Biology subjects

Roberts, S.

Publications and source records attributed to Roberts, S..

45 records · Page 3Linked to original sources

bioRxiv2020

Optoacoustic imaging of GLP-1 Receptor with a near-infrared exendin-4 analog

Limitations in current imaging tools have long challenged the imaging of small pancreatic islets in animal models. Here, we report the first development and in vivo validation testing of a broad spectrum and high absorbance near infrared optoacoustic contrast agent, E4x12-Cy7. Our near infrared tracer (E4x12-Cy7) is based on the amino acid sequence of exendin-4 and targets the glucagon-like peptide-1 receptor (GLP-1R). Cell assays confirmed that E4x12-Cy7 has a high binding affinity (IC50 = 4.6 {+/-} 0.8 nM). Using the multi-spectral optoacoustic tomography (MSOT), we imaged E4x12-Cy7 and optoacoustically visualized {beta}-cell insulinoma xenografts in vivo for the first time. In the future, similar optoacoustic tracers that are specific for {beta}-cells and combines optoacoustic and fluorescence imaging modalities could prove to be important tools for monitoring the pancreas for the progression of diabetes.

bioengineering↗

bioRxiv2020

A common analgesic enhances the anti-tumour activity of 5-aza-2'-deoxycytidine through induction of oxidative stress

The DNA demethylating agent 5-aza-2-deoxycytidine (DAC, decitabine) has anti-cancer therapeutic potential, but its clinical efficacy is hindered by DNA damage-related side effects. Here we describe how paracetamol augments the effects of DAC on cancer cell proliferation and differentiation, without enhancing DNA damage. Firstly, DAC specifically upregulates cyclooxygenase-2-prostaglandin E2 pathway, inadvertently increasing cancer cell survival, while the addition of paracetamol offsets this effect. Secondly, combined treatment leads to glutathione depletion and ROS accumulation with oxidative stress further enhanced by DAC suppressing anti-oxidant and thioredoxin responses. The benefits of combined treatment are demonstrated here in head and neck squamous cell carcinoma (HNSCC) and acute myeloid leukaemia cell lines, further corroborated in a HNSCC xenograft mouse model and through mining of publicly available DAC and paracetamol responses. In summary, the addition of paracetamol could allow for DAC dose reduction, widening its clinical usability and providing a strong rationale for consideration in cancer therapy.

cancer biology↗

bioRxiv2020

General DNA methylation patterns and environmentally-induced differential methylation in the eastern oyster (Crassostrea virginica)

Epigenetic modification, specifically DNA methylation, is one possible mechanism for intergenerational plasticity. Before inheritance of methylation patterns can be characterized, we need a better understanding of how environmental change modifies the parental epigenome. To examine the influence of experimental ocean acidification on eastern oyster (Crassostrea virginica) gonad tissue, oysters were cultured in the laboratory under control (491 {+/-} 49 atm) or high (2550 {+/-} 211 atm) pCO2 conditions for four weeks. DNA from reproductive tissue was isolated from five oysters per treatment, then subjected to bisulfite treatment and DNA sequencing. Irrespective of treatment, DNA methylation was primarily found in gene bodies with approximately 22% of CpGs (2.7% of total cytosines) in the C. virginica genome predicted to be methylated. In response to elevated pCO2, we found 598 differentially methylated loci primarily overlapping with gene bodies. A majority of differentially methylated loci were in exons (61.5%) with less intron overlap (31.9%). While there was no evidence of a significant tendency for the genes with differentially methylated loci to be associated with distinct biological processes, the concentration of these loci in gene bodies, including genes involved in protein ubiquitination and biomineralization suggests DNA methylation may be important for transcriptional control in response to ocean acidification. Changes in gonad methylation also indicate potential for these methylation patterns to be inherited by offspring. Understanding how experimental ocean acidification conditions modify the oyster epigenome, and if these modifications are inherited, allows for a better understanding of how ecosystems will respond to environmental change.

