bluuebunny/crossref_metadata_2025 huggingface dataset:
Copredication and Meaning Transfer
Authors: Liebesman David , Magidor Ofra
Published: April 2023

Copredication occurs when a sentence receives a true reading despite prima facie ascribing categorically incompatible properties to a single entity. For example, ‘The red book is by Tolstoy’ can have a true reading even though it seems that being red is only a property of physical copies, while being by Tolstoy is only a property of informational texts.

A tempting strategy for resolving this tension is to claim that at least one of the predicates has a non-standard interpretation, with the salient proposal involving reinterpretation via meaning transfer. For example, in ‘The red book is by Tolstoy’, one could hold that the predicate ‘by Tolstoy’ is reinterpreted (or on the more specific proposal, transferred) to ascribe a property that physical copies can uncontroversially instantiate, such as expresses an informational text by Tolstoy. On this view, the truth of the copredicational sentence is no longer mysterious. Furthermore, such a reinterpretation view can give a straightforward account of a range of puzzling copredicational sentences involving counting an individuation.

Despite these substantial virtues, we will argue that reinterpretation approaches to copredication are untenable. In §1 we introduce reinterpretation views of copredication and contrast them with key alternatives. In §2 we argue against a general reinterpretation theory of copredication on which every copredicational sentence contains at least one reinterpreted predicate. We also raise additional problems for the more specific proposal of implementing reinterpretation via meaning transfer. In §3 we argue against more limited appeals to reinterpretation on which only some copredicational sentences contain reinterpretation. In §4 we criticize a series of arguments in favour of reinterpretation theories. The upshot is that reinterpretation theories of copredication, and in particular, meaning transfer-based accounts, should be rejected.
Idiopathic Left Ventricular Apical Aneurysm in a Sailor With Moderate Transient Chest Pain: A Unique Perspective on an Atypical Presentation in the Military Population
Authors: Wilinski Michael S , Porter Ian M
Published: April 2023

Left ventricular (LV) apical aneurysm is a rare condition that carries a high risk of fatal cardiac rupture. Wall ruptures are an uncommon catastrophic complication after acute transmural myocardial infarction. Rarely is the rupture only contained by an adherent pericardium or hematoma creating a pseudoaneurysm. This clinical finding calls for emergent surgical intervention. If no ruptures are detectable and myocardium wall integrity is verified, the diagnosis of a true aneurysm can be made to be repaired via elective surgery. The etiological differential for a patient with an LV aneurysm in the setting of normal coronaries and in the absence of prior cardiac surgery remains broad, including traumatic, infectious, and infiltrative causes. In this case report, we demonstrate an atypical and rare presentation of an idiopathic LV apical aneurysm in a physically fit, active duty male in the U.S. Navy.
Electricity, Agency and Class in Lagos Colony,
c
.1860s–1914
Authors: Adebayo Adewumi Damilola
Published: April 2023

European states gradually established colonial rule in Africa between the mid nineteenth century and the beginning of the First World War. Historians have assessed the infrastructure introduced during this period through the lens of colonial state-building and resource extraction. This article offers another perspective by reconstructing the early history of electrification in Lagos Colony, one of the first British colonies in West Africa, within the contexts of African agency (that is, knowledge and socio-political influence) and class. It argues that electricity was not a novelty to Africans when the government opened the first power station in 1898. The principles of electricity were already being taught in the classroom and through public lectures in the 1860s, and temporary exhibitions of electric light had been a feature of Lagos society since the 1880s. Furthermore, because of some demographic advantages, the Africans of nineteenth-century Lagos were able to shape colonial policies, including on financing electricity. Lastly, contrary to colonial African case studies in which scholars have argued that racial politics affected access to electricity, extensive primary sources affirm that a rising number of Africans in Lagos enjoyed electric lighting on the streets, at religious centres and at home from 1898.
Hydraulic tradeoffs underlie enhanced performance of polyploid trees under soil water deficit
Authors: Losada Juan M , Blanco-Moure Nuria , Fonollá Andrés , Martínez-Ferrí Elsa , Hormaza José I
Published: April 2023

The relationships between aerial organ morpho-anatomy of woody polyploid plants with their functional hydraulics under water stress remain largely understudied. We evaluated growth-associated traits, aerial organ xylem anatomy, and physiological parameters of diploid, triploid, and tetraploid genotypes of atemoyas (Annona cherimola × Annona squamosa), which belong to the woody perennial genus Annona (Annonaceae), testing their performance under long-term soil water reduction. The contrasting phenotypes of vigorous triploids and dwarf tetraploids consistently showed stomatal size-density tradeoff. The vessel elements in aerial organs were ∼1.5 times wider in polyploids compared with diploids, and triploids displayed the lowest vessel density. Plant hydraulic conductance was higher in well-irrigated diploids while their tolerance to drought was lower. The phenotypic disparity of atemoya polyploids associated with contrasting leaf and stem xylem porosity traits that coordinate to regulate water balances between the trees and the belowground and aboveground environments. Polyploid trees displayed better performance under soil water scarcity, and consequently, could present more sustainable agricultural and forestry genotypes to cope with water stress.
Examining medical student volunteering during the COVID-19 pandemic as a prosocial behaviour during an emergency
Authors: Byrne Matthew H V , Ashcroft James , Wan Jonathan C M , Alexander Laith , Harvey Anna , Arora Anmol , Schindler Nicholas , Brown Megan E L , Brassett Cecilia
Published: April 2023

Purpose

Understanding the factors that influence prosocial behaviour during the COVID-19 pandemic is essential due to the disruption to healthcare provision.

