ADAM10 Cell Surface Expression but Not Activity Is Critical for Staphylococcus aureus α-Hemolysin-Mediated Activation of the NLRP3 Inflammasome in Human Monocytes

The Staphylococcus aureus toxin, α-hemolysin, is an important and well-studied virulence factor in staphylococcal infection. It is a soluble monomeric protein that, once secreted by the bacterium, forms a heptameric pore in the membrane of a broad range of host cell types. Hemolysin was recently discovered to bind and activate a disintegrin and metalloprotease 10 (ADAM10). In epithelial and endothelial cells, ADAM10 activation is required for the toxin’s activity against these cells. In host monocytic cells, α-hemolysin activates the nucleotide-binding domain and leucine-rich repeat containing gene family, pyrin domain containing 3 (NLRP3) inflammasome leading to production of pro-inflammatory cytokines and cell death. We now show that ADAM10 is critical for α-hemolysin-mediated activation of the NLRP3 inflammasome in human monocytes as siRNA knockdown or chemical blockade of ADAM10-α-hemolysin interaction leads to diminished inflammasome activation and cell death by reducing the available ADAM10 on the cell surface. Unlike epithelial cell and endothelial cell damage, which requires α-hemolysin induced ADAM10 activation, ADAM10 protease activity was not required for NLRP3 inflammasome activation. This work confirms the importance of ADAM10 in immune activation by α-hemolysin, but indicates that host cell signal induction by the toxin is different between host cell types

Suppression of Lymphoma and Epithelial Malignancies Effected by Interferon γ

The immunosurveillance of transformed cells by the immune system remains one of the most controversial and poorly understood areas of immunity. Gene-targeted mice have greatly aided our understanding of the key effector molecules in tumor immunity. Herein, we describe spontaneous tumor development in gene-targeted mice lacking interferon (IFN)-γ and/or perforin (pfp), or the immunoregulatory cytokines, interleukin (IL)-12, IL-18, and tumor necrosis factor (TNF). Both IFN-γ and pfp were critical for suppression of lymphomagenesis, however the level of protection afforded by IFN-γ was strain specific. Lymphomas arising in IFN-γ-deficient mice were very nonimmunogenic compared with those derived from pfp-deficient mice, suggesting a comparatively weaker immunoselection pressure by IFN-γ. Single loss of IL-12, IL-18, or TNF was not sufficient for spontaneous tumor development. A significant incidence of late onset adenocarcinoma observed in both IFN-γ– and pfp-deficient mice indicated that some epithelial tissues were also subject to immunosurveillance

Clinical pharmacists in general practice:An initial evaluation of activity in one English primary care organisation

Objectives: This aim of this research was to characterise the breadth and volume of activity conducted by clinical pharmacists in general practice in Dudley Clinical Commissioning Group (CCG), and to provide quantitative estimates of both the savings in general practitioner (GP) time and the financial savings attributable to such activity. Methods: This descriptive observational study retrospectively analysed quantitative data collected by Dudley CCG concerning the activity of clinical pharmacists in GP practices during 2015. Key findings: Over the 9-month period for which data were available, the 5.4 whole time equivalent clinical pharmacists operating in GP practices within Dudley CCG identified 23 172 interventions. Ninety-five per cent of the interventions identified were completed within the study period saving the CCG in excess of £1 000 000. During the 4 months for which resource allocation data were available, the clinical pharmacists saved 628 GP appointments plus an additional 647 h that GPs currently devote to medication review and the management of repeat prescribing. Conclusions: This research suggests that clinical pharmacists in general practice in Dudley CCG are able to deliver clinical interventions efficiently and in high volume. In doing so, clinical pharmacists were able to generate considerable financial returns on investment. Further work is recommended to examine the effectiveness and cost-effectiveness of clinical pharmacists in general practice in improving outcomes for patients