genomics↗

bioRxiv2019

Social bonding, gestural complexity and displacement behaviour of wild chimpanzee

Kinship and demography affect social affiliation in many different contexts such as co-feeding, resting, travel, grooming, visual attention and proximity. Chimpanzees may coordinate these social interactions by using gestural communication to make signallers goal transparent to the recipient and also by increasing commitment of the recipient through including rewarding property in communication. The rewards of gesturing can be measured through the rates of displacement behaviour made in response to these gestures by the recipient. We tested hypothesis that gestural communication affects social affiliation after controlling for kinship and demography in wild, adult chimpanzees living in Budongo Forest, Uganda. We found that affiliative but not antagonistic gestures positively predicted social affiliation. Contexts differed in their association with gestures according to complexity and association with displacement behaviour. More complex, less intense gestures predicted mutual grooming, travel, visual attention whereas less complex, more intense gestures predicted unidirectional grooming. Mirroring these patterns, reduced displacement activity occurred in response to gestures associated with unidirectional grooming but not other contexts. We highlight that these tactical decisions that wild chimpanzees make in their use of gestural communication may be driven by complexity of social environment that influences effectiveness with which signalers can influence the recipient.

animal behavior and cognition↗

bioRxiv2019

A Porcine Model of Peripheral Nerve Injury Enabling Ultra-Long Regenerative Distances: Surgical Approach, Recovery Kinetics, and Clinical Relevance

Approximately 20 million Americans currently experience residual deficits from traumatic peripheral nerve injury. Despite recent advancements in surgical technique, peripheral nerve repair typically results in poor functional outcomes due to prolonged periods of denervation resulting from long regenerative distances coupled with relatively slow rates of axonal regeneration. Development of novel surgical solutions requires valid preclinical models that adequately replicate the key challenges of clinical peripheral nerve injury. Our team has developed a porcine model using Yucatan minipigs that provides an opportunity to investigate peripheral nerve regeneration using different nerves tailored for a specific mechanism of interest, such as (1) nerve modality: motor, sensory, and mixed-modality; (2) injury length: short versus long gap; and (3) total regenerative distance: proximal versus distal injury. Here, we describe a comprehensive porcine model of two challenging clinically relevant procedures for repair of long segmental lesions ([≥] 5 cm) - the deep peroneal nerve repaired using a sural nerve autograft and the common peroneal nerve repaired using a saphenous nerve autograft - each featuring ultra-long total regenerative distances (up to 20 cm and 27 cm, respectively) to reach distal targets. This paper includes a detailed characterization of the relevant anatomy, surgical approach/technique, functional/electrophysiological outcomes, and nerve morphometry for baseline and autograft repaired nerves. These porcine models of major peripheral nerve injury are suitable as preclinical, translatable models for evaluating the efficacy, safety, and tolerability of next-generation artificial nerve grafts prior to clinical deployment.

neuroscience↗

bioRxiv2019

Heritability of skewed X-inactivation in female twins is tissue-specific and dependent on age

To balance the X-linked transcriptional dosages between the sexes, one of the two X-chromosomes is randomly selected to be inactivated in somatic tissues of female placental mammals. Non-random, or skewed X-chromosome inactivation (XCI) toward one parental X has been observed in female somatic tissues, and this skewing effect has been associated with several complex human traits. However, the extent of the influence of genetic and environmental factors on XCI skewing is largely unknown. Here, we use RNA-seq and DNA-seq data taken from a large cohort of female twins to quantify the degree of skewing of XCI (DS) in multiple tissues and to study the relationship of XCI with age, genetic factors and complex traits. We show that the XCI patterns are highly tissue-specific with a higher prevalence of skewed XCI in blood-derived tissues than in fat or skin tissue. We also show that the DS in blood-derived tissues is associated with age and that the acquired DS occurs uniquely in blood-derived tissues with an inflection point at approximately 55 years of age. Heritability analysis indicates that the heritability of DS is both age and tissue specific; DS is heritable in blood tissue of females >55 years-old (h2 = 0.34) but is not heritable in blood tissues of females <55 years-old (h2 = 0), nor in skin and fat tissues at any age. We find a positive association between the DS and smoking status in blood tissues of older females (P = 0.02). The high tissue specificity of XCI patterns in human indicates the existence of tissue-specific mechanisms influencing XCI patterns, including genetic and environmental factors. We conclude that the heritability of XCI skewing in blood-derived tissues is dependent on age, representing a Gene x Age interaction that can shift the functional allelic dosage of an entire chromosome in a tissue-restricted manner.