Methods

We conducted an in-depth, mixed-methods cross-sectional survey, from 2 May 2020 to 15 June 2020, of medical students at medical schools in the United Kingdom. Data analysis was informed by Latané and Darley’s theory of prosocial behaviour during an emergency.

Results

A total of 1145 medical students from 36 medical schools responded. Although 947 (82.7%) of students were willing to volunteer, only 391 (34.3%) had volunteered. Of the students, 92.7% understood they may be asked to volunteer; however, we found deciding one’s responsibility to volunteer was mitigated by a complex interaction between the interests of others and self-interest. Further, concerns revolving around professional role boundaries influenced students’ decisions over whether they had the required skills and knowledge.

Conclusion

We propose two additional domains to Latané and Darley’s theory that medical students consider before making their final decision to volunteer: ‘logistics’ and ‘safety’. We highlight modifiable barriers to prosocial behaviour and provide suggestions regarding how the conceptual framework can be operationalized within educational strategies to address these barriers. Optimizing the process of volunteering can aid healthcare provision and may facilitate a safer volunteering process.

Key messages 

What is already known on this topic: 

There is a discrepancy between the number of students willing to volunteer during pandemics and disasters, and those who actually volunteer. Understanding the factors that influence prosocial behaviour during the current COVID-19 pandemic and future pandemics and disasters is essential.

What this study adds: 

We expanded on Latané and Darley’s theory of prosocial behaviour in an emergency and used this to conceptualize students’ motivations to volunteer, highlighting a number of modifiable barriers to prosocial behaviour during the COVID-19 pandemic.

How this study might affect research, practice, or policy: 

We provide suggestions regarding how the conceptual framework can be operationalized to support prosocial behaviours during emergencies for the ongoing COVID-19 pandemic and future crises.
NOTCH signaling inhibition after DAPT treatment exacerbates alveolar echinococcosis hepatic fibrosis by blocking M1 and enhancing M2 polarization
Authors: Li Bin , Wang Liang , Qi Xinwei , Liu Yumei , Li Jiajun , Lv Jie , Zhou Xuan , Cai Xuanlin , Shan Jiaoyu , Ma Xiumin
Published: April 2023

Alveolar echinococcosis (AE) is a lethal helminthic liver disease caused by persistent infection with Echinococcus multilocularis (E. multilocularis). Although more and more attention has been paid to the macrophages in E. multilocularis infection, the mechanism of macrophage polarization, a critical player in liver immunity, is seldom studied. NOTCH signaling is involved in cell survival and macrophage‐mediated inflammation, but the role of NOTCH signaling in AE has been equally elusive. In this study, liver tissue samples from AE patients were collected and an E. multilocularis infected mouse model with or without blocking NOTCH signaling was established to analyze the NOTCH signaling, fibrotic and inflammatory response of the liver after E. multilocularis infection. Changes in polarization and origin of hepatic macrophages were analyzed by flow cytometry. In vitro qRT‐PCR and Western blot assays were performed to analyze key receptors and ligands in NOTCH signaling. Our data demonstrated that hepatic fibrosis develops after AE, and the overall blockade of NOTCH signaling caused by DAPT treatment exacerbates the levels of hepatic fibrosis and alters the polarization and origin of hepatic macrophages. Blocking NOTCH signaling in macrophages after E. multilocularis infection downregulates M1 and upregulates M2 expression. The downregulation of NTCH3 and DLL‐3 in the NOTCH signaling pathway is significant. Therefore, NOTCH3/DLL3 may be the key pathway in NOTCH signaling regulating macrophage polarization affecting fibrosis caused by AE.
Regulation of VEGFR2 and AKT signaling by Musashi-2 in lung cancer
Authors: Bychkov Igor , Topchu Iuliia , Makhov Petr , Kudinov Alexander , Patel Jyoti D. , Boumber Yanis
Published: April 2023

Lung cancer is the most frequently diagnosed cancer type and the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) represents most of the lung cancer. Vascular endothelial growth factor receptor-2 (VEGFR2) is a member of the VEGF family of receptor tyrosine kinase proteins, expressed on both endothelial and tumor cells which is one of the key proteins contributing to cancer development and involved in drug resistance. We previously showed that Musashi-2 (MSI2) RNA-binding protein is associated with NSCLC progression by regulating several signaling pathways relevant to NSCLC. In this study, we performed Reverse Protein Phase Array (RPPA) analysis of murine lung cancer which nominated VEGFR2 protein as strongly positively regulated by MSI2. Next, we validated VEGFR2 protein regulation by MSI2 in several human NSCLC cell line models. Additionally, we found that MSI2 affected AKT signaling via negativePTENmRNA translation regulation. In silico prediction analysis suggested that both VEGFR2 and PTEN mRNAs have predicted binding sites for MSI2. We next performed RNA immunoprecipitation coupled with quantitative PCR which confirmed that MSI2 directly binds to VEGFR2 and PTEN mRNAs, suggesting direct regulation mechanism. Finally, MSI2 expression positively correlated with VEGFR2 and VEGF-A protein levels in human NSCLC samples. We conclude that MSI2/VEGFR2 axis contributes to NSCLC progression and is worth further investigations and therapeutic targeting.
Hyperconnectivity of two separate long-range cholinergic systems contributes to the reorganization of the brain functional connectivity during nicotine withdrawal in male mice
Authors: Carrette Lieselot L.G. , Kimbrough Adam , Davoudian Pasha A. , Kwan Alex C. , Collazo Andres , George Olivier
Published: April 2023

