bluuebunny/crossref_metadata_2025_split huggingface dataset:
BMP antagonist CHRDL2 enhances the cancer stem cell phenotype and increases chemotherapy resistance in Colorectal Cancer
Authors: Clarkson Eloise , Lewis Annabelle 
Published: January 2024

SummaryChordin-like-2 (CHRDL2) is a secreted BMP antagonist, with overexpression and genomic variants associated with colorectal cancer (CRC) risk. BMP signalling in the normal intestinal epithelium operates in opposition to the WNT signalling pathway, which maintains stem-cells and self-renewal. Elevated WNT signalling leads to expansion of the stem cell compartment and hyperproliferation, defining characteristics of CRC.Here, we explored the impact of CHRDL2 overexpression on CRC cells and normal intestinal organoids to investigate whether CHRDL2’s inhibition of BMP signalling intensified WNT signalling, and enhanced the cancer stem-cell phenotype.CHRDL2 increased cell survival during chemotherapy and irradiation with associated activation of DNA damage response pathways. Organoids treated with secreted CHRDL2 exhibited elevated levels of stem cell markers and reduced differentiation. RNA-seq analysis revealed that CHRDL2 increased the expression of stem cell markers and well-established cancer-associated pathways. We suggest that CHRDL2 overexpression can augment the stem-cell potential of CRC and normal intestinal cells.Graphical abstract
Cell Type Specific Responses of the Endoplasmic Reticulum Dynamics to Environmental Stress
Authors: Zhang Yiheng , Liu Jiazheng , Sun Zhengzhe , Guo Jinyue , Yuan Jingbin , Xue Yajun , Qiu Tianbao , Wang Pei , Yin Benfeng , Yang Honglan , Zhai Liting , Han Hua , Li Xiaojuan 
Published: January 2024

AbstractTo overcome the challenge of balancing imaging speecd and resolution, which currently limits the accurate identification of structural and dynamic changes in the study of endoplasmic reticulum (ER) in plant cells. This research employs structured illumination microscopy techniques to achieve super-resolution real-time imaging of the ER in live Arabidopsis materials. Additionally, a self-supervised denoising framework (Blind2Unblind) was optimized to further enhance the signal-to-noise ratio of rapid microscopic imaging. Based on the images with high quality, a method for quantitative analysis of ER structures using time-lapse images is developed. Moreover, detections of changes in ER structures under environmental stress are conducted to verify the effectiveness of the method. Moreover, correlation analyses of various parameters indicate a significant positive correlation between the area and length of tubular ER with the number of growth tips and tricellular junctions, while the area of ER cisternae and bulk flow exhibits a significant negative correlation with the area and length of tubules. The super-resolution imaging and dynamic analysis method developed in this study will provide new technical approaches for further elucidating the function and regulatory mechanisms of the plant ER.
A Bayesian overhaul of thermal tolerance landscape models: Predicting ectotherm lethality buildup and survival amid heatwaves
Authors: Vajedsamiei Jahangir , Warlo Niklas , Meier H. E. Markus , Melzner Frank 
Published: January 2024

ABSTRACT1. In the face of escalating heatwaves, accurately forecasting ectotherm population mortality is a pressing ecological challenge. Current Thermal Tolerance Landscape (TTL) models, while surpassing single-threshold metrics by incorporating individual survival times, are constrained by frequentist regression parametrization reliant on constant-temperature experiments, omitting probabilistic outcomes.2. This study addresses these limitations by pioneering the application of Approximate Bayesian Computation-Sequential Monte Carlo (ABC-SMC) to analyze survival data from BalticMytilusmussels subjected to both microcosm (constant temperature) and mesocosm (dynamic temperature) heatwave regimes.3. The ABC-SMC yields probabilistic predictions of individual lethality buildup and population survival trajectories, closely aligned with observed survival data across both experimental conditions. Informed by more realistic dynamic data, the TTL model predicts local mussel resilience against the most extreme summer heatwaves projected for this century, albeit with considerations for sublethal impacts and potential recruitment declines.4. Our approach can enhance the predictive accuracy concerning the sensitivity of key marine populations amidst intensifying heatwaves, addressing the urgent need for accurate modeling tools to inform conservation practices and ecosystem management, ultimately aiding in the preservation of marine biodiversity.
The interplay between moult of flight feathers and fuelling conducted on the breeding grounds of the Great SnipeGallinago mediafrom the eastern European, lowland population
Authors: Witkowska Marta , Korniluk Michał , Pinchuk Pavel , Tumiel Tomasz , Karlionova Natalia , Meissner Włodzimierz 
Published: January 2024

