Determining the variability in the lung microbiome throughout the course of mycobacterium tuberculosis infection

Tuberculosis remains a major health threat throughout the world, despite having a vaccine and treatments. Mycobacterium tuberculosis (Mtb) infects alveolar macrophages in the lung and inflammation occurs after infection. The lung microbiome in regards to Mtb infection is poorly understood, and whether inflammation from infection affects the lung microbiome is unknown. The goal of our study is to determine whether Mtb induces a significant and durable change in the lung microbiome of cynomolgus macaques. We investigated and compared the community clusters between the lung and oral cavity, assessed how the diversity of the lung microbiota changes throughout infection, and associated these changes in the lung with inflammation. Bronchoalveolar lavage (BAL) was obtained pre-infection and at several time points post-Mtb infection, as well as oral wash and saline bronchoscope control samples from respective macaques. Operational taxonomic units (OTUs) were generated after 16s rRNA sequencing was performed once DNA was extracted from collected samples. We profiled microbial communities to see the community structure differences between oral and lung environment and show how the microbiome changes throughout infection. PET/CT imaging was used to visualize and quantify inflammation over the course of infection by using FDG avidity (total PET HOT). Our results show that the oral and lung compartments are distinct with regard to community structure, distinct bacterial taxa are more relatively abundant in certain lobes, and lung inflammation and lung microbiome changes are variable within macaques and between macaques. Analysis of the first cohort of macaques (N=10) did not reveal correlations between lung inflammation and relative abundance or alpha-diversity, but our data is preliminary and based on small sample size. Our sample size will greatly increase after the second cohort of macaques are fully sequenced and analyzed. These changes and disruptions in the lung microbiome may have public health relevance in regards to overall lung health and may also play a role in the outcome of Mtb infection

Antimicrobial Effects of Essential Oils on Staphylococcus aureus

Essential oils are aromatic volatile compounds obtained from plants through a distillation process. The many components of these oils confer different properties, making them useful in many different fields such as food, perfumery, cosmetics, and medicine. Essential oils are an effective form of alternative medicine because they possess many antibacterial, antifungal, and antiviral properties and can be purchased over the counter without a prescription. The goal of our research is to evaluate the antimicrobial effectiveness of two essential oils: saro (Cinnamosma fragrans), and patchouli (Pogostemom cablin) (Aromatics International). We tested the antimicrobial properties of these oils in vitro on Staphylococcus aureus, a strain of bacteria that is able to cause skin infections. Additionally, we determined if these oils act synergistically when the two essential oils were blended together. We used a time kill assay to evaluate the antimicrobial effectiveness of the oils. The microorganisms were inoculated in suspensions containing distilled water, a surfactant, and different concentrations of essential oil (1%, 2%, and 3%). These solutions were then plated onto trypticase soy agar at different time intervals to evaluate how quickly and effectively the essential oil inhibited bacterial growth. The minimum inhibitory concentration (MIC) was calculated for each oil. After plating the different concentrations of single oils, we then combined the two oils together in a blend, repeating the above process. To determine if synergistic effects occurred, we used the MIC values to calculate the fractional inhibition concentration index (FICindex). The FICindex gave us insight to see whether antagonistic, additive, or synergistic effects took place when the oils were blended

Microservice Transition and its Granularity Problem: A Systematic Mapping Study

Microservices have gained wide recognition and acceptance in software industries as an emerging architectural style for autonomic, scalable, and more reliable computing. The transition to microservices has been highly motivated by the need for better alignment of technical design decisions with improving value potentials of architectures. Despite microservices' popularity, research still lacks disciplined understanding of transition and consensus on the principles and activities underlying "micro-ing" architectures. In this paper, we report on a systematic mapping study that consolidates various views, approaches and activities that commonly assist in the transition to microservices. The study aims to provide a better understanding of the transition; it also contributes a working definition of the transition and technical activities underlying it. We term the transition and technical activities leading to microservice architectures as microservitization. We then shed light on a fundamental problem of microservitization: microservice granularity and reasoning about its adaptation as first-class entities. This study reviews state-of-the-art and -practice related to reasoning about microservice granularity; it reviews modelling approaches, aspects considered, guidelines and processes used to reason about microservice granularity. This study identifies opportunities for future research and development related to reasoning about microservice granularity.Comment: 36 pages including references, 6 figures, and 3 table

