bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deciphering the Cofilin Oligomers via Intermolecular Disulfide Bond Formation: A Coarse-grained Molecular Dynamics Approach to Understanding Cofilin’s Regulation on Actin Filaments
Authors: Li Chengxuan , Wei Tingyi , Cheung Margaret S , Tsai Min-Yeh 
Published: December 2023

AbstractCofilin, a key actin-binding protein, orchestrates the dynamics of the actomyosin network through its actin-severing activity and by promoting the recycling of actin monomers. Recent experimental work suggests that cofilin also forms functionally distinct oligomers through thiol post-translational modification (PTM) that encourages actin nucleation and assembly. Despite these advances, the structural conformations of cofilin oligomers that modulate actin activity remain elusive because there are combinatorial ways to oxidize thiols in cysteines to form disulfide bonds rapidly. This study employs molecular dynamics simulations to investigate human cofilin 1 as a case study for exploring cofilin dimers via disulfide bond formation. Using the free energy profiling, our simulations unveil a range of probable cofilin dimer structures not represented in current Protein Data Bank entries. These candidate dimers are characterized by their distinct population distributions and relative free energies. Of particular note is a dimer featuring an interface between cysteines 139 and 147 residues, which demonstrates stable free energy characteristics and intriguingly symmetrical geometry. In contrast, the experimentally proposed dimer structure exhibits a less stable free energy profile. We also evaluate frustration quantification based on the energy landscape theory in the protein-protein interactions at the dimer interfaces. Notably, the 39-39 dimer configuration emerges as a promising candidate for forming cofilin tetramers, as substantiated by frustration analysis. Additionally, docking simulations with actin filaments further evaluate the stability of these cofilin dimer-actin complexes. Our findings thus offer a computational framework for understanding the role of thiol post-translational modification of cofilin proteins in regulating oligomerization, and the subsequent cofilin-mediated actin dynamics in the actomyosin network.
Nifurpirinol: A potent inducer of FSGS-like glomerular injury in transgenic zebrafish
Authors: Klawitter Marianne , Siegerist Florian , Daniel Sophie , Schindler Maximilian , Endlich Nicole 
Published: December 2023

SummaryIdentifying effective drugs for focal segmental glomerulosclerosis (FSGS) treatment holds significant importance. Our high-content drug screening on zebrafish larvae relies on nitroreductase/metronidazole (NTR/MTZ)-induced podocyte ablation to generate FSGS-like injury. A crucial factor for successful drug screenings is minimizing variability in injury induction. For this, we introduce Nifurpirinol (NFP) as a more reliable prodrug for targeted podocyte depletion. NFP showed a 2.3-fold increase in efficiency at concentrations 1600-fold lower compared to MTZ-mediated injury induction. Integration into the screening workflow validated its suitability for the high-content drug screening. The presence of crucial FSGS hallmarks, including podocyte foot process effacement, proteinuria, and activation of parietal epithelial cells, was observed. In this study, we demonstrate that NFP serves as remarkably effective prodrug for inducing an FSGS-like phenotype in zebrafish larvae and proves to be well-suited for a high-content drug screening, aiding in the identification of potential candidates for FSGS treatment.
Mechanical strengthening of cell-cell adhesion during mouse embryo compaction
Authors: de Plater Ludmilla , Firmin Julie , Maître Jean-Léon 
Published: December 2023

