bluuebunny/crossref_metadata_2025_split huggingface dataset:
Arterial spin labelling perfusion MRI analysis for the Human Connectome Project Lifespan Ageing and Development studies
Authors: Kirk Thomas F. , Kennedy McConnell Flora A. , Toner Jack , Craig Martin S. , Carone Davide , Li Xiufeng , Suzuki Yuriko , Coalson Timothy S. , Harms Michael P. , Glasser Matthew F. , Chappell Michael A. 
Published: September 2024

AbstractThe Human Connectome Project Lifespan studies cover the Development (5-21) and Aging (36-100+) phases of life. Arterial spin labelling (ASL) was included in the imaging protocol, resulting in one of the largest datasets collected to-date of high spatial resolution multiple delay ASL covering 3,000 subjects. The HCP-ASL minimal processing pipeline was developed specifically for this dataset to pre-process the image data and produce perfusion estimates in both volumetric and surface template space. Applied to the whole dataset, the outputs of the pipeline revealed significant and expected differences in perfusion between the Development and Ageing cohorts. Visual inspection of the group average surface maps showed that cortical perfusion often followed cortical areal boundaries, suggesting differential regulation of cerebral perfusion within brain areas at rest. Group average maps of arterial transit time also showed differential transit times in core and watershed areas of the cerebral cortex, which are useful for interpreting haemodynamics of functional MRI images. The pre-processed dataset will provide a valuable resource for understanding haemodynamics across the human lifespan.
Constitutive expression of IκBζ promotes tumor growth and immunotherapy resistance in melanoma
Authors: Kolb Antonia , Kulis-Mandic Ana-Marija , Klein Matthias , Stastny Anna , Haist Maximilian , Weidenthaler-Barth Beate , Sinnberg Tobias , Sucker Antje , Allies Gabriele , Albrecht Lea Jessica , Tasdogan Alpaslan , Tuettenberg Andrea , Stege Henner , Schadendorf Dirk , Grabbe Stephan , Schulze-Osthoff Klaus , Kramer Daniela 
Published: September 2024

AbstractBackgroundIκBζ, a rather unknown co-regulator of NF-κB, is mostly inducibly expressed and can either activate or repress a specific subset of NF-κB target genes. While its role as a transcriptional regulator of various cytokines and chemokines in immune cells has been revealed, IκBζ’s function in solid cancer remains unclear.MethodsWe investigated IκBζ expression in melanoma, and assessed its impact on target gene expression, tumor growth, and response to immunotherapy in melanoma cell lines, mouse models, and patient samples.ResultsUnlike in other cell types, IκBζ protein was found to be constitutively expressed in a subfraction of melanoma cell lines, and around 35% of melanoma cases. This atypical expression pattern of IκBζ did not correlate with its mRNA levels or known driver mutations, but instead seemed to result from changes in its post-transcriptional or post-translational regulation. Deleting constitutively expressed IκBζ abrogated the activity and chromatin association of STAT3 and p65, leading to reduced expression of the pro-proliferative cytokines IL-1β and IL-6 in melanoma cells. Consequently, loss of tumor-derived IκBζ suppressed self-sustained melanoma cell growth bothin vitroandin vivo. Additionally, constitutive IκBζ expression suppressed the induction of the chemokinesCXCL9,CXCL10, andCCL5, which impaired the recruitment of NK and CD8+T-cells to the tumor, causing resistance to α-PD-1 immunotherapy in mice. Furthermore, the expression of tumor-derived IκBζ also correlated with the absence of CD8+T-cells in human melanoma samples and progressive disease during immunotherapy.ConclusionWe propose that tumor-derived IκBζ could serve as a new therapeutic target and prognostic marker that characterizes melanoma with high tumor cell proliferation, cytotoxic T- and NK-cell exclusion, and unfavorable immunotherapy responses. Targeting IκBζ expression might open up a new therapy option to re-establish the recruitment of cytotoxic cells, thereby resensitizing for immunotherapy.Graphical Abstract
Cardiovascular Disease-Associated Non-Coding Variants Disrupt GATA4-DNA Binding and Regulatory Functions
Authors: Peña-Martínez Edwin G. , Messon-Bird Jean L. , Rodríguez-Ríos Jessica M. , Velázquez-Roig Rosalba , Pomales-Matos Diego A. , Rivera-Madera Alejandro , Sanabria-Alberto Leandro , Barreiro-Rosario Adriana C. , Valle Jeancarlos Rivera-Del , Muñoz-Páez Nicole E. , Peterson-Peguero Esther A. , Rodríguez-Martínez José A. 
Published: September 2024

