A metaproteomic approach to study human-microbial ecosystems at the mucosal luminal interface

Aberrant interactions between the host and the intestinal bacteria are thought to contribute to the pathogenesis of many digestive diseases. However, studying the complex ecosystem at the human mucosal-luminal interface (MLI) is challenging and requires an integrative systems biology approach. Therefore, we developed a novel method integrating lavage sampling of the human mucosal surface, high-throughput proteomics, and a unique suite of bioinformatic and statistical analyses. Shotgun proteomic analysis of secreted proteins recovered from the MLI confirmed the presence of both human and bacterial components. To profile the MLI metaproteome, we collected 205 mucosal lavage samples from 38 healthy subjects, and subjected them to high-throughput proteomics. The spectral data were subjected to a rigorous data processing pipeline to optimize suitability for quantitation and analysis, and then were evaluated using a set of biostatistical tools. Compared to the mucosal transcriptome, the MLI metaproteome was enriched for extracellular proteins involved in response to stimulus and immune system processes. Analysis of the metaproteome revealed significant individual-related as well as anatomic region-related (biogeographic) features. Quantitative shotgun proteomics established the identity and confirmed the biogeographic association of 49 proteins (including 3 functional protein networks) demarcating the proximal and distal colon. This robust and integrated proteomic approach is thus effective for identifying functional features of the human mucosal ecosystem, and a fresh understanding of the basic biology and disease processes at the MLI. © 2011 Li et al

Conservatives and the Constabulary in Great Britain: cross-dressing conundrums

Purpose This chapter is devoted to analysing the historical peculiarity of the contemporary British politics of policing. Methodology/approach Research is based on an analysis of policy statements and debates, news reports, and official statistics, in the light of historical studies of the earlier politics of policing. Findings The Conservative government’s police reform programme severely diminishes the resources, powers, status and independence of the police, reversing the Tory’s traditional unquestioning support of the police. The package is shown to reflect broader changes in political economy and culture under neoliberalism. Originality/value There has been no previous academic analysis bringing together the various aspects of the reform programme, contrasting it with previous historical understanding of the politics of policing, and linking it to broader contemporary change

The development of policing in Britain in the next five years.

The British police service is currently going through a radical transformation phase. The present Tory-led coalition government has set out an agenda to bring about drastic changes in policing. These proposed changes are unprecedented in the history of policing since 1829. The police service is governed by a tripartite arrangement of checks and balances laid down under the Police Act 1964. By this I mean that there are three key players in relation to police governance in Britain: the Home Secretary, the local police authority and the chief constable. The future of policing in the next five years is set out clearly by the Home Secretary, Theresa May MP, under the Police Reform and Social Responsibility Bill, which is currently being reviewed in the House of Lords. The recent phone hacking scandal has made it imperative for the British public to have a closer look at the police service in relation to proper accountability. There have been references to police corruption as far back as the era of 'parish constables', dating back to 1800, when it was alleged that police officers took bribes, got drunk whilst on duty and lacked moral credibility to protect and serve us (Critchley, 1978). In the seventies and eighties the British public was informed of another scandal involving members of Scotland Yard and criminal gangs in the East End of London. In this article, I shall argue that the issue of police corruption is not a new phenomenon. It is has been an ongoing issue that has haunted the police for over a century. This article is divided into three parts. In the first part of the article I present the following issues: the Metropolitan Police policing plan 2011-2014; the merits and demerits of the policing plan; tripartite police accountability and its shortcomings; democratic accountability and localisation of policing; the professionalisation of policing and the creation of the Police Body; review of police pay and benefits; and the impact of this on police officers' morale. In the second part of my article I present some of the criticisms levelled against the ongoing police reforms. I will look at the criticisms from both internal and external perspectives. By internal criticism, I mean police officers' opposition to the reforms. By external criticism, I mean criticisms from criminologists and members of the British public. In the third part of my article I made my position clear on where I stand in relation to the ongoing police reforms. I shall argue that the current ongoing job cuts in the police service are a disaster waiting to happen, and that our safety has been compromised by politicians. We are now living at the mercy of criminals and law breakers due to manpower shortage. We are all living witnesses to the ongoing public disturbances in Tottenham, Enfield, Brixton, Peckham, Walthamstow and Croydon, in London. The speed of the spread of these riots to other cities like Bristol, Birmingham, Manchester and Liverpool occurred on an unimaginable scale. We all watched how difficult it was for the police to restore order and normality. Rioters looted and plundered goods and burnt down buildings as if no laws existed in our country. A complete breakdown of law and order put the lives of citizens at risk. My article makes a passionate appeal to the present coalition government to rethink the issue of reducing the numbers of police officers protecting us. I shall argue that we need more police officers in Britain not fewer. The level of anger and social discontent is higher than the government ever anticipated, partly because of economic hardship. My argument is that economic hardship is not an excuse to commit burglary, theft, arson, murder and criminal damage with intent to endanger life. Rioters are shameless opportunists, a bunch of hoodlums, criminals who have no place in any civilised society, who should be made to face the due process of law

