bluuebunny/crossref_metadata_2025_split huggingface dataset:
T Cell Receptor Diversity, Cancer and Sex: Insights from 30,000 TCRβRepertoires
Authors: Zahid H. Jabran , Taniguchi Ruth , Noceda Marco Garcia , Robins Harlan , Greissl Julia 
Published: October 2024

AbstractCancer is a widespread disease claiming millions of lives each year, yet the relationship between cancer risk and age-related immune system decline (i.e., immunosenescence), specifically the ability of T cells to detect and eliminate cancerous cells, remains poorly understood. Here we analyze T cell receptor (TCR)βrepertoires from ∼30,000 subjects demonstrating that TCR diversity—a key measure of immunocompetency—systematically declines between the ages of 20 and 80 years. Notably, this decline occurs 11 years later in females compared to males and coincides with their lower incidence of cancer, reinforcing the link between TCR diversity and cancer risk. Thus, we model rising cancer incidence with age as the combined effect of accumulating mutations and the increasing probability that cells harboring these mutations evade immune detection due to loss of TCR diversity. Our analysis suggests that both of these processes significantly contribute to the risk of cancer and that lower cancer incidence in females is due to the delayed onset of immunosenescence. Our results highlight the importance of understanding immunosenescence in carcinogenesis, potentially providing new opportunities for immunotherapies targeting an aging immune system as well as personalized care leveraging TCR diversity as a biomarker.
EFP Analyzer: A fast, accurate, and easy-to-teach program for analyzing Extracellular Field Potentials from iPSC-derived cardiomyocytes
Authors: Patel Nidhi , Shen Alex , Wada Yuko , Blair Marcia , Mitchell Devyn , Vanags Loren , Woo Suah , Ku Matthew , Dauda Kundivy , Morris William , Yang Minjoo , Knollmann Björn C. , Roden Dan M. , Salem Joe-Elie , Glazer Andrew M. , Kroncke Brett M. 
Published: October 2024

ABSTRACTRationaleInduced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are an emerging model for determining drug effects and modeling disease. Specialized devices can generate Extracellular Field Potential (EFP) measurements from these cells, analogous to the ventricular complex of the electrocardiogram.ObjectiveThe objective of this study was to develop an easy-to-use, easy-to-teach, reproducible software tool to measure EFPs.Methods-ResultsWe present the EFP-Analyzer (EFPA), a semi-automized analyzer for EFP traces, which identifies and averages beats, identifies landmarks, and calculates intervals. We evaluated the tool in an analysis of 358 EFP traces from 22 patient-derived lines. We analyzed spontaneously beating iPSC-CMs, as well as optically paced iPSC-CMs through channelrhodopsin. We developed stringent quality criteria and measured EFP intervals, including Field Potential Duration (FPD). FPD from optically paced iPSC-CMs were shorter than those of spontaneously beating iPSC-CMs (283.7.0±54.2 vs. 293.0±47.5, p: 0.32, respectively). We further analyzed the usability and data replicability of EFPA through an inter-intra observer analysis. Correlation coefficient for inter-reader tangent and threshold measurements for these FPD ranged between r: 0.93-1.00. Bland-Altman plots comparing inter observer results for spontaneously beating and paced iPSC-CMs showed 95% limits of agreement (−13.6 to 19.4ms and −13.2 to 15.3ms, respectively). The EFP-analyzer could accurately detect FPD prolongation due to drug (moxifloxacin) or pathogenic loss of function mutations (CACNA1CN639T). This program is available for download athttps://github.com/kroncke-lab/EFPA. The instructions will be available at the same listed website under the README section of the Github main page.ConclusionsThe EFP-Analyzer tool is a useful tool that enables the efficient use of iPSC-CMs as a model to study drug effects and disease.
hsa-miR-9-5p highly expressed in syncytiotrophoblast-derived extracellular vesicles from early-onset preeclampsia impairs cerebral microvascular endothelial cell pro-angiogenic capacity
Authors: Logenthiran Prassana , Awoyemi Toluwalase , Davis Jones Gabriel , Rahbar Maryam , Akbar Naveed , Cerdeira Ana Sofia , Escudero Carlos , Vatish Manu 
Published: October 2024