AbstractGenome-wide association studies have mapped over 90% of cardiovascular disease (CVD)-associated variants within the non-coding genome. Non-coding variants in regulatory regions of the genome, such as promoters, enhancers, silencers, and insulators, can alter the function of tissue-specific transcription factors (TFs) proteins and their gene regulatory function. In this work, we used a computational approach to identify and test CVD-associated single nucleotide polymorphisms (SNPs) that alter the DNA binding of the human cardiac transcription factor GATA4. Using a gapped k-mer support vector machine (GKM-SVM) model, we scored CVD-associated SNPs localized in gene regulatory elements in expression quantitative trait loci (eQTL) detected in cardiac tissue to identify variants altering GATA4-DNA binding. We prioritized four variants that resulted in a total loss of GATA4 binding (rs1506537 and rs56992000) or the creation of new GATA4 binding sites (rs2941506 and rs2301249). The identified variants also resulted in significant changes in transcriptional activity proportional to the altered DNA-binding affinities. In summary, we present a comprehensive analysis comprised of in silico, in vitro, and cellular evaluation of CVD-associated SNPs predicted to alter GATA4 function.Graphical AbstractHighlightsAn integrative computational approach combining functional genomics data and machine learning was implemented to prioritize potential causal genetic variants associated with cardiovascular disease (CVD).We prioritized and validated CVD-associated SNPs that created or destroyed genomic binding sites of the cardiac transcription factor GATA4.Changes in GATA4-DNA binding resulted in significant changes in GATA4-dependent transcriptional activity in human cells.Our results contribute to the mechanistic understanding of cardiovascular disease-associated non-coding variants impacting GATA4 function.
habtools: an R package to calculate 3D metrics for surfaces and objects
Authors: Schiettekatte Nina , Asbury Mollie , Chen Guan-Yan , Dornelas Maria , Reichert Jessica , Torres-Pulliza Damaris , Zawada Kyle J.A. , Madin Joshua S. 
Published: September 2024

AbstractTechnological advances in three-dimensional imaging techniques have opened the door to advanced morphological analyses and habitat mapping for biologists and ecologists.At the same time, the challenge of translating complex 3D data into meaningful metrics that can be used in conjunction with biological data currently hinders progress and accessibility.We introducehabtools, an R package that provides R functions to efficiently calculate complexity and shape metrics from DEMs, 3D meshes and 2D shapes as well as some helper functions to facilitate workflow.We expect the functionality ofhabtoolsto continue to expand as new metrics and faster methods become available, and welcome new contributions and ideas.
Proteomic analysis of papillary thyroid carcinoma in the context of Hashimoto’s thyroiditis
Authors: Zhou Hui , Sun Hui , Iqbal Muhammad Asad , Zhao Ziou , Hou Jie , Wang Xian , Pan Donggang 
Published: September 2024

AbstractObjectiveTo analyze the proteomic characteristics of papillary thyroid carcinoma in the context of Hashimoto’s thyroiditis by mass spectrometry and screen the corresponding differential proteins.MethodsPostoperative paraffin specimens of 3 patients with Hashimoto’s thyroiditis combined with papillary thyroid carcinoma and 3 patients with Hashimoto’s thyroiditis and benign nodules were collected. The differential proteins were obtained by qualitative and quantitative analysis using Q ExactiveTM mass spectrometer. Functional enrichment cluster analysis and protein interaction analysis were then performed on these differential proteins. Finally, key proteins were screened out and immunohistochemical verification was performed.Results72 up-regulated differentially expressed proteins and 21 down-regulated differentially expressed proteins were screened out. THBS2 and COL12A1 were further identified by bioinformatics analysis. After immunohistochemical verification, it was concluded that COL12A1 can be used as a specific tumor marker.ConclusionThere are differentially expressed proteins between the Hashimoto’s thyroiditis combined with papillary thyroid carcinoma group and the Hashimoto’s thyroiditis combined with benign nodules group. The up-regulated expression of COL12A1 can become an auxiliary diagnostic marker for papillary thyroid carcinoma with Hashimoto’s thyroiditis.
AsaruSim: a single-cell and spatial RNA-Seq Nanopore long-reads simulation workflow
Authors: Hamraoui Ali , Jourdren Laurent , Thomas-Chollier Morgane 
Published: September 2024

