bluuebunny/crossref_metadata_2025 huggingface dataset:
KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development
Authors: Tinsley Samantha L. , Shelley Rebecca A. , Mall Gaganpreet K. , Chianis Ella Rose D. , Dhiman Alisha , Baral Garima , Kothandaraman Harish , Thoma Mary C. , Daniel Colin J. , Lanman Nadia Atallah , Pasca di Magliano Marina , Narla Goutham , Solorio Luis , Dykhuizen Emily C. , Sears Rosalie C. , Allen-Petersen Brittany L.
Published: July 2023

Oncogenic mutations in KRAS are present in approximately 95% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and are considered the initiating event of pancreatic intraepithelial neoplasia (PanIN) precursor lesions. While it is well established that KRAS mutations drive the activation of oncogenic kinase cascades during pancreatic oncogenesis, the effects of oncogenic KRAS signaling on regulation of phosphatases during this process is not fully appreciated. Protein Phosphatase 2A (PP2A) has been implicated in suppressing KRAS-driven cellular transformation. However, low PP2A activity is observed in PDAC cells compared to non-transformed cells, suggesting that suppression of PP2A activity is an important step in the overall development of PDAC. In the current study, we demonstrate that KRASG12Dinduces the expression of both an endogenous inhibitor of PP2A activity, Cancerous Inhibitor of PP2A (CIP2A), and the PP2A substrate, c-MYC. Consistent with these findings, KRASG12Dsequestered the specific PP2A subunit responsible for c-MYC degradation, B56α, away from the active PP2A holoenzyme in a CIP2A-dependent manner. During PDAC initiationin vivo, knockout of B56α promoted KRASG12Dtumorigenesis by accelerating acinar-to-ductal metaplasia (ADM) and the formation of PanIN lesions. The process of ADM was attenuatedex vivoin response to pharmacological re-activation of PP2A utilizing direct small molecule activators of PP2A (SMAPs). Together, our results suggest that suppression of PP2A-B56α through KRAS signaling can promote the MYC-driven initiation of pancreatic tumorigenesis.
Imaging proteins sensitive to direct fusions using transient peptide-peptide interactions
Authors: Gidden Zoe , Oi Curran , Johnston Emily , Bhaskar Haresh , Rosser Susan , Mochrie Simon G. J. , Horrocks Mathew H. , Regan Lynne
Published: July 2023

Fluorescence microscopy enables specific visualization of proteins in living cells and has played an important role in our understanding of protein subcellular location and function. Some proteins, however, show altered localization and/or function when labeled using direct fusions to fluorescent proteins, making them difficult to study in live cells. Additionally, the resolution of fluorescence microscopy is limited to ∼200 nm, which is two orders of magnitude larger than the size of most proteins. To circumvent these challenges, we previously developed LIVE-PAINT, a live-cell super-resolution approach that takes advantage of short interacting peptides to transiently bind a fluorescent protein to the protein-of-interest. Here, we successfully use LIVE-PAINT to image yeast membrane proteins that do not tolerate the direct fusion of a fluorescent protein by using peptide tags as short as 5-residues. We also demonstrate that it is possible to resolve multiple proteins at the nanoscale concurrently using orthogonal peptide interaction pairs.

FOR TABLE OF CONTENTS ONLY
A Serum- and Feeder-Free System to Generate CD4 and Regulatory T Cells from Human iPSCs
Authors: Fong Helen , Mendel Matthew , Jascur John , Najmi Laeya , Kim Ken , Lew Garrett , Garimalla Swetha , Schock Suruchi , Hu Jing , Villegas Andres , Conway Anthony , Fontenot Jason D. , Zompi Simona
Published: July 2023

iPSCs can serve as a renewable source of a consistent edited cell product, overcoming limitations of primary cells. While feeder-free generation of clinical grade iPSC-derived CD8 T cells has been achieved, differentiation of iPSC-derived CD4sp and regulatory T cells requires mouse stromal cells in an artificial thymic organoid. Here we report a serum- and feeder-free differentiation process suitable for large-scale production. Using an optimized concentration of PMA/Ionomycin, we generated iPSC-CD4sp T cells at high efficiency and converted them to Tregs using TGFβ and ATRA. Using genetic engineering, we demonstrated high, non-viral, targeted integration of an HLA-A2 CAR in iPSCs. iPSC-Tregs +/- HLA-A2-targeted CAR phenotypically, transcriptionally and functionally resemble primary Tregs and suppress T cell proliferationin vitro. Our work is the first to demonstrate an iPSC-based platform amenable to manufacturing CD4 T cells to complement iPSC-CD8 oncology products and functional iPSC-Tregs to deliver Treg cell therapies at scale.
Fusion of Electronic Health Records and Radiographic Images for a Multimodal Deep Learning Prediction Model of Atypical Femur Fractures
Authors: Schilcher Jörg , Nilsson Alva , Andlid Oliver , Eklund Anders
Published: July 2023

