bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alignment of multiple protein sequences without using amino acid frequencies
Authors: Shelyekhova Veronika , Shirokov Roman 
Published: June 2024

AbstractCurrent algorithms for aligning protein sequences use substitutability scores that combine the probability to find an amino acid in a specific pair of amino acids and marginal probability to find this amino acid in any pair. However, the positional probability of finding the amino acid at a place in alignment is also conditional on the amino acids at the sequence itself. Content-dependent corrections overparameterize protein alignment models. Here, we propose an approach that is based on (dis)similarily measures, which do not use the marginal probability, and score only probabilities of finding amino acids in pairs. The dissimilarity scoring matrix endows a metric space on the set of aligned sequences. This allowed us to develop new heuristics. Our aligner does not use guide trees and treats all sequences uniformly. We suggest that such alignments that are done without explicit evolution-based modeling assumptions should be used for testing hypotheses about evolution of proteins (e.g., molecular phylogenetics).
A nanobody-enzyme fusion protein targeting PD-L1 and sialic acid exerts anti-tumor effects by affecting tumor associated macrophages
Authors: Tong Yongliang , Chen Runqiu , Lu Xinrong , Chen Cuiying , Sun Guiqin , Yu Xiaolu , Lyu Shaoxian , Feng Meiqing , Long Yiru , Gong Likun , Chen Li 
Published: June 2024

AbstractCancer cells employ various mechanisms to evade immune surveillance. Their surface features, including a protective “sugar coat” and immune checkpoints like PD-L1 (programmed death ligand 1), can impede immune cell recognition. Sialic acids, which carry negative charges, may hinder cell contact through electrostatic repulsion, while PD-L1 transmits immunosuppressive signals to T cells. Furthermore, cancer cells manipulate macrophages within the tumor microenvironment to facilitate immune escape. Prior research has demonstrated the effectiveness of separately blocking the PD-L1 and sialic acid pathways in eliciting anti-tumor effects. In this study, we investigated the relationship between PD-L1 expression and genes associated with sialic acid in clinical databases. Subsequently, we developed a novel nanobody enzyme fusion protein termed Nb16-Sia to simultaneously target both PD-L1 and sialic acid pathways. In vivo experiments confirmed the anti-tumor activity of Nb16-Sia and highlighted its dependence on macrophages. Further investigations revealed that Nb16-Sia could polarize macrophages towards the M1 phenotype through the C-type lectin pathway in vitro and eliminate tumor-associated macrophages in vivo. In conclusion, our findings demonstrate that the fusion of PD-L1 nanobody with sialidase effectively targets tumor-associated macrophages, resulting in significant anti-tumor effects. This approach holds promise for drug development aimed at enhancing immune responses against cancer.
An organoid platform reveals MEK-PARP co-targeting to enhance radiation response in rectal cancer
Authors: Xiao Qiyun , Riedesser Julian E. , Mulholland Theresa , Li Zhenchong , Buchloh Jonas , Albrecht Philipp , Li Moying , Venkatachalam Nachiyappan , Skabkina Olga , Klupsch Anna , Eichhorn Ella , Wang Li , Belle Sebastian , Schulte Nadine , Schmitz Daniel , Froelich Matthias F. , Valentini Erica , Boonekamp Kim E. , Petersen Yvonne , Miersch Thilo , Burgermeister Elke , Herskind Carsten , Veldwijk Marlon R. , Brochhausen Christoph , Ihnatko Robert , Krijgsveld Jeroen , Kurth Ina , Boutros Michael , Ebert Matthias P. , Zhan Tianzuo , Betge Johannes 
Published: June 2024

AbstractLocally advanced rectal cancer is usually treated by neoadjuvant chemoradiotherapy. However, tumor response rates to this treatment vary greatly. Thus, most patients do not reach a complete remission and have to undergo tumor resection. In the present study, we introduce a patient-derived rectal cancer organoid platform that reflects clinical radiosensitivity and use this to screen 1596 drug-radiation combinations. We identify inhibitors of RAS-MAPK signaling, especially MEK inhibitors, strongly synergizing with radiation response. Mechanistically, MEK inhibitors suppressed radiation-induced activation of RAS-MAPK signaling, and selectively downregulated the homologous recombination DNA repair pathway component RAD51, thereby achieving radio-enhancement. Through testing drug-drug-radiation combinations in organoids and cell lines, we identified synergism between PARP and MEK inhibitors to further enhance the effect of radiation. Our data support clinical testing of combined MEK and PARP inhibition with radiotherapy in locally advanced rectal cancers.Graphical Abstract
Comprehensive multimodal and multiomic profiling reveals epigenetic and transcriptional reprogramming in lung tumors
Authors: Wu Peiyao , Liu Zhengzhi , Zheng Lina , Zhou Zirui , Wang Wei , Lu Chang 
Published: June 2024

