Systems Biology
The coral microbiome in sickness, in health and in a changing world
Nat Rev Microbiol. 2024 Mar 4. doi: 10.1038/s41579-024-01015-3. Online ahead of print.
ABSTRACT
Stony corals, the engines and engineers of reef ecosystems, face unprecedented threats from anthropogenic environmental change. Corals are holobionts that comprise the cnidarian animal host and a diverse community of bacteria, archaea, viruses and eukaryotic microorganisms. Recent research shows that the bacterial microbiome has a pivotal role in coral biology. A healthy bacterial assemblage contributes to nutrient cycling and stress resilience, but pollution, overfishing and climate change can break down these symbiotic relationships, which results in disease, bleaching and, ultimately, coral death. Although progress has been made in characterizing the spatial-temporal diversity of bacteria, we are only beginning to appreciate their functional contribution. In this Review, we summarize the ecological and metabolic interactions between bacteria and other holobiont members, highlight the biotic and abiotic factors influencing the structure of bacterial communities and discuss the impact of climate change on these communities and their coral hosts. We emphasize how microbiome-based interventions can help to decipher key mechanisms underpinning coral health and promote reef resilience. Finally, we explore how recent technological developments may be harnessed to address some of the most pressing challenges in coral microbiology, providing a road map for future research in this field.
PMID:38438489 | DOI:10.1038/s41579-024-01015-3
Regulation of developmental gatekeeping and cell fate transition by the calpain protease DEK1 in Physcomitrium patens
Commun Biol. 2024 Mar 4;7(1):261. doi: 10.1038/s42003-024-05933-z.
ABSTRACT
Calpains are cysteine proteases that control cell fate transitions whose loss of function causes severe, pleiotropic phenotypes in eukaryotes. Although mainly considered as modulatory proteases, human calpain targets are directed to the N-end rule degradation pathway. Several such targets are transcription factors, hinting at a gene-regulatory role. Here, we analyze the gene-regulatory networks of the moss Physcomitrium patens and characterize the regulons that are misregulated in mutants of the calpain DEFECTIVE KERNEL1 (DEK1). Predicted cleavage patterns of the regulatory hierarchies in five DEK1-controlled subnetworks are consistent with a pleiotropic and regulatory role during cell fate transitions targeting multiple functions. Network structure suggests DEK1-gated sequential transitions between cell fates in 2D-to-3D development. Our method combines comprehensive phenotyping, transcriptomics and data science to dissect phenotypic traits, and our model explains the protease function as a switch gatekeeping cell fate transitions potentially also beyond plant development.
PMID:38438476 | DOI:10.1038/s42003-024-05933-z
Adipose Stromal Cell-Derived Cancer-Associated Fibroblasts Suppress FGFR Inhibitor Efficacy
Cancer Res. 2024 Mar 4;84(5):648-649. doi: 10.1158/0008-5472.CAN-23-3904.
ABSTRACT
Cancer aggressiveness has been linked with obesity, and studies have shown that adipose tissue can enhance cancer progression. In this issue of Cancer Research, Hosni and colleagues discover a paracrine mechanism mediated by adipocyte precursor cells through which urothelial carcinomas become resistant to erdafitinib, a recently approved therapy inhibiting fibroblast growth factor receptors (FGFR). They identified neuregulin 1 (NRG1) secreted by adipocyte precursor cells as an activator of HER3 signaling that enables resistance. The NRG1-mediated FGFR inhibitor resistance was amenable to intervention with pertuzumab, an antibody blocking the NRG1/HER3 axis. To investigate the nature of the resistance-associated NRG1-expressing cells in human patients, the authors analyzed published single-cell RNA sequencing data and observed that such cells appear in a cluster assigned as inflammatory cancer-associated fibroblasts (iCAF). Notably, the gene signature corresponding to these CAFs is highly similar to that shared by adipose stromal cells (ASC) in fat tissue and fibro-adipogenic progenitors (FAP) in skeletal muscle of cancer-free individuals. Because fibroblasts with the ASC/FAP signature are enriched in various carcinomas, it is possible that the paracrine signaling conferred by NRG1 is a pan-cancer mechanism of FGFR inhibitor resistance and tumor aggressiveness. See related article by Hosni et al., p. 725.