Atypical femur fractures (AFF) represent a very rare type of fracture that can be difficult to discriminate radiologically from normal femur fractures (NFF). AFFs are associated with drugs that are administered to prevent osteoporosis-related fragility fractures, which are highly prevalent in the elderly population. Given that these fractures are rare and the radiologic changes are subtle currently only 7% of AFFs are correctly identified, which hinders adequate treatment for most patients with AFF. Deep learning models could be trained to classify automatically a fracture as AFF or NFF, thereby assisting radiologists in detecting these rare fractures. Historically, for this classification task, only imaging data have been used, using convolutional neural networks (CNN) or vision transformers applied to radiographs. However, to mimic situations in which all available data are used to arrive at a diagnosis, we adopted an approach of deep learning that is based on the integration of image data and tabular data (from electronic health records) for 159 patients with AFF and 914 patients with NFF. We hypothesized that the combinatorial data, compiled from all the radiology departments of 72 hospitals in Sweden and the Swedish National Patient Register, would improve classification accuracy, as compared to using only one modality. At the patient level, the area under the ROC curve (AUC) increased from 0.966 to 0.987 when using the integrated set of imaging data and seven pre-selected variables, as compared to only using imaging data. More importantly, the sensitivity increased from 0.796 to 0.903. We found a greater impact of data fusion when only a randomly selected subset of available images was used to make the image and tabular data more balanced for each patient. The AUC then increased from 0.949 to 0.984, and the sensitivity increased from 0.727 to 0.849. These AUC improvements are not large, mainly because of the already excellent performance of the CNN (AUC of 0.966) when only images are used. However, the improvement is clinically highly relevant considering the importance of accuracy in medical diagnostics. We expect an even greater effect when imaging data from a clinical workflow, comprising a more diverse set of diagnostic images, are used.
Preventable suicides involving medicines before the covid-19 pandemic: a systematic case series of coroners’ reports in England and Wales
Authors: Anthony Grace , Aronson Jeffrey K. , Brittain Richard , Heneghan Carl , Richards Georgia C.
Published: July 2023

Background

Over 5000 suicides are registered in England and Wales each year. Coroners’ Prevention of Future Deaths reports (PFDs) share concerns to promote actions to reduce the risks of similar deaths.

Aims

To systematically review coroners’ PFDs involving suicides in which a medicine caused or contributed to the death, to identify lessons for suicide prevention.

Methods

3037 PFDs were screened for eligibility between July 2013 and December 2019. Following data extraction, descriptive statistics and content analysis were performed to assess coroners’ concerns, the recipients, and the response rates to reports.

Results

There were 734 suicide-related PFDs, with 100 reporting a medicine. Opioids (40%) were the most common class involved in suicide-related PFDs, followed by antidepressants (30%). There was wide geographical variation in the writing of PFDs; coroners in Manchester wrote the most (18%). Coroners expressed 237 concerns; the most common were procedural inadequacies (14%, n=32), inadequate documentation and communication (10%, n=22), and inappropriate prescription access (9%, n=21). 203 recipients received these PFDs, most being sent to NHS trusts (31%), clinical commissioning groups (10%), and general practices (10%), of which only 58% responded to the coroner.

Conclusions

Concerns raised by coroners in suicide-related PFDs involving medicines highlight essential gaps in care that require actions from the Government, health services, and prescribers. To aid suicide prevention, PFDs should be disseminated nationally, and responses should be enforced so that actions are taken to prevent suicides.

Study protocol registration:

https://doi.org/10.17605/OSF.IO/EXJK3
Genomic context sensitizes regulatory elements to genetic disruption
Authors: Ordoñez Raquel , Zhang Weimin , Ellis Gwen , Zhu Yinan , Ashe Hannah J. , Ribeiro-dos-Santos André M. , Brosh Ran , Huang Emily , Hogan Megan S. , Boeke Jef D. , Maurano Matthew T.
Published: July 2023

Enhancer function is frequently investigated piecemeal using truncated reporter assays or single deletion analysis. Thus it remains unclear to what extent enhancer function at native loci relies on surrounding genomic context. Using the Big-IN technology for targeted integration of large DNAs, we analyzed the regulatory architecture of the murineIgf2/H19locus, a paradigmatic model of enhancer selectivity. We assembled payloads containing a 157-kb functionalIgf2/H19locus and engineered mutations to genetically direct CTCF occupancy at the imprinting control region (ICR) that switches the target gene of theH19enhancer cluster. Contrasting activity of payloads delivered at the endogenousIgf2/H19locus or ectopically atHprtrevealed that theIgf2/H19locus includes additional, previously unknown long-range regulatory elements. Exchanging components of theIgf2/H19locus with the well-studiedSox2locus showed that theH19enhancer cluster functioned poorly out of context, and required its native surroundings to activateSox2expression. Conversely, theSox2locus control region (LCR) could activate bothIgf2andH19outside its native context, but its activity was only partially modulated by CTCF occupancy at the ICR. Analysis of regulatory DNA actuation across different cell types revealed that, while theH19enhancers are tightly coordinated within their native locus, theSox2LCR acts more independently. We show that these enhancer clusters typify broader classes of loci genome-wide. Our results show that unexpected dependencies may influence even the most studied functional elements, and our synthetic regulatory genomics approach permits large-scale manipulation of complete loci to investigate the relationship between locus architecture and function.

HIGHLIGHTS

Composite enhancer elements are subject to genomic context effects mapped to a specific architecture of their endogenous loci.

Igf2/H19expression is affected by long-range regulatory elements beyond the canonically defined locus, and theH19enhancer cluster in particular relies on the surrounding context at its endogenous locus.

TheSox2LCR functions as an autonomous enhancer without requiring additional surrounding context.