Predicting flow reversals in chaotic natural convection using data assimilation

A simplified model of natural convection, similar to the Lorenz (1963) system, is compared to computational fluid dynamics simulations in order to test data assimilation methods and better understand the dynamics of convection. The thermosyphon is represented by a long time flow simulation, which serves as a reference "truth". Forecasts are then made using the Lorenz-like model and synchronized to noisy and limited observations of the truth using data assimilation. The resulting analysis is observed to infer dynamics absent from the model when using short assimilation windows. Furthermore, chaotic flow reversal occurrence and residency times in each rotational state are forecast using analysis data. Flow reversals have been successfully forecast in the related Lorenz system, as part of a perfect model experiment, but never in the presence of significant model error or unobserved variables. Finally, we provide new details concerning the fluid dynamical processes present in the thermosyphon during these flow reversals

The Importance of Context and Cognitive Agency in Developing Police Knowledge: Going Beyond the Police Science Discourse

This paper argues the current exposition of police knowledge through the discourses of police science and evidenced based policing (EBP) leads to exaggerated claims about what is, and can be, known in policing. This new orthodoxy underestimates the challenges of applying knowledge within culturally-mediated police practice. The paper draws upon virtue epistemology highlighting the role cognitive agency plays in establishing knowledge claims. We challenge the assumption that it is possible to derive what works in all instances of certain aspects of policing and suggest it would be more apt to speak about what worked within a specific police context

Update on HER-2 as a target for cancer therapy: HER2/neu peptides as tumour vaccines for T cell recognition

During the past decade there has been renewed interest in the use of vaccine immunotherapy for the treatment of cancer. This review focuses on HER2/neu, a tumour-associated antigen that is overexpressed in 10–40% of breast cancers and other carcinomata. Several immunogenic HER2/neu peptides recognized by T lymphocytes have been identified to be included in cancer vaccines. Some of these peptides have been assessed in clinical trials of patients with breast and ovarian cancer. Although it has been possible to detect immunological responses against the peptides in the immunized patients, no clinical responses have so far been described. Immunological tolerance to self-antigens like HER2/neu may limit the functional immune responses against them. It will be of interest to determine whether immune responses against HER2/neu epitopes can be of relevance to cancer treatment

Efficacy and Safety of Duvelisib Following Disease Progression on Ofatumumab in Patients with Relapsed/Refractory CLL or SLL in the DUO Crossover Extension Study