Chronic nicotine results in dependence with withdrawal symptoms upon discontinuation of use, through desensitization of nicotinic acetylcholine receptors and altered cholinergic neurotransmission. Nicotine withdrawal is associated with increased whole-brain functional connectivity and decreased network modularity, however, the role of cholinergic neurons in those changes is unknown. To identify the contribution of nicotinic receptors and cholinergic regions to changes in the functional network, we analyzed the contribution of the main cholinergic regions to brain-wide activation of the immediate early-gene FOS during withdrawal in male mice and correlated these changes with the expression of nicotinic receptor mRNA throughout the brain. We show that the main functional connectivity modules included the main long-range cholinergic regions, which were highly synchronized with the rest of the brain. However, despite this hyperconnectivity they were organized into two anticorrelated networks that were separated into basal forebrain projecting and brainstem-thalamic projecting cholinergic regions, validating a long-standing hypothesis of the organization of the brain cholinergic systems. Moreover, baseline (without nicotine) expression ofChrna2,Chrna3,Chrna10, andChrndmRNA of each brain region correlated with withdrawal-induced changes in FOS expression. Finally, by mining the Allen Brain mRNA expression database, we were able to identify 1755 gene candidates and three pathways (Sox2-Oct4-Nanog, JAK-STAT, and MeCP2-GABA) that may contribute to nicotine withdrawal-induced FOS expression. These results identify the dual contribution of the basal forebrain and brainstem-thalamic cholinergic systems to whole-brain functional connectivity during withdrawal; and identify nicotinic receptors and novel cellular pathways that may be critical for the transition to nicotine dependence.

Significance Statement

Discontinuation of nicotine use in dependent users is associated with increased whole-brain activation and functional connectivity and leads to withdrawal symptoms. Here we investigated the contribution of the nicotinic cholinergic receptors and main cholinergic projecting brain areas in the whole-brain changes associated with withdrawal. This not only allowed us to visualize and confirm the previously described duality of the cholinergic brain system using this novel methodology, but also identify nicotinic receptors together with 1751 other genes that contribute, and could thus be targets for treatments against, nicotine withdrawal and dependence.
Vimentin cysteine 328 modifications finely tune network organization and influence actin remodeling under oxidative and electrophilic stress
Authors: González-Jiménez Patricia , Duarte Sofia , Martínez Alma E. , Navarro-Carrasco Elena , Lalioti Vasiliki , Pajares María A. , Pérez-Sala Dolores
Published: April 2023

Cysteine residues can undergo multiple posttranslational modifications with diverse functional consequences, potentially behaving as tunable sensors. The intermediate filament protein vimentin has important implications in pathophysiology, including cancer progression, infection, and fibrosis, and maintains a close interplay with other cytoskeletal structures, such as actin filaments and microtubules. We previously showed that the single vimentin cysteine, C328, is a key target for oxidants and electrophiles. Here, we demonstrate that structurally diverse cysteine-reactive agents, including electrophilic mediators, oxidants and drug-related compounds, disrupt the vimentin network eliciting morphologically distinct reorganizations. As most of these agents display broad reactivity, we pinpointed the importance of C328 by confirming that local perturbations introduced through mutagenesis provoke structure-dependent vimentin rearrangements. Thus, GFP-vimentin wild type (wt) forms squiggles and short filaments in vimentin-deficient cells, the C328F, C328W, and C328H mutants generate diverse filamentous assemblies, and the C328A and C328D constructs fail to elongate yielding dots. Remarkably, vimentin C328H structures resemble the wt, but are strongly resistant to electrophile-elicited disruption. Therefore, the C328H mutant allows elucidating whether cysteine-dependent vimentin reorganization influences other cellular responses to reactive agents. Electrophiles such as 1,4-dinitro-1H-imidazole and 4-hydroxynonenal induce robust actin stress fibers in cells expressing vimentin wt. Strikingly, under these conditions, vimentin C328H expression blunts electrophile-elicited stress fiber formation, apparently acting upstream of RhoA. Analysis of additional vimentin C328 mutants shows that electrophile-sensitive and assembly-defective vimentin variants permit induction of stress fibers by reactive species, whereas electrophile-resistant filamentous vimentin structures prevent it. Together, our results suggest that vimentin acts as a break for actin stress fibers formation, which would be released by C328-aided disruption, thus allowing full actin remodeling in response to oxidants and electrophiles. These observations postulate C328 as a “sensor” transducing structurally diverse modifications into fine-tuned vimentin network rearrangements, and a gatekeeper for certain electrophiles in the interplay with actin.
E-Protein Protonation Titration-induced Single Particle Chemical Force Spectroscopy for Microscopic Understanding and pI Estimation of Infectious DENV
Authors: Ghosal Manorama , Rakhshit Tatini , Bhattacharya Shreya , Bhattacharyya Sankar , Satpati Priyadarshi , Senapati Dulal
Published: April 2023

