Biomed Pharmacother. 2023 Sep 11;167:115450. doi: 10.1016/j.biopha.2023.115450. Online ahead of print.

ABSTRACT

The blood-brain barrier (BBB) plays a critical role in determining the effectiveness of systemic treatments for brain diseases. Over the years, several innovative approaches in BBB opening and drug delivery have been developed and progressed into clinical testing phases, including focused ultrasound (FUS) with circulating microbubbles, mannitol-facilitated delivery of anti-neoplastic drugs, receptor-mediated transcytosis (RMT) by antibody-drug conjugates (ADCs), and viral vectors for gene therapy. We provided a comprehensive review of the most recent clinical applications of these approaches in managing brain tumors and Alzheimer's disease (AD), two major devastating brain diseases. Moreover, the spatial-temporal molecular heterogeneity of the BBB under disease states emphasized the importance of utilizing emerging spatial systems biology approaches to unravel novel targets for intervention within BBB and tailor strategies for enhancing drug delivery to the brain. SEARCH STRATEGY AND SELECTION CRITERIA: Data for this Review were identified by searches of clinicaltrials.gov, MEDLINE, Current Contents, PubMed, and references from relevant articles using the search terms "blood-brain barrier", "CNS drug delivery", "BBB modulation", "clinical trials", "systems biology", "primary or metastatic brain tumors", "Alzheimer's disease". Abstracts and reports from meetings were included only when they related directly to previously published work. Only articles published in English between 1980 and 2023 were included.

PMID:37703663 | DOI:10.1016/j.biopha.2023.115450

Virol J. 2023 Sep 13;20(1):211. doi: 10.1186/s12985-023-02171-3.

ABSTRACT

Grapevine Pinot gris virus (GPGV; genus Trichovirus in the family Betaflexiviridae) was detected in Australia in 2016, but its impact on the production of nursery material and fruit in Australia is still currently unknown. This study investigated the prevalence and genetic diversity of GPGV in Australia. GPGV was detected by reverse transcription-polymerase chain reaction (RT-PCR) in a range of rootstock, table and wine grape varieties from New South Wales, South Australia, and Victoria, with 473/2171 (21.8%) samples found to be infected. Genomes of 32 Australian GPGV isolates were sequenced and many of the isolates shared high nucleotide homology. Phylogenetic and haplotype analyses demonstrated that there were four distinct clades amongst the 32 Australian GPGV isolates and that there were likely to have been at least five separate introductions of the virus into Australia. Recombination and haplotype analysis indicate the emergence of new GPGV strains after introduction into Australia. When compared with 168 overseas GPGV isolates, the analyses suggest that the most likely origin of Australian GPGV isolates is from Europe. There was no correlation between specific GPGV genotypes and symptoms such as leaf mottling, leaf deformation, and shoot stunting, which were observed in some vineyards, and the virus was frequently found in symptomless grapevines.

PMID:37705082 | DOI:10.1186/s12985-023-02171-3

Nature. 2023 Sep 13. doi: 10.1038/s41586-023-06510-w. Online ahead of print.

ABSTRACT

Proteins are key to all cellular processes and their structure is important in understanding their function and evolution. Sequence-based predictions of protein structures have increased in accuracy1, and over 214 million predicted structures are available in the AlphaFold database2. However, studying protein structures at this scale requires highly efficient methods. Here, we developed a structural-alignment-based clustering algorithm-Foldseek cluster-that can cluster hundreds of millions of structures. Using this method, we have clustered all of the structures in the AlphaFold database, identifying 2.30 million non-singleton structural clusters, of which 31% lack annotations representing probable previously undescribed structures. Clusters without annotation tend to have few representatives covering only 4% of all proteins in the AlphaFold database. Evolutionary analysis suggests that most clusters are ancient in origin but 4% seem to be species specific, representing lower-quality predictions or examples of de novo gene birth. We also show how structural comparisons can be used to predict domain families and their relationships, identifying examples of remote structural similarity. On the basis of these analyses, we identify several examples of human immune-related proteins with putative remote homology in prokaryotic species, illustrating the value of this resource for studying protein function and evolution across the tree of life.

PMID:37704730 | DOI:10.1038/s41586-023-06510-w

Nat Commun. 2023 Sep 13;14(1):5644. doi: 10.1038/s41467-023-41173-1.