AbstractThe Great Snipe as a long-distant migrant wintering in Africa, faces the challenge of accumulating sufficient energy reserves before the departure from European breeding grounds. Despite possible trade-offs in resource allocation, this species additionally initiates moult of flight feathers before southward migration. Here we discuss the strategy of flight feather moult and fuelling, exploring their scheduling, constrained by the timing of breeding and departure for female and male Great Snipes from the European lowland population. We found significant intrasexual differences in both moult initiation date and moult duration. Males start flight feather replacement more than two weeks earlier and moult faster compared to females. However, neither sex completed this process on breeding grounds before the migration, as late in the season all males and half of the females had suspended their primary moult, with the remaining females not moulting at all. Moult of secondaries occurred exceptionally in the studied population. We observed a non-linear energetic stores gain in the studied period, where both sexes maintained a stable and low body condition until the end of July, coinciding with the primary moulting period. Subsequently, there was an increase in body condition, of approximately 1% of the lean body mass per day, indicating a shift towards fuelling for migratory flight. The overlap between stages of maintaining a stable and low body condition and moulting suggests a resource allocation towards feather growth before initiating fuelling. Our study describes moult strategy in Great Snipe conducted on their breeding grounds, highlighting the intrasexual differences, likely resulting from different parental duties of males and females of this lekking species.
Robust Evaluation of Deep Learning-based Representation Methods for Survival and Gene Essentiality Prediction on Bulk RNA-seq Data
Authors: Gross Baptiste , Dauvin Antonin , Cabeli Vincent , Kmetzsch Virgilio , Khoury Jean El , Dissez Gaëtan , Ouardini Khalil , Grouard Simon , Davi Alec , Loeb Regis , Esposito Christian , Hulot Louis , Ghermi Ridouane , Blum Michael , Darhi Yannis , Durand Eric Y. , Romagnoni Alberto 
Published: January 2024

AbstractDeep learning (DL) has shown potential to provide powerful representations of bulk RNA-seq data in cancer research. However, there is no consensus regarding the impact of design choices of DL approaches on the performance of the learned representation, including the model architecture, the training methodology and the various hyperparameters. To address this problem, we evaluate the performance of various design choices of DL representation learning methods using TCGA and DepMap pan-cancer datasets, and assess their predictive power for survival and gene essentiality predictions. We demonstrate that non DL-based baseline methods achieve comparable or superior performance compared to more complex models on survival predictions tasks. DL representation methods, however, are the most efficient to predict the gene essentiality of cell lines. We show that auto-encoders (AE) are consistently improved by techniques such as masking and multi-head training. Our results suggest that the impact of DL representations and of pre-training are highly task- and architecture-dependent, highlighting the need for adopting rigorous evaluation guidelines. These guidelines for robust evaluation are implemented in a pipeline made available to the research community.
Measurement of solubility product in a model condensate reveals the interplay of small oligomerization and self-association
Authors: Chattaraj Aniruddha , Baltaci Zeynep , Mayer Bruce J. , Loew Leslie M. , Ditlev Jonathon A. 
Published: January 2024