AbstractEpigenomic mechanisms are critically involved in mediation of genetic and environmental factors that underlie cancer development. Histone modifications represent highly informative epigenomic marks that reveal activation and repression of gene activities and dysregulation of transcriptional control due to tumorigenesis. Here, we present a comprehensive epigenomic and transcriptomic mapping of 18 tumor and 20 non-neoplastic tissues from non-small cell lung adenocarcinoma patients. Our profiling covers 5 histone marks including activating (H3K4me3, H3K4me1, and H3K27ac) and repressive (H3K27me3 and H3K9me3) marks and the transcriptome using only 20 mg of tissue per sample, enabled by low-input omic technologies. Using advanced integrative bioinformatic analysis, we uncovered cancer-driving signaling cascade networks, changes in 3D genome modularity, and differential expression and functionalities of transcription factors and noncoding RNAs. Many of these identified genes and regulatory molecules showed no significant change in their expression or a single epigenomic modality, emphasizing the power of integrative multimodal and multiomic analysis using patient samples.
EEG is better when cleaning effectively targets artifacts
Authors: Bailey Neil W , Hill Aron T , Godfrey Kate , Perera M. Prabhavi N. , Rogasch Nigel C. , Fitzgibbon Bernadette M. , Fitzgerald Paul B 
Published: June 2024

AbstractElectroencephalography (EEG) is a useful tool to measure neural activity. However, EEG data are usually contaminated with non-neural artifacts, including voltage shifts generated by eye movements and muscle activity, and other artifacts that are less easily characterizable. The confounding influence of artifacts is often addressed by decomposing data into components, subtracting probable artifactual components, then reconstructing data back into the electrode space. This approach is commonly applied using independent component analysis (ICA). Here, we demonstrate the counterintuitive finding that due to imperfect component separation, component subtraction can artificially inflate effect sizes for event-related potentials (ERPs) and connectivity measures, bias source localisation estimates, and remove neural signals. To address this issue, we developed a method that targets cleaning to the artifact periods of eye movement components and artifact frequencies of muscle components. When tested across different EEG systems and cognitive tasks, our results showed that the targeted artifact reduction method is effective in cleaning artifacts while also reducing the artificial inflation of ERP and connectivity effect sizes and minimizing source localisation biases. Our results suggest EEG pre-processing is better when targeted cleaning is applied, as this improves preservation of neural signals and mitigates effect size inflation and source localisation biases that result from approaches which subtract artifact components across the entire time-series. These improvements enhance the reliability and validity of EEG data analysis. Our method is provided in the freely available RELAX pipeline, which includes a graphical user interface for ease of use and is available as an EEGLAB plugin (https://github.com/NeilwBailey/RELAX).
Optimal control of Multiple Myeloma assuming drug evasion and off-target effects
Authors: Lefevre James G. , Lawson Brodie A.J. , Burrage Pamela M. , Donovan Diane M. , Burrage Kevin 
Published: June 2024

