iScience. 2023 Sep 14;26(10):107917. doi: 10.1016/j.isci.2023.107917. eCollection 2023 Oct 20.

ABSTRACT

The activation of IKK/NF-κB by genotoxic stress is a crucial process in the DNA damage response. Due to the anti-apoptotic impact of NF-κB, it can affect cell-fate decisions upon DNA damage and therefore interfere with tumor therapy-induced cell death. Here, we developed a dynamical model describing IKK/NF-κB signaling that faithfully reproduces quantitative time course data and enables a detailed analysis of pathway regulation. The approach elucidates a pathway topology with two hubs, where the first integrates signals from two DNA damage sensors and the second forms a coherent feedforward loop. The analyses reveal a critical role of the sensor protein PARP-1 in the pathway regulation. Introducing a method for calculating the impact of changes in individual components on pathway activity in a time-resolved manner, we show how irradiation dose influences pathway activation. Our results give a mechanistic understanding relevant for the interpretation of experimental and clinical studies.

PMID:37817938 | PMC:PMC10561052 | DOI:10.1016/j.isci.2023.107917

iScience. 2023 Sep 15;26(10):107914. doi: 10.1016/j.isci.2023.107914. eCollection 2023 Oct 20.

ABSTRACT

Epidemiological data and research highlight increased neuropathy and chronic pain prevalence among females, spanning metabolic and normometabolic contexts, including murine models. Prior findings demonstrated diverse immune and neuroimmune responses between genders in neuropathic pain (NeP), alongside distinct protein expression in sciatic nerves. This study unveils adipose tissue's (AT) role in sex-specific NeP responses after peripheral nerve injury. Metabolic assessments, metabolomics, energy expenditure evaluations, AT proteomic analyses, and adipokine mobilization depict distinct AT reactions to nerve damage. Females exhibit altered lipolysis, fatty acid oxidation, heightened energy expenditure, and augmented steroids secretion affecting glucose and insulin metabolism. Conversely, male neuropathy prompts glycolysis, reduced energy expenditure, and lowered unsaturated fatty acid levels. Males' AT promotes regenerative molecules, oxidative stress defense, and stimulates peroxisome proliferator-activated receptors (PPAR-γ) and adiponectin. This study underscores AT's pivotal role in regulating gender-specific inflammatory and metabolic responses to nerve injuries, shedding light on female NeP susceptibility determinants.

PMID:37817933 | PMC:PMC10561049 | DOI:10.1016/j.isci.2023.107914

Proc Biol Sci. 2023 Oct 11;290(2008):20231029. doi: 10.1098/rspb.2023.1029. Epub 2023 Oct 11.

ABSTRACT

Variation in formant frequencies has been shown to affect social interactions and sexual competition in a range of avian species. Yet, the anatomical bases of this variation are poorly understood. Here, we investigated the morphological correlates of formants production in the vocal apparatus of African penguins. We modelled the geometry of the supra-syringeal vocal tract of 20 specimens to generate a population of virtual vocal tracts with varying dimensions. We then estimated the acoustic response of these virtual vocal tracts and extracted the centre frequency of the first four predicted formants. We demonstrate that: (i) variation in length and cross-sectional area of vocal tracts strongly affects the formant pattern, (ii) the tracheal region determines most of this variation, and (iii) the skeletal size of penguins does not correlate with the trachea length and consequently has relatively little effect on formants. We conclude that in African penguins, while the variation in vocal tract geometry generates variation in resonant frequencies supporting the discrimination of conspecifics, such variation does not provide information on the emitter's body size. Overall, our findings advance our understanding of the role of formant frequencies in bird vocal communication.

PMID:37817600 | DOI:10.1098/rspb.2023.1029

Proc Biol Sci. 2023 Oct 11;290(2008):20231494. doi: 10.1098/rspb.2023.1494. Epub 2023 Oct 11.