The ionization state of amino acids on the outer surface of a virus regulates its physicochemical properties toward the sorbent surface. Serologically different strain of dengue virus (DENV) shows different extents of infectivity depending upon their interactions with a receptor on the host cell. To understand the structural dependence of E-protein protonation over its sequence dependence, we have followed E-protein titration kinetics both experimentally and theoretically for two differentially infected dengue serotypes, namely DENV-2 and DENV-4. We have performed an E-protein protonation titration-induced single particle chemical force spectroscopy using an atomic force microscope (AFM) to measure the surface chemistry of DENV in physiological aqueous solutions not only to understand the charge distribution dynamics on virus surface but also to estimate the isoelectric point (pI) accurately for infectious dengue viruses. Cryo-EM structure-based theoretical pI calculations of DENV-2 surface protein were shown to be consistent with the evaluated pI value from force spectroscopy measurements. This is a comprehensive study to understand how the cumulative charge distribution on the outer surface of a specific serotype of DENV regulates a prominent role of infectivity over minute changes at the genetic level.
The human superior colliculus motor region does not respond to finger movements
Authors: Prabhu Nikhil G , Knodel Nicole , Himmelbach Marc
Published: April 2023

Electrophysiological studies in macaques and functional neuroimaging in humans revealed a motor region in the superior colliculus (SC) for upper limb reaching movements. Connectivity studies in macaques reported direct connections between this SC motor region and cortical premotor arm, hand, and finger regions. These findings motivated us to investigate if the human SC is also involved in sequential finger tapping movements. We analysed fMRI task data of 130 participants executing simple finger tapping from the Human Connectome Project (HCP). While we found strong signals in the SC for visual cues, we found no signals related to simple finger tapping. Assuming a differential effect owing to simple and complex finger tapping sequences, we searched for responses in the SC corresponding to complex finger tapping above simple finger tapping sequences. We observed expected signal differences in cortical motor and premotor regions, but our analyses provided no evidence for signals related to simple or complex finger tapping in the SC. Despite evidence for direct anatomical connections of the SC motor region and cortical premotor hand and finger areas in macaques, our results suggest that the SC is not involved in simple or complex finger tapping in humans.
Evaluation of surface-based hippocampal registration using ground-truth subfield definitions
Authors: DeKraker Jordan , Palomero-Gallagher Nicola , Kedo Olga , Ladbon-Bernasconi Neda , Muenzing Sascha E.A. , Axer Markus , Amunts Katrin , Khan Ali R. , Bernhardt Boris , Evans Alan C.
Published: April 2023

The hippocampus is an archicortical structure, consisting of subfields with unique circuits. Understanding its microstructure, as proxied by these subfields, can improve our mechanistic understanding of learning and memory and has clinical potential for several neurological disorders. One prominent issue is how to parcellate, register, or retrieve homologous points between two hippocampi with grossly different morphologies. Here, we present a surface-based registration method that solves this issue in a contrast-agnostic, topology-preserving manner. Specifically, the entire hippocampus is first analytically unfolded, and then samples are registered in 2D unfolded space based on thickness, curvature, and gyrification. We demonstrate this method in seven 3D histology samples and show superior alignment with respect to subfields using this method over more conventional registration approaches.

Highlights

Hippocampal subfields contain microcircuits that are critical for memory and vulnerable to neurological disease.

Hippocampi have variable folding patterns between individuals, making them hard to register or parcellate.

We present a surface-based hippocampal registration method that is analogous to neocortical inflation to a sphere and registration.

Testing in seven detailed 3D histology samples revealed successful registration with respect to hippocampal subfields, and outperformed more conventional methods.

This method provides groundwork for detailed multimodal hippocampal mapping across subjects and datasets in the future.

Data availability

The methodological advancements described here are made easily accessible in the latest version of open source software HippUnfold1. Code used in the development and testing of these methods, as well as preprocessed images, manual segmentations, and results, are openly available2.
Cryo-EM Structures of Amyloid-β Fibrils from Alzheimer’s Disease Mouse Models
Authors: Zielinski Mara , Reyes Fernanda S. Peralta , Gremer Lothar , Schemmert Sarah , Frieg Benedikt , Willuweit Antje , Donner Lili , Elvers Margitta , Nilsson Lars N. G. , Syvänen Stina , Sehlin Dag , Ingelsson Martin , Willbold Dieter , Schröder Gunnar F.
Published: April 2023

The development of novel drugs for Alzheimer’s disease has proven difficult, with a high failure rate in clinical trials. Typically, transgenic mice displaying amyloid-β peptide brain pathology are used to develop therapeutic options and to test their efficacy in preclinical studies. However, the properties of Aβ in such mice have not been systematically compared to Aβ from the patient brains. Here, we determined the structures of nineex vivoAβ fibrils from six different mouse models by cryo-EM. We found novel Aβ fibril structures in the APP/PS1, ARTE10, and tg-SwDI models, whereas the human familial type II fibril fold was found in the ARTE10, tg-APPSwe, and APP23 models. The tg-APPArcSwemice showed an Aβ fibril whose structure resembles the human sporadic type I fibril. These structural elucidations are key to the selection of adequate mouse models for the development of novel plaque-targeting therapeutics and PET imaging tracers.

