RSC Med Chem. 2024 Jul 24;15(8):2882-2899. doi: 10.1039/d4md00364k. eCollection 2024 Aug 14.

ABSTRACT

Phosphodiesterase 5 (PDE5), an enzyme responsible for catalyzing the degradation of cyclic guanosine monophosphate (cGMP), has been linked to the development of cancer. PDE5 inhibitors (PDE5i), such as sildenafil (Viagra) and tadalafil (Cialis), work by blocking the action of PDE5 and are used primarily as treatments for erectile dysfunction and arterial hypertension. Some studies suggested a potential link between PDE5i and increased cancer risk, while other studies showed preferable antitumor effects. The present study is attempting to shed light on the systems biology effects of PDE5i by applying an integrative informatics approach followed by experimental validation methods including cell viability, cell motility, and proliferation capacity. Cell cycle and apoptosis analyses were carried out using flow cytometry, while real-time polymerase chain reaction (PCR) and western blotting were used to determine the relative gene and protein expression respectively. Our results indicated that the examined PDE5i significantly inhibited the proliferation of lung cancer cells, in addition to reducing wound closure and the mean colony count and size. Furthermore, PDE5i increased the early and late apoptotic activities and suppressed the gene and protein expression of PDE5 in lung cancer cells. The combination of cisplatin and raloxifene with PDE5i resulted in a synergistic effect. This study provides solid evidence supporting the anti-tumorigenic effect of PDE5i in lung cancer cells.

PMID:39149110 | PMC:PMC11324042 | DOI:10.1039/d4md00364k

Chem Sci. 2024 Jun 26;15(32):12861-12878. doi: 10.1039/d4sc00690a. eCollection 2024 Aug 14.

ABSTRACT

The development of reliable and extensible molecular mechanics (MM) force fields-fast, empirical models characterizing the potential energy surface of molecular systems-is indispensable for biomolecular simulation and computer-aided drug design. Here, we introduce a generalized and extensible machine-learned MM force field, espaloma-0.3, and an end-to-end differentiable framework using graph neural networks to overcome the limitations of traditional rule-based methods. Trained in a single GPU-day to fit a large and diverse quantum chemical dataset of over 1.1 M energy and force calculations, espaloma-0.3 reproduces quantum chemical energetic properties of chemical domains highly relevant to drug discovery, including small molecules, peptides, and nucleic acids. Moreover, this force field maintains the quantum chemical energy-minimized geometries of small molecules and preserves the condensed phase properties of peptides and folded proteins, self-consistently parametrizing proteins and ligands to produce stable simulations leading to highly accurate predictions of binding free energies. This methodology demonstrates significant promise as a path forward for systematically building more accurate force fields that are easily extensible to new chemical domains of interest.

PMID:39148808 | PMC:PMC11322960 | DOI:10.1039/d4sc00690a

Emerg Microbes Infect. 2024 Aug 15:2386136. doi: 10.1080/22221751.2024.2386136. Online ahead of print.

ABSTRACT

AbstractBabesiosis, caused by protozoan parasites of the genus Babesia, is an emerging tick-borne disease of significance for both human and animal health. Babesia parasites infect erythrocytes of vertebrate hosts where they develop and multiply rapidly to cause the pathological symptoms associated with the disease. The identification of new Babesia species underscores the ongoing risk of zoonotic pathogens capable of infecting humans, a concern amplified by anthropogenic activities and environmental changes. One such pathogen, Babesia MO1, previously implicated in severe cases of human babesiosis in the United States, was initially considered a subspecies of B. divergens, the predominant agent of human babesiosis in Europe. Here we report comparative multiomics analyses of B. divergens and B. MO1 that offer insight into their biology and evolution. Our analysis shows that despite their highly similar genomic sequences, substantial genetic and genomic divergence occurred throughout their evolution resulting in major differences in gene functions, expression and regulation, replication rates and susceptibility to antiparasitic drugs. Furthermore, both pathogens have evolved distinct classes of multigene families, crucial for their pathogenicity and adaptation to specific mammalian hosts. Leveraging genomic information for B. MO1, B. divergens, and other members of the Babesiidae family within Apicomplexa provides valuable insights into the evolution, diversity, and virulence of these parasites. This knowledge serves as a critical tool in preemptively addressing the emergence and rapid transmission of more virulent strains.

PMID:39148308 | DOI:10.1080/22221751.2024.2386136

Am J Primatol. 2024 Aug 15:e23671. doi: 10.1002/ajp.23671. Online ahead of print.