The influence of genomic context is buffered at intact loci, but manifests more strongly as key regulatory elements are deleted or repositioned.
Surfactant-mediated effects on hydrological and physical soil properties: a data synthesis
Authors: Lehmann Anika , Flaig Maximilian , Dueñas Juan F. , Rillig Matthias C.
Published: July 2023

Soils are under threat of a multitude of anthropogenic factors affecting the complex interplay of various physical and hydrological soil processes and properties. One such factor is the group of surface-active compounds. Surfactants have a broad range of applications, and can reduce solid-liquid interfacial forces and increase wettability and dispersion of particles. Surfactant effects are context-dependent, giving rise to a wide range of reported effects on different soil processes and properties.

Here, we evaluate the evidence base of surfactant research on 11 hydrological and physical soil variables. Our goal was to identify knowledge gaps and to test the robustness of proposed surfactant effects.

We found that the current knowledge base is insufficient to reach strong data-backed conclusions about effects of surfactants in soils. We identified a unique case of bias in the data as a result of conflated patterns of lab and field studies. We could not support the hypothesis that surfactant charge determines soil effects for any of the tested soil variables.

We believe that further experiments on surfactant mediated effects on soil properties and processes are urgently required, paying attention in particular to improving experimental design and data reporting standards.

Graphical abstract
Conformational features and interaction mechanisms of VHH antibodies with β-hairpin-like CDR-H3: A case of Nb8-HigB2 interaction
Authors: Yamamoto Koichi , Nagatoishi Satoru , Nakakido Makoto , Kuroda Daisuke , Tsumoto Kouhei
Published: July 2023

β-hairpin conformation is regarded as an important basic motif to form and regulate protein-protein interactions. Single-domain VHH antibodies are potential therapeutic and diagnostic tools, and the third complementarity-determining regions of the heavy chains (CDR-H3s) of these antibodies are critical for antigen recognition. Although the sequences and conformations of the CDR-H3s are diverse, CDR-H3s sometimes adopt β-hairpin-like conformations. However, characteristic features and interaction mechanisms of β-hairpin-like CDR-H3s remain to be fully elucidated. In this study, we investigated the molecular recognition of the anti-HigB2 VHH antibody Nb8, which has a CDR-H3 that forms a β-hairpin-like conformation. The interaction was analyzed by evaluation of alanine-scanning mutants, molecular dynamics simulations, and hydrogen/deuterium exchange mass spectrometry. These experiments demonstrated that positions 93 and 94 (Chothia numbering) in framework region 3, which is right outside CDR-H3 by definition, play pivotal roles in maintaining structural stability and binding properties of Nb8. These findings will facilitate design and optimization of single-domain antibodies.
Targeting CD25-positive lymphoma cells with the antibody-drug conjugate camidanlumab tesirine as single agent or in combination with targeted agents
Authors: Spriano Filippo , Tarantelli Chiara , Cascione Luciano , Gaudio Eugenio , Golino Gaetanina , Scalise Lorenzo , Zucca Emanuele , Stathis Anastasios , Van Berkel Patrick H. , Zammarchi Francesca , Bertoni Francesco
Published: July 2023

Introduction

Camidanlumab tesirine (ADCT-301) is a CD25 specific antibody-drug conjugate (ADC) employing SG3199, a highly cytotoxic DNA minor groove cross-linking pyrrolobenzodiazepine dimer. Camidanlumab tesirine has shown early clinical anti-tumor activity in various cancer types, including B- and T-cell lymphomas. Here, we assessed its preclinical activity as single agent in 57 lymphoma cell lines and in combination with selected drugs in T cell lymphomas-derived cell lines.

Methods

Cell lines were exposed to increasing concentrations of camidanlumab tesirine or to SG3199 for 96h followed by MTT proliferation assay. CD25 expression was measured both at cell surface level via fluorescence quantitation and at RNA level, using various technologies. Combination studies were performed exposing cells to increasing doses of camidanlumab tesirine and of additional drugs.

Results

Camidanlumab tesirine presented much stronger single agentin vitrocytotoxic activity in T than B cell lymphomas.In vitroactivity was highly correlated with CD25 expression both at cell surface level and RNA level. Based on the higher activity in T cell lymphomas, camidanlumab tesirine-containing combinations were evaluated in cell lines derived from peripheral T cell lymphoma, ALK-pos or ALK-neg anaplastic large cell lymphoma. The most active combination partners were everolimus, copanlisib, venetoclax, vorinostat and pralatrexate, followed by bortezomib, romidepsin, bendamustine and 5-azacytidine.

Conclusion

The strong camidanlumab tesirine single agent anti-lymphoma activity and the observedin vitrosynergisms with targeted agents support further clinical development of camidanlumab tesirine and identify potential combination partners for future clinical studies.
Cognitive rehabilitation can improve brain injury-induced deficits in behavioral flexibility and impulsivity linked to impaired reward-feedback activity
Authors: Koloski Miranda F. , O’Hearn Christopher M. , Frankot Michelle , Giesler Lauren P. , Ramanathan Dhakshin S. , Vonder Haar Cole
Published: July 2023