AbstractCompaction is the first morphogenetic movement of the eutherian mammals and involves a developmentally regulated adhesion process. Previous studies investigated cellular and mechanical aspects of compaction. During mouse and human compaction, cells spread onto each other as a result of a contractility-mediated increase in surface tension pulling at the edges of their cell-cell contacts. However, how compaction may affect the mechanical stability of cell-cell contacts remains unknown. Here, we used a dual pipette aspiration assay on cell doublets to quantitatively analyze the mechanical stability of compacting mouse embryos. We measured increased mechanical stability of contacts with rupture forces growing from 40 to 70 nN, which was highly correlated with cell-cell contact expansion. Analyzing the dynamic molecular reorganization of cell-cell contacts, we find minimal recruitment of the cell-cell adhesion molecule Cdh1 (also known as E-cadherin) to contacts but we observe its reorganization into a peripheral adhesive ring. However, this reorganization is not associated with increased effective bond density, contrary to previous reports in other adhesive systems. Using genetics, we reduce the levels of Cdh1 or replace it with a chimeric adhesion molecule composed of the extracellular domain of Cdh1 and the intracellular domain of Cdh2 (also known as N-cadherin). We find that reducing the levels of Cdh1 impairs the mechanical stability of cell-cell contacts due to reduced contact growth, which nevertheless show higher effective bond density than WT contacts of similar size. On the other hand, chimeric adhesion molecules cannot form large or strong contacts indicating that the intracellular domain of Cdh2 is unable to reorganize contacts and/or is mechanically weaker than the one of Cdh1 in mouse embryos. Together, we find that mouse embryo compaction mechanically strengthens cell-cell adhesion via the expansion of Cdh1 adhesive rings that maintain pre-compaction levels of effective bond density.
TGF-beta dynamically controls epithelial identity in a 3D model of human epiblast
Authors: Zorzan Irene , Carbognin Elena , Lauria Andrea , Proserpio Valentina , Benegnù Davide , Dalrio Caterina , Arboit Mattia , Paolucci Irene , Drusin Andrea , Sledziowska Monika , Amadei Gianluca , Oliviero Salvatore , Martello Graziano 
Published: December 2023

AbstractPluripotency is the ability to give rise to all cell types of the body and is first observed in a mass of disorganised cells of the embryo. Upon implantation, pluripotent cells form a columnar epithelium and undergo lumenogenesis. At gastrulation, a portion of the pluripotent epiblast will undergo epithelial to mesenchymal transition (EMT), forming the primitive streak (PS).It still remains unclear what molecular mechanism supports the epithelial identity of the pluripotent epiblast before gastrulation. Here we developed an optimised, chemically defined 3D model of human pluripotent epiblast formation in which conventional pluripotent stem cells (PSCs) self-organise into a columnar epithelium with a lumen in 48 hours. From 72 hours we observed spontaneous symmetry breaking and specification of PS-like cells, as confirmed by single-cell RNA sequencing.We found that Insulin and FGF signalling are both required for the proliferation and survival of the pluripotent epiblast model. Conversely, TGF-beta signalling maintains epithelial identity. Epithelial identity appears uncoupled from the expression of canonical pluripotency markers OCT4, NANOG and PRDM14, but under the control of ZNF398. Once the pluripotent epithelium is established, TGF-beta inhibition is inconsequential, and stimulation with Activin A leads to highly efficient PS induction. We conclude that TGF-beta dynamically orchestrates epithelial identity of human pluripotent cells.
Changes in ADAR1 activity duringPlasmodiuminfection contribute to protection from malaria
Authors: Quin Jaclyn , Kopel Eli , Gawish Riem , Eidelman Michelle , Vukić Dragana , Linhartová Pavla , Melicherová Janka , Sinigaglia Ketty , Ghodrati Sajjad , Arama Charles , Nebie Issa , Troye-Blomberg Marita , Sverremark-Ekström Eva , Knapp Sylvia , Modry David , Östlund-Farrants Ann-Kristin , Levanon Erez , Keegan Liam P. , O’Connell Mary A. 
Published: December 2023

SummaryAdenosine deaminase acting on RNA 1 (ADAR1) suppresses the activation of multiple antiviral immune response pathways. Here, we investigate the role of ADAR1 during infection with thePlasmodiumparasite, which causes malaria and is responsible for over almost a half million childhood deaths every year. Reduced activity of ADAR1 duringPlasmodiuminfection is associated with populations protected from clinical malaria. In animal models,Adar+/-mice are protected fromP. yoeliiparasitemia, via a previously unreported pathway. These mice display elevated Type-I IFN responses and CD8+T cell activation, but no detrimental immune responses. Our results suggest that a decrease in the levels of ADAR1 occurs during infection and can drive both innate and adaptive immune responses, and this presents a previously unrecognized opportunity for targeting ADAR1 in diverse infectious diseases.
Self-renewing Sox9+ osteochondral stem cells in the postnatal skeleton
Authors: Farhat Stephanie , Tilouche Bahaeddine , Short Spencer , Piron Medjie , Campbell T. Mark , Fernandes Alex , Somyk Mariya , Bandukwala Hina , Arezza Eric , Sastourne-Arrey Quentin , Reilly Katherine , Chakra Maria Abou , Bader Gary , Kunz Leo , Schroeder Timm , Carsen Sasha , Mattar Pierre , Dilworth Jeffrey , Coutu Daniel L. 
Published: December 2023

