bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell and spatial transcriptome characterize coinhibitory cell-cell communications during histological progression of lung adenocarcinoma
Authors: Hui Liu , Gao Qianman , Luo Judong 
Published: June 2024

AbstractLung adenocarcinoma, a prevalent and lethal malignancy globally, is characterized by significant tumor heterogeneity and a complex tumor immune microenvironment during its histologic pattern progression. Understanding the intricate interplay between tumor and immune cells is of paramount importance as it could potentially pave the way for the development of effective therapeutic strategies for lung adenocar-cinoma. In this study, we run comparative analysis of the single-cell transcriptomic data derived from tumor tissues exhibiting four distinct histologic patterns, lepidic, papillary, acinar and solid, in lung adeno-carcinoma. Our analysis unveiled several co-inhibitory receptor-ligand interactions, including PD1-PDL1, PVR-TIGIT and TIGIT-NECTIN2, that potentially exert a pivotal role in recruiting immunosuppressive cells such as M2 macrophages and Tregs into LUAD tumor, thereby establishing immunosuppressive microenvironment and inducing T cells to exhaustion state. Furthermore, The expression level of these co-inhibitory factors, such as NECTIN2 and PVR, were strongly correlated with low immune infiltration, unfavorable patient clinical outcomes and limited efficacy of immunotherapy. Furthermore, we conducted immunofluorescence assay and spatial transcriptomic sequencing to validated the spatial co-localization of typical co-inhibitory factors. We believe this study provides valuable insights into the heterogeneity of molecular, cellular interactions leading to immunosuppressive microenvironment during the histological progression of lung adenocarcinoma. The findings could facilitate the development of novel immunotherapy for lung cancer.
EuDockScore: euclidean graph neural networks for scoring protein-protein interfaces
Authors: McFee Matthew , Kim Jisun , Kim Philip M. 
Published: June 2024

AbstractProtein-protein interactions are essential for a variety of biological phenomena including mediating bio-chemical reactions, cell signaling, and the immune response. Proteins seek to form interfaces which reduce overall system energy. Although determination of single polypeptide chain protein structures has been revolutionized by deep learning techniques, complex prediction has still not been perfected. Additionally, experimentally determining structures is incredibly resource and time expensive. An alternative is the technique of computational docking, which takes the solved individual structures of proteins to produce candidate interfaces (decoys). Decoys are then scored using a mathematical function that predicts the energy of the system, know as a scoring functions. Beyond docking, scoring functions are a critical component of assessing structures produced by many protein generative models. Scoring models are also used as a final filtering in many generative deep learning models including those that generate antibody binders, and those which perform docking. In this work we present improved scoring functions for protein-protein interactions which utilizes cutting-edge euclidean graph neural network architectures, to assess protein-protein interfaces. These euclidean docking score models are known as EuDockScore, and EuDockScore-Ab with the latter being antibody-antigen dock specific. Finally, we provided EuDockScore-AFM a model trained on antibody-antigen outputs from AlphaFold-Multimer which proves useful in re-ranking large numbers of AlphaFold-Multimer outputs. The code for these models is available athttps://gitlab.com/mcfeemat/eudockscore.
A structure-guided approach to predict MHC-I restriction of T cell receptors for public antigens
Authors: Gupta Sagar , Sgourakis Nikolaos G. 
Published: June 2024

AbstractPeptides presented by class I major histocompatibility complex (MHC-I) proteins provide biomarkers for therapeutic targeting using T cell receptors (TCRs), TCR-mimicking antibodies (TMAs), or other engineered protein binders. Despite the extreme sequence diversity of the Human Leucocyte Antigen (HLA, the human MHC), a given TCR or TMA is restricted to recognize epitopic peptides in the context of a limited set of different HLA allotypes. Here, guided by our analysis of 96 TCR:pHLA complex structures in the Protein Data Bank (PDB), we identify TCR contact residues and classify 148 common HLA allotypes into T-cell cross-reactivity groups (T-CREGs) on the basis of their interaction surface features. Insights from our work have actionable value for resolving MHC-I restriction of TCRs, guiding therapeutic expansion of existing therapies, and informing the selection of peptide targets for forthcoming immunotherapy modalities.
Plant cold acclimation and its impact on sensitivity of carbohydrate metabolism
Authors: Adler Stephan O. , Kitashova Anastasia , Bulović Ana , Nägele Thomas , Klipp Edda 
Published: June 2024

