Publications by authors named "Neil Hall"

156 Publications

Inter-kingdom relationships in Crohn's disease explored using a multi-omics approach.

Gut Microbes 2021 Jan-Dec;13(1):1930871

Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.

The etiology of Crohn's disease (CD) is multifactorial. Bacterial and fungal microbiota are involved in the onset and/or progression of the disease. A bacterial dysbiosis in CD patients is accepted; however, less is known about the mycobiome and the relationships between the two communities. We investigated the interkingdom relationships, their metabolic consequences, and the changes in the fungal community during relapse and remission in CD.Two cohorts were evaluated: a British cohort (n = 63) comprising CD and ulcerative colitis patients, and controls. The fungal and bacterial communities of biopsy and fecal samples were analyzed, with the fecal volatiles; datasets were also integrated; and a Dutch cohort (n = 41) comprising CD patients and healthy controls was analyzed for stability of the gut mycobiome.A dysbiosis of the bacterial community was observed in biopsies and stool. Results suggest is likely key in CD and may modulate colonization. A dysbiosis of the fungal community was observed only in the Dutch cohort; and were increased in patients taking immunosuppressants. Longitudinal analysis showed an increase in in relapse. was dominant in all fecal samples, but not in biopsies, some of which did not yield fungal reads; amino acid degradation was the main metabolic change associated with CD and both bacteria and fungi might be implicated.We have shown that and yeasts may play a role in CD; understanding their role and relationship in the disease would shed new light on the development and treatment of CD.
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http://dx.doi.org/10.1080/19490976.2021.1930871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274447PMC
July 2021

Subtelomeric assembly of a multi-gene pathway for antimicrobial defense compounds in cereals.

Nat Commun 2021 05 7;12(1):2563. Epub 2021 May 7.

National Centre for Gene Research, CAS-JIC Centre of Excellence for Plant and Microbial Science (CEPAMS), Centre of Excellence for Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (CAS), Shanghai, China.

Non-random gene organization in eukaryotes plays a significant role in genome evolution. Here, we investigate the origin of a biosynthetic gene cluster for production of defence compounds in oat-the avenacin cluster. We elucidate the structure and organisation of this 12-gene cluster, characterise the last two missing pathway steps, and reconstitute the entire pathway in tobacco by transient expression. We show that the cluster has formed de novo since the divergence of oats in a subtelomeric region of the genome that lacks homology with other grasses, and that gene order is approximately colinear with the biosynthetic pathway. We speculate that the positioning of the late pathway genes furthest away from the telomere may mitigate against a 'self-poisoning' scenario in which toxic intermediates accumulate as a result of telomeric gene deletions. Our investigations reveal a striking example of adaptive evolution underpinned by remarkable genome plasticity.
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http://dx.doi.org/10.1038/s41467-021-22920-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105312PMC
May 2021

Ecological niche adaptation of Salmonella Typhimurium U288 is associated with altered pathogenicity and reduced zoonotic potential.

Commun Biol 2021 04 23;4(1):498. Epub 2021 Apr 23.

Quadram Institute Biosciences, Norwich Research Park, Norwich, NR4 7UQ, UK.

The emergence of new bacterial pathogens is a continuing challenge for agriculture and food safety. Salmonella Typhimurium is a major cause of foodborne illness worldwide, with pigs a major zoonotic reservoir. Two phylogenetically distinct variants, U288 and ST34, emerged in UK pigs around the same time but present different risk to food safety. Here we show using genomic epidemiology that ST34 accounts for over half of all S. Typhimurium infections in people while U288 less than 2%. That the U288 clade evolved in the recent past by acquiring AMR genes, indels in the virulence plasmid pU288-1, and accumulation of loss-of-function polymorphisms in coding sequences. U288 replicates more slowly and is more sensitive to desiccation than ST34 isolates and exhibited distinct pathogenicity in the murine model of colitis and in pigs. U288 infection was more disseminated in the lymph nodes while ST34 were recovered in greater numbers in the intestinal contents. These data are consistent with the evolution of S. Typhimurium U288 adaptation to pigs that may determine their reduced zoonotic potential.
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http://dx.doi.org/10.1038/s42003-021-02013-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065163PMC
April 2021

Extensive microbial diversity within the chicken gut microbiome revealed by metagenomics and culture.

PeerJ 2021 6;9:e10941. Epub 2021 Apr 6.

Quadram Institute Bioscience, Norwich, UK.

Background: The chicken is the most abundant food animal in the world. However, despite its importance, the chicken gut microbiome remains largely undefined. Here, we exploit culture-independent and culture-dependent approaches to reveal extensive taxonomic diversity within this complex microbial community.

Results: We performed metagenomic sequencing of fifty chicken faecal samples from two breeds and analysed these, alongside all ( = 582) relevant publicly available chicken metagenomes, to cluster over 20 million non-redundant genes and to construct over 5,500 metagenome-assembled bacterial genomes. In addition, we recovered nearly 600 bacteriophage genomes. This represents the most comprehensive view of taxonomic diversity within the chicken gut microbiome to date, encompassing hundreds of novel candidate bacterial genera and species. To provide a stable, clear and memorable nomenclature for novel species, we devised a scalable combinatorial system for the creation of hundreds of well-formed Latin binomials. We cultured and genome-sequenced bacterial isolates from chicken faeces, documenting over forty novel species, together with three species from the genus , including the newly named species .

Conclusions: Our metagenomic and culture-based analyses provide new insights into the bacterial, archaeal and bacteriophage components of the chicken gut microbiome. The resulting datasets expand the known diversity of the chicken gut microbiome and provide a key resource for future high-resolution taxonomic and functional studies on the chicken gut microbiome.
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http://dx.doi.org/10.7717/peerj.10941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035907PMC
April 2021

Taxon-Specific Proteins of the Pathogenic Species and .

Front Cell Infect Microbiol 2021 19;11:641472. Epub 2021 Mar 19.

Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.