AbstractMultiple Myeloma (MM) is a plasma cell cancer that occurs in the bone marrow. A leading treatment for MM is the monoclonal antibody Daratumumab, targeting the CD38 receptor, which is highly overexpressed in myeloma cells. In this work we model drug evasion via loss of CD38 expression, which is a proposed mechanism of resistance to Daratumumab treatment. We develop an ODE model that includes drug evasion via two mechanisms: a direct effect in which CD38 expression is lost without cell death in response to Daratumumab, and an indirect effect in which CD38 expression switches on and off in the cancer cells; myeloma cells that do not express CD38 have lower fitness but are shielded from the drug action. The model also incorporates competition with healthy cells, death of healthy cells due to off-target drug effects, and a Michaelis-Menten type immune response. Using optimal control theory, we study the effect of the drug evasion mechanisms and the off-target drug effect on the optimal treatment regime. We identify a general increase in treatment duration and costs, with varying patterns of response for the different controlling parameters. Several distinct optimal treatment regimes are identified within the parameter space.Author summaryIn this work we investigate a model of Multiple Myeloma, a cancer of the bone marrow, and its treatment with the drug Daratumumab. The model incorporates proposed mechanisms by which the cancer evades Daratumumab by reduced expression of the receptor CD38, which is the drug target and normally abundent in the cancer cells. The model includes an off-target effect, meaning that the drug treatment destroys some healthy cells alongside the targeted cancer cells. Both mechanisms can reasonably be expected to reduce the efficacy of the drug. We investigate the model using optimal control methods, which are used to find the drug dose over time which best balances the financial and health costs of treatment against cancer persistence, according to a specified cost function. We show that this drug resistence and off-target effect prolongs the optimal treatment and increase the burden of both the disease and drug. We analyse the distinct effects of the controlling parameters on each of these costs factors as well as the time course, and identify conditions under which extended treatment is required, with either intermittant treatment or a steady reduced dose. Extended treatment may be indefinite or for a fixed period.
Diversity-enhanced canopy space occupation and leaf functional diversity jointly promote overyielding in tropical tree communities
Authors: Ray Tama , Fichtner Andreas , Kunz Matthias , Proß Tobias , Bradler Pia M. , Bruelheide Helge , Georgi Louis , Haider Sylvia , Hildebrand Michaela , Potvin Catherine , Schnabel Florian , Oheimb Goddert von 
Published: June 2024

AbstractUnderstanding the mechanisms that drive biodiversity-productivity relationships is critical for guiding forest restoration. Although complementarity among trees in the canopy space has been suggested as a key mechanism for greater productivity in mixed-species tree communities, empirical evidence remains limited. Here, we used data from a tropical tree diversity experiment to disentangle the effects of tree species richness and community functional characteristics (community-weighted mean and functional diversity of leaf traits) on canopy space filling, and how these effects are related to overyielding. We found that canopy space filling was largely explained by species identity effects rather than tree diversity effects. Communities with a high abundance of species with conservative leaf traits were those with most densely packed canopies. Overall, a higher canopy space filling translated into an enhanced wood productivity, with communities associated with a high taxonomic and functional diversity being the most productive. Importantly, most communities (83%) produced more wood volume than the average of their constituent species in monoculture (i.e. most communities overyielded). Our results show that overyielding increased with leaf functional diversity and positive net biodiversity effects on canopy space filling, which mainly arose due to a high taxonomic diversity. These findings suggest that both taxonomic diversity-enhanced canopy space filling and canopy leaf diversity are important drivers for overyielding in mixed-species forests. Consequently, restoration initiatives should promote stands with functionally diverse canopies by selecting tree species with large interspecific differences in leaf nutrition, as well as leaf and branch morphology to optimize carbon capture in young forest stands.
Cilia to basement membrane signalling is a biomechanical driver of autosomal dominant polycystic kidney disease
Authors: Mazloum Manal , Lapin Brice , Viau Amandine , Alghamdi Rushdi , Burtin Martine , Houillier Pascal , Cheval Lydie , Crambert Gilles , Aka Amandine , Kuehn E. Wolfgang , Cohen Camille , Descroix Stéphanie , Busch Tilman , Köttgen Michael , Garbay Serge , Verpont Marie-Christine , Lelongt Brigitte , Coscoy Sylvie , Terzi Fabiola , Bienaimé Frank 
Published: June 2024

AbstractAutosomal dominant polycystic kidney disease (ADPKD), which affects around 4 million patients worldwide, is characterized by the formation of multiple tubule derived cysts, which grossly enlarge both kidneys and progressively compromise renal function. ADPKD mainly results from mutations inPKD1, leading to the loss of polycystin-1 protein, which localizes to primary cilia. Primary cilia are required for cyst formation but the biomechanical changes underlying cystogenesis upon loss of polycytin-1 are unknown. We find that cilia and polycystin-1 shape the tubular basement membrane (TBM). Combining orthologous mouse models with a tubule-on-chip approach allowing manipulations of TBM stiffness, we find that cilia regulate the composition and biomechanical properties of the TBM. In the setting of polycytin-1 loss, reduced TBM stiffness and increased luminal pressure act as biomechanical drivers of cyst formation. These findings suggest a novel biomechanical model for ADPKD and unveil that cilia to TBM signalling controls kidney shape.
Observation of Higher-Order Assemblies Controlled by Protein One-dimensional Movement
Authors: Han Xiao-Peng , Rao Ming , Wu Shu-Rui , Zhang Qiurong , Hou Fajian , Zhang Shao-Qing , Chen Ling-Ling , Liu Jiaquan 
Published: June 2024

