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PubMed2023

Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models.

Approximately 10% of Cystic Fibrosis (CF) patients, particularly those with CF transmembrane conductance regulator (CFTR) gene nonsense mutations, lack effective treatments. The potential of gene correction therapy through delivery of the CRISPR/Cas system to CF-relevant organs/cells is hindered by the lack of efficient genome editor delivery carriers. Herein, we report improved Lung Selective Organ Targeting Lipid Nanoparticles (SORT LNPs) for efficient delivery of Cas9 mRNA, sgRNA, and donor ssDNA templates, enabling precise homology-directed repair-mediated gene correction in CF models. Optimized Lung SORT LNPs deliver mRNA to lung basal cells in Ai9 reporter mice. SORT LNP treatment successfully corrected the CFTR mutations in homozygous G542X mice and in patient-derived human bronchial epithelial cells with homozygous F508del mutations, leading to the restoration of CFTR protein expression and chloride transport function. This proof-of-concept study will contribute to accelerating the clinical development of mRNA LNPs for CF treatment through CRISPR/Cas gene correction.

Humans↗

PubMed2024

A novel mouse model recapitulates the effects of rs2254524 variant in the lanosterol synthase gene on salt sensitivity and organ damage.

OBJECTIVE: The blood pressure (BP) response to salt intake (salt sensitivity) shows great variability among individuals and is more frequent in hypertensive patients. Elevated levels of the steroid hormone Endogenous Ouabain (EO) are associated with hypertension (HT) and salt sensitivity. The lanosterol synthase gene ( LSS ) plays a key role in the biosynthesis of steroids and its rs2254524 variant (Val642Leu) is linked to salt sensitivity in humans. This study aims to investigate the pathophysiological significance of the Lss missense variation in a new knock-in mouse model of salt-sensitive HT onset. METHODS: We generated a mouse model carrying the murine homolog (Val643Leu) of the human LSS variant. C57BL/6N LssV643L/V643L mice were fed different NaCl diets (low-salt, LSD; normal-salt, NSD; high-salt, HSD) and were characterized at functional, histological, and molecular levels. RESULTS: At baseline, mutant mice showed an enlarged kidney compared to the wild-type (WT) counterpart, but the Lss V643L variant did not affect EO biosynthesis nor systolic BP at 3 and 12 months. In HSD, we observed an increased systolic BP only in 12-month-old LssV643L/V643L mice, compared to NSD. Moreover, only the HSD LssV643L/V643L mice showed cardiac hypertrophy and a higher incidence of cardiac fibrosis compared to WT at 12 months. Finally, the Lss mRNA level was differentially regulated by HSD in the adrenal gland, liver, and heart of LssV643L/V643L mice compared to WT. CONCLUSIONS: The novel Lss mouse model resembles the salt-sensitive HT phenotype observed in hypertensive patients and provides a good model of salt-sensitive HT and HT-mediated organ damage.

Animals↗

PubMed1979

Asymmetric and globular forms of acetylcholinesterase in mammals and birds.

We have identified six molecular forms of acetylcholinesterase (AcChoE: acetylcholine hydrolase, EC 3.1.1.7) in extracts from bovine superior cervical ganglia. We show that three of them resemble the collagen-tailed forms of Electrophorus AcChoE in their hydrodynamic parameters, low-salt aggregation properties, and collagenase sensitivity. The six molecular forms of bovine AcChoE appear structurally homologous to the six forms of electric fish AcChoE that have previously been characterized. They include globular molecules (monomers, dimers, and tetramers) and asymmetric aggregating molecules that possess a collagen-like tail associated with one, two, and three tetramers. We propose to call the globular forms G1, G2, and G4 and the asymmetric forms A4, A8, and A12, the subscripts indicating the number of catalytic subunits. In spite of quantitative differences in their molecular parameters, the AcChoE forms from rat and chicken are clearly homologous to those of bovine AcChoE. Thus the nomenclature we introduce is very probably valid for the main AcChoE molecular forms, at least in vertebrates, and should help to clarify structural relationships and homologies among them. This model, however, does not claim to represent entirely the complex polymorphism of AcChoE, because more or less hydrophobic variants of the G forms have been observed, and because other molecular associations cannot be excluded. We discuss the significance of the globular and collagen-tailed structure for the molecular localization of AcChoE.

Acetylcholinesterase↗

PubMed2025

Integrative genomics elucidates the evolutionary, temporal, and developmental origins of a hydrocephalus risk gene.