The human protozoan parasite can live in the human intestine for months or years without generating any symptoms in the host. For unknown reasons, amoebae can suddenly destroy the intestinal mucosa and become invasive. This can lead to amoebic colitis or extraintestinal amoebiasis whereby the amoebae spread to other organs the blood vessels, most commonly the liver where abscesses develop. is the closest genetic relative of and is found in wild macaques. Another close relative is , which asyptomatically infects the human intestine. Although all three species are closely related, only and are able to penetrate their host's intestinal epithelium. Lineage-specific genes and gene families may hold the key to understanding differences in virulence among species. Here we discuss those genes found in that have relatives in only one or neither of its sister species, with particular focus on the peptidase, AIG, Ariel, and BspA families.
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http://dx.doi.org/10.3389/fcimb.2021.641472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017271PMC
July 2021

Dissecting the molecular diversity and commonality of bovine and human treponemes identifies key survival and adhesion mechanisms.

PLoS Pathog 2021 03 29;17(3):e1009464. Epub 2021 Mar 29.

Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Leahurst Campus, Neston, United Kingdom.

Here, we report the first complete genomes of three cultivable treponeme species from bovine digital dermatitis (DD) skin lesions, two comparative human treponemes, considered indistinguishable from bovine DD species, and a bovine gastrointestinal (GI) treponeme isolate. Key genomic differences between bovine and human treponemes implicate microbial mechanisms that enhance knowledge of how DD, a severe disease of ruminants, has emerged into a prolific, worldwide disease. Bovine DD treponemes have additional oxidative stress genes compared to nearest human-isolated relatives, suggesting better oxidative stress tolerance, and potentially explaining how bovine strains can colonize skin surfaces. Comparison of both bovine DD and GI treponemes as well as bovine pathogenic and human non-pathogenic saprophyte Treponema phagedenis strains indicates genes encoding a five-enzyme biosynthetic pathway for production of 2,3-diacetamido-2,3-dideoxy-d-mannuronic acid, a rare di-N-acetylated mannuronic acid sugar, as important for pathogenesis. Bovine T. phagedenis strains further differed from human strains by having unique genetic clusters including components of a type IV secretion system and a phosphate utilisation system including phoU, a gene associated with osmotic stress survival. Proteomic analyses confirmed bovine derived T. phagedenis exhibits expression of PhoU but not the putative secretion system, whilst the novel mannuronic acid pathway was expressed in near entirety across the DD treponemes. Analysis of osmotic stress response in water identified a difference between bovine and human T. phagedenis with bovine strains exhibiting enhanced survival. This novel mechanism could enable a selective advantage, allowing environmental persistence and transmission of bovine T. phagedenis. Finally, we investigated putative outer membrane protein (OMP) ortholog families across the DD treponemes and identified several families as multi-specific adhesins capable of binding extra cellular matrix (ECM) components. One bovine pathogen specific adhesin ortholog family showed considerable serodiagnostic potential with the Treponema medium representative demonstrating considerable disease specificity (91.6%). This work has shed light on treponeme host adaptation and has identified candidate molecules for future diagnostics, vaccination and therapeutic intervention.
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http://dx.doi.org/10.1371/journal.ppat.1009464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049484PMC
March 2021

The Mastigamoeba balamuthi Genome and the Nature of the Free-Living Ancestor of Entamoeba.

Mol Biol Evol 2021 05;38(6):2240-2259

Department of Parasitology, Faculty of Science, Charles University, BIOCEV, Vestec, Czech Republic.

The transition of free-living organisms to parasitic organisms is a mysterious process that occurs in all major eukaryotic lineages. Parasites display seemingly unique features associated with their pathogenicity; however, it is important to distinguish ancestral preconditions to parasitism from truly new parasite-specific functions. Here, we sequenced the genome and transcriptome of anaerobic free-living Mastigamoeba balamuthi and performed phylogenomic analysis of four related members of the Archamoebae, including Entamoeba histolytica, an important intestinal pathogen of humans. We aimed to trace gene histories throughout the adaptation of the aerobic ancestor of Archamoebae to anaerobiosis and throughout the transition from a free-living to a parasitic lifestyle. These events were associated with massive gene losses that, in parasitic lineages, resulted in a reduction in structural features, complete losses of some metabolic pathways, and a reduction in metabolic complexity. By reconstructing the features of the common ancestor of Archamoebae, we estimated preconditions for the evolution of parasitism in this lineage. The ancestor could apparently form chitinous cysts, possessed proteolytic enzyme machinery, compartmentalized the sulfate activation pathway in mitochondrion-related organelles, and possessed the components for anaerobic energy metabolism. After the split of Entamoebidae, this lineage gained genes encoding surface membrane proteins that are involved in host-parasite interactions. In contrast, gene gains identified in the M. balamuthi lineage were predominantly associated with polysaccharide catabolic processes. A phylogenetic analysis of acquired genes suggested an essential role of lateral gene transfer in parasite evolution (Entamoeba) and in adaptation to anaerobic aquatic sediments (Mastigamoeba).
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http://dx.doi.org/10.1093/molbev/msab020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136499PMC
May 2021

COVID-19 evolution during the pandemic - Implications of new SARS-CoV-2 variants on disease control and public health policies.

Virulence 2021 12;12(1):507-508

Center of Excellence for Bionanoscience Research, King Abdul Aziz University , Jeddah, Saudi Arabia.

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http://dx.doi.org/10.1080/21505594.2021.1877066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849743PMC
December 2021

Characteristics of Salmonella Recovered From Stools of Children Enrolled in the Global Enteric Multicenter Study.

Clin Infect Dis 2021 08;73(4):631-641

Medical Research Council Unit, The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia.

Background: The Global Enteric Multicenter Study (GEMS) determined the etiologic agents of moderate-to-severe diarrhea (MSD) in children under 5 years old in Africa and Asia. Here, we describe the prevalence and antimicrobial susceptibility of nontyphoidal Salmonella (NTS) serovars in GEMS and examine the phylogenetics of Salmonella Typhimurium ST313 isolates.