ABSTRACT

Supergenes, tightly linked sets of alleles, offer some of the most spectacular examples of polymorphism persisting under long-term balancing selection. However, we still do not understand their evolution and persistence, especially in the face of accumulation of deleterious elements. Here, we show that an overdominant supergene in seaweed flies, Coelopa frigida, modulates male traits, potentially facilitating disassortative mating and promoting intraspecific polymorphism. Across two continents, the Cf-Inv(1) supergene strongly affected the composition of male cuticular hydrocarbons (CHCs) but only weakly affected CHC composition in females. Using gas chromatography-electroantennographic detection, we show that females can sense male CHCs and that there may be differential perception between genotypes. Combining our phenotypic results with RNA-seq data, we show that candidate genes for CHC biosynthesis primarily show differential expression for Cf-Inv(1) in males but not females. Conversely, candidate genes for odorant detection were differentially expressed in both sexes but showed high levels of divergence between supergene haplotypes. We suggest that the reduced recombination between supergene haplotypes may have led to rapid divergence in mate preferences as well as increasing linkage between male traits, and overdominant loci. Together this probably helped to maintain the polymorphism despite deleterious effects in homozygotes.

PMID:37817592 | DOI:10.1098/rspb.2023.1494

Electrophoresis. 2023 Oct 10. doi: 10.1002/elps.202300030. Online ahead of print.

ABSTRACT

The bamboo shoot of Pleioblastus amarus (Keng) Keng f. is a medicinal and edible resource in China. In this study, three separation techniques were applied to identify the primary and secondary metabolites component of P. amarus bamboo shoots, including sheathless capillary electrophoresis electrospray ionization-mass spectrometry (CESI-MS), reverse-phase liquid chromatography-MS (RPLC-MS), and hydrophilic interaction liquid chromatography-MS (HILIC-MS). A total of 201 metabolites were identified by the three methods. Among those metabolites, 146 were identified by RPLC-MS, 85 were identified by HILIC-MS, and 46 were identified by sheathless CESI-MS. These methods were complementary and had a linear coefficient. CESI-MS presented advantages in the identification of isomers, high sensitivity, very low sample usage, and good detection of polar and nonpolar metabolites, showing its unique applications in food analysis and prospects in metabolic research.

PMID:37817363 | DOI:10.1002/elps.202300030

Microb Physiol. 2023 Oct 10. doi: 10.1159/000534425. Online ahead of print.

ABSTRACT

The denitrifying betaproteobacterium Aromatoleum aromaticum EbN1T is a facultative anaerobic degradation specialist and belongs to the environmental bacteria studied best on the proteogenomic level. This review summarizes the current state of knowledge about the anaerobic and aerobic degradation (to CO2) of 47 organic growth substrates (23 aromatic, 21 aliphatic, and 3 amino acids) as well as the modes of respiratory energy conservation (denitrification vs. O2-respiration). The constructed catabolic network is comprised of 256 genes, which occupy ~7.5% of the coding regions of the genome. In total 219 encoded proteins have been identified by differential proteomics, yielding a proteome coverage of ~74% of the network. Its degradation section is composed of 31 peripheral and 4 central pathways, with several peripheral modules (e.g., for 4-ethylphenol, 2-phenylethylamine, indoleacetate, and phenylpropanoids) discovered only after the complete genome [Rabus et al., Arch Microbiol 2005 Jan;183(1):27‒36] and a first proteomic survey [Wöhlbrand et al., Proteomics 2007 Jun;7(13):2222‒39] of A. aromaticum EbN1T were reported. The activation of recalcitrant aromatic compounds involves a suite of biochemically intriguing reactions ranging from CH-bond activation (e.g., ethylbenzene dehydrogenase) via carboxylation (e.g., acetophenone carboxylase) to oxidative deamination (e.g., benzylamine), reductive dearomatization (benzoyl-CoA), and epoxide-forming oxygenases (e.g., phenylacetyl-CoA). The peripheral reaction sequences are substrate-specifically induced, mediated by specific transcriptional regulators with in vivo response thresholds in the nanomolar range. While lipophilic substrates (e.g., phenolics) enter the cells via passive diffusion, polar ones require active uptake that is driven by specific transporters. Next to the protein repertoire for canonical complexes I‒III, denitrification and O2-respiration (low and high affinity oxidases), the genome encodes an Ndh-II, a tetrathionate reductase, two ETF:quinone oxidoreductases, and two Rnf-type complexes, broadening the electron transfer flexibility of the strain. Taken together, the detailed catabolic network presented here forms a solid basis for future systems biology level studies with A. aromaticum EbN1T.