SUMMARYRIG-I-like receptors (RLRs) detect cytosolic viral RNAs and initiate innate immune response. MDA5 is an RLR that recognizes viral long double-stranded RNA (dsRNA). The central helicase and C-terminal domains of MDA5 form a ring-like clamp around dsRNA, and its activation requires the oligomerization of N-terminal caspase activation and recruitment domains (CARDs). Another RLR, LGP2, lacks CARDs but plays essential roles in MDA5 signaling. However, the mechanisms underlying MDA5 CARDs assembly and the collaborative mechanics between MDA5 and LGP2 remain largely unresolved. Here we found the MDA5 ring-like clamp operates as an ATP-hydrolysis-driven motor, with the self-assembly of its CARDs strictly suppressed by the protein one-dimensional (1D) translocation along dsRNA. LGP2 recognizes a mobile MDA5 and inhibits the motor’s movement, thereby allowing MDA5 CARDs to assemble into oligomers that can further interact with downstream components. These findings highlight how RLR sensors orchestrate higher-order assemblies through 1D movement to direct immune response.
Fast and Tuning-free Nonlinear Data Embedding and Integration based on DCOL
Authors: Liu Shengjie , Yu Tianwei 
Published: June 2024

AbstractThe rapid progress of single-cell technology has facilitated faster and more cost-effective acquisition of diverse omics data, enabling biologists to unravel the intricacies of cell populations, disease states, and developmental lineages. Additionally, the advent of multimodal single-cell omics technologies has opened up new avenues for studying interactions within biological systems. However, the high-dimensional, noisy, and sparse nature of single-cell omics data poses significant analytical challenges. Therefore, dimension reduction (DR) techniques play a vital role in analyzing such data. While many DR methods have been developed, each has its limitations. For instance, linear methods like PCA struggle to capture the highly diverse and complex associations between cell types and states effectively. In response, nonlinear techniques have been introduced; however, they may face scalability issues in high-dimensional settings, be restricted to single omics data, or primarily focus on visualization rather than producing informative embeddings for downstream tasks. Here, we formally introduce DCOL (Dissimilarity based on Conditional Ordered List) correlation, a functional dependency measure for quantifying nonlinear relationships between variables. Based on this measure, we propose DCOL-PCA and DCOL-CCA, for dimension reduction and integration of single- and multi-omics data. In simulation studies, our methods outperformed eight other DR methods and four joint dimension reduction (jDR) methods, showcasing stable performance across various settings. It proved highly effective in extracting essential factors even in the most challenging scenarios. We also validated these methods on real datasets, with our method demonstrating its ability to detect intricate signals within and between omics data and generate lower-dimensional embeddings that preserve the essential information and latent structures in the data.
An epigenetically distinct HSC subset supports thymic reconstitution
Authors: Elias Harold K. , Mitra Sneha , da Silva Marina B. , Rajagopalan Adhithi , Gipson Brianna , Lee Nicole , Kousa Anastasia I. , Ali Mohamed A.E. , Grassman Simon , Zhang Xiaoqun , DeWolf Susan , Smith Melody , Andrlova Hana , Argyropoulos Kimon V. , Sharma Roshan , Fei Teng , Sun Joseph C , Dunbar Cynthia E. , Park Christopher Y , Leslie Christina S. , Bhandoola Avinash , van den Brink Marcel R.M. 
Published: June 2024