Methods: Salmonella isolated from children with MSD or diarrhea-free controls were identified by classical clinical microbiology and serotyped using antisera and/or whole-genome sequence data. We evaluated antimicrobial susceptibility using the Kirby-Bauer disk-diffusion method. Salmonella Typhimurium sequence types were determined using multi-locus sequence typing, and whole-genome sequencing was performed to assess the phylogeny of ST313.

Results: Of 370 Salmonella-positive individuals, 190 (51.4%) were MSD cases and 180 (48.6%) were diarrhea-free controls. The most frequent Salmonella serovars identified were Salmonella Typhimurium, serogroup O:8 (C2-C3), serogroup O:6,7 (C1), Salmonella Paratyphi B Java, and serogroup O:4 (B). The prevalence of NTS was low but similar across sites, regardless of age, and was similar among both cases and controls except in Kenya, where Salmonella Typhimurium was more commonly associated with cases than controls. Phylogenetic analysis showed that these Salmonella Typhimurium isolates, all ST313, were highly genetically related to isolates from controls. Generally, Salmonella isolates from Asia were resistant to ciprofloxacin and ceftriaxone, but African isolates were susceptible to these antibiotics.

Conclusions: Our data confirm that NTS is prevalent, albeit at low levels, in Africa and South Asia. Our findings provide further evidence that multidrug-resistant Salmonella Typhimurium ST313 can be carried asymptomatically by humans in sub-Saharan Africa.
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http://dx.doi.org/10.1093/cid/ciab051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366818PMC
August 2021

Stepwise evolution of Salmonella Typhimurium ST313 causing bloodstream infection in Africa.

Nat Microbiol 2021 03 21;6(3):327-338. Epub 2020 Dec 21.

Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.

Bloodstream infections caused by nontyphoidal Salmonella are a major public health concern in Africa, causing ~49,600 deaths every year. The most common Salmonella enterica pathovariant associated with invasive nontyphoidal Salmonella disease is Salmonella Typhimurium sequence type (ST)313. It has been proposed that antimicrobial resistance and genome degradation has contributed to the success of ST313 lineages in Africa, but the evolutionary trajectory of such changes was unclear. Here, to define the evolutionary dynamics of ST313, we sub-sampled from two comprehensive collections of Salmonella isolates from African patients with bloodstream infections, spanning 1966 to 2018. The resulting 680 genome sequences led to the discovery of a pan-susceptible ST313 lineage (ST313 L3), which emerged in Malawi in 2016 and is closely related to ST313 variants that cause gastrointestinal disease in the United Kingdom and Brazil. Genomic analysis revealed degradation events in important virulence genes in ST313 L3, which had not occurred in other ST313 lineages. Despite arising only recently in the clinic, ST313 L3 is a phylogenetic intermediate between ST313 L1 and L2, with a characteristic accessory genome. Our in-depth genotypic and phenotypic characterization identifies the crucial loss-of-function genetic events that occurred during the stepwise evolution of invasive S. Typhimurium across Africa.
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http://dx.doi.org/10.1038/s41564-020-00836-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018540PMC
March 2021

Identification of oligo-adenylated small RNAs in the parasite Entamoeba and a potential role for small RNA control.

BMC Genomics 2020 Dec 9;21(1):879. Epub 2020 Dec 9.

Division of Infectious Diseases, Department of Internal Medicine, Stanford University School of Medicine, S-143 Grant Building, 300 Pasteur Drive, Stanford, CA, 94305-5107, USA.

Background: The RNA interference (RNAi) pathway is a gene regulation mechanism that utilizes small RNA (sRNA) and Argonaute (Ago) proteins to silence target genes. Our previous work identified a functional RNAi pathway in the protozoan parasite Entamoeba histolytica, including abundant 27 nt antisense sRNA populations which associate with EhAgo2-2 protein. However, there is lack of understanding about the sRNAs that are bound to two other EhAgos (EhAgo2-1 and 2-3), and the mechanism of sRNA regulation itself is unclear in this parasite. Therefore, identification of the entire pool of sRNA species and their sub-populations that associate with each individual EhAgo protein would be a major step forward.

Results: In the present study, we sequenced sRNA libraries from both total RNAs and EhAgo bound RNAs. We identified a new population of 31 nt sRNAs that results from the addition of a non-templated 3-4 adenosine nucleotides at the 3'-end of the 27 nt sRNAs, indicating a non-templated RNA-tailing event in the parasite. The relative abundance of these two sRNA populations is linked to the efficacy of gene silencing for the target gene when parasites are transfected with an RNAi-trigger construct, indicating that non-templated sRNA-tailing likely play a role in sRNA regulation in this parasite. We found that both sRNA populations (27 nt and 31 nt) are present in the related parasite Entamoeba invadens, and are unchanged during the development. In sequencing the sRNAs associating with the three EhAgo proteins, we observed that despite distinct cellular localization, all three EhAgo sRNA libraries contain 27 nt sRNAs with 5'-polyphosphate (5'-polyP) structure and share a largely overlapping sRNA repertoire. In addition, our data showed that a fraction of 31 nt sRNAs associate with EhAgo2-2 but not with its mutant protein (C-terminal deletion), nor other two EhAgos, indicating a specific EhAgo site may be required for sRNA modification process in the parasite.

Conclusion: We identified a new population of sRNA with non-templated oligo-adenylation modification, which is the first such observation amongst single celled protozoan parasites. Our sRNA sequencing libraries provide the first comprehensive sRNA dataset for all three Entamoeba Ago proteins, which can serve as a useful database for the amoeba community.
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http://dx.doi.org/10.1186/s12864-020-07275-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724847PMC
December 2020

Salmonella identified in pigs in Kenya and Malawi reveals the potential for zoonotic transmission in emerging pork markets.

PLoS Negl Trop Dis 2020 11 24;14(11):e0008796. Epub 2020 Nov 24.

Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom.

