ hybridization (DNAscope) and freshly HPV16-infected as well as established HPV16-positive cell lines, we observed that viral genome is amplified in each S phase of undifferentiated keratinocytes cultured as monolayers. Nuclear viral genome copy number is reset to pre-S phase levels during mitosis. The majority of viral genome fails to tether to host chromosomes and is lost to the cytosol. Cytosolic viral genome gradually decreases during cell cycle progression. Loss of cytosolic genome is blocked in presence of NH4Cl or other drugs interfering with lysosomal acidification, suggesting the involvement of autophagy in viral genome degradation. These observations were also made with HPV31 cell lines obtained from patient samples. Cytosolic viral genome was not detected in UMSCC47 cells carrying integrated HPV16 DNA. Analyses of organotypic raft cultures derived from keratinocytes harboring episomal HPV16 revealed the presence of cytosolic viral genome as well. We conclude that HPV maintains viral genome copy number by balancing viral genome amplification during S phase with loss of viral genome that is lost to the cytosol during mitosis. It seems plausible that restrictions to viral genome tethering to mitotic chromosomes resets genome copy number in each cell cycle.

IMPORTANCE

HPV genome maintenance is currently being thought to be achieved by regulating expression and activity of viral replication factors E1 and E2. In addition, the E8^E2 repressor has been shown to be important for restricting genome copy number by competing with E1 and E2 for binding to the viral origin of replication and by recruitment of repressor complexes. Herein, we demonstrate that HPV viral genome is amplified in each S phase. Nuclear genome copy number is reset during mitosis by a failure of the majority of genomes to tether to mitotic chromosomes. Rather, they accumulate in the cytoplasm of freshly divided cells. Cytosolic viral DNA is quickly degraded in G1 in a lysosome dependent manner contributing to the genome copy reset. Our data imply that the mode of replication during establishment and maintenance is the same and further suggest that restrictions to genome tethering significantly contributes to viral genome maintenance.
Assessing the role of information and communication technology in reducing the gap between rich and poor: the case of South Asia
Authors: Ahmad Seemab , Khan Dilawar , Haq Ihtisham ul
Published: June 2022

Purpose

The widening income gap between rich and poor has gained worldwide recognition in recent decades. This income gap between rich and poor is defined as the extent of income unevenly distributed in a host country. This study provides an empirical view of the association between information and communication technology and the widening of the income gap.

Design/methodology/approach

The study used panel data from 2005 to 2019. To detect unit root issues, Levin and Lin (LL) and Im, Pesaran and Shin (IPS) tests were first employed. The pooled mean group and mean group estimators were employed to investigate the short and long -term impact of information and communication technology and other control factors on reducing the gap between rich and poor in South Asia.

Findings

The results showed that the Pooled mean group's findings are more efficient and consistent as compared to mean group estimators. The results of the paper showed that the greater penetration of information and communication technologies in the economy negatively and significantly affects income inequality. Moreover, the information and communication technology, foreign remittances and foreign direct investment (FDI) significantly reduce the gap between rich and poor in the long run.

Practical implications

At last, the findings of the study serve as an excellent roadmap for policymakers seeking to address the issue of growing income inequality in the South Asian regions and worldwide.

Originality/value

Based on the findings of this study, South Asia can reduce the gap between rich and poor by investing more in the information and communication technology sector.

Peer review

The peer review history for this article is available at:https://publons.com/publon/10.1108/IJSE-10-2021-0638
Audit fees under the COVID-19 pandemic: evidence from Oman
Authors: Al-Qadasi Adel , Baatwah Saeed Rabea , Omer Waddah Kamal
Published: June 2022

Purpose

The worldwide spread of the coronavirus disease 2019 (COVID-19) has significant effects on financial markets and companies, causing an unprecedented level of uncertainty in reporting and auditing companies' financial statements. This study explores whether and how COVID-19 affects audit fees.

Design/methodology/approach

Using a sample of 268 firm-year observations from the Omani capital market between 2017 and 2020, the ordinary least squares (OLS) regression with a robust standard error is applied to answer the research question of this study.

Findings

The authors find that the pandemic has a significant and positive association with audit fees and abnormal audit fees. This finding suggests that the threat of risk, complexity and legal liability circumstances resulting from the pandemic can be compensated by charging higher audit fees. In addition, the authors provide evidence that Big4 audit firms are those most responding to COVID-19 by charging higher audit fees. Finally, the authors conclude that large companies are less sensitive to the pandemic.

Practical implications

Users of financial reports and audit firms should anticipate changes in the audit efforts resulting in increased audit fees during COVID-19. Thus, this paper may guide practitioners and businesses in determining the audit fees and associated costs of any potential pandemic.

Originality/value

The study results are among the earliest empirical insights into the effect of COVID-19 on audit fees in Oman.
Longitudinal study of perceived environmental uncertainty. An application of Rasch methodology to SMES
Authors: García-Pérez Ana María , Yanes-Estévez Vanessa
Published: June 2022

Purpose

This work develops a longitudinal analysis of perceived environmental uncertainty applying the Rasch methodology (1960). The environmental uncertainty is defined as an individual's perceived inability to predict the environment accurately (Milliken, 1987). The study focuses on analysing the state uncertainty from the perspective of the information and under the cognitive approach to the business reality.

Design/methodology/approach

Rasch measurement theory (1960) is applied, specifically the differential item functioning analysis based on the responses to a survey of SMEs.

