Chlamydia pneumoniae: An Etiologic Agent for Late-Onset Dementia

The disease known as late-onset Alzheimer\u27s disease is a neurodegenerative condition recognized as the single most common form of senile dementia. The condition is sporadic and has been attributed to neuronal damage and loss, both of which have been linked to the accumulation of protein deposits in the brain. Significant progress has been made over the past two decades regarding our overall understanding of the apparently pathogenic entities that arise in the affected brain, both for early-onset disease, which constitutes approximately 5% of all cases, as well as late-onset disease, which constitutes the remainder of cases. Observable neuropathology includes: neurofibrillary tangles, neuropil threads, neuritic senile plaques and often deposits of amyloid around the cerebrovasculature. Although many studies have provided a relatively detailed knowledge of these putatively pathogenic entities, understanding of the events that initiate and support the biological processes generating them and the subsequent observable neuropathology and neurodegeneration remain limited. This is especially true in the case of late-onset disease. Although early-onset Alzheimer\u27s disease has been shown conclusively to have genetic roots, the detailed etiologic initiation of late-onset disease without such genetic origins has remained elusive. Over the last 15 years, current and ongoing work has implicated infection in the etiology and pathogenesis of late-onset dementia. Infectious agents reported to be associated with disease initiation are various, including several viruses and pathogenic bacterial species. We have reported extensively regarding an association between late-onset disease and infection with the intracellular bacterial pathoge

Rhinovirus induction of fractalkine (CX3CL1) in airway and peripheral blood mononuclear cells in asthma

Rhinovirus infection is associated with the majority of asthma exacerbations. The role of fractalkine in anti-viral (type 1) and pathogenic (type 2) responses to rhinovirus infection in allergic asthma is unknown. To determine whether (1) fractalkine is produced in airway cells and in peripheral blood leucocytes, (2) rhinovirus infection increases production of fractalkine and (3) levels of fractalkine differ in asthmatic compared to non-asthmatic subjects. Fractalkine protein and mRNA levels were measured in bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMCs) from non-asthmatic controls (n = 15) and mild allergic asthmatic (n = 15) subjects. Protein levels of fractalkine were also measured in macrophages polarised ex vivo to give M1 (type 1) and M2 (type 2) macrophages and in BAL fluid obtained from mild (n = 11) and moderate (n = 14) allergic asthmatic and non-asthmatic control (n = 10) subjects pre and post in vivo rhinovirus infection. BAL cells produced significantly greater levels of fractalkine than PBMCs. Rhinovirus infection increased production of fractalkine by BAL cells from non-asthmatic controls (P<0.01) and in M1-polarised macrophages (P<0.05), but not in BAL cells from mild asthmatics or in M2 polarised macrophages. Rhinovirus induced fractalkine in PBMCs from asthmatic (P<0.001) and healthy control subjects (P<0.05). Trends towards induction of fractalkine in moderate asthmatic subjects during in vivo rhinovirus infection failed to reach statistical significance. Fractalkine may be involved in both immunopathological and anti-viral immune responses to rhinovirus infection. Further investigation into how fractalkine is regulated across different cell types and into the effect of stimulation including rhinovirus infection is warranted to better understand the precise role of this unique dual adhesion factor and chemokine in immune cell recruitment

The Paradox of Power in CSR: A Case Study on Implementation

Purpose Although current literature assumes positive outcomes for stakeholders resulting from an increase in power associated with CSR, this research suggests that this increase can lead to conflict within organizations, resulting in almost complete inactivity on CSR. Methods A single in-depth case study, focusing on power as an embedded concept. Results Empirical evidence is used to demonstrate how some actors use CSR to improve their own positions within an organization. Resource dependence theory is used to highlight why this may be a more significant concern for CSR. Conclusions Increasing power for CSR has the potential to offer actors associated with it increased personal power, and thus can attract opportunistic actors with little interest in realizing the benefits of CSR for the company and its stakeholders. Thus power can be an impediment to furthering CSR strategy and activities at the individual and organizational level

Beyond links and chains in food supply: a community OR perspective

This theoretical paper complements traditional OR approaches to improve micro-businesses’ performance. When looking at local micro-businesses, we find that current supply chain and operations theory that focuses on efficiency and economic-based criteria for chain and network integration, is inapplicable and external organisation inappropriate. An illustration shows how traditional modelling exercises may fall short in better-informing independent-minded micro-entrepreneurs on how to collaborate, even though they recognise benefits from such endeavour. The illustration concerns consideration of food micro-producers, not as links constituting a chain, but as members of a community. This paper explores two different approaches to apply Community OR research principles. On one hand, the application of OR methods to phenomena in the ‘community’; on the other, the development of research on ‘community operations’; which are symbolised as C+OR and CO+R respectively. These approaches are associated to two different research languages: of needs and for interactions. Main contributions of this paper are: first, we show that collaboration does not always need shared aims. Second, we offer a circular process where the identification of collective actions may help organisations to improve individually; and vice versa. Third, we suggest how to develop the role of a stronger collective actor by means of collaboration

Inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface

Drug discovery efforts against the pathogen Mycobacterium tuberculosis (Mtb) have been advanced through phenotypic screens of extensive compound libraries. Such a screen revealed sulfolane 1 and indoline-5-sulfonamides 2 and 3 as potent inhibitors of mycobacterial growth. Optimization in the sulfolane series led to compound 4, which has proven activity in an in vivo murine model of Mtb infection. Here we identify the target and mode of inhibition of these compounds based on whole genome sequencing of spontaneous resistant mutants, which identified mutations locating to the essential α- and β-subunits of tryptophan synthase. Over-expression studies confirmed tryptophan synthase as the biological target. Biochemical techniques probed the mechanism of inhibition, revealing the mutant enzyme complex incurs a fitness cost but does not prevent inhibitor binding. Mapping of the resistance conferring mutations onto a low-resolution crystal structure of Mtb tryptophan synthase showed they locate to the interface between the α- and β-subunits. The discovery of anti-tubercular agents inhibiting tryptophan synthase highlights the therapeutic potential of this enzyme and draws attention to the prospect of other amino acid biosynthetic pathways as future Mtb drug targets

Mycobacterium indicus pranii Supernatant Induces Apoptotic Cell Death in Mouse Peritoneal Macrophages In Vitro

Mycobacterium indicus pranii (MIP), also known as Mw, is a saprophytic, non-pathogenic strain of Mycobacterium and is commercially available as a heat-killed vaccine for leprosy and recently tuberculosis (TB) as part of MDT. In this study we provide evidence that cell-free supernatant collected from original MIP suspension induces rapid and enhanced apoptosis in mouse peritoneal macrophages in vitro. It is demonstrated that the MIP cell-free supernatant induced apoptosis is mitochondria-mediated and caspase independent and involves mitochondrial translocation of Bax and subsequent release of AIF and cytochrome c from the mitochondria. Experiments with pharmacological inhibitors suggest a possible role of PKC in mitochondria-mediated apoptosis of macrophages

Studies of a Ring-Cleaving Dioxygenase Illuminate the Role of Cholesterol Metabolism in the Pathogenesis of Mycobacterium tuberculosis

Mycobacterium tuberculosis, the etiological agent of TB, possesses a cholesterol catabolic pathway implicated in pathogenesis. This pathway includes an iron-dependent extradiol dioxygenase, HsaC, that cleaves catechols. Immuno-compromised mice infected with a ΔhsaC mutant of M. tuberculosis H37Rv survived 50% longer than mice infected with the wild-type strain. In guinea pigs, the mutant disseminated more slowly to the spleen, persisted less successfully in the lung, and caused little pathology. These data establish that, while cholesterol metabolism by M. tuberculosis appears to be most important during the chronic stage of infection, it begins much earlier and may contribute to the pathogen's dissemination within the host. Purified HsaC efficiently cleaved the catecholic cholesterol metabolite, DHSA (3,4-dihydroxy-9,10-seconandrost-1,3,5(10)-triene-9,17-dione; kcat/Km = 14.4±0.5 µM−1 s−1), and was inactivated by a halogenated substrate analogue (partition coefficient<50). Remarkably, cholesterol caused loss of viability in the ΔhsaC mutant, consistent with catechol toxicity. Structures of HsaC:DHSA binary complexes at 2.1 Å revealed two catechol-binding modes: bidentate binding to the active site iron, as has been reported in similar enzymes, and, unexpectedly, monodentate binding. The position of the bicyclo-alkanone moiety of DHSA was very similar in the two binding modes, suggesting that this interaction is a determinant in the initial substrate-binding event. These data provide insights into the binding of catechols by extradiol dioxygenases and facilitate inhibitor design

Quantum biology: an update and perspective

This is the final version. Available from MDPI via the DOI in this record. Data Availability Statement: Not applicable.Understanding the rules of life is one of the most important scientific endeavours and has revolutionised both biology and biotechnology. Remarkable advances in observation tech-niques allow us to investigate a broad range of complex and dynamic biological processes in which living systems could exploit quantum behaviour to enhance and regulate biological functions. Recent evidence suggests that these non-trivial quantum mechanical effects may play a crucial role in maintaining the non-equilibrium state of biomolecular systems. Quantum biology is the study of such quantum aspects of living systems. In this review, we summarise the latest progress in quantum biology, including the areas of enzyme-catalysed reactions, photosynthesis, spin-dependent reactions, DNA, fluorescent proteins, and ion channels. Many of these results are expected to be fundamental building blocks towards understanding the rules of life.Leverhulme Trus

'The debatable territory where geology and archaeology meet': reassessing the early archaeobotanical work of Clement Reid and Arthur Lyell at Roman Silchester

The first large-scale archaeobotanical study in Britain, conducted from 1899 to 1909 by Clement Reid and Arthur Lyell at Silchester, provided the first evidence for the introduction of Roman plant foods to Britain, yet the findings have thus far remained unverified. This paper presents a reassessment of these archaeobotanical remains, now stored as part of the Silchester Collection in Reading Museum. The documentary evidence for the Silchester study is summarised, before the results are presented for over a 1000 plant remains including an assessment of preservation, identification and modern contamination. The dataset includes both evidence for the presence of nationally rare plant foods, such as medlar, and several archaeophytes. The methodologies and original interpretations of Reid and Lyell’s study are reassessed in light of current archaeobotanical knowledge. Spatial and contextual patterns in the distribution of plant foods and ornamental taxa are also explored. Finally, the legacy of the study for the development of archaeobotany in the 20th century is evaluated