One Sentence Summary

Cryo-EM structures of Aβ fibrils extracted from brains of mouse models used for Alzheimer’s disease preclinical research are presented.
Fatty links between multisystem proteinopathy and Small VCP-Interacting Protein
Authors: Ramzan Firyal , Abrar Fatima , Kumar Ashish , Liao Lucia Meng Qi , Campbell Zurie E. , Gray Rachel V. , Akanni Oluwadurotimi , Guyn Colm , Martin Dale D. O.
Published: April 2023

Multisystem proteinopathy (MSP) is a rare dominantly-inherited disorder that includes a cluster of diseases, including frontotemporal dementia, inclusion body myopathy, and Paget’s disease of bone. MSP is caused by mutations in the gene encoding Valosin-Containing Protein (VCP). Patients with the same mutation, even within the same family, can present with a different combination of any or all of the above diseases, along with amyotrophic lateral sclerosis (ALS). The pleiotropic effects may be linked to the greater than 50 VCP cofactors that direct VCP’s many roles in the cell. Small VCP-Interacting Protein (SVIP) is a small protein that directs VCP to autophagosomes and lysosomes. We found that SVIP directs VCP localization to autophagosomes in an acylation-dependent manner. We demonstrate that SVIP is myristoylated at glycine 2 and palmitoylated at cysteines 4 and 7. Acylation of SVIP is required to mediate cell death in the presence of the MSP-associated VCP variant (R155H-VCP), whereas blocking SVIP myristoylation prevents cytotoxicity. Therefore, SVIP acylation may present a novel target in MSP.
Metabolic reprogramming provides a novel approach to overcome resistance to BH3-mimetics in Malignant Pleural Mesothelioma
Authors: Sun Xiao-Ming , Miles Gareth J , Powley Ian R , Craxton Andrew , Galavotti Sarah , Chernova Tatyana , Dawson Alan , Nakas Apostolos , Willis Anne E , Cain Kelvin , MacFarlane Marion
Published: April 2023

Malignant pleural mesothelioma (MPM) is an aggressive malignancy linked to asbestos exposure and highly resistant to chemotherapy, potentially due to upregulated expression of the pro-survival proteins, BCL2/BCL-XL/MCL-1. Using clinically-relevant models of MPM we show that patient-derived primary MPM cell lines andex-vivo3D tumour explants are highly resistant to apoptosis induced by the BCL2/BCL-XL inhibitor, ABT-737. Importantly, we discover that 2-deoxyglucose (2DG), a glycolytic inhibitor, can sensitize MPM cells to ABT-737 and show this correlates with loss of the pro-survival protein, MCL-1. siRNA knockdown of MCL-1 (MCL-1 KD) combined with ABT-737 induced BAX/BAK-dependent, but BIM/PUMA-independent apoptosis, mimicking 2DG/ABT-737 treatment. MCL-1 KD/ABT-737 induced mitochondrial cytochromecrelease and caspase-independent inhibition of mitochondrial respiration. Moreover, we observed a hitherto unreported caspase-dependent cleavage of glycolytic enzymes and subsequent inhibition of glycolysis. 2DG inhibited ERK/STAT3 activity, decreased MCL-1 mRNA and protein levels, with concurrent activation of AKT, which limited loss of MCL-1 protein. However, co-treatment with a specific AKT inhibitor, AZD5363, and 2DG/ABT-737 potently induced cell death and inhibited clonogenic cell survival, while in MPM 3D tumour explants MCL-1 protein expression decreased significantly following 2DG or 2DG/AZD5363 treatment. Notably, a similar synergy was observed in MPM cell lines and MPM 3D tumour explants using ABT-737 in combination with the recently developed MCL-1 inhibitor, S63845. Importantly, our study provides a mechanistic explanation for the chemoresistance of MPM and highlights how this can be overcome by a combination of metabolic reprogramming and/or simultaneous targeting of MCL-1 and BCL-2/BCL-XL using BH3-mimetics.
C9orf72-linked arginine-rich dipeptide repeats aggravate pathological phase separation of G3BP1
Authors: Nerom Margot Van , Ahmed Junaid , Lazar Tamas , Lindt Joris Van , Pancsa Rita , Maes Dominique , Tompa Peter
Published: April 2023

