Biology subjects

Holland, C.

Publications and source records attributed to Holland, C..

10 recordsLinked to original sources

bioRxiv2025

Screening of a kinase library in human Huntington disease iPSC derived striatal precursor neurons reveals a neuroprotective effect of PKC alpha and PKC beta1 inhibition

The loss of striatal medium spiny neurons is a hallmark of Huntingtons disease (HD). To identify potential disease-modifying treatments, we previously developed a human neuronal model by immortalizing and differentiating HD patient-derived iPSCs into highly homogeneous striatal precursor neurons (ISPNs). Using a 96-well screening platform, and two rounds of re-screening, we tested a kinase inhibitor library and identified 5 compounds that protected HD ISPNs from mutant huntingtin (mHTT)-induced toxicity. Among these, we prioritized the PKC-/{beta}1 inhibitor GO6976, which rescued HD ISPNs from mHTT toxicity in a dose-dependent manner. Further, we found increased phosphorylation of PKC- and PKC-{beta}1 in HD cells and tissues, while their overexpression was toxic to HD ISPNs. Knockdown of PKC-/{beta}1 protected the neurons, and both isoforms interacted and colocalized with HTT. These results suggest that PKC-/{beta}1 plays a role in HD neurodegeneration, and that inhibiting their activity may offer a potential therapeutic approach for HD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/677178v2_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@256d6org.highwire.dtl.DTLVardef@1931e7borg.highwire.dtl.DTLVardef@1b6598borg.highwire.dtl.DTLVardef@b0bbb5_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIHD patient-derived iPSC-based striatal precursor neurons (ISPNs) were used to screen and identify neuroprotective compounds. C_LIO_LIThe PKC-/{beta}1 inhibitor GO6976 rescues HD ISPNs from mutant huntingtin (HTT)-induced toxicity. C_LIO_LIThe phosphorylation of PKC-/{beta}1 is elevated in HD cell and tissues, and PKC-/{beta}1 interact with both wild-type and mutant huntingtin. C_LIO_LIOverexpression of PKC-/{beta}1 is toxic to HD ISPNs, while its knockdown protects the neurons. C_LI

neuroscience↗

bioRxiv2024

Engaging cancer patients on their attitudes towards microbiome engineering technologies

Microbiome engineering aims to develop engineered live biotherapeutic products to diagnose and treat human disease. One of the most active areas is in the engineering of modified bacteria that act as cancer therapeutics, with many products currently in clinical trials. With the emergence of any novel technologies, it is important to consult the public and end users throughout their development to address any concerns that may arise from their use. This is particularly true for therapeutics, for which it is vital that both clinicians and patients have confidence in the treatments that are available to them. Here, we surveyed a cohort of cancer patients and their relatives to gauge their knowledge of modern microbiome engineering techniques. We focus predominately on the use of bacterial eLBPs to treat cancer. Overall, most participants indicated that they would be comfortable taking cancer treatment options based on microbiome engineering technologies.

scientific communication and education↗

bioRxiv2023

Building the bioeconomy: A targeted assessment approach to identifying biobased technologies, challenges and opportunities in the UK

We explore opportunities, challenges, and strategies to translate and responsibly scale innovative biobased technologies to build more sustainable bioeconomies. The pandemic and other recent disruptions have increased exposure to issues of resilience and regional imbalance and raised attention to pathways that could shift production and consumption regimes based more on local biobased resources and dispersed production. The paper reviews potential biobased technologies strategies and then identifies promising and feasible options with a focus on the United Kingdom. Initial landscape and bibliometric analyses identified 50 potential existing and emerging potential biobased technologies. These technologies were assessed for their ability to fulfil requirements related to biobased production, national applicability, and economic, societal, and environmental benefits, leading to identification of 18 promising biobased production technologies. Through further analysis and focus group discussion with industrial, governmental, academic, agricultural, and social stakeholders, three technology clusters were identified for targeted assessment, drawing on cellulose-, lignin-, and seaweed-feedstocks. Case studies for each of these clusters were developed, addressing conversations around sustainable management and the use of biomass feedstocks, and associated environmental, social, and economic challenges. These cases are presented with discussion of insights and implications for policy. The approach presented in the paper is put forward as a scalable assessment method which can be useful in prompting, informing, and advancing discussion and deliberation on opportunities and challenges for biobased transformations.

synthetic biology↗

bioRxiv2023

Silk Road Revealed: Mechanism of silk fibre formation in Bombyx mori

The transition of silk fibroin from liquid to solid is fundamental to silk-fibre production and key to the superior materials properties of native silks. Here we discover that the fibroin heavy chain from the silkworm moth Bombyx mori folds into a novel {beta}-solenoid structure, where the N-terminal domain (NTD) promotes higher-order oligomerization driven by pH reduction. These findings elucidate the complex rheological behaviour of silk and the liquid crystalline textures within the silk gland. We also find that NTD undergoes hydrolysis during standard regeneration, explaining differences between native and regenerated silk feedstocks. Overall, this study establishes a fibroin heavy chain fold, which could be relevant for other similar proteins, and explains mechanistically its liquid-to-solid transition, driven by pH reduction and stress. One sentence summaryThis study redefines the molecular structure of fibroin heavy chain and its role in the transition from solution to fibre.

biochemistry↗

bioRxiv2022

The timid invasion: Behavioral adjustments favor range expansion in a non-native rodent

In biological invasion processes animal behavior moderates the success of invasive species, and the native faunas ability to adapt. The importance of behavioral syndromes and flexibility of invading species for invasion success remains debated. We investigated behavior of rodents, the bank vole (Myodes glareolus) currently invading Ireland, and the native wood mouse (Apodemus sylvaticus) that declines with vole invasion, at replicated sites at pre-invasion, edge, and source of the invasion. We found that individual rodents varied consistently in risk-taking behaviors, and mice had not adapted to the presence of invasive voles. Voles at the invasion edge were more careful but also more flexible compared to voles the invasion source. The ability to develop timid and flexible phenotypes may contribute to the invasion success of rodents worldwide.

