bluuebunny/crossref_metadata_2025_split huggingface dataset:
Telomerase reverse transcriptase induces targetable alterations in glutathione and nucleotide biosynthesis in glioblastomas
Authors: Udutha Suresh , Taglang Céline , Batsios Georgios , Gillespie Anne Marie , Tran Meryssa , Ronen Sabrina M , ten Hoeve Johanna , Graeber Thomas G , Viswanath Pavithra 
Published: November 2023

ABSTRACTTelomerase reverse transcriptase (TERT) is essential for glioblastoma (GBM) proliferation. Delineating metabolic vulnerabilities induced by TERT can lead to novel GBM therapies. We previously showed that TERT upregulates glutathione (GSH) pool size in GBMs. Here, we show that TERT acts via the FOXO1 transcription factor to upregulate expression of the catalytic subunit of glutamate-cysteine ligase (GCLC), the rate-limiting enzyme ofde novoGSH synthesis. Inhibiting GCLC using siRNA or buthionine sulfoximine (BSO) reduces synthesis of13C-GSH from [U-13C]-glutamine and inhibits clonogenicity. However, GCLC inhibition does not induce cell death, an effect that is associated with elevated [U-13C]-glutamine metabolism to glutamate and pyrimidine nucleotide biosynthesis. Mechanistically, GCLC inhibition activates MYC and leads to compensatory upregulation of two key glutamine-utilizing enzymes i.e., glutaminase (GLS), which generates glutamate from glutamine, and CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotatase), the enzyme that converts glutamine to the pyrimidine nucleotide precursor dihydroorotate. We then examined the therapeutic potential of inhibiting GLS and CAD in combination with GCLC. 6-diazo-5-oxy-L-norleucin (DON) is a potent inhibitor of glutamine-utilizing enzymes including GLS and CAD. The combination of BSO and DON suppresses GSH and pyrimidine nucleotide biosynthesis and is synergistically lethal in GBM cells. Importantly,in vivostable isotope tracing indicates that combined treatment with JHU-083 (a brain-penetrant prodrug of DON) and BSO abrogates synthesis of GSH and pyrimidine nucleotides from [U-13C]-glutamine and induces tumor shrinkage in mice bearing intracranial GBM xenografts. Collectively, our studies exploit a mechanistic understanding of TERT biology to identify synthetically lethal metabolic vulnerabilities in GBMs.SIGNIFICANCEUsingin vivostable isotope tracing, metabolomics, and loss-of-function studies, we demonstrate that TERT expression is associated with metabolic alterations that can be synergistically targeted for therapy in glioblastomas.
The neurons that drive infradian sleep-wake and mania-like behavioral rhythms
Authors: Markam Pratap S. , Bourguignon Clément , Zhu Lei , Darvas Martin , Sabatini Paul V. , Kokoeva Maia V. , Giros Bruno , Storch Kai-Florian 
Published: November 2023

SummaryInfradian mood and sleep-wake rhythms with periods of 48 hr and beyond have been observed in bipolar disorder (BD) subjects that even persist in time isolation, indicating an endogenous origin. Here we show that mice exposed to methamphetamine (Meth) in drinking water develop infradian locomotor rhythms with periods of 48 hr and beyond which extend to sleep length and mania-like behaviors in support of a model for cycling in BD. This cycling capacity is abrogated upon genetic disruption of DA production in DA neurons of the ventral tegmental area (VTA) or ablation of nucleus accumbens (NAc) projecting, dopamine (DA) neurons. Chemogenetic activation of NAc-projecting DA neurons leads to locomotor period lengthening in clock deficient mice, while cytosolic calcium in DA processes of the NAc was found fluctuating synchronously with locomotor behavior. Together, our findings argue that BD cycling relies on infradian rhythm generation that depends on NAc-projecting DA neurons.
Utilizing the Scale-Invariant Feature Transform Algorithm to Align Distance Matrices Facilitates Systematic Protein Structure Comparison
Authors: Guo Zhengyang , Wang Yang , Ou Guangshuo 
Published: November 2023