ABSTRACT

To navigate through diverse tissues, migrating cells must balance persistent self-propelled motion with adaptive behaviors to circumvent obstacles. We identify a curvature-sensing mechanism underlying obstacle evasion in immune-like cells. Specifically, we propose that actin polymerization at the advancing edge of migrating cells is inhibited by the curvature-sensitive BAR domain protein Snx33 in regions with inward plasma membrane curvature. The genetic perturbation of this machinery reduces the cells' capacity to evade obstructions combined with faster and more persistent cell migration in obstacle-free environments. Our results show how cells can read out their surface topography and utilize actin and plasma membrane biophysics to interpret their environment, allowing them to adaptively decide if they should move ahead or turn away. On the basis of our findings, we propose that the natural diversity of BAR domain proteins may allow cells to tune their curvature sensing machinery to match the shape characteristics in their environment.

PMID:37704612 | DOI:10.1038/s41467-023-41173-1

Nat Commun. 2023 Sep 13;14(1):5652. doi: 10.1038/s41467-023-41395-3.

ABSTRACT

The Aurora family of kinases orchestrates chromosome segregation and cytokinesis during cell division, with precise spatiotemporal regulation of its catalytic activities by distinct protein scaffolds. Plasmodium spp., the causative agents of malaria, are unicellular eukaryotes with three unique and highly divergent aurora-related kinases (ARK1-3) that are essential for asexual cellular proliferation but lack most canonical scaffolds/activators. Here we investigate the role of ARK2 during sexual proliferation of the rodent malaria Plasmodium berghei, using a combination of super-resolution microscopy, mass spectrometry, and live-cell fluorescence imaging. We find that ARK2 is primarily located at spindle microtubules in the vicinity of kinetochores during both mitosis and meiosis. Interactomic and co-localisation studies reveal several putative ARK2-associated interactors including the microtubule-interacting protein EB1, together with MISFIT and Myosin-K, but no conserved eukaryotic scaffold proteins. Gene function studies indicate that ARK2 and EB1 are complementary in driving endomitotic division and thereby parasite transmission through the mosquito. This discovery underlines the flexibility of molecular networks to rewire and drive unconventional mechanisms of chromosome segregation in the malaria parasite.

PMID:37704606 | DOI:10.1038/s41467-023-41395-3

Sci Adv. 2023 Sep 15;9(37):eadi2562. doi: 10.1126/sciadv.adi2562. Epub 2023 Sep 13.

ABSTRACT

Norovirus is a leading cause of epidemic viral gastroenteritis, with no currently approved vaccines or antivirals. Murine norovirus (MNoV) is a well-characterized model of norovirus pathogenesis in vivo, and persistent strains exhibit lifelong intestinal infection. Interferon-λ (IFN-λ) is a potent antiviral that rapidly cures MNoV. We previously demonstrated that IFN-λ signaling in intestinal epithelial cells (IECs) controls persistent MNoV, and here demonstrate that IFN-λ acts on tuft cells, the exclusive site of MNoV persistence, to limit infection. While interrogating the source of IFN-λ to regulate MNoV, we confirmed that MDA5-MAVS signaling, required for IFN-λ induction to MNoV in vitro, controls persistent MNoV in vivo. We demonstrate that MAVS in IECs and not immune cells controls MNoV. MAVS in nonsusceptible enterocytes, but not in tuft cells, restricts MNoV, implicating noninfected cells as the IFN-λ source. Our findings indicate that host sensing of MNoV is distinct from cellular tropism, suggesting intercellular communication between IECs for antiviral signaling induction in uninfected bystander cells.

PMID:37703370 | DOI:10.1126/sciadv.adi2562

Sci Adv. 2023 Sep 15;9(37):eadg7668. doi: 10.1126/sciadv.adg7668. Epub 2023 Sep 13.

ABSTRACT

Immune responses are tightly regulated by a diverse set of interacting immune cell populations. Alongside decision-making processes such as differentiation into specific effector cell types, immune cells initiate proliferation at the beginning of an inflammation, forming two layers of complexity. Here, we developed a general mathematical framework for the data-driven analysis of collective immune cell dynamics. We identified qualitative and quantitative properties of generic network motifs, and we specified differentiation dynamics by analysis of kinetic transcriptome data. Furthermore, we derived a specific, data-driven mathematical model for T helper 1 versus T follicular helper cell-fate decision dynamics in acute and chronic lymphocytic choriomeningitis virus infections in mice. The model recapitulates important dynamical properties without model fitting and solely by using measured response-time distributions. Model simulations predict different windows of opportunity for perturbation in acute and chronic infection scenarios, with potential implications for optimization of targeted immunotherapy.