AbstractCellular condensates often consist of 10s to 100s of distinct interacting molecular species. Because of the complexity of these interactions, predicting the point at which they will undergo phase separation into discrete compartments is daunting. Using experiments and computation, we therefore studied a simple model system consisting of 2 proteins, polySH3 and polyPRM, designed for pentavalent heterotypic binding. We tested whether the peak solubility product, the product of dilute phase monomer concentrations, is a predictive parameter for the onset of phase separation. Titrating up equal total concentrations of each component showed that the maximum solubility product does approximately coincide with the threshold for phase separation in both the experiments and models. However, we found that measurements of dilute phase concentration include contributions from small oligomers, not just monomers; therefore, a quantitative comparison of the experiments and models required inclusion of small oligomers in the model analysis. We also examined full phase diagrams where the model results were almost symmetric along the diagonal, but the experimental results were highly asymmetric. This led us to perform dynamic light scattering experiments, where we discovered a weak homotypic interaction for polyPRM; when this was added to the computational model, it was able to recapitulate the experimentally observed asymmetry. Thus, comparing experiments to simulation reveals that the solubility product can be predictive of phase separation, even if small oligomers and low affinity homotypic interactions preclude experimental measurement of monomer concentration.
Divergent mechanisms of steroid inhibition in the human ρ1 GABAAreceptor
Authors: Fan Chen , Cowgill John , Howard Rebecca J. , Lindahl Erik 
Published: January 2024

Abstractρ-type γ-aminobutyric acid-A (GABAA) receptors are widely distributed in the retina and brain, and are potential drug targets for the treatment of visual, sleep and cognitive disorders. Endogenous neuroactive steroids including β-estradiol and pregnenolone sulfate negatively modulate the function of ρ1 GABAAreceptors, but their inhibitory mechanisms are not clear. By combining four new cryo-EM structures with electrophysiology and molecular dynamics simulations, we characterize binding sites and negative modulation mechanisms of β-estradiol and pregnenolone sulfate at the human ρ1 GABAAreceptor. β-estradiol binds in a pocket at the interface between extracellular and transmembrane domains, apparently specific to the ρ subfamily, and disturbs allosteric conformational transitions linking GABA binding to pore opening. In contrast, pregnenolone sulfate binds inside the pore to block ion permeation, with a preference for activated structures. These results illuminate contrasting mechanisms of ρ1 inhibition by two different neuroactive steroids, with potential implications for subtype-specific gating and pharmacological design.
Functional studies of deafness-associated pendrin and prestin variants
Authors: Takahashi Satoe , Kojima Takashi , Wasano Koichiro , Homma Kazuaki 
Published: January 2024

ABSTRACTPendrin and prestin are evolutionary conserved membrane proteins that are essential for normal hearing. Pendrin is an anion transporter required for normal development and maintenance of ion homeostasis in the inner ear, while prestin is a voltage-dependent motor responsible for cochlear amplification essential for high sensitivity and frequency selectivity of mammalian hearing. Dysfunction of these proteins result in hearing loss in humans, and numerous deafness-associated pendrin and prestin variants have been identified in patients. However, the pathogenic impacts of many of these variants are ambiguous. Here we report results from our ongoing efforts in experimentally characterizing pendrin and prestin variants usingin vitrofunctional assays, providing invaluable information regarding their pathogenicity.
ATP-Binding Cassette Family C member 1 constrains metabolic responses to high-fat diet in male mice
Authors: Villalobos Elisa , Miguelez-Crespo Allende , Morgan Ruth A. , Ivatt Lisa , Kurian Dominic , Aguilar Judit , Kline Rachel A. , Wishart Thomas M. , Morton Nicholas , Stimson Roland H. , Andrew Ruth , Walker Brian R. , Nixon Mark 
Published: January 2024

ABSTRACTGlucocorticoids modulate glucose homeostasis, acting on metabolically active tissues such as liver, skeletal muscle, and adipose tissue. Intra-cellular regulation of glucocorticoid action in adipose tissue impacts metabolic responses to obesity. ATP-Binding Cassette Family C member 1 (ABCC1) is a transmembrane glucocorticoid transporter known to limit the accumulation of exogenously administered corticosterone in adipose tissue. However, the role of ABCC1 in the regulation of endogenous glucocorticoid action and its impact on fuel metabolism has not been studied. Here, we investigate the impact ofAbcc1deficiency on glucocorticoid action and high fat-diet (HFD)-induced obesity. In lean mice, deficiency ofAbcc1increased endogenous corticosterone levels in skeletal muscle and adipose tissue but did not impact insulin sensitivity. In contrast,Abcc1-deficient mice on HFD displayed impaired glucose and insulin tolerance, and fasting hyperinsulinemia, without alterations in tissue corticosterone levels. Proteomics and bulk RNA sequencing in adipose tissue and skeletal muscle revealed thatAbcc1deficiency amplified the transcriptional response to an obesogenic diet in adipose tissue. Moreover, theAbcc1deficiency impairs key signalling pathways related to glucose metabolism in both skeletal muscle and adipose tissue, in particular those related to OXPHOS machinery and Glut4. Together, our results highlight a role for ABCC1 in regulating glucose homeostasis, demonstrating diet-dependent effects that are not associated with altered tissue glucocorticoid concentrations.
TimberTracer: A Comprehensive Framework for the Evaluation of Carbon Sequestration by Forest Management and Substitution of Harvested Wood Products
Authors: Boukhris I. , Collalti A. , Lahssini S. , Dalmonech D. , Nakhle F. , Testolin R. , Chiriacò M. V. , Santini M. , Valentini R. 
Published: January 2024