Ras GTPase-activating protein-binding protein 1 (G3BP1) is the key protein driving the formation of cytoplasmic stress granules (SGs) by liquid-liquid phase separation (LLPS). It is a switch-like protein held in a closed and inactive state by intramolecular electrostatic interactions competitively opened by RNA, activating the protein and initiating its LLPS. Here we show that C9orf72-derived arginine-rich dipeptide repeats PR30 and GR30 (R-DPRs) present in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), also bind to G3BP1, switching it to an LLPS-competent open state much more effectively than RNA. Whereas RNA binds G3BP1 with micromolar affinity, and cannot initiate LLPS without crowding agents, R-DPRs exhibit a thousand-fold stronger binding to G3BP1, eliciting rapid LLPS even without crowding. The pathogenic effect of R-DPRs is also underscored by the slow transition of R-DPR-G3BP1 liquid droplets to aggregated, ThS-positive states that can recruit the ALS-linked protein hnRNPA2. Deletion constructs and molecular simulations show that R-DPR binding and LLPS are mediated via binding through the negatively charged intrinsically disordered region 1 (IDR1) of the protein, allosterically regulated by the positively charged IDR3. Bioinformatic analyses point to the strong mechanistic parallels of these effects with the interaction of R-DPRs with nuclear nucleophosmin (NPM1) and also suggest that R-DPRs also interact with many other similar nucleolar and stress-granule proteins, extending the underlying mechanism of R-DPR toxicity in cells.
Nucleoporin Nsp1 surveils the phase state of FG-Nups
Authors: Otto Tegan A. , Bergsma Tessa , Dekker Maurice , Mouton Sara N. , Gallardo Paola , Wolters Justina C. , Steen Anton , Onck Patrick R. , Veenhoff Liesbeth M.
Published: April 2023

Transport through the NPC relies on intrinsically disordered FG-Nups forming a selective barrier. Away from the NPC, FG-Nups readily form condensates and aggregates, and we address how this behavior is surveilled in cells. FG-Nups, including Nsp1, together with nuclear transport receptor Kap95, form a native cytosolic condensate in yeast. In aged cells this condensate disappears as cytosolic Nsp1 levels decline. Biochemical assays and modeling show that Nsp1 is a modulator of FG-Nup liquid-liquid phase separation, promoting a liquid-like state. Nsp1’s presence in the cytosol and condensates is critical, as a reduction of cytosolic levels in young cells induces NPC assembly and transport defects and a general decline in protein quality control, all quantitatively mimicking aging phenotypes. Excitingly, these phenotypes can be rescued by cytosolic Nsp1. We conclude that Nsp1 is a phase state regulator that surveils FG-Nups and impacts general protein homeostasis.

Highlights

Nups form native cytosolic condensates

Nsp1 reduction mimics NPC aging phenotypes

Nsp1 acts as phase state modulator of FG-Nups

Nsp1 shares surveillance function with classical chaperones
An intermembrane space protein facilitates completion of mitochondrial division in yeast
Authors: Connor Olivia M. , Matta Srujan K. , Friedman Jonathan R.
Published: April 2023

Mitochondria are highly dynamic double membrane-bound organelles that maintain their shape in part through fission and fusion. Mitochondrial fission is performed by the dynamin-related protein Dnm1 (Drp1 in humans), a large GTPase that constricts and divides the mitochondria in a GTP hydrolysis-dependent manner. However, it is unclear whether factors inside mitochondria help coordinate the process and if Dnm1/Drp1 activity alone is sufficient to complete fission of both mitochondrial membranes. Here, we identify an intermembrane space protein required for mitochondrial fission in yeast, which we propose to name Mdi1. Loss of Mdi1 leads to hyper-fused mitochondria networks due to defects in mitochondrial fission, but not lack of Dnm1 recruitment to mitochondria. Mdi1 plays a conserved role in fungal species and its homologs contain a putative amphipathic α-helix, mutations in which disrupt mitochondrial morphology. One model to explain these findings is that Mdi1 associates with and distorts the mitochondrial inner membrane to enable Dnm1 to robustly complete fission. Our work reveals that Dnm1 cannot efficiently divide mitochondria without the coordinated function of a protein that resides inside mitochondria.
Transfer learning for cross-context prediction of protein expression from 5’UTR sequence
Authors: Gilliot Pierre-Aurélien , Gorochowski Thomas E.
Published: April 2023

Model-guided DNA sequence design can accelerate the reprogramming of living cells. It allows us to engineer more complex biological systems by removing the need to physically assemble and test each potential design. While mechanistic models of gene expression have seen some success in supporting this goal, data-centric, deep learning-based approaches often provide more accurate predictions. This accuracy, however, comes at a cost — a lack of generalisation across genetic and experimental contexts, which has limited their wider use outside the context in which they were trained. Here, we address this issue by demonstrating how a simple transfer learning procedure can effectively tune a pre-trained deep learning model to predict protein translation rate from 5’ untranslated region sequence (5’UTR) for diverse contexts inEscherichia coliusing a small number of new measurements. This allows for important model features learnt from expensive massively parallel reporter assays to be easily transferred to new settings. By releasing our trained deep learning model and complementary calibration procedure, this study acts as a starting point for continually refined model-based sequence design that builds on previous knowledge and future experimental efforts.
Intention to dropout and study satisfaction: testing item bias and structural invariance of measures for South African first-year university students
Authors: Mostert Karina , van Rensburg Clarisse , Machaba Reitumetse
Published: April 2023

Purpose

This study examined the psychometric properties of intention to drop out and study satisfaction measures for first-year South African students. The factorial validity, item bias, measurement invariance and reliability were tested.