INTRODUCTION: A prior integrative, multi-omics human genetics and functional genomics study identified maelstrom (MAEL), a gene involved in regulation of DNA transposon activity and genome structure, as a transcriptome-wide predictor of hydrocephalus (HC) in the brain cortex. Here we expand on this discovery and further characterize the evolutionary origin and expression of MAEL across developmental timescales and cell-lineages in the neonatal human brain towards a mechanistic understanding how variation in MAEL expression may cause HC. OBJECTIVE: To characterize the evolutionary, temporal, developmental, and lineages of MAEL expression in HC and the developing human brain. METHODS: Ensembl was used to delineate the evolution and taxonomy of MAEL across species. Analysis of single-cell RNA sequencing (scRNA-seq) of 49 brain regions across pre- and post-natal timescales from the Developing Human Brain Atlas (Allen Institute) identified temporal and spatial MAEL expression patterns. We quantified MAEL expression in primary cortical brain tissue obtained during the surgical treatment of HC. RESULTS: We performed taxonomic gene-mapping to define the evolutionary origin of MAEL to assess suitability for mechanistic characterization in vitro and in vivo across species. We find that MAEL is among the top 0.01% human-specific genes and < 50% sequence homology among commonly used model organisms with highly divergent functions, necessitating mechanistic validation in human tissue. scRNA-seq of the non-disease prenatal human brain identified MAEL expression enriched in cortical excitatory neurons, which was recapitulated in primary HC brain tissue obtained during surgery. Finally, using scRNA-seq of primary HC brain tissue, we functionally validated reduced MAEL expression, consistent with a prior human TWAS analysis. CONCLUSIONS: We identify the evolutionary, temporal, and developmental expression pattern of MAEL in the neonatal human brain. We also provide direct evidence for reduced MAEL expression in human HC brain tissue. These data, at least in part, implicate reduced MAEL expression underlying human HC across etiologies.

Journal Article↗

PubMed1975

Laboratory model of membranous glomerulonephritis in rats induced by pronase-digested homologous renal tubular epithelial antigen.

The laboratory counterpart of tubular antigen-mediated membranous glomerulonephritis in humans was produced in rats by a single injection of homologous nephritogenic tubular antigen with adjuvant. The rat developed membranous glomerulonephritis with typical clinicopathologic features of human nephritis mediated by the tubular antigen, i.e., massive proteinuria and diffuse thickening of glomerular basement membranes due to deposition of tubular antigen-antibody complexes which were demonstrated by immunofluorescent technique. The nephritogenic tubular antigen was solubilized by pronase digestion, further purified by gel filtration, and demonstrated to have the same physicochemical properties as the human tubular antigen which was found in the deposits together with beta1C- and immunoglobulins in the glomeruli of patients with membranous glomerulonephritis.

Animals↗

PubMed2023

Homologous chromosome recognition via nonspecific interactions.

In many organisms, most notably Drosophila, homologous chromosomes in somatic cells associate with each other, a phenomenon known as somatic homolog pairing. Unlike in meiosis, where homology is read out at the level of DNA sequence complementarity, somatic homolog pairing takes place without double strand breaks or strand invasion, thus requiring some other mechanism for homologs to recognize each other. Several studies have suggested a "specific button" model, in which a series of distinct regions in the genome, known as buttons, can associate with each other, presumably mediated by different proteins that bind to these different regions. Here we consider an alternative model, which we term the "button barcode" model, in which there is only one type of recognition site or adhesion button, present in many copies in the genome, each of which can associate with any of the others with equal affinity. An important component of this model is that the buttons are non-uniformly distributed, such that alignment of a chromosome with its correct homolog, compared with a non-homolog, is energetically favored; since to achieve nonhomologous alignment, chromosomes would be required to mechanically deform in order to bring their buttons into mutual register. We investigated several types of barcodes and examined their effect on pairing fidelity. We found that high fidelity homolog recognition can be achieved by arranging chromosome pairing buttons according to an actual industrial barcode used for warehouse sorting. By simulating randomly generated non-uniform button distributions, many highly effective button barcodes can be easily found, some of which achieve virtually perfect pairing fidelity. This model is consistent with existing literature on the effect of translocations of different sizes on homolog pairing. We conclude that a button barcode model can attain highly specific homolog recognition, comparable to that seen in actual cells undergoing somatic homolog pairing, without the need for specific interactions. This model may have implications for how meiotic pairing is achieved.

Preprint↗

PubMed2022

Lurbinectedin, a selective inhibitor of oncogenic transcription, in patients with pretreated germline BRCA1/2 metastatic breast cancer: results from a phase II basket study.

