Biology subjects

Riga, A.

Publications and source records attributed to Riga, A..

6 recordsLinked to original sources

bioRxiv2026

Coordinated immune architecture underlies durable survival in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterised by profound immune dysfunction and limited response to immunotherapy. Although tertiary lymphoid structures (TLSs) are associated with improved outcomes, most studies focus on their presence or density, providing limited insight into how their organisation contributes to tumour control. Here, we analyse a unique cohort of treatment-naive PDAC patients enriched for exceptionally rare long-term survivors (LTS, n = 23; >5-year survival) alongside more common short-term survivors (STS, n = 24), enabling direct interrogation of mechanisms underlying durable tumour control. We develop a multi-scale spatial framework integrating multiplex imaging, computational modelling, and transcriptomics to quantify TLS architecture. By modelling TLSs as higher-order immune assemblies, we define their structural states, spatial organisation, assembly rules and tissue context-dependency within the tumour microenvironment. We show that long-term survival is associated with organised, spatially integrated TLSs exhibiting coordinated B and T cell zoning, whereas short-term survival is characterised by disorganised, Treg-enriched, and spatially isolated TLSs, despite similar immune cell abundance. These architectural differences align with transcriptional programmes: LTS tumours display coordinated lymphoid and NF-{kappa}B-driven chemokine signalling, while STS tumours exhibit inflammation uncoupled from immune organisation. Together, these findings demonstrate that durable anti-tumour immunity in PDAC is defined by coordinated transcriptional, cellular, and spatial organisation, rather than immune presence alone. This study provides a blueprint for structure-informed strategies to reprogram the tumour microenvironment and improve outcomes in PDAC. Statement of significanceIntegrating multiplex imaging, computational modelling and transcriptomics in treatment-naive PDAC enriched for exceptional survivors shows that durable tumour control is associated with organised TLS architecture rather than immune abundance alone, providing a framework for immune-architecture-based biomarkers and therapeutic reprogramming.

cancer biology↗

bioRxiv2025

LGL-1 and the RhoGAP protein PAC-1 redundantly control polarization of the C. elegans embryonic epidermal epithelium

Apical-basal polarity is essential for epithelial organization and function and is established by conserved cortical polarity proteins. However, the requirements for canonical polarity factors vary between tissues and organisms. For example, the basolateral protein lethal giant larvae (Lgl) is essential for epithelial polarity in Drosophila but dispensable in C. elegans. To better define the epithelial polarity program in C. elegans, we performed a genome-wide RNAi screen for synthetic lethality with lgl-1. Combined loss of LGL-1 and the RhoGAP PAC-1 caused embryonic lethality due to elongation defects and epidermal rupture. Epidermal cells showed expansion of the apical domain and aPKC, accompanied by mislocalization of junctional proteins and LET-413Scribble. These defects indicate overactivity of apical polarity determinants. Consistently, partial inactivation of aPKC or CDC-42 suppressed lethality in pac-1; lgl-1 animals. Together, our results identify PAC-1 and LGL-1 as redundant inhibitors of apical polarity in the C. elegans embryonic epidermis and provide new insights into how conserved mechanisms are adapted across species.

developmental biology↗

bioRxiv2021

Caenorhabditis elegans LET-413 Scribble is essential in the epidermis for growth, viability, and directional outgrowth of epithelial seam cells

The conserved adapter protein Scribble (Scrib) plays essential roles in a variety of cellular processes, including polarity establishment, proliferation, and directed cell migration. While the mechanisms through which Scrib promotes epithelial polarity are beginning to be unraveled, its roles in other cellular processes including cell migration remain enigmatic. In C. elegans, the Scrib ortholog LET-413 is essential for apical-basal polarization and junction formation in embryonic epithelia. However, whether LET-413 is required for postembryonic development or plays a role in migratory events is not known. Here, we use inducible protein degradation to investigate the functioning of LET-413 in larval epithelia. We find that LET-413 is essential in the epidermal epithelium for growth, viability, and junction maintenance. In addition, we identify a novel role for LET-413 in the polarized outgrowth of the epidermal seam cells. These stem cell-like epithelial cells extend anterior and posterior directed apical protrusions in each larval stage to reconnect to their neighbors. We show that the role of LET-413 in seam cell outgrowth is mediated at least in part by the junctional component DLG-1 discs large, which appears to restrict protrusive activity to the apical domain. Finally, we demonstrate that the Rho-family GTPases CED-10 Rac and CDC-42 can regulate seam cell outgrowth and may also function downstream of LET-413. Our data uncover multiple essential functions for LET-413 in larval development and shed new light on the regulation of polarized outgrowth of the seam cells.

