bluuebunny/crossref_metadata_2025_split huggingface dataset:
KRAS G12 mutant alleles differentially control glutamine metabolism via FOXO1
Authors: Ber Suzan , Yang Ming , Sciacovelli Marco , Samarajiwa Shamith , Patel Khushali , Nikitopoulou Efterpi , Howitt Annie , Cook Simon J. , Venkitaraman Ashok R. , Frezza Christian , Esposito Alessandro 
Published: October 2024

SUMMARYMutations in KRAS, particularly at codon 12, are frequent in adenocarcinomas of the colon, lungs and pancreas, driving carcinogenesis by altering cell signalling and reprogramming metabolism. However, the specific mechanisms by which different KRAS G12 alleles initiate distinctive patterns of metabolic reprogramming is unclear. Using isogenic panels of colorectal cell lines harbouring the G12A, G12C, G12D and G12V heterozygous mutations and employing transcriptomics, metabolomics, and extensive biochemical validation, we demonstrate distinctive features of each allele. We also demonstrate that cells harbouring the common G12D and G12V oncogenic mutations significantly alter glutamine metabolism and nitrogen recycling through FOXO1-mediated regulation compared to parental lines. Moreover, with a combination of small molecule inhibitors targeting glutamine and glutamate metabolism, we also identify a common vulnerability that eliminates mutant cells selectively. These results highlight a previously unreported mutant-specific effect of KRAS alleles on metabolism and signalling that could be potentially harnessed for cancer therapy.In briefBeret al.reveal common and distinct features of oncogenic KRAS mutant isogenic cell lines. Mutant lines upregulate different nitrogen-recycling metabolic pathways and show sensitivity to combinatorial drugging of glutamine metabolism.HighlightsDifferent KRAS mutations trigger distinct metabolic phenotypes in colorectal cell linesGlutamine metabolism and nitrogen recycling are upregulated in KRAS mutant cellsFOXO1 is a key regulator of KRAS-induced rewiring of glutamine and nitrogen metabolismInhibition of glutamine synthetase and glutaminase selectively kills mutant KRAS lines
Superimposed inhibitory surrounds underlying Saliency-based Stimulus Selection in avian Midbrain isthmi pars magnocellularis
Authors: Qian Longlong , Jia Chongchong , Wang Jiangtao , Li Shi , Wang Songwei 
Published: October 2024

AbstractIn the avian midbrain network, bottom-up spatial attention is directed by saliency-based stimulus selection. However, it remains unclear whether the isthmi pars magnocellularis (Imc), the first site in the midbrain network to represent stimulus selection, can represent stimulus salience and what is the mechanism by which the midbrain network computes salience. Here, we used two separate translational motion stimuli as the main stimulation protocols and conducted in vivo electrophysiological experiments in the pigeon’s Imc. By combining bio-plausible model validation, we found two types of inhibitory surrounds of the Imc neuron receptive field, homogenous inhibitory surrounds (HIS) and non-homogenous inhibitory surrounds (non-HIS), and elucidated the mechanism by which both arise. While HIS is local and depends on stimulus feature similarity, which can be used to compute stimulus saliency, non-HIS is global and doesn’t depend on stimulus feature similarity, which can be used to compute stimulus selection. Moreover, the superimposition of HIS and non-HIS modulates the neural response of Imc. The two inhibitory surrounds of Imc identified in this study more clearly elucidate the full process of achieving bottom-up stimulus selection based on saliency in the midbrain network and show that Imc is a nucleus that can represent both stimulus saliency and stimulus selection.
Artificial Selection and the Skin Microbiome Independently Predict Parasite Resistance
Authors: Kramp Rachael D. , Janecka Mary J. , Tardent Nadine , Jokela Jukka , Kohl Kevin D. , Stephenson Jessica F. 
Published: October 2024