BACKGROUND: Lurbinectedin, a selective inhibitor of oncogenic transcription, has shown preclinical antitumor activity against homologous recombination repair-deficient models and preliminary clinical activity in BRCA1/2 breast cancer. PATIENTS AND METHODS: This phase II basket multitumor trial (NCT02454972) evaluated lurbinectedin 3.2 mg/m2 1-h intravenous infusion every 3 weeks in a cohort of 21 patients with pretreated germline BRCA1/2 breast cancer. Patients with any hormone receptor and human epidermal growth factor receptor 2 status were enrolled. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Confirmed partial response (PR) was observed in six patients [ORR = 28.6%; 95% confidence interval (CI) 11.3% to 52.2%] who had received a median of two prior advanced chemotherapy lines. Lurbinectedin was active in both BRCA mutations: four PRs in 11 patients (36.4%) with BRCA2 and two PRs in 10 patients (20.0%) with BRCA1. Median DoR was 8.6 months, median PFS was 4.1 months and median OS was 16.1 months. Stable disease (SD) was observed in 10 patients (47.6%), including 3 with unconfirmed response in a subsequent tumor assessment [ORR unconfirmed = 42.9% (95% CI 21.8% to 66.0%)]. Clinical benefit rate (PR + SD ≥ 4 months) was 76.2% (95% CI 52.8% to 91.8%). No objective response was observed among patients who had received prior poly (ADP-ribose) polymerase inhibitors. The most common treatment-related adverse events (AEs) were nausea (61.9%), fatigue (38.1%) and vomiting (23.8%). These AEs were mostly grade 1/2. The most common grade 3/4 toxicity was neutropenia (42.9%: grade 4, 23.8%: with no febrile neutropenia). CONCLUSIONS: This phase II study met its primary endpoint and showed activity of lurbinectedin in germline BRCA1/2 breast cancer. Lurbinectedin showed a predictable and manageable safety profile. Considering the exploratory aim of this trial as well as previous results in other phase II studies, further development of lurbinectedin in this indication is warranted.

Humans↗

PubMed1979

Structural studies of synthetic filaments prepared from column-purified myosin.

Synthetic filaments prepared from column-purified rabbit skeletal myosin by slow dialysis exhibit characteristic bipolar organization and 14-nm axial subunit spacing. Backbone substructure can be discerned in high resolution micrographs in the form of striations of 3--4-nm width and slight angular tilt from the direction of the filament axis. Filament backbone diameters vary over the population, although remaining relatively constant for a single filament. Approximately 25% of the filaments appear poorly stained and frayed, which may be due to collapse on the electron microscope grid. Optical diffraction studies reveal a 43-nm axial repeat as well as the 14.3-nm subunit repeat, indicating a structural homology with natural filaments. A model for synthetic filament aggregation is presented that is consistent with observations of backbone diameter variation, absence of bare zones, and the presence of fraying filaments.

Animals↗

PubMed2026

Genome-Wide Identification and Bioinformatics Analysis of the FAD Gene Family in Walnut (Juglans regia L.).

Fatty acid desaturase (FAD) is a core catalytic enzyme in plants for the synthesis of unsaturated fatty acids, profoundly affecting plant growth, development, and adaptability to various environmental stresses. The walnut (Juglans regia L.) is an important woody oil tree species, and its kernel is rich in unsaturated fatty acids. Systematic identification of the walnut FAD gene family and analysis of its function are of great significance for revealing the molecular mechanisms underlying unsaturated fatty acid metabolism in the walnut. Based on walnut whole-genome data, this study used homology alignment and hidden Markov model search methods to identify the JrFAD gene family members. Subsequently, a variety of bioinformatics tools were used to systematically analyze their structural characteristics, evolutionary expansion mechanism, expression regulation, and function. A total of 21 JrFAD gene family members were identified and classified into five subfamilies. The family genes were unevenly distributed on nine chromosomes. WGD/segmental duplication was the main expansion method, and the duplicated gene pairs experienced strong purification selection. The family gene promoter sequence is rich in regulatory elements that respond to light, plant hormones, and various stresses. The expression pattern analysis showed that JrFAD3.1 and JrFAD2.3 showed high expression specifically during the rapid accumulation of walnut kernel oil. This study clarified the composition and evolutionary characteristics of the FAD gene family in the walnut, which provides useful information for in-depth analyses of its functional mechanism in the regulation of lipid metabolism, and also identified potential candidate gene resources for the genetic improvement of walnut varieties with high amounts of unsaturated fatty acids.