developmental biology↗

bioRxiv2020

Epidermal PAR-6 and PKC-3 are essential for postembryonic development of Caenorhabditis elegans and control non-centrosomal microtubule organization

The cortical polarity regulators PAR-6, PKC-3 and PAR-3 are essential for the polarization of a broad variety of cell types in multicellular animals, from the first asymmetric division of the C. elegans zygote to apical-basal polarization of epithelial cells. In C. elegans, the roles of the PAR proteins in embryonic development have been extensively studied, yet little is known about their functions during larval development. Using auxin-inducible protein depletion, we here show that PAR-6 and PKC-3, but not PAR-3, are essential for postembryonic development. We also demonstrate that PAR-6 and PKC-3 are required in the epidermal epithelium to support animal growth and molting, and the proper timing and pattern of seam cell divisions. Finally, we uncovered a novel role for PAR-6 in controlling the organization of non-centrosomal microtubule arrays in the epidermis. PAR-6 was required for the localization of the microtubule organizer NOCA-1/Ninein, and microtubule defects in a noca-1 mutant are highly similar to those caused by epidermal PAR-6 depletion. As NOCA-1 physically interacts with PAR-6, we propose that PAR-6 promotes non-centrosomal microtubule organization through localization of NOCA-1/Ninein. SummaryUsing inducible protein degradation, we show that PAR-6 and PKC-3/aPKC are essential for postembryonic development of C. elegans and control the organization of non-centrosomal microtubule bundles in the epidermis, likely through recruitment of NOCA-1/Ninein.

cell biology↗

bioRxiv2019

Root caries on a Paranthropus robustus third molar from Drimolen

Objectives Dental caries is often perceived as a modern human disease. However, their presence is documented in many early human groups, various non-human primates and, increasingly, our hominin ancestors and relatives. In this study we describe an antemortem lesion on the root of a Paranthropus robustus third molar from Drimolen, South Africa, which likely represents another example of caries in fossil hominins.Materials and Methods The molar, DNH 40, is dated to 2.0–1.5 Ma and displays a lesion on the mesial root surface, extending from the cementoenamel junction 3 mm down toward the apex. The position and severity of the lesion was macroscopically recorded and micro-CT scanned to determine the extent of dentine involvement.Results A differential diagnosis indicates root caries, as the lesion is indistinguishable from clinical examples. Although necrotic in appearance, external tertiary dentine is evident on a micro CT scan. Gingival recession and/or continuous eruption of the tooth as a result of extensive occlusal wear would have occurred to facilitate caries formation. Therefore, the lesion is likely linked to relative old age of this individual.Discussion This new example increases the total number of carious lesions described in P. robustus teeth to 12, on occlusal, interproximal and, now, root surfaces. Beyond the consumption of caries-causing food(s), caries formation would have also required the presence of requisite intra-oral cariogenic bacteria in this individual and the species. Of interest, the presence of tertiary dentine on the outward surface suggests the DNH 40 lesion may have been arrested, i.e., no longer active, perhaps relating to a change in diet or oral microbiome just prior to the individual’s death.View Full Text

paleontology↗

bioRxiv2017

Patterns in protein flexibility: a comparison of NMR "ensembles", MD trajectories and crystallographic B-factors

Proteins are molecular machines requiring flexibility to function. Crystallographic B-factors and Molecular Dynamics (MD) simulations both provide insights into protein flexibility on an atomic scale. Nuclear Magnetic Resonance (NMR) lacks a universally accepted analog of the B-factor, however, a lack of convergence in atomic coordinates in an NMR-based structure calculation also suggests atomic mobility. This paper describes a pattern in the coordinate uncertainties of backbone heavy atoms in NMR-derived structural \"ensembles\" first noted in the development of FindCore2 (previously called Expanded FindCore: DA Snyder, J Grullon, YJ Huang, R Tejero, GT Montelione, Proteins: Structure, Function, and Bioinformatics 82 (S2), 219-230) and demonstrates that this pattern exists in coordinate variances across MD trajectories but not in crystallographic B-factors. This either suggests that MD trajectories and NMR \"ensembles\" capture motional behavior of peptide bond units not captured by B-factors or indicates a deficiency common to force fields used in both NMR and MD calculations. Additionally, a comparison of C B-factors with C coordinate variability in NMR \"ensembles\" and MD trajectories shows that NMR-derived coordinate uncertainties measure variability in atomic positions as well as crystallographic B-factors and superimpositions of MD trajectories do.

biophysics↗