ABSTRACT

Contagious yawning (CY)-linked to physiological synchronization and possibly emotional contagion-occurs when one individual's yawn induces yawning in others. CY was investigated over different time windows (minutes from the triggering stimulus) via naturalistic or experimental studies (using real and video yawns, respectively) with contrasting results, especially in bonobos. We verified whether in bonobos result divergences may derive from different methods. We gathered yawning data on 13 bonobos at Twycross Zoo (UK) via a naturalistic (all-occurrences observations) and experimental approach (by showing yawn/control video stimuli). Based on literature, we used 1- and 3-min windows to detect CY. Due to fission-fusion management, individuals could form permanent or non-permanent associations (more/less familiar subjects under naturalistic setting). Video yawn stimuli may come from group mates/stranger models (more/less familiar subjects under the experimental setting). Stimulus type and time window affected CY modulating factors but not CY detection. Familiarity and age effect on CY showed opposite trends in 3-min trials and 1-min observations. CY was highest in oldest, non-permanently (rather than permanently) associated subjects in the naturalistic setting, but in the youngest subjects and with ingroup (rather than outgroup) models in trials. The age effect differences on CY might be due to decontextualized yawns and immature subject curiosity toward videos. The reversed familiarity effect suggests CY's context-dependent function in promoting social synchronization with socially distant group mates, as failing to coordinate as a group may lead to social disruption. Complementary methods are needed to fully understand motor replication phenomena.

PMID:39148223 | DOI:10.1002/ajp.23671

Biochim Biophys Acta Mol Cell Res. 2024 Aug 13:119812. doi: 10.1016/j.bbamcr.2024.119812. Online ahead of print.

ABSTRACT

Protein kinase D (PKD) is a family of serine/threonine kinases that play important roles in various signalling pathways in cells, including neuronal cells. In the nervous system, PKD has been shown to be involved in learning and memory formation by regulating neurotransmitter release, neurite outgrowth and dendrite development, synapse formation and synaptic plasticity. In addition, PKD has been implicated in pain perception or neuroprotection during oxidative stress. Dysregulation of PKD expression and activity has been linked to several neurological disorders, including autism and epilepsy. In this review, we summarize the current knowledge on the function of the PKD family members in neuronal cells, including the spatial regulation of their downstream signalling pathways. We will further discuss the potential role of PKD in the pathogenesis of neurological disorders.

PMID:39147241 | DOI:10.1016/j.bbamcr.2024.119812

J Proteomics. 2024 Aug 13:105280. doi: 10.1016/j.jprot.2024.105280. Online ahead of print.

ABSTRACT

Metabolomics significantly impacts drug discovery and precise disease management. This study meticulously assesses the metabolite profiles of cells treated with Crocin, Dexamethasone, and mesenchymal stem cells (MSCs) under oxidative stress induced by 2-chloroethyl ethyl sulfide (CEES). Gas chromatography/mass spectrometry (GC/MS) analysis unequivocally identified substantial changes in 37 metabolites across the treated groups. Notably, pronounced alterations were observed in pathways associated with aminoacyl-tRNA biosynthesis and the metabolism of aspartate, serine, proline, and glutamate. These findings demonstrate the potent capacity of the analyzed treatments to effectively reduce inflammation, mitigate reactive oxygen species production, and enhance cell survival rates. SIGNIFICANCE.

PMID:39147238 | DOI:10.1016/j.jprot.2024.105280

Free Radic Biol Med. 2024 Aug 13:S0891-5849(24)00598-7. doi: 10.1016/j.freeradbiomed.2024.08.012. Online ahead of print.

ABSTRACT

Despite the overwhelming number of sports supplements on the market, only seven are currently recognized as effective. Biological functions are largely regulated through redox reactions, yet no comprehensive analysis of the redox properties of these supplements has been compiled. Here, we analyze the redox characteristics of these seven supplements: bicarbonates, beta-alanine, caffeine, creatine, nitrates, carbohydrates, and proteins. Our findings suggest that all sports supplements exhibit some degree of redox activity. However, the precise physiological implications of these redox properties remain unclear. Future research, employing unconventional perspectives and methodologies, will reveal new redox pixels of the exercise physiology and sports nutrition picture.

PMID:39147071 | DOI:10.1016/j.freeradbiomed.2024.08.012

Mol Cell Proteomics. 2024 Aug 13:100829. doi: 10.1016/j.mcpro.2024.100829. Online ahead of print.