AbstractPostnatal skeletal growth, homeostatic maintenance, and regeneration is driven by skeletal stem cells. In addition, it is well established that skeletal tissues lose their regenerative potential with age, comorbidities, and repeated trauma, possibly through stem cell exhaustion or loss of function. However, it is largely unknown where these cells reside in skeletal tissues, what molecular mechanisms regulate their self-renewal and fate decisions, and how to isolate, purify, and expand them ex vivo. Therefore, there is an urgent need for a deeper understanding of postnatal skeletal stem cells. Here, we used genetic lineage tracing, thymidine analogues retention, whole bone microscopy, imaging cytometry, in vitro assays, and single cell transcriptomics and provide the first experimental evidence for the existence of self-renewing osteochondral stem cells in the postnatal skeleton in both males and females. We also show direct comparisons between adult, fetal, mouse, and human skeletal stem cells at the transcriptome level.
Translation inhibition efficacy does not determine thePlasmodium bergheiliver stage antiplasmodial efficacy of protein synthesis inhibitors
Authors: McLellan James L. , Hanson Kirsten K. 
Published: December 2023

AbstractProtein synthesis is a core cellular process, necessary throughout the complex lifecycle ofPlasmodiumparasites, thus specific translation inhibitors would be a valuable class of antimalarial drugs, capable of both treating symptomatic infections in the blood and providing chemoprotection by targeting the initial parasite population in the liver, preventing both human disease and parasite transmission back to the mosquito host. As increasing numbers of antiplasmodial compounds are identified that converge mechanistically at inhibition of cytoplasmic translation, regardless of molecular target or mechanism, it would be useful to gain deeper understanding of how their effectiveness as liver stage translation inhibitors relates to their chemoprotective potential. Here, we probed that relationship using theP. berghei-HepG2 liver stage infection model. Using o-propargyl puromycin-based labeling of the nascent proteome inP. berghei-infected HepG2 monolayers coupled with automated confocal feedback microscopy to generate unbiased, single parasite image sets ofP. bergheiliver stage translation, we determined translation inhibition EC50sfor five compounds, encompassing parasite-specific aminoacyl tRNA synthetase inhibitors, compounds targeting the ribosome in both host and parasite, as well as DDD107498, which targetsPlasmodiumeEF2, and is a leading antimalarial candidate compound being clinically developed as cabamiquine. Compounds were then tested at equivalent effective concentrations to compare the parasite response to, and recovery from, a brief period of translation inhibition in early schizogony, with parasites followed up to 120 hours post-infection to assess liver stage antiplasmodial effects of the treatment. Our data conclusively show that translation inhibition efficacyper sedoes not determine a translation inhibitor’s antiplasmodial efficacy. DDD107498 was the least effective translation inhibitor, yet exerted the strongest antimalarial effects at both 5x- and 10x EC50concentrations. We show compound-specific heterogeneity in single parasite and population responses to translation inhibitor treatment, with no single metric strongly correlated to release of hepatic merozoites for all compound, demonstrate that DDD107498 is capable of exerting antiplasmodial effects on translationally arrested liver stage parasites, and uncover unexpected growth dynamics during the liver stage. Our results demonstrate that translation inhibition efficacy cannot function as a proxy for antiplasmodial effectiveness, and highlight the importance of exploring the ultimate, as well as proximate, mechanisms of action of these compounds on liver stage parasites.
“Off-pore” nucleoporins relocalize heterochromatic breaks through phase separation
Authors: Merigliano Chiara , Ryu Taehyun , See Colby D. , Caridi Christopher P. , Li Xiao , Butova Nadejda L. , Reynolds Trevor W. , Deng Changfeng , Chenoweth David M. , Capelson Maya , Chiolo Irene 
Published: December 2023

