Bioinformatics. 2024 Aug 20:btae512. doi: 10.1093/bioinformatics/btae512. Online ahead of print.

ABSTRACT

MOTIVATION: Single cell RNA sequencing (scRNA-seq) data is widely used to study cancer cell states and their heterogeneity. However, the tumour microenvironment is usually a mixture of healthy and cancerous cells and it can be difficult to fully separate these two populations based on transcriptomics alone. If available, somatic single nucleotide variants (SNVs) observed in the scRNA-seq data could be used to identify the cancer population and match that information with the single cells' expression profile. However, calling somatic SNVs in scRNA-seq data is a challeng-ing task, as most variants seen in the short read data are not somatic, but can instead be germline variants, RNA edits or transcription, sequencing or processing errors. Additionally, only variants present in actively transcribed regions for each individual cell will be seen in the data.

RESULTS: To address these challenges, we develop CCLONE (Cancer Cell Labelling On Noisy Expression), an interpretable tool adapted to handle the uncertainty and sparsity of SNVs called from scRNA-seq data. CCLONE jointly identifies cancer clonal populations, and their associated variants. We apply CCLONE on two acute myeloid leukaemia datasets and one lung adenocarcinoma dataset and show that CCLONE captures both genetic clones and somatic events for multiple patients. These results show how CCLONE can be used to gather insight into the course of the disease and the origin of cancer cells in scRNA-seq data.

AVAILABILITY AND IMPLEMENTATION: Source code is available at github.com/HaghverdiLab/CCLONE.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:39163479 | DOI:10.1093/bioinformatics/btae512

Cell Rep. 2024 Aug 19;43(8):114640. doi: 10.1016/j.celrep.2024.114640. Online ahead of print.

ABSTRACT

Functional enhancer annotation is critical for understanding tissue-specific transcriptional regulation and prioritizing disease-associated non-coding variants. However, unbiased enhancer discovery in disease-relevant contexts remains challenging. To identify enhancers pertinent to diabetes, we conducted a CRISPR interference (CRISPRi) screen in the human pluripotent stem cell (hPSC) pancreatic differentiation system. Among the enhancers identified, we focused on an enhancer we named ONECUT1e-664kb, ∼664 kb from the ONECUT1 promoter. Previous studies have linked ONECUT1 coding mutations to pancreatic hypoplasia and neonatal diabetes. We found that homozygous deletion of ONECUT1e-664kb in hPSCs leads to a near-complete loss of ONECUT1 expression and impaired pancreatic differentiation. ONECUT1e-664kb contains a type 2 diabetes-associated variant (rs528350911) disrupting a GATA motif. Introducing the risk variant into hPSCs reduced binding of key pancreatic transcription factors (GATA4, GATA6, and FOXA2), supporting its causal role in diabetes. This work highlights the utility of unbiased enhancer discovery in disease-relevant settings for understanding monogenic and complex disease.

PMID:39163202 | DOI:10.1016/j.celrep.2024.114640

Mol Biotechnol. 2024 Aug 20. doi: 10.1007/s12033-024-01251-1. Online ahead of print.

ABSTRACT

Non-alcoholic fatty acid liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) are the fatal liver diseases which encompass a spectrum of disease severity associated with increased risk of type 2 diabetes mellitus (T2DM), a metabolic disorder. Heat shock proteins serve as markers in early prognosis and diagnosis of early stages of liver diseases associated with metabolic disorder. This review aims to comprehensively investigate the significance of HSP90 isoforms in T2DM and liver diseases. Additionally, we explore the collective knowledge on plant-based drug compounds that regulate HSP90 isoform targets, highlighting their potential in treating T2DM-associated liver diseases. Furthermore, this review focuses on the computational systems' biology and next-generation sequencing technology approaches that are used to unravel the potential medicine for the treatment of pleiotropy of these 2 diseases and to further elucidate the mechanism.

PMID:39162909 | DOI:10.1007/s12033-024-01251-1

FASEB J. 2024 Aug 31;38(16):e70002. doi: 10.1096/fj.202401191R.

