Borrelia burgdorferi Enolase Is a Surface-Exposed Plasminogen Binding Protein

Borrelia burgdorferi is the causative agent of Lyme disease, the most commonly reported arthropod-borne disease in the United States. B. burgdorferi is a highly invasive bacterium, yet lacks extracellular protease activity. In order to aid in its dissemination, B. burgdorferi binds plasminogen, a component of the hosts' fibrinolytic system. Plasminogen bound to the surface of B. burgdorferi can then be activated to the protease plasmin, facilitating the bacterium's penetration of endothelial cell layers and degradation of extracellular matrix components. Enolases are highly conserved proteins with no sorting sequences or lipoprotein anchor sites, yet many bacteria have enolases bound to their outer surfaces. B. burgdorferi enolase is both a cytoplasmic and membrane associated protein. Enolases from other pathogenic bacteria are known to bind plasminogen. We confirmed the surface localization of B. burgdorferi enolase by in situ protease degradation assay and immunoelectron microscopy. We then demonstrated that B. burgdorferi enolase binds plasminogen in a dose-dependent manner. Lysine residues were critical for binding of plasminogen to enolase, as the lysine analog εaminocaproic acid significantly inhibited binding. Ionic interactions did not play a significant role in plasminogen binding by enolase, as excess NaCl had no effects on the interaction. Plasminogen bound to recombinant enolase could be converted to active plasmin. We conclude that B. burgdorferi enolase is a moonlighting cytoplasmic protein which also associates with the bacterial outer surface and facilitates binding to host plasminogen

Environmental health impacts of unconventional natural gas development: a review of the current strength of evidence

Rapid global expansion of unconventional natural gas development (UNGD) raises environmental health concerns. Many studies present information on these concerns, yet the strength of epidemiological evidence remains tenuous. This paper is a review of the strength of evidence in scientific reporting of environmental hazards from UNGD activities associated with adverse human health outcomes. Studies were drawn from peer-reviewed and grey literature following a systematic search. Five databases were searched for studies published from January 1995 through March 2014 using key search terms relevant to environmental health. Studies were screened, ranked and then reviewed according to the strength of the evidence presented on adverse environmental health outcomes associated with UNGD. The initial searches yielded >1000 studies, but this was reduced to 109 relevant studies after the ranking process. Only seven studies were considered highly relevant based on strength of evidence. Articles spanned several relevant topics, but most focussed on impacts on typical environmental media, such as water and air, with much of the health impacts inferred rather than evidenced. Additionally, the majority of studies focussed on short-term, rather than long-term, health impacts, which is expected considering the timeframe of UNGD; therefore, very few studies examined health outcomes with longer latencies such as cancer or developmental outcomes. Current scientific evidence for UNGD that demonstrates associations between adverse health outcomes directly with environmental health hazards resulting from UNGD activities generally lacks methodological rigour. Importantly, however, there is also no evidence to rule out such health impacts. While the current evidence in the scientific research reporting leaves questions unanswered about the actual environmental health impacts, public health concerns remain intense. This is a clear gap in the scientific knowledge that requires urgent attention

All-age hospitalization rates in coal seam gas areas in Queensland, Australia, 1995–2011

Background: Unconventional natural gas development (UNGD) is expanding globally, with Australia expanding development in the form of coal seam gas (CSG). Residents and other interest groups have voiced concerns about the potential environmental and health impacts related to CSG. This paper compares objective health outcomes from three study areas in Queensland, Australia to examine potential environmentally-related health impacts. Methods: Three study areas were selected in an ecologic study design: A CSG area, a coal mining area, and a rural/agricultural area. Admitted patient data, as well as population data and additional factors, were obtained for each calendar year from 1995 through 2011 to calculate all-age hospitalization rates and age-standardized rates in each of these areas. The three areas were compared using negative binomial regression analyses (unadjusted and adjusted models) to examine increases over time of hospitalization rates grouped by primary diagnosis (19 ICD chapters), with rate ratios serving to compare the within-area regression slopes between the areas. Results: The CSG area did not have significant increases in all-cause hospitalization rates over time for all-ages compared to the coal and rural study areas in adjusted models (RR: 1.02, 95 % CI: 1.00-1.04 as compared to the coal mining area; RR: 1.01, 95 % CI: 0.99-1.04 as compared to the rural area). While the CSG area did not show significant increases in specific hospitalization rates compared to both the coal mining and rural areas for any ICD chapters in the adjusted models, the CSG area showed increases in hospitalization rates compared only to the rural area for neoplasms (RR: 1.09, 95 % CI: 1.02-1.16) and blood/immune diseases (RR: 1.14, 95 % CI: 1.02-1.27). Conclusions: This exploratory study of all-age hospitalization rates for three study areas in Queensland suggests that certain hospital admissions rates increased more quickly in the CSG study area than in other study areas, particularly the rural area, after adjusting for key sociodemographic factors. These findings are an important first step in identifying potential health impacts of CSG in the Australian context and serve to generate hypotheses for future studies