AbstractThe ability to acclimate to changing environmental conditions is essential for the fitness and survival of plants. Not only are seasonal differences challenging for plants growing in different habitats but, facing climate change, the likelihood of encountering extreme weather events increases. In order to better assess and respond to associated future challenges and risks it is important to understand the processes happening during acclimation. Previous studies of acclimation processes ofArabidopsis thalianato changes in temperature and light conditions have revealed a multigenic trait comprising and affecting multiple layers of molecular organization. Here, a combination of experimental and computational methods was applied to study the effects of changing light intensities during cold acclimation on the central carbon metabolism ofArabidopsis thalianaleaves. Mathematical modeling, simulation and sensitivity analysis predicted an important role of hexose phosphate balance for stabilization of photosynthetic CO2fixation. Experimental validation revealed a profound effect of temperature on the sensitivity of carbohydrate metabolism.
FDA-approved PDE4 inhibitors reduce the dominant toxicity of ALS–FTD-associatedCHCHD10S59L
Authors: Maitra Swati , Baek Minwoo , Choe Yun-Jeong , Kim Nam Chul 
Published: June 2024

ABSTRACTMutations in coiled-coil-helix-coiled-coil-helix domain containing 10(CHCHD10) have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivoDrosophilamodel expressing C2C10HS81L, and human cell models expressing CHCHD10S59L, we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10S59L. Evidences usingin vitro/ in vivogenetic and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10S59L-induced diseases. Therefore, we have investigated cellular pathways that can modulate the PINK1/Parkin pathway and reduce CHCHD10S59L-induced cytotoxicity. Here, we report that FDA-approved PDE4 inhibitors reduced CHCHD10S59L-induced morphological and functional mitochondrial defects in human cells and anin vivo Drosophilamodel expressing C2C10HS81L. Multiple PDE4 inhibitors decreased PINK1 accumulation and downstream mitophagy induced by CHCHD10S59L. These findings suggest that PDE4 inhibitors currently available in the market may be repositioned to treat CHCHD10S59L-induced ALS-FTD and possibly other related diseases.
Spatial localization of hippocampal replay requires dopamine signaling
Authors: Kleinman Matthew R. , Foster David J. 
Published: June 2024

AbstractSequenced reactivations of hippocampal neurons called replays, concomitant with sharp-wave ripples in the local field potential, are critical for the consolidation of episodic memory, but whether replays depend on the brain’s reward or novelty signals is unknown. Here we combined chemogenetic silencing of dopamine neurons in ventral tegmental area (VTA) and simultaneous electrophysiological recordings in dorsal hippocampal CA1, in freely behaving male rats experiencing changes to reward magnitude and environmental novelty. Surprisingly, VTA silencing did not prevent ripple increases where reward was increased, but caused dramatic, aberrant ripple increases where reward was unchanged. These increases were associated with increased reverse-ordered replays. On familiar tracks this effect disappeared, and ripples tracked reward prediction error, indicating that non-VTA reward signals were sufficient to direct replay. Our results reveal a novel dependence of hippocampal replay on dopamine, and a role for a VTA-independent reward prediction error signal that is reliable only in familiar environments.
An updated compendium and reevaluation of the evidence for nuclear transcription factor occupancy over the mitochondrial genome
Authors: Marinov Georgi K. , Ramalingam Vivekanandan , Greenleaf William J. , Kundaje Anshul 
Published: June 2024

