bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and diversity of TAL effector-like proteins in fungal endosymbiotic Mycetohabitans spp.
Authors: Carpenter Sara C. D. , Bogdanove Adam J. , Abbot Bhuwan , Stajich Jason E. , Uehling Jessie K. , Lovett Brian , Kasson Matt T. , Carter Morgan E.
Published: June 2024

Endofungal Mycetohabitans (formerly Burkholderia) spp. rely on a type III secretion system to deliver mostly unidentified effector proteins when colonizing their host fungus, Rhizopus microsporus. The one known secreted effector family from Mycetohabitans consists of homologues of transcription activator-like (TAL) effectors, which are used by plant pathogenic Xanthomonas and Ralstonia spp. to activate host genes that promote disease. These ‘Burkholderia TAL-like (Btl)’ proteins bind corresponding specific DNA sequences in a predictable manner, but their genomic target(s) and impact on transcription in the fungus are unknown. Recent phenotyping of Btl mutants of two Mycetohabitans strains revealed that the single Btl in one Mycetohabitans endofungorum strain enhances fungal membrane stress tolerance, while others in a Mycetohabitans rhizoxinica strain promote bacterial colonization of the fungus. The phenotypic diversity underscores the need to assess the sequence diversity and, given that sequence diversity translates to DNA targeting specificity, the functional diversity of Btl proteins. Using a dual approach to maximize capture of Btl protein sequences for our analysis, we sequenced and assembled nine Mycetohabitans spp. genomes using long-read PacBio technology and also mined available short-read Illumina fungal–bacterial metagenomes. We show that btl genes are present across diverse Mycetohabitans strains from Mucoromycota fungal hosts yet vary in sequences and predicted DNA binding specificity. Phylogenetic analysis revealed distinct clades of Btl proteins and suggested that Mycetohabitans might contain more species than previously recognized. Within our data set, Btl proteins were more conserved across M. rhizoxinica strains than across M. endofungorum, but there was also evidence of greater overall strain diversity within the latter clade. Overall, the results suggest that Btl proteins contribute to bacterial–fungal symbioses in myriad ways.
Altered T cell reactivity to β-amyloid-related antigens in early Alzheimer’s disease
Authors: Rickenbach Chiara , Mallone Anna , Häusle Lars , Frei Larissa , Seiter Sarina , Sparano Colin , Kirabali Tunahan , Blennow Kaj , Zetterberg Henrik , Ferretti Maria Teresa , Kulic Luka , Hock Christoph , Nitsch Roger M. , Treyer Valerie , Gietl Anton , Gericke Christoph
Published: June 2024

There is growing evidence that the adaptive immune system and neurodegenerative Alzheimer’s disease (AD) are intertwined in multiple ways. Recent studies have reported alterations of the adaptive immune system in early AD stages, such as preclinical AD and mild cognitive impairment (MCI) due to AD. However, the identity of specific antigenic targets and whether the respective response is beneficial or detrimental during disease progression are still open questions. Herein, we describe cross-sectional analyses of blood and cerebrospinal fluid from three different study populations covering early AD stages. We employed high-dimensional mass cytometry, single-cell RNA-sequencing,in vitroT cell secretome analysis, and antigen presentation assays to achieve a comprehensive characterization of adaptive immune cell populations. Our results show that subjects at the stage of asymptomatic, preclinical AD can mount a CD4+T helper cell response towards β- amyloid peptide and display an early enrichment of cytotoxic CD8+effector/TEMRA cells in CSF, combined with a less immunosuppressive gene signature of peripheral regulatory T cells. Conversely, in MCI due to AD, we observed increased frequencies of CD8+effector/TEMRA cells in the periphery, characterized by a pro-inflammatory gene expression profile and an overall decrease in antigen responsiveness. Our results demonstrate the complexity of adaptive immune changes in early AD and suggest that it may be beneficial in the preclinical stage to promote specific CD4+T cell responses, while in MCI it may be important to therapeutically target CD8+T cell responses if these prove to be harmful.
Increased stomach-brain coupling indexes a dimensional signature of negative mental health symptoms
Authors: Banellis Leah , Rebollo Ignacio , Nikolova Niia , Allen Micah
Published: June 2024