PMID:37816339 | DOI:10.1159/000534425

Nat Commun. 2023 Oct 10;14(1):6328. doi: 10.1038/s41467-023-42093-w.

ABSTRACT

Metabolic reprogramming is one of the hallmarks of tumorigenesis. Here, we show that nuclear myosin 1 (NM1) serves as a key regulator of cellular metabolism. NM1 directly affects mitochondrial oxidative phosphorylation (OXPHOS) by regulating mitochondrial transcription factors TFAM and PGC1α, and its deletion leads to underdeveloped mitochondria inner cristae and mitochondrial redistribution within the cell. These changes are associated with reduced OXPHOS gene expression, decreased mitochondrial DNA copy number, and deregulated mitochondrial dynamics, which lead to metabolic reprogramming of NM1 KO cells from OXPHOS to aerobic glycolysis.This, in turn, is associated with a metabolomic profile typical for cancer cells, namely increased amino acid-, fatty acid-, and sugar metabolism, and increased glucose uptake, lactate production, and intracellular acidity. NM1 KO cells form solid tumors in a mouse model, suggesting that the metabolic switch towards aerobic glycolysis provides a sufficient carcinogenic signal. We suggest that NM1 plays a role as a tumor suppressor and that NM1 depletion may contribute to the Warburg effect at the onset of tumorigenesis.

PMID:37816864 | DOI:10.1038/s41467-023-42093-w

Acta Pharmacol Sin. 2023 Oct 10. doi: 10.1038/s41401-023-01164-w. Online ahead of print.

ABSTRACT

Extracellular regulated protein kinases 1/2 (ERK1/2) are key members of multiple signaling pathways, including the ErbB axis. Ectopic ERK1/2 activation contributes to various types of cancer, especially drug resistance to inhibitors of RTK, RAF and MEK, and specific ERK1/2 inhibitors are scarce. In this study, we identified a potential novel covalent ERK inhibitor, Laxiflorin B, which is a herbal compound with anticancer activity. However, Laxiflorin B is present at low levels in herbs; therefore, we adopted a semi-synthetic process for the efficient production of Laxiflorin B to improve the yield. Laxiflorin B induced mitochondria-mediated apoptosis via BAD activation in non-small-cell lung cancer (NSCLC) cells, especially in EGFR mutant subtypes. Transcriptomic analysis suggested that Laxiflorin B inhibits amphiregulin (AREG) and epiregulin (EREG) expression through ERK inhibition, and suppressed the activation of their receptors, ErbBs, via a positive feedback loop. Moreover, mass spectrometry analysis combined with computer simulation revealed that Laxiflorin B binds covalently to Cys-183 in the ATP-binding pocket of ERK1 via the D-ring, and Cys-178 of ERK1 through non-inhibitory binding of the A-ring. In a NSCLC tumor xenograft model in nude mice, Laxiflorin B also exhibited strong tumor suppressive effects with low toxicity and AREG and EREG were identified as biomarkers of Laxiflorin B efficacy. Finally, Laxiflorin B-4, a C-6 analog of Laxiflorin B, exhibited higher binding affinity for ERK1/2 and stronger tumor suppression. These findings provide a new approach to tumor inhibition using natural anticancer compounds.

PMID:37816856 | DOI:10.1038/s41401-023-01164-w

NPJ Syst Biol Appl. 2023 Oct 10;9(1):50. doi: 10.1038/s41540-023-00310-8.