AbstractIn most eukaryotes, mitochondrial organelles contain their own genome, usually circular, which is the remnant of the genome of the ancestral bacterial endosymbiont that gave rise to modern mitochondria. Mitochondrial genomes are dramatically reduced in their gene content due to the process of endosymbiotic gene transfer to the nucleus; as a result most mitochondrial proteins are encoded in the nucleus and imported into mitochondria. This includes the components of the dedicated mitochondrial transcription and replication systems and regulatory factors, which are entirely distinct from the information processing systems in the nucleus. However, since the 1990s several nuclear transcription factors have been reported to act in mitochondria, and previously we identified 8 human and 3 mouse transcription factors (TFs) with strong localized enrichment over the mitochondrial genome using ChIP-seq (Chromatin Immunoprecipitation) datasets from the second phase of the ENCODE (Encyclopedia of DNA Elements) Project Consortium. Here, we analyze the greatly expanded in the intervening decade ENCODE compendium of TF ChIP-seq datasets (a total of 6,153 ChIP experiments for 942 proteins, of which 763 are sequence-specific TFs) combined with interpretative deep learning models of TF occupancy to create a comprehensive compendium of nuclear TFs that show evidence of association with the mitochondrial genome. We find some evidence for chrM occupancy for 50 nuclear TFs and two other proteins, with bZIP TFs emerging as most likely to be playing a role in mitochondria. However, we also observe that in cases where the same TF has been assayed with multiple antibodies and ChIP protocols, evidence for its chrM occupancy is not always reproducible. In the light of these findings, we discuss the evidential criteria for establishing chrM occupancy and reevaluate the overall compendium of putative mitochondrial-acting nuclear TFs.
MetaPathways v3.5: Modularity and Scalability Improvements for Pathway Inference from Environmental Genomes
Authors: McLaughlin Ryan J. , Liu Tony X. , Altman Tomer , Nallan Aditi N. , Hahn Aria S. , Anstett Julia , Morgan-Lang Connor , Konwar Kishori M. , Hallam Steven J. 
Published: June 2024

AbstractOver the past decade MetaPathwayshas advanced as a modular pipeline for constructing environmental pathway genome databases (ePGDBs), increasing our understanding of microbial metabolism at the individual, population and community levels of biological organization. With this release, we have addressed several user experience issues related to installation, module integration, and database management. With a refactored code base, MetaPathwaysv3.5 enhances the user experience through streamlined installation via package indexes or containers, refined modules, and interface upgrades. It boasts updated algorithm support for sequence feature prediction, annotation, metabolic inference, and coverage metrics including genome resolved metagenomes. Tested and refined on synthetic datasets, MetaPathwaysv3.5 demonstrates improved performance and usability; facilitating more in-depth exploration of microbial interactions and metabolic functions in environmental genomes that scales with con-temporary sequencing throughput.Availability and ImplementationMetaPathwaysv3.5 is availableviaAnaconda, Docker, and Apptainer. The source code is available on BitBucket:https://bitbucket.org/BCB2/metapathways/The documentation is available via ReadTheDocs:https://metapathways.readthedocs.ioContactshallam@mail.ubc.ca
Convergent evolution of type I antifreeze proteins from four different progenitors in response to global cooling
Authors: Graham Laurie A. , Davies Peter L. 
Published: June 2024

AbstractThe alanine-rich, alpha-helical type I antifreeze proteins (AFPs) in fishes are thought to have arisen independently in the last 30 ma on at least four occasions. This hypothesis has recently been proven for the flounder and sculpin AFPs that both originated by gene duplication and divergence followed by substantial gene copy number expansion. Here we have examined the origins of the cunner (wrasse) and snailfish (liparid) AFPs. The cunner AFP has arisen by a similar route from the duplication and divergence of a GIMAP gene. The coding region for this AFP stems from an alanine-rich region flanking the GTPase domain of GIMAPa. The AFP gene has remained in the GIMAP gene locus and undergone amplification there along with some GIMAPa genes. The AFP gene originated after the cunner diverged from the common ancestor to the closely related spotty and ballan wrasses that have a similar gene synteny but are completely lacking the AFP genes. Snailfish AFPs have also recently evolved because they are confined to a single genus of this family. In these AFP-producing species the AFP locus does not share any similarity to functional genes. Instead, it is replete with repetitive DNAs and transposons several stretches of which could code for tracts of alanine with a dominant codon (GCC) that matches the bias seen in the AFP genes. All four known instances of type I AFPs occurring in fishes are independent evolutionary events that happened soon after the onset of northern hemisphere Cenozoic glaciation events. Collectively they provide a remarkable example of convergent evolution to one AFP type.
Haptic perception is contingent to hemispaces, not to hands
Authors: Hartcher-O’Brien Jess , Terekhov Alexander V. , Hayward Vincent 
Published: June 2024

