Regulation Of Cell Death And Inflammation In Antibacterial Immunity

Many pathogens interfere with the activation of innate immune signaling responses. However, pro-survival and cell death-inducing signals are coupled downstream of innate immune receptors, such that survival signals prevent cell death in the context of inflammatory stimuli. Blockade of key signaling pathways by pathogen virulence factors uncouples this coordinate regulation, resulting in activation of programed cell death. Thus, cell death may act as a conserved host protective mechanism for inducing inflammation in response to pathogens that interfere with immune signaling pathways. The YopJ virulence factor of the gram-negative bacterial pathogen Yersinia pseudotuberculosis potently inhibits NF-κB and MAPK signaling, resulting in death of infected innate immune cells. This cell death occurs through a pathway involving caspase-8 and receptor-interacting serine/threonine kinase 1 (RIPK1) downstream of toll-like receptor 4 (