AbstractBackgroundCerebrovascular complications are the leading cause of maternal mortality associated with preeclampsia. Extracellular vesicles (EVs) containing microRNAs (miRNAs) and derived from syncytiotrophoblast (STB-EVs) are suspected to play a role in these complications. Previously, we found that STB-EVs from the placentas of women with preeclampsia have a higher content of the angiogenesis regulator hsa-miR-9-5p. We now investigate the effects of hsa-miR-9-5p on the proangiogenic properties of brain endothelial cells and identify potential protein targets involved in these processes.MethodsBrain endothelial cells (hCMEC/D3) were treated with hsa-miR-9-5p (0, 5 and 10 nM) to assess cell viability and proliferation. Additionally, cell migration and proteomic profile in hCMEC/D3 treated with hsa-miR-9-5p (10 nM) were also analyzed.ResultsCompared to control, hsa-miR-9-5p significantly reduced hCMEC/D3 cell proliferation and migration without affecting cell viability. Proteomic analysis identified several vital proteins potentially mediating these effects, including vascular endothelial growth factor type C (VEGFC), placental growth factor (PLGF or PGF), and platelet-derived growth factor B (PDGFB). Treatment with hsa-miR-9-5p did not impair the capacity of hCMEC/D3 to respond to tumour necrosis factor-α (TNF-α).Conclusionhsa-miR-9-5p reduces hCMEC/D3 cell proliferation and migration, and modulates the expression of angiogenic regulators such as VEGFC, PLGF, and PDGFB, without affecting TNF-α mediated activation of hCMEC/D3. This suggests that STB-EVs cargo hsa-miR-9-5p may selectively inhibit the proangiogenic capacity of brain endothelial cells. These findings enhance our understanding of cerebrovascular alterations in preeclampsia and may guide future studies and therapeutic interventions.
“Single-Nuclei Analysis of the Unfolded Protein Response (SNUPR) reveals bortezomib resistance mechanisms in Multiple Myeloma”
Authors: Gigan Julien P. , Garcia-Gonzalez Paulina , Galliot Lou , Reynaud Alexandre , Ghaffar Yoan , Flores-Santibáñez Felipe , Seillier Eve , Lavignolle-Heguy Rosario , Dos Santos Daniela Barros , Fischaux Sharon , Combes Alexis , Narita Miwako , Gatti Evelina , Nal Beatrice , Rocchi Stéphane , Moreaux Jerome , Pierre Philippe , Argüello Rafael J. 
Published: October 2024

AbstractThe unfolded protein response (UPR) is a key stress resistance pathway that has become a key potential target for improving the efficacy of cancer chemotherapy. The UPR involves the activation of three ER-resident stress sensors: PERK, IRE-1 and ATF6 with different signalling outcomes leading to cell death or survival. These cell-fate decisions are difficult to predict and are the result of the complex interaction of PERK, IRE-1 and ATF6 downstream events that have differences in their dynamics and their interplay. These characteristics of the UPR are still poorly defined due to lack of methods to monitor their activation simultaneously at single-cell level. We developed SNUPR (Single Nuclei analysis of the Unfolded Protein Response), an accessible technique that allows the profiling of the three UPR branches in nuclear suspensions by flow cytometry, and applied it to study UPR dynamics in a cancer-specific context. By performing transcriptomic analysis, we found that ER-stress sensor specific gene signatures correlate with patient survival in several blood malignancies, and by using SNUPR, we detected high heterogeneity during UPR activationin vitroin different human cancer cell lines, which could not be have been predicted by the level of expression of the sensors. Our SNUPR analyses further indicate that this heterogeneity is explained by variations in the intensity and duration of ER stress-induced protein synthesis inhibition via PERK, acting as upstream regulator of both the IRE-1/XBP1 and ATF6 dependent transcriptional programs. We extend the relevance of these observations by demonstrating that IRE-1/XBP1s pathway plays a critical role in bortezomib resistance of multiple myeloma cells and patients. We present here SNUPR, that can be used to monitor UPR dynamics with single-cell resolution and identified clinical contexts in which targeting a specific UPR branch could be detrimental or help circumventing chemotherapy resistance.One Sentence SummarySNUPR method enable single-cell UPR profiling and reveals the role of IRE-1 axis in predicting bortezomib resistance in multiple myeloma.HighlightsSNUPR allows simultaneous profiling of PERK, IRE-1 and ATF6 activation with single- cell resolution.Inhibition of protein synthesis via PERK control the activation levels of the IRE-1/XBP1s and ATF6 pathway.IRE-1 activation and associated transcriptional signatures predict the outcome of patients with multiple myeloma treated with Bortezomib.IRE-1 activity, but not PERK or ATF6, is essential to acquire bortezomib resistance in multiple myeloma cell lines.Graphical abstract
Comprehensive structure-function analysis reveals gain- and loss-of-function mechanisms impacting oncogenic KRAS activity
Authors: Kwon Jason J. , Dilly Julien , Liu Shengwu , Kim Eejung , Bian Yuemin , Dharmaiah Srisathiyanarayanan , Tran Timothy H. , Kapner Kevin S. , Ly Seav Huong , Yang Xiaoping , Rabara Dana , Waybright Timothy J. , Giacomelli Andrew O. , Hong Andrew L. , Misek Sean , Wang Belinda , Ravi Arvind , Doench John G. , Beroukhim Rameen , Lemke Christopher T. , Haigis Kevin M. , Esposito Dominic , Root David E. , Nissley Dwight V. , Stephen Andrew G. , McCormick Frank , Simanshu Dhirendra K. , Hahn William C. , Aguirre Andrew J. 
Published: October 2024