Juglans↗

PubMed1978

A computer aided oligonucleotide analysis provides a model sequence for RNA polymerase-promoter recognition in E.coli.

A novel computer procedure has been used to search for homology among 17 known procaryotic promoter sequences. A model sequence, :formula: (see text), is compatible with the properties of all known promoter and operator mutations, predicts base positions for the initiation of RNA synthesis coinciding with those determined experimentally, is compatible with current models for the regulation of transcription, suggests that RNA polymerase could recognize the DNA double helix firstly in the B conformation then in the A.

Base Sequence↗

PubMed1979

Do homologous chromosomes differ? A preliminary investigation based on DNA measurements.

This paper is concerned with the problem of deciding whether measurements from homologous chromosomes differ. First, a general mathematical model is proposed for studying the distribution of chromosome measurements. Next, log-likelihood ratios are used to test for correlation between homolog pairs and for differences between homolog means and variances. The tests are applied to measurments on 1946 pairs of chromosomes from 10 normal individuals. Test results are interpreted taking into account the large number (2025 total tests) required by the study. Our results demonstrate that, at the current level of resolution, most homologs do not show differences in DNA content. However, there is some evidence that several homologs pairs differ by small amounts of DNA (less than 0.2% of the autosomal genome). Power studies indicate that sample sizes of 20 to 30 measurements are required to detect differences of this size.

Chromosomes, Human↗

PubMed1978

[Study of the enterotoxic action of the neurotoxin of the Sonne dysentery microbe in a rabbit small intestine loop model].

The enterotoxic action of neurotoxin from Sonne dysentery microbes (obtained by the method of Mesrobeanu et al.), and also of the culture autolysates and homologous Boiven's endotoxin was studied on a model of the isolated loop of the rabbit small intestine. Neurotoxin preparations obtained from virulent strains as well as autolysates of these cultures possessed enterotoxic activity, whereas purifed endotoxin preparations in doses of 1--10 mg failed to cause any dilatation of the isolated intestinal segment. A significant individual rabbit sensitivity to the enterotoxic action of the neurotoxin preparation was revealed. Lyophilization of neurotoxin preparation did not influence its enterotoxicity. However dialysis against distilled water and boiling of the neurotoxin preparations led to the loss of enterotoxic activity.

Animals↗

PubMed1977

Correlation of the serial-dilution protamine sulfate test with models of "hypercoagulability" and thrombosis in dogs.

In a dog model, combinations of venous-injury thrombosis, homologous serum-induced "hypercoagulability," and fibrinolytic blockade were evaluated to determine the factors involved in the generation of a positive serial-dilution protamine sulfate test. Stasis and operative procedures did not produce a positive test. Small local thrombi induced by electrical current produced a positive test that tended to persist only during the initial formation and propagation of the thrombus, and was blocked by pretreatment with epsilon-aminocaproic acid, suggesting in this model that the test was detecting mainly early fibrin degradation products. Homologous serum infusion without venous-injury thrombosis also produced positive serial-dilution protamine sulfate test results that could not be blocked with epsilon-aminocaproic acid suggesting here that the serial-dilution protamine sulfate test was detecting mainly soluble complexes of fibrin monomer rather than early fibrin degradation products. The serial-dilution protamine sulfate test is therefore capable of detecting both small local thrombi and serum-induced "hypercoagulability" without thrombosis in the dog model.

Animals↗

PubMed2024

The immediate-early protein 1 of human herpesvirus 6B interacts with NBS1 and inhibits ATM signaling.

Viral infection often trigger an ATM serine/threonine kinase (ATM)-dependent DNA damage response in host cells that suppresses viral replication. Viruses evolved different strategies to counteract this antiviral surveillance system. Here, we report that human herpesvirus 6B (HHV-6B) infection causes genomic instability by suppressing ATM signaling in host cells. Expression of immediate-early protein 1 (IE1) phenocopies this phenotype and blocks homology-directed double-strand break repair. Mechanistically, IE1 interacts with NBS1, and inhibits ATM signaling through two distinct domains. HHV-6B seems to efficiently inhibit ATM signaling as further depletion of either NBS1 or ATM do not significantly boost viral replication in infected cells. Interestingly, viral integration of HHV-6B into the host's telomeres is not strictly dependent on NBS1, challenging current models where integration occurs through homology-directed repair. Given that spontaneous IE1 expression has been detected in cells of subjects with inherited chromosomally-integrated form of HHV-6B (iciHHV-6B), a condition associated with several health conditions, our results raise the possibility of a link between genomic instability and the development of iciHHV-6-associated diseases.