AbstractProtein structure comparison is pivotal for deriving homological relationships, elucidating protein functions, and understanding evolutionary developments. The burgeoning field ofin-silicoprotein structure prediction now yields billions of models with near-experimental accuracy, necessitating sophisticated tools for discerning structural similarities among proteins, particularly when sequence similarity is limited. Here, we have developed the ADAMS pipeline, which synergizes the distance matrix alignment method with the scale-invariant feature transform (SIFT) algorithm, streamlining protein structure comparison on a proteomic scale. Utilizing a computer vision-centric strategy for contrasting disparate distance matrices, ADAMS adeptly alleviates challenges associated with proteins characterized by a high degree of structural flexibility. Our findings indicate that ADAMS achieves a level of performance and accuracy on par with Foldseek, while maintaining similar speed. Crucially, ADAMS overcomes certain limitations of Foldseek in handling structurally flexible proteins, establishing it as an efficacious tool for in-depth protein structure analysis with heightened accuracy.
Remodelling of skeletal muscle myosin metabolic states in hibernating mammals
Authors: Lewis Christopher T. A. , Melhedegaard Elise G. , Ognjanovic Marija M. , Olsen Mathilde S. , Laitila Jenni , Seaborne Robert A. E. , Grønset Magnus Nørregaard , Zhang Chengxin , Iwamoto Hiroyuki , Hessel Anthony L. , Kuehn Michel N. , Merino Carla , Amigó Nuria , Fröbert Ole , Giroud Sylvain , Staples James F. , Goropashnaya Anna V. , Fedorov Vadim B. , Barnes Brian M. , Tøien Øivind , Drew Kelly L. , Sprenger Ryan J. , Ochala Julien 
Published: November 2023

AbstractHibernation is a period of metabolic suppression utilized by many small and large mammal species to survive during winter periods. As the underlying cellular and molecular mechanisms remain incompletely understood, our study aimed to determine whether skeletal muscle myosin and its metabolic efficiency undergo alterations during hibernation to optimize energy utilization. We isolated muscle fibers from small hibernators,Ictidomys tridecemlineatusandEliomys quercinusand larger hibernators,Ursus arctosandUrsus americanus. We then conducted loaded Mant-ATP chase experiments alongside X-ray diffraction to measure resting myosin dynamics and its ATP demand. In parallel, we performed multiple proteomics analyses. Our results showed a preservation of myosin structure inU. arctosandU. americanusduring hibernation, whilst inI. tridecemlineatusandE. quercinus, changes in myosin metabolic states during torpor unexpectedly led to higher levels in energy expenditure of type II, fast-twitch muscle fibers at ambient lab temperatures (20°C). Upon repeating loaded Mant-ATP chase experiments at 8°C (near the body temperature of torpid animals), we found that myosin ATP consumption in type II muscle fibers was reduced by 77-107% during torpor compared to active periods. Additionally, we observed Myh2 hyper-phosphorylation during torpor inI. tridecemilineatus, which was predicted to stabilize the myosin molecule. This may act as a potential molecular mechanism mitigating myosin-associated increases in skeletal muscle energy expenditure during periods of torpor in response to cold exposure. Altogether, we demonstrate that resting myosin is altered in hibernating mammals, contributing to significant changes to the ATP consumption of skeletal muscle. Additionally, we observe that it is further altered in response to cold exposure and highlight myosin as a potentially contributor to skeletal muscle non-shivering thermogenesis.
Elucidating Partial Folding State of Bovine Pancreatic Trypsin Inhibitor by a Combined Study of Molecular Dynamics Simulations, Information Theory, Molecular Graph Theory, and Machine Learning
Authors: Kamberaj Hiqmet 
Published: November 2023