AbstractTo dissect variant-function relationships in the KRAS oncoprotein, we performed deep mutational scanning (DMS) screens for both wild-type and KRASG12Dmutant alleles. We defined the spectrum of oncogenic potential for nearly all possibleKRASvariants, identifying several novel transforming alleles and elucidating a model to describe the frequency ofKRASmutations in human cancer as a function of transforming potential, mutational probability, and tissue-specific mutational signatures. Biochemical and structural analyses of variants identified in a KRASG12Dsecond-site suppressor DMS screen revealed that attenuation of oncogenic KRAS can be mediated by protein instability and conformational rigidity, resulting in reduced binding affinity to effector proteins, such as RAF and PI3-kinases, or reduced SOS-mediated nucleotide exchange activity. These studies define the landscape of single amino acid alterations that modulate the function of KRAS, providing a resource for the clinical interpretation of KRAS variants and elucidating mechanisms of oncogenic KRAS inactivation for therapeutic exploitation.
Epigenetic control of Topoisomerase 1 activity presents a cancer vulnerability
Authors: Lee Tae-Hee , Qiao Colina X , Kuzin Vladislav , Shi Yuepeng , Ramanaranayan Vijayalalitha , Wu Tongyu , Zhou Xianzhen , Corujo David , Buschbeck Marcus , Baranello Laura , Oberdoerffer Philipp 
Published: October 2024

AbstractDNA transactions introduce torsional constraints that pose an inherent risk to genome integrity. While topoisomerase 1 (TOP1) activity is essential for removing DNA supercoiling, aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs) can result in cytotoxic DNA lesions. What protects genomic hot spots of topological stress from aberrant TOP1 activity remains unknown. Here, we identify chromatin context as an essential means to coordinate TOP1cc resolution. Through its ability to bind poly(ADP-ribose) (PAR), a protein modification required for TOP1cc repair, the histone variant macroH2A1.1 establishes a TOP1-permissive chromatin environment, while the alternatively spliced macroH2A1.2 isoform is unable to bind PAR or protect from TOP1ccs. By visualizing transcription-induced topological stress in single cells, we find that macroH2A1.1 facilitates PAR-dependent recruitment of the TOP1cc repair effector XRCC1 to protect from ssDNA damage. Impaired macroH2A1.1 splicing, a frequent cancer feature, was predictive of increased sensitivity to TOP1 poisons in a pharmaco-genomic screen in breast cancer cells, and macroH2A1.1 inactivation mirrored this effect. Consistent with this, low macroH2A1.1 expression correlated with improved survival in cancer patients treated with TOP1 inhibitors. We propose that macroH2A1 alternative splicing serves as an epigenetic modulator of TOP1-associated genome maintenance and a potential cancer vulnerability.
Angiogenic and Immune Predictors of Neoadjuvant Axitinib Response in Renal Cell Carcinoma with Venous Tumour Thrombus
Authors: Wray Rebecca , Paverd Hania , Machado Ines , Barbieri Johanna , Easita Farhana , Edwards Abigail R , Gallagher Ferdia A , Mendichovszky Iosif A , Mitchell Thomas J , de la Roche Maike , Shields Jaqueline D , Ursprung Stephan , Wallis Lauren , Warren Anne Y , Welsh Sarah J , Crispin-Ortuzar Mireia , Stewart Grant D , Jones James O 
Published: October 2024