AbstractHost responses to parasite infection involve several interacting systems. Host genetics determine much of the response, but it is increasingly clear that the host-associated microbiome also plays a role. Genetically determined systems and the microbiome can also interact; for example, the microbiome can modulate the host immune response, andvice versa. However, it remains unclear how such interactions between the host immune system and the microbiome may influence the host’s overall response to parasites.Host sex is an important source of variation in both immune response and the microbiome across systems, so interactions between them may also therefore differ between males and females, potentially explaining sex-specificity in response to parasites.To investigate how host genetics and the microbiome interact to shape responses to parasites, we imposed truncation selection on the response of Trinidadian guppies (Poecilia reticulata) to the specialist ectoparasiteGyrodactylus turnbulli. Following experimental infection, we used the 30% of guppies with the lowest parasite load to found the resistant line, the 30% with the highest load to found the susceptible line, and randomly chosen uninfected fish to found the control line. After 3-6 generations of breeding without parasites, we sampled the skin-associated microbiome and then infected fish from each line. We applied machine-learning to identify bacterial community types across lines and evaluated how selection line and community type explained variations in infection severity.Our findings showed that among females, the resistant line had significantly lower infection severity, while the susceptible line had higher infection severity than other lines. Interestingly, females in the resistant line lost more mass per parasite, i.e., exhibited lower parasite tolerance, than in the control or susceptible lines. Among males, the susceptible line experienced higher infection severity than the other lines, but there was no difference between the resistant and control lines.We found that the microbiome and host genetics independently explain similar variation in infection severity, highlighting the microbiome’s active role in host-parasite interactions. Our results also indicate sex specificity in the evolution of host defenses.
Targeting the acetyltransferase NAT10 corrects pathologies in human frontotemporal dementia neurons and extends lifespan in an in vivoDrosophilatauopathy model
Authors: Paonessa Francesco , Bizzini Bernardo Delarue , Campbell Tom , Solanki Ravi , Butler Richard , Smith James , Davidson Catherine M. , Larrieu Delphine , Brand Andrea H. , Livesey Frederick J. 
Published: October 2024

ABSTRACTDisruption of the neuronal nuclear membrane and perturbation of nucleocytoplasmic transport are features of neurodegenerative diseases, including Alzheimer’s disease, that involve the microtubule-associated protein tau (MAPT). We previously identified that missense and splicing mutations in the MAPT gene, causal for frontotemporal dementia, result in nuclear envelope deformation and disrupted nucleocytoplasmic transport in human neurons. This is most likely due to microtubule mechanical stress, similar to that observed in Hutchinson-Gilford Progeria Syndrome (HGPS). A small molecule inhibitor of the acetyltransferase NAT10 has been shown to correct nuclear membrane defects in HGPS by modulating microtubule dynamics. We report here that NAT10 inhibition alters microtubule dynamics and corrects nuclear lamina defects and aberrant nucleocytoplasmic transport in human iPSC-derived FTD-MAPT neurons. Similarly, NAT10 inhibition and haploinsufficiency correct neuronal nuclear shape defects and extend lifespanin vivoin aDrosophilamodel of tauopathy. Our results show that NAT10 mediates neuronal pathologies in tauopathies and is a promising new therapeutic target in these diseases.
Exploiting pathogen defence trade-offs to manage risks of crop pests evolving resistance to biocontrol
Authors: Mangan Rosie , Tinsley Matthew C. , Ferrari Ester , Polanczyk Ricardo A. , Bussière Luc F. 
Published: October 2024

AbstractPathogens often exert strong selection, yet host populations maintain considerable genetic variation for resistance, possibly due to environmental heterogeneity causing fitness trade-offs. These trade-offs could help explain genetic variation for pathogen defence, and also constrain resistance evolution to microbial pesticides (an underappreciated risk). However, the presence and strength of such trade-offs remain unclear. We investigate whether pathogen identity or host diet has a stronger effect on the fitness of resistance alleles. We quantify genetic variation and covariation for pathogen resistance in an insect pest across distinct pathogen and plant diet combinations. We demonstrate substantial heritability, indicating considerable risks of biopesticide resistance. Contrary to conventional thinking in host-pathogen biology, we found no strong genetic trade-offs for resisting two fungal pathogen species, but changes in plant diet dramatically altered selection for resistance, revealing diet-mediated genetic trade-offs affecting pest survival. Our data suggest that trade-offs not strictly related to immunocompetence could nevertheless maintain genetic variation for pathogen defence in natural and agricultural landscapes.
Membrane-Dependent Dynamics and Dual Translocation Mechanisms of ABCB4: Insights from Molecular Dynamics Simulations
Authors: Crespi Veronica , Tóth Ágota , Janaszkiewicz Angelika , Falguières Thomas , Di Meo Florent 
Published: October 2024

