bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractCysteine 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

ABSTRACTThe 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

AbstractElectrophysiological 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

AbstractThe 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.HighlightsHippocampal 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 availabilityThe 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

AbstractThe 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 SummaryCryo-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

ABSTRACTMultisystem 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

AbstractMalignant 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

AbstractRas 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

AbstractTransport 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.HighlightsNups form native cytosolic condensatesNsp1 reduction mimics NPC aging phenotypesNsp1 acts as phase state modulator of FG-NupsNsp1 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

AbstractMitochondria 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

ABSTRACTModel-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

PurposeThis 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/approachA 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.FindingsA 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 implicationsIn 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/valueThis 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

PurposeThe 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/approachCorrelation analysis has been conducted between prediction accuracy rates, which are obtained by seven different machine learning algorithms and Corruption Perception Index (CPI) levels.FindingsIt 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/implicationsThe 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 implicationsAccording 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/valueIn 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.