Recent Cases

Constitutional Law -- Newsperson\u27s Privilege - The First Amendment Guarantee of a Free Press Protects Against Compelled Disclosure of a Journalist\u27s Exercise of Editorial Control and Judgment Plaintiff, a former army officer who had achieved national prominence by claiming that his superiors ignored his reports of atrocities by American forces in Vietnam,\u27 brought a libel suit against defendant television producer, reporter, and network for broadcasting a program that cast doubt upon plaintiff\u27s allegations. Contending that defendant did not present available information corroborating plaintiff\u27s claims, plaintiff sought discovery of the producer\u27s beliefs, opinions, intent, and conclusions in preparing the program. Alan William Duncan ===================== Income Taxation--Alternative Tax--In Computing Alternative Tax Under Section 1201 of the Internal Revenue Code Taxpayer May Not Deduct from Net Long-Term Capital Gain That Portion of Capital Gain Required To Be Set Aside Permanently for Charitable Organizations Decedent\u27s will required taxpayer estate to distribute to specified charitable organizations a specific portion, of net long-term capital gain realized upon the sale of any securities included in the residue of the estate.\u27 In calculating the alternative tax\u27 on the capital gains realized by the estate in 1967 and 1968, taxpayer deducted from capital gains the amounts required to be set aside for charities.: The Internal Revenue Service disallowed the taxpayer\u27s computation method, contending that a deduction for charitable set asides and payments was not allowable under section 1201. Elton Gregory Snowden ========================= Income Taxation-Corporate Reorganization-Stock Received Under Contingent Payment Plan Is Subject to Imputed Interest Provisions of Section 483 of the Internal Revenue Code Decedent\u27s will required taxpayer estate to distribute to specified charitable organizations a specific portion, of net long-term cap-ital gain realized upon the sale of any securities included in the residue of the estate.\u27 In calculating the alternative tax\u27 on the capital gains realized by the estate in 1967 and 1968, taxpayer deducted from capital gains the amounts required to be set aside for charities. Joseph W. Gibbs ==================== Torts-Independent Contractors-Employer Is Liable for Tortious Conduct of His Financially Irresponsible Independent Contractor All rules affecting the master-servant relationship derive from the historic legal principle that employers are liable for the tortious conduct of their employees occurring in the course of employment. Respondeat superior, which imputes employee negligence to the employer, is not premised on fault. Instead, because the employer has the right to select, control, and dismiss employees\u27 and because he is assumed to be in a better financial position to respond to judgments, the employer is held vicariously liable for tortious acts of his employees within the scope of employment. William Arthur Holb

Utility of the MMPI–2-RF (Restructured Form) Validity Scales in Detecting Malingering in a Criminal Forensic Setting: A Known-Groups Design

The current study examined the utility of the recently released Minnesota Multiphasic Personality Inventory—2 Restructured Form (MMPI–2-RF; Ben-Porath & Tellegen, 2008) validity scales to detect feigned psychopathology in a criminal forensic setting. We used a known-groups design with the Structured Interview of Reported Symptoms (SIRS; Rogers, Bagby, & Dickens, 1992) as the external criterion to determine groups of probable malingering versus nonmalingering. A final sample of 125 criminal defendants, who were administered both the SIRS and the MMPI–2-RF during their evaluations, was examined. The results indicated that the two MMPI–2-RF validity scales specifically designed to detect overreported psychopathology, F-r and FP-r, best differentiated between the malingering and nonmalingering groups. These scales added incremental predictive utility to one another in this differentiation. Classification accuracy statistics substantiated the recommended cut scores in the MMPI–2-RF manual (Ben-Porath & Tellegen, 2008) in this forensic setting. Implications for these results in terms of forensic assessment and detection of malingering are discussed. DOI: 10.1037/a001822

Proceedings of the CUNY Games Conference 6.0

The CUNY Games Network is an organization dedicated to encouraging research, scholarship and teaching in the developing field of games-based learning. We connect educators from every campus and discipline at CUNY and beyond who are interested in digital and non-digital games, simulations, and other forms of interactive teaching and inquiry-based learning. These proceedings summarize the CUNY Games Conference 6.0, where scholars shared research findings at a three-day event to promote and discuss game-based pedagogy in higher education. Presenters could share findings in oral presentations, posters, demos, or play testing sessions. The conference also included workshops on how to modify existing games for the classroom, how to incorporate elements of play into simulations and critical thinking activities, math games, and how to create computer games