PMID:37703364 | DOI:10.1126/sciadv.adg7668

Elife. 2023 Sep 13;12:e85275. doi: 10.7554/eLife.85275.

ABSTRACT

Cyborg control of insect movement is promising for developing miniature, high-mobility, and efficient biohybrid robots. However, considering the inter-individual variation of the insect neuromuscular apparatus and its neural control is challenging. We propose a hierarchical model including inter-individual variation of muscle properties of three leg muscles involved in propulsion (retractor coxae), joint stiffness (pro- and retractor coxae), and stance-swing transition (protractor coxae and levator trochanteris) in the stick insect Carausius morosus. To estimate mechanical effects induced by external muscle stimulation, the model is based on the systematic evaluation of joint torques as functions of electrical stimulation parameters. A nearly linear relationship between the stimulus burst duration and generated torque was observed. This stimulus-torque characteristic holds for burst durations of up to 500ms, corresponding to the stance and swing phase durations of medium to fast walking stick insects. Hierarchical Bayesian modeling revealed that linearity of the stimulus-torque characteristic was invariant, with individually varying slopes. Individual prediction of joint torques provides significant benefits for precise cyborg control.

PMID:37703327 | DOI:10.7554/eLife.85275

Methods Mol Biol. 2024;2716:51-99. doi: 10.1007/978-1-0716-3449-3_4.

ABSTRACT

Modeling and simulation (M&S), including in silico (clinical) trials, helps accelerate drug research and development and reduce costs and have coined the term "model-informed drug development (MIDD)." Data-driven, inferential approaches are now becoming increasingly complemented by emerging complex physiologically and knowledge-based disease (and drug) models, but differ in setup, bottlenecks, data requirements, and applications (also reminiscent of the different scientific communities they arose from). At the same time, and within the MIDD landscape, regulators and drug developers start to embrace in silico trials as a potential tool to refine, reduce, and ultimately replace clinical trials. Effectively, silos between the historically distinct modeling approaches start to break down. Widespread adoption of in silico trials still needs more collaboration between different stakeholders and established precedence use cases in key applications, which is currently impeded by a shattered collection of tools and practices. In order to address these key challenges, efforts to establish best practice workflows need to be undertaken and new collaborative M&S tools devised, and an attempt to provide a coherent set of solutions is provided in this chapter. First, a dedicated workflow for in silico clinical trial (development) life cycle is provided, which takes up general ideas from the systems biology and quantitative systems pharmacology space and which implements specific steps toward regulatory qualification. Then, key characteristics of an in silico trial software platform implementation are given on the example of jinkō.ai (nova's end-to-end in silico clinical trial platform). Considering these enabling scientific and technological advances, future applications of in silico trials to refine, reduce, and replace clinical research are indicated, ranging from synthetic control strategies and digital twins, which overall shows promise to begin a new era of more efficient drug development.

PMID:37702936 | DOI:10.1007/978-1-0716-3449-3_4

FASEB J. 2023 Oct;37(10):e23194. doi: 10.1096/fj.202300486R.

ABSTRACT

MAP2 is a critical cytoskeletal regulator in neurons. The phosphorylation of MAP2 (MAP2-P) is well known to regulate core functions of MAP2, including microtubule (MT)/actin binding and facilitation of tubulin polymerization. However, site-specific studies of MAP2-P function in regions outside of the MT-binding domain (MTBD) are lacking. We previously identified a set of MAP2 phosphopeptides which are differentially expressed and predominantly increased in the cortex of individuals with schizophrenia relative to nonpsychiatric comparison subjects. The phosphopeptides originated not from the MTBD, but from the flanking proline-rich and C-terminal domains of MAP2. We sought to understand the contribution of MAP2-P at these sites on MAP2 function. To this end, we isolated a series of phosphomimetic MAP2C constructs and subjected them to cell-free tubulin polymerization, MT-binding, actin-binding, and actin polymerization assays. A subset of MAP2-P events significantly impaired these functions, with the two domains displaying different patterns of MAP2 regulation: proline-rich domain mutants T293E and T300E impaired MT assembly and actin-binding affinity but did not affect MT-binding, while C-terminal domain mutants S426E and S439D impaired all three functions. S443D also impaired MT assembly with minimal effects on MT- or actin-binding. Using heterologous cells, we also found that S426E but not T293E had a lower capability for process formation than the wild-type protein. These findings demonstrate the functional utility of MAP2-P in the proline-rich and C-terminal domains and point to distinct, domain-dependent regulations of MAP2 function, which can go on to affect cellular morphology.