PMID:38437636 | DOI:10.1158/0008-5472.CAN-23-3904
Unlocking protein-protein interactions in plants: A comprehensive review of established and emerging techniques
J Exp Bot. 2024 Mar 4:erae088. doi: 10.1093/jxb/erae088. Online ahead of print.
ABSTRACT
Protein-protein interactions orchestrate plant development and serve as crucial elements for cellular and environmental communication. Understanding these interactions offers a gateway to unravel complex protein networks that will allow a better understanding of nature. Methods for the characterization of protein-protein interactions have been around for a long time, yet the complexity of some of these interactions fuels the development of new techniques that provide a better understanding of the underlying dynamics. In many cases, the application of these techniques is limited by the nature of the available sample. While some methods require an in vivo set up, others solely depend on protein sequences to study protein-protein interactions via an in silico set up. The vast amount of techniques available to date calls for a way to select the appropriate tools for the study of specific interactions. Here, we classify widely spread tools and new emerging techniques for the characterization of protein-protein interactions based on sample requirements while providing insights into the information that they can potentially deliver. We provide a comprehensive overview of commonly used techniques and elaborate on the most recent developments, showcasing their implementation in plant research.
PMID:38437582 | DOI:10.1093/jxb/erae088
Enhancing TCR specificity predictions by combined pan- and peptide-specific training, loss-scaling, and sequence similarity integration
Elife. 2024 Mar 4;12:RP93934. doi: 10.7554/eLife.93934.
ABSTRACT
Predicting the interaction between Major Histocompatibility Complex (MHC) class I-presented peptides and T-cell receptors (TCR) holds significant implications for vaccine development, cancer treatment, and autoimmune disease therapies. However, limited paired-chain TCR data, skewed towards well-studied epitopes, hampers the development of pan-specific machine-learning (ML) models. Leveraging a larger peptide-TCR dataset, we explore various alterations to the ML architectures and training strategies to address data imbalance. This leads to an overall improved performance, particularly for peptides with scant TCR data. However, challenges persist for unseen peptides, especially those distant from training examples. We demonstrate that such ML models can be used to detect potential outliers, which when removed from training, leads to augmented performance. Integrating pan-specific and peptide-specific models alongside with similarity-based predictions, further improves the overall performance, especially when a low false positive rate is desirable. In the context of the IMMREP22 benchmark, this modeling framework attained state-of-the-art performance. Moreover, combining these strategies results in acceptable predictive accuracy for peptides characterized with as little as 15 positive TCRs. This observation places great promise on rapidly expanding the peptide covering of the current models for predicting TCR specificity. The NetTCR 2.2 model incorporating these advances is available on GitHub (https://github.com/mnielLab/NetTCR-2.2) and as a web server at https://services.healthtech.dtu.dk/services/NetTCR-2.2/.
PMID:38437160 | DOI:10.7554/eLife.93934
Benchmarking enrichment analysis methods with the disease pathway network
Brief Bioinform. 2024 Jan 22;25(2):bbae069. doi: 10.1093/bib/bbae069.
ABSTRACT
Enrichment analysis (EA) is a common approach to gain functional insights from genome-scale experiments. As a consequence, a large number of EA methods have been developed, yet it is unclear from previous studies which method is the best for a given dataset. The main issues with previous benchmarks include the complexity of correctly assigning true pathways to a test dataset, and lack of generality of the evaluation metrics, for which the rank of a single target pathway is commonly used. We here provide a generalized EA benchmark and apply it to the most widely used EA methods, representing all four categories of current approaches. The benchmark employs a new set of 82 curated gene expression datasets from DNA microarray and RNA-Seq experiments for 26 diseases, of which only 13 are cancers. In order to address the shortcomings of the single target pathway approach and to enhance the sensitivity evaluation, we present the Disease Pathway Network, in which related Kyoto Encyclopedia of Genes and Genomes pathways are linked. We introduce a novel approach to evaluate pathway EA by combining sensitivity and specificity to provide a balanced evaluation of EA methods. This approach identifies Network Enrichment Analysis methods as the overall top performers compared with overlap-based methods. By using randomized gene expression datasets, we explore the null hypothesis bias of each method, revealing that most of them produce skewed P-values.