AbstractMotivationThe combination of long-read sequencing technologies like Oxford Nanopore with single-cell RNA sequencing (scRNAseq) assays enables the detailed exploration of transcriptomic complexity, including isoform detection and quantification, by capturing full-length cDNAs. However, challenges remain, including the lack of advanced simulation tools that can effectively mimic the unique complexities of scRNAseq long-read datasets. Such tools are essential for the evaluation and optimization of isoform detection methods dedicated to single-cell long read studies.ResultsWe developed AsaruSim, a workflow that simulates synthetic single-cell long-read Nanopore datasets, closely mimicking real experimental data. AsaruSim employs a multi-step process that includes the creation of a synthetic UMI count matrix, generation of perfect reads, optional PCR amplification, introduction of sequencing errors, and comprehensive quality control reporting. Applied to a dataset of human peripheral blood mononuclear cells (PBMCs), AsaruSim accurately reproduced experimental read characteristics.Availability and implementationThe source code and full documentation are available at:https://github.com/GenomiqueENS/AsaruSim.Data availabilityThe 1,090 Human PBMCs count matrix and cell type annotation files are accessible on zenodo under DOI: 10.5281/zenodo.12731408.
The Role of ATP Synthase Subunit e (ATP5I) in Mediating the Metabolic and Antiproliferative Effects of Biguanides
Authors: Lefrançois Guillaume , Lavallée Emilie , Rowell Marie-Camille , Bourdeau Véronique , Mohebali Farzaneh , Berthomeu Thierry , Tyers Mike , Gravel Simon-Pierre , Schmitzer Andréea R. , Ferbeyre Gerardo 
Published: September 2024

AbstractHere we identify the subunit e of F1Fo-ATP synthase (ATP5I) as a target of medicinal biguanides. ATP5I maintains the stability of F1Fo-ATP synthase dimers which is crucial for shaping cristae morphology. Although its roles have been mainly studied in yeast models, its function in cellular energy metabolism within the context of cancer remains poorly characterized. In this study, we demonstrate that ATP5I interacts with a biguanide analoguein vitroand disabling its expression by CRISPR-Cas9 in pancreatic cancer cells leads to the same phenotype as biguanide treated cells including a decrease in the levels of some respiratory complex subunits, mitochondrial morphology alterations, inhibition of oxidative phosphorylation (OXPHOS) and a compensatory increase in glycolysis. Moreover, ATP5I knockout (KO) cells exhibit resistance to the antiproliferative effects of biguanides, but reintroduction of ATP5I rescues the metabolic and anti-proliferative effects of metformin and phenformin. These findings highlight ATP5I as a significant antineoplastic mitochondrial target of medicinal biguanides, opening new opportunities for the development of mitochondrial-targeted therapies.
Comparative analysis of protein expression between oesophageal adenocarcinoma and normal adjacent tissue
Authors: Nicholas Ben , Bailey Alistair , McCann Katy J , Walker Robert C. , Johnson Peter , Elliott Tim , Underwood Tim J. , Skipp Paul 
Published: September 2024

AbstractOesophageal adenocarcinoma (OAC) is the 7th most common cancer in the United Kingdom and remains a significant health challenge. This study presents a proteomic analysis of seven OAC donors complementing our previous neoantigen identification study of their human leukocyte antigen (HLA) immunopeptidomes. Using label-free mass spectrometry proteomics, we compared OAC tumour tissue to matched normal adjacent tissue (NAT) to identify differentially expressed proteins.We identified differential expression of a number of proteins previously linked to OAC and other cancers. We observed enrichment of processes and pathways relating RNA processing and the immune system. Our findings also offer insight into the role of the protein stability in the generation of the neoantigen we previously identified. These results provide independent corroboration of existing oesophageal adenocarcinoma biomarker studies that may inform future diagnostic and therapeutic research.
Safeguarding Privacy in Genome Research: A Comprehensive Framework for Authors
Authors: Ghasemian Maryam , Gerido Lynette Hammond , Ayday Erman 
Published: September 2024