PMID:37702880 | DOI:10.1096/fj.202300486R

Med Klin Intensivmed Notfmed. 2023 Sep 13. doi: 10.1007/s00063-023-01059-y. Online ahead of print.

NO ABSTRACT

PMID:37702782 | DOI:10.1007/s00063-023-01059-y

J Immunol. 2023 Sep 13:ji2200809. doi: 10.4049/jimmunol.2200809. Online ahead of print.

ABSTRACT

IFN-γ-producing invariant NKT (iNKT)1 cells are lipid-reactive innate-like lymphocytes that are resident in the thymus and peripheral tissues where they protect against pathogenic infection. The thymic functions of iNKT1 cells are not fully elucidated, but subsets of thymic iNKT cells modulate CD8 T cell, dendritic cell, B cell, and thymic epithelial cell numbers or function. In this study, we show that a subset of murine thymic iNKT1 cells required TGF-β-induced signals for their postselection development, to maintain hallmark TGF-β-induced genes, and for expression of the adhesion receptors CD49a and CD103. However, the residency-associated receptor CD69 was not TGF-β signaling-dependent. Recently described CD244+ c2 thymic iNKT1 cells, which produce IFN-γ without exogenous stimulation and have NK-like characteristics, reside in this TGF-β-responsive population. Liver and spleen iNKT1 cells do not share this TGF-β gene signature, but nonetheless TGF-β impacts liver iNKT1 cell phenotype and function. Our findings provide insight into the heterogeneity of mechanisms guiding iNKT1 cell development in different tissues and suggest a close association between a subset of iNKT1 cells and TGF-β-producing cells in the thymus that support their development.

PMID:37702745 | DOI:10.4049/jimmunol.2200809

J Med Virol. 2023 Sep;95(9):e29099. doi: 10.1002/jmv.29099.

ABSTRACT

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease with high mortality in Eastern Asia. The disease is caused by the SFTS virus (SFTSV), also known as Dabie bandavirus, which has a segmented RNA genome consisting of L, M, and S segments. Previous studies have suggested differential viral virulence depending on the genotypes of SFTSV; however, the critical viral factor involved in the differential viral virulence is unknown. Here, we found a significant difference in viral replication in vitro and virulence in vivo between two Korean isolates belonging to the F and B genotypes, respectively. By generating viral reassortants using the two viral strains, we demonstrated that the L segment, which encodes viral RNA-dependent RNA polymerase (RdRp), is responsible for the enhanced viral replication and virulence. Comparison of amino acid sequences and viral replication rates revealed a point variation, E251K, on the surface of RdRp to be the most significant determinant for the enhanced viral replication rate and in vivo virulence. The effect of the variation was further confirmed using recombinant SFTSV generated by reverse genetic engineering. Therefore, our results indicate that natural variations affecting the viral replicase activity could significantly contribute to the viral virulence of SFTSV.

PMID:37702580 | DOI:10.1002/jmv.29099

Carcinogenesis. 2023 Sep 13:bgad062. doi: 10.1093/carcin/bgad062. Online ahead of print.