AbstractUsing a notably large amount of data in investigating physical and chemical phenomena demands new statistical and computational approaches; besides, the cross-validations require well-established theoretical frameworks. This study aims to validate the statistical efficiency of alternative definitions for the information-theoretic measures, such as transfer entropy, using the so-called (α, q)-framework. The primary goal is to find measurements of high-order correlations that preserve information-theoretic properties of information transfer between the components of a dynamical system (such as a protein) due to local operations. Besides, this study aims to decode the information contained in the amino acid sequence establishing a three-dimensional protein structure by comparing the amino acids physical-chemical properties with their ranked role in the protein interaction network topology using new graph-theoretic measures based on the constructed digraph models of (α, q) information transfer within a heat flow kernel embedding framework. Moreover, this study aims to use the Deep Graph Convolution Neural Networks for classifying the role of each amino acid in a protein trained upon short equilibrium structure fluctuations at sub-nanosecond time scales.In particular, this study examines the influence of disulphide bridges on the three-dimensional structure of the Bovine Pancreatic Trypsin Inhibitor wild type and mutated analogue protein.
Automated Model Refinement Using Perturbation-Observation Pairs
Authors: Park Kyu Hyong , Rozum Jordan C. , Albert Réka 
Published: November 2023

AbstractNetwork-based dynamic modeling is useful for studying the responses of complex biomolecular systems to environmental changes and internal perturbations. In modeling signal transduction and other regulatory networks, it is common to integrate evidence from perturbation (e.g. gene knockout) - observation pairs, where the perturbed and observed variables may be distant in the network. For a model to capture these non-local effects, its construction, validation, and refinement necessarily involve trial and error, constrained by domain knowledge.We propose and implement a genetic algorithm-based workflow to streamline model refinement. This workflow applies to any biological system for which an interaction network and enough perturbation experiments exist. We implement our workflow for Boolean networks, which are a popular and successful tool for modeling biological systems. The algorithm we introduce adjusts the functions of the model to enhance agreement with a corpus of curated experimental results and leverages existing mechanistic knowledge to automatically limit the search space to biologically plausible models. To account for the interdependence of experimental results, we develop a hierarchical scoring technique for assessing model performance. Our implementation is available as the open-source Python libraryboolmore.We demonstrateboolmore’s effectiveness in a published plant signaling model that exemplifies the challenges of manual model construction and refinement. This model describes how plant stomata close in response to the drought hormone abscisic acid. After several hours of automatic refinement on a personal computer, the fittest models recapture and surpass the accuracy gain achieved over two years of manual revision. The refined models yield new, testable predictions, such as explanations for the role of reactive oxygen species in drought response. By automating the laborious task of model validation and refinement, this workflow is a step towards fast, fully automated, and reliable model construction.
A large-scale assessment of sequence database search tools for homology-based protein function prediction
Authors: Zhang Chengxin , Freddolino P. Lydia 
Published: November 2023

ABSTRACTSequence database searches followed by homology-based function transfer form one of the oldest and most popular approaches for predicting protein functions, such as Gene Ontology (GO) terms. Although sequence search tools are the basis of homology-based protein function prediction, previous studies have scarcely explored how to select the optimal sequence search tools and configure their parameters to achieve the best function prediction. In this paper, we evaluate the effect of using different options from among popular search tools, as well as the impacts of search parameters, on protein function prediction. When predicting GO terms on a large benchmark dataset, we found that BLASTp and MMseqs2 consistently exceed the performance of other tools, including DIAMOND - one of the most popular tools for function prediction - under default search parameters. However, with the correct parameter settings, DIAMOND can perform comparably to BLASTp and MMseqs2 in function prediction. This study emphasizes the critical role of search parameter settings in homology-based function transfer.
Small dams driveAnophelesabundance during the dry season in a high malaria burden area of Malawi
Authors: Zembere Kennedy , Jones Christopher M , Mthawanji Rhosheen , Nkolokosa Clinton , Kamwezi Richard , Kalonde Patrick Ken , Stanton Michelle C 
Published: November 2023