ABSTRACT

Listeria monocytogenes is a foodborne intracellular bacterial model pathogen. Protective immunity against Listeria depends on an effective CD8+ T cell response, but very few T cell epitopes are known in mice as a common animal infection model for listeriosis. To identify epitopes we screened for Listeria immunopeptides presented in the spleen of infected mice by mass spectrometry-based immunopeptidomics. We mapped more than 6,000 mouse self-peptides presented on MHC Class I molecules, including 12 high confident Listeria peptides from 12 different bacterial proteins. Bacterial immunopeptides with confirmed fragmentation spectra were further tested for their potential to activate CD8+ T cells, revealing VTYNYINI from the putative cell wall surface anchor family protein LMON_0576 as a novel bona fide peptide epitope. The epitope showed high biological potency in a prime boost model and can be used as a research tool to probe CD8+ T cell responses in mouse models of Listeria infection. Together, our results demonstrate the power of immunopeptidomics for bacterial antigen identification.

PMID:39147027 | DOI:10.1016/j.mcpro.2024.100829

Cell Stem Cell. 2024 Aug 6:S1934-5909(24)00256-X. doi: 10.1016/j.stem.2024.07.006. Online ahead of print.

ABSTRACT

Endogenous retroviruses (ERVs) occupy a significant part of the human genome, with some encoding proteins that influence the immune system or regulate cell-cell fusion in early extra-embryonic development. However, whether ERV-derived proteins regulate somatic development is unknown. Here, we report a somatic developmental function for the primate-specific ERVH48-1 (SUPYN/Suppressyn). ERVH48-1 encodes a fragment of a viral envelope that is expressed during early embryonic development. Loss of ERVH48-1 led to impaired mesoderm and cardiomyocyte commitment and diverted cells to an ectoderm-like fate. Mechanistically, ERVH48-1 is localized to sub-cellular membrane compartments through a functional N-terminal signal peptide and binds to the WNT antagonist SFRP2 to promote its polyubiquitination and degradation, thus limiting SFRP2 secretion and blocking repression of WNT/β-catenin signaling. Knockdown of SFRP2 or expression of a chimeric SFRP2 with the ERVH48-1 signal peptide rescued cardiomyocyte differentiation. This study demonstrates how ERVH48-1 modulates WNT/β-catenin signaling and cell type commitment in somatic development.

PMID:39146934 | DOI:10.1016/j.stem.2024.07.006

Eur J Med Chem. 2024 Aug 6;277:116746. doi: 10.1016/j.ejmech.2024.116746. Online ahead of print.

ABSTRACT

Metal complexes showing dual activity against cancer and bacterial infections are currently the focus of significant interest for their potential in treating life-threatening diseases. Aiming to investigate the impact of ligand substituents on these bioactivity properties of Group 11 d10 metal complexes, we herein present a series of mononuclear Cu(I) and Ag(I) complexes featuring the bis-NH2-substituted heterocyclic thioamide dap2SH (=4,6-diaminopyrimidine-2-thione), namely [AgCl(dap2SH)(PPh3)2] (1), [CuBr(dap2SH)(PPh3)2] (2), [CuBr(dap2SH)(xantphos)] (3), [Ag(dap2S)(xantphos)] (4), and [Cu(dap2S)(xantphos)] (5) (xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene). Complexes were characterized by means of different physicochemical methods (i.e., single crystal X-ray diffraction as well as FTIR, NMR, UV-Vis and fluorescence spectroscopy), and studied in-vitro for their antibacterial and anticancer activity against a variety of bacterial strains and cancer cell lines. Complexes 1-3 effectively inhibited both Gram (+) and Gram (-) bacterial growth, while cellular uptake studies for the most potent complex 1 against E. coli bacteria revealed the accumulation of Ag(I) ions in the periplasm of the bacteria. A high anti-proliferative effect was observed for 1 and 5 against A549, MCF7 and PC3 cancer cell lines, with 1 being capable of inducing apoptosis in A549 cells, as suggested by flow cytometry analysis. DNA interaction studies revealed the capacity of 1 to intercalate between base-pairs of CT DNA. All complexes had a moderate-to-high capacity to scavenge free radicals preventing oxidative stress. Molecular docking calculations, in combination with the experimentally obtained data, provided insights for potential mechanisms of the bioactivity of the complexes.

PMID:39146831 | DOI:10.1016/j.ejmech.2024.116746

Nat Protoc. 2024 Aug 15. doi: 10.1038/s41596-024-01030-x. Online ahead of print.