Salmonella is a major cause of foodborne disease globally. Pigs can carry and shed non-typhoidal Salmonella (NTS) asymptomatically, representing a significant reservoir for these pathogens. To investigate Salmonella carriage by African domestic pigs, faecal and mesenteric lymph node samples were taken at slaughter in Nairobi, Busia (Kenya) and Chikwawa (Malawi) between October 2016 and May 2017. Selective culture, antisera testing and whole genome sequencing were performed on samples from 647 pigs; the prevalence of NTS carriage was 12.7% in Busia, 9.1% in Nairobi and 24.6% in Chikwawa. Two isolates of S. Typhimurium ST313 were isolated, but were more closely related to ST313 isolates associated with gastroenteritis in the UK than bloodstream infection in Africa. The discovery of porcine NTS carriage in Kenya and Malawi reveals potential for zoonotic transmission of diarrhoeal strains to humans in these countries, but not for transmission of clades specifically associated with invasive NTS disease in Africa.
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http://dx.doi.org/10.1371/journal.pntd.0008796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748489PMC
November 2020

Whole-genome epidemiology links phage-mediated acquisition of a virulence gene to the clonal expansion of a pandemic serovar Typhimurium clone.

Microb Genom 2020 11;6(11)

Quadram Institute Bioscience, Norwich Research Park, Norwich, UK.

Epidemic and pandemic clones of bacterial pathogens with distinct characteristics continually emerge, replacing those previously dominant through mechanisms that remain poorly characterized. Here, whole-genome-sequencing-powered epidemiology linked horizontal transfer of a virulence gene, , to the emergence and clonal expansion of a new epidemic serovar Typhimurium (. Typhimurium) clone. The gene is sporadically distributed within the genus and rare in . Typhimurium lineages, but was acquired multiple times during clonal expansion of the currently dominant pandemic monophasic . Typhimurium sequence type (ST) 34 clone. Ancestral state reconstruction and time-scaled phylogenetic analysis indicated that was not present in the common ancestor of the epidemic clade, but later acquisition resulted in increased clonal expansion of -containing clones that was temporally associated with emergence of the epidemic, consistent with increased fitness. The gene was mainly associated with a temperate bacteriophage mTmV, but recombination with other bacteriophage and apparent horizontal gene transfer of the gene cassette resulted in distribution among at least four mobile genetic elements within the monophasic . Typhimurium ST34 epidemic clade. The mTmV prophage lysogenic transfer to other serovars was limited, but included the common pig-associated . Derby (. Derby). This may explain mTmV in . Derby co-circulating on farms with monophasic . Typhimurium ST34, highlighting the potential for further transfer of the virulence gene in nature. We conclude that whole-genome epidemiology pinpoints potential drivers of evolutionary and epidemiological dynamics during pathogen emergence, and identifies targets for subsequent research in epidemiology and bacterial pathogenesis.
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http://dx.doi.org/10.1099/mgen.0.000456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725340PMC
November 2020

Expanded genome-wide comparisons give novel insights into population structure and genetic heterogeneity of Leishmania tropica complex.

PLoS Negl Trop Dis 2020 09 18;14(9):e0008684. Epub 2020 Sep 18.

Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Byblos, Lebanon.

Leishmania tropica is one of the main causative agents of cutaneous leishmaniasis (CL). Population structures of L. tropica appear to be genetically highly diverse. However, the relationship between L. tropica strains genomic diversity, protein coding gene evolution and biogeography are still poorly understood. In this study, we sequenced the genomes of three new clinical L. tropica isolates, two derived from a recent outbreak of CL in camps hosting Syrian refugees in Lebanon and one historical isolate from Azerbaijan to further refine comparative genome analyses. In silico multilocus microsatellite typing (MLMT) was performed to integrate the current diversity of genome sequence data in the wider available MLMT genetic population framework. Single nucleotide polymorphism (SNPs), gene copy number variations (CNVs) and chromosome ploidy were investigated across the available 18 L. tropica genomes with a main focus on protein coding genes. MLMT divided the strains in three populations that broadly correlated with their geographical distribution but not populations defined by SNPs. Unique SNPs profiles divided the 18 strains into five populations based on principal component analysis. Gene ontology enrichment analysis of the protein coding genes with population specific SNPs profiles revealed various biological processes, including iron acquisition, sterols synthesis and drug resistance. This study further highlights the complex links between L. tropica important genomic heterogeneity and the parasite broad geographic distribution. Unique sequence features in protein coding genes identified in distinct populations reveal potential novel markers that could be exploited for the development of more accurate typing schemes to further improve our knowledge of the evolution and epidemiology of the parasite as well as highlighting protein variants of potential functional importance underlying L. tropica specific biology.
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http://dx.doi.org/10.1371/journal.pntd.0008684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526921PMC
September 2020

High Levels of Genetic Diversity within Nilo-Saharan Populations: Implications for Human Adaptation.

Am J Hum Genet 2020 09 10;107(3):473-486. Epub 2020 Aug 10.

College of Veterinary Medicine, Animal Resources and Biosecurity, Makerere University, P.O. Box 7062, Kampala, Uganda. Electronic address:

Africa contains more human genetic variation than any other continent, but the majority of the population-scale analyses of the African peoples have focused on just two of the four major linguistic groups, the Niger-Congo and Afro-Asiatic, leaving the Nilo-Saharan and Khoisan populations under-represented. In order to assess genetic variation and signatures of selection within a Nilo-Saharan population and between the Nilo-Saharan and Niger-Congo and Afro-Asiatic, we sequenced 50 genomes from the Nilo-Saharan Lugbara population of North-West Uganda and 250 genomes from 6 previously unsequenced Niger-Congo populations. We compared these data to data from a further 16 Eurasian and African populations including the Gumuz, another putative Nilo-Saharan population from Ethiopia. Of the 21 million variants identified in the Nilo-Saharan population, 3.57 million (17%) were not represented in dbSNP and included predicted non-synonymous mutations with possible phenotypic effects. We found greater genetic differentiation between the Nilo-Saharan Lugbara and Gumuz populations than between any two Afro-Asiatic or Niger-Congo populations. F3 tests showed that Gumuz contributed a genetic component to most Niger-Congo B populations whereas Lugabara did not. We scanned the genomes of the Lugbara for evidence of selective sweeps. We found selective sweeps at four loci (SLC24A5, SNX13, TYRP1, and UVRAG) associated with skin pigmentation, three of which already have been reported to be under selection. These selective sweeps point toward adaptations to the intense UV radiation of the Sahel.
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http://dx.doi.org/10.1016/j.ajhg.2020.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477016PMC
September 2020

Author Correction: A transcriptomic analysis of the phylum Nematoda.