ABSTRACT

Deep neural networks display impressive performance but suffer from limited interpretability. Biology-inspired deep learning, where the architecture of the computational graph is based on biological knowledge, enables unique interpretability where real-world concepts are encoded in hidden nodes, which can be ranked by importance and thereby interpreted. In such models trained on single-cell transcriptomes, we previously demonstrated that node-level interpretations lack robustness upon repeated training and are influenced by biases in biological knowledge. Similar studies are missing for related models. Here, we test and extend our methodology for reliable interpretability in P-NET, a biology-inspired model trained on patient mutation data. We observe variability of interpretations and susceptibility to knowledge biases, and identify the network properties that drive interpretation biases. We further present an approach to control the robustness and biases of interpretations, which leads to more specific interpretations. In summary, our study reveals the broad importance of methods to ensure robust and bias-aware interpretability in biology-inspired deep learning.

PMID:37816807 | DOI:10.1038/s41540-023-00310-8

NPJ Syst Biol Appl. 2023 Oct 10;9(1):49. doi: 10.1038/s41540-023-00311-7.

ABSTRACT

Proteomics technologies, which include a diverse range of approaches such as mass spectrometry-based, array-based, and others, are key technologies for the identification of biomarkers and disease mechanisms, referred to as mechanotyping. Despite over 15,000 published studies in 2022 alone, leveraging publicly available proteomics data for biomarker identification, mechanotyping and drug target identification is not readily possible. Proteomic data addressing similar biological/biomedical questions are made available by multiple research groups in different locations using different model organisms. Furthermore, not only various organisms are employed but different assay systems, such as in vitro and in vivo systems, are used. Finally, even though proteomics data are deposited in public databases, such as ProteomeXchange, they are provided at different levels of detail. Thus, data integration is hampered by non-harmonized usage of identifiers when reviewing the literature or performing meta-analyses to consolidate existing publications into a joint picture. To address this problem, we present ProHarMeD, a tool for harmonizing and comparing proteomics data gathered in multiple studies and for the extraction of disease mechanisms and putative drug repurposing candidates. It is available as a website, Python library and R package. ProHarMeD facilitates ID and name conversions between protein and gene levels, or organisms via ortholog mapping, and provides detailed logs on the loss and gain of IDs after each step. The web tool further determines IDs shared by different studies, proposes potential disease mechanisms as well as drug repurposing candidates automatically, and visualizes these results interactively. We apply ProHarMeD to a set of four studies on bone regeneration. First, we demonstrate the benefit of ID harmonization which increases the number of shared genes between studies by 50%. Second, we identify a potential disease mechanism, with five corresponding drug targets, and the top 20 putative drug repurposing candidates, of which Fondaparinux, the candidate with the highest score, and multiple others are known to have an impact on bone regeneration. Hence, ProHarMeD allows users to harmonize multi-centric proteomics research data in meta-analyses, evaluates the success of the ID conversions and remappings, and finally, it closes the gaps between proteomics, disease mechanism mining and drug repurposing. It is publicly available at https://apps.cosy.bio/proharmed/ .

PMID:37816770 | DOI:10.1038/s41540-023-00311-7

Sci Rep. 2023 Oct 10;13(1):17066. doi: 10.1038/s41598-023-43602-z.