ABSTRACT

Complex cellular functions occur via the coordinated formation and dissociation of protein complexes. Functions such as the response to a signaling ligand can incorporate dozens of proteins and hundreds of complexes. Until recently, it has been difficult to measure multiple protein complexes at the single-cell level. Here, we present a step-by-step procedure for proximity sequencing, which enables the simultaneous measurement of proteins, mRNA and hundreds of protein complexes located on the outer membrane of cells. We guide the user through probe creation, sample preparation, staining, sequencing and computational quantification of protein complexes. This protocol empowers researchers to study, for example, the interplay between transcriptional states and cellular functions by coupling measurements of transcription to measurements of linked effector molecules, yet could be generalizable to other paired events. The protocol requires roughly 16 h spread over several days to complete by users with expertise in basic molecular biology and single-cell sequencing.

PMID:39147984 | DOI:10.1038/s41596-024-01030-x

Nat Metab. 2024 Aug 15. doi: 10.1038/s42255-024-01127-3. Online ahead of print.

NO ABSTRACT

PMID:39147935 | DOI:10.1038/s42255-024-01127-3

Acad Radiol. 2024 Aug 14:S1076-6332(24)00571-3. doi: 10.1016/j.acra.2024.08.008. Online ahead of print.

ABSTRACT

RATIONALE AND OBJECTIVES: To determine whether concurrent contrast-enhanced diagnostic CT (DxCT) confers added diagnostic certainty compared to PSMA-PET/CT alone.

MATERIALS AND METHODS: This retrospective multi-reader study analyzed imaging comprising combined F-18-piflufolastat PSMA-PET/CT with diagnostic chest/abdominopelvic CT from prostate cancer patients within the first 6 months of FDA-approval of the PET agent. Six nuclear radiology readers were randomly presented with PSMA-PET/CT studies with or without DxCT and asked to report their diagnostic certainty for PSMA-avid lesions found on PET. Subsequently, readers re-reviewed the same study after an interlude (with the CT if not previously presented and vice-versa) to determine if DxCT altered their diagnostic assessment. Inter-rater concordance was assessed on a subset of images read by all readers. Diagnostic certainties for PSMA-PET/CT with and without DxCT were compared, and the variables for which DxCT may add value were examined.

RESULTS: Good inter-rater concordance across readers was noted for both PET/CT (Finn's coefficient of reliability for overall scan certainty: 0.85,p < 0.01) and combined DxCT-PET/CT (0.59,p < 0.01). Overall certainty and concordance between PET/CT and combined DxCT-PET/CT datasets were similar (overall scan certainty: 92% ± 16 vs. 92% ± 17,p = 0.43), with no significant advantage for adding DxCT across different anatomic locations or clinical parameters. A slight predilection for combined DxCT-PET/CT was noted when interpreting images acquired for the initial staging of prostate cancer (89% ± 16 vs. 93% ± 17,p = 0.08).

CONCLUSION: Good inter-reader concordance can be achieved across different training levels with PSMA-PET/CT. Furthermore, using DxCT concurrent with PSMA-PET/CT does not significantly improve diagnostic certainty for most indications but may be useful for initial staging.

PMID:39147641 | DOI:10.1016/j.acra.2024.08.008

ACS Appl Bio Mater. 2024 Aug 15. doi: 10.1021/acsabm.4c00615. Online ahead of print.

ABSTRACT

Hydrogel microfibers are hydrogel materials engineered into fiber structures. Techniques such as wet spinning, microfluidic spinning, and 3D bioprinting are often used to prepare microfibers due to their ability to precisely control the size, morphology, and structure of the microfibers. Microfibers with different structural morphologies have different functions; they provide a flow-through culture environment for cells to improve viability, and can also be used to induce the differentiation of cells such as skeletal muscle and cardiac muscle cells to eventually form functional organs in vitro through special morphologies. This Review introduces recent advances in microfluidics, 3D bioprinting, and wet spinning in the preparation of microfibers, focusing on the materials and fabrication methods. The applications of microfibers in tissue engineering are highlighted by summarizing their contributions in engineering biomimetic blood vessels, vascularized tissues, bone, heart, pancreas, kidney, liver, and fat. Furthermore, applications of engineered fibers in tissue repair and drug screening are also discussed.

PMID:39145987 | DOI:10.1021/acsabm.4c00615

Elife. 2024 Aug 15;13:e85794. doi: 10.7554/eLife.85794. Online ahead of print.