ABSTRACT

Breast cancer is one of the threatening malignant tumors with the highest mortality and incidence rate over the world. There are a lot of breast cancer patients dying every year due to the lack of effective and safe therapeutic drugs. Therefore, it is highly necessary to develop more effective drugs to overcome breast cancer. As a glycoside derivative of apigenin, cosmosiin is characterized by low toxicity, high water solubility, and wide distribution in nature. Additionally, cosmosiin has been shown to perform anti-tumor effects in cervical cancer, hepatocellular carcinoma and melanoma. However, its pharmacological effects on breast cancer and its mechanisms are still unknown. In our study, the anti-breast cancer effect and mechanism of cosmosiin were investigated by using breast cancer models in vivo and in vitro. The results showed that cosmosiin inhibited the proliferation, migration, and adhesion of breast cancer cells in vitro and suppressed the growth of tumor in vivo through binding with AhR and inhibiting it, thus regulating the downstream CYP1A1/AMPK/mTOR and PPARγ/Wnt/β-catenin signaling pathways. Collectively, our findings have made contribution to the development of novel drugs against breast cancer by targeting AhR and provided a new direction for the research in the field of anti-breast cancer therapy.

PMID:39162680 | DOI:10.1096/fj.202401191R

Elife. 2024 Aug 20;13:e84955. doi: 10.7554/eLife.84955. Online ahead of print.

ABSTRACT

Accumulating evidence to make decisions is a core cognitive function. Previous studies have tended to estimate accumulation using either neural or behavioral data alone. Here we develop a unified framework for modeling stimulus-driven behavior and multi-neuron activity simultaneously. We applied our method to choices and neural recordings from three rat brain regions - the posterior parietal cortex (PPC), the frontal orienting fields (FOF), and the anterior-dorsal striatum (ADS) - while subjects performed a pulse-based accumulation task. Each region was best described by a distinct accumulation model, which all differed from the model that best described the animal's choices. FOF activity was consistent with an accumulator where early evidence was favored while the ADS reflected near perfect accumulation. Neural responses within an accumulation framework unveiled a distinct association between each brain region and choice. Choices were better predicted from all regions using a comprehensive, accumulation-based framework and different brain regions were found to differentially reflect choice-related accumulation signals: FOF and ADS both reflected choice but ADS showed more instances of decision vacillation. Previous studies relating neural data to behaviorally-inferred accumulation dynamics have implicitly assumed that individual brain regions reflect the whole-animal level accumulator. Our results suggest that different brain regions represent accumulated evidence in dramatically different ways and that accumulation at the whole-animal level may be constructed from a variety of neural-level accumulators.

PMID:39162374 | DOI:10.7554/eLife.84955

Food Funct. 2024 Aug 20. doi: 10.1039/d4fo01446d. Online ahead of print.

ABSTRACT

Management of inflammatory bowel disease (IBD) poses significant challenges, and there is a need for innovative therapeutic approaches. This study investigates the anti-inflammatory properties of the dietary sesquiterpene lactone (SL) 11β,13-dihydrolactucin, which can be found in chicory, in three distinct complementary models of intestinal inflammation (two cell models and a zebrafish model), offering comprehensive insights into its potential application for IBD treatment alternatives. In a triple cell co-culture composed of Caco-2, HT29-MTX-E12, and Raji B, 11β,13-dihydrolactucin demonstrated remarkable anti-inflammatory activity at several levels of the cellular inflammatory response. Notably, 11β,13-dihydrolactucin prevented the activation of critical signalling pathways associated with inflammation, namely NF-κB and MAPK p38. This SL also decreased the release of the neutrophil-recruiting chemokine IL-8. Additionally, the compound reduced the gene expression of IL-6 and TNF-α, as well as the gene and protein expression of the inflammatory inducible enzymes iNOS and COX-2. In a myofibroblast-like human cell model, 11β,13-dihydrolactucin decreased the release of the cytokine TNF-α and the COX-2-derived inflammation mediator PGE2. Finally, in a zebrafish model of gut inflammation, 11β,13-dihydrolactucin effectively reduced neutrophil infiltration, further supporting its anti-inflammatory efficacy in a physiological context. Collectively, our findings highlight the promising anti-inflammatory potential of 11β,13-dihydrolactucin across various facets of intestinal inflammation, providing a foundation for the consideration of chicory as a promising candidate for incorporation in food or nutraceutical products for the potential prevention of IBD.

PMID:39162124 | DOI:10.1039/d4fo01446d

Adv Sci (Weinh). 2024 Aug 20:e2400176. doi: 10.1002/advs.202400176. Online ahead of print.