Traumatic brain injury (TBI) affects a large population, resulting in severe cognitive impairments. Although cognitive rehabilitation is an accepted treatment for some deficits, studies in patients are limited in ability to probe physiological and behavioral mechanisms. Therefore, animal models are needed to optimize strategies. Frontal TBI in a rat model results in robust and replicable cognitive deficits, making this an ideal candidate for investigating cognitive rehabilitation. In this study, we report three distinct frontal TBI experiments assessing behavior well into the chronic post-injury period using male Long-Evans rats. First, we evaluated the impact of frontal injury on local field potentials recorded simultaneously from 12 brain regions during a probabilistic reversal learning task (PbR). Next, rats were tested on reversal learning (PbR) or impulsivity (differential reinforcement of low-rate behavior: DRL) and half received salient cues associated with reinforcement contingencies as a form of “cognitive rehabilitation”. After rehabilitation on the PbR task, brains were stained for markers of activity. On the DRL, cues were devalued to determine if beneficial effects persisted on impulsive behavior. TBI resulted in outcome salience deficits evident in task performance and reward-feedback signals occurring at beta frequencies in orbitofrontal cortex (OFC) and associated frontostriatal regions. Cognitive rehabilitation improved flexibility and increased OFC activity. Rehabilitation also reduced impulsivity, even after cues were degraded, which was partially mediated by improvements in timing behavior. The current study established a robust platform for investigating cognitive rehabilitation in animals and identified a strong role for dysfunctional OFC signaling after frontal TBI.
Dual-species proteomics and targeted intervention of animal-pathogen interactions
Authors: Liu Yang Sylvia , Zhang Chengqian , Khoo Bee Luan , Hao Piliang , Chua Song Lin
Published: July 2023

Complexity in host-pathogen interactions drives the need to develop sensitive and accurate biochemical techniques to elucidate host and pathogen protein expressions. Current proteomics techniques reveal information from the point of view of either the host or pathogen, but do not provide data on the corresponding partner. While dual-species transcriptomics is increasingly used to study RNA expression in host and pathogen, it remains challenging to simultaneously study host-pathogen proteomes that reflect the direct competition between host and pathogen. UsingCaenorhabditis elegans-Pseudomonas aeruginosainfection model as proof-of-concept, we established a forward+reverse SILAC proteomics approach to simultaneously label and quantify newly-expressed proteins of host and pathogen without physical isolation. We observed iron competition between pathogen iron scavenger and host iron uptake protein, whereP. aeruginosaupregulated pyoverdine synthesis protein (PvdA) and secreted pyoverdine, andC. elegansexpressed ferritin (FTN-2) respectively. Using Galangin as a novel PvdA inhibitor identified by structure-based virtual-screening, targeted intervention of iron competition eliminatedP. aeruginosainfection, and enabled animal survival. Our work provides insights into the mechanisms dictating host-pathogen interactions and offers novel strategies for anti-infective therapy.
Dynamics of giant vesicle assembly from thin lipid films
Authors: Pazzi Joseph , Subramaniam Anand Bala
Published: July 2023

Giant unilamellar vesicles (GUVs) are micrometer-scale lipid assemblies that emulate key characteristics of biological cell membranes. GUVs can be obtained when solid-supported thin films of lipids are hydrated in aqueous solutions. However, a comprehensive understanding of their assembly dynamics has been lacking, impeding mechanistic insights. Here, we report the time dependence of the distribution of sizes and molar yield of GUVs obtained through a novel ‘stopped-time’ technique. We compare three commonly used techniques, PAPYRUS (Paper-Abetted amPhiphile hYdRation in aqUeous Solutions) gentle hydration, and electroformation. We demonstrate that all three techniques show sigmoidal yield curves. Yields increase monotonically before reaching a plateau, with surprisingly high yields 60 seconds after hydration. Gentle hydration shows limited time evolution in contrast to PAPYRUS and electroformation. Exploration of bud dynamics on the surfaces uncovers bud emergence, diameter growth, and merging phenomena. To provide a comprehensive explanation of our observations, we employ the thermodynamic budding and merging model. This work expands our understanding of GUV assembly dynamics and offers fundamental insights into the underlying thermodynamic principles governing this process.
WITHDRAWN: Biallelic mutation ofSUPV3L1causes an inherited leukodystrophy-associated neurodevelopmental disorder due to aberrant mitochondrial double stranded RNA processing
Authors: Green Lydia , Hamilton Noémie , Elpidorou Marilena , Harris Erica L. , Douglas Andrew , Ounap Katrin , Maroofian Reza , Rose Ailsa M.S. , Elworthy Stone , Renshaw Stephen A , Low Elizabeth C. , Prescott Trine , Soberg Kristoffer , Al-Maawali Almunder , Al-Zuhaibi Sana , Futaisi Amna Al , Calame Daniel , Al-Thihli Khalid , Sheridan Eamonn G. , Johnson Colin A. , Livingston John , Crow Yanick J. , Poulter James A
Published: July 2023

Withdrawal Statement

The authors have withdrawn their manuscript owing to an error identified by the corresponding author. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Burden of diarrhea and antibiotic use among children in low-resource settings preventable byShigellavaccination: a simulation study
Authors: Brennhofer Stephanie A , Platts-Mills James A , Lewnard Joseph A , Liu Jie , Houpt Eric R , Rogawski McQuade Elizabeth T
Published: July 2023

Background

Shigellais a leading cause of diarrhea and dysentery in children in low resource settings, which is frequently treated with antibiotics. The primary goal of aShigellavaccine would be to reduce mortality and morbidity associated withShigelladiarrhea. However, ancillary benefits could include reducing antibiotic use and antibiotic exposures for bystander pathogens carried at the time of treatment, specifically for fluoroquinolones and macrolides (F/M), which are the recommended drug classes to treat dysentery.

