Biology subjects

Moran, M.

Publications and source records attributed to Moran, M..

4 recordsLinked to original sources

bioRxiv2026

Collagen IV of basement membrane: V. Bromide-mediated sulfilimine bonds interlock the quaternary structure of NC1-hexamer of scaffolds enabling metazoan evolution.

Collagen-IV (Col-IV) scaffolds, a primordial basement membrane component, enabled animal multicellularity, evolution and adaptation. These scaffolds provide tensile strength and tether macromolecules, forming supramolecular complexes that interact with cell-surface receptors and influence cell-behavior. Triple-helical Col-IV protomers, composed of three -chains, with a trimeric globular NC1-domain at the C-terminus, oligomerize forming a NC1-hexamer structure that connects adjoining protomers of Col-IV121, Col-IV556--121, and Col-IV345 scaffolds. Hexamer formation and stability are driven by the extracellular chloride concentration-"chloride pressure". Hexamer structure is reinforced by six sulfilimine bonds forming covalent crosslinks that weld together trimeric NC1-domains of adjoining protomers. We recently found evidence that sulfilimine bonds, independent of chloride, stabilize the quaternary structure of the Col-IV345 hexamer of the Col-IV345 scaffold. Here, we sought to determine whether this function also pertains to the Col-IV121 scaffold that occurs ubiquitously across the animal kingdom, and whether bromine, a cofactor of peroxidasin in bond formation, are evolutionary conserved. We found that sulfilimine bonds stabilized the quaternary structure of the Col-IV121 hexamer of bovine, mouse and a basal cnidarian, Nematostella vectensis, and that the mechanism of bond formation mediated by peroxidasin and bromide is evolutionary conserved. Analyses of the crystal structure of the NC1-hexamer revealed that sulfilimine bonds covalently fasten a clasp-motif across the trimer-trimer interface, interlocking the domain-swapping region of neighboring subunits, which reinforces the hexamer quaternary structure imposed by chloride conformational constraints. Collectively, our findings reveal that the sulfilimine-bond reinforcement is a critical event in Col-IV scaffold assembly enabling multicellularity, evolution and adaptation of metazoans, beginning with ancient cnidarians.

molecular biology↗

bioRxiv2024

LooMS: a novel peptide identification tools for data independent acquisition

Advancements in mass spectrometry (MS)-based proteomics have produced large-scale datasets, necessitating the development of effective tools for peptide identification. Here, we present LooMS, a novel tool specifically designed for identifying peptides in data-independent acquisition (DIA) datasets. LooMS employs an innovative approach, using an unbiased generation strategy for positive and negative samples, which reduces the risk of overfitting in peptide identification with deep learning models. Additionally, LooMS addresses various critical aspects of DIA mass spectra data analysis, constructing a comprehensive set of 43 features for training deep learning models, which cover different stages of DIA data analysis. Notably, we propose a false discovery rate (FDR) control strategy that integrates results from both LooMS and DiaNN, another leading peptide identification tool. Our results demonstrate significant improvements in peptide identification performance, with enhancements of 40.61% and 26.60% at the unique peptide level for human and mouse datasets, respectively. HighlightsO_LILooMS is a novel tool for identifying peptides in DIA datasets that adopts an innovative unbiased positive and negative sample generation strategy, which aim to avoid the overfilling in peptide identification with deep learning model. C_LIO_LILooMS comprehensively considers various aspects of data analysis for DIA mass spectra and builds 43 useful features for training deep learning models, which involve different stages of DIA data analysis. C_LIO_LIA FDR control strategy for integration of results from both LooMS and DiaNN is proposed, which can significantly improve the identification of peptides due to the differences in the features involved in peptide detection during their respective design. C_LI

bioinformatics↗

bioRxiv2023

Immigration and seasonal bottlenecks: High inbreeding despite high genetic diversity in an oscillating population of the biting midge, Culicoides sonorensis (Diptera: Ceratopogonidae)