PMID:38436561 | DOI:10.1093/bib/bbae069
Techniques for Rapidly Sampling Six Crucial Organs in Adult Xenopus
J Vis Exp. 2024 Feb 16;(204). doi: 10.3791/66489.
ABSTRACT
Xenopus has been a powerful model organism for understanding vertebrate development and disease for over a hundred years. While experimental analysis and dissection techniques of the embryo have been well documented, descriptions of adult Xenopus structures and organs, together with techniques for working with adults, have not been updated to take into consideration the requirements of such modern approaches as quantitative proteomics and single-cell transcriptomics. The cell-type and gene-centric perspectives require contrasting observations in embryonic stages to those in adult tissues. The organs of the larva undergo significant changes in their overall structure, morphology, and anatomical location all along the larval to adult transition, most notably during massive metamorphosis remodeling. Establishing robust standards for organ identification and dissection is crucial to ensure datasets resulting from studies performed at different laboratories can be consistent. The present protocol identifies six of the organs in the adult Xenopus, demonstrating methods for dissection and sampling of the heart ventricle, liver, fat body, pancreas, paired kidney, and skin of the adult Xenopus. Depending on the preservation methods, the dissected organs can be used for quantitative proteomics, single cell/nuclei transcriptomics, in situ hybridization, immunohistochemistry, histology, etc. This protocol aims to standardize tissue sampling and facilitate multi-lab investigations of the adult organ systems.
PMID:38436453 | DOI:10.3791/66489
Heatwaves inflict reproductive but not survival costs to male insects
J Exp Biol. 2024 Mar 4:jeb.246698. doi: 10.1242/jeb.246698. Online ahead of print.
ABSTRACT
Climate change is having a dramatic effect on the environment with rising global temperatures and more frequent extreme climatic events, such as heatwaves, that can hamper organisms' biological functions. Although it is clear that sudden and extreme temperatures can damage reproductive processes, there is limited understanding of the effects of heatwaves on male mating behaviour and reproductive success. We test for the effects of heat stress derived by ecologically-relevant heatwaves (33°C and 39°C for five consecutive days) on the mating behaviour, reproductive success, body mass and survival of male field crickets Gryllus bimaculatus, paired with untreated females. We predicted life-history and reproductive costs to increase with increasing heatwave intensity. Consistent with our expectations, males exposed to the highest heatwave temperature produced the fewest offspring, while having to increase courtship effort to successfully mate. Males also gained relatively more weight following heatwave exposure. Given that we found no difference in lifetime survival, our results suggest a potential trade-off in resource allocation between somatic maintenance and reproductive investment. Taken together, our findings indicate that sublethal effects of heatwaves could reduce the growth and persistence of animal populations by negatively impacting reproductive rates. These findings highlight the need for considering thermal ecologies, life-history and behaviour to better understand the consequences of extreme climatic events on individuals and populations.
PMID:38436413 | DOI:10.1242/jeb.246698
Deciphering the Association of Epstein-Barr Virus and Its Glycoprotein M Peptide with Neuropathologies in Mice
ACS Chem Neurosci. 2024 Mar 4. doi: 10.1021/acschemneuro.4c00012. Online ahead of print.
