bluuebunny/crossref_metadata_2025_split huggingface dataset:
WNT Signalling Promotes NF-κB Activation and Drug Resistance in KRAS-Mutant Colorectal Cancer
Authors: Cong Bojie , Stamou Evangelia , Pennel Kathryn , Mckenzie Molly , Matly Amna , Gopinath Sindhura , Edwards Joanne , Cagan Ross 
Published: December 2023

AbstractApproximately 40% of colorectal cancer (CRC) cases are characterized by KRAS mutations, rendering them insensitive to most CRC therapies. While the reasons for this resistance remain incompletely understood, one key aspect is genetic complexity: in CRC, oncogenic KRAS is most commonly paired with mutations that alter WNT and P53 activities (“RAP”). Here, we demonstrate that elevated WNT activity upregulates canonical (NF-κB) signalling in bothDrosophilaand human RAS mutant tumours. This upregulation required Toll-1 and Toll-9 and resulted in reduced efficacy of RAS pathway targeted drugs such as the MEK inhibitor trametinib. Inhibiting WNT activity pharmacologically significantly suppressed trametinib resistance in RAP tumours and more genetically complex RAP-containing ‘patient avatar’ models. WNT/MEK drug inhibitor combinations were further improved by targetingbrm,shg,ago,rhoGAPp190andupf1, highlighting these genes as candidate biomarkers for patients sensitive to this duel approach. These findings shed light on how genetic complexity impacts drug resistance and proposes a therapeutic strategy to reverse this resistance.
Colon Cancer Cells Evade Drug Action by Enhancing Drug Metabolism
Authors: Cong Bojie , Thakur Teena , Uribe Alejandro Huerta , Stamou Evangelia , Gopinath Sindhura , Maddocks Oliver , Cagan Ross 
Published: December 2023

AbstractColorectal cancer (CRC) is the second most deadly cancer worldwide. One key reason is the failure of therapies that target RAS proteins, which represent approximately 40% of CRC cases. Despite the recent discovery of multiple alternative signalling pathways that contribute to resistance, durable therapies remain an unmet need. Here, we use liquid chromatography/ mass spectrometry (LC/MS) analyses onDrosophilaCRC tumour models to identify multiple metabolites in the glucuronidation pathway—a toxin clearance pathway—as upregulated in trametinib-resistantRAS/APC/P53(“RAP”) tumours compared to trametinib-sensitiveRASG12Vtumours. Elevating glucuronidation was sufficient to direct trametinib resistance inRASG12Vanimals while, conversely, inhibiting different steps along the glucuronidation pathway strongly reversedRAPresistance to trametinib. For example, blocking an initial HDAC1-mediated deacetylation step with the FDA-approved drug vorinostat strongly suppressed trametinib resistance inDrosophila RAPtumours. We provide functional evidence that pairing oncogenic RAS with hyperactive WNT activity strongly elevates PI3K/AKT/GLUT signalling, which in turn directs elevated glucose and subsequent glucuronidation. Finally, we show that this mechanism of trametinib resistance is conserved in anKRAS/APC/TP53mouse CRC tumour organoid model. Our observations demonstrate a key mechanism by which oncogenic RAS/WNT activity promotes increased drug clearance in CRC. The majority of targeted therapies are glucuronidated, and our results provide a specific path towards abrogating this resistance in clinical trials.s
Virion morphology and on-virus spike protein structures of diverse SARS-CoV-2 variants
Authors: Ke Zunlong , Peacock Thomas P. , Brown Jonathan C. , Sheppard Carol M. , Croll Tristan I. , Kotecha Abhay , Goldhill Daniel H. , Barclay Wendy S. , Briggs John A.G. 
Published: December 2023

AbstractThe evolution of SARS-CoV-2 variants with increased fitness has been accompanied by structural changes in the spike (S) proteins that are the major target for the adaptive immune response. Single-particle cryo-EM analysis of soluble S from SARS-CoV-2 variants has revealed this structural adaptation at high-resolution. The analysis of S trimers in situ on intact virions has the potential to provide more functionally relevant insights into S structure and virion morphology. Here, we characterized B.1, Alpha, Beta, Gamma, Delta, Kappa, and Mu variants by cryo-electron microscopy and tomography, assessing S cleavage, virion morphology, S incorporation, “in-situ” high-resolution S structures and the range of S conformational states. We found no evidence for adaptive changes in virion morphology, but describe multiple different positions in the S protein where amino acid changes alter local protein structure. Considered together, our data is consistent with a model where amino acid changes at multiple positions from the top to the base of the spike cause structural changes that can modulate the conformational dynamics of S.
Efficacy of Drpitor1a, a Dynamin-Related Protein 1 inhibitor, in Pulmonary Arterial Hypertension
Authors: Wu Danchen , Jansen-van Vuuren Ross D. , Dasgupta Asish , Al-Qazazi Ruaa , Chen Kuang-Hueih , Martin Ashley , Mewburn Jeffrey D. , Alizadeh Elahe , Lima Patricia D.A. , Jones Oliver , Colpman Pierce , Breault Nolan M. , Emon Isaac M. , Jedlovčnik Luka , Zhao Yuan Yuan , Wells Michael , Sutendra Gopinath , Archer Stephen L. 
Published: December 2023