SUMMARYPhase separation forms membraneless compartments in the nuclei, including by establishing heterochromatin “domains” and repair foci. Pericentromeric heterochromatin mostly comprises repeated sequences prone to aberrant recombination, and “safe” homologous recombination (HR) repair of these sequences requires the movement of repair sites to the nuclear periphery before Rad51 recruitment and strand invasion. How this mobilization initiates is unknown, and the contribution of phase separation to these dynamics is unclear. Here, we show that Nup98 nucleoporin is recruited to heterochromatic repair sites before relocalization through Sec13 or Nup88 nucleoporins, and downstream from the Smc5/6 complex and SUMOylation. Remarkably, the phase separation properties of Nup98 are required and sufficient to mobilize repair sites and exclude Rad51, thus preventing aberrant recombination while promoting HR repair. Disrupting this pathway results in heterochromatin repair defects and widespread chromosome rearrangements, revealing a novel “off-pore” role for nucleoporins and phase separation in nuclear dynamics and genome integrity in a multicellular eukaryote.HighlightsNup88 and Sec13 recruit Nup98 to heterochromatic DSBs downstream from Smc5/6Nup88, Sec13 and Nup98 promote repair focus mobilization in heterochromatin ‘off-pore’Nup98 excludes Rad51 from repair sites inside the heterochromatin domainPhase separation by Nup98 is required and sufficient for relocalization and Rad51 exclusion
A temporal allocation of amino acid resources ensures fitness and body allometry
Authors: Valzania Luca , Alami Aya , Léopold Pierre 
Published: December 2023

SUMMARYOrganisms have evolved strategies to store resources and overcome periods of low or no nutrient access including transient shortages or longer non-feeding developmental transitions. Holometabolous insects likeDrosophilarepresent an attractive model to study resource allocation during development since they alternate feeding and non-feeding periods. Amino acids are essential components for tissue growth and renewal, but the strategies used for their storage remain largely unexplored. Here, we uncover a 2-step mechanism for the temporal production, storage and use of specific storage proteins called hexamerins. Moreover, we show that modulating amino acid storage affects the relative growth of organs across developmental phases and, as a consequence, alters body allometry and adult fitness.
Filamin protects myofibrils from contractile damage through changes in its mechanosensory region
Authors: Fisher Lucas AB , Carriquí-Madroñal Belén , Mulder Tiara , Huelsmann Sven , Schöck Frieder , González-Morales Nicanor 
Published: December 2023

AbstractFilamins are mechanosensitive actin crosslinking proteins that organize the actin cytoskeleton in a variety of shapes and tissues. In muscles, filamin crosslinks actin filaments from opposing sarcomeres, the smallest contractile units of muscles. This happens at the Z-disc, the actin-organizing center of sarcomeres. In flies and vertebrates, filamin mutations lead to fragile muscles that appear ruptured, suggesting filamin helps counteract muscle rupturing during muscle contractions either by providing elastic support or through signaling. The mechanistic details of filamin in this process are largely unknown. Here we use the indirect flight muscles of Drosophila to interrogate the molecular details by which filamin provides cohesion to the Z-disc. We made novel filamin mutations affecting the C-terminal region and detected two Z-disc phenotypes: dissociation of actin filamins and Z-disc rupture. We focused on the ruptured defect and tested a constitutively closed filamin mutant, which results in ruptured Z-discs, and a constitutively open mutant which gives rise to enlarged Z-discs. Finally, we show that muscle contraction is required for Z-disc rupture. We therefore propose that filamin senses myofibril damage by elastic changes in its mechanosensory region, which induces myofibril repair.
Differentiating erythroblasts adapt to turbulent flow by accelerating maturation and activating cholesterol biosynthesis
Authors: Iacono Giulia , Abay Asena , Gallego Murillo Joan S. , Aglialoro Francesca , Yagci Nurcan , Fu Kerly , Svendsen Arthur F. , von Lindern Marieke , van den Akker Emile 
Published: December 2023

