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biocause_train_0
Acid pH activation of the PmrA/PmrB two-component regulatory system of Salmonella enterica Acid pH often triggers changes in gene expression. However, little is known about the identity of the gene products that sense fluctuations in extracytoplasmic pH. The Gram-negative pathogen Salmonella enterica serovar Typhimuri...
[ [ 405, 598 ], [ 792, 921 ], [ 922, 1014 ], [ 615, 790 ] ]
biocause_train_1
Introduction Free-living organisms often encounter wide variations in the pH of their surroundings. Thus, pH may act as a signal that triggers cellular responses designed to cope with a new environment. The Gram-negative bacterium Salmonella enterica serovar Typhimurium, for example, experiences a number of acidic env...
[ [ 2220, 2237 ], [ 2356, 2413 ], [ 2108, 2198 ], [ 2440, 2459 ], [ 2108, 2198 ], [ 2108, 2198 ], [ 2486, 2507 ], [ 1417, 1458 ], [ 2313, 2327 ], [ 2108, 2198 ], [ 1708, 1787 ], [ 17...
biocause_train_2
Results Mild acid pH induces transcription of PmrA-regulated genes To examine the mild acid pH induction of PmrA-activated genes, we grew Salmonella cells harbouring chromosomal lacZYA transcriptional fusions to the PmrA-regulated genes pbgP, pmrC and ugd (Wosten and Groisman, 1999) in N-minimal media buffered at pH 5...
[ [ 2032, 2208 ], [ 666, 716 ], [ 541, 639 ], [ 2235, 2364 ], [ 331, 440 ], [ 442, 492 ] ]
biocause_train_3
The PmrB protein is necessary for the mild acid activation of PmrA The PmrB protein is necessary for activation of the PmrA protein in low Mg2+ (Kox et al., 2000; Kato and Groisman, 2004) and in the presence of Fe3+ (Wosten et al., 2000), consistent with the notion that PmrB is the major phosphodonor for PmrA. We inve...
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biocause_train_4
The PmrD protein is necessary for normal PmrA activation at pH 5.8 The PhoP-activated PmrD protein favours the phosphorylated state of the PmrA protein (Fig. 1) (Kato and Groisman, 2004). Thus, we tested the possibility of PmrD participating in the PmrA-dependent response to acidic conditions, and thus contributing to...
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biocause_train_5
Conserved histidine and glutamic acid residues in the periplasmic domain of PmrB are required for signalling in response to mild acid pH The results described above established that PmrB is required for activation of PmrA in response to mild acid pH. This could be because PmrB is directly involved in sensing extracyto...
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biocause_train_6
Mild acid pH induces resistance to the antimicrobial peptide polymyxin B What role could the mild acid pH-dependent activation of PmrA-regulated genes play in Salmonella's lifestyle? Because the PmrA/PmrB system is required for resistance to the antimicrobial peptide polymyxin B (Roland et al., 1993), we hypothesized ...
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biocause_train_7
Discussion We have established that the sensor kinase PmrB is the primary sensor that activates the PmrA protein when Salmonella experiences mild acid pH, resulting in transcription of PmrA-activated genes (Fig. 1). That PmrB is likely to sense changes in pH directly is supported by three findings: (i) the mild acid p...
[ [ 169, 206 ], [ 2684, 2771 ], [ 2535, 2671 ], [ 37, 154 ] ]
biocause_train_8
Novel Algorithms Reveal Streptococcal Transcriptomes and Clues about Undefined Genes Bacteria-host interactions are dynamic processes, and understanding transcriptional responses that directly or indirectly regulate the expression of genes involved in initial infection stages would illuminate the molecular events that...
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biocause_train_9
Introduction Microarray technology is now commonly used to reveal genome-wide transcriptional changes in bacterial pathogens during interactions with the host. Several factors, however, limit the power of such analyses, including inadequate statistical analysis and insufficient sample replication, both of which do not...
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biocause_train_10
Results/Discussion Adherence-Mediated Differential Expression We developed spotted oligonucleotide arrays of the S. pyogenes SF370 (an M1 serotype) genome [14] and compared the transcriptomes of streptococci that adhere to Detroit 562 human pharyngeal cells to non-adherent ("associated") streptococci within the same e...
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biocause_train_11
Verification by Quantitative Real-Time PCR We conducted TaqMan (qRT-PCR) analysis [23] of 11 differentially expressed genes to validate selected microarray hybridization results (see Table S2 for genes and primer-probe sequences). Five genes chosen for validation demonstrated statistically significant fold changes in ...
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biocause_train_12
Virulence Factors Streptococci elaborate several factors implicated in infection, including surface-exposed adhesins and secreted toxigenic proteins (reviewed in [7,14,24]). The initial statistical analysis identified four differentially expressed virulence genes (Tables 1 and 2). Genes encoding streptolysin O (slo or...
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biocause_train_13
Phage-Encoded Genes SF370 contains one inducible prophage (370.1) and three defective prophages (370.2, 370.3, and 370.4) that produce no infectious phage [39]. We identified 11 differentially expressed phage 370.2 genes, suggesting that this defective phage is not transcriptionally silent (Table 1). The speH gene (sp...