AbstractRationaleDynamin-related protein 1 (Drp1), a large GTPase, mediates mitochondrial fission. Increased Drp1-mediated fission permits accelerated mitosis, contributing to hyperproliferation of pulmonary artery smooth muscle cells (PASMC), which characterizes pulmonary arterial hypertension (PAH). We developed a Drp1 inhibitor, Drpitor1a, and tested its ability to regress PAH.ObjectivesAssess Drpitor1a’s efficacy and toxicity in: a)normal and PAH human PASMC (hPASMC); b)normal rats versus rats with established monocrotaline (MCT)-induced PAH.MethodsDrpitor1a’s effects on recombinant and endogenous Drp1-GTPase activity, mitochondrial fission, and cell proliferation were studied in hPASMCs (normal=3; PAH=5). Drpitor1a’s pharmacokinetics and tissue concentrations were measured (n=3 rats/sex). In a pilot study (n=3-4/sex/dose), Drpitor1a (1mg/kg/48-hours, intravenous) reduced adverse PA remodeling only in females. Consequently, we compared Drpitor1a to vehicle in normal (n=6 versus 8) and MCT-PAH (n=9 and 11) females, respectively. Drpitor1a treatment began 17-days post-MCT with echocardiography and cardiac catheterization performed 28-29 days post-MCT.ResultsDrpitor1a inhibited recombinant and endogenous Drp1 GTPase activity, which was increased in PAH hPASMC. Drpitor1a inhibited mitochondrial fission and proliferation and induced apoptosis, in PAH hPASMC but not normal hPASMC. Drpitor1a tissue levels were higher in female versus male RVs. In MCT-PAH females, Drpitor1a regressed PA obstruction, lowered pulmonary vascular resistance, and improved RV function, without hematologic, renal, or hepatic toxicity.ConclusionsDrpitor1a inhibits Drp1 GTPase, reduces mitochondrial fission, and inhibits cell proliferation in PAH hPASMC. Drpitor1a caused no toxicity in MCT-PAH and had no significant effect on normal rats or hPASMCs. Drpitor1a is a potential PAH therapeutic which displays an interesting therapeutic sexual dimorphism.
A Novel Pathway Implicated in Regulating Cognitive disfunction in aDrosophilaAlzheimer’s Disease Model through Acer Inhibition and CG2233 Modulation
Authors: Ghalayini Judy , Lee Shin-Hann , Gluscencova Oxana , Iliadi Konstantin G. , Boulianne Gabrielle L. 
Published: December 2023

AbstractAlzheimer’s disease (AD) is a progressive neurodegenerative disorder, accounting for most dementia cases worldwide. Current therapies for AD have limited effectiveness in slowing disease progression or delivering a cure. As such, there is an immediate need for ongoing research and innovative strategies to tackle this multifaceted disease. Recently, several studies have implicated the renin-angiotensin system (RAS), known to regulate blood pressure, as a possible therapeutic target for AD. RAS-inhibiting drugs, including angiotensin-converting enzyme inhibitors (ACE-Is), have been shown to reduce the incidence and progression of AD. However, the literature describing their beneficial effects is inconsistent, with contradictory findings reporting no effects. How these drugs may function in AD remains poorly understood. Our previous work inDrosophilamodels expressing AD-related transgenes investigated the benefits of captopril, an ACE-I, and found it effectively rescued AD-related phenotypes including cognitive performance independent of Aβ42 changes. Importantly, our study implicated Acer, a homolog of mammalian ACE, as a key player. In our current study, we demonstrate that the beneficial outcomes of Acer inhibition depend on preventing its catalytic activity and downstream target processing. We identify CG2233 as a prospective target and reveal its functional interaction with Acer. Furthermore, we show CG2233 is implicated in AD-related pathways in Aβ42 expressing flies. Together, these findings provide a new avenue to study the role of ACE in AD.Significance StatementAD is a devastating neurodegenerative disorder with limited therapeutic success. Emerging research highlights the potential of inhibiting the renin-angiotensin system (RAS) in AD. Epidemiological findings and experimental studies have shown promising outcomes with RAS-targeting drugs including angiotensin-converting enzyme inhibitors (ACE-Is). Our previous work inDrosophilaAD models revealed the efficacy of captopril, an ACE-I, in improving AD-related phenotypes. Moreover, we identified Acer as a key player in these mechanisms. Our current study further elucidates the role of Acer, identifies CG2233 as a potential target, and uncovers their functional interaction, shedding light on pathways relevant to AD phenotypes. This research underscores the significance of investigating ACE and ACE-I mechanisms in AD, offering potential innovative means for AD therapy.
Environmental DNA reveals fine scale spatial and temporal variation of prey species for marine mammals in a Scottish marine protected area
Authors: Boyse Elizabeth , Robinson Kevin P. , Beger Maria , Carr Ian M. , Taylor Morag , Valsecchi Elena , Goodman Simon J. 
Published: December 2023