Nat Genet 2020 Jul;52(7):750

School of Biological Sciences, University of Edinburgh, Edinburgh, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41588-020-0658-6DOI Listing
July 2020

Evolution of Salmonella enterica serotype Typhimurium driven by anthropogenic selection and niche adaptation.

PLoS Genet 2020 06 8;16(6):e1008850. Epub 2020 Jun 8.

Quadram Institute Biosciences, Norwich Research Park, Norwich, United Kingdom.

Salmonella enterica serotype Typhimurium (S. Typhimurium) is a leading cause of gastroenteritis and bacteraemia worldwide, and a model organism for the study of host-pathogen interactions. Two S. Typhimurium strains (SL1344 and ATCC14028) are widely used to study host-pathogen interactions, yet genotypic variation results in strains with diverse host range, pathogenicity and risk to food safety. The population structure of diverse strains of S. Typhimurium revealed a major phylogroup of predominantly sequence type 19 (ST19) and a minor phylogroup of ST36. The major phylogroup had a population structure with two high order clades (α and β) and multiple subclades on extended internal branches, that exhibited distinct signatures of host adaptation and anthropogenic selection. Clade α contained a number of subclades composed of strains from well characterized epidemics in domesticated animals, while clade β contained multiple subclades associated with wild avian species. The contrasting epidemiology of strains in clade α and β was reflected by the distinct distribution of antimicrobial resistance (AMR) genes, accumulation of hypothetically disrupted coding sequences (HDCS), and signatures of functional diversification. These observations were consistent with elevated anthropogenic selection of clade α lineages from adaptation to circulation in populations of domesticated livestock, and the predisposition of clade β lineages to undergo adaptation to an invasive lifestyle by a process of convergent evolution with of host adapted Salmonella serotypes. Gene flux was predominantly driven by acquisition and recombination of prophage and associated cargo genes, with only occasional loss of these elements. The acquisition of large chromosomally-encoded genetic islands was limited, but notably, a feature of two recent pandemic clones (DT104 and monophasic S. Typhimurium ST34) of clade α (SGI-1 and SGI-4).
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http://dx.doi.org/10.1371/journal.pgen.1008850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302871PMC
June 2020

Gene Expression Profiling to Delineate the Anticancer Potential of a New Alkaloid Isopicrinine From .

Integr Cancer Ther 2020 Jan-Dec;19:1534735420920711

King Abdulaziz University, Jeddah, Saudi Arabia.

has been used as a folkloric medicinal herb for treating various diseases such as diabetes, inflammatory disorders, and sore throat. Several studies have revealed the potential of this plant as an important source of phytochemicals with anticancer properties. The present study was designed to isolate a novel anticancer compound from and elucidate its mechanism of action using genomics approach. leaves extract was prepared, and several alkaloids were purified and characterized. These alkaloids were screened for their anticancer potential. One of the alkaloids, termed as isopicrinine, showed efficient cytotoxicity against MCF7 breast cancer cell line and was selected for further analysis. RNA-Seq transcription profiling was conducted to identify the affected genes and cellular pathways in MCF7 cells after treatment with isopicrinine alkaloid. In vitro studies revealed that newly identified isopicrinine alkaloid possess efficient anticancer activity. Exposure of MCF7 cells with isopicrinine affected the expression of various genes involved in p53 signaling pathway. One of the crucial proapoptotic genes, significantly upregulated in MCF7 after exposure to alkaloid, was (p53 upregulated modulator of apoptosis), which is involved in p53-dependent and -independent apoptosis. Moreover, exposure of sublethal dose of isopicrinine alkaloid in breast cancer cell line led to the downregulation of survivin, which is involved in negative regulation of apoptosis. Besides, several genes involved in mitosis and cell proliferation were significantly downregulated. In this article, we report the determination of a new alkaloid isopicrinine from the aerial parts of with anticancer property. This compound has the potential to be developed as a drug for curing cancer.
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http://dx.doi.org/10.1177/1534735420920711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262827PMC
July 2021

Copy number variation in human genomes from three major ethno-linguistic groups in Africa.

BMC Genomics 2020 Apr 10;21(1):289. Epub 2020 Apr 10.

College of Veterinary Medicine, Animal Resources and Biosecurity, Makerere University, P. O. Box 7062, Kampala, Uganda.

Background: Copy number variation is an important class of genomic variation that has been reported in 75% of the human genome. However, it is underreported in African populations. Copy number variants (CNVs) could have important impacts on disease susceptibility and environmental adaptation. To describe CNVs and their possible impacts in Africans, we sequenced genomes of 232 individuals from three major African ethno-linguistic groups: (1) Niger Congo A from Guinea and Côte d'Ivoire, (2) Niger Congo B from Uganda and the Democratic Republic of Congo and (3) Nilo-Saharans from Uganda. We used GenomeSTRiP and cn.MOPS to identify copy number variant regions (CNVRs).

Results: We detected 7608 CNVRs, of which 2172 were only deletions, 2384 were only insertions and 3052 had both. We detected 224 previously un-described CNVRs. The majority of novel CNVRs were present at low frequency and were not shared between populations. We tested for evidence of selection associated with CNVs and also for population structure. Signatures of selection identified previously, using SNPs from the same populations, were overrepresented in CNVRs. When CNVs were tagged with SNP haplotypes to identify SNPs that could predict the presence of CNVs, we identified haplotypes tagging 3096 CNVRs, 372 CNVRs had SNPs with evidence of selection (iHS > 3) and 222 CNVRs had both. This was more than expected (p < 0.0001) and included loci where CNVs have previously been associated with HIV, Rhesus D and preeclampsia. When integrated with 1000 Genomes CNV data, we replicated their observation of population stratification by continent but no clustering by populations within Africa, despite inclusion of Nilo-Saharans and Niger-Congo populations within our dataset.