genetics↗

bioRxiv2018

The WT1-BASP1 complex is required to maintain the differentiated state of taste receptor cells

The WT1-BASP1 complex is a transcriptional repressor that is involved in cell differentiation; however, the mechanisms underlying its effects are not well-characterized in vivo. In the peripheral taste system which endogenously expresses these proteins, BASP1 co-expression with WT1 begins at the end of development, suggesting a role for the WT1-BASP1 complex in terminal cell differentiation within this system. Using a conditional BASP1 mouse, we demonstrate that BASP1 is critical to maintain the differentiated state of adult cells by inhibiting the activation of WT1-dependent target genes. Our results uncover a central role for the WT1-BASP1 complex in maintaining cell differentiation.

cell biology↗

bioRxiv2018

Intentional gestures predict complex sociality in wild chimpanzee

A key challenge for primates is coordinating behavior with conspecifics in large, complex social groups. Gestures play a key role in this process and chimpanzees show considerable flexibility communicating through single gestures, sequences of gestures interspersed with periods of response waiting (persistence) and rapid sequences where gestures are made in quick succession, too rapid for the response waiting to have occurred. Previous studies examined behavioral reactions to single gestures and sequences, but whether this complexity is associated with more complex sociality at the level of the dyad partner and the group as a whole is not well understood. We used social network analysis to examine how the production of single gestures and sequences of gestures was related to the duration of time spent in proximity and individual differences in proximity in wild East African chimpanzees (Pan troglodytes schweinfurthii). Pairs of chimpanzees that spent a longer duration of time in proximity had higher rates of persistence, but not a higher rate of single gesture or rapid sequences. Central individuals in the social network received higher rates of persistence, but not rapid sequence or single gesture. Intentional gestural communication plays an important role in regulating social interactions in complex primate societies.

animal behavior and cognition↗

bioRxiv2017

Genetic And Epigenetic Insight Into Morphospecies In A Reef Coral

Incongruence between conventional and molecular systematics has left the delineation of many species unresolved. Reef-building corals are no exception, with phenotypic plasticity among the most plausible explanations for alternative morphospecies. As potential molecular signatures of phenotypic plasticity, epigenetic processes may contribute to our understanding of morphospecies. We compared genetic and epigenetic variation in Caribbean branching Porites spp., testing the hypothesis that epigenetics-- specifically, differential patterns of DNA methylation--play a role in alternative morphotypes of a group whose taxonomic status has been questioned. We used reduced representation genome sequencing to analyze over 1,000 single nucleotide polymorphisms and CpG sites in 27 Porites spp. exhibiting a range of morphotypes from a variety of habitats in Belize. We found stronger evidence for genetic rather than epigenetic structuring, identifying three well-defined genetic groups. One of these groups exhibited significantly thicker branches, and branch thickness was a better predictor of genetic groups than depth, habitat, or symbiont type. Epigenetic patterns were more subtle, with no clear groups. The more thickly branched individuals in one of the genetic groups exhibited some epigenetic similarity, suggesting potential covariation of genetics and epigenetics. This covariation was further supported by a positive association between pairwise genetic and epigenetic distance. We speculate that epigenetic patterns are a complex mosaic reflecting inheritance and diverse environmental histories. Given the role of genetics in branching Porites spp. morphospecies we were able to detect with genome-wide sequencing, use of such techniques throughout the geographic range may help settle their phylogeny.

molecular biology↗