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biocause_train_14
Allelic Replacement of speH Increased expression of speH during pharyngeal cell adherence suggests that the SpeH exotoxin is either necessary for adherence, or is a component of a downstream infection process. Adherence-mediated upregulation of speH is likely not the result of phage induction, as the remaining phage 3...
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biocause_train_15
Differential Expression of Genes from Diverse Functional Categories We identified a number of genes encoding proteins involved in housekeeping processes (such as carbohydrate and coenzyme metabolism) that were differentially expressed, indicating a shift in metabolic processes due to host cell adherence (Tables 1 and ...
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biocause_train_16
Neighbor Clustering Our initial analysis revealed the differential expression of a wide range of functionally diverse genes and provided insight into the adaptive response of streptococci to host cell contact. However, despite a rigorous statistical approach, this analysis, like many previous microarray studies, ident...
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biocause_train_17
Type I Clusters: Intact Metabolic Pathways and Multimeric Proteins We measured the performance of our algorithm by examining whether it identified gene groupings known to be functionally related (Type I clusters). Only four (16%) of 25 Type I clusters (spy0080-0081, spy1236-1237, spy1707-1711, spy2041-2042) could have...
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biocause_train_18
Type II Clusters Based on the Type I cluster results, we speculated that genes contained in Type II clusters might be related by function or regulation. Type II groupings contain a combination of both known and unknown gene members and could provide preliminary clues about the function of unknown genes within a partic...
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biocause_train_19
Allelic Replacement of spy0129 We created a spy0129 deletion mutant in strain SF370 (SF370Deltaspy0129) to determine if genes contained within the spy0127-0130 cluster were directly involved in adherence to pharyngeal cells. We posited that a deletion in the spy0129 sortase gene may have the greatest overall effect on...
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biocause_train_20
Additional Type II Cluster Example Another cluster, spy1725-1719, contained six genes that together (though not individually) exhibited significant downregulation. The genes spy1724, spy1722, spy1721, and spy1719 share transcriptional order and predicted function with homologs in the nusA-infB protein biosynthesis ope...
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biocause_train_21
Neighbor Clustering and Operons Although neighbor clustering is not an operon-predicting method, we wanted to identify additional putative operons among the groupings since neighbor clusters by definition share certain operon characteristics (tandemly arranged genes, separated by <300 bp, with similar expression patte...
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biocause_train_22
Analysis of Previously Published Array Data We applied the statistical analysis and the GenomeCrawler algorithms to data from a recently published streptococcal microarray study that is relevant for comparison to our own data (same streptococcal strain, similar array platform) [57]. In this study, the transciptomes of...
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biocause_train_23
Concluding Remarks Although GenomeCrawler improves bacterial array analyses, it has limitations: it cannot identify regulons comprising genes dispersed throughout the genome by virtue of its design, it does not specifically interrogate single-gene operons, and it only applies to genomes with available and accurate exp...
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biocause_train_24
Porphyromonas gingivalis short fimbriae are regulated by a FimS/FimR two-component system Porphyromonas gingivalis possesses two distinct fimbriae. The long (FimA) fimbriae have been extensively studied. Expression of the fimA gene is tightly controlled by a two-component system (FimS/FimR) through a cascade regulatio...
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biocause_train_25
Introduction Porphyromonas gingivalis is a gram-negative bacterium, which is considered to be a major periodontal pathogen (Socransky & Haffajee, 2005). It is also a pathogen that may be involved in coronary heart disease and preterm births (Boggess et al., 2005; Brodala et al., 2005; Chou et al., 2005). The ability o...
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biocause_train_26
Results Role of FimR in mfa1 expression The fimA gene is the only gene known to be tightly controlled by the FimS/FimR system. It was postulated that the expression of other genes may also be controlled by this two component regulatory system. To investigate effects of FimR on expression of the mfa1 gene, an insertion...
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biocause_train_27
Identification of the transcriptional start site of the mfa1 gene To identify the promoter region of mfa1, the transcriptional start site was first determined. The RACE experiment was first conducted with mfa1-specific reverse primers MfaTSR1 located at 135 bp up-stream of the potential start codon and MfaTSR2 located...