AbstractBackgroundHarvested wood products (HWPs) have a pivotal role in climate change mitigation, a recognition solidified in many Nationally Determined Contributions (NDCs) under the Paris Agreement. Integrating HWPs’ greenhouse gas (GHG) emissions and removals into accounting requirements relies on typical decision-oriented tools known as wood product models (WPMs). The study introduces the ‘TimberTracer’ (TT) framework, designed to simulate HWP carbon stock, substitution effects, and emissions from wood decay and bioenergy.ResultsCoupled with the 3D-CMCC-FEM forest growth model,TimberTracerwas applied to Laricio Pine (Pinus nigrasubsp.laricio) in Italy’s Bonis watershed, evaluating three forest management practices (clearcut, selective thinning, and shelterwood) and four wood-use scenarios (business as usual, increased recycling rate, extended average lifespan, and a simultaneous increase in both the recycling rate and the average lifespan) over a 140-year planning horizon, to assess the overall carbon balance of HWPs. Furthermore, this study evaluates the consequences of disregarding landfill methane emissions and relying on static substitution factors, assessing their impact on the mitigation potential of various options. This investigation, covering HWPs stock, carbon (C) emissions, and the substitution effect, revealed that selective thinning emerged as the optimal forest management scenario. Furthermore, a simultaneous 10% increase in both the recycling rate and half-life, under the so-called “sustainability” scenario, proved to be the optimal wood-use strategy. Finally, the analysis shows that failing to account for landfill methane emissions and the use of dynamic substitution can significantly overestimate the mitigation potential of various forest management and wood-use options, which underscores the critical importance of a comprehensive accounting in climate mitigation strategies involving HWPs.ConclusionOur study highlights the critical role of harvested wood products (HWPs) in climate change mitigation, as endorsed by multiple Nationally Determined Contributions (NDCs) under the Paris Agreement. Utilizing the ‘TimberTracer’ framework coupled with the 3D-CMCC-FEM forest growth model, we identified selective thinning as the optimal forest management practice. Additionally, enhancing recycling rates and extending product lifespans effectively bolstered the carbon balance. Moreover, this study emphasizes the necessity of accounting for landfill methane emissions and dynamic product substitution, as failing to do so may significantly overestimate the mitigation potential of implemented projects. These findings offer actionable insights to optimize forest management strategies and advance climate change mitigation efforts.
Context-dependent effects ofCDKN2Aand other 9p21 gene losses during the evolution of oesophageal cancer
Authors: Ganguli Piyali , Basanta Celia C. , Acha-Sagredo Amelia , Misetic Hrvoje , Armero Maria , Mendez Akram , Zahra Aeman , Devonshire Ginny , Kelly Gavin , Freeman Adam , Green Mary , Nye Emma , Bichisecchi Anita , Bonfanti Paola , Clinical Oesophageal Cancer ,   Molecular Stratification (OCCAMS) Consortium, Rodriguez-Justo Manuel , Spencer Jo , Fitzgerald Rebecca C. , Ciccarelli Francesca D. 
Published: January 2024