‘Subjects and Objects: Material Expressions of Love and Loyalty in Seventeenth-Century England’, in special section on ‘Loyalties and Allegiances in Early Modern England’ in Journal of British Studies Vol. 48: 4 (October, 2009)

This article investigates how and where the emotive relations between subject and state were forged and how these ideas were manifested in early modern England. McShane describes an affective economy of loyalty, embodied in cheap and accessible political commodities: decorated objects made of clay, metals, and paper, on which precious household resources of time, money and emotion were spent. She argues that by engendering, inculcating and insinuating codes of political love into people’s ‘emotional, sensual, representational, and communicative’ lives, ‘loyal’ goods acted as vehicles and texts for what Victoria Kahn describes as ‘the supplementary role of the passions’ in ‘forging political obligation’ and the reformulation of ‘the duty to love’ of both subject and king in 17th-century England. McShane’s research contributes to a growing theme in scholarship, namely the active consumption of politically significant goods. This essay extends the range of objects under examination to include quotidian household items, shedding light on the dissemination and construction of early modern loyalty across a much wider social scale. The research draws on an extensive survey of collections held at the V&A, the Museum of London, Ashmolean Museum, Fitzwilliam Museum and Burrell Collection. Importantly, by putting illustrated print products back together with other political commodities in the early modern home, creating a broad archive of objects and text-objects where each informs the other, McShane’s approach challenges the typical social historical methodology, which uses material culture as merely illustrative of textual sources. This article was part of a special section on loyalty and allegiance in early modern England, co-edited by McShane with Dr Ted Vallance for one of the leading scholarly journals in the field. The material was drawn from a workshop on the topic held at the University of Liverpool funded by the British Academy, University of Liverpool and the Scouloudi Foundation (2007)

High-risk and multiple human papillomavirus (HPV) infections in cancer-free Jamaican women

<p>Abstract</p> <p>Background</p> <p>Vaccines, that target human papillomavirus (HPV) high risk genotypes 16 and 18, have recently been developed. This study was aimed at determining genotypes commonly found in high-risk and multiple-HPV infections in Jamaican women. Two hundred and fifty three (253) women were enrolled in the study. Of these, 120 pregnant women, aged 15–44 years, were recruited from the Ante Natal Clinic at the University Hospital of the West Indies and 116 non-pregnant, aged 19–83, from a family practice in Western Jamaica. Cervical cell samples were collected from the women and HPV DNA was detected using Polymerase Chain Reaction and Reverse Line Hybridization. HPV genotypes were assessed in 236 women. Data were collected from January 2003 to October 2006.</p> <p>Results</p> <p>HPV DNA was detected in 87.7% (207/236) and of these 80.2% were positive for high-risk types. The most common high-risk HPV types were: HPV 45 (21.7%), HPV 58 (18.8%), HPV 16 (18.4%), HPV 35 (15.0%), HPV 18 (14.5%), HPV 52 (12.0%) and HPV 51(11.1%). Other high-risk types were present in frequencies of 1.4% – 7.2%.</p> <p>Multivariate regression analyses showed that bacterial vaginosis predicted the presence of multiple infections (OR 3.51; CI, 1.26–9.82) and that alcohol use (OR 0.31; CI, 0.15–0.85) and age at first sexual encounter (12–15 years: OR 3.56; CI, 1.41–9.12; 16–19 years, OR 3.53, CI, 1.22–10.23) were significantly associated with high risk infections. Cervical cytology was normal in the majority of women despite the presence of high-risk and multiple infections.</p> <p>Conclusion</p> <p>HPV genotype distribution in this group of Jamaican women differs from the patterns found in Europe, North America and some parts of Asia. It may be necessary therefore to consider development of other vaccines which target genotypes found in our and similar populations. HPV genotyping as well as Pap smears should be considered.</p

Inhibition of β-catenin signalling in dermal fibroblasts enhances hair follicle regeneration during wound healing.