Methods

We used data from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study to estimate the impact of two one-dose (6 or 9 months) and three two-dose (6 & 9 months, 9 & 12 months, and 12 & 15 months)Shigellavaccines on diarrheal episodes, overall antibiotic use, and F/M use. Further, we considered additional protection through indirect and boosting effects. To estimate the absolute and relative reductions in the incidence of diarrhea and antibiotic use under each vaccination scenario, Monte Carlo simulations with random sampling were performed.

Findings

We analyzed 9392 diarrhea episodes and 15697 antibiotic courses among 1715 children in the MAL-ED birth cohort study. There were 273.8 diarrhea episodes, 30.6 shigellosis episodes, and 457.6 antibiotic courses per 100-child years. AShigellavaccine given at 9 & 12 months prevented 1.7 (95% CI: 1.3, 2.1) severeShigelladiarrhea episodes (46.5% reduction), 11.0 (95% CI: 10.0, 11.9)Shigelladiarrhea episodes of any severity (35.9% reduction), 3.1 (95% CI: 2.6, 3.7) F/M courses (2.9% reduction overall), 5.8 (95% CI: 5.2, 6.6) antibiotic courses (1.0% reduction overall), and 6.3 (95% CI: 5.2, 7.5) F/M (3.2% reduction) and 11.2 (95% CI: 9.7, 12.9) antibiotic (1.2% reduction) exposures to bystander pathogens, respectively, per 100-child years.

Interpretation

AShigellavaccine could make substantial reductions inShigelladiarrhea, antibiotic use to treat shigellosis, and bystander exposures due to shigellosis treatment. However, the reductions in overall diarrhea episodes and antibiotic use would be modest.

Funding

Wellcome Trust, Bill & Melinda Gates Foundation
Navigating the chaos of psychedelic fMRI brain-entropy via multi-metric evaluations of acute psilocybin effects
Authors: McCulloch Drummond E-Wen , Olsen Anders Stevnhoved , Ozenne Brice , Stenbaek Dea Siggard , Armand Sophia , Madsen Martin Korsbak , Knudsen Gitte Moos , Fisher Patrick MacDonald
Published: July 2023

A prominent theory of psychedelics is that they increase brain entropy. Twelve studies have evaluated psychedelic effects on fMRI brain entropy quantifications, no findings have been replicated. Here we evaluated these metrics in an independent 28-participant healthy cohort with 121 pre- and post-psilocybin fMRI scans. We assessed relations between brain entropy and plasma psilocin, brain serotonin 2A receptor occupancy, and a subjective drug intensity rating using linear mixed-effects models. We observed significant positive associations for Shannon entropy of path-length, instantaneous correlation distributions, and divergent associations of sample entropy at varying time-scales. We did not observe significant effects for 8 of 13 entropy metrics. Brain entropy quantifications showed limited inter-measure correlations. Our observations support a nuanced acute psychedelic effect on brain entropy, underscoring the need for replication and that these metrics do not reflect a singular construct. Our findings highlight candidate brain entropy metrics that may mediate clinical effects of psychedelics.
The structural covariance of reading-related brain regions in adults and children with typical reading skills and developmental dyslexia
Authors: Haugg Amelie , Frei Nada , Lutz Christina , Di Pietro Sarah V. , Karipidis Iliana I. , Brem Silvia
Published: July 2023

Structural covariance (SC) is a promising approach for investigating brain organization within the domain of literacy and developmental disorders as it thought to reflect both functional and structural information. This study presents a first-of-its-kind exploration of SC in reading-related brain regions across different ages and reading abilities.

Whole-brain SC analyses were conducted for six key regions of the reading network, including an anterior and posterior subdivision of the visual word form area (VWFA). We compared SC matrices of typically reading adults (N=134) and children (N=110), and between typically reading children and children with dyslexia (N=68).

Our results showed significant associations between reading-related brain regions in typically reading adults. We observed significant SC between the posterior VWFA and the left occipital cortex, and between the anterior VWFA and the left superior temporal gyrus and left inferior frontal gyrus. Typical-reading adults and children did not differ significantly in SC. However, typically reading children demonstrated significantly higher SC between the inferior parietal lobule (IPL) and other reading-related brain regions than children with dyslexia.

Our findings provide support for a functional and structural division of the VWFA and underscore the crucial role of the IPL in fluent reading.
Accurate and Rapid Molecular Subgrouping of High-Grade Glioma via Deep-learning-assisted Label-free Fiberoptic Raman Spectroscopy
Authors: Liu Chang , Wang Jiejun , Shen Jianghao , Chen Xun , Ji Nan , Yue Shuhua
Published: July 2023