AbstractMarine mammal foraging grounds are popular focal points for marine protected area (MPA) implementation, but may be temporally dynamic, requiring continuous monitoring to infer prey availability and abundance. Marine mammal distributions are assumed to be driven by their prey in foraging areas, but limited understanding of prey distributions often prevents us from exploring how shifting prey availability impacts both seasonal and long-term marine mammal distributions. Environmental DNA (eDNA) metabarcoding could enhance understanding of marine mammal habitat use in relation to their prey through simultaneous monitoring of both. However, eDNA applications focused on marine mammals or predator-prey dynamics have been limited to date. In this study, we assess spatiotemporal changes in the availability and abundance of minke whale (Balaenoptera acutorostrata) prey species in a newly established MPA, employing eDNA metabarcoding. We recovered 105 molecular operational taxonomic units (OTUs) from marine vertebrates using two primer sets targeting 12S and 16S genes, along with 112 OTUs from a broader eukaryotic primer set targeting 18S rRNA. Overall, key forage fish prey species, sandeels and clupeids, were the most abundant teleost fishes detected, although their availability varied temporally and with distance from shore. We also found clear spatial partitioning between coastal bottlenose dolphins and the more pelagic minke whales and harbour porpoises, paralleling availability of their main prey species. Other species of conservation interest were also detected including the critically endangered European eel (Anguilla anguilla), blue fin tuna (Thunnus thynnus), and the invasive pink salmon (Oncorhynchus gorbuscha). This study demonstrates the application of eDNA to detect spatiotemporal trends in the occurrence and abundance of cetacean predators and their prey, furthering our understanding of fine-scale habitat use within MPAs. Future, long-term monitoring of predator-prey dynamics with eDNA could improve our ability to predict climate-induced shifts in foraging grounds and enhance rapid responses with appropriate management actions.
Quantifying population resistance to climatic variability: The invasive spotted lanternfly grape pest is buffered against temperature extremes in California
Authors: Lewkiewicz Stephanie M. , Seibold Benjamin , Helmus Matthew R. 
Published: December 2023

AbstractTemperature time series data are a composition of average trends and stochastic variability that together shape population dynamics. However, models of temperature-dependent species often overlook variability, focusing solely on growth rate under average conditions. When models omit variability, they can inaccurately predict the dynamics that underlie the establishment of invasive pests sensitive to temperature fluctuations. Here, we conduct a stochastic modeling study of spotted lanternfly (Lycorma delicatula), a univoltine grape pest, which has invaded grape growing regions of the eastern U.S. due to human transport leading to frequent establishment of populations in urban and suburban areas. As spotted lanternfly continues to be transported to new grape growing regions and climate change alters variability, it is vital to predict its establishment potential. Although it overwinters as diapausing eggs, experiments suggest that diapause is plastic and not necessary for survival. We developed a deterministic stage-age-structured partial differential equation model of diapausing and non-diapausing populations. We derived a new metric quantifying population resistance to climatic variability defined as the level of stochasticity that leads to negative growth compared to average conditions. We simulated growth rate and resistance to variability across a range of average temperature conditions and stochasticity. We then analyzed how variability and diapause interact with survival, fecundity, and development to affect population dynamics. Finally, we estimated establishment potential across all U.S. cities. Diapausing populations were typically more resistant than non-diapausing populations because diapause enhances overwintering egg survival during winter cold waves, while allowing accelerated development and increased fecundity during summer and fall heat waves. Establishment potential is especially underestimated in important grape growing regions of California if models of diapausing populations omit variability. By quantifying population resistance to climatic variability, we gain a fuller understanding of invasive species establishment in today’s stochastic and changing climate.
Biosynthesis of the proteins containing neurotoxinβ-N-methylamino-L-alanine in marine diatoms
Authors: Zheng Xianyao , Li Aifeng , Qiu Jiangbing , Yan Guowang , Zhao Peng , Li Min , Meng Fanping 
Published: December 2023