Conclusions: Novel CNVRs in the current study increase representation of African diversity in the database of genomic variants. Over-representation of CNVRs in SNP signatures of selection and an excess of SNPs that both tag CNVs and are subject to selection show that CNVs may be the actual targets of selection at some loci. However, unlike SNPs, CNVs alone do not resolve African ethno-linguistic groups. Tag haplotypes for CNVs identified may be useful in predicting African CNVs in future studies where only SNP data is available.
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http://dx.doi.org/10.1186/s12864-020-6669-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147055PMC
April 2020

Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine Tumors.

Cell Mol Gastroenterol Hepatol 2020 28;10(1):113-132. Epub 2020 Jan 28.

Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; Liverpool University Hospitals, National Health Service Foundation Trust, Liverpool, United Kingdom. Electronic address:

Background & Aims: In patients with autoimmune atrophic gastritis and achlorhydria, hypergastrinemia is associated with the development of type 1 gastric neuroendocrine tumors (gNETs). Twelve months of treatment with netazepide (YF476), an antagonist of the cholecystokinin B receptor (CCKBR or CCK2R), eradicated some type 1 gNETs in patients. We investigated the mechanisms by which netazepide induced gNET regression using gene expression profiling.

Methods: We obtained serum samples and gastric corpus biopsy specimens from 8 patients with hypergastrinemia and type 1 gNETs enrolled in a phase 2 trial of netazepide. Control samples were obtained from 10 patients without gastric cancer. We used amplified and biotinylated sense-strand DNA targets from total RNA and Affymetrix (Thermofisher Scientific, UK) Human Gene 2.0 ST microarrays to identify differentially expressed genes in stomach tissues from patients with type 1 gNETs before, during, and after netazepide treatment. Findings were validated in a human AGS gastric adenocarcinoma cell line that stably expresses human CCK2R, primary mouse gastroids, transgenic hypergastrinemic INS-GAS mice, and patient samples.

Results: Levels of pappalysin 2 (PAPPA2) messenger RNA were reduced significantly in gNET tissues from patients receiving netazepide therapy compared with tissues collected before therapy. PAPPA2 is a metalloproteinase that increases the bioavailability of insulin-like growth factor (IGF) by cleaving IGF binding proteins (IGFBPs). PAPPA2 expression was increased in the gastric corpus of patients with type 1 gNETs, and immunohistochemistry showed localization in the same vicinity as CCK2R-expressing enterochromaffin-like cells. Up-regulation of PAPPA2 also was found in the stomachs of INS-GAS mice. Gastrin increased PAPPA2 expression with time and in a dose-dependent manner in gastric AGS cells and mouse gastroids by activating CCK2R. Knockdown of PAPPA2 in AGS cells with small interfering RNAs significantly decreased their migratory response and tissue remodeling in response to gastrin. Gastrin altered the expression and cleavage of IGFBP3 and IGFBP5.

Conclusions: In an analysis of human gNETS and mice, we found that gastrin up-regulates the expression of gastric PAPPA2. Increased PAPPA2 alters IGF bioavailability, cell migration, and tissue remodeling, which are involved in type 1 gNET development. These effects are inhibited by netazepide.
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http://dx.doi.org/10.1016/j.jcmgh.2020.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215182PMC
May 2021

Increasing prevalence of a fluoroquinolone resistance mutation amongst Campylobacter jejuni isolates from four human infectious intestinal disease studies in the United Kingdom.

PLoS One 2020 30;15(1):e0227535. Epub 2020 Jan 30.

Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.

Background: Campylobacter jejuni is the most common bacterial cause of human infectious intestinal disease.

Methods: We genome sequenced 601 human C. jejuni isolates, obtained from two large prospective studies of infectious intestinal disease (IID1 [isolates from 1993-1996; n = 293] and IID2 [isolates from 2008-2009; n = 93]), the INTEGRATE project [isolates from 2016-2017; n = 52] and the ENIGMA project [isolates from 2017; n = 163].

Results: There was a significant increase in the prevalence of the T86I mutation conferring resistance to fluoroquinolone between each of the three later studies (IID2, INTEGRATE and ENIGMA) and IID1. Although the distribution of major multilocus sequence types (STs) was similar between the studies, there were changes in both the abundance of minority STs associated with the T86I mutation, and the abundance of clones within single STs associated with the T86I mutation.

Discussion: Four population-based studies of community diarrhoea over a 25 year period revealed an increase over time in the prevalence of the T86I amongst isolates of C. jejuni associated with human gastrointestinal disease in the UK. Although associated with many STs, much of the increase is due to the expansion of clones associated with the resistance mutation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227535PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992184PMC
April 2020

Molecular evolution of cytochrome C oxidase-I protein of insects living in Saudi Arabia.

PLoS One 2019 4;14(11):e0224336. Epub 2019 Nov 4.

Department of Biological Sciences, Faculty of Science, King Abdulaziz University (KAU), Jeddah, Saudi Arabia.

The study underpins barcode characterization of insect species collected from Saudi Arabia and explored functional constraints during evolution at the DNA and protein levels to expect the possible mechanisms of protein evolution in insects. Codon structure designated AT-biased insect barcode of the cytochrome C oxidase I (COI). In addition, the predicted 3D structure of COI protein indicated tyrosine in close proximity with the heme ligand, depicted substitution to phenylalanine in two Hymenopteran species. This change resulted in the loss of chemical bonding with the heme ligand. The estimated nucleotide substitution matrices in insect COI barcode generally showed a higher probability of transversion compared with the transition. Computations of codon-by-codon nonsynonymous substitutions in Hymenopteran and Hemipteran species indicated that almost half of the codons are under positive evolution. Nevertheless, codons of COI barcode of Coleoptera, Lepidoptera and Diptera are mostly under purifying selection. The results reinforce that codons in helices 2, 5 and 6 and those in loops 2-3 and 5-6 are mostly conserved and approach strong purifying selection. The overall results argue the possible evolutionary position of Hymenopteran species among those of other insects.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224336PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827904PMC
April 2020

Single cell ecology.