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biocause_train_28
Binding of FimR to the promoter region of mfa1 The previous study has shown that the mechanism of FimR activation of the fimA gene involves a regulatory cascade (Nishikawa et al., 2004). It was postulated that different mechanisms might be involved in FimR-mediated mfa1 expression, since expression regulation of mfa1 ...
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biocause_train_29
Discussion The two-component regulatory system is a major mechanism of signal transduction and is widespread in bacteria. Six putative two-component regulatory systems were detected by surveying the P. gingivalis W83 genome database for homologues of the two-component sensor histidine kinase (Hasegawa et al., 2003). A...
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biocause_train_30
Control of M. tuberculosis ESAT-6 Secretion and Specific T Cell Recognition by PhoP Analysis of mycobacterial strains that have lost their ability to cause disease is a powerful approach to identify yet unknown virulence determinants and pathways involved in tuberculosis pathogenesis. Two of the most widely used atten...
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biocause_train_31
Introduction 125 years of intense research on the major human pathogen Mycobacterium tuberculosis have passed since its discovery by Robert Koch, resulting in a huge body of knowledge. In spite of the great progress that has been made in the understanding of some basic features of its pathogenesis, tuberculosis remain...
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biocause_train_32
Results Microarray-Based Comparative Genome Sequencing of M. tuberculosis H37Ra The genome-wide comparative mutational analysis of H37Ra and H37Rv was carried out by NimbleGen Systems following a previously published method [13]. Putative SNPs with high probability scores were separated into synonymous and non-synonym...
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biocause_train_33
Rationale for Knock-Ins To evaluate the phenotypic effect of the different SNPs and to assess their potential contribution to the attenuation process, we undertook functional genomic analyses using knock-ins of H37Ra, as described previously [18]. Clones spanning the different genomic regions of non-synonymous SNPs we...
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biocause_train_34
Ex Vivo Virulence Studies Changes in the regulatory potential of a pathogen are often accompanied by altered virulence. In a first attempt to determine the virulence of the complemented H37Ra knock-in strains relative to wild-type H37Ra and H37Rv, bone marrow-derived murine macrophages (BMM) were infected with the dif...
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biocause_train_35
Virulence Studies of H37Ra Complemented Mutants in a Mouse Model Further assessment of the in vivo growth of different H37Ra knock-in strains was carried out by intravenous infection of severe combined immuno-deficient (SCID) mice. Complementation of H37Ra with the PhoP-expressing cosmid increased the virulence of the...
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biocause_train_36
Link between Mutation in phoP and Secretion of ESAT-6 As PhoP fulfills important regulatory functions in M. tuberculosis [21,22], it was of primary interest to identify and study potential effector molecules whose involvement in host pathogen interaction were influenced by the point mutation in phoP of H37Ra. Since se...
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biocause_train_37
Functional Characterization of Knock-In Mutants We have previously shown that antigen-specific IFN-gamma production of splenocytes is a reliable readout system to evaluate whether or not ESAT-6 was secreted by recombinant strains [23,24,26]. Thus, in order to determine the reason for the observed failure of H37Ra to i...
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biocause_train_38
Discussion The attenuated H37Ra strain was obtained at the Trudeau Institute in the 1930s in an attempt to dissociate virulent and avirulent forms of the tubercle bacillus H37. Steenken et al. have shown that the virulence of the H37 strain was associated with colony morphology and that the avirulent variant H37Ra fai...
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biocause_train_39
Comparative analysis of the Photorhabdus luminescens and the Yersinia enterocolitica genomes: uncovering candidate genes involved in insect pathogenicity Background Photorhabdus luminescens and Yersinia enterocolitica are both enteric bacteria which are associated with insects. P. luminescens lives in symbiosis with s...
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biocause_train_40
Background Pathogenicity as well as symbiosis plays a key role in the interaction of bacteria with their hosts including invertebrates. Despite the relevance of this relationship for the evolution of bacterial pathogenicity, few studies have addressed this subject at the genomic level. We therefore decided to perform ...
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biocause_train_41
Results and Discussion The genomes of P. luminescens ssp. laumondii TT01 and Y. enterocolitica 8081 have completely been sequenced. The genome of the latter strain has a size of ~4.6 Mbp and encodes 4037 putative proteins [23]. Its genome size is exceeded by the ~5.7 Mbp genome of P. luminescens encoding 4839 putative...
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biocause_train_42