New hair follicles (HFs) do not form in adult mammalian skin unless epidermal Wnt signalling is activated genetically or within large wounds. To understand the postnatal loss of hair forming ability we monitored HF formation at small circular (2 mm) wound sites. At P2, new HFs formed in back skin, but HF formation was markedly decreased by P21. Neonatal tail also formed wound-associated HFs, albeit in smaller numbers. Postnatal loss of HF neogenesis did not correlate with wound closure rate but with a reduction in Lrig1-positive papillary fibroblasts in wounds. Comparative gene expression profiling of back and tail dermis at P1 and dorsal fibroblasts at P2 and P50 showed a correlation between loss of HF formation and decreased expression of genes associated with proliferation and Wnt/β-catenin activity. Between P2 and P50, fibroblast density declined throughout the dermis and clones of fibroblasts became more dispersed. This correlated with a decline in fibroblasts expressing a TOPGFP reporter of Wnt activation. Surprisingly, between P2 and P50 there was no difference in fibroblast proliferation at the wound site but Wnt signalling was highly upregulated in healing dermis of P21 compared with P2 mice. Postnatal β-catenin ablation in fibroblasts promoted HF regeneration in neonatal and adult mouse wounds, whereas β-catenin activation reduced HF regeneration in neonatal wounds. Our data support a model whereby postnatal loss of hair forming ability in wounds reflects elevated dermal Wnt/β-catenin activation in the wound bed, increasing the abundance of fibroblasts that are unable to induce HF formation

Rapid turnover of long noncoding RNAs and the evolution of gene expression.

A large proportion of functional sequence within mammalian genomes falls outside protein-coding exons and can be transcribed into long RNAs. However, the roles in mammalian biology of long noncoding RNA (lncRNA) are not well understood. Few lncRNAs have experimentally determined roles, with some of these being lineage-specific. Determining the extent by which transcription of lncRNA loci is retained or lost across multiple evolutionary lineages is essential if we are to understand their contribution to mammalian biology and to lineage-specific traits. Here, we experimentally investigated the conservation of lncRNA expression among closely related rodent species, allowing the evolution of DNA sequence to be uncoupled from evolution of transcript expression. We generated total RNA (RNAseq) and H3K4me3-bound (ChIPseq) DNA data, and combined both to construct catalogues of transcripts expressed in the adult liver of Mus musculus domesticus (C57BL/6J), Mus musculus castaneus, and Rattus norvegicus. We estimated the rate of transcriptional turnover of lncRNAs and investigated the effects of their lineage-specific birth or death. LncRNA transcription showed considerably greater gain and loss during rodent evolution, compared with protein-coding genes. Nucleotide substitution rates were found to mirror the in vivo transcriptional conservation of intergenic lncRNAs between rodents: only the sequences of noncoding loci with conserved transcription were constrained. Finally, we found that lineage-specific intergenic lncRNAs appear to be associated with modestly elevated expression of genomically neighbouring protein-coding genes. Our findings show that nearly half of intergenic lncRNA loci have been gained or lost since the last common ancestor of mouse and rat, and they predict that such rapid transcriptional turnover contributes to the evolution of tissue- and lineage-specific gene expression

Associations between schizotypal traits and antisocial behaviours in a sub-Saharan sample

