Biology subjects

Shih, B.

Publications and source records attributed to Shih, B..

7 recordsLinked to original sources

bioRxiv2022

West Nile Virus spread in Europe - phylogeographic pattern analysis and key drivers

Spread and emergence of West Nile virus (WNV) in Europe have been very different from those observed in North America. Here, we describe key drivers by combining viral genome sequences with epidemiological data and possible factors of spread into phylodynamic models. WNV in Europe has greater lineage diversity than other regions of the world, suggesting repeated introductions and local amplification. Among the six lineages found in Europe, WNV-2a is predominant, has spread to at least 14 countries and evolved into two major co-circulating clusters (A and B). Both of these seem to originate from regions of Central Europe. Viruses of Cluster A emerged earlier and have spread towards the west of Europe with higher genetic diversity. Amongst multiple drivers, high agriculture activities were associated with both spread direction and velocity. Our study suggests future surveillance activities should be strengthened in Central Europe and Southeast European countries, and enhanced monitoring should be targeted to areas with high agriculture activities.

evolutionary biology↗

bioRxiv2021

Stem cell-derived macrophages as a new platform for studying host-pathogen interactions in livestock

Infectious diseases of farmed and wild animals pose a recurrent threat to food security and human health. The macrophage, a key component of the innate immune system, is the first line of defence against many infectious agents and plays a major role in shaping the adaptive immune response. However, this phagocyte is a target and host for many pathogens. Understanding the molecular basis of interactions between macrophages and pathogens is therefore crucial for the development of effective strategies to combat important infectious diseases. We explored how pluripotent stem cells (PSCs) can provide a limitless in vitro supply of genetically and experimentally tractable macrophages from livestock. Porcine and bovine PSC-derived macrophages (PSCdMs) exhibited molecular and functional characteristics of ex vivo primary macrophages. Pig PSCdMs were productively infected by Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) and African Swine Fever Virus (ASFV), two of the most economically important and devastating viruses in pig farming. Moreover, Pig PSCdMs were readily amenable to genetic modification by CRISPR/Cas9 gene editing applied in parental stem cells, or directly by lentiviral vector transduction. PSCs and differentiated derivatives therefore provide a useful and ethical experimental platform to investigate the genetic and molecular basis of host-pathogen interactions in livestock.

immunology↗

bioRxiv2021

Defining the pig microglial transcriptome reveals their core signature, regional heterogeneity, and similarity with humans

Microglia play key roles in brain homeostasis as well as responses to neurodegeneration and neuroinflammatory processes caused by physical disease and psychosocial stress. The pig is a physiologically-relevant model species for studying human neurological disorders, many of which are associated with microglial dysfunction. Furthermore, pigs are an important agricultural species, and there is a need to understand how microglial function affects their welfare. As a basis for improved understanding to enhance biomedical and agricultural research, we sought to characterise pig microglial identity at genome-wide scale and conduct inter-species comparisons. We isolated pig hippocampal tissue and microglia from frontal cortex, hippocampus and cerebellum, as well as alveolar macrophages from the lungs and conducted RNA-sequencing (RNAseq). By comparing the transcriptomic profiles between microglia, macrophages, and hippocampal tissue, we derived a set of 365 highly-enriched genes defining the porcine core microglial signature. We found brain regional heterogeneity based on 215 genes showing significant (adjusted p<0.01) regional variations and that cerebellar microglia were most distinct. We compared normalized gene expression for microglia from human, mice and pigs using microglia signature gene lists derived from each species and demonstrated that a core microglial marker gene signature is conserved across species, but that species-specific expression subsets also exist. Importantly, pig and human microglia shared greater similarity than pig and murine microglia. Our data provide a valuable resource defining the pig microglial transcriptome signature that highlights pigs as a useful large animal species bridging between rodents and humans in which to study the role of microglia during homeostasis and disease. Main Points- Defined a pig microglial transcriptome signature comprising 365 genes. - Demonstrated regional variance in the pig microglial transcriptome across the brain. - Revealed greater similarity between pig and human microglia than mouse.

bioinformatics↗

bioRxiv2021

A novel strain of lumpy skin disease virus causes clinical disease in cattle in Hong Kong