Visceral rhythms orchestrate the physiological states underlying human emotion. Chronic aberrations in these brain-body interactions are implicated in a broad spectrum of mental health disorders. However, the specific contributions of the gastric-brain coupling to affective symptoms remain poorly understood. We investigated the relationship between this novel interoceptive axis and mental health symptoms in 243 participants, using a cross validated machine learning approach. We find that frontal parietal brain coupling to the gastric rhythm indexes a dimensional signature of mental health spanning anxiety, depression, stress, and well-being. Control analyses confirm the specificity of these interactions to the gastric-brain axis. Our study establishes coupling between the stomach and brain as a factor in the pathology of mental health, and offers new targets for interventions remediating aberrant brain-body coupling.
Targeting DOT1L and EZH2 synergizes in breaking the germinal center identity of Diffuse Large B Cell Lymphoma
Authors: Göbel Camiel , Niccolai Rachele , de Groot Marnix H.P. , Jayachandran Jayashree , Traets Joleen , Morris Ben , Song Ji-Ying , Azarang Leyla , Kasa Eirini , de Groot Daniel , Kreft Maaike , Kersten Marie José , Aslam Muhammad A. , van Leeuwen Fred , Jacobs Heinz
Published: June 2024

Differentiation of antigen-activated B cells into pro-proliferative germinal center (GC) B cells depends on the activity of the transcription factor MYC and the epigenetic writers DOT1L and EZH2. GCB-like Diffuse Large B Cell Lymphomas (GCB-DLBCLs) arise from GC B cells and closely resemble their cell of origin. Given the dependency of GC B cells on DOT1L and EZH2, we investigated the role of these epigenetic regulators in GCB-DLBCL cell lines and observed that GCB-DLBCLs synergistically depend on the combined activity of DOT1L and EZH2. Mechanistically, inhibiting both enzymes led to enhanced derepression of PRC2 target genes compared to EZH2 single treatment, along with the suppression of MYC target genes. The sum of all these alterations results in a ‘cell-identity crisis,’ wherein GCB-DLBCLs lose their pro-proliferative GC identity and partially undergo plasma cell differentiation, a state associated with poor survival. In support of this model, combined epi-drugging of DOT1L and EZH2 prohibited the outgrowth of human GCB-DLBCL xenograftsin vivo. We conclude that the malignant behavior of GCB-DLBCLs strictly depends on DOT1L and EZH2 and that combined targeting of both epigenetic writers may provide an alternative differentiation-based treatment modality for GCB-DLBCL.

Key points

MYC-driven GCB-DLBCL depends on DOT1L and EZH2 and combined targeting provides an alternative differentiation-based therapy.

DOT1L and EZH2 cooperatively repress PRC2 target genes which is essential for acquiring a plasma cell-like state in GC B cell-like DLBCL.
New insight in cyclic monoterpenoids mechanism of action: an in silico approach
Authors: Pezzola Silvia , Sabuzi Federica , Galloni Pierluca , Conte Valeria , Venanzi Mariano , Bocchinfuso Gianfranco
Published: June 2024

Clarifying the mechanism of action of natural terpenoids is challenging. Further, their efficacy is inspiring in developing new antimycotic agents. Among all, thymol, carvacrol and thymyl acetate are largely scrutinized, while the new brominate thymol, namely bromothymol (4-bromo-2-isopropyl-5-methylphenol), needs deeper investigation. Here its antimycotic efficacy was evaluated and, in parallel, a careful in silico investigation of the mechanism of action was proposed. In vivo experiments, on species of acclaimed resistance, demonstrated that bromothymol had a Minimum Inhibitory Concentration (MIC) equal ∼40 μg/ml, 6 times more active than thymol. Partition coefficient (LogP) in heptane, determined through density functional theory (DFT), and Molecular Dynamics (MD) simulations, based on a Minimum Bias Approach, in the presence of neutral bilayers, indicated that bromothymol inserts into cellular membrane, such as thymol, carvacrol, and Thymyl acetate. Monoterpenoids bearing the hydroxyl group induces a shrinkage of the membrane thickness, while only thymol affected membrane density of the leaflets in which it inserted. Thymol, carvacrol, and bromothymol interacted with the polar head of the lipids causing an electrostatic imbalance into the membrane, justifying their biological activity. For the first time a detailed in silico characterization on the mechanism of these compounds is afforded, returning a coherent and clear picture of their mechanism of action.
Beta-adrenergic signaling and T-lymphocyte-produced catecholamines are necessary for interleukin 17A synthesis
Authors: Lauten Tatlock H. , Elkhatib Safwan K. , Natour Tamara , Reed Emily C. , Jojo Caroline N. , Case Adam J.
Published: June 2024