AbstractABCB4 is an ATP-binding cassette transporter expressed at the canalicular membrane of hepatocytes and responsible for translocating phosphatidylcholine into bile. Despite the recent cryo-EM structures of ABCB4, knowledge about the molecular mechanism of phosphatidylcholine transport remains fragmented. In this study, we used all-atom molecular dynamics simulations to investigate ABCB4 dynamics during its transport cycle, leveraging both symmetric and asymmetric membrane models. Our results demonstrate that membrane composition influences the local conformational dynamics of ABCB4, revealing distinct lipid-binding patterns across different conformers, particularly for cholesterol. We explored the two potential mechanisms for phosphatidylcholine translocation: the canonical ATP-driven alternating access model and the “credit-card swipe” model. Critical residues were identified for phosphatidylcholine binding and transport pathway modulation, supporting the canonical mechanism while also indicating a possible additional pathway. The conformer-specific roles of kinking in transmembrane helices (TMH4 and TMH10) were highlighted as key events in substrate translocation. Overall, ABCB4 may utilize a cooperative transport mechanism, integrating elements of both models to facilitate efficient phosphatidylcholine motion across the membrane. This study provides new insights into the relationship between membrane environment and ABCB4 function, contributing to our understanding of its role in bile physiology and susceptibility to genetic and xenobiotic influences.
Understanding the development of enzalutamide resistance based on a functional single-cell approach
Authors: Xue Changhui , Ko Hyun-Kyung , Shi Kasen , Pittsenbarger Janet , Dao Lucien Vu , Shi Kaiyo , Libmann Maximilian , Geng Hao , Qian David Z. 
Published: October 2024

ABSTRACTMost metastatic prostate cancers (PCa) initially depend on androgen for survival and proliferation. Thus, anti-androgen or castration therapies are the mainstay treatment. Although effective at first, androgen-dependent PCa (ADPC) universally develops therapy resistance, thereby evolving to the incurable disease, called castration resistant PCa (CRPC). Currently, mechanisms underlying the emergence of CRPC from ADPC are largely unclear. We used single-cell RNA-sequencing (scRNA-Seq) to determine how a therapy-naïve ADPC cell line – LNCaP responds to the anti-androgen drug, enzalutamide. We found that most cells expressed the drug-target androgen receptor (AR+), while a small subpopulation (∼12%) expressed low or no AR (ARlow/-). Gene set enrichment analysis (GSEA) revealed that AR+ and ARlow/-cells were enriched with significantly different gene expressions and signaling pathways. Unexpectedly, ARlow/-cells displayed robust transcriptional response, including upregulations of genes and pathways involved in clinical CRPC. Next, we isolate ARlow/-and AR+ cells from the LNCaP cell line, and functionally confirmed the enzalutamide resistant phenotype of ARlow/-cells in vitro and in xenograft models in vivo. Finally, to explore a therapeutic option for ARlow/-cells, we found that ARlow/-cells expressed low levels of NAD+ biosynthesis genes, notably NAPRT, indicating a possible vulnerability to inhibitors blocking NAD+ synthesis. Indeed, treating ARlow/-cells with NAD+ synthesis inhibitors, FK866 and OT-82, significantly inhibited the survival and proliferation of ARlow/-cells, thus suggesting a possible novel therapeutic option for ADT and enzalutamide resistant PCa.SUMMARYSingle-cell RNA-Sequencing reveals heterogeneities of tumor cell populations. In most cases, however, the functional significance of the observed heterogeneity is not tested. In this study, we first identified a possible therapy-resistant prostate cancer cell subpopulation with scRNA-Seq, then confirmed the resistant phenotype with single cell and colony – based cloning and functional testing. In addition, we also identified a therapeutic vulnerability of the resistant cells.
Raising awareness of potential biases in medical machine learning: Experience from a Datathon
Authors: Hochheiser Harry , Klug Jesse , Mathie Thomas , Pollard Tom J. , Raffa Jesse D. , Ballard Stephanie L. , Conrad Evamarie A. , Edakalavan Smitha , Joseph Allan , Alnomasy Nader , Nutman Sarah , Hill Veronika , Kapoor Sumit , Claudio Eddie Pérez , Kravchenko Olga V. , Li Ruoting , Nourelahi Mehdi , Diaz Jenny , Taylor W. Michael , Rooney Sydney R. , Woeltje Maeve , Celi Leo Anthony , Horvat Christopher M. 
Published: October 2024