Purpose: In the phase 3 DUO trial, duvelisib, an oral dual PI3K-δ,γ inhibitor, demonstrated significantly improved efficacy vs ofatumumab (median [m]PFS, 13.3 vs 9.9 months [HR, 0.52; P < .0001]; ORR, 74% vs 45% [P < .0001]), with a manageable safety profile in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report results from patients with progressive disease (PD) after ofatumumab who crossed over to duvelisib in the DUO trial. Experimental Design: Patients with radiographically confirmed PD after ofatumumab received duvelisib 25 mg twice daily in 28-day cycles until PD, intolerance, death, or study withdrawal. The primary endpoint was ORR per investigator. Secondary endpoints included duration of response (DOR), PFS, and safety. Results: As of December 14, 2018, 90 ofatumumab-treated patients in the DUO trial prior to crossover had an ORR of 29%, mDOR of 10.4 months, and mPFS of 9.4 months. After crossover, 77% of patients (69/90) achieved a response, with an mDOR of 14.9 months and mPFS of 15.7 months. Patients with del(17p) and/or TP53 mutations had similar outcomes (ORR, 77% [20/26]; mPFS, 14.7 months). Notably, 73% of patients (47/64) with disease previously refractory to ofatumumab achieved a response. The most frequent any-grade/grade 3/4 treatment-emergent adverse events were diarrhea (47%/23%), neutropenia (26%/23%), pyrexia (24%/4%), cutaneous reactions (23%/4%), and thrombocytopenia (10%/6%). Conclusions: Duvelisib demonstrated high response rates with good durability and a manageable safety profile in patients with R/R CLL/SLL who progressed on ofatumumab, including patients with high-risk disease and disease previously refractory to ofatumumab

Auditor Change Disclosures as Signals of Earnings Management and Risk

Auditor resignations are considered more negative signals than auditor dismissals, but firms’ self-reported distinction between the two may not offer a complete or reliable representation of the nature of the auditor change. 8-K regulations require the disclosure of the adjournment of an audit engagement even if a successor auditor has not yet been named. In compliance with this requirement, some firms file two 8-k’s related to the same auditor change. Exploiting these dual 8-K filings, we create a new measure of the nature of auditor changes and show that 1) both self-reported auditor resignations and dual 8-K filings are related to measures of earnings management and risk; and 2) auditor changes identified as both self-reported resignations and dual 8-K filings are associated with the most negative economic implications (as reflected by the likelihood of financial statement manipulation and bankruptcy risk). We suggest that dual 8-K filings and self-reported resignations are complementary negative signals each capturing unique dimensions of the underlying economic factors

The contributions of fibre atrophy, fibre loss, in situ specific force and voluntary activation to weakness in sarcopenia

The contributions of fibre atrophy, fibre loss, in situ specific force and voluntary activation to weakness in sarcopenia remain unclear. To investigate, forty older (20 women; age 72±4yrs) and 31 younger adults (15 women, age 22±3yrs) completed measurements. The knee extensor maximal voluntary torque (MVC) was measured as well as voluntary activation, patella tendon moment arm length, muscle volume and fascicle architecture to estimate in situ specific force. Fibre cross-sectional area (FCSA), fibre numbers and connective tissue contents were also estimated from vastus lateralis biopsies. The MVC, quadriceps volume and specific force were 39%, 28% and 17% lower, respectively, in old compared with young, but voluntary activation was not different. The difference in muscle size was due in almost equal proportions to lower type II FCSA and fewer fibres. Five years later (n=23) the MVC, muscle volume and voluntary activation in old decreased an additional 12%, 6% and 4%, respectively, but there was no further change in specific force. Conclusions: in situ specific force declines relatively early in older age and reduced voluntary activation occurs later, but the overall weakness in sarcopenia is mainly related to loss of both type I and II fibres and type II fibre atrophy

Angiotensin II for the Treatment of Vasodilatory Shock

BACKGROUND Vasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. METHODS We randomly assigned patients with vasodilatory shock who were receiving more than 0.2 mu g of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. RESULTS A total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P<0.001). At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (-1.75 vs. -1.28, P = 0.01). Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group. Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P = 0.12). CONCLUSIONS Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors. (Funded by La Jolla Pharmaceutical Company; ATHOS-3 ClinicalTrials.gov number, NCT02338843.)Peer reviewe