ABSTRACT

In Saccharomyces cerevisiae, intracellular glucose levels impact glucose transport and regulate carbon metabolism via various glucose sensors. To investigate mechanisms of glucose sensing, it is essential to know the intracellular glucose concentrations. Measuring intracellular glucose concentrations, however, is challenging when cells are grown on glucose, as glucose in the water phase around cells or stuck to the cell surface can be carried over during cell sampling and in the following attributed to intracellular glucose, resulting in an overestimation of intracellular glucose concentrations. Using lactose as a carryover marker in the growth medium, we found that glucose carryover originates from both the water phase and from sticking to the cell surface. Using a hexokinase null strain to estimate the glucose carryover from the cell surface, we found that glucose stuck on the cell surface only contributes a minor fraction of the carryover. To correct the glucose carryover, we revisited L-glucose as a carryover marker. Here, we found that L-glucose slowly enters cells. Thus, we added L-glucose to yeast cultures growing on uniformly 13C-labeled D-glucose only shortly before sampling. Using GC-MS to distinguish between the two differently labeled sugars and subtracting the carryover effect, we determined the intracellular glucose concentrations among two yeast strains with distinct kinetics of glucose transport to be at 0.89 mM in the wild-type strain and around 0.24 mM in a mutant with compromised glucose uptake. Together, our study provides insight into the origin of the glucose carryover effect and suggests that L-glucose added to the culture shortly before sampling is a possible method that yet has limitations with regard to measurement accuracy.

PMID:37816759 | DOI:10.1038/s41598-023-43602-z

Anal Chem. 2023 Oct 10. doi: 10.1021/acs.analchem.3c01673. Online ahead of print.

ABSTRACT

Cross-linking mass spectrometry (MS) is currently transitioning from a routine tool in structural biology to enabling structural systems biology. MS-cleavable cross-linkers could substantially reduce the associated search space expansion by allowing a MS3-based approach for identifying cross-linked peptides. However, MS2 (MS/MS)-based approaches currently outperform approaches utilizing MS3. We show here that the sensitivity and specificity of triggering MS3 have been hampered algorithmically. Our four-step MS3-trigger algorithm greatly outperformed currently employed methods and comes close to reaching the theoretical limit.

PMID:37816155 | DOI:10.1021/acs.analchem.3c01673

Hepatology. 2023 Oct 9. doi: 10.1097/HEP.0000000000000629. Online ahead of print.

ABSTRACT

BACKGROUND AIMS: Hepatocellular carcinoma (HCC) is closely associated with inflammation and immune modulation, and combined chemotherapy with other strategies is under extensive investigation to achieve better efficacy. HCC is accompanied by zinc deficiency. This study aims to understand how zinc could affect macrophage function and its application for HCC therapy.

APPROACH RESULTS: Zn2+ and the zinc transporter 1 (ZNT1, SLC30A1) were markedly reduced in intrahepatic macrophages from HCC patients and mouse liver tumors. Lower ZNT1 expression was associated with higher IL-6 production and shorter survival time in HCC patients. Critically, ZNT1 regulated endosomal Zn2+ levels for endocytosis of TLR4 and PD-L1, thereby decreasing macrophage-induced inflammation and immunosuppression to protect from liver tumors. Myeloid-specific deletion of ZNT1 in mice increased chronic inflammation, liver fibrosis, tumor numbers, and size. Notably, zinc supplementation could reduce inflammation and surface PD-L1 expression in macrophages with the increased CD8+ T cell cytotoxicity, which synergized the anti-tumor efficacy of Sorafenib/Lenvatinib.

CONCLUSIONS: Our study proposes a new concept that ZNT1 and zinc regulate endosome endocytosis to maintain surface receptors and zinc supplements might be synergized with chemotherapy to treat inflammation-associated tumors, especially those containing PD-L1+ myeloid cells.

PMID:37816045 | DOI:10.1097/HEP.0000000000000629

PLoS One. 2023 Oct 10;18(10):e0286846. doi: 10.1371/journal.pone.0286846. eCollection 2023.