ABSTRACTVenous tumour thrombus (VTT), where the primary tumour invades the renal vein and inferior vena cava, affects 10-15% of renal cell carcinoma (RCC) patients. Curative surgery for VTT is high-risk, but neoadjuvant therapy may improve outcomes. The NAXIVA trial demonstrated a 35% VTT response rate after 8 weeks of neoadjuvant axitinib, a VEGFR-directed therapy. However, understanding non-response is critical for better treatment. We conducted a multiparametric investigation of samples collected during NAXIVA using digital pathology, flow cytometry, plasma cytokine profiling and RNA sequencing. Responders had higher baseline microvessel density and increased induction of VEGF-A and PlGF during treatment. A multi-modal machine learning model integrating features predicted response with an AUC of 0.868, improving to 0.945 when using features from week 3. Key predictive features included plasma CCL17 and IL-12. These findings may guide future treatment strategies for VTT, improving the clinical management of this challenging scenario.One Sentence SummaryA comprehensive multiparametric assessment of the effect of neoadjuvant axitinib in renal cell carcinoma patients with venous tumour thrombus was performed on tissue and peripheral blood, including an integrative machine learning model, which identified both angiogenic and immune determinants of response to therapy.
Deep generalizable prediction of RNA secondary structure via base pair motif energy
Authors: Zhu Heqin , Tang Fenghe , Quan Quan , Chen Ke , Xiong Peng , Zhou S. Kevin 
Published: October 2024

AbstractRNA secondary structure plays essential roles in modeling RNA tertiary structure and further exploring the function of non-coding RNAs. Computational methods, especially deep learning methods, have demonstrated great potential and performance for RNA secondary structure prediction. However, the generalizability of deep learning models is a common unsolved issue in the situation of unseen out-of-distribution cases, which hinders the further improvement of accuracy and robustness of deep learning methods. Here we construct a base pair motif library which enumerates the complete space of locally adjacent three-neighbor base pair and records the thermodynamic energy of corresponding base pair motifs through de novo modeling of tertiary structures, and we further develop a deep learning approach for RNA secondary structure prediction, named BPfold, which employs hybrid transformer and convolutional neural network architecture and an elaborately designed base pair attention block to jointly learn representative features and relationship between RNA sequence and the energy map of base pair motif generated from the above motif library. Quantitative and qualitative experiments on sequence-wise datasets and family-wise datasets have demonstrated the great superiority of BPfold compared to other state-of-the-art approaches in both accuracy and generalizability. The significant performance of BPfold will greatly boost the development of deep learning methods for predicting RNA secondary structure and the further discovery of RNA structures and functionalities.
Trait matching without traits: using correspondence analysis to analyze the latent structure of interaction networks
Authors: Nicvert Lisa , Fritz Hervé , Dray Stéphane 
Published: October 2024

AbstractSpecies interactions occurring in ecological communities are often represented as networks. The structure of these networks is thought to be linked to species’ interaction niches (or Eltonian niches), which are intimately related to the notion of trait matching, which posits that a species interacts preferentially with partners whose traits are complementary to their own.Multivariate methods are commonly used to quantify species environmental niches (or Grinnellian niches). More recently, they have also been used to study the interaction niche, but these methods consider only the niche optimum and require trait data.In this paper, we use the correspondence analysis (CA) framework to study interaction networks and investigate trait matching without requiring traits data, using the notion of latent traits. We use reciprocal scaling, a method related to CA, to estimate niche optima and breadths, defined respectively as the mean and standard deviation of latent traits of interacting partners in CA space. We present the method, test its performance using a simulation model we designed, and analyze a real mutalistic bird-fruits interaction network.The simulation study shows that the method is able to recover niche breadths and optima for data generated with parameters values typical of ecological networks. The bird-fruit network analysis shows strong relationships between species niche optima and niche breadths: a posteriori correlation with species traits suggest that this latent structure is related to measured traits. In this network, birds and plants of intermediate size tend to have the widest niches and birds with pointed wings (preferentially foraging in the canopy) have smaller niches than birds with rounded wings (preferentially foraging in the understory).CA and reciprocal scaling are described as fruitful methods to characterize species interaction profiles, provide an ecologically meaningful graphical representation of interaction niches and allow to explore the effect of latent traits on network structure.
Structural Basis for Voltage Gating and Dalfampridine Binding in the Shaker Potassium Channel
Authors: Pinto-Anwandter Bernardo I 
Published: October 2024