AbstractObjectiveTo challenge clinicians and informaticians to learn about potential sources of bias in medical machine learning models through investigation of data and predictions from an open-source severity of illness score.MethodsOver a two-day period (total elapsed time approximately 28 hours), we conducted a datathon that challenged interdisciplinary teams to investigate potential sources of bias in the Global Open Source Severity of Illness Score. Teams were invited to develop hypotheses, to use tools of their choosing to identify potential sources of bias, and to provide a final report.ResultsFive teams participated, three of which included both informaticians and clinicians. Most (4/5) used Python for analyses, the remaining team used R. Common analysis themes included relationship of the GOSSIS-1 prediction score with demographics and care related variables; relationships between demographics and outcomes; calibration and factors related to the context of care; and the impact of missingness. Representativeness of the population, differences in calibration and model performance among groups, and differences in performance across hospital settings were identified as possible sources of bias.DiscussionDatathons are a promising approach for challenging developers and users to explore questions relating to unrecognized biases in medical machine learning algorithms.Author summaryDisadvantaged groups are at risk of being adversely impacted by biased medical machine learning models. To avoid these undesirable outcomes, developers and users must understand the challenges involved in identifying potential biases. We conducted a datathon aimed at challenging a diverse group of participants to explore an open-source patient severity model for potential biases. Five groups of clinicians and informaticians used tools of their choosing to evaluate possible sources of biases, applying a range of analytic techniques and exploring multiple features. By engaging diverse participants with hands-on data experience with meaningful data, datathons have the potential to raise awareness of potential biases and promote best practices in developing fair and equitable medical machine learning models.
Home and Epigenome: DNA Methylation as a Link Between Poor Housing Quality and Depressive Symptoms
Authors: Sanders Faye , Baltramonaityte Vilte , Lussier Alexandre A. , Smith Andrew D.A.C. , Dunn Erin C , Walton Esther 
Published: October 2024

AbstractPoor housing quality associates with risk for depression. However, previous research often lacks consideration of socioeconomic status (SES) baseline depressive symptoms and biological processes, leading to concerns of confounding and reverse causation.In a sample of up to 9,566 adults, we investigated cross-sectional and longitudinal associations between housing quality (assessed at age 28, 1- and 2-year follow-ups) and depressive symptoms (at four intervals between enrolment and 18-year follow-up). In sub-samples (n=871, n=731), we investigated indirect effects via DNA methylation.Poor housing quality associated with depressive symptoms cross-sectionally (beta range: 0.02 to 0.06, allp-values<.023) after controlling for SES and other factors. Longitudinally, this association persisted at the ∼2-year, but not the ∼18-year follow-up period. Indirect effects linked to genes related to aging, obesity, and brain health.These results highlight poor housing quality as a risk factor for depression and the potential role of DNA methylation in this association.
Asbestos as contaminant in the mining of non-asbestos minerals: Case of a “marble” waste slurry dump-yard from Rajasthan, India
Authors: Singh Raja , Fitzgerald Sean , Dada Rima , Frank Arthur L 
Published: October 2024

AbstractAsbestos is fibrous minerals, some of which can naturally occur in certain types of marble, including asbestiform tremolite, actinolite, anthophyllite, and chrysotile, with tremolite the most common among those associated asbestos types. This is of concern as miners and stone workers may not be aware of this and may never be considered by physicians treating them for lung related ailments. Wet marble dust in slurry form is disposed of at designated waste collection points, including in Rajsamand, Rajasthan. unfortunately, this location is now open to the public as a tourist attraction. Dust from this location was tested using Transmission Electron Microscopy (TEM) and tremolite asbestos fibres were found. The presence of tremolite means the workers, bystanders and tourists to the waste collection spots may be exposed to this carcinogen and this may become the etiological factor for mesothelioma or lung cancer among other asbestos related diseases. The marble industry in general should also be subjected to the same regulations as the asbestos industry due to the presence of naturally occurring asbestos in such mines. This is particularly germane in India where asbestos is widely being used and studies show a significant and increasing number of asbestos related lung and pleural, malignant and non-malignant diseases including cancers, such as mesothelioma. This study aims to highlight the occupational and environmental health hazard among workers and the general public.
Home Blood Pressure and Asymptomatic Intracranial and Extracranial Arterial Stenosis in Hypertension Patients
Authors: Cai Enheng , An Dewei , Zhang Jin , Tang Xiaofeng , Li Yan , Wang Yan , Zhu Dingliang 
Published: October 2024