ABSTRACT

Fruits play a crucial role in seed dispersal. They open along dehiscence zones. Fruit dehiscence zone formation has been intensively studied in Arabidopsis thaliana. However, little is known about the mechanisms and genes involved in the formation of fruit dehiscence zones in species outside the Brassicaceae. The dehiscence zone of A. thaliana contains a lignified layer, while dehiscence zone tissues of the emerging orchid model Erycina pusilla include a lipid layer. Here we present an analysis of evolution and development of fruit dehiscence zones in orchids. We performed ancestral state reconstructions across the five orchid subfamilies to study the evolution of selected fruit traits and explored dehiscence zone developmental genes using RNA-seq and qPCR. We found that erect dehiscent fruits with non-lignified dehiscence zones and a short ripening period are ancestral characters in orchids. Lignified dehiscence zones in orchid fruits evolved multiple times from non-lignified zones. Furthermore, we carried out gene expression analysis of tissues from different developmental stages of E. pusilla fruits. We found that fruit dehiscence genes from the MADS-box gene family and other important regulators in E. pusilla differed in their expression pattern from their homologs in A. thaliana. This suggests that the current A. thaliana fruit dehiscence model requires adjustment for orchids. Additionally, we discovered that homologs of A. thaliana genes involved in the development of carpel, gynoecium and ovules, and genes involved in lipid biosynthesis were expressed in the fruit valves of E. pusilla, implying that these genes may play a novel role in formation of dehiscence zone tissues in orchids. Future functional analysis of developmental regulators, lipid identification and quantification can shed more light on lipid-layer based dehiscence of orchid fruits.

PMID:37815982 | DOI:10.1371/journal.pone.0286846

Glycobiology. 2023 Oct 10:cwad076. doi: 10.1093/glycob/cwad076. Online ahead of print.

ABSTRACT

Galectin-3, well characterized as a glycan binding protein, has been identified as a putative RNA binding protein, possibly through participation in pre-mRNA maturation through interactions with splicosomes. Given recent developments with cell surface RNA biology, the putative dual-function nature of galectin-3 evokes a possible non-classical connection between glycobiology and RNA biology. However, with limited functional evidence of a direct RNA interaction, many molecular-level observations rely on affinity reagents and lack appropriate genetic controls. Thus, evidence of a direct interaction remains elusive. We demonstrate that antibodies raised to endogenous human galectin-3 can isolate RNA-protein crosslinks, but this activity remains insensitive to LGALS3 knock-out. Proteomic characterization of anti-galectin-3 IPs revealed enrichment of galectin-3, but high abundance of hnRNPA2B1, an abundant, well-characterized RNA-binding protein with weak homology to the N-terminal domain of galectin-3, in the isolate. Genetic ablation of HNRNPA2B1, but not LGALS3, eliminates the ability of the anti-galectin-3 antibodies to isolate RNA-protein crosslinks, implying either an indirect interaction or cross-reactivity. To address this, we introduced an epitope tag to the endogenous C-terminal locus of LGALS3. Isolation of the tagged galectin-3 failed to reveal any RNA-protein crosslinks. This result suggests that the galectin-3 does not directly interact with RNA and may be misidentified as an RNA-binding protein, at least in HeLa where the putative RNA associations were first identified. We encourage further investigation of this phenomenon employ gene deletions and, when possible, endogenous epitope tags to achieve the specificity required to evaluate potential interactions.

PMID:37815932 | DOI:10.1093/glycob/cwad076

Elife. 2023 Oct 10;12:RP87406. doi: 10.7554/eLife.87406.

ABSTRACT

Metabolic capacity can vary substantially within a bacterial species, leading to ecological niche separation, as well as differences in virulence and antimicrobial susceptibility. Genome-scale metabolic models are useful tools for studying the metabolic potential of individuals, and with the rapid expansion of genomic sequencing there is a wealth of data that can be leveraged for comparative analysis. However, there exist few tools to construct strain-specific metabolic models at scale. Here, we describe Bactabolize, a reference-based tool which rapidly produces strain-specific metabolic models and growth phenotype predictions. We describe a pan reference model for the priority antimicrobial-resistant pathogen, Klebsiella pneumoniae, and a quality control framework for using draft genome assemblies as input for Bactabolize. The Bactabolize-derived model for K. pneumoniae reference strain KPPR1 performed comparatively or better than currently available automated approaches CarveMe and gapseq across 507 substrate and 2317 knockout mutant growth predictions. Novel draft genomes passing our systematically defined quality control criteria resulted in models with a high degree of completeness (≥99% genes and reactions captured compared to models derived from matched complete genomes) and high accuracy (mean 0.97, n=10). We anticipate the tools and framework described herein will facilitate large-scale metabolic modelling analyses that broaden our understanding of diversity within bacterial species and inform novel control strategies for priority pathogens.