ABSTRACT

Hepatocellular carcinoma (HCC) is one of the leading cancer types with increasing annual incidence and high mortality in the United States. MicroRNAs (miRNAs) have emerged as valuable prognostic indicators in cancer patients. To identify a miRNA signature predictive of survival in patients with HCC, we developed a machine learning-based HCC survival estimation method, HCCse, using the miRNA expression profiles of 122 patients with HCC. The HCCse method was designed using an optimal feature selection algorithm incorporated with support vector regression. HCCse identified a robust miRNA signature consisting of 32 miRNAs and obtained a mean correlation coefficient (R) and mean absolute error (MAE) of 0.87±0.02 and 0.73 years between the actual and estimated survival times of patients with HCC; and the Jack-knife test achieved an R and MAE of 0.73 and 0.97 years between actual and estimated survival times, respectively. The identified signature has seven prognostic miRNAs (hsa-miR-146a-3p, hsa-miR-200a-3p, hsa-miR-652-3p, hsa-miR-34a-3p, hsa-miR-132-5p, hsa-miR-1301-3p, and hsa-miR-374b-3p) and four diagnostic miRNAs (hsa-miR-1301-3p, hsa-miR-17-5p, hsa-miR-34a-3p, and hsa-miR-200a-3p). Notably, three of these miRNAs, hsa-miR-200a-3p, hsa-miR-1301-3p, and hsa-miR-17-5p, also displayed association with tumor stage, further emphasizing their clinical relevance. Furthermore, we performed pathway enrichment analysis and found that the target genes of the identified miRNA signature were significantly enriched in the hepatitis B pathway, suggesting its potential involvement in HCC pathogenesis.

PMID:37701974 | DOI:10.1093/carcin/bgad062

iScience. 2023 Aug 23;26(9):107703. doi: 10.1016/j.isci.2023.107703. eCollection 2023 Sep 15.

ABSTRACT

Bladder cancer (BLCA) is more common in men but more aggressive in women. Sex-based differences in cancer biology are commonly studied using a murine model with BLCA generated by N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). While tumors in the BBN model have been profiled, these profiles provide limited information on the tumor microenvironment. Here, we applied single-cell RNA sequencing to characterize cell-type specific transcriptional differences between male and female BBN-induced tumors. We found proportional and gene expression differences in epithelial and non-epithelial subpopulations between male and female tumors. Expression of several genes predicted sex-specific survival in several human BLCA datasets. We identified novel and clinically relevant sex-specific transcriptional signatures including immune cells in the tumor microenvironment and it validated the relevance of the BBN model for studying sex differences in human BLCA. This work highlights the importance of considering sex as a biological variable in the development of new and accurate cancer markers.

PMID:37701814 | PMC:PMC10494466 | DOI:10.1016/j.isci.2023.107703

Trans Am Clin Climatol Assoc. 2023;133:24-33.

ABSTRACT

Glucose toxicity is central to the myriad complications of diabetes and is now believed to encompass neurodegenerative diseases and cancer as well as microvascular and macrovascular disease. Due to the widespread benefits of SGLT2 inhibitors, which affect glucose uptake in the kidney proximal tubular cell, a focus on cell metabolism in response to glucose has important implications for overall health. We previously found that a -Warburg-type effect underlies diabetic kidney disease and involves metabolic reprogramming. This is now supported by quantitative measurements of superoxide measurement in the diabetic kidney and systems biology analysis of urine metabolites in patients. Further exploration of mechanisms underlying mediators of mitochondrial suppression will be critical in understanding the chronology of glucose-induced toxicity and developing new therapeutics to arrest the systemic glucose toxicity of diabetes.

PMID:37701600 | PMC:PMC10493723

Ecol Evol. 2023 Sep 10;13(9):e10489. doi: 10.1002/ece3.10489. eCollection 2023 Sep.

ABSTRACT

Many applications in science and engineering involve data defined at specific geospatial locations, which are often modeled as random fields. The modeling of a proper correlation function is essential for the probabilistic calibration of the random fields, but traditional methods were developed with the assumption to have observations with evenly spaced data. Available methods dealing with irregularly spaced data generally require either interpolation or computationally expensive solutions. Instead, we propose a simple approach based on least square regression to estimate the autocorrelation function. We first tested our methodology on an artificially produced dataset to assess the performance of our method. The accuracy of the method and its robustness to the level of noise in the data indicate that it is suitable for use in realistic problems. In addition, the methodology was used on a major application, the modeling of animal species connected with zoonotic diseases. Understanding the population dynamics of reservoirs of zoonotic diseases, such as bats, is a crucial first step to predict and prevent potential spillover of deadly viruses like Ebola. Due to the limited data on bats across Africa, their density and migrations can only be studied with probabilistic numerical models based on samples of the ecological bare carrying capacity (K0). For this purpose, the bare carrying capacity was modeled as a random field and its statistics calibrated with the available data. The bare carrying capacity of bats was found to be denser in central Africa. This is because climatic and environmental conditions are more suitable for the survival of bats. The proposed methodology for random field calibration was shown to be a promising approach, which can cope with large gaps in data and with complex applications involving large geographical areas and high resolution.