AbstractBackgroundWe aim to analyze the effect of home blood pressure (HBP) level and variability on both asymptomatic intracranial (aICAS) and extracranial arterial stenosis (aECAS).MethodsA total of 534 patients completed HBP measurements (HBP) on at least 3 days. The stenoses of ICAS and ECAS were evaluated by CTA. HBP variability (HBPV) was quantified using the standard deviation and maximum--minimum difference between measures. The association of HBP level and variability with both aICAS and aECAS was evaluated using multivariate logistic regression.ResultsMorning HBPV was significantly associated with isolated aICAS, isolated aECAS, and concurrent aICAS and aECAS, respectively, even after being adjusted for HBP level. Besides, HBP were independently related to concurrent aICAS and aECAS (P<0.05). Instead, neither morning nor evening HBP associated with isolated aICAS or aECAS.ConclusionThe findings of this study confirmed the strong correlation of aICAS/aECAS with HBP in the hypertensive population, particularly morning HBPV.
Ectomycorrhizal symbiosis evolved independently and by convergent gene duplication in rosid lineages
Authors: van Beveren Fabian , Boele Yvet , Puginier Camille , Bianconi Matheus , Libourel Cyril , Bonhomme Maxime , Keller Jean , Delaux Pierre-Marc 
Published: October 2024

AbstractMany land plants rely on mutualistic symbiotic associations to thrive, starting with their common ancestor associating with arbuscular mycorrhizal (AM) fungi. Similar to AM symbiosis, multiple other intracellular symbiotic interactions have evolved in a variety of land plants. Ectomycorrhizal (ECM) symbiosis contrasts with these relationships as there is no intracellular accommodation of the symbiont inside the plant cell, but only intercellular colonization. This symbiotic relationship is common in a variety of seed plants, mostly trees and shrubs such as pines, willows and oaks.Although it is known which plant lineages are involved in ECM symbiosis, there has been little investigation into the evolutionary origin of ECM symbiosis in these lineages. Furthermore, the genetic innovations and transcriptomic response related to this symbiosis have been studied largely in a genus or species-specific context, which hinders the study of their evolutionary origins. In this study, we reconstruct the origin of ECM in the rosid clade, showing at least 16 independent origins, resulting in the 17 known extant ECM rosid lineages. Moreover, comparative genomics of these lineages highlight genes involved in cell wall remodeling which underwent duplications in a convergent manner across ectomycorrhizal lineages.
The ecological and economic benefits of sustainable agricultural practices: Evidence from on-farm trials in broad-acre grain crops
Authors: Mata Luis , McGrane Leo , Maino James , Sims Grant , Drum Craig , Umina Paul A. 
Published: October 2024

AbstractSustainable agricultural practices are essential for mitigating the negative environmental impacts of conventional agriculture while ensuring food security. However, widespread adoption of these practices requires robust evidence of their efficacy and economic viability.We co-designed a two-year field trial with farmers and agronomy advisors in Australia, to evaluate the ecological and economic benefits of sustainable agricultural practices for managing the redlegged earth mite, a major pest of Australian grain crops. We compared ‘Novel’ treatments representing long-term farmer-implemented sustainable agricultural practices based on biological control with ‘Conventional’ treatments and ‘Plus’ treatments designed as counterfactuals to disentangle the effects of specific pest control and plant nutrient components.Redlegged earth mite densities remained below economic thresholds across all treatments and years, demonstrating effective pest control in both conventional and sustainable systems. Notably, the Novel treatment supported higher densities of beneficial arthropods, indicating increased biological control potential.Yield and gross profit margins were generally similar between the treatments, indicating that sustainable agriculture practices can maintain profitability while fostering biodiversity.Practical implication. Our study provides evidence that biological control and biofertiliser supplementation can be effectively used to manage agricultural pests and demonstrates the value of close collaboration with farmers and agronomy advisors to conduct ecological field research that has practical applications.