Humans↗

PubMed2025

Human xenobiotic metabolism proteins have full-length and split homologs in the gut microbiome.

Xenobiotics, including pharmaceutical drugs, can be metabolized by both host and microbiota, in some cases by homologous enzymes. We conducted a systematic search for all known human proteins with gut microbial homologs. Because gene fusion and fission can obscure homology detection, we built a pipeline to identify not only full-length homologs, but also cases where microbial homologs were split across multiple adjacent genes in the same neighborhood or operon ("split homologs"). We found that human proteins with full-length gut microbial homologs disproportionately participate in xenobiotic metabolism. While this included many different enzyme classes, short-chain and aldo-keto reductases were the most frequently detected, especially in prevalent gut microbes, while cytochrome P450 homologs were largely restricted to lower-prevalence facultative anaerobes. In contrast, human proteins with split homologs tended to play roles in central metabolism, especially of nucleobase-containing compounds. We identify twelve specific drugs that gut microbial split homologs may metabolize; 2 of these, 6-mercaptopurine by xanthine dehydrogenase and 5-fluorouracil by dihydropyrimidine dehydrogenase, have been recently confirmed in mouse models. This work provides a comprehensive map of homology between the human and gut microbial proteomes, indicates which human xenobiotic enzyme classes are most likely to be shared by gut microorganisms, and finally demonstrates that split homology may be an underappreciated explanation for microbial contributions to drug metabolism.

Humans↗

PubMed1979

Homografts of the middle ear. Privileged tissue or privileged site.

To explain the survival and behavior of homografts, we have tried, by means of discussion and use of biological models, to resolve a problem with three unknowns, ie, the tympanic membrane, the ossicle, and the middle ear, with the notions of privileged tissue and privileged site. The tympanic membrane survives because of the relative stability of its fibers and the absence of mechanical trauma. Later, the membrane is sheathed by fibrous tissue. The ossicle is not only tolerated by the host but is also invaded and ossified.

Ear Ossicles↗

PubMed1979

Intensive therapy of acute hepatic insufficiency in dogs by heterotopic liver allotransplant.

The efficacy of heterotopic liver transplantation to support life and to correct metabolic disturbances in the presence of acute hepatic failure was tested in 70 dogs. Acute hepatic failure was induced by two-stage ischaemic damage to the animals' livers and by biliary obstruction. The donor liver was stored for 3 h by the method of intermittent perfusion. The graft was placed in the right paravertebral gutter. The inflow was arterial only. No immunosuppressive agents were administered. During the postoperative period the main biochemical indices decreased and returned to almost normal values by the fourth day. The auxiliary liver was able to correct the clotting of blood. There was significant regression of encephalopathy, which was confirmed by encephalographic monitoring. Special attention was paid to the adaptation of the stored graft after revascularization. Resuscitation from hepatic failure and subsequent survival of transplanted animals confirmed the significant therapeutic effect of heterotopic allotransplant.

Acute Disease↗

PubMed2026

Ramu stunt virus genome reveals previously unreported segments and nucleocapsid domain duplication in Mechlorovirus.

Ramu stunt virus (RmSV), a member of the genus Mechlorovirus within the family Phenuiviridae, was previously described as a six-segmented RNA virus infecting sugarcane. In this study, we re-examined type material and additional isolates using high-throughput sequencing and RT-PCR validation, revealing that RmSV possesses a nine-segmented genome, making it the largest reported in the Phenuiviridae. This expanded architecture includes duplicated RNA segments (RNA 2a and RNA 2b) encoding nucleocapsid-like proteins and two novel segments (RNA 7 and RNA 8). Comparative analysis showed that RNA 2a and 2b share about 84% amino acid identity, while RNA 5 encodes a third nucleocapsid homolog, indicating unprecedented domain redundancy. Structural modeling confirmed that all three nucleocapsid proteins maintain a conserved fold despite low sequence identity, with electrostatic mapping suggesting differential RNA-binding potential. Additionally, RNA 6 encodes a hypothetical protein structurally similar to the rice stripe virus disease-specific S-protein, implicating a role in symptom development. Transcript abundance analysis revealed RNA 6 as the most highly expressed segment across isolates. These findings revise the genomic composition of RmSV, highlight mechanisms of genome plasticity and adaptive evolution in plant-infecting bunyaviruses, and underscore practical implications for diagnostic assay design, resistance breeding, and biosecurity surveillance.

Genome, Viral↗