PMID:37701021 | PMC:PMC10493194 | DOI:10.1002/ece3.10489

Sheng Wu Gong Cheng Xue Bao. 2022 Nov 25;38(11):4200-4218. doi: 10.13345/j.cjb.220611.

ABSTRACT

Fermentation is a green, low-carbon and sustainable process for the production of food, chemicals, fuels, and materials by using microbial strains as biocatalysts and renewable resources such as starch and biomass as feedstocks. China has the world's largest fermentation industry, the scale of amino acids, vitamins, and some other fermentation products accounted for 60%-80% of the global market share. The development of fermentation industry is of great significance for the strategic goal of "carbon neutralization and carbon peak" and the development of bioeconomy. Microbial strains are the core of fermentation industry, which directly decide what kind of chemical can be produced from what kind of feedstock at what cost. Innovating industrial strains to improve the conversion efficiency of raw materials, increase the production level, and expand product portfolio is the key to the high-quality development of fermentation industry. In recent years, the development of synthetic biology and systems biology has further deepened the understanding of the physiological and metabolic mechanisms of microbial chassis and accelerated the development of gene editing and other enabling technologies for strain design and engineering. All these advances have provided new driving force for the upgrading of industrial strains. This review focused on the representative fermentation products including amino acids, B vitamins, citric acid, and bio-ethanol. The latest progress of strain development for fermentation industry was reviewed from the perspective of basic research and technology innovation for industrial microbial chassis. How the integration of artificial intelligence and automation with life science will reshape the upgrading of industrial strains was also discussed.

PMID:37699686 | DOI:10.13345/j.cjb.220611

RNA. 2023 Sep 12:rna.079758.123. doi: 10.1261/rna.079758.123. Online ahead of print.

ABSTRACT

The conserved TREX complex has multiple functions in gene expression such as transcription elongation, 3' end processing, mRNP assembly and nuclear mRNA export as well as the maintenance of genomic stability. In S. cerevisiae, TREX is composed of the pentameric THO complex, the DEAD-box RNA helicase Sub2, the nuclear mRNA export adaptor Yra1 and the SR-like proteins Gbp2 and Hrb1. Here, we present the structural analysis of the endogenous TREX complex of S. cerevisiae purified from its native environment. To this end, we used cross-linking mass spectrometry to gain structural information on regions of the complex that are not accessible to classical structural biology techniques. We also used negative-stain electron microscopy to investigate the organization of the cross-linked complex used for XL-MS by comparing our endogenous TREX complex with recently published structural models of recombinant THO-Sub2 complexes. According to our analysis, the endogenous yeast TREX complex preferentially assembles into a dimer.

PMID:37699651 | DOI:10.1261/rna.079758.123

Mol Cell. 2023 Sep 6:S1097-2765(23)00651-2. doi: 10.1016/j.molcel.2023.08.015. Online ahead of print.

ABSTRACT

Aging is associated with progressive phenotypic changes. Virtually all cellular phenotypes are produced by proteins, and their structural alterations can lead to age-related diseases. However, we still lack comprehensive knowledge of proteins undergoing structural-functional changes during cellular aging and their contributions to age-related phenotypes. Here, we conducted proteome-wide analysis of early age-related protein structural changes in budding yeast using limited proteolysis-mass spectrometry (LiP-MS). The results, compiled in online ProtAge catalog, unraveled age-related functional changes in regulators of translation, protein folding, and amino acid metabolism. Mechanistically, we found that folded glutamate synthase Glt1 polymerizes into supramolecular self-assemblies during aging, causing breakdown of cellular amino acid homeostasis. Inhibiting Glt1 polymerization by mutating the polymerization interface restored amino acid levels in aged cells, attenuated mitochondrial dysfunction, and led to lifespan extension. Altogether, this comprehensive map of protein structural changes enables identifying mechanisms of age-related phenotypes and offers opportunities for their reversal.

PMID:37699397 | DOI:10.1016/j.molcel.2023.08.015