AbstractNeurotoxinβ-N-methylamino-L-alanine (BMAA) has been deemed a pathogenic factor for human neurodegenerative diseases. It is an important issue to disclose the biosynthesis mechanism of BMAA in marine diatoms. In the present study, the iron (Fe) limitation (1/3 × Fe) was found to suppress the growth of diatoms but stimulate the production of BMAA-containing proteins, maximum 7.7 fold inThalassiosira minima. Transcriptome analysis showed that energy metabolism, protein biosynthesis and carbon fixation functions were mainly affected by the Fe limitation in the diatom. Analysis of subcellular distribution of BMAA showed that BMAA-containing proteins were mainly detected in the endoplasmic reticulum and the Golgi apparatus. Combination results of the responses of the diatom to Fe deficiency and co-culture with cyanobacteria in our previous study, we speculate that cysteine embedded in peptide chains and methylamine produced by the diatom itself are possibly catalyzed by the cysteine synthase (cysK) to form the BMAA structure in situ. Spiked methylamine in culture media significantly stimulated the production of BMAA, and BMAA amounts were correlated with the expression of cysK gene in different diatoms. The reduced ubiquitination-mediated proteolysis and vesicle trafficking precision through the COPII system would aggravate the accumulation of BMAA-containing proteins in the diatom.Significance StatementWith the detection of neurotoxin BMAA in diverse marine diatoms, the pathogenic risk of BMAA has been further concerned to human neurodegenerative diseases such as Alzheimer’s disease. Interestingly, BMAA-containing proteins are the dominant forms of this neurotoxin in diatoms. It is a keystone issue to disclose the biosynthesis mechanism of BMAA in marine diatoms. We found Fe-limitation could stimulate the production of BMAA-containing proteins in diatoms and explored its biosynthesis using transcriptomics in this study. Results suggested that cysteine embedded in peptides and methylamine in cytoplasm were catalyzed by the cysteine synthase (cysK) to form BMAA. This study hints that the biosynthesis of BMAA would be improved by the worldwide prevalence of iron deficiency in the coastal waters.
A common regulatory switch controls a suite of C4 traits in multiple cell types
Authors: Camo-Escobar Daniel , Alcalá-Gutiérrez Carlos , Palafox-Figueroa Ernesto , Guillotin Bruno , Hernández-Coronado Marcela , Coyac-Rodríguez José L. , Cerbantez-Bueno Vincent E. , Vélez-Ramírez Aarón , de Folter Stefan , Birnbaum Kenneth D. , Ortiz-Ramírez Carlos 
Published: December 2023

AbstractThe C4 photosynthetic pathway provided a major advantage to plants growing in hot, dry environments, including the ancestors of our most productive crops. Two traits were essential for the evolution of this pathway: increased vein density and the functionalization of bundle sheath cells for photosynthesis. Although GRAS transcriptional regulators, including SHORT ROOT (SHR), have been implicated in mediating leaf patterning in both C3 and C4 species, little is known about what controls the specialized features of the cells that mediate C4 metabolism and physiology. We show in the model monocot,Setaria viridis, that SHR regulates components of multiple cell identities, including chloroplast biogenesis and photosynthetic gene expression in bundle sheath cells, a central feature of C4 plants. Furthermore, we found that it also contributes to the two-cell compartmentalization of the characteristic four-carbon shuttle pathway. Disruption of SHR function clearly reduced photosynthetic capacity and seed yield in mutant plants under heat stress. Together, these results show how cell identities are remodeled bySHRto host the suite of traits characteristic of C4 regulation, which are a main engineering target in non-C4 crops to improve climate resilience.
Development of a robotic cluster for automated and scalable cell therapy manufacturing
Authors: Melocchi Alice , Schmittlein Brigitte , Jones Alexis L. , Ainane Yasmine , Rizvi Ali , Chan Darius , Dickey Elaine , Pool Kelsey , Harsono Kenny , Szymkiewicz Dorothy , Scarfogliero Umberto , Bhatia Varun , Sivanantham Amlesh , Kreciglowa Nadia , Hunter Allison , Gomez Miguel , Tanner Adrian , Uboldi Marco , Batish Arpit , Balcerek Joanna , Kutova-Stoilova Mariella , Paruthiyil Sreenivasan , Acevedo Luis A. , Stadnitskiy Rachel , Carmichael Sabrina , Aulbach Holger , Hewitt Matthew , De Mollerat Du Jeu Xavier , Robilant Benedetta di , Parietti Federico , Esensten Jonathan H. 
Published: December 2023