ABSTRACT
The reactivation of ubiquitously present Epstein-Barr virus (EBV) is known to be involved with numerous diseases, including neurological ailments. A recent in vitro study from our group unveiled the association of EBV and its 12-amino acid peptide glycoprotein M146-157 (gM146-157) with neurodegenerative diseases, viz., Alzheimer's disease (AD) and multiple sclerosis. In this study, we have further validated this association at the in vivo level. The exposure of EBV/gM146-157 to mice causes a decline in the cognitive ability with a concomitant increase in anxiety-like symptoms through behavioral assays. Disorganization of hippocampal neurons, cell shrinkage, pyknosis, and apoptotic appendages were observed in the brains of infected mice. Inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were found to be elevated in infected mouse brain tissue samples, whereas TNF-α exhibited a decline in the serum of these mice. Further, the altered levels of nuclear factor-kappa B (NF-kB) and neurotensin receptor 2 affirmed neuroinflammation in infected mouse brain samples. Similarly, the risk factor of AD, apolipoprotein E4 (ApoE4), was also found to be elevated at the protein level in EBV/gM146-157 challenged mice. Furthermore, we also observed an increased level of myelin basic protein in the brain cortex. Altogether, our results suggested an integral connection of EBV and its gM146-157 peptide to the neuropathologies.
PMID:38436259 | DOI:10.1021/acschemneuro.4c00012
Convergent and/or parallel evolution of RNA-binding proteins in angiosperms after polyploidization
New Phytol. 2024 Mar 4. doi: 10.1111/nph.19656. Online ahead of print.
ABSTRACT
Increasing studies suggest that the biased retention of stress-related transcription factors (TFs) after whole-genome duplications (WGDs) could rewire gene transcriptional networks, facilitating plant adaptation to challenging environments. However, the role of posttranscriptional factors (e.g. RNA-binding proteins, RBPs) following WGDs has been largely ignored. Uncovering thousands of RBPs in 21 representative angiosperm species, we integrate genomic, transcriptomic, regulatomic, and paleotemperature datasets to unravel their evolutionary trajectories and roles in adapting to challenging environments. We reveal functional enrichments of RBP genes in stress responses and identify their convergent retention across diverse angiosperms from independent WGDs, coinciding with global cooling periods. Numerous RBP duplicates derived from WGDs are then identified as cold-induced. A significant overlap of 29 orthogroups between WGD-derived and cold-induced RBP genes across diverse angiosperms highlights a correlation between WGD and cold stress. Notably, we unveil an orthogroup (Glycine-rich RNA-binding Proteins 7/8, GRP7/8) and relevant TF duplicates (CCA1/LHY, RVE4/8, CBF2/4, etc.), co-retained in different angiosperms post-WGDs. Finally, we illustrate their roles in rewiring circadian and cold-regulatory networks at both transcriptional and posttranscriptional levels during global cooling. Altogether, we underline the adaptive evolution of RBPs in angiosperms after WGDs during global cooling, improving our understanding of plants surviving periods of environmental turmoil.
PMID:38436132 | DOI:10.1111/nph.19656
Advances in the Application of Single-Cell Transcriptomics in Plant Systems and Synthetic Biology
Biodes Res. 2024 Feb 29;6:0029. doi: 10.34133/bdr.0029. eCollection 2024.
ABSTRACT
Plants are complex systems hierarchically organized and composed of various cell types. To understand the molecular underpinnings of complex plant systems, single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool for revealing high resolution of gene expression patterns at the cellular level and investigating the cell-type heterogeneity. Furthermore, scRNA-seq analysis of plant biosystems has great potential for generating new knowledge to inform plant biosystems design and synthetic biology, which aims to modify plants genetically/epigenetically through genome editing, engineering, or re-writing based on rational design for increasing crop yield and quality, promoting the bioeconomy and enhancing environmental sustainability. In particular, data from scRNA-seq studies can be utilized to facilitate the development of high-precision Build-Design-Test-Learn capabilities for maximizing the targeted performance of engineered plant biosystems while minimizing unintended side effects. To date, scRNA-seq has been demonstrated in a limited number of plant species, including model plants (e.g., Arabidopsis thaliana), agricultural crops (e.g., Oryza sativa), and bioenergy crops (e.g., Populus spp.). It is expected that future technical advancements will reduce the cost of scRNA-seq and consequently accelerate the application of this emerging technology in plants. In this review, we summarize current technical advancements in plant scRNA-seq, including sample preparation, sequencing, and data analysis, to provide guidance on how to choose the appropriate scRNA-seq methods for different types of plant samples. We then highlight various applications of scRNA-seq in both plant systems biology and plant synthetic biology research. Finally, we discuss the challenges and opportunities for the application of scRNA-seq in plants.