AbsractIt is known that human haptic perception is lateralised, for example, object shape is felt differently according to the hand used to explore objects. Here we show that it is not the hand but the hemispace in which the exploring hand is located that determines differences in perception. This finding implies that our lateralised somatosensory processing depends on hand localisation in space rather than on the hand itself.
Elucidating key determinants of engineered scFv antibody in MMP-9 binding using high throughput screening and machine learning
Authors: Kalantar Masoud , Kalanther Ifthichar , Kumar Sachin , Buxton Elham Khorasani , Raeeszadeh-Sarmazdeh Maryam 
Published: June 2024

ABSTRACTAn imbalance in matrix metalloproteinase-9 (MMP-9) regulation can lead to numerous diseases, including neurological disorders, cancer, and pre-term labor. Engineering single-chain antibody fragments (scFvs) Targeting MMP-9 to develop novel therapeutics for such diseases is desirable. We screened a synthetic scFv antibody library displayed on the yeast surface for binding improvement to MMP-9 using FACS (fluorescent-activated cell sorting). The scFv antibody clones isolated after FACS showed improvement in binding to MMP-9 compared to the endogenous inhibitor. To understand molecular determinants of binding between engineered scFv antibody variants and MMP-9, next-generation DNA sequencing, and computational protein structure analysis were used. Additionally, a deep-learning language model was trained on the synthetic library to predict the binding of scFv variants using their CDR-H3 sequences.
Assessing the Stability of Photon-Counting CT: Insights from a Two-Year Longitudinal Study
Authors: Liu Leening P. , Pasyar Pouyan , Liu Fang , Cao Quy , Sandvold Olivia F. , Rybertt Martin V. , Sahbaee Pooyan , Shinohara Russell T. , Litt Harold I. , Noël Peter B. 
Published: June 2024

AbstractObjectiveAmong the advancements in computed tomography (CT) technology, photon-counting computed tomography (PCCT) stands out as a significant innovation, providing superior spectral imaging capabilities while simultaneously reducing radiation exposure. Its long-term stability is important for clinical care, especially longitudinal studies, but is currently unknown. This study sets out to comprehensively analyze the long-term stability of a first-generation clinical PCCT scanner.MethodsOver a two-year period, from November 2021 to November 2023, we conducted weekly identical experiments utilizing the same multi-energy CT protocol. Throughout this period, notable software and hardware modifications were meticulously recorded. Various tissue-mimicking inserts were scanned weekly to rigorously assess the stability of Hounsfield Units (HU) and image noise in Virtual Monochromatic Images (VMIs) and iodine density maps.ResultsSpectral results consistently demonstrated the quantitative stability of PCCT. VMIs exhibited stable HU values, such as variation in relative error for VMI 70 keV measuring 0.11% and 0.30% for single-source and dual-source modes, respectively. Similarly, noise levels remained stable with slight fluctuations linked to software changes for VMI 40 and 70 keV that corresponded to changes of 8 and 1 HU, respectively. Furthermore, iodine density quantification maintained stability and showed significant improvement with software and hardware changes, especially in dual-source mode with nominal errors decreasing from 1.44 to 0.03 mg/mL. Conclusion This study provides the first long-term reproducibility assessment of quantitative PCCT imaging, highlighting its potential for the clinical arena.Key PointsQuestion:Photon-counting CT (PCCT) provides critical spectral imaging for improved diagnostic accuracy, but its long-term quantitative stability over time is still unknown.Findings:The clinical PCCT system demonstrated stable Hounsfield Units (HU) and image noise over two years, ensuring reliable quantitative imaging and improving diagnostic accuracy.Clinical Relevance:This study showcased the exceptional value of PCCT in diagnostic radiology, particularly for its application in longitudinal studies.
Deconvoluting synovial fluid molecular endotypes in knee osteoarthritis: primary results from the STEpUP OA Consortium
Authors: Perry T.A. , Deng Y. , Hulley P. , Maciewicz R.A. , Mitchelmore J. , Larsson S. , Gogain J. , Brachat S. , Struglics A. , Appleton C.T. , Kluzek S. , Arden N.K. , Price A.J. , Felson D. , Bondi L. , Kapoor M. , Lohmander L.S. , Welting T.J. , Walsh D.A. , Valdes A.M. ,   the STEpUP OA Consortium, Jostins-Dean L. , Watt F.E. , Tom B.D.M. , Vincent T.L. 
Published: June 2024