ABSTRACTHematopoietic stem cells (HSCs) with multilineage potential are critical for effective T cell reconstitution and restoration of the adaptive immune system after allogeneic Hematopoietic Cell Transplantation (allo-HCT). The Kitlosubset of HSCs is enriched for multipotential precursors,1, 2but their T-cell lineage potential has not been well-characterized. We therefore studied the thymic reconstituting and T-cell potential of KitloHSCs. Using a preclinical allo-HCT model, we demonstrate that KitloHSCs support better thymic recovery, and T-cell reconstitution resulting in improved T cell responses to infection post-HCT. Furthermore, KitloHSCs with augmented BM lymphopoiesis mitigate age-associated thymic alterations, thus enhancing T-cell recovery in middle-aged hosts. We find the frequency of the Kitlosubset declines with age, providing one explanation for the reduced frequency of T-competent HSCs and reduced T-lymphopoietic potential in BM precursors of aged mice.3, 4, 5Chromatin profiling revealed that KitloHSCs exhibit higher activity of lymphoid-specifying transcription factors (TFs), includingZbtb1. Deletion ofZbtb1in KitloHSCs diminished their T-cell potential, while reinstatingZbtb1in megakaryocytic-biased KithiHSCs rescued T-cell potential,in vitroandin vivo. Finally, we discover an analogous KitloHSC subset with enhanced lymphoid potential in human bone marrow. Our results demonstrate that KitloHSCs with enhanced lymphoid potential have a distinct underlying epigenetic program.
Mechanical Rejuvenation of Mesenchymal Stem Cells from Aged Patients
Authors: Massidda Miles W. , Demkov Andrei , Sices Aidan , Lee Muyoung , Lee Jason , Paull Tanya T. , Kim Jonghwan , Baker Aaron B. 
Published: June 2024

AbstractMesenchymal stem cells (MSC) are an appealing therapeutic cell type for many diseases. However, patients with poor health or advanced age often have MSCs with poor regenerative properties. A major limiter of MSC therapies is cellular senescence, which is marked by limited proliferation capability, diminished multipotency, and reduced regenerative properties. In this work, we explored the ability of applied mechanical forces to reduce cellular senescence in MSCs. Our studies revealed that mechanical conditioning caused a lasting enhancement in proliferation, overall cell culture expansion potential, multipotency, and a reduction of senescence in MSCs from aged donors. Mechanistic studies suggested that these functional enhancements were mediated by oxidative stress and DNA damage repair signaling with mechanical load altering the expression of proteins of the sirtuin pathway, the DNA damage repair protein ATM, and antioxidant proteins. In addition, our results suggest a biophysical mechanism in which mechanical stretch leads to improved recognition of damaged DNA in the nucleus. Analysis of the cells through RNA-seq and ATAC-seq, demonstrated that mechanical loading alters the cell’s genetic landscape to cause broad shifts in transcriptomic patterns that related to senescence. Overall, our results demonstrate that mechanical conditioning can rejuvenate mesenchymal stem cells derived from aged patients and improve their potential as a therapeutic cell type.GRAPHICAL ABSTRACT
Overexpression of enhanced yellow fluorescent protein fused with Channelrhodopsin-2 causes contractile dysfunction in skeletal muscle
Authors: Lamia Syeda N. , Davis Carol S. , Macpherson Peter C.D. , Willingham T. Brad , Zhang Yingfan , Liu Chengyu , Iannucci Leanne , Ganji Elahe , Harden Desmond , Bhattacharya Iman , Abraham Adam C. , Brooks Susan V. , Glancy Brian , Killian Megan L. 
Published: June 2024

ABSTRACTSkeletal muscle activation using optogenetics has emerged as a promising technique for inducing noninvasive muscle contraction and assessing muscle function both in vivo and in vitro. Transgenic mice overexpressing the optogenetic fusion protein, Channelphodopsin2-EYFP (ChR2-EYFP) in skeletal muscle are widely used; however, overexpression of fluorescent proteins can negatively impact the functionality of activable tissues. In this study, we characterized the contractile properties of ChR2-EYFP skeletal muscle and introduced the ChR2-only mouse model that expresses light-responsive ChR2 without the fluorescent EYFP in their skeletal muscles. We found a significant reduction in the contractile ability of ChR2-EYFP muscles compared to ChR2-only and WT mice, observed under both electrical and optogenetic stimulation paradigms. Bulk RNAseq identified downregulation of genes associated with transmembrane transport and metabolism in ChR2-EYFP muscle, while the ChR2-only muscle did not demonstrate any notable deviations from WT muscle. The RNAseq results were further corroborated by a reduced protein-level expression of ion-channel-related HCN2 in ChR2-EYFP muscles and gluconeogenesis-modulating FBP2 in both ChR2-EYFP and ChR2-only muscles. Overall, this study reveals an intrinsic skeletal dysfunction in the widely used ChR2-EYFP mice model and underscores the importance of considering alternative optogenetic models, such as the ChR2-only, for future research in skeletal muscle optogenetics.