Lumpy skin disease virus (LSDV) is an emerging poxviral pathogen of cattle that is currently spreading throughout Asia. The disease situation is of high importance for farmers and policy makers in Asia. In October 2020, feral cattle in Hong Kong developed multifocal cutaneous nodules consistent with lumpy skin disease (LSD). Gross and histological pathology further supported the diagnosis and samples were sent to the OIE Reference Laboratory at The Pirbright Institute for confirmatory testing. LSDV was detected using quantitative polymerase chain reaction (qPCR) and additional molecular analyses. This is the first report of LSD in Hong Kong. Whole genome sequencing (WGS) of the strain LSDV/HongKong/2020 and phylogenetic analysis were carried out in order to identify connections to previous outbreaks of LSD, and better understand the drivers of LSDV emergence. Analysis of the 90 core poxvirus genes revealed LSDV/HongKong/2020 was a novel strain most closely related to the live-attenuated Neethling vaccine strains of LSDV and more distantly related to wildtype LSDV isolates from Africa, the Middle East and Europe. Analysis of the more variable regions located towards the termini of the poxvirus genome revealed genes in LSDV/HongKong/2020 with different patterns of grouping when compared to previously published wildtype and vaccine strains of LSDV. This work reveals that the LSD outbreak in Hong Kong in 2020 was caused by a different strain of LSDV than the LSD epidemic in the Middle East and Europe in 2015-2018. The use of WGS is highly recommended when investigating LSDV disease outbreaks.

microbiology↗

bioRxiv2020

Hacking the diversity of SARS-CoV-2 and SARS-like coronaviruses in human, bat and pangolin populations

In 2019, a novel coronavirus, SARS-CoV-2/nCoV-19, emerged in Wuhan, China, and has been responsible for the current COVID-19 pandemic. The evolutionary origins of the virus remain elusive and understanding its complex mutational signatures could guide vaccine design and development. As part of the international "CoronaHack" in April 2020 (https://www.coronahack.co.uk/), we employed a collection of contemporary methodologies to compare the genomic sequences of coronaviruses isolated from human (SARS-CoV-2;n=163), bat (bat-CoV;n=215) and pangolin (pangolin-CoV;n=7) available in public repositories. Following de novo gene annotation prediction, analyses of gene-gene similarity network, codon usage bias and variant discovery were undertaken. Strong host-associated divergences were noted in ORF3a, ORF6, ORF7a, ORF8 and S, and in codon usage bias profiles. Lastly, we have characterised several high impact variants (inframe insertion/deletion or stop gain) in bat-CoV and pangolin-CoV populations, some of which are found in the same amino acid position and may be highlighting loci of potential functional relevance.

genomics↗

bioRxiv2019

A detailed graphical and computational model of the mammalian renal circadian clock

Here we describe the construction of a detailed graphical and computational model of the mammalian circadian clock. We use it to simulate the clock activity within the kidney, where it plays a pivotal role in regulating blood pressure. First, we assembled a network-based process diagram, which includes all known components of the clock and the interactions between them. Parameterisation of the model for Petri net-based simulation experiments used mRNA levels in the kidney to define initial conditions. With empirical testing, model parameterisation was further refined such that the simulated activity of core genes closely matched their measured activity. Furthermore, virtual knockout experiments performed on the model were shown to reflect experimental gene knockout data. It also identified points at which canonical clock genes may integrate with downstream genes likely to affect blood pressure and other aspects of kidney function. We believe that the model provides new insights into the complexity and function of this most central of physiological pathways and provides a valuable resource for the research community.

systems biology↗

bioRxiv2018

A core transcriptional signature of human microglia: derivation and utility in describing region-dependent alterations associated with Alzheimer’s disease

Growing recognition of the pivotal role microglia play in neurodegenerative and neuroinflammatory disorders has accentuated the need to better characterize their function in health and disease. Studies in mouse, have applied transcriptome-wide profiling of microglia to reveal key features of microglial ontogeny, functional profile and phenotypic diversity. Whilst similar in many ways, human microglia exhibit clear differences to their mouse counterparts, underlining the need to develop a better understanding of the human microglial profile. On examining published microglia gene signatures, little consistency was observed between studies. Hence, we set out to define a conserved microglia signature of the human central nervous system (CNS), through a comprehensive meta-analysis of existing transcriptomic resources. Nine datasets derived from cells and tissue, isolated from different regions of the CNS across numerous donors, were subjected independently to an unbiased correlation network analysis. From each dataset, a list of coexpressing genes corresponding to microglia was identified. Comparison of individual microglia clusters showed 249 genes highly conserved between them. This core gene signature included all known markers and improves upon published microglial signatures. The utility of this signature was demonstrated by its use in detecting qualitative and quantitative region-specific alterations in aging and Alzheimers disease. These analyses highlighted the reactive response of microglia in vulnerable brain regions such as the entorhinal cortex and hippocampus, additionally implicating pathways associated with disease progression. We believe this resource and the analyses described here, will support further investigations in the contribution of human microglia towards the CNS in health and disease.\n\nTable of ContentsMain points O_LIPublished microglial transcriptional signatures in mouse and human show poor consensus.\nC_LIO_LIA core transcriptional signature of human microglia with 249 genes was derived and found conserved across brain regions, encompassing the CNS.\nC_LIO_LIThe signature revealed region-dependent microglial alterations in Alzheimers, highlighting susceptible CNS regions and the involvement of TYROBP signaling.\nC_LI

neuroscience↗