PMID:38435807 | PMC:PMC10905259 | DOI:10.34133/bdr.0029
A flow cytometric assay to detect viability and persistence of <em>Salmonella enterica</em> subsp. <em>enterica</em> serotypes in nuclease-free water at 4 and 25°C
Front Microbiol. 2024 Feb 16;15:1342478. doi: 10.3389/fmicb.2024.1342478. eCollection 2024.
ABSTRACT
Salmonella spp. is one of the most isolated microorganisms reported to be responsible for human foodborne diseases and death. Water constitutes a major reservoir where the Salmonella spp. can persist and go undetected when present in low numbers. In this study, we assessed the viability of 12 serotypes of Salmonella enterica subsp. enterica for 160 days in nuclease-free water at 4 and 25°C using flow cytometry and Tryptic Soy Agar (TSA) plate counts. The results show that all 12 serotypes remain viable after 160 days in distilled water using flow cytometry, whereas traditional plate counts failed to detect ten serotypes incubated at 25°C. Moreover, the findings demonstrate that 4°C constitutes a more favorable environment where Salmonella can remain viable for prolonged periods without nutrients. Under such conditions, however, Salmonella exhibits a higher susceptibility to all tested antibiotics and benzalkonium chloride (BZK). The pre-enrichment with Universal Pre-enrichment Broth (UP) and 1/10 × Tryptic Soy broth (1/10 × TSB) resuscitated all tested serotypes on TSA plates, nevertheless cell size decreased after 160 days. Furthermore, phenotype microarray (PM) analysis of S. Inverness and S. Enteritidis combined with principal component analysis (PCA) revealed an inter-individual variability in serotypes with their phenotype characteristics, and the impact of long-term storage at 4 and 25°C for 160 days in nuclease-free water. This study provides an insight to Salmonella spp. long-term survivability at different temperatures and highlights the need for powerful tools to detect this microorganism to reduce the risk of disease transmission of foodborne pathogens via nuclease-free water.
PMID:38435692 | PMC:PMC10906097 | DOI:10.3389/fmicb.2024.1342478
Editorial: Physiological response to exercise-induced stress and stressful environmental stimuli: insights from systems biology
Front Vet Sci. 2024 Feb 16;11:1369154. doi: 10.3389/fvets.2024.1369154. eCollection 2024.
NO ABSTRACT
PMID:38435372 | PMC:PMC10904460 | DOI:10.3389/fvets.2024.1369154
Leveraging genomics, transcriptomics and epigenomics to understand chemoimmunotherapy resistance in chronic lymphocytic leukemia
Cancer Drug Resist. 2024 Feb 28;7:7. doi: 10.20517/cdr.2023.98. eCollection 2024.
ABSTRACT
Patients with chronic lymphocytic leukemia (CLL) have differing clinical outcomes. Recent advances integrating multi-omic data have uncovered molecular subtypes in CLL with different prognostic implications and may allow better prediction of therapy response. While finite-duration chemoimmunotherapy (CIT) has enabled deep responses and prolonged duration of responses in the past, the advent of novel targeted therapy for the treatment of CLL has dramatically changed the therapeutic landscape. In this review, we discuss the latest genomic, transcriptomic, and epigenetic alterations regarded as major drivers of resistance to CIT in CLL. Further advances in genomic medicine will allow for better prediction of response to therapy and provide the basis for rational selection of therapy for long-term remissions with minimal toxicity.