Quorum sensing-like gene regulation Regulation by AHL-LuxR-like receptors Virulence, bioluminescence, mutualism, antibiotic production and biofilm formation are often regulated by LuxI/LuxR quorum sensing systems in Gram-negative bacteria. They produce membrane diffusible signalling molecules, acyl homoserine lactones...
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biocause_train_43
Regulation by AI-2 Beside AHL, other putative quorum sensing signalling molecules have been identified. One of them is autoinductor 2 (AI-2), furanosyl borate diester, which is synthesized by the luxS product [39,40] of which homologues are present in P. luminescens and Y. enterocolitica (plu1253, ye0839). It has been...
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biocause_train_44
Regulation by PAS_4/LuxR-like receptors In P. luminescens, the amount of luxR-like genes is overrepresented with 39 copies in the genome. 35 of these potential LuxR-like receptors exhibit PAS_4 signal binding domains instead of an AHL-binding domain, and two have a signalling domain with a yet unidentified motif (Fig....
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biocause_train_45
Regulation by uncommon LuxR-like receptors LuxR-like receptors in Y. enterocolitica with a yet unidentified signalling binding-site are YE2705 and YE3014, both of which are also present in Y. pestis (YPO2955 and YPO2593) and in S. glossinidius (SGP1_007, SG1174, SG1480, and SG1698), but not in P. luminescens (Fig. 3)....
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biocause_train_46
Universal stress proteins Universal stress proteins (Usp) are small soluble proteins found in bacteria, archaea and plants. The production of these proteins is induced upon global stress conditions such as nutrient starvation, heat stress, osmotic stress, oxidative stress, or the presence of toxic compounds. The prote...
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biocause_train_47
Regulation via c-di-GMP as a second messenger Cyclic diguanylate (c-di-GMP) is a bacterial second messenger that activates biofilm formation while inhibiting motility, thus regulating the switch between a planktonic and a sessile lifestyle. In addition to phenotypes that affect virulence properties indirectly, c-di-GM...
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biocause_train_48
Virulence factors So-called offensive virulence factors actively contribute to a successful infection by colonization of and toxicity towards the host organism. We compared both genomes with respect to genes encoding toxins, adhesins or invasines that are common to both pathogens. All virulence factors described in th...
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biocause_train_49
Hemolysins or hemagglutinin-related proteins These extracellular toxins target red blood cells to provide access to iron, but often show activity against immune cells, thus contributing to the bacterial response to the immune system of hosts, including phagocytosis by insect blood cells [64]. Hemolysins or surface-ass...
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biocause_train_50
Repeats-in-toxin (RTX) and other toxins RTX proteins constitute another family of toxins that may contribute to the insecticidal activity of the two pathogens. A putative RTX-family toxin transporter is common to both pathogens (YE1998-2000, Plu0634/Plu0635). The P. luminescens genome comprises a gene cluster encoding...
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biocause_train_51
Adhesins and invasins Colonization and penetration of epithelial cells, and interaction with immune cells, are key steps during the host infection by pathogens. Many of the pathogen-receptor molecules such as Toll-like receptors or integrins are conserved between invertebrates and mammalians [79]. We therefore investi...
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biocause_train_52
Defensive mechanisms Antimicrobials The production of antibiotics is mainly restricted to P. luminescens, whereas factors combating antimicrobial host substances play an important role during the infection process of both pathogens compared here. In the genome of P. luminescens ssp. laumondii strain TT01, many loci in...
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biocause_train_53
Oxygenases and hydrolases P. luminescens produces proteins similar to monooxygenases, dioxygenases and hydroxylases that have been suggested to play a role in rapid elimination of insect polyphenols or in the detoxification of reactive oxygen species generated by the invaded host [24]. Examples are the product of plu4...
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biocause_train_54
Secretion and exoenzymes In Y. enterocolitica, two type-III secretion systems (T3SS) essential for virulence in the mammalian host are encoded on pYV and by the ysa operon (YE3533-3561) [23,82]. The P. luminescens genome encodes one T3SS which is highly similar to the plasmid-encoded T3SS of Y. enterocolitica and prob...
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biocause_train_55
Metabolism While many specific virulence factors, which enable the microbes to overcome the various physical and biochemical barriers of the infected hosts, have been investigated in detail, little attention has been given to the metabolic requirements and substrate availability of bacteria in vivo. Both in insects an...
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biocause_train_56