Background

Post-traumatic stress disorder (PTSD) is a debilitating psychological disorder that also presents with neuroimmune irregularities. Patients display elevated sympathetic tone and are at an increased risk of developing secondary autoimmune diseases. Previously, using a preclinical model of PTSD, we demonstrated that elimination of sympathetic signaling to T-lymphocytes specifically limited their ability to produce pro-inflammatory interleukin 17A (IL-17A); a cytokine implicated in the development of many autoimmune disorders. However, the mechanism linking sympathetic signaling to T-lymphocyte IL-17A production remained unclear.

Methods

Using a modified version of repeated social defeat stress (RSDS) that allows for both males and females, we assessed the impact of adrenergic receptor blockade (genetically and pharmacologically) and catecholamine depletion on T-lymphocyte IL-17A generation. Additionally, we explored the impact of adrenergic signaling and T-lymphocyte-produced catecholamines on both CD4+ and CD8+ T-lymphocytes polarized to IL-17A-producing phenotypes ex vivo.

Results

Only pharmacological inhibition of the beta 1 and 2 adrenergic receptors (β1/2) significantly decreased circulating IL-17A levels after RSDS, but did not impact other pro-inflammatory cytokines (e.g., IL-6, TNF-α, and IL-10). This finding was confirmed using RSDS with both global β1/2 receptor knock-out mice, as well as by adoptively transferring β1/2 knock-out T-lymphocytes into immunodeficient hosts. Furthermore, ex vivo polarized T-lymphocytes produced significantly less IL-17A with the blockade of β1/2 signaling, even in the absence of exogenous sympathetic neurotransmitter supplementation, which suggested T-lymphocyte-produced catecholamines may be involved in IL-17A production. Indeed, pharmacological depletion of catecholamines both in vivo and ex vivo abrogated T-lymphocyte IL-17A production demonstrating the importance of immune-generated neurotransmission in pro-inflammatory cytokine generation.

Conclusions

Our data depict a novel role for β1/2 adrenergic receptors and autologous catecholamine signaling during T-lymphocyte IL-17A production. These findings provide a new target for pharmacological therapy in both psychiatric and autoimmune diseases associated with IL-17A-related pathology.
Fecal microbiota and metabolite composition associates with stool consistency in young children
Authors: Aatsinki Anna-Katariina , Isokääntä Heidi , Kråkström Matilda , Lahti Leo , Lukkarinen Minna , Munukka Eveliina , Karlsson Hasse , Karlsson Linnea , Oresic Matej , Dickens Alex M , Lamichhane Santosh
Published: June 2024

Stool consistency explains a large proportion of inter-individual variation in gut microbiota and represents a useful measure of gut transit time, which is pivotal for bacterial metabolism andvice versa. However, in infants and small children, a detailed understanding of how gut microbiota and the metabolome associate with stool consistency is lacking. We analyzed both stool microbiota and metabolome of 2.5 (n=360), 6 (n=229), 14 (n=274), and 30-month-old children (n=169) from the FinnBrain Birth Cohort Study using 16s rRNA sequencing and mass spectrometry-based targeted techniques. We used stool water content and parent-reported stool consistency as proxies for stool consistency. We found that microbiota community composition as well as the relative abundance of specific genera such asClostridium,Hungatella, andLactobacilluswere associated with stool consistency. Of the metabolites, lower concentrations of conjugated bile acids and acetic acid were associated with having constipation and lower water content. Branched short-chain fatty acid concentrations were negatively associated with stool water content. The findings reflect a shift in bacterial saccharolytic to proteolytic metabolism in the gut. Parental crude reports agreed with the objective measure of child stool consistency, and associated with similar features in the stool metabolome. Overall, our findings support the concept that stool consistency and total water content associate with gut microbiota composition and metabolic activity in infants and young children.
Effect of TIMPs and Their Minimally Engineered Variants in Blocking Invasion and Migration of Brain Cancer Cells
Authors: Taheri Elham , Raeeszadeh-Sarmazdeh Maryam
Published: June 2024