Glioma are often impossible to visualize discrimination within different grades and staging, especially for glioma molecular subgrouping which is highly related with surgery strategy and prognosis. Based on glioma guideline published on 2021, molecular subgroups such as IDH, 1p/19q etc. need to be detected to classify the subgroups (astrocytoma, oligodendroglioma, GBM) from high-grade glioma and guide the personalized treatment. However, timely intraoperative technology is limited to identify molecular subgroups of glioma tissues. To address this problem, we develop a deep learning-guided fiberoptic Raman diagnostic platform to assess its ability of real-time high-grade glioma molecular subgrouping. The robust Raman diagnostic platform is established using convolutional neural networks (ResNet) together with fingerprint spectra acquired within 3 seconds. We have acquired a total of 2358 Raman spectra from 743 tissue sites (astrocytoma: 151; oligodendroglioma:150; GBM: 442) of 44 high-grade glioma patients (anaplastic astrocytoma: 7; anaplastic oligodendroglioma:8; GBM: 29). The optimized ResNet model provides an overall mean diagnostic accuracy of 84.1% (sensitivity of 87.1% and specificity of 81.5%) for identifying 7 molecular subgroups (e.g., IDH, 1p/19q, MGMT, TERT, EGFR, Chromosome 7/10, CDKN2A/B) of high-grade glioma, which is superior to the best diagnosis performance using PCA-SVM and UMAP. We further investigate the saliency map of the best ResNet models using the correctly predicted Raman spectra. The specific Raman features that are related to the tumor-associated biomolecules (e.g., collagens, and lipids) validate the robustness of ResNet diagnostic model. This potential intraoperative technology may therefore be able to diagnosis molecular subgroups of high-grade glioma in real time, making it an ideal guide for surgical resection and instant post-operative decision-making.
A RabGAP-Rab GTPase pair regulates plant autophagy and immunity
Authors: Yuen Enoch Lok Him , Leary Alexandre Y , Clavel Marion , Tumtas Yasin , Mohseni Azadeh , Picchianti Lorenzo , Jamshidiha Mostafa , Pandey Pooja , Duggan Cian , Cota Ernesto , Dagdas Yasin , Bozkurt Tolga O
Published: July 2023

Plants rely on autophagy and membrane trafficking to tolerate stress, combat infections, and maintain cellular homeostasis. However, the molecular interplay between autophagy and membrane trafficking is poorly understood. Using an AI-assisted approach, we identified Rab3GAP-like (Rab3GAPL) as an important membrane trafficking node that controls plant autophagy negatively. Rab3GAPL suppresses autophagy by binding to ATG8, the core autophagy adaptor, and deactivating Rab8a, a small GTPase essential for autophagosome formation and defense-related secretion. Rab3GAPL fromNicotiana benthamiana, but not its mutated form deficient in ATG8 binding, reduced autophagic flux inN. benthamianaand Arabidopsis. Furthermore,Rab3GAPL-knockout mutants of the liverwortMarchantia polymorphaexhibited enhanced autophagic flux under both normal and heat stress conditions, suggesting that Rab3GAPL’s negative regulatory role in autophagy is conserved in land plants. Beyond autophagy regulation, Rab3GAPL modulates focal immunity against the oomycete pathogenPhytophthora infestansby preventing defense-related secretion. Altogether, our results suggest that Rab3GAPL acts as a molecular rheostat to coordinate autophagic flux and defense-related secretion by restraining Rab8a-mediated trafficking. This unprecedented interplay between a RabGAP-Rab pair and ATG8 sheds new light on the intricate membrane transport mechanisms underlying plant autophagy and immunity.
A Neanderthal/Denisovan GLI3 variant contributes to anatomical variations in mice
Authors: Agata Ako , Ohtsuka Satoshi , Noji Ryota , Gotoh Hitoshi , Ono Katsuhiko , Nomura Tadashi
Published: July 2023

Changes in genomic structures underlie phenotypic diversification in organisms. Amino acid-changing mutations affect pleiotropic functions of proteins, although little is known about how mutated proteins are adapted in existing developmental programs. Here we investigate the biological effects of a variant of the GLI3 transcription factor (GLI3R1537C) carried in Neanderthals and Denisovans, which are extinct hominins close to modern humans. R1537C does not compromise protein stability or GLI3 activator-dependent transcriptional activities. In contrast, R1537C affects the regulation of downstream target genes associated with developmental processes. Furthermore, genome-edited mice carrying the Neanderthal/Denisovan GLI3 mutation exhibited various alterations in skeletal morphology. Our data suggest that an extinct hominin-type GLI3 contributes to species-specific anatomical variations, which were tolerated by relaxed constraint in developmental programs during human evolution.
Several independent adaptations of archaea to hypersaline environments
Authors: Baker Brittany A. , Gutiérrez-Preciado Ana , Rodríguez del Río Álvaro , McCarthy Charley G. P. , López-García Purificación , Huerta-Cepas Jaime , Susko Edward , Roger Andrew J. , Eme Laura , Moreira David
Published: July 2023

Several archaeal lineages thrive in high, saturating salt concentrations. These extremely halophilic archaea, including Halobacteria, Nanohaloarchaeota, Methanonatronarchaeia, and Haloplasmatales, must maintain osmotic equilibrium with their environment. For this, they use a ‘salt-in’ strategy, which involves pumping molar concentrations of potassium into the cells, which, in turn, has led to extensive proteome-wide modifications to prevent protein aggregation. However, the evolutionary history underlying these adaptations remains poorly understood. In particular, the number of times that these dramatic proteome-sweeping changes occurred is unclear due to the conflicting phylogenetic positions found for several of these lineages. Here, we present a resolved phylogeny of extremely halophilic archaea obtained using improved taxon sampling and state-of-the-art phylogenetic approaches designed to cope with the strong compositional biases of their proteomes. We describe two new uncultured lineages, Afararchaeaceae and Asboarchaeaceae, which break the long branches at the base of Haloarchaea and Nanohaloarchaeota, respectively. Our extensive phylogenomic analyses show that at least four independent adaptations to extreme halophily occurred during archaeal evolution. Finally, gene-tree/species-tree reconciliation suggests that gene duplication and horizontal gene transfer played an important role in this process, for example, by spreading key genes (such as those encoding potassium transporters) across the various extremely halophilic lineages.
Non-destructive real-time monitoring of underground root development with distributed fiber optic sensing
Authors: Tei Mika , Soma Fumiyuki , Barbieri Ettore , Uga Yusaku , Kawahito Yosuke
Published: July 2023