Design/methodology/approach

A cross-sectional design was used. For the study on intention to drop out, 1,820 first-year students participated, whilst 780 first-year students participated in the study on satisfaction with studies. Confirmatory factor analysis (CFA), differential item functioning (DIF), measurement invariance and internal consistency were used to test the scales.

Findings

A one-factor structure was confirmed for both scales. For the intention to drop out scale, Items 3 and 4 were identified with statistically significant item bias; however, these differences had no practical impact. Except for scalar invariance for language, sufficient measurement invariance was established. No problematic items were identified for the study satisfaction scale.

Practical implications

In essence, this study provides evidence of two short measures that are culturally sensitive that could be used as short and valid measures across contextual boundaries as practically valuable tools to measure intention to drop out and study satisfaction in diverse and multicultural contexts.

Originality/value

This study contributes to limited research on bias and invariance analyses for scales that can be used in interventions to identify students at risk of leaving the university and utilising psychometric analyses to ensure the applicability of these two scales in diverse and multicultural settings.
Weak-form market efficiency and corruption: a cross-country comparative analysis
Authors: İcan Özgür , Çelik Taha Buğra
Published: April 2023

Purpose

The economic and administrative conditions of countries normatively have an effect on the economy and level of market development. Moreover, it is of great importance for a healthy economy whether the public institutions and organizations are transparent and functioning in accordance with their purpose. The aim of this study is to show whether there is a relationship between transparency and market efficiency.

Design/methodology/approach

Correlation analysis has been conducted between prediction accuracy rates, which are obtained by seven different machine learning algorithms and Corruption Perception Index (CPI) levels.

Findings

It has been statistically shown that the indices of countries with low corruption levels are harder to predict, which, in turn, can be interpreted as having higher weak-form market efficiency. According to that, an intermediate negative correlation has been found between CPI scores and predictability levels of stock indices. Considering the findings, it can be interpreted that the markets of countries with relatively more transparent and well-functioning public sector have more weak-form market efficiency.

Research limitations/implications

The study can be extended with cutting-edge machine learning and deep learning techniques in future studies. There are very few studies which try to explain factors related to market efficiency. Thus, the authors claim that there is still room for further research in order to determine the factors related to market efficiency, implying that current literature is still far from explaining the causation behind the inefficiencies.

Practical implications

According to findings, the markets of countries with relatively more transparent and well-functioning public sector have more weak-form market efficiency. Based on these findings, in practice, it can be said that more successful predictions can be made using machine learning algorithms in countries with relatively lower CPI scores.

Originality/value

In literature, the factors related to market efficiency are still far from explaining the causation behind the inefficiencies. Thus, it has been investigated whether transparent and well-functioning public institutions and organizations have any relation with market efficiency.
Game of algorithms: ChatGPT implications for the future of tourism education and research
Authors: Ivanov Stanislav , Soliman Mohammad
Published: April 2023

Purpose

The paper aims to evaluate the ways ChatGPT is going to disrupt tourism education and research.

Design/methodology/approach

This is a conceptual paper.

Findings

ChatGPT has the potential to revolutionize tourism education and research because it can do what students and researchers should do, namely, generate text (assignments and research papers). Universities will need to reevaluate their teaching and assessment strategies and incorporate generative language models in teaching. Publishers will need to be more receptive toward manuscripts that are partially generated by artificial intelligence. In the future, digital teachers and research assistants will take over many of the cognitive tasks of tourism educators and researchers.

Originality/value

To the authors’ best knowledge, this is one of the first academic papers that investigates the implications of ChatGPT to tourism education and research.
Exploring EFL female teachers' and undergraduate students' perceptions regarding written corrective feedback
Authors: Alhumaid Anwar
Published: April 2023

Purpose

The purpose of this study is to explore the perceptions of teachers’ and undergraduate students concerning the provision of written corrective feedback (WCF) in Saudi EFL writing classrooms in the form of a case study.

Design/methodology/approach

The sample consisted of three teachers and five students, whose views on WCF were recorded via individual semi-structured interviews to gather qualitative data.

Findings

The results revealed some divergent viewpoints between students and teachers and among peers in both groups.

Originality/value

By offering the best WCF practice and considering students' interests, this research is important for improving the pedagogical approaches used by EFL instructors for teaching writing to university learners. It will, therefore, have more of an impact on EFL writing instruction.
Quelling inflation: The role of the public
Authors: Holmes Douglas R.
Published: April 2023

Members of the Monetary Policy Committee (MPC) of the Bank of England seek to subdue inflation using ‘monetary policy’ to regulate the availability of money and credit to the financial system. The central bank ‘policy rate’ is the blunt instrument conventionally employed to affect the pacing of economic activity, stimulating or retarding growth. Credibly explaining that the rise in interest rates – the ‘tightening’ of monetary policy – underway at the moment will continue suppressing demand for goods and services until an inflation target of around 2 per cent is achieved is the emphatic message the bank seeks to convey. Such intentionally destructive and potentially brutal interventions are the critical aim of current bank policy. This article demonstrates how the design of the contemporary monetary regime, which presents itself unequivocally as the outcome of macroeconomic developments, can be recast in anthropological terms, thus revealing the role of the public in the unfolding monetary drama.
Crises all around: Do recent predicaments and their responses imperil ‘neoliberalism’?
Authors: Myhre Knut Christian
Published: April 2023