Matrix metalloproteinases (MMPs) play a pivotal role in extracellular matrix (ECM) remodeling, influencing various aspects of cancer progression including migration, invasion, angiogenesis, and metastasis. Overexpression of MMPs, particularly MMP-2 and MMP-9, is notably pronounced in glioblastoma multiforme (GBM), a highly aggressive primary brain tumor characterized by diffuse and infiltrative behavior. Previous attempts to develop small molecule MMP inhibitors have failed in clinical trials, necessitating the exploration of more stable and selective alternatives. Tissue inhibitors of metalloproteinases (TIMPs), endogenous human proteins, offer promising potential due to their stability and broader interaction interfaces compared to small molecule inhibitors. In this study, we examined the effectiveness of wild-type human TIMP-1 and TIMP-3, alongside engineered minimal TIMP variants (mTC1 and mTC3), specifically designed for targeted MMP inhibition to reduce the migratory and invasive capabilities of GBM cells. Our investigation focused on these minimal TIMP variants, which provide enhanced tissue penetration and cellular uptake due to their small molecular weight, aiming to validate their potential as therapeutic agents. The results demonstrated that mTC1 and mTC3 effectively inhibit MMP activity, a critical factor in GBM aggressiveness, thereby highlighting their promise in controlling tumor spread. Given the lethality of GBM and the limited effectiveness of current treatments, the application of engineered TIMP variants represents a novel and potentially transformative therapeutic approach. By offering targeted MMP inhibition, these variants may significantly improve patient outcomes, providing new avenues for treatment and enhancing the survival and quality of life for patients with this devastating disease.
Alignment of multiple protein sequences without using amino acid frequencies
Authors: Shelyekhova Veronika , Shirokov Roman
Published: June 2024

Current 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

Cancer 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

Locally 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

Epigenomic 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

Electroencephalography (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

Multiple 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 summary

In 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

Understanding 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

Autosomal 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

RIG-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

The 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

Hematopoietic 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

Mesenchymal 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

Skeletal 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.
High variability of migration strategies in a re-established Trumpeter Swan population
Authors: Wolfson David W. , Knapik Randall T. , Thomas Anna Buckardt , Harms Tyler M. , Kearns Laura J. , Kiss Brian W. , Poole Timothy F. , Fowler Drew N. , Finger Taylor A. , Matteson Sumner W. , Moriarty John J. , Mayo Tiffany , Smith Margaret , Herwig Christine M. , Andersen David E. , Fieberg John R.
Published: June 2024

Background

The Interior Population (IP) of trumpeter swans (Cygnus buccinator), formerly extirpated by market hunting, was re-established in eastern North America by releasing individuals from both migratory and non-migratory populations. Their current annual movement patterns are largely unknown. Our goal was to describe their seasonal movements and quantify the proportion of the IP that is migratory, the extent and phenology of seasonal movements, and associations between movement patterns and breeding status and breeding location.

Methods

We deployed 113 GPS-GSM transmitters on IP trumpeter swans in six U.S. states and one Canadian province across the current IP breeding range. Using data from 252 ‘swan-years’, we estimated dates of migration events by segmenting the annual cycle using piecewise regression models fit to each yearly time-series of displacement from the breeding site. We fit a latent-state model to characterize population-level associations between breeding latitude and maximum extent of migration, and linear mixed models to quantify associations between individual characteristics (e.g., breeding status, sex) and migration phenology.

Results

At the individual level, 59% of swans moved to distant non-breeding-period areas (long-distance migration, defined as moving >100 km from the breeding site), 16% exhibited regional migration (25-100 km from breeding site), 19% exhibited non-migratory but local movements (<25 km from breeding site), and 6% exhibited multiple migration strategies. Swans breeding at more-northern latitudes departed their territories earlier in autumn and returned later in the spring than those breeding at more southern latitudes. Breeding swans departed later in the autumn than non-breeders, but breeding status did not have a strong association with arrival in the spring.