animal behavior and cognition↗

bioRxiv2022

In situ identification of secondary structures in unpurified Bombyx mori silk fibrils using polarized two-dimensional infrared spectroscopy

The mechanical properties of biomaterials are dictated by the interactions and conformations of their building blocks, typically proteins. Although the macroscopic behaviour of biomaterials is widely studied, our understanding of the underlying molecular properties is generally limited. Among the non-invasive and label-free methods to investigate molecular structures, infrared spectroscopy is one of the most commonly used tools, because the absorption bands of the amide groups strongly depend on protein secondary structure. However, spectral congestion usually complicates the analysis of the amide spectrum. Here, we apply polarized two-dimensional (2D) infrared spectroscopy (IR) to directly identify the protein secondary structures in native silk filks cast from Bombyx mori silk feedstock. Without any additional analysis, such as peak fitting, we find that the initial effect of hydration is an increase of the random-coil content at the expense of the -helix content, while the {beta}-sheet content is unchanged, and only increases at a later stage. This paper demonstrates that 2D-IR can be a valuable tool for characterizing biomaterials.

biophysics↗

bioRxiv2022

Species-typical chemical signals mediate reproductive isolation in a teleost fish

The authors have withdrawn their manuscript because they can no longer stand by the behavioral data set and corresponding manuscript as submitted to bioRxiv. A colleague downloaded the data and noted seven instances where pairs of values were duplicated across trials for different pairs of stimuli (data set with duplicated values highlighted is available as supplementary data). While omitting these values from the data set does not qualitatively change the conclusions presented, we have no means to validate the remaining data and therefore feel the best course of action is to treat the whole dataset as invalid. Consequently, analyses and conclusions based wholly or partly on behavioral data are invalid as well. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

animal behavior and cognition↗

bioRxiv2021

Conditional deletion of HIF-1α provides new insight regarding the murine response to gastrointestinal infection with Salmonella Typhimurium

The hypoxia-inducible transcription factor 1 (HIF-1) has been shown to ameliorate different bacterial infections through enhancement of microbial killing. While the impact of HIF-1 on inflammatory diseases of the gut has been studied intensively, its function in bacterial infections of the intestine remains largely elusive. With the help of a publicly available gene expression data set, we could infer significant activation of the HIF-1 transcription factor after oral infection of mice with Salmonella Typhimurium. This prompted us to apply lineage-restricted deletion of the Hif1a locus in mice to examine cell type-specific functions of HIF-1 in this model. We show hypoxia-independent induction of HIF-1 activity upon Salmonella infection in the intestinal epithelium as well as in macrophages. Surprisingly, Hif1a deletion in intestinal epithelial cells impacted neither disease outcome nor inflammatory activity. The conditional knockout of Hif1a in myeloid cells enhanced the mRNA expression of the largely pro-inflammatory chemokine Cxcl2, revealing a potentially inflammatory effect of HIF-1 deficiency in myeloid cells in the gut in vivo. Again, the disease outcome was not affected. In vitro HIF-1-deficient macrophages showed an overall impaired transcription of pro-inflammatory factors, however, Salmonella bypassed direct intracellular, bactericidal HIF-1-dependent mechanisms in a Salmonella pathogenicity island (SPI)-2 independent manner. Taken together, our data suggest that HIF-1 in intestinal epithelial and myeloid cells is either dispensable or compensable in the immune defense against Salmonella Typhimurium.

microbiology↗

bioRxiv2017

Natural selection interacts with the local recombination rate to shape the evolution of hybrid genomes

While hybridization between species is increasingly appreciated to be a common occurrence, little is known about the forces that govern the subsequent evolution of hybrid genomes. We considered this question in three independent, naturally-occurring hybrid populations formed between swordtail fish species Xiphophorus birchmanni and X. malinche. To this end, we built a fine-scale genetic map and inferred patterns of local ancestry along the genomes of 690 individuals sampled from the three populations. In all three cases, we found hybrid ancestry to be more common in regions of high recombination and where there is linkage to fewer putative targets of selection. These same patterns are also apparent in a reanalysis of human-Neanderthal admixture. Our results lend support to models in which ancestry from the \"minor\" parental species persists only where it is rapidly uncoupled from alleles that are deleterious in hybrids, and show the retention of hybrid ancestry to be at least in part predictable from genomic features. Our analyses further indicate that in swordtail fish, the dominant source of selection on hybrids stems from deleterious combinations of epistatically-interacting alleles.\n\nOne sentence summaryThe persistence of hybrid ancestry is predictable from local recombination rates, in three replicate hybrid populations as well as in humans.

evolutionary biology↗

bioRxiv2016

Repeated losses of PRDM9-directed recombination despite the conservation of PRDM9 across vertebrates

Studies of highly diverged species have revealed two mechanisms by which meiotic recombination is directed to the genome--through PRDM9 binding or by targeting promoter-like features--that lead to dramatically different evolutionary dynamics of hotspots. Here, we identify PRDM9 orthologs from genome and transcriptome data in 225 species. We find the complete PRDM9 ortholog across distantly related vertebrates but, despite this broad conservation, infer a minimum of six partial and three complete losses. Strikingly, taxa carrying the complete ortholog of PRDM9 are precisely those with rapid evolution of its predicted binding affinity, suggesting that all domains are necessary for directing recombination. Indeed, as we show, swordtail fish carrying only a partial but conserved ortholog share recombination properties with PRDM9 knock-outs.

evolutionary biology↗