AbstractIn vitroculture of erythroblasts (EBL) and production of mature erythrocytes for transfusions requires upscaling in fluidic-turbulent bioreactors, resulting in membrane shear stress. For the implementation of erythroid cultures in bioreactors, understanding the effects of mechanical stress on terminal EBL differentiation is required. To this end, we investigated the effect of orbital shaking-induced shear stress on differentiating CD49d+CD235lowprimary human EBL towards enucleated reticulocytes at the molecular, cellular, and functional level. Orbital shaking at the onset of EBL differentiation enhanced cell maturation increasing enucleation percentage compared to static cultures, without cell viability loss. Transcriptome analysis uncovered 505 genes differentially expressed between static and dynamic cultures, with genes involved in lipid and cholesterol biosynthesis upregulated in dynamic conditions. In line with this, cells differentiated in orbital-shakers showed increased cholesterol concentration and osmotic resistance compared to static cultures. HMGCR (3-Hydroxy-3-Methylglutaryl-CoA-Reductase), rate-limiting enzyme of the cholesterol biosynthesis pathway, showed earlier and significantly higher induction during differentiation in dynamic. The severe loss of EBL in dynamic, but not in static conditions, due to HMGCR inhibition confirmed the ability of EBL to adapt to shear stress through modulating of their transcriptional program and upregulation of cholesterol biosynthesis. This work sheds light into specific mechanisms that will assist the successful upscaling of erythroid differentiation in turbulent bioreactors. In addition, as shear-stress on hematopoietic cells is also occurring within the bone marrow niche, these results introduces a potential novel signalling axis that need to be integrated into the known transduction pathways that control erythropoiesis.
Novel fuel-saving detumbling strategy for post-capture combined spacecraft
Authors: Zhou Qing , Liu Yuanqing , Liu Xiaofeng , Cai Guoping 
Published: December 2023

Purpose
In the post-capture stage, the tumbling target rotates the combined spacecraft system, and the detumbling operation performed by the space robot is required. To save the costly onboard fuel of the space robot, this paper aims to present a novel post-capture detumbling strategy.

Design/methodology/approach
Actuated by the joint rotations of the manipulator, the combined system is driven from three-axis tumbling state to uniaxial rotation about its maximum principal axis. Only unidirectional thrust perpendicular to the axis is needed to slow down the uniaxial rotation, thus saving the thruster fuel. The optimization problem of the collision-free detumbling trajectory of the space robot is described, and it is optimized by the particle swarm optimization algorithm.

Findings
The numerical simulation results show that along the trajectory planned by the detumbling strategy, the maneuver of the manipulator can precisely drive the combined system to rotate around its maximum principal axis, and the final kinetic energy of the combined system is smaller than the initial. The unidirectional thrust and the lower kinetic energy can ensure the fuel-saving in the subsequent detumbling stage.

Originality/value
This paper presents a post-capture detumbling strategy to drive the combined system from three-axis tumbling state to uniaxial rotation about its maximum principal axis by redistributing the angular momentum of the parts of the combined system. The strategy reduces the thrust torque for detumbling to effectively save the thruster fuel.
IPR of Lays variety potato – Is it a matter of public or private interests?
Authors: S Jayakrishnan 
Published: December 2023

Learning outcomes
The objectives of the case study are to provide an overview of intellectual property rights and intellectual property rights in Indian context; understand the intellectual property rights implementation and challenges for implementing it in emerging economies; understand what would be the best approach that companies can adopt when the companies face backlash in such circumstances; and explore the scope for redefining the intellectual property rights in the changing global environment.

Case overview/synopsis
In December 2021, the Protection of Plant Varieties and Farmers’ Rights Authority (PPV&FRA) in India revoked the plant variety protection (PVP) certificate granted to PepsiCo India Holding (PHI) for its Lays variety potato (FL-2027, known as FC-5). The FC-5 variety possessed low moisture content which made it suitable for making potato chips. The controversy started with Pepsi suing the small and marginal farmers of Gujarat for alleged patent infringement and cultivating the patented variety. Pepsi’s legal suit against nine marginal potato farmers in Gujarat initiated the dispute over how intellectual property (IP) rights are used to intimidate small, marginal farmers and its infringement of farmers’ rights. But, on the other side, the interesting aspect was how IP infringement could be a setback for the companies that made the capital investment to develop the variety. The case study discusses the backlash Pepsi faced due to this IP rights legal suit and the punitive aspects of IP rights (IPR) law. Moreover, in the context of the global pandemic, the case study helped discuss the need to redefine the intellectual property rights regime keeping in mind global welfare.

Complexity academic level
The case is intended for use in postgraduate-level management courses in agricultural marketing, agribusiness, international business and economics. This study can help management students understand how IPR is defined, the apparent complexities associated with it and the adverse effect of it on small and marginal farmers in emerging economies.

Supplementary materials
Teaching notes are available for educators only.

Subject code
CSS 5: International business.