ABSTRACTBackgroundOsteoarthritis (OA) has a lifetime risk of over 40%, imposing a huge societal burden. Clinical variability suggests that it could be more than one disease.Synovial fluidTo detectEndotypes byUnbiasedProteomics in OA (STEpUP OA) was established to test the hypothesis that there are detectable distinct molecular endotypes in knee OA.MethodsOA knee synovial fluid (SF) samples (N=1361) were from pre-existing OA cohorts with cross-sectional clinical (radiographic and pain) data. Samples were divided into Discovery (N = 708) and Replication (N=653) datasets. Proteomic analysis was performed using SomaScan V4.1 assay (6596 proteins). Unsupervised clustering was performed using k-means, assessed using the f(k) metric, with and without adjustments for potential confounders. Regression analyses were used to assess protein associations with radiographic (Kellgren and Lawrence) and knee pain (WOMAC pain), with and without stratification by body mass index (BMI) or biological sex. Adjustments were made for cohort (random intercept) or intracellular protein, using an intracellular protein score (IPS). Analyses were carried out in R according to a pre-published plan.ResultsNo distinct SF molecular endotypes were identified in OA but two indistinct clusters were defined in non-IPS regressed data which were stable across subgroup analyses. Clustering was lost after IPS regression adjustment. Strong, replicable protein associations were observed with radiographic disease severity, which were retained after adjustment for cohort or IPS. Pathway analysis identified a strong “epithelial to mesenchymal transition (EMT)” pathway, and weaker associations with “angiogenesis”, “complement” and “coagulation”. The latter were variably lost after adjustment for BMI or biological sex. Associations with patient reported pain were weaker.ConclusionThese data support knee OA as a biologically continuous disease in which disease severity is associated with a strong, robust, tissue remodelling signature. Subtle differences were found in pathways after stratification by BMI or sex.
Eicosapentaenoic acid and Arachidonic acid Protection Against Left Ventricle Pathology: the Multi-Ethnic Study of Atherosclerosis
Authors: Shearer Gregory C. , Block Robert C. , Huang Shue , Liu Linxi , Herrington David M. , Tsai Michael Y. , Tintle Nathan , O’Connell Timothy D. 
Published: June 2024

ABSTRACTBackgroundWe have shown that ω3 polyunsaturated fatty acids (PUFAs) reduce risk for heart failure, regardless of ejection fraction status. Ventricular remodeling and reduced ventricular performance precede overt hear failure, however there is little insight into how PUFAs contribute to maladaptive signaling over time. PUFAs are agonists for regulatory activity at g-protein coupled receptors such as Ffar4, and downstream as substrates for monooxygenases (e.g lipoxygenase, cytochrome p450, or cyclooxygenase (COX)) which mediate intracellular adaptive signaling.MethodsPlasma phospholipid PUFA abundance at Exam 1 as mass percent EPA, DHA, and arachidonic acid (AA) from the Multi-Ethnic Study of Atherosclerosis (MESA) were evaluated using pathway modeling to determine the association with time-dependent changes in left ventricular (LV) mass (LVM), end-diastolic LV volume (EDV), and end-systolic volume (ESV) measured by cardiac MRI at Exams 1 and 5. Ejection fraction (EF) and mass:volume (MV) were calculated posteriorly from the first three.Results2,877 subjects had available MRI data. Participants with low AA and EPA had accelerated age-dependent declines in LVM. Males with low AA and EPA also had accelerated declines in EDV, but among females there was no PUFA association with EDV declines and exam 5 EDV status was positively associated with AA. Both sexes had nearly the same positive association of AA with changes in ESV.ConclusionPlasma phospholipid AA and EPA are prospectively associated with indices of heart remodeling, including ventricular remodeling and performance. Combined AA and EPA scarcity was associated with the most accelerated age-related changes and exam 5 status, while the greatest benefits were found among participants with both PUFAs. This suggests that both PUFAs are required for optimal slowing of age-related declines in ventricular function.