ABSTRACTCDKN2Ais a tumour suppressor located in chromosome 9p21 and frequently lost in Barrett’s oesophagus (BO) and oesophageal adenocarcinoma (OAC). HowCDKN2Aand other 9p21 gene co-deletions affect OAC evolution remains understudied. We explored the effects of 9p21 loss in OACs and cancer progressor and non-progressor BOs with matched genomic, transcriptomic, and clinical data. Despite its cancer driver role,CDKN2Aloss in BO prevents OAC initiation by counter-selecting subsequentTP53alterations. 9p21 gene co-deletions predict poor patient survival in OAC but not BO through context-dependent effects on cell cycle, oxidative phosphorylation, and interferon response. Immune quantifications using bulk transcriptome, RNAscope and high-dimensional tissue imaging showed thatIFNEloss reduces immune infiltration in BO but not OAC. Mechanistically,CDKN2Aloss suppresses the maintenance of squamous epithelium, contributing to a more aggressive phenotype. Our study demonstrates context-dependent roles of cancer genes during disease evolution, with consequences for cancer detection and patient management.
ER-located PIN5 transporter generates potent auxin sinks driven by the IAA decarboxylation pathway
Authors: Čovanová Milada , Müller Karel , Klierová Nikoleta , Abdollahi Sisi Nayyer , Skůpa Petr , Smetana Ondřej , Dobrev Petre Ivanov , Růžička Kamil , Petrášek Jan 
Published: January 2024

ABSTRACTAuxin is an essential and well-investigated regulator of plant development. Still, many aspects determining its (sub-)cellular distribution, as well as its metabolic turnover, are obscure. PIN5 is a transporter that resides on the endoplasmic reticulum and is presumed to influence internal auxin homeostasis by direct sequestration and subsequent degradation. Due to its distinct expression pattern and incomplete metabolomics analyses, the exact role of PIN5 protein and the identity of downstream auxin degradation products show significant gaps. To this end, we utilized morphologically homogeneous tobacco BY-2 cell cultures. We show that the expression ofArabidopsis thaliana AtPIN5in the BY-2 system phenocopies so-called auxin starvation defects. Moreover, we reveal that the activity ofAtPIN5 leads, in extreme cases, to the broad range of processes accompanying programmed cell death (PCD). Notably, based on the recently updated knowledge on auxin metabolism, we also show that a significant part of auxin metabolites downstream of theAtPIN5 activity are part of the re-emerging auxin decarboxylation pathway. Taking together, we report the direct induction of PCD by auxin stimulus and propose the physiological framework of the auxin decarboxylation route.
Diversity and structure of the deep-sea sponge microbiome in the equatorial Atlantic Ocean
Authors: Williams Sam E. , Varliero Gilda , Lurgi Miguel , Stach Jem , Race Paul R. , Curnow Paul 
Published: January 2024

AbstractSponges (phylum Porifera) harbour specific microbial communities that drive the ecology and evolution of the host. Understanding the structure and dynamics of these communities is emerging as a primary focus in marine microbial ecology research. Much of the work to date has focused on sponges from warm and shallow coastal waters, while sponges from the deep ocean remain less well-studied. Here, we present a metataxonomic analysis of the microbial consortia associated with 23 deep-sea sponges. We identify a high abundance of archaea relative to bacteria across these communities, with certain sponge microbiomes comprising more than 90% archaea. Specifically, the archaeal familyNitrosopumilaceaeare prolific, comprising over 99% of all archaeal reads. Our analysis revealed sponge microbial communities mirror the host sponge phylogeny, indicating a key role for host taxonomy in defining microbiome composition. Our work confirms the contribution of both evolutionary and environmental processes to the composition of microbial communities in deep-sea sponges.ImportanceThe deep ocean is the largest biome on Earth, accounting for >90% of the planet’s marine environment. Despite this it remains a largely unexplored ecosystem, with less than 0.01% of the deep seafloor having been quantitatively sampled. Deep-sea sponges are ancient metazoans which harbour complex microbial communities and much still remains to be learned about the composition and diversity of these unique microbiomes. In an effort to address this, here we report a metataxonomic analysis of the microbial consortia associated with 23 deep-sea sponges from the equatorial Atlantic Ocean. Our findings reveal intricate, species-specific microbial communities dominated by ammonia-oxidizing archaea. This study highlights the significant role sponges play in shaping microbial consortia, providing new insights into deep-sea ecosystem dynamics. Importantly, our findings provide a scientific basis for understanding the evolutionary relationships between sponges and their symbiotic microorganisms.