Schizophrenic symptoms have often been associated with antisocial behaviours (ASBs). Most studies have focused on violence. The association between schizophrenia and violence is often confounded by socio demographic characteristics of patients. Overemphasis on diagnosis, rather than traits, and the traditional focus on violence may have obscured associations between psychotic features and antisocial behaviour. In this study, an analogue sample (n = 604, females = 54.4%, mean age = 21.46, SD = 5.89) completed self-report measures of schizotypy and antisocial behaviours. The aim was to identify the strength of associations between different schizotypal traits/symptoms (unusual experiences, cognitive disorganisation, impulsivity & introvertive anhedonia) and different forms of antisocial behaviour (rule breaking, physical aggression & social aggression). Differential patterns of association between genders were also considered. Traits akin to positive symptoms were more strongly associated with antisocial behaviours. Impulsive non-conformity was associated with rule breaking, physical aggression and social aggression for both males and females whilst unusual experiences traits were associated with physical and social aggression in both males and females but had only a weak (gender-nonspecific) association with rule breaking. Finally, cognitive disorganisation was not associated with any class of ASB for males but was associated with physical and social aggression in females. These specific associations could inform the development of more targeted treatment approaches for specific types of ASBs in males and females

Regulatory Divergence of Transcript Isoforms in a Mammalian Model System.

Phenotypic differences between species are driven by changes in gene expression and, by extension, by modifications in the regulation of the transcriptome. Investigation of mammalian transcriptome divergence has been restricted to analysis of bulk gene expression levels and gene-internal splicing. Using allele-specific expression analysis in inter-strain hybrids of Mus musculus, we determined the contribution of multiple cellular regulatory systems to transcriptome divergence, including: alternative promoter usage, transcription start site selection, cassette exon usage, alternative last exon usage, and alternative polyadenylation site choice. Between mouse strains, a fifth of genes have variations in isoform usage that contribute to transcriptomic changes, half of which alter encoded amino acid sequence. Virtually all divergence in isoform usage altered the post-transcriptional regulatory instructions in gene UTRs. Furthermore, most genes with isoform differences between strains contain changes originating from multiple regulatory systems. This result indicates widespread cross-talk and coordination exists among different regulatory systems. Overall, isoform usage diverges in parallel with and independently to gene expression evolution, and the cis and trans regulatory contribution to each differs significantly

Association of Breast Cancer Odds with Background Parenchymal Enhancement Quantified Using a Fully Automated Method at MRI: The IMAGINE Study.

Background Background parenchymal enhancement (BPE) at breast MRI has been associated with increased breast cancer risk in several independent studies. However, variability of subjective BPE assessments have precluded its use in clinical practice. Purpose To examine the association between fully objective measures of BPE at MRI and odds of breast cancer. Materials and Methods This prospective case-control study included patients who underwent a bilateral breast MRI examination and were receiving care at one of three centers in the United States from November 2010 to July 2017. Breast volume, fibroglandular tissue (FGT) volume, and BPE were quantified using fully automated software. Fat volume was defined as breast volume minus FGT volume. BPE extent was defined as the proportion of FGT voxels with enhancement of 20% or more. Spearman rank correlation between quantitative BPE extent and Breast Imaging Reporting and Data System (BI-RADS) BPE categories assigned by an experienced board-certified breast radiologist was estimated. With use of multivariable logistic regression, breast cancer case-control status was regressed on tertiles (low, moderate, and high) of BPE, FGT volume, and fat volume, with adjustment for covariates. Results In total, 536 case participants with breast cancer (median age, 48 years [IQR, 43-55 years]) and 940 cancer-free controls (median age, 46 years [IQR, 38-55 years]) were included. BPE extent was positively associated with BI-RADS BPE (rs = 0.54; P &lt; .001). Compared with low BPE extent (range, 2.9%-34.2%), high BPE extent (range, 50.7%-97.3%) was associated with increased odds of breast cancer (odds ratio [OR], 1.74 [95% CI: 1.23, 2.46]; P for trend = .002) in a multivariable model also including FGT volume (OR, 1.39 [95% CI: 0.97, 1.98]) and fat volume (OR, 1.46 [95% CI: 1.04, 2.06]). The association of high BPE extent with increased odds of breast cancer was similar for premenopausal and postmenopausal women (ORs, 1.75 and 1.83, respectively; interaction P = .73). Conclusion Objectively measured BPE at breast MRI is associated with increased breast cancer odds for both premenopausal and postmenopausal women. Clinical trial registration no. NCT02301767 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Bokacheva in this issue