Crop genetic engineering for better root systems can offer practical solutions for food security and carbon sequestration; however, soil layers prevent direct visualization. Here, we demonstrate an original device with a distributed fiber-optic sensor for fully automated, real-time monitoring of underground root development. We demonstrate that spatially encoding an optical fiber with a flexible and durable polymer film in a spiral pattern can significantly enhance sensor detection. After signal processing, the resulting device can detect the penetration of a submillimeter-diameter object in the soil, indicating more than a magnitude higher spatiotemporal resolution than previously reported with underground monitoring techniques. We also developed computational models to visualize the roots of root crops and monocotyledons, and then applied them to radish and rice to compare the results with those of X-ray computed tomography. The device’s groundbreaking sensitivity and spatiotemporal resolution enable seamless and laborless phenotyping of root systems that are otherwise invisible underground.
Crowder titrations enable the quantification of driving forces for macromolecular phase separation
Authors: Chauhan Gaurav , Bremer Anne , Dar Furqan , Mittag Tanja , Pappu Rohit V.
Published: July 2023

Macromolecular solubility is an important contributor to the driving forces for phase separation. Formally, the driving forces in a binary mixture comprising a macromolecule dissolved in a solvent can be quantified in terms of the saturation concentration, which is the threshold macromolecular concentration above which the mixture separates into coexisting dense and dilute phases. Additionally, the second virial coefficient, which measures the effective strength of solvent-mediated intermolecular interactions provides direct assessments of solvent quality. The sign and magnitude of second virial coefficients will be governed by a combination of solution conditions and the nature of the macromolecule of interest. Here, we show, using a combination of theory, simulation, andin vitroexperiments, that titrations of crowders, providing they are true depletants, can be used to extract the intrinsic driving forces for macromolecular phase separation. This refers to saturation concentrations in the absence of crowders and the second virial coefficients that quantify the magnitude of the incompatibility between macromolecules and the solvent. Our results show how the depletion-mediated attractions afforded by crowders can be leveraged to obtain comparative assessments of macromolecule-specific, intrinsic driving forces for phase separation.

SIGNIFICANCE

Phase separation has emerged as a process of significant relevance to sorting macromolecules into distinct compartments, thereby enabling spatial and temporal control over cellular matter. Considerable effort is being invested into uncovering the driving forces that enable the separation of macromolecular solutions into coexisting phases. At its heart, this process is governed by the balance of macromolecule-solvent, inter-macromolecule, and solvent-solvent interactions. We show that the driving forces for phase separation, including the coefficients that measure interaction strengths between macromolecules, can be extracted by titrating the concentrations of crowders that enable macromolecules to phase separate at lower concentrations. Our work paves the way to leverage specific categories of measurements for quantitative characterizations of driving forces for phase separation.
Microenvironmental Stiffness Induces Metabolic Reprogramming in Glioblastoma
Authors: Sohrabi Alireza , Lefebvre Austin E. Y. T , Harrison Mollie J. , Condro Michael C. , Sanazzaro Talia M. , Safarians Gevick , Solomon Itay , Bastola Soniya , Kordbacheh Shadi , Toh Nadia , Kornblum Harley I. , Digman Michelle A. , Seidlits Stephanie K.
Published: July 2023

The mechanical properties of solid tumors influence tumor cell phenotype and ability to invade into surrounding tissues. Using bioengineered scaffolds to provide a matrix microenvironment for patient-derived glioblastoma (GBM) spheroids, this study demonstrates that a soft, brain-like matrix induces GBM cells to shift to a glycolysis-weighted metabolic state which supports invasive behavior. We first show that orthotopic murine GBM tumors are stiffer than peri-tumoral brain tissues, but tumor stiffness is heterogenous where tumor edges are softer than the tumor core. Then, we developed three-dimensional scaffolds with µ-compressive moduli resembling either stiffer, tumor core or softer, peri-tumoral brain tissue. We demonstrate that the softer matrix microenvironment induces a shift in GBM cell metabolism toward glycolysis which manifests in lower proliferation rate and increased migration activities. Finally, we show that these mechanical cues are transduced from the matrix via CD44 and integrin receptors to induce metabolic and phenotypic changes in cancer cells.
Gain-probability diagrams as an alternative to significance testing in economics and finance
Authors: Trafimow David , Wang Ziyuan , Tong Tingting , Wang Tonghui
Published: July 2023

Purpose

The purpose of this article is to show the gains that can be made if researchers were to use gain-probability (G-P) diagrams.

Design/methodology/approach

The authors present relevant mathematical equations, invented examples and real data examples.

Findings

G-P diagrams provide a more nuanced understanding of the data than typical summary statistics, effect sizes or significance tests.

Practical implications

Gain-probability diagrams provided a much better basis for making decisions than typical summary statistics, effect sizes or significance tests.