Findings

The main sources of uncertainty for all the SMEs in the sample are two sectors in their general environment: economic and political-legal ones. These segments are the only ones in the environment that generate uncertainty that in 2016 is significantly different from that in 2019, being lower in the latter year.

Originality/value

This is a pioneering analysis of uncertainty both for its longitudinal nature and the methodology applied.
EggLib 3: A python package for population genetics and genomics
Authors: Siol Mathieu , Coudoux Thomas , Ravel Sébastien , De Mita Stéphane
Published: June 2022

Rapid and repeatable polymorphism analyses have become a necessity with the current amount of genomic data that can be collected in many organisms. Traditionally, such analyses are conducted using a variety of tools in combination, often requiring numerous format translation and manipulation. Here, we present a massively updated version of our previous software package egglib, intended to alleviate such costly and error‐prone tinkering with the data. egglib has been streamlined into a python package and thoroughly updated and optimized to accommodate modern‐day sized dataset. We show the main characteristics of the package making it a tool of choice to perform population genetics analyses. Once the data are imported (whatever their encoding), they can be filtered, edited, analysed and compared to coalescent simulations very easily and efficiently. Furthermore, the list of diversity and polymorphism statistics that can now be calculated has been greatly expanded. The software and its full documentation are available at https://egglib.org/.
The Effect of Reporting Opacity on Trading Opacity: New Evidence from American Depositary Receipt Trades in Dark Pools*
Authors: Boulton Thomas J. , Braga‐Alves Marcus V. , Chakrabarty Bidisha
Published: June 2022

Trading volume is increasingly shifting to dark venues, and the causes of this move are not well understood. We examine whether a firm's reporting opacity affects its dark pool trading and provide robust evidence that (partly) explains this volume migration. Exploiting the exogenous variation in home‐country reporting opacity in a sample of American Depositary Receipts (ADRs) and using multiple metrics for reporting opacity, we find that greater opacity associates with increased dark pool trading. This relation holds after controlling for firms' information environments, country‐specific governance issues, observable differences between ADRs and other securities that trade in dark pools (matched sample analysis), volume migration to dark pools during earnings announcements, informed trading in lit versus dark venues, ADR levels, IFRS reporting requirements, and the possible endogenous determination of home‐country reporting opacity and dark pool volume. The positive relation is stronger for ADRs held by (quasi‐indexing) institutions with low turnover and diversified holdings and weaker for ADRs favored by (transient) institutions that trade frequently and (dedicated) institutions that hold concentrated portfolios. Bid‐ask spreads are greater for higher opacity ADRs that trade in dark pools, indicating that reporting opacity is associated with the negative effect of dark pool trading on market quality. Our findings help inform the current debate on off‐exchange trading by showing how reporting regimes affect the trading venue choice.
TheWeight: A simple and flexible algorithm for simulating non‐ideal, age‐structured populations
Authors: Waples Robin S.
Published: June 2022

The Wright–Fisher model, which directs how matings occur and how genes are transmitted across generations, has long been a lynchpin of evolutionary biology. This model is elegantly simple, analytically tractable and easy to implement, but it has one serious limitation: essentially no real species satisfies its many assumptions. With growing awareness of the importance of jointly considering both ecology and evolution in eco‐evolutionary models, this limitation has become more apparent, causing many researchers to search for more realistic simulation models.

A recently described variation retains most of the Wright–Fisher simplicity but provides greater flexibility to accommodate departures from model assumptions. This generalized Wright–Fisher model relaxes the assumption that all individuals have identical expected reproductive success by introducing a vector of parental weights w that specifies relative probabilities different individuals have of producing offspring. With parental weights specified this way, expectations of key demographic parameters are simple functions of w. This allows researchers to quantitatively predict the consequences of non‐Wright–Fisher features incorporated into their models.

An important limitation of the Wright–Fisher model is that it assumes discrete generations, whereas most real species are age structured. Here I show how an algorithm (TheWeight) that implements the generalized Wright–Fisher model can be used to model evolution in age‐structured populations with overlapping generations. Worked examples illustrate simulation of seasonal and lifetime reproductive success and show how the user can pick vectors of weights expected to produce a desired level of reproductive skew or a desired Ne/N ratio. Alternatively, weights can be associated with heritable traits to provide a simple, quantitative way to model natural selection. Using TheWeight, it is easy to generate positive or negative correlations of individual reproductive success over time, thus allowing explicit modelling of common biological processes like skip breeding and persistent individual differences.

Code is provided to implement basic features of TheWeight and applications described here, including one scenario implemented in SLiM. However, required coding changes to the Wright–Fisher model are modest, so the real value of the new algorithm is to encourage users to adopt its features into their own or others' models.
Former auditors on the audit committee and earnings management: Evidence from African banks
Authors: Mnif Yosra , Slimi Imen
Published: June 2022

This paper investigates whether former auditors on the audit committee constrain earnings management through loan loss provisions. Based on an analysis of the annual reports of 82 African listed banks over the period 2011–2016, findings show that the presence of former auditors on an audit committee is associated with lower earnings management. This result suggests that audit committee members with auditing expertise and background contribute to effective monitoring of management’s accounting practices. Furthermore, results reveal that the reducing effect on earnings management of former auditors is strongest for directors who are unaffiliated with the bank’s current external auditor.