PMID:37815531 | DOI:10.7554/eLife.87406

Adv Sci (Weinh). 2023 Oct 9:e2303576. doi: 10.1002/advs.202303576. Online ahead of print.

ABSTRACT

The efficient activation of professional antigen-presenting cells-such as dendritic cells (DC)-in tumors and lymph nodes is critical for the design of next-generation cancer vaccines and may be able to provide anti-tumor effects by itself through immune stimulation. The challenge is to stimulate these cells without causing excessive toxicity. It is hypothesized that a multi-pronged combinatorial approach to DC stimulation would allow dose reductions of innate immune receptor-stimulating TLR3 agonists while enhancing drug efficacy. Here, a hybrid lipid nanoparticle (LNP) platform is developed and tested for double-stranded RNA (polyinosinic:polycytidylic acid for TLR3 agonism) and immune modulator (L-CANDI) delivery. This study shows that the ≈120 nm hybrid nanoparticles-in-nanoparticles effectively eradicate tumors by themselves and generate long-lasting, durable anti-tumor immunity in mouse models.

PMID:37814359 | DOI:10.1002/advs.202303576

Genome Biol. 2023 Oct 9;24(1):225. doi: 10.1186/s13059-023-03072-y.

ABSTRACT

Application of the widely used droplet-based microfluidic technologies in single-cell sequencing often yields doublets, introducing bias to downstream analyses. Especially, doublet-detection methods for single-cell chromatin accessibility sequencing (scCAS) data have multiple assay-specific challenges. Therefore, we propose scIBD, a self-supervised iterative-optimizing model for boosting heterotypic doublet detection in scCAS data. scIBD introduces an adaptive strategy to simulate high-confident heterotypic doublets and self-supervise for doublet-detection in an iteratively optimizing manner. Comprehensive benchmarking on various simulated and real datasets demonstrates the outperformance and robustness of scIBD. Moreover, the downstream biological analyses suggest the efficacy of doublet-removal by scIBD.

PMID:37814314 | DOI:10.1186/s13059-023-03072-y

Microbiome. 2023 Oct 9;11(1):222. doi: 10.1186/s40168-023-01669-w.

ABSTRACT

BACKGROUND: Host genetics can shape microbiome composition, but to what extent it does, remains unclear. Like any other complex trait, this important question can be addressed by estimating the heritability (h2) of the microbiome-the proportion of variance in the abundance in each taxon that is attributable to host genetic variation. However, unlike most complex traits, microbiome heritability is typically based on relative abundance data, where taxon-specific abundances are expressed as the proportion of the total microbial abundance in a sample.

RESULTS: We derived an analytical approximation for the heritability that one obtains when using such relative, and not absolute, abundances, based on an underlying quantitative genetic model for absolute abundances. Based on this, we uncovered three problems that can arise when using relative abundances to estimate microbiome heritability: (1) the interdependency between taxa can lead to imprecise heritability estimates. This problem is most apparent for dominant taxa. (2) Large sample size leads to high false discovery rates. With enough statistical power, the result is a strong overestimation of the number of heritable taxa in a community. (3) Microbial co-abundances lead to biased heritability estimates.

CONCLUSIONS: We discuss several potential solutions for advancing the field, focusing on technical and statistical developments, and conclude that caution must be taken when interpreting heritability estimates and comparing values across studies. Video Abstract.

PMID:37814275 | DOI:10.1186/s40168-023-01669-w

Nat Commun. 2023 Oct 9;14(1):6302. doi: 10.1038/s41467-023-42168-8.

NO ABSTRACT

PMID:37813889 | DOI:10.1038/s41467-023-42168-8