Most population genetic studies concern spatial genetic differentiation, but far fewer aim at analyzing the temporal genetic changes that occur within populations. Vector species, including mosquitoes and biting midges, are often characterized by oscillating adult population densities, which may affect their dispersal, selection, and genetic diversity over time. Here, we used a population of Culicoides sonorensis from a single site in California to investigate short-term (intra-annual) and long-term (inter-annual) temporal variation in genetic diversity over a three year period. This biting midge species is the primary vector of several viruses affecting both wildlife and livestock, thus a better understanding of the population dynamics of this species can help inform epidemiological studies. We found no significant genetic differentiation between months or years, and no correlation between adult populations and the inbreeding coefficient (FIS). However, we show that repeated periods of low adult abundance during cooler winter months resulted in recurring bottleneck events. Interestingly, we also found a high number of private and rare alleles, which suggests both a large, stable population, as well as a constant influx of migrants from nearby populations. Overall, we showed that the high number of migrants maintains a high level of genetic diversity by introducing new alleles, while this increased diversity is counterbalanced by recurrent bottleneck events potentially purging unfit alleles each year. These results highlight the temporal influences on population structure and genetic diversity in C. sonorensis and provide insight into factors effecting genetic variation that may occur in other vector species with fluctuating populations.

molecular biology↗

bioRxiv2016

Multi-omic analysis of urothelial cancer patients treated with PD-L1 blockade demonstrates the contribution of both systemic and somatic factors to the biology of response and resistance

BackgroundInhibition of programmed death-ligand one (PD-L1) with atezolizumab can induce durable clinical benefit (DCB) in patients with metastatic urothelial cancers, including complete remissions in patients with chemotherapy refractory disease. Although mutation load and PD-L1 immune cell (IC) staining have been associated with response, they lack sufficient sensitivity and specificity for clinical use. Thus, there is a need to evaluate the peripheral blood immune environment and to conduct detailed analyses of mutation load, predicted neoantigens and immune cellular infiltration in tumors to enhance our understanding of the biologic underpinnings of response and resistance.\n\nMethods and FindingsThe goals of this study were to (1) evaluate the association of mutation load and predicted neoantigen load with therapeutic benefit, and (2) determine whether intratumoral and peripheral blood T cell receptor (TCR) clonality inform clinical outcomes in urothelial carcinoma treated with atezolizumab. We hypothesized that an elevated mutation load in combination with T cell clonal dominance among intratumoral lymphocytes prior to treatment or among peripheral T cells after treatment would be associated with effective tumor control upon treatment with anti-PD-L1 therapy. We performed whole exome sequencing (WES), RNA sequencing (RNA-seq), and T cell receptor sequencing (TCR-seq) of pre-treatment tumor samples as well as TCR sequencing of matched, serially collected peripheral blood collected before and after treatment with atezolizumab. These parameters were assessed for correlation with DCB (defined as progression free survival (PFS) > 6 months), PFS, and overall survival (OS), both alone and in the context of clinical and intratumoral parameters known to be predictive of survival in this disease state.\n\nPatients with DCB displayed a higher proportion of tumor infiltrating T lymphocytes (TIL) (n=24, Mann-Whitney p=0.047). Pre-treatment peripheral blood TCR clonality below the median was associated with improved PFS (n=29, log-rank p=0.048) and OS (n=29, log-rank p=0.011). Patients with DCB also demonstrated more substantial expansion of tumor-associated TCR clones in the peripheral blood 3 weeks after starting treatment (n=22, Mann-Whitney p=0.022). The combination of high pre-treatment peripheral blood TCR clonality with elevated PD-L1 IC staining in tumor tissue was strongly associated with poor clinical outcomes (n=10, HR (mean)=89.88, HR (median)=23.41, 95% CI (2.43, 506.94), p(HR>1)=0.0014). Marked variations in mutation loads were seen with different somatic variant calling methodologies, which in turn impacted associations with clinical outcomes. Missense mutation load, predicted neoantigen load and expressed neoantigen load did not demonstrate significant association with DCB (n=25, Mann-Whitney p=0.22, n=25, Mann-Whitney p=0.55, and n=25, Mann-Whitney p=0.29 respectively). Instead, we found evidence of time-varying effects of somatic mutation load on progression-free survival in this cohort (n=25, p=0.044). A limitation of our study is its small sample size (n=29), a subset of the patients treated on IMvigor 210 (NCT02108652). Given the number of exploratory analyses performed, we intend for these results to be hypothesis-generating.\n\nConclusionsThese results demonstrate the complex nature of immune response to checkpoint blockade and the compelling need for greater interrogation and data integration of both host and tumor factors. Incorporating these variables in prospective studies will facilitate identification and treatment of resistant patients.

cancer biology↗