AbstractAs genomic research continues to advance, sharing of genomic data and research outcomes has become increasingly important for fostering collaboration and accelerating scientific discovery. However, such data sharing must be balanced with the need to protect the privacy of individuals whose genetic information is being utilized. This paper presents a bidirectional framework for evaluating privacy risks associated with data shared (both in terms of summary statistics and research datasets) in genomic research papers, particularly focusing on re-identification risks such as membership inference attacks (MIA). The framework consists of a structured workflow that begins with a questionnaire designed to capture researchers’ (authors’) self-reported data sharing practices and privacy protection measures. Responses are used to calculate the risk of re-identification for their study (paper) when compared with the National Institutes of Health (NIH) genomic data sharing policy. Any gaps in compliance help us to identify potential vulnerabilities and encourage the researchers to enhance their privacy measures before submitting their research for publication. The paper also demonstrates the application of this framework, using published genomic research as case study scenarios to emphasize the importance of implementing bidirectional frameworks to support trustworthy open science and genomic data sharing practices.
Structural and dynamic consequences of inosine, 2′-O-methylation, and N6-methyladenosine modifications in RNA G-quadruplex: A molecular dynamics study
Authors: Dutta Nivedita , Deb Indrajit , Sarzynska Joanna , Lahiri Ansuman 
Published: September 2024

AbstractRNA G-quadruplexes (rG4) are stable non-canonical structures, often found to regulate important biological processes such as transcription, translation, splicing, RNA localization, and other steps in gene expression. rG4 structures can also influence DNA-related processes e.g. DNA replication, telomere elongation and homeostasis, and recombination. Due to the involvement of rG4s in such important processes, these structures are potential therapeutic targets against different diseases e.g., viral infection and cancer. Hence, a better understanding of the structure and stability of rG4s and their role in various therapeutically important cellular processes can help in the design of effective therapeutic strategies for targeting such structures. In the present study, we present our findings on the structural and dynamic effect of RNA modifications (inosine; 2′-O-methylation, and m6A-methylation) on RNA G-quadruplex structure from molecular dynamics simulations. Additionally, we also report the dynamic and energetic aspects of inter-quadruplex interactions and the influence of non-G purine tetrads neighboring the inter-quadruplex junction on the interactions.
Efficacy and Safety of Acupuncture for Acute Gouty Arthritis: A Systematic Review and Network Meta-Analysis
Authors: Cai Yuxiao , Liu Yifan , Kang Qinglong , Zhu Shiji , Wang Qianqian , Sun Chunmei , Gu Yin 
Published: September 2024

AbstractAcute gouty arthritis (AGA) severely affects the quality of life of patients due to its persistent, recurrent, and debilitating characteristics. Acupuncture holds a pivotal role as a classical alternative therapy in managing gouty arthritis. This study aimed to assess the clinical effectiveness of various acupuncture methods used in conjunction with conventional medications for treating acute gouty arthritis. We conducted a search of seven English and Chinese databases up to February 10, 2024, and analyzed the data using R software version 4.4.0.The study included a total of 37 randomized controlled trials(RCT), encompassing 2,801 patients. The network meta-analysis (NMA) results are as follows: Fire acupuncture demonstrated the highest effectiveness in improving cure rates. Acupuncture combined with conventional medication was found to be the most effective for reducing VAS scores. Additionally, Acupuncture combined with conventional medication proved most effective in lowering uric acid levels. For reducing ESR, the combination of blood-letting therapy and conventional drugs showed the greatest efficacy. No statistically significant differences were found among the different interventions regarding the reduction of TCMSS and CRP levels. In conclusion, fire acupuncture showed the greatest overall effectiveness. Acupuncture with conventional medication best reduced VAS scores and uric acid levels, while blood-letting therapy combined with conventional drugs was most effective in lowering ESR.
Prediction and design of transcriptional repressor domains with large-scale mutational scans and deep learning
Authors: Valbuena Raeline , Nigam AkshatKumar , Tycko Josh , Suzuki Peter , Spees Kaitlyn , Aradhana  , Arana Sophia , Du Peter , Patel Roshni A. , Bintu Lacramiora , Kundaje Anshul , Bassik Michael C. 
Published: September 2024