AbstractThe production of commercial autologous cell therapies such as chimeric antigen receptor T cells requires complex manual manufacturing processes. Skilled labor costs and challenges in manufacturing scale-out have contributed to high prices for these products. Here, we present a robotic system that uses industry-standard cell therapy manufacturing equipment to automate the steps involved in cell therapy manufacturing. The robotic cluster consists of a robotic arm and customized modules, allowing the robot to manipulate a variety of standard cell therapy instruments and materials such as incubators, bioreactors, and reagent bags. This system enables existing manual manufacturing processes to be rapidly adapted to robotic manufacturing, without having to adopt a completely new technology platform. Proof-of-concept for the robotic cluster’s expansion module was demonstrated by activating and expanding human CD8+ T cells. The robotic cultures showed comparable cell yields, viability, and identity to those manually performed. Such modular robotic solutions may support scale-up and scale-out of cell therapies that are developed using classical manual methods in academic laboratories and biotechnology companies.
Grid cells perform path integration in multiple reference frames during self-motion-based navigation
Authors: Peng Jing-Jie , Throm Beate , Jazi Maryam Najafian , Yen Ting-Yun , Monyer Hannah , Allen Kevin 
Published: December 2023

AbstractWith their periodic firing pattern, grid cells are considered a fundamental unit of a neural network performing path integration. The periodic firing patterns of grid cells have been observed mainly during behaviors with little navigational demands, and the firing patterns of grid cells in animals navigating 2D environments using path integration are largely unknown. Here, we recorded the activity of grid cells in mice performing the AutoPI task, a task assessing homing based on path integration. Using artificial deep neural networks to decode the animal’s moment-to-moment movement vectors, we found that grid cells perform path integration over short trajectories and change their reference frames within single trials. More specifically, grid cell modules re-anchor to a task-relevant object via a translation of the grid pattern. The code for movement direction in grid modules drifts as the animal navigates using self-motion cues, and this drift predicts the homing direction of the mouse. These results reveal the computations in grid cell circuits during self-motion-based navigation.
Identification of ligands binding to MB327-PAM-1, a binding pocket relevant for resensitization of nAChRs
Authors: Kaiser Jesko , Gertzen Christoph G.W. , Bernauer Tamara , Nitsche Valentin , Höfner Georg , Niessen Karin V. , Seeger Thomas , Paintner Franz F. , Wanner Klaus T. , Steinritz Dirk , Worek Franz , Gohlke Holger 
Published: December 2023

AbstractDesensitization of nicotinic acetylcholine receptors (nAChRs) can be induced by overstimulation with acetylcholine (ACh) caused by an insufficient degradation of ACh after poisoning with organophosphorus compounds (OPCs). Currently, there is no generally applicable treatment for OPC poisoning that directly targets the desensitized nAChR. The bispyridinium compound MB327, an allosteric modulator of nAChR, has been shown to act as a resensitizer of nAChRs, indicating that drugs binding directly to nAChRs can have beneficial effects after OPC poisoning. However, MB327 also acts as an inhibitor of nAChRs at higher concentrations and can thus not be used for OPC poisoning treatment. Consequently, novel, more potent resensitizers are required. To successfully design novel ligands, the knowledge of the binding site is of utmost importance. Recently, we performedin silicostudies to identify a new potential binding site of MB327, MB327-PAM-1, for which a more affine ligand, UNC0646, has been described. In this work, we performed ligand-based screening approaches to identify novel analogs of UNC0646 to help further understand the structure-affinity relationship of this compound class. Furthermore, we used structure-based screenings and identified compounds representing four new chemotypes binding to MB327-PAM-1. One of these compounds, cycloguanil, is the active metabolite of the antimalaria drug proguanil and shows a higher affinity towards MB327-PAM-1 than MB327. Furthermore, cycloguanil can reestablish the muscle force in soman-inhibited rat muscles. These results can act as a starting point to develop more potent resensitizers of nAChR and to close the gap in the treatment after OPC poisoning.