AbstractThis study explores the influence of small dams on the exposure to malaria vectors during the dry season in Kasungu district, Malawi, an area recently identified as high priority for malaria interventions by the National Malaria Control Programme. Small dam impoundments provide communities with a continuous supply of water for domestic and agricultural activities across sub-Saharan Africa and are considered vital to food security and climate change resilience. However, these permanent water bodies also create ideal breeding sites for mosquitoes in typically arid landscapes. The study focuses on a specific dam impoundment and its vicinity, aiming to assess its spatial and temporal influence on indoor vector densities.Throughout May to August 2021, CDC light traps were used to measure indoor mosquito densities for two consecutive nights per month in three communities located at increasing distances from the dam (0km, ∼1km, ∼2km). Simultaneously, drone imagery was captured for each community, enabling the identification of additional standing water within approximately 400 meters of selected households. Larval sampling was carried out within the impoundment periphery and in additional water bodies identified in the drone imagery. Generalised linear mixed models (GLMMs) were employed to analyse the indoorAnophelesabundance data, estimating the effects of household structure (open/closed eaves), month, temperature, and water proximity on malaria vector exposure.Throughout 685 trapping nights, a total of 1,256 mosquitoes were captured, with 33% (412) being femaleAnopheles. Among these, 91% were morphologically identified asAn. funestuss.l., and 5% asAn. gambiaes.l. Catches progressively declines in each consecutive trapping month as the environment became drier. This decline was much slower in Malangano, the community next to the dam, with abundance being notably higher in June and July. Further, the majority ofAn. gambiaes.l. were caught in May, with none identified in July and August.Anopheleslarvae were found both in the impoundment and other smaller water bodies such as irrigation wells in each survey month, however the presence of these smaller water bodies did not have a significant impact on adult female mosquito catches in the GLMM. The study concludes that proximity to the dam impoundment was the primary driver of differences between survey communities with the abundance in Chikhombwe (∼1km away) and Chiponde (∼2km away) being 0.35 (95% CI 0.19-0.66) and 0.28 (95% CI 0.16-0.47) lower than Malangano respectively after adjusting for other factors.These findings underscore the importance of targeted interventions, such as larval source management or housing improvements, near small dams to mitigate malaria transmission risks during the dry season. Further research is needed to develop cost-effective strategies for vector control within and around these impoundments.
TLR8-Activating miR-146a-3p is an Intermediate Signal Contributing to Fetal Membrane Inflammation in Response to Bacterial LPS
Authors: Georges Hanah M. , Cassin Caterina , Tong Mancy , Abrahams Vikki M. 
Published: November 2023

AbstractPreterm birth is the largest contributor to neonatal morbidity and is often associated with chorioamnionitis, defined as inflammation/infection of the fetal membranes (FMs). Chorioamnionitis is characterized by neutrophil infiltration of the FMs and is associated with elevated levels of the neutrophil chemoattractant, interleukin (IL)-8, and the proinflammatory cytokine, IL-1β. While FMs can respond to infections through innate immune sensors, such as Toll-like receptors (TLRs), the downstream mechanisms by which chorioamnionitis arises are not fully understood. A novel group of non-classical microRNAs (miR-21a, miR-29a, miR-146a-3p, Let-7b) function as endogenous danger signals by activating the ssRNA viral sensors TLR7 and TLR8. In this study, the pro-inflammatory roles of TLR7/TLR8-activating miRs were examined as mediators of FM inflammation in response to bacterial lipopolysaccharide (LPS) using anin vitrohuman FM explant system, anin vivomouse model of pregnancy, and human clinical samples. Following LPS exposure, miR-146a-3p was significantly increased in both human FM explants and in wildtype mouse FMs. Expression of miR-146a-3p was also significantly elevated in FMs from women with preterm birth and chorioamnionitis. FM IL-8 and inflammasome-mediated IL-1β production in response to LPS was dependent on miR-146a-3p and TLR8, downstream of TLR4 activation. In wildtype mice, LPS exposure increased FM IL-8 and IL-1β production and induced preterm birth. InTLR7−/−/TLR8−/−mice, LPS exposure was able to initiate, but not sustain preterm birth, and FM inflammation was reduced. Together, we demonstrate a novel signaling mechanism at the maternal-fetal interface in which TLR8-activating miR-146a-3p acts as an intermediate danger signal to drive FM inflammasome-dependent and -independent mechanisms of inflammation and thus, may play a role in chorioamnionitis and subsequent preterm birth.
Analyzing photoactivation with diffusion models to study transport in the Endoplasmic Reticulum network
Authors: Dora M. , Paquin-Lefebvre F. , Holcman D. 
Published: November 2023

