Biology subjects

Holmes, T.

Publications and source records attributed to Holmes, T..

5 recordsLinked to original sources

bioRxiv2026

ADT-030, a novel PDE10 inhibitor, demonstrates potent antitumor activity in pancreatic ductal adenocarcinoma

Phosphodiesterase 10 (PDE10) has been noted to be highly expressed in multiple types of cancer and is crucial for the growth and maintenance of cancer cells found in colon, lung, and ovarian cancers. Here, we studied a novel orally bioavailable PDE10 inhibitor, ADT-030, and found that it potently inhibits the proliferation and clonogenicity of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) cells at levels that block recombinant PDE10. ADT-030 also inhibited PDAC cell motility and triggered G2/M cell cycle halt and programmed cell death. These impacts were facilitated by raised cAMP/cGMP levels, activation of PKA/PKG, reduced {beta}-catenin and RAS signaling. Notably, ADT-030 diminished the proliferation of PDAC cells with KRASG12D and KRASG12C mutations that were resistant to both allele-specific and pan-RAS inhibitors. When administered orally, ADT-030 markedly decreased tumor growth, lowered the metastasis to the lungs and liver, and enhanced survival rates without causing systemic toxicity in both syngeneic and patient-derived xenograft (PDX) models of PDAC. ADT-030 also increased chemotherapy response in orthotopic PDAC models. Immune phenotyping and single-cell RNA sequencing revealed remodeling of the tumor microenvironment by ADT-030 with a more favorable anti-tumor immune profile. The findings suggest that ADT-030 holds promise as a potential drug development candidate for treating KRAS-mutant PDAC by simultaneously targeting key oncogenic signaling pathways, resulting in tumor-intrinsic and immunomodulatory effects.

cancer biology↗

bioRxiv2024

A scientific case for revisiting the embryonic chicken model in biomedical research

The availability of fertilised chicken eggs and the accessibility and rapid development of the avian embryo, have been utilised in biomedical scientific research to make fundamental discoveries including of developmental processes that are common to all vertebrates, advances in teratology, the understanding of tumour growth and metastasis, angiogenesis, cancer drug assessment and vaccine development as well as advances in understanding avian specific biology. However, recent innovations in chicken transgenesis, genome engineering and surrogate host technology in chickens have only been utilised in a few of these fields of research, specifically some areas of developmental biology, avian sex determination and immunology. To understand why other biomedical fields have not adopted modern chicken transgenic tools, we investigated the non-technical summaries of projects granted in the UK under the Animals (Scientific Procedures) Act 1986 between 2017-2023 to assess when and how chicken embryos are used in research, and if they were considered as a Replacement model for other species. HighlightsO_LIEvidence for a lack of uptake of the chicken embryo as a partial replacement model C_LIO_LICase examples of the reduction in animal numbers when chicken models are used C_LIO_LIProposed action plan for the avian developmental biology community C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/623941v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@a78644org.highwire.dtl.DTLVardef@6007d4org.highwire.dtl.DTLVardef@a21fb3org.highwire.dtl.DTLVardef@1cf5b90_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2022

Integrating analog and digital modes of gene expression at Arabidopsis FLC

Quantitative gene regulation at the cell population-level can be achieved by two fundamentally different modes of regulation at individual gene copies. A "digital" mode involves binary ON/OFF expression states, with population-level variation arising from the proportion of gene copies in each state, while an "analog" mode involves graded expression levels at each gene copy. At the Arabidopsis floral repressor FLOWERING LOCUS C (FLC), "digital" Polycomb silencing is known to facilitate quantitative epigenetic memory in response to cold. However, whether FLC regulation before cold involves analog or digital modes is unknown. Using quantitative fluorescent imaging of FLC mRNA and protein, together with mathematical modelling, we find that FLC expression before cold is regulated by both analog and digital modes. We observe a temporal separation between the two modes, with analog preceding digital. The analog mode can maintain intermediate expression levels at individual FLC gene copies, before subsequent digital silencing, consistent with the copies switching OFF stochastically and heritably without cold. This switch leads to a slow reduction in FLC expression at the cell population-level. These data present a new paradigm for gradual repression, elucidating how analog transcriptional and digital epigenetic memory pathways can be integrated.

molecular biology↗

bioRxiv2020

Robust Population Single Neuronal Calcium Signal Extraction Using SCOUT Allows for Longitudinal Analysis of Behavior-associated Neural Ensemble Dynamics

In vivo calcium imaging enables simultaneous recording of large neuronal ensembles while engaged in operations such as learning and memory. However, such in vivo optical recordings are typically subject to motion artifact and background contamination from neurons and blood vessels. Further, population cell tracking across multiple recordings is complicated by non-rigid transformation induced by cell movements and field shifts. We introduce the novel method SCOUT for Single-Cell SpatiOtemporal LongitUdinal Tracking, consisting of two crucial parts: (1) imposition of spatial constraints on neuronal footprints extracted from individual optical recordings to improve ROI selection and eliminate false discoveries, and (2) application of a predictor-corrector, using spatiotemporal correlation of extracted neurons across sessions, for population cell tracking across multiple sessions. SCOUT empirically outperforms current methods for cell extraction and tracking in long-term multi-session imaging experiments across multiple brain regions. Application of this method allows for robust longitudinal analysis of contextual discrimination associated neural ensemble dynamics in the hippocampus up to 60 days.

neuroscience↗

bioRxiv2019

Many unreported crop pests and pathogens are probably already present

Biotic invasions threaten global biodiversity and ecosystem function, and present challenges to agriculture where invasive pest species require major economic investment in control and can cause significant production losses. Pest Risk Analysis (PRA) is key to prioritizing agricultural biosecurity efforts, but is hampered by incomplete knowledge of current crop pest and pathogen distributions. Here we develop predictive models of current pest distributions and test these models using new observations at sub-national resolution. We apply generalized linear models (GLM) to estimate presence probabilities for 1901 crop pests in the CABI pest distribution database. We test model predictions for 100 unobserved pests in the Peoples Republic of China (PRC), against observations of these pests abstracted from the Chinese literature which has hitherto been omitted from databases on global pest distributions. Finally, we predict occurrences of all unobserved pests globally. Presence probability increases with host presence, presence in neighbouring regions, and global prevalence, and decreases with mean distance from coast, per capita GDP, and host number. The models are good predictors of pest presence in Provinces of the PRC, with AUC values of 0.76 - 0.80. Large numbers of currently unobserved, but probably present pests, are predicted in China, India, southern Brazil and some countries of the former USSR. GLMs can predict presences of pseudo-absent pests at sub-national resolution. Controlling for countries scientific capacity improves model fit. The Chinese scientific literature has been largely inaccessible to Western academia but contains important information that can support PRA. Prior studies have often assumed that unreported pests in a global distribution database is a true absence. Our analysis provides a method for quantifying pseudo-absences to enable improved PRA and species distribution modelling.

ecology↗