ABSTRACT

Environmental DNA (eDNA) is becoming an increasingly important tool in diverse scientific fields from ecological biomonitoring to wastewater surveillance of viruses. The fundamental challenge in eDNA analyses has been the bioinformatical assignment of reads to taxonomic groups. It has long been known that full probabilistic methods for phylogenetic assignment are preferable, but unfortunately, such methods are computationally intensive and are typically inapplicable to modern Next-Generation Sequencing data. We here present a fast approximate likelihood method for phylogenetic assignment of DNA sequences. Applying the new method to several mock communities and simulated datasets, we show that it identifies more reads at both high and low taxonomic levels more accurately than other leading methods. The advantage of the method is particularly apparent in the presence of polymorphisms and/or sequencing errors and when the true species is not represented in the reference database.

PMID:39145536 | DOI:10.7554/eLife.85794

ACS Synth Biol. 2024 Aug 15. doi: 10.1021/acssynbio.4c00383. Online ahead of print.

ABSTRACT

Flavonoids, a significant group of natural polyphenolic compounds, possess a broad spectrum of pharmacological effects. Recent advances in the systematic metabolic engineering of yeast cell factories (YCFs) provide new opportunities for enhanced flavonoid production. Herein, we outline the latest research progress on typical flavonoid products in YCFs. Advanced engineering strategies involved in flavonoid biosynthesis are discussed in detail, including enhancing precursor supply, cofactor engineering, optimizing core pathways, eliminating competitive pathways, relieving transport limitations, and dynamic regulation. Additionally, we highlight the existing problems in the biosynthesis of flavonoid glucosides in yeast, such as endogenous degradation of flavonoid glycosides, substrate promiscuity of UDP-glycosyltransferases, and an insufficient supply of UDP-sugars, with summaries on the corresponding solutions. Discussions also cover other typical postmodifications like prenylation and methylation, and the recent biosynthesis of complex flavonoid compounds in yeast. Finally, a series of advanced technologies are envisioned, i.e., semirational enzyme engineering, ML/DL algorithn, and systems biology, with the aspiration of achieving large-scale industrial production of flavonoid compounds in the future.

PMID:39145487 | DOI:10.1021/acssynbio.4c00383

Adv Sci (Weinh). 2024 Aug 15:e2405829. doi: 10.1002/advs.202405829. Online ahead of print.

ABSTRACT

Targeted protein degradation has been widely adopted as a new approach to eliminate both established and previously recalcitrant therapeutic targets. Here, it is reported that the development of small molecule degraders of the envelope (E) protein of dengue virus. Two classes of bivalent E-degraders are developed by linking two previously reported E-binding small molecules, GNF-2, and CVM-2-12-2, to a glutarimide-based recruiter of the CRL4CRBN ligase to effect proteosome-mediated degradation of the E protein. ZXH-2-107 (based on GNF-2) is an E-degrader with ABL inhibitory activity while ZXH-8-004 (based on CVM-2-12-2) is a selective and potent E-degrader. These two compounds provide proof of concept that difficult-to-drug targets such as a viral envelope protein can be effectively eliminated using a bivalent degrader and provide starting points for the future development of a new class of direct-acting antiviral drugs.

PMID:39145423 | DOI:10.1002/advs.202405829

Front Cell Infect Microbiol. 2024 Jul 31;14:1425624. doi: 10.3389/fcimb.2024.1425624. eCollection 2024.

ABSTRACT

Type IV pili (T4P) are versatile proteinaceous protrusions that mediate diverse bacterial processes, including adhesion, motility, and biofilm formation. Aeromonas hydrophila, a Gram-negative facultative anaerobe, causes disease in a wide range of hosts. Previously, we reported the presence of a unique Type IV class C pilus, known as tight adherence (Tad), in virulent Aeromonas hydrophila (vAh). In the present study, we sought to functionalize the role of Tad pili in the pathogenicity of A. hydrophila ML09-119. Through a comprehensive comparative genomics analysis of 170 A. hydrophila genomes, the conserved presence of the Tad operon in vAh isolates was confirmed, suggesting its potential contribution to pathogenicity. Herein, the entire Tad operon was knocked out from A. hydrophila ML09-119 to elucidate its specific role in A. hydrophila virulence. The absence of the Tad operon did not affect growth kinetics but significantly reduced virulence in catfish fingerlings, highlighting the essential role of the Tad operon during infection. Biofilm formation of A. hydrophila ML09-119 was significantly decreased in the Tad operon deletant. Absence of the Tad operon had no effect on sensitivity to other environmental stressors, including hydrogen peroxide, osmolarity, alkalinity, and temperature; however, it was more sensitive to low pH conditions. Scanning electron microscopy revealed that the Tad mutant had a rougher surface structure during log phase growth than the wildtype strain, indicating the absence of Tad impacts the outer surface of vAh during cell division, of which the biological consequences are unknown. These findings highlight the role of Tad in vAh pathogenesis and biofilm formation, signifying the importance of T4P in bacterial infections.