Cohomogeneity One Manifolds of Spin(7) and G(2) Holonomy

In this paper, we look for metrics of cohomogeneity one in D=8 and D=7 dimensions with Spin(7) and G_2 holonomy respectively. In D=8, we first consider the case of principal orbits that are S^7, viewed as an S^3 bundle over S^4 with triaxial squashing of the S^3 fibres. This gives a more general system of first-order equations for Spin(7) holonomy than has been solved previously. Using numerical methods, we establish the existence of new non-singular asymptotically locally conical (ALC) Spin(7) metrics on line bundles over \CP^3, with a non-trivial parameter that characterises the homogeneous squashing of CP^3. We then consider the case where the principal orbits are the Aloff-Wallach spaces N(k,\ell)=SU(3)/U(1), where the integers k and \ell characterise the embedding of U(1). We find new ALC and AC metrics of Spin(7) holonomy, as solutions of the first-order equations that we obtained previously in hep-th/0102185. These include certain explicit ALC metrics for all N(k,\ell), and numerical and perturbative results for ALC families with AC limits. We then study D=7 metrics of $G_2$ holonomy, and find new explicit examples, which, however, are singular, where the principal orbits are the flag manifold SU(3)/(U(1)\times U(1)). We also obtain numerical results for new non-singular metrics with principal orbits that are S^3\times S^3. Additional topics include a detailed and explicit discussion of the Einstein metrics on N(k,\ell), and an explicit parameterisation of SU(3).Comment: Latex, 60 pages, references added, formulae corrected and additional discussion on the asymptotic flow of N(k,l) cases adde

“Till the muddle in my mind have cleared awa”: can we help shape policy using systems modelling?

This paper considers how some well-documented deficiencies of mental models make it difficult to create effective policies, and suggests that systems modelling can begin to address this issue. To illustrate the argument three short cases are presented. These relate to specific domains but demonstrate how systems modelling can illuminate different general phenomena: effects on labour costs (unintended consequences and feedback); fishery management (accumulation and non-linearity) and child protection (worldviews and sense-making). Six levers for increasing the use of systems modelling in the policy arena are then discussed. The paper closes by emphasising the opportunities for systems modellers in the Anthropocene Era

The Aminopeptidase CD13 Induces Homotypic Aggregation in Neutrophils and Impairs Collagen Invasion.

Aminopeptidase N (CD13) is a widely expressed cell surface metallopeptidase involved in the migration of cancer and endothelial cells. Apart from our demonstration that CD13 modulates the efficacy of tumor necrosis factor-α-induced apoptosis in neutrophils, no other function for CD13 has been ascribed in this cell. We hypothesized that CD13 may be involved in neutrophil migration and/or homotypic aggregation. Using purified human blood neutrophils we confirmed the expression of CD13 on neutrophils and its up-regulation by pro-inflammatory agonists. However, using the anti-CD13 monoclonal antibody WM-15 and the aminopeptidase enzymatic inhibitor bestatin we were unable to demonstrate any direct involvement of CD13 in neutrophil polarisation or chemotaxis. In contrast, IL-8-mediated neutrophil migration in type I collagen gels was significantly impaired by the anti-CD13 monoclonal antibodies WM-15 and MY7. Notably, these antibodies also induced significant homotypic aggregation of neutrophils, which was dependent on CD13 cross-linking and was attenuated by phosphoinositide 3-kinase and extracellular signal-related kinase 1/2 inhibition. Live imaging demonstrated that in WM-15-treated neutrophils, where homotypic aggregation was evident, the number of cells entering IL-8 impregnated collagen I gels was significantly reduced. These data reveal a novel role for CD13 in inducing homotypic aggregation in neutrophils, which results in a transmigration deficiency; this mechanism may be relevant to neutrophil micro-aggregation in vivo.This work was funded by a Medical Research Council Research Training Fellowship to CAF (G0900329), Addenbrooke’s Charitable Trust (ACT), CUHNHSFT, Papworth Hospital NHS Foundation Trust and the NIHR Cambridge Biomedical Research Centre. CAF received a Raymond and Beverly Sackler Studentship.This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pone.016010