AbstractPhotoactivation is a paradigm consisting in local molecular fluorescent activation by laser illumination in a chosen region (source) while measuring the concentration at a target region. Data-driven modeling is concern with the following questions: how from the measurement in these two regions, is it possible to infer the properties of molecular propagation? How is it possible to use such reponses to infer motions occurring in networks such as the endoplasmic reticulum? In this article, we present a data-driven analysis based on diffusion-transport models and numerical simulations to interpret the photoactivation dynamics and extract biophysical parameters. Finally we discuss modeling approaches to reconstruct local network properties from photoactivation transients.
Proteomic characterisation of Sarculator nomogram-defined risk groups in soft tissue sarcomas of the extremities and trunk wall
Authors: Chadha Madhumeeta , Iadecola Sara , Jenks Andrew , Burns Jessica , Arthur Amani , Pankova Valeriya , Wilding Christopher P , Callegaro Dario , Strauss Dirk C , Thway Khin , Gronchi Alessandro , Jones Robin L , Miceli Rosalba , Pasquali Sandro , Huang Paul H 
Published: November 2023

AbstractBackgroundHigh-risk soft tissue sarcomas of the extremities and trunk wall (eSTS), as defined by the Sarculator nomogram, are more likely to benefit from (neo)adjuvant anthracycline-based therapy compared to low/intermediate-risk patients. The biology underpinning these differential treatment outcomes remain unknown.MethodsWe analysed proteomic profiles and clinical outcomes of 123 eSTS patients. A Cox model for overall survival including the Sarculator was fitted to individual data to define 4 risk groups. A DNA replication protein signature - Sarcoma Proteomic Module 6 (SPM6) was evaluated for association with clinicopathological factors and risk groups. SPM6 was added as a covariate together with Sarculator in a multivariable Cox model to assess improvement in prognostic risk stratification.ResultsDNA replication and cell cycle proteins were upregulated in high risk versus very low risk patients. Evaluation of the functional effects of CRISPR-Cas9 gene knockdown of proteins enriched in high risk patients identified candidate drug targets. SPM6 was significantly associated with tumour malignancy grade (p = 1.6e-06), histology (p = 1.4e-05) and risk groups (p = 2.6e-06). Cox model analysis showed that SPM6 substantially contributed to a better calibration of the Sarculator nomogram (Index of Prediction Accuracy =0.109 for Sarculator alone versus 0.165 for Sarculator + SPM6).ConclusionsRisk stratification of patient with STS is defined by distinct biological pathways across a range of cancer hallmarks. Incorporation of SPM6 protein signature improves prognostic risk stratification of the Sarculator nomogram. This study highlights the utility of integrating protein signatures for the development of next-generation nomograms.
Ocean acidification alters the transcriptomic response in the nervous system ofAplysia californicaduring reflex behaviour
Authors: Sourisse Jade M. , Schunter Celia 
Published: November 2023

AbstractOcean acidification (OA) has numerous impacts on marine organisms including behaviour. While behaviours are controlled in the neuro system, its complexity makes linking behavioural impairments to environmental change difficult. Here we use a neurological modelAplysia californicawith well-studied simple neuro system and behaviours. By exposingAplysiato current day (∼500 µatm) or near-future CO2conditions (∼1100 µatm), we test the effect of OA on their tail withdrawal reflex (TWR) and the underlying neuromolecular response of the pleural-pedal ganglia, responsible for the behaviour. Under OA,Aplysiarelax tails faster due to increased sensorin-A expression, an inhibitor of mechanosensory neurons. We further investigate how OA affects habituation, which produced a “sensitization-like” behaviour and affected vesicle transport and stress response, revealing an influence of OA on neuronal and behavioural outputs associated with learning. Finally, we test whether GABA-mediated neurotransmission is involved in impaired TWR, but exposure to gabazine did not restore normal behaviour and provoked little molecular response, rejecting the involvement in TWR impairment. Instead, vesicular transport and cellular signalling link other neurotransmitter processes directly with TWR impairment. Our study shows effects of OA on neurological tissue parts that control for behaviour revealing the neurological mechanisms when faced with OA.