Iron uptake Bacteria use two different strategies to acquire sufficient amounts of iron, namely the expression and secretion of high-affinity iron-binding compounds called siderophores, and the production of receptors for iron carriers such as heme. Genes involved in the biosynthesis, transport and regulation of the s...
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biocause_train_57
Tricarboxylate utilization The TctE/TctD system is the only TCS of P. luminescens without homologue in Y. enterocolitica (see section "Two-component signal transduction", Fig. 2). It controls the expression of the tctCBA operon encoding the tricarboxylic acid transport system TctCBA [107]. The transporter is supposed ...
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biocause_train_58
Temperature-dependent genes Temperature is a key environmental signal to enable bacterial adaptation to diverse hosts. In Yersinia, temperature-dependent gene expression has been described to be an important theme in bacterial mechanisms of pathogenesis towards humans [116]. However, the biological role of genes repre...
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biocause_train_59
Evolution of pathogenicity It has been suggested that bacteria-invertebrate interactions do not only play a role in the transmission of human pathogens but have also shaped their evolution [79]. We identified several common loci representing ancestral clusters of genes important in Y. enterocolitica and P. luminescens...
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biocause_train_60
Conclusion The comparison of Y. enterocolitica and P. luminescens at the genomic level performed here provides the database for a better understanding of the genetic basis for their distinct behaviour towards invertebrates and mammals. Y. enterocolitica is expected to switch between two pathogenicity phases against in...
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biocause_train_61
SalK/SalR, a Two-Component Signal Transduction System, Is Essential for Full Virulence of Highly Invasive Streptococcus suis Serotype 2 Background Streptococcus suis serotype 2 (S. suis 2, SS2) has evolved into a highly infectious entity, which caused the two recent large-scale outbreaks of human SS2 epidemic in China...
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biocause_train_62
Introduction Streptococcus suis (S. suis) is considered an important zoonotic pathogen causing a variety of life-threatening infections that include meningitis, arthritis, septicaemia and even sudden death in pigs and humans [1], [2]. Among the known 35 serotypes [1], [2], S. suis serotype 2 (S. suis 2 or SS2) is the ...
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biocause_train_63
Results Discovery and Characterization of SalK/SalR The newly decoded genomic sequence of S. suis 05ZYH33 makes it possible to systematically investigate the genetic basis of streptococcal pathogenicity. We focused on the putative 89K PAI to perform further molecular analysis. On the negative strand of 89K, peptides e...
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biocause_train_64
Transcriptional Analysis of the salKR Locus and its Flanking Sequences To confirm the predicted transcripts of salKR and the flanking genes, RNA extracted from S. suis 05ZYH33 cells was subjected to RT-PCR analysis by using primers amplifying each intergenic region of salKR and the flanking genes. As shown in Fig. 2B,...
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biocause_train_65
Construction of DeltasalKR To test the role of SalK/SalR in the pathogenesis of SS2, we constructed a homologous suicide plasmid, pUC::salKR with a SpcR cassette (Fig. 3A), and electrotransformed the competent cells of 05ZYH33. Positive transformants were first screened on THB agar plates under the selective pressure ...
[ [ 1865, 1950 ], [ 1555, 1811 ] ]
biocause_train_66
Role of SalK/SalR in Virulence Given the multiple roles of TCSTS in bacteria, we evaluated the effect of salKR deletion on the general biological characteristics of SS2 prior to in vivo work. First, the ability of the mutant strain to retain spectinomycin resistance was assessed. The spectinomycin resistance phenotype...
[ [ 2130, 2226 ], [ 1872, 1997 ] ]
biocause_train_67
Decreased Resistance of DeltasalKR to PMN-Mediated Killing Together with the wild type strain, DeltasalKR was subjected to PMN-mediated killing assays. We found that the mortality rate of both strains (WT and DeltasalKR) increased coordinately with the extension of the co-culture time with PMN cells (Fig. 6). However,...
[ [ 321, 478 ], [ 539, 571 ] ]
biocause_train_68
Expression Microarray Analysis of the Mutant Strain DeltasalKR To gain further insights into the network/circuit mediated by SalK/SalR, whole-genome DNA microarray was applied to reveal the differential transcription profiles between DeltasalKR and WT [13], [19]. For identifying genes whose expression was significantl...
[ [ 436, 460 ], [ 468, 560 ] ]
biocause_train_69
Genes revolved in recombination/repair and transcription Together with some elements of DNA recombination/repair (05SSU0063, 05SSU0588 and 05SSU0953), two transcription regulators (05SSU0503 and 05SSU1233) were also under the regulation of SalK/SalR. Although these genes were found to be down-regulated in the mutant, ...
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This repository integrates the BioCause corpus into hf datasets. Please find the original dataset here. The data is sourced from the CREST aggregation. Please see the citations at the end of this README.