Returning to Text: Affect, meaning making and literacies

Existing work on literacy and affect has posed important questions for how we think about meanings and how and where they get made. The authors contribute to such work by focusing on the relation between text and affect. This is a topic that has received insufficient attention in recent work but is of pressing concern for education as text interweaves in new ways with human activity, through social media, surveillance capitalism, and artificial intelligence—ways that can be unpredictable and poorly understood. Adopting a sociomaterial sensibility that foregrounds the relations between bodies (people and things), the authors provide conceptual tools for considering how texts affect and are affected by the heterogeneous entanglements from which they emerge. In situating their argument, the authors outline influential readings of Spinoza’s theories of affect, explore how these have been mobilized in literacy research, and identify how text has been accommodated within such research. Using texts from a political episode in the United Kingdom, the authors explore the idea of social-material-textual affects to articulate relationships among humans, nonhumans, meaning making, and literacies. The authors conclude by identifying four ways in which text participates in what happens, raising questions about how different materializations of text (or indeed “not text”) are significant to the diversifying communicative practices that inflect social, cultural, economic, and political life

Running GAGs: myxoid matrix in tumor pathology revisited: What’s in it for the pathologist?

Ever since Virchow introduced the entity myxoma, abundant myxoid extracellular matrix (ECM) has been recognized in various reactive and neoplastic lesions. Nowadays, the term “myxoid” is commonly used in daily pathological practice. But what do today’s pathologists mean by it, and what does the myxoid ECM tell the pathologist? What is known about the exact composition and function of the myxoid ECM 150 years after Virchow? Here, we give an overview of the composition and constituents of the myxoid ECM as known so far and demonstrate the heterogeneity of the myxoid ECM among different tumors. We discuss the possible role of the predominant constituents of the myxoid ECM and attempt to relate them to differences in clinical behavior. Finally, we will speculate on the potential relevance of this knowledge in daily pathological practice

Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating and fatal motor neuron disease. Diagnosis typically occurs in the fifth decade of life and the disease progresses rapidly leading to death within ~ 2–5 years of symptomatic onset. There is no cure, and the few available treatments offer only a modest extension in patient survival. A protein central to ALS is the nuclear RNA/DNA-binding protein, TDP-43. In > 95% of ALS patients, TDP-43 is cleared from the nucleus and forms phosphorylated protein aggregates in the cytoplasm of affected neurons and glia. We recently defined that poly(ADP-ribose) (PAR) activity regulates TDP-43-associated toxicity. PAR is a posttranslational modification that is attached to target proteins by PAR polymerases (PARPs). PARP-1 and PARP-2 are the major enzymes that are active in the nucleus. Here, we uncovered that the motor neurons of the ALS spinal cord were associated with elevated nuclear PAR, suggesting elevated PARP activity. Veliparib, a small-molecule inhibitor of nuclear PARP-1/2, mitigated the formation of cytoplasmic TDP-43 aggregates in mammalian cells. In primary spinal-cord cultures from rat, Veliparib also inhibited TDP-43-associated neuronal death. These studies uncover that PAR activity is misregulated in the ALS spinal cord, and a small-molecular inhibitor of PARP-1/2 activity may have therapeutic potential in the treatment of ALS and related disorders associated with abnormal TDP-43 homeostasis