AbstractThe generation and propagation of action potentials in neurons depend on the coordinated activation of voltage-dependent sodium and potassium channels. Potassium channels of the Shaker family regulate neuronal excitability through voltage-dependent opening and closing of their ion conduction pore. This family of channels is an important therapeutic target, particularly in multiple sclerosis where the inhibitor dalfampridine (4-aminopyridine) is used to improve nerve conduction. The molecular details of how the voltage sensor domain drives opening of the pore domain has been limited by the lack of closed-state structures, also impairing the search for novel drugs. Using AlphaFold2-based conformational sampling methods we identify a structural model for the closed Shaker potassium channel where movement of the voltage sensor drives the opening trough interactions between the S4-S5 linker and S6 helix. We show experimentally that breakage of a backbone hydrogen bond is a critical part of the activation pathway. Through docking we identify a hydrophobic cavity formed by the pore domain helices that binds dalfampridine in the closed state. Our results demonstrate how voltage sensor movement drives pore opening and provide a structural framework for developing new therapeutic agents targeting the closed state. We anticipate this work will enable structure-based drug design efforts focused on state-dependent modulation of voltage-gated ion channels for the treatment of neurological disorders.
CRISPR knockout of winter-biasedSUT4alters phenology, biomass accrual, and fertility of field-grown hybrid poplar
Authors: Tuma Trevor T. , McInnes Holly A. , Pham Hongduyen , Bewg William P. , Deguchi Michihito , Zhou Ran , Surber Samantha M. , Lipzen Anna , Barry Kerrie W. , Lieb Brent , Weber Wyneken Daniela L. , Harman-Ware Anne E. , Dahlen Joseph , Harding Scott A. , Tsai Chung-Jui 
Published: October 2024

AbstractWoody perennial trees annually transition between photoautotrophic and heterotrophic states. As carbohydrate accumulation and utilization patterns shift, so does the expression of genes encoding various sucrose-proton symporters (SUTs). The poplar genome contains fiveSUTgene family members involved in intracellular and long-distance sucrose transport. Among these, only the single-copySUT4and theSUT5/SUT6genome duplicates are expressed year-round, withSUT4strongly expressed in winter. Using CRISPR mutagenesis, we investigated the role of winter-expressedSUTsin carbohydrate allocation, biomass accrual, seasonal phenology, and sexual reproduction inPopulus tremula×P. albaunder field conditions. Insut4mutants, fall leaf senescence occurred earlier and spring bud flush was delayed compared to controls, resulting in reduced diameter and overall height growth. These mutants also exhibited altered sugar partitioning and reduced levels of raffinose family oligosaccharides, which are typically associated with cold and desiccation tolerance. Knockouts ofSUT5andSUT6, whether single or double, did not affect seasonal phenology or overall tree growth. All genotypes flowered precociously after two years in the field, butsut4catkins accumulated abnormally high levels of sucrose, galactinol, and raffinose. Transcriptome profiling showed down-regulation of genes associated with proanthocyanidin biosynthesis and vacuolar transport, and up-regulation of genes involved in protein oligomerization, misfolding, and refolding responses. Development ofsut4ovules was compromised, and no seeds were produced insut4catkins following controlled pollination. Our findings suggest that the single-copy tonoplast SUT4 may be more critical than other SUTs for mitigating stress associated with winter fitness and growth transitions during cool seasons.
Transcriptional profiling provides insights on sublethal thermal stress thresholds in juvenile bull trout
Authors: Best C. , Durhack T. C. , Chapelsky A. J. , Aminot M. , Islam S. S. , Heath D. D. , Mochnacz N. J. , Jeffries K. M. 
Published: October 2024

AbstractBull trout (Salvelinus confluentus) inhabit mainly cold-water streams in their Western North American range. Multiple anthropogenic stressors, including climate change, have caused population declines and range reduction, leading to classification of bull trout as threatened. Characterizing how fish respond to increasing temperature can identify key thresholds beyond which fish health is impacted, which is useful for developing species recovery strategies.Juvenile bull trout were acclimated to a range of relevant temperatures (6-21 °C), after which mRNA transcripts involved in responding to thermal stress were measured using high- throughput qPCR, and their upper thermal tolerance (critical thermal maximum,CTmax) was determined. Beyond 18 °C appears to be a critical sublethal threshold for bull trout: capacity to increaseCTmaxthrough acclimation was lost, growth and survival decreased, and transcriptional data suggest widespread activation of cellular stress and growth suppression. Below 18 °C, transcriptional data suggest subtler metabolic adjustments in response to acclimation temperature, preceding changes in whole-animal performance. Altogether, these data provide insight into thermal responses in bull trout, and their capacity to cope with climate-change related warming.