AbstractRegulatory proteins have evolved diverse repressor domains (RDs) to enable precise context-specific repression of transcription. However, our understanding of how sequence variation impacts the functional activity of RDs is limited. To address this gap, we generated a high-throughput mutational scanning dataset measuring the repressor activity of 115,000 variant sequences spanning more than 50 RDs in human cells. We identified thousands of clinical variants with loss or gain of repressor function, including TWIST1 HLH variants associated with Saethre-Chotzen syndrome and MECP2 domain variants associated with Rett syndrome. We also leveraged these data to annotate short linear interacting motifs (SLiMs) that are critical for repression in disordered RDs. Then, we designed a deep learning model called TENet (TranscriptionalEffectorNetwork) that integrates sequence, structure and biochemical representations of sequence variants to accurately predict repressor activity. We systematically tested generalization within and across domains with varying homology using the mutational scanning dataset. Finally, we employed TENet within a directed evolution sequence editing framework to tune the activity of both structured and disordered RDs and experimentally test thousands of designs. Our work highlights critical considerations for future dataset design and model training strategies to improve functional variant prioritization and precision design of synthetic regulatory proteins.
MAX inactivation deregulates the MYC network and induces neuroendocrine neoplasia in multiple tissues
Authors: Freie Brian , Ibrahim Ali H. , Carroll Patrick A. , Bronson Roderick T , Augert Arnaud , MacPherson David , Eisenman Robert N. 
Published: September 2024

AbstractThe MYC transcription factor requires MAX for DNA binding and widespread activation of gene expression in both normal and neoplastic cells. Surprisingly, inactivating mutations inMAXare associated with a subset of neuroendocrine cancers including pheochromocytoma, pituitary adenoma and small cell lung cancer. Neither the extent nor the mechanisms of MAX tumor suppression are well understood. DeletingMaxacross multiple mouse neuroendocrine tissues, we findMaxinactivation alone produces pituitary adenomas whileMaxloss cooperates withRb1/Trp53loss to accelerate medullary thyroid C-cell and pituitary adenoma development. In the thyroid tumor cell lines, MAX loss triggers a striking shift in genomic occupancy by other members of the MYC network (MNT, MLX, MondoA) supporting metabolism, survival and proliferation of neoplastic neuroendocrine cells. Our work reveals MAX as a broad suppressor of neuroendocrine tumorigenesis through its ability to maintain a balance of genomic occupancies among the diverse transcription factors in the MYC network.TeaserMAXinactivation deregulates multiple transcription factors to induce neuroendocrine cancers
Assessment of the relationship between synaptic density and metabotropic glutamate receptors in early Alzheimer’s disease: a multi-tracer PET study
Authors: Salardini Elaheh , O’Dell Ryan S. , Tchorz Em , Nabulsi Nabeel B. , Huang Yiyun , Carson Richard E. , van Dyck Christopher H. , Mecca Adam P. 
Published: September 2024

AbstractBackgroundThe pathological effects of amyloid β oligomers (Aβo) may be mediated through the metabotropic glutamate receptor subtype 5 (mGluR5), leading to synaptic loss in Alzheimer’s disease (AD). Positron emission tomography (PET) studies of mGluR5 using [18F]FPEB indicate a reduction of receptor binding that is focused in the medial temporal lobe in AD. Synaptic loss due to AD measured through synaptic vesicle glycoprotein 2A (SV2A) quantification with [11C]UCB-J PET is also focused in the medial temporal lobe, but with clear widespread reductions is commonly AD-affected neocortical regions. In this study, we used [18F]FPEB and [11C]UCB-J PET to investigate the relationship between mGluR5 and synaptic density in early AD.MethodsFifteen amyloid positive participants with early AD and 12 amyloid negative, cognitively normal (CN) participants underwent PET scans with both [18F]FPEB to measure mGluR5 and [11C]UCB-J to measure synaptic density. ParametricDVRimages using equilibrium methods were generated from dynamic. For [18F]FPEB PET,DVRwas calculated using equilibrium methods and a cerebellum reference region. For [11C]UCB-J PET,DVRwas calculated with a simplified reference tissue model – 2 and a whole cerebellum reference region.ResultA strong positive correlation between mGluR5 and synaptic density was present in the hippocampus for participants with AD (r= 0.81,p< 0.001) and in the CN group (r= 0.74,p= 0.005). In the entorhinal cortex, there was a strong positive correlation between mGluR5 and synaptic in the AD group (r= 0.85,p<0.001), but a weaker non-significant correlation in the CN group (r= 0.36,p= 0.245). Exploratory analyses within and between other brain regions suggested significant positive correlations between mGluR5 in the medial temporal lobe and synaptic density in a broader set of commonly AD-affected regions.ConclusionMedial temporal loss of mGluR5 in AD is associated with synaptic loss in both medial temporal regions and more broadly in association cortical regions, indicating that mGluR5 mediated Aβo toxicity may lead to early synaptic loss more broadly in AD-affected networks. In CN individuals, an isolated strong association between lower mGluR5 and lower synaptic density may indicate non-AD related synaptic loss.