Conclusion

IP trumpeter swans are partial migrants, with a continuum of strategies each year, from local movements to long-distance migration. Much of the variability in movement patterns was related to factors tied to natural history demands (e.g., breeding status) and response to environmental conditions (e.g., through associations with breeding latitude).
Corticosteroids prevent pathological angiogenesis yet compromise reparative vascular remodeling in the retina
Authors: Hata Masayuki , Hata Maki , Dejda Agnieszka , Pilon Frédérique , Diaz Roberto , Fournier Frédérik , Joyal Jean-Sebastien , Cagnone Gael , Ochi Yotaro , Crespo-Garcia Sergio , Wilson Ariel , Sapieha Przemyslaw
Published: June 2024

Tissue inflammation is often broadly associated with cellular damage, yet sterile inflammation also plays critical roles in beneficial tissue remodeling. In the central nervous system (CNS), this is observed through a predominantly innate immune response in retinal vascular diseases such as age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity. Here we set out to elucidate the dynamics of the immune response during progression and regression of pathological neovascularization in retinopathy. In a mouse model of oxygen-induced retinopathy, we report that broad spectrum corticosteroid drugs such as dexamethasone suppress initial formation of pathological pre-retinal neovascularization in early stages of disease, yet blunt successive waves of reparative inflammation and hence prevent beneficial vascular remodeling. Using genetic depletion of distinct components of the innate immune response, we demonstrate that CX3C chemokine receptor 1 (CX3CR1)-expressing microglia contribute to angiogenesis. Conversely, myeloid cells expressing Lyz-M (lysozyme 2) are recruited to sites of damaged blood vessels and pathological neovascularization where they partake in a reparative process that ultimately restores circulatory homeostasis to the retina. Hence, the Janus-faced properties of anti-inflammatory drugs should be considered when treating retinal vascular disease and particularly in stages associated with persistent neovascularization.
Spatial frequency adaptation modulates population receptive field sizes
Authors: Altan Ecem , Morgan Catherine A , Dakin Steven C , Schwarzkopf D. Sam
Published: June 2024

The spatial tuning of neuronal populations in the early visual cortical regions is related to the spatial frequency (SF) selectivity of neurons. However, there has been no direct investigation into how this relationship is reflected in population receptive field (pRF) sizes despite the common application of pRF mapping in visual neuroscience. We hypothesised that adaptation to high/low SF would decrease the sensitivity of neurons with respectively small/large receptive field sizes, resulting in a change in pRF sizes as measured by functional magnetic resonance imaging (fMRI). To test this hypothesis, we first quantified the SF aftereffect using a psychophysical paradigm where observers made SF judgments following adaptation to high/low SF noise patterns. We then incorporated the same adaptation technique into a standard pRF mapping procedure, to investigate the spatial tuning of the early visual cortex following SF adaptation. Results showed that adaptation to a low/high SF resulted in smaller/larger pRFs respectively, as hypothesised. Our results provide the most direct evidence to date that the spatial tuning of the visual cortex, as measured by pRF mapping, is related to the SF selectivity of visual neural populations. This has implications for various domains of visual processing, including size perception and visual acuity.
The CYP1A1 connection between enterolactone and breast cancer risk
Authors: Hatwik Juana , Sonia Ningthoujam , Limaye Anil M.
Published: June 2024

Enterolactone (EL), a mammalian enterolignan, is a gut microbe-generated plant-lignan derivative. Although observational data are controversial, meta-analyses have affirmed that plant lignan-rich diets, or high serum EL reduce breast cancer risk, or the associated mortality, in post-menopausal women. However, the mechanistic basis is unknown. Here we show that EL antagonizes AHR to reduceCYP1A1mRNA expression in MCF-7 breast cancer cells. Intriguingly, it increases CYP1A1 protein, a mediator of xenobiotic response, which is frequently expressed in breast tumors, and implicated in cell proliferation and survival. EL’s effect on CYP1A1 expression is similar to estrogen, and mediated via ERα. But, by virtue of partial ERα agonism/antagonism, EL attenuates estrogen-mediated increase in CYP1A1 protein. These data suggest potential mechanisms underlying EL’s beneficial effects in breast cancer. In the face of xenobiotic exposure, its AHR antagonism may reduce the generation of cancer-inducing genotoxic agents. With declining levels of estrogen in post-menopausal women, EL may antagonize estrogen-mediated induction of CYP1A1 protein, and the associated proliferation of mammary epithelial cells.