The announcement of a record trade surplus for Norway in 2022, and a proposal to create a guarantee fund for investments in renewable energy for Ukraine, Europe and beyond, indicate how the economic and financial situation of the Norwegian state is intimately linked to the predicaments or crises that pertain to the contemporary world. While these phenomena at first glance appear legible in terms of neoliberalism, the article sketches how they instead concern a longstanding history and experience, where commercial corporations, financial markets and private profits are deployed for public benefit. While these dynamics suggest that neoliberalism never was relevant for the Norwegian context, the ascendancy of similar notions and practices elsewhere raises the question of whether current predicaments and their policy responses also spell a crisis for this analytic. Is it time to let the concept go?
Shifting ground or moving furniture around: Youth participatory action research in Kakuma Refugee Camp
Authors: Bellino Michelle J.
Published: April 2023

This reflection is drawn from a youth participatory action research (YPAR) collaboration set in Kakuma Refugee Camp in Kenya. It explores the ways youth co‐researchers employed YPAR tools to both critique and uphold their limited educational opportunity structure. It also questions the limits of transformative methodologies that embolden young people to critique the structures that govern their lives, especially for stateless peoples whose survival depends on continued access to those same structures.
Stage IA melanoma follow‐up: Exploring the level of confidence of South Australian general practitioners in undertaking surveillance skin checks including considerations for shared care
Authors: Mathew Thomas , Ianno Damian J. , Sidhu Shireen K.
Published: April 2023

Background

The literature highlights the role of Australian general practitioners (GP) in the management of skin cancers. With melanoma incidences on the rise, there have been discussions into whether lower‐risk stage IA patients could safely be followed up by their GPs for annual surveillance full skin examinations (FSE). This study explores the level of confidence of South Australian (SA) GPs in undertaking FSEs including factors that could support discussions around shared care between GPs and dermatology units for lower‐risk patients.

Methods

An online survey was designed and distributed to SA GPs via email, newsletters and social media between 5 December 2021 and 30 January 2022. Descriptive statistics were used to describe survey responses. Pearson's Chi‐squared analysis was used to investigate associations between key variables of interest and explanatory variables. Logistic regression analysis was used to model odds ratios for associations between the dependent variable and independent variables.

Results

A total of 135 responses were obtained. Forty‐four per cent of GPs were comfortable undertaking annual FSEs, 41% were uncomfortable and 15% were unsure. Scope of work, >20 years experience and additional training had statistically significant relationships (p < 0.05). Dermoscopy and detecting melanoma recurrences were reported to be skills with lower levels of confidence. With regards to shared care, 77% indicated that they would feel supported undertaking FSEs if rapid access referral pathways were allocated for patients who developed suspicious lesions. Preferred upskilling modalities included, face‐to‐face sessions in a dermatology unit (39%), dermatologist run webinars (25%) and certificate courses (20%).

Conclusions

At present, there is a subset of SA GPs who are comfortable undertaking FSEs and therefore could be engaged in shared care with specialists. Further considerations have to be made in the areas of upskilling and supporting the workforce to enhance engagement in shared care.
Inconsistencies of absolute drug–drug contraindication reports: Analysis of Summaries of Product Characteristics of commonly prescribed drugs
Authors: Weisbach Laura , Schuster Anna K. , Hartmann Michael , Dürr Pauline , Then Melanie I. , Andrikyan Wahram , Fromm Martin F. , Maas Renke , Farker Katrin
Published: April 2023

Aims

Prescribing information should follow a defined structure to help prescribers easily find required information. Often information appears in different sections of Summaries of Product Characteristics (SmPCs) in an inconsistent way. Still unknown is how this inconsistency affects absolute contraindications and how it can be improved. Thisstudy aimed to evaluate the structure of absolute contraindications in SmPCs based on absolute drug–drug contraindications (DDCI) in the section ‘contraindications’ and references to sections ‘special warnings and precautions for use’ (here as ‘warnings’) and ‘interaction with other medicinal products and other forms of interaction’ (here as ‘interactions’).

Methods

SmPCs of 693 commonly prescribed drugs were analysed regarding absolute DDCI in ‘contraindications’ sections. References to sections on ‘warnings’ and ‘interactions’ were evaluated to characterize information provided about DDCI.

Results

Of 693 analysed SmPCs, 138 (19.9%) contained ≥1 absolute DDCI. Of 178 SmPCs that referred to sections on ‘warnings’ or ‘interactions’, 131 (73.6%) did not contain further information on absolute DDCI, whereas 47 (26.4%) did. Such additional information was found in sections on ‘interactions’ and ‘warnings’ in 41 (87.2%) and 9 (19.1%) SmPCs, respectively.

Conclusions

Information regarding absolute DDCI was found not only in sections on ‘contraindications’ but also in sections on ‘warnings’ and ‘interactions’. Information was not given with consistently straightforward phrasing and structure and so can leave uncertainty for prescribers. To improve drug safety, clear definitions and wording for absolute and relative contraindications should be provided, ideally in tables.