Usage

Causality Detection

from datasets import load_dataset
dataset = load_dataset("thagen/BioCause", "causality detection")

Causal Candidate Extraction

from datasets import load_dataset
dataset = load_dataset("thagen/BioCause", "causal candidate extraction")

Causality Identification

from datasets import load_dataset
dataset = load_dataset("thagen/BioCause", "causality identification")

Citations

The BioCause paper by Mihaila et al., 2013:

@article{mihaila:2013,
  title = {{{BioCause}}: {{Annotating}} and Analysing Causality in the Biomedical Domain},
  shorttitle = {{{BioCause}}},
  author = {Mihaila, Claudiu and Ohta, Tomoko and Pyysalo, Sampo and Ananiadou, Sophia},
  year = {2013},
  journal = {BMC Bioinform.},
  volume = {14},
  pages = {2},
  doi = {10.1186/1471-2105-14-2}
}

CREST by Hosseini et al., 2021 — whose aggregation we used to source the BioCause data:

@article{hosseini:2021,
  title = {Predicting {{Directionality}} in {{Causal Relations}} in {{Text}}},
  author = {Hosseini, Pedram and Broniatowski, David A. and Diab, Mona T.},
  year = {2021},
  journal = {CoRR},
  volume = {abs/2103.13606},
  eprint = {2103.13606},
  archiveprefix = {arXiv}
}
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