Philos Trans R Soc Lond B Biol Sci 2019 11 7;374(1786):20190076. Epub 2019 Oct 7.

Earlham Institute, Norwich Research Park, Norwich, NR4 7UZ, UK.

Cells are the building blocks of life, from single-celled microbes through to multi-cellular organisms. To understand a multitude of biological processes we need to understand how cells behave, how they interact with each other and how they respond to their environment. The use of new methodologies is changing the way we study cells allowing us to study them on minute scales and in unprecedented detail. These same methods are allowing researchers to begin to sample the vast diversity of microbes that dominate natural environments. The aim of this special issue is to bring together research and perspectives on the application of new approaches to understand the biological properties of cells, including how they interact with other biological entities. This article is part of a discussion meeting issue 'Single cell ecology'.
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http://dx.doi.org/10.1098/rstb.2019.0076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792453PMC
November 2019

Multilocus Analysis Resolves the European Finch Epidemic Strain of Trichomonas gallinae and Suggests Introgression from Divergent Trichomonads.

Genome Biol Evol 2019 08;11(8):2391-2402

University of East Anglia, School of Medicine, Biomedical Research Centre, Norwich, Norfolk, United Kingdom.

In Europe, Trichomonas gallinae recently emerged as a cause of epidemic disease in songbirds. A clonal strain of the parasite, first found in the United Kingdom, has become the predominant strain there and spread to continental Europe. Discriminating this epidemic strain of T. gallinae from other strains necessitated development of multilocus sequence typing (MLST). Development of the MLST was facilitated by the assembly and annotation of a 54.7 Mb draft genome of a cloned stabilate of the A1 European finch epidemic strain (isolated from Greenfinch, Chloris chloris, XT-1081/07 in 2007) containing 21,924 protein coding genes. This enabled construction of a robust 19 locus MLST based on existing typing loci for Trichomonas vaginalis and T. gallinae. Our MLST has the sensitivity to discriminate strains within existing genotypes confidently, and resolves the American finch A1 genotype from the European finch epidemic A1 genotype. Interestingly, one isolate we obtained from a captive black-naped fruit dove Ptilinopsus melanospilus, was not truly T. gallinae but a hybrid of T. gallinae with a distant trichomonad lineage. Phylogenetic analysis of the individual loci in this fruit dove provides evidence of gene flow between distant trichomonad lineages at 2 of the 19 loci examined and may provide precedence for the emergence of other hybrid trichomonad genomes including T. vaginalis.
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http://dx.doi.org/10.1093/gbe/evz164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735722PMC
August 2019

DNA extraction and amplicon production strategies deeply inf luence the outcome of gut mycobiome studies.

Sci Rep 2019 06 27;9(1):9328. Epub 2019 Jun 27.

Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Ashton Street, Liverpool, L69 3GE, UK.

Microbial ecology studies are often performed through extraction of metagenomic DNA followed by amplification and sequencing of a marker. It is known that each step may bias the results. These biases have been explored for the study of bacterial communities, but rarely for fungi. Our aim was therefore to evaluate methods for the study of the gut mycobiome. We first evaluated DNA extraction methods in fungal cultures relevant to the gut. Afterwards, to assess how these methods would behave with an actual sample, stool from a donor was spiked with cells from the same cultures. We found that different extraction kits favour some species and bias against others. In terms of amplicon sequencing, we evaluated five primer sets, two for ITS2 and one for ITS1, 18S and 28S rRNA. Results showed that 18S rRNA outperformed the other markers: it was able to amplify all the species in the mock community and to discriminate among them. ITS primers showed both amplification and sequencing biases, the latter related to the variable length of the product. We identified several biases in the characterisation of the gut mycobiome and showed how crucial it is to be aware of these before drawing conclusions from the results of these studies.
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http://dx.doi.org/10.1038/s41598-019-44974-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597572PMC
June 2019

The diversity, evolution and ecology of Salmonella in venomous snakes.

PLoS Negl Trop Dis 2019 06 4;13(6):e0007169. Epub 2019 Jun 4.

Department of Functional and Comparative Genomics, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.

Background: Reptile-associated Salmonella bacteria are a major, but often neglected cause of both gastrointestinal and bloodstream infection in humans globally. The diversity of Salmonella enterica has not yet been determined in venomous snakes, however other ectothermic animals have been reported to carry a broad range of Salmonella bacteria. We investigated the prevalence and diversity of Salmonella in a collection of venomous snakes and non-venomous reptiles.

Methodology/principle Findings: We used a combination of selective enrichment techniques to establish a unique dataset of reptilian isolates to study Salmonella enterica species-level evolution and ecology and used whole-genome sequencing to investigate the relatedness of phylogenetic groups. We observed that 91% of venomous snakes carried Salmonella, and found that a diverse range of serovars (n = 58) were carried by reptiles. The Salmonella serovars belonged to four of the six Salmonella enterica subspecies: diarizonae, enterica, houtanae and salamae. Subspecies enterica isolates were distributed among two distinct phylogenetic clusters, previously described as clade A (52%) and clade B (48%). We identified metabolic differences between S. diarizonae, S. enterica clade A and clade B involving growth on lactose, tartaric acid, dulcitol, myo-inositol and allantoin.

Significance: We present the first whole genome-based comparative study of the Salmonella bacteria that colonise venomous and non-venomous reptiles and shed new light on Salmonella evolution. Venomous snakes examined in this study carried a broad range of Salmonella, including serovars which have been associated with disease in humans such as S. Enteritidis. The findings raise the possibility that venomous snakes could be a reservoir for Salmonella serovars associated with human salmonellosis.
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http://dx.doi.org/10.1371/journal.pntd.0007169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548357PMC
June 2019

Analysis of the recombination landscape of hexaploid bread wheat reveals genes controlling recombination and gene conversion frequency.

Genome Biol 2019 04 15;20(1):69. Epub 2019 Apr 15.

Earlham Institute, Norwich, NR4 7UZ, UK.