Originality/value

G-P diagrams provide a completely new way to traverse the distance from data to decision-making implications.
Readability of auditor reports: does audit market competition matter? Empirical evidence from Iran
Authors: Rajabalizadeh Javad
Published: July 2023

Purpose

While existing research explores the impact of audit market competition on audit fees and audit quality, there is limited investigation into how competition in the audit market influences auditors' writing style. This study examines the relationship between audit market competition and the readability of audit reports in Iran, where competition is particularly intense, especially among private audit firms.

Design/methodology/approach

The sample comprises 1,050 firm-year observations in Iran from 2012 to 2018. Readability measures, including the Fog index, Flesch-Reading-Ease (FRE) and Simple Measure of Gobbledygook (SMOG), are employed to assess the readability of auditors' reports. The Herfindahl–Hirschman Index (HHI) is utilized to measure audit market competition, with lower index values indicating higher auditor competition. The concentration measure is multiplied by −1 to obtain the competition measure (AudComp). Alternative readability measures, such as the Flesch–Kincaid (FK) and Automated Readability Index (ARI) are used in additional robustness tests. Data on textual features of audit reports, auditor characteristics and other control variables are manually collected from annual reports of firms listed on the Tehran Stock Exchange (TSE).

Findings

The regression analysis results indicate a significant and positive association between audit market competition and audit report readability. Furthermore, a stronger positive and significant association is observed among private audit firms, where competition is more intense compared to state audit firms. These findings remain robust when using alternative readability measures and other sensitivity checks. Additional analysis reveals that the positive effect of competition on audit report readability is more pronounced in situations where the auditor remains unchanged and the audit market size is small.

Originality/value

This paper expands the existing literature by examining the impact of audit market competition on audit report readability. It focuses on a unique audit market (Iran), where competition among audit firms is more intense than in developed countries due to the liberalization of the Iranian audit market in 2001 and the establishment of numerous private audit firms.
Sustailient supplier selection using neutrosophic best–worst approach: a case study of additively manufactured trinkets
Authors: Ambilkar Priya , Verma Priyanka , Das Debabrata
Published: July 2023

Purpose

This research work has developed an integrated fuzzy Delphi and neutrosophic best–worst framework for selecting the sustailient (sustainable and resilient) supplier for an additive manufacturing (AM)-enabled industry.

Design/methodology/approach

An integrated fuzzy Delphi method (FDM) and neutrosophic best–worst method (N-BWM) approach is developed. 34 supplier evaluation criteria falling under 4 groups, that is, traditional, sustainable, resilient, and AM specific, are identified and validated using the FDM. Afterward, the weights of each criterion are measured by N-BWM. Later on, the performance evaluation is carried out to determine the best-suited supplier. Finally, sensitivity analysis is performed to know the stability and robustness of the proposed framework.

Findings

The outcome indicates the high performance of the suggested decision-making framework. The analysis reveals that supplier 4 (S4) is selected as the most appropriate for a given firm based on the FDM and N-BWM method.

Research limitations/implications

The applicability of this framework is demonstrated through an industrial case of a 3D-printed trinket manufacturer. The proposed research helps AM decision-makers better understand resiliency, sustainability, and AM-related attributes. With this, the practitioners working in AM business can prioritize the supplier selection criteria.

Originality/value

This is the primitive study to undertake the most critical aspect of supplier selection for AM-enabled firms. Apart from this, an integrated FDM-N-BWM framework is a novel contribution to the literature on supplier selection.
Effects of contractual completeness on opportunistic behaviors, multilevel transaction costs and relationship termination intention: the moderating effect of alternative attractiveness
Authors: Yi Ho-Taek , Lee Minkyung , Amenuvor Fortune Edem
Published: July 2023

Purpose

This study which is positioned in the ambit of control research investigates the impact of ex ante contractual completeness on opportunistic behaviors and ex post transaction costs, while assessing how these affect relationship termination intention. This study aims to examine alternative attractiveness as a necessary moderator of the nexus between transaction cost and relationship termination intention.

Design/methodology/approach

Data gathered from 211 companies in South Korea that have installed and run outsourced vending machines are analyzed and used to validate the study’s theoretical and empirical contributions.

Findings

The findings, which rely only on data from companies that outsource and those that run outsourced vending machines, show that contractual completeness negatively affects both active and passive opportunism. The study also discovers that active opportunism positively affects both bargaining costs and monitoring costs, whereas passive opportunism has a positive and direct effect on maladaptation costs but a negative effect on monitoring costs. It further finds that both bargaining and maladaptation costs have positive and direct effects on relationship termination intention, while monitoring costs have a negative effect on the same. Furthermore, it is observed that alternative attractiveness moderates the relationships between bargaining costs and relationship termination intention, as well as maladaptation costs and relationship termination intention.

Practical implications

This study demonstrates that contractual completeness can serve as an important ex ante control mechanism, whereas the two types of opportunism can raise transaction costs. Furthermore, alternative attractiveness is identified as a driver of the impact of transaction costs on relationship termination intention.

Originality/value

A key point of the departure of this study is that it examines the moderating role of alternative attractiveness in the relationship between transaction cost and relationship termination intention. The paper also advances the control literature by emphasizing the critical role that contractual completeness plays in reducing the occurrence of (both active and passive) opportunism in business relationships (especially companies that outsource).