ABSTRACT

Tuberculosis (TB), the leading cause of death from bacterial infections worldwide, results from infection with Mycobacterium tuberculosis (Mtb). The antitubercular agents delamanid (DLM) and pretomanid (PMD) are nitroimidazole prodrugs that require activation by an enzyme intrinsic to Mtb; however, the mechanism(s) of action and the associated metabolic pathways are largely unclear. Profiling of the chemical-genetic interactions of PMD and DLM in Mtb using combined CRISPR screening reveals that the mutation of rv2073c increases susceptibility of Mtb to these nitroimidazole drugs both in vitro and in infected mice, whereas mutation of rv0078 increases drug resistance. Further assays show that Rv2073c might confer intrinsic resistance to DLM/PMD by interfering with inhibition of the drug target, decaprenylphophoryl-2-keto-b-D-erythro-pentose reductase (DprE2), by active nicotinamide adenine dinucleotide (NAD) adducts. Characterization of the metabolic pathways of DLM/PMD in Mtb using a combination of chemical genetics and comparative liquid chromatography-mass spectrometry (LC-MS) analysis of DLM/PMD metabolites reveals that Rv0077c, which is negatively regulated by Rv0078, mediates drug resistance by metabolizing activated DLM/PMD. These results might guide development of new nitroimidazole prodrugs and new regimens for TB treatment.

PMID:39162029 | DOI:10.1002/advs.202400176

iScience. 2024 Jul 15;27(8):110529. doi: 10.1016/j.isci.2024.110529. eCollection 2024 Aug 16.

ABSTRACT

The cellular and molecular heterogeneity of tumors is a major obstacle to cancer immunotherapy. Here, we use a systems biology approach to derive a signature of the main sources of heterogeneity in the tumor microenvironment (TME) from lung cancer transcriptomics. We demonstrate that this signature, which we called iHet, is conserved in different cancers and associated with antitumor immunity. Through analysis of single-cell and spatial transcriptomics data, we trace back the cellular origin of the variability explaining the iHet signature. Finally, we demonstrate that iHet has predictive value for cancer immunotherapy, which can be further improved by disentangling three major determinants of anticancer immune responses: activity of immune cells, immune infiltration or exclusion, and cancer-cell foreignness. This work shows how transcriptomics data can be integrated to derive a holistic representation of the phenotypic heterogeneity of the TME and to predict its unfolding and fate during immunotherapy with immune checkpoint blockers.

PMID:39161957 | PMC:PMC11331718 | DOI:10.1016/j.isci.2024.110529

Phys Rev E. 2024 Jul;110(1-1):014405. doi: 10.1103/PhysRevE.110.014405.

ABSTRACT

Plants are a paradigm for active shape control in response to stimuli. For instance, it is well known that a tilted plant will eventually straighten vertically, demonstrating the influence of both an external stimulus, gravity, and an internal stimulus, proprioception. These effects can be modulated when a potted plant is additionally rotated along the plant's axis, as in a rotating clinostat, leading to intricate shapes. We use a previously derived rod model to study the response of a growing plant and the joint effects of both stimuli at all rotation speeds. In the absence of rotation, we identify a universal planar shape towards which all shoots eventually converge. With rotation, we demonstrate the existence of a stable family of three-dimensional dynamic equilibria where the plant axis is fixed in space. Further, the effect of axial growth is to induce steady behaviors, such as solitary waves. Overall, this study offers insight into the complex out-of-equilibrium dynamics of a plant in three dimensions and further establishes that internal stimuli in active materials are key for robust shape control.

PMID:39160906 | DOI:10.1103/PhysRevE.110.014405

Nat Metab. 2024 Aug 19. doi: 10.1038/s42255-024-01105-9. Online ahead of print.

ABSTRACT

Metastases arise from subsets of cancer cells that disseminate from the primary tumour1,2. The ability of cancer cells to thrive in a new tissue site is influenced by genetic and epigenetic changes that are important for disease initiation and progression, but these factors alone do not predict if and where cancers metastasize3,4. Specific cancer types metastasize to consistent subsets of tissues, suggesting that primary tumour-associated factors influence where cancers can grow. We find primary and metastatic pancreatic tumours have metabolic similarities and that the tumour-initiating capacity and proliferation of both primary-derived and metastasis-derived cells is favoured in the primary site relative to the metastatic site. Moreover, propagating cells as tumours in the lung or the liver does not enhance their relative ability to form large tumours in those sites, change their preference to grow in the primary site, nor stably alter aspects of their metabolism relative to primary tumours. Primary liver and lung cancer cells also exhibit a preference to grow in their primary site relative to metastatic sites. These data suggest cancer tissue of origin influences both primary and metastatic tumour metabolism and may impact where cancer cells can metastasize.

PMID:39160333 | DOI:10.1038/s42255-024-01105-9

Nat Cell Biol. 2024 Aug 19. doi: 10.1038/s41556-024-01476-x. Online ahead of print.

ABSTRACT

Cells migrating through complex three-dimensional environments experience considerable physical challenges, including tensile stress and compression. To move, cells need to resist these forces while also squeezing the large nucleus through confined spaces. This requires highly coordinated cortical contractility. Microtubules can both resist compressive forces and sequester key actomyosin regulators to ensure appropriate activation of contractile forces. Yet, how these two roles are integrated to achieve nuclear transmigration in three dimensions is largely unknown. Here, we demonstrate that compression triggers reinforcement of a dedicated microtubule structure at the rear of the nucleus by the mechanoresponsive recruitment of cytoplasmic linker-associated proteins, which dynamically strengthens and repairs the lattice. These reinforced microtubules form the mechanostat: an adaptive feedback mechanism that allows the cell to both withstand compressive force and spatiotemporally organize contractility signalling pathways. The microtubule mechanostat facilitates nuclear positioning and coordinates force production to enable the cell to pass through constrictions. Disruption of the mechanostat imbalances cortical contractility, stalling migration and ultimately resulting in catastrophic cell rupture. Our findings reveal a role for microtubules as cellular sensors that detect and respond to compressive forces, enabling movement and ensuring survival in mechanically demanding environments.

PMID:39160291 | DOI:10.1038/s41556-024-01476-x

Commun Biol. 2024 Aug 19;7(1):1015. doi: 10.1038/s42003-024-06695-4.

ABSTRACT

The deep-sea remains the biggest challenge to biodiversity exploration, and anthropogenic disturbances extend well into this realm, calling for urgent management strategies. One of the most diverse, productive, and vulnerable ecosystems in the deep sea are sponge grounds. Currently, environmental DNA (eDNA) metabarcoding is revolutionising the field of biodiversity monitoring, yet complex deep-sea benthic ecosystems remain challenging to assess even with these novel technologies. Here, we evaluate the effectiveness of whole-community metabarcoding to characterise metazoan diversity in sponge grounds across the North Atlantic by leveraging the natural eDNA sampling properties of deep-sea sponges themselves. We sampled 97 sponge tissues from four species across four North-Atlantic biogeographic regions in the deep sea and screened them using the universal COI barcode region. We recovered unprecedented levels of taxonomic diversity per unit effort, especially across the phyla Chordata, Cnidaria, Echinodermata and Porifera, with at least 406 metazoan species found in our study area. These assemblages identify strong spatial patterns in relation to both latitude and depth, and detect emblematic species currently employed as indicators for these vulnerable habitats. The remarkable performance of this approach in different species of sponges, in different biogeographic regions and across the whole animal kingdom, illustrates the vast potential of natural samplers as high-resolution biomonitoring solutions for highly diverse and vulnerable deep-sea ecosystems.

PMID:39160260 | DOI:10.1038/s42003-024-06695-4

PLoS Biol. 2024 Aug 19;22(8):e3002615. doi: 10.1371/journal.pbio.3002615. Online ahead of print.

ABSTRACT

Dynamic properties are essential for microtubule (MT) physiology. Current techniques for in vivo imaging of MTs present intrinsic limitations in elucidating the isotype-specific nuances of tubulins, which contribute to their versatile functions. Harnessing the power of the AlphaFold2 pipeline, we engineered a strategy for the minimally invasive fluorescence labeling of endogenous tubulin isotypes or those harboring missense mutations. We demonstrated that a specifically designed 16-amino acid linker, coupled with sfGFP11 from the split-sfGFP system and integration into the H1-S2 loop of tubulin, facilitated tubulin labeling without compromising MT dynamics, embryonic development, or ciliogenesis in Caenorhabditis elegans. Extending this technique to human cells and murine oocytes, we visualized MTs with the minimal background fluorescence and a pathogenic tubulin isoform with fidelity. The utility of our approach across biological contexts and species set an additional paradigm for studying tubulin dynamics and functional specificity, with implications for understanding tubulin-related diseases known as tubulinopathies.

PMID:39159282 | DOI:10.1371/journal.pbio.3002615

mSystems. 2024 Aug 19:e0024224. doi: 10.1128/msystems.00242-24. Online ahead of print.

ABSTRACT

Although long-read sequencing has enabled obtaining high-quality and complete genomes from metagenomes, many challenges still remain to completely decompose a metagenome into its constituent prokaryotic and viral genomes. This study focuses on decomposing an estuarine metagenome to obtain a more accurate estimate of microbial diversity. To achieve this, we developed a new bead-based DNA extraction method, a novel bin refinement method, and obtained 150 Gbp of Nanopore sequencing. We estimate that there are ~500 bacterial and archaeal species in our sample and obtained 68 high-quality bins (>90% complete, <5% contamination, ≤5 contigs, contig length of >100 kbp, and all ribosomal and tRNA genes). We also obtained many contigs of picoeukaryotes, environmental DNA of larger eukaryotes such as mammals, and complete mitochondrial and chloroplast genomes and detected ~40,000 viral populations. Our analysis indicates that there are only a few strains that comprise most of the species abundances.

IMPORTANCE: Ocean and estuarine microbiomes play critical roles in global element cycling and ecosystem function. Despite the importance of these microbial communities, many species still have not been cultured in the lab. Environmental sequencing is the primary way the function and population dynamics of these communities can be studied. Long-read sequencing provides an avenue to overcome limitations of short-read technologies to obtain complete microbial genomes but comes with its own technical challenges, such as needed sequencing depth and obtaining high-quality DNA. We present here new sampling and bioinformatics methods to attempt decomposing an estuarine microbiome into its constituent genomes. Our results suggest there are only a few strains that comprise most of the species abundances from viruses to picoeukaryotes, and to fully decompose a metagenome of this diversity requires 1 Tbp of long-read sequencing. We anticipate that as long-read sequencing technologies continue to improve, less sequencing will be needed.

PMID:39158287 | DOI:10.1128/msystems.00242-24

Front Cell Neurosci. 2024 Aug 2;18:1434459. doi: 10.3389/fncel.2024.1434459. eCollection 2024.

ABSTRACT

Mitochondria are responsible for maintaining cellular energy levels, and play a major role in regulating homeostasis, which ensures physiological function from the molecular to whole animal. Sirtuin 3 (SIRT3) is the major protein deacetylase of mitochondria. SIRT3 serves as a nutrient sensor; under conditions of mild metabolic stress, SIRT3 activity is increased. Within the mitochondria, SIRT3 regulates every complex of the electron transport chain, the tricarboxylic acid (TCA) and urea cycles, as well as the mitochondria membrane potential, and other free radical scavengers. This article reviews the role of SIRT3 in regulating homeostasis, and thus physiological function. We discuss the role of SIRT3 in regulating reactive oxygen species (ROS), ATP, immunological function and mitochondria dynamics.

PMID:39157755 | PMC:PMC11327144 | DOI:10.3389/fncel.2024.1434459

IEEE Trans Circuits Syst I Regul Pap. 2023 Jan;70(1):3-16. doi: 10.1109/tcsi.2022.3199561. Epub 2022 Aug 24.

ABSTRACT

This paper describes an adaptive noise generator circuit suitable for on-chip simulations of stochastic chemical kinetics. The circuit uses amplified BJT white noise and adaptive low-pass filtering to emulate the power spectrum and autocorrelation of random telegraph signals (RTS) with Poisson-distributed level transitions. A current-mode implementation in the AMS 0.35 μm BiCMOS process shows excellent agreement with theoretical results from the Gillespie stochastic simulation algorithm over a 60 dB range in mean current levels (modeling molecule count numbers). The circuit has an estimated layout area of 0.032 mm2 and typically consumes 400 μA, which are 73% and 50% less, respectively, than prior implementations. Moreover, it does not require any off-chip capacitors. Experimental results from a discrete board-level implementation of the circuit are in good agreement with theoretical predictions.

PMID:39157673 | PMC:PMC11329235 | DOI:10.1109/tcsi.2022.3199561

IEEE Open J Eng Med Biol. 2024 Jul 12;5:573-575. doi: 10.1109/OJEMB.2024.3426912. eCollection 2024.

ABSTRACT

The study of biological processes involving live microscopy techniques requires adequate temperature control to respect the physiology of the organism under study. We present here a design strategy for a microscope temperature stage based on thermoelectric elements. The design allows the user to access a range of temperatures below and above room temperature and can accommodate samples of different geometries. In addition, by cooling simultaneously the sample insert and the objective, we minimize the temperature gradients along the sample for large magnification objectives requiring immersion oil. We illustrate how this design can be used to study the physiology of the zebrafish embryo over the temperature tolerance of this species. We envision that this device could benefit the communities using model and non-model organisms with physiological temperatures different from typical mammalian cell culture incubation in biomedical research.

PMID:39157062 | PMC:PMC11329223 | DOI:10.1109/OJEMB.2024.3426912

Cancer Heterog Plast. 2024;1(1):0004. doi: 10.47248/chp2401010004. Epub 2024 Jul 25.

ABSTRACT

Single-cell analysis has become an essential tool in modern biological research, providing unprecedented insights into cellular behavior and heterogeneity. By examining individual cells, this approach surpasses conventional population-based methods, revealing critical variations in cellular states, responses to environmental cues, and molecular signatures. In the context of cancer, with its diverse cell populations, single-cell analysis is critical for investigating tumor evolution, metastasis, and therapy resistance. Understanding the phenotype-genotype relationship at the single-cell level is crucial for deciphering the molecular mechanisms driving tumor development and progression. This review highlights innovative strategies for selective cell isolation based on desired phenotypes, including robotic aspiration, laser detachment, microraft arrays, optical traps, and droplet-based microfluidic systems. These advanced tools facilitate high-throughput single-cell phenotypic analysis and sorting, enabling the identification and characterization of specific cell subsets, thereby advancing therapeutic innovations in cancer and other diseases.

PMID:39156821 | PMC:PMC11328949 | DOI:10.47248/chp2401010004

J Infect Public Health. 2024 Aug 10;17(9):102516. doi: 10.1016/j.jiph.2024.102516. Online ahead of print.

ABSTRACT

BACKGROUND: Toxoplasmosis is potentially avoidable, treatable, and curable by simple and direct preventive measures. Knowledge, attitudes, and practices (KAP) assessments concerning gestational toxoplasmosis were evaluated in a cohort of pregnant women from Armenia-Quindío (Colombia, South America).

METHODS: This cross-sectional descriptive KAP-type study was performed with informed consent between October 2021 and March 2022. The intervention involved a ten-minute talk administered by prenatal clinic nurses to pregnant women. This took place in the public health clinic RedSalud and the private clinic Happy Maternity with a post-KAP survey after pregnancy.

RESULTS: The findings of the initial KAP survey revealed that approximately 42.8 % of the 250 mothers surveyed had IgG anti-T. gondii antibodies present. A strong correlation was observed between a lower frequency of antibodies and a higher level of education. Following an educational intervention, 73 seronegative women demonstrated a significant improvement in their knowledge and behavior. Among the 111 mothers who received the intervention, 42 (37 %) were followed until delivery. Unfortunately, their level of compliance with prenatal serological follow-up was lower compared to previous historical records of cohort of mothers in the same health center during pre-pandemic periods. No seroconversion occurred, although the small number of cases makes the outcome inconclusive with respect to statistical significance.

CONCLUSIONS: Education plays a crucial role in imparting valuable knowledge and fostering effective practices. It holds significant potential to prevent toxoplasmosis in pregnant seronegative mothers. Prenatal check-ups have proven to be a critical determinant in leveraging the benefits of education for seronegative mothers. Reporting and observed behaviors differed, identifying areas for improvement.

PMID:39154433 | DOI:10.1016/j.jiph.2024.102516

Commun Biol. 2024 Aug 18;7(1):1013. doi: 10.1038/s42003-024-06676-7.

ABSTRACT

Yersinia pestis has been infecting humans since the Late Neolithic (LN). Whether those early infections were isolated zoonoses or initiators of a pandemic remains unclear. We report Y. pestis infections in two individuals (of 133) from the LN necropolis at Warburg (Germany, 5300-4900 cal BP). Our analyses show that the two genomes belong to distinct strains and reflect independent infection events. All LN genomes known today (n = 4) are basal in the phylogeny and represent separate lineages that probably originated in different animal hosts. In the LN, an opening of the landscape resulted in the introduction of new rodent species, which may have acted as Y. pestis reservoirs. Coincidentally, the number of dogs increased, possibly leading to Y. pestis infections in canines. Indeed, we detect Y. pestis in an LN dog. Collectively, our data suggest that Y. pestis frequently entered human settlements at the time without causing significant outbreaks.

PMID:39155318 | DOI:10.1038/s42003-024-06676-7