Background: Sequence exchange between homologous chromosomes through crossing over and gene conversion is highly conserved among eukaryotes, contributing to genome stability and genetic diversity. A lack of recombination limits breeding efforts in crops; therefore, increasing recombination rates can reduce linkage drag and generate new genetic combinations.

Results: We use computational analysis of 13 recombinant inbred mapping populations to assess crossover and gene conversion frequency in the hexaploid genome of wheat (Triticum aestivum). We observe that high-frequency crossover sites are shared between populations and that closely related parents lead to populations with more similar crossover patterns. We demonstrate that gene conversion is more prevalent and covers more of the genome in wheat than in other plants, making it a critical process in the generation of new haplotypes, particularly in centromeric regions where crossovers are rare. We identify quantitative trait loci for altered gene conversion and crossover frequency and confirm functionality for a novel RecQ helicase gene that belongs to an ancient clade that is missing in some plant lineages including Arabidopsis.

Conclusions: This is the first gene to be demonstrated to be involved in gene conversion in wheat. Harnessing the RecQ helicase has the potential to break linkage drag utilizing widespread gene conversions.
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http://dx.doi.org/10.1186/s13059-019-1675-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463664PMC
April 2019

Genetic Diversity and Gene Family Expansions in Members of the Genus Entamoeba.

Genome Biol Evol 2019 03;11(3):688-705

Earlham Institute, Norwich Research Park, Norwich, United Kingdom.

Amoebiasis is the third-most common cause of mortality worldwide from a parasitic disease. Although the primary etiological agent of amoebiasis is the obligate human parasite Entamoeba histolytica, other members of the genus Entamoeba can infect humans and may be pathogenic. Here, we present the first annotated reference genome for Entamoeba moshkovskii, a species that has been associated with human infections, and compare the genomes of E. moshkovskii, E. histolytica, the human commensal Entamoeba dispar, and the nonhuman pathogen Entamoeba invadens. Gene clustering and phylogenetic analyses show differences in expansion and contraction of families of proteins associated with host or bacterial interactions. They intimate the importance to parasitic Entamoeba species of surface-bound proteins involved in adhesion to extracellular membranes, such as the Gal/GalNAc lectin and members of the BspA and Ariel1 families. Furthermore, E. dispar is the only one of the four species to lack a functional copy of the key virulence factor cysteine protease CP-A5, whereas the gene's presence in E. moshkovskii is consistent with the species' potentially pathogenic nature. Entamoeba moshkovskii was found to be more diverse than E. histolytica across all sequence classes. The former is ∼200 times more diverse than latter, with the four E. moshkovskii strains tested having a most recent common ancestor nearly 500 times more ancient than the tested E. histolytica strains. A four-haplotype test indicates that these E. moshkovskii strains are not the same species and should be regarded as a species complex.
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http://dx.doi.org/10.1093/gbe/evz009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414313PMC
March 2019

Brain and spinal stimulation therapies for phantom limb pain: a systematic review.

Health Technol Assess 2018 11;22(62):1-94

Centre for Reviews and Dissemination (CRD), University of York, York, UK.

Background: Although many treatments exist for phantom limb pain (PLP), the evidence supporting them is limited and there are no guidelines for PLP management. Brain and spinal cord neurostimulation therapies are targeted at patients with chronic PLP but have yet to be systematically reviewed.

Objective: To determine which types of brain and spinal stimulation therapy appear to be the best for treating chronic PLP.

Design: Systematic reviews of effectiveness and epidemiology studies, and a survey of NHS practice.

Population: All patients with PLP.

Interventions: Invasive interventions - deep brain stimulation (DBS), motor cortex stimulation (MCS), spinal cord stimulation (SCS) and dorsal root ganglion (DRG) stimulation. Non-invasive interventions - repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS).

Main Outcome Measures: Phantom limb pain and quality of life.

Data Sources: Twelve databases (including MEDLINE and EMBASE) and clinical trial registries were searched in May 2017, with no date limits applied.

Review Methods: Two reviewers screened titles and abstracts and full texts. Data extraction and quality assessments were undertaken by one reviewer and checked by another. A questionnaire was distributed to clinicians via established e-mail lists of two relevant clinical societies. All results were presented narratively with accompanying tables.

Results: Seven randomised controlled trials (RCTs), 30 non-comparative group studies, 18 case reports and 21 epidemiology studies were included. Results from a good-quality RCT suggested short-term benefits of rTMS in reducing PLP, but not in reducing anxiety or depression. Small randomised trials of tDCS suggested the possibility of modest, short-term reductions in PLP. No RCTs of invasive therapies were identified. Results from small, non-comparative group studies suggested that, although many patients benefited from short-term pain reduction, far fewer maintained their benefits. Most studies had important methodological or reporting limitations and few studies reported quality-of-life data. The evidence on prognostic factors for the development of chronic PLP from the longitudinal studies also had important limitations. The results from these studies suggested that pre-amputation pain and early PLP intensity are good predictors of chronic PLP. Results from the cross-sectional studies suggested that the proportion of patients with severe chronic PLP is between around 30% and 40% of the chronic PLP population, and that around one-quarter of chronic PLP patients find their PLP to be either moderately or severely limiting or bothersome. There were 37 responses to the questionnaire distributed to clinicians. SCS and DRG stimulation are frequently used in the NHS but the prevalence of use of DBS and MCS was low. Most responders considered SCS and DRG stimulation to be at least sometimes effective. Neurosurgeons had mixed views on DBS, but most considered MCS to rarely be effective. Most clinicians thought that a randomised trial design could be successfully used to study neurostimulation therapies.

Limitation: There was a lack of robust research studies.

Conclusions: Currently available studies of the efficacy, effectiveness and safety of neurostimulation treatments do not provide robust, reliable results. Therefore, it is uncertain which treatments are best for chronic PLP.

Future Work: Randomised crossover trials, randomised N-of-1 trials and prospective registry trials are viable study designs for future research.

Study Registration: The study is registered as PROSPERO CRD42017065387.

Funding: The National Institute for Health Research Health Technology Assessment programme.
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http://dx.doi.org/10.3310/hta22620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6253324PMC
November 2018
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