PMID:39145307 | PMC:PMC11322086 | DOI:10.3389/fcimb.2024.1425624

J Hematol Oncol. 2024 Aug 14;17(1):67. doi: 10.1186/s13045-024-01586-x.

ABSTRACT

BACKGROUND: The interleukin-1 receptor accessory protein (IL1RAP) is highly expressed on acute myeloid leukemia (AML) bulk blasts and leukemic stem cells (LSCs), but not on normal hematopoietic stem cells (HSCs), providing an opportunity to target and eliminate the disease, while sparing normal hematopoiesis. Herein, we report the activity of BIF002, a novel anti-IL1RAP/CD3 T cell engager (TCE) in AML.

METHODS: Antibodies to IL1RAP were isolated from CD138+ B cells collected from the immunized mice by optoelectric positioning and single cell sequencing. Individual mouse monoclonal antibodies (mAbs) were produced and characterized, from which we generated BIF002, an anti-human IL1RAP/CD3 TCE using Fab arm exchange. Mutations in human IgG1 Fc were introduced to reduce FcγR binding. The antileukemic activity of BIF002 was characterized in vitro and in vivo using multiple cell lines and patient derived AML samples.

RESULTS: IL1RAP was found to be highly expressed on most human AML cell lines and primary blasts, including CD34+ LSC-enriched subpopulation from patients with both de novo and relapsed/refractory (R/R) leukemia, but not on normal HSCs. In co-culture of T cells from healthy donors and IL1RAPhigh AML cell lines and primary blasts, BIF002 induced dose- and effector-to-target (E:T) ratio-dependent T cell activation and leukemic cell lysis at subnanomolar concentrations. BIF002 administered intravenously along with human T cells led to depletion of leukemic cells, and significantly prolonged survival of IL1RAPhigh MOLM13 or AML patient-derived xenografts with no off-target side effects, compared to controls. Of note, BiF002 effectively redirects T cells to eliminate LSCs, as evidenced by the absence of disease initiation in secondary recipients of bone marrow (BM) from BIF002+T cells-treated donors (median survival not reached; all survived > 200 days) compared with recipients of BM from vehicle- (median survival: 26 days; p = 0.0004) or isotype control antibody+T cells-treated donors (26 days; p = 0.0002).

CONCLUSIONS: The novel anti-IL1RAP/CD3 TCE, BIF002, eradicates LSCs and significantly prolongs survival of AML xenografts, representing a promising, novel treatment for AML.

PMID:39143574 | DOI:10.1186/s13045-024-01586-x

Nature. 2024 Aug 14. doi: 10.1038/s41586-024-07830-1. Online ahead of print.

ABSTRACT

The genomes of living lungfishes can inform on the molecular-developmental basis of the Devonian sarcopterygian fish-tetrapod transition. We de novo sequenced the genomes of the African (Protopterus annectens) and South American lungfishes (Lepidosiren paradoxa). The Lepidosiren genome (about 91 Gb, roughly 30 times the human genome) is the largest animal genome sequenced so far and more than twice the size of the Australian (Neoceratodus forsteri)1 and African2 lungfishes owing to enlarged intergenic regions and introns with high repeat content (about 90%). All lungfish genomes continue to expand as some transposable elements (TEs) are still active today. In particular, Lepidosiren's genome grew extremely fast during the past 100 million years (Myr), adding the equivalent of one human genome every 10 Myr. This massive genome expansion seems to be related to a reduction of PIWI-interacting RNAs and C2H2 zinc-finger and Krüppel-associated box (KRAB)-domain protein genes that suppress TE expansions. Although TE abundance facilitates chromosomal rearrangements, lungfish chromosomes still conservatively reflect the ur-tetrapod karyotype. Neoceratodus' limb-like fins still resemble those of their extinct relatives and remained phenotypically static for about 100 Myr. We show that the secondary loss of limb-like appendages in the Lepidosiren-Protopterus ancestor was probably due to loss of sonic hedgehog limb-specific enhancers.

PMID:39143221 | DOI:10.1038/s41586-024-07830-1