PMID:38434768 | PMC:PMC10905154 | DOI:10.20517/cdr.2023.98
Identification of high-performing antibodies for Vacuolar protein sorting-associated protein 35 (hVPS35) for use in Western Blot, immunoprecipitation and immunofluorescence
F1000Res. 2023 Oct 16;12:452. doi: 10.12688/f1000research.133696.2. eCollection 2023.
ABSTRACT
Vacuolar protein sorting-associated protein 35 is a subunit of the retromer complex, a vital constituent of the endosomal protein sorting pathway. The D620N mutation in the VPS35 gene has been reported to be linked to type 17 Parkinson's Disease progression, the exact molecular mechanism remains to be solved. The scientific community would benefit from the accessibility of validated and high-quality anti-hVPS35 antibodies. In this study, we characterized thirteen hVPS35 commercial antibodies for Western Blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.
PMID:38434631 | PMC:PMC10905012 | DOI:10.12688/f1000research.133696.2
LncRNA <em>Litchi</em> is a regulator for harmonizing maturity and resilient functionality in spinal motor neurons
iScience. 2024 Feb 10;27(3):109207. doi: 10.1016/j.isci.2024.109207. eCollection 2024 Mar 15.
ABSTRACT
Long noncoding RNAs (lncRNAs) play pivotal roles in modulating gene expression during development and disease. Despite their high expression in the central nervous system (CNS), understanding the precise physiological functions of CNS-associated lncRNAs has been challenging, largely due to the in vitro-centric nature of studies in this field. Here, utilizing mouse embryonic stem cell (ESC)-derived motor neurons (MNs), we identified an unexplored MN-specific lncRNA, Litchi (Long Intergenic RNAs in Chat Intron). By employing an "exon-only" deletion strategy in ESCs and a mouse model, we reveal that Litchi deletion profoundly impacts MN dendritic complexity, axonal growth, and altered action potential patterns. Mechanistically, voltage-gated channels and neurite growth-related genes exhibited heightened sensitivity to Litchi deletion. Our Litchi-knockout mouse model displayed compromised motor behaviors and reduced muscle strength, highlighting Litchi's critical role in motor function. This study unveils an underappreciated function of lncRNAs in orchestrating MN maturation and maintaining robust electrophysiological properties.
PMID:38433925 | PMC:PMC10906515 | DOI:10.1016/j.isci.2024.109207
Differential alternative splicing landscape identifies potentially functional RNA binding proteins in early embryonic development in mammals
iScience. 2024 Feb 2;27(3):109104. doi: 10.1016/j.isci.2024.109104. eCollection 2024 Mar 15.
ABSTRACT
Alternative splicing (AS) as one of the important post-transcriptional regulatory mechanisms has been poorly studied during embryogenesis. In this study, we comprehensively collected and analyzed the transcriptome data of early embryos from human and mouse. We found that AS plays an important role in this process and predicted candidate RNA binding protein (RBP) regulators that are associated with reproductive development. The predicted RBPs such as EIF4A3, MAK16, SRSF2, and UTP23 were found to be associated with reproductive disorders. By Smart-seq2 sequencing analysis, we identified 5445 aberrant alternative splicing events in Eif4a3-knockdown embryos. These events were preferentially associated with RNA processing. In conclusion, our work on the landscape and potential function of alternative splicing events will boost further investigation of detailed mechanisms and key factors regulating mammalian early embryo development and promote the inspiration of pharmaceutical approaches for disorders in this crucial biology process.
PMID:38433915 | PMC:PMC10904927 | DOI:10.1016/j.isci.2024.109104
Cross-sectional analyses of metabolites across biological samples mediating dietary acid load and chronic kidney disease
iScience. 2024 Feb 5;27(3):109132. doi: 10.1016/j.isci.2024.109132. eCollection 2024 Mar 15.
ABSTRACT
Chronic kidney disease (CKD) is a major public health burden, with dietary acid load (DAL) and gut microbiota playing crucial roles. As DAL can affect the host metabolome, potentially via the gut microbiota, we cross-sectionally investigated the interplay between DAL, host metabolome, gut microbiota, and early-stage CKD (TwinsUK, n = 1,453). DAL was positively associated with CKD stage G1-G2 (Beta (95% confidence interval) = 0.34 (0.007; 0.7), p = 0.046). After adjusting for covariates and multiple testing, we identified 15 serum, 14 urine, 8 stool, and 7 saliva metabolites, primarily lipids and amino acids, associated with both DAL and CKD progression. Of these, 8 serum, 2 urine, and one stool metabolites were found to mediate the DAL-CKD association. Furthermore, the stool metabolite 5-methylhexanoate (i7:0) correlated with 26 gut microbial species. Our findings emphasize the gut microbiota's therapeutic potential in countering DAL's impact on CKD through the host metabolome. Interventional and longitudinal studies are needed to establish causality.
PMID:38433906 | PMC:PMC10907771 | DOI:10.1016/j.isci.2024.109132
Single-cell RNA sequencing reveals epithelial cells driving brain metastasis in lung adenocarcinoma
iScience. 2024 Feb 16;27(3):109258. doi: 10.1016/j.isci.2024.109258. eCollection 2024 Mar 15.
ABSTRACT
Brain metastases (BM) of lung adenocarcinoma (LUAD) are the most common intracranial malignancy leading to death. However, the cellular origins and drivers of BM from LUAD have not been clarified. Cellular composition was characterized by single-cell sequencing analysis of primary lung adenocarcinoma (pLUAD), BM and lymph node metastasis (LNM) samples in GSE131907. Our study briefly analyzed the tumor microenvironment (TME), focusing on the role of epithelial cells (ECs) in BM. We have discovered a population of brain metastasis-associated epithelial cells (BMAECs) expressing SPP1, SAA1, and CDKN2A, and it has been observed that this population is mainly composed of aneuploid cells from pLUAD, playing a crucial role in brain metastasis. Our study concluded that both LNM and BM in LUAD originated from pLUAD lesions, but there is currently insufficient evidence to prove a direct association between BM lesions and LNM lesions, which provides inspiration for further investigation of the TME in BM.
PMID:38433899 | PMC:PMC10905006 | DOI:10.1016/j.isci.2024.109258
B cell repertoire sequencing of HIV-1 pediatric elite-neutralizers identifies multiple broadly neutralizing antibody clonotypes
Front Immunol. 2024 Feb 16;15:1272493. doi: 10.3389/fimmu.2024.1272493. eCollection 2024.
ABSTRACT
INTRODUCTION: A limited subset of HIV-1 infected adult individuals typically after at least 2-3 years of chronic infection, develop broadly neutralizing antibodies (bnAbs), suggesting that highly conserved neutralizing epitopes on the HIV-1 envelope glycoprotein are difficult for B cell receptors to effectively target, during natural infection. Recent studies have shown the evolution of bnAbs in HIV-1 infected infants.
METHODS: We used bulk BCR sequencing (BCR-seq) to profile the B cell receptors from longitudinal samples (3 time points) collected from a rare pair of antiretroviralnaïve, HIV-1 infected pediatric monozygotic twins (AIIMS_329 and AIIMS_330) who displayed elite plasma neutralizing activity against HIV-1.
RESULTS: BCR-seq of both twins revealed convergent antibody characteristics including V-gene use, CDRH3 lengths and somatic hypermutation (SHM). Further, antibody clonotypes with genetic features similar to highly potent bnAbs isolated from adults showed ongoing development in donor AIIMS_330 but not in AIIMS_329, corroborating our earlier findings based on plasma bnAbs responses. An increase in SHM was observed in sequences of the IgA isotype from AIIMS_330.
DISCUSSION: This study suggests that children living with chronic HIV-1 can develop clonotypes of HIV-1 bnAbs against multiple envelope epitopes similar to those isolated from adults, highlighting that such B cells could be steered to elicit bnAbs responses through vaccines aimed to induce bnAbs against HIV-1 in a broad range of people including children.
PMID:38433846 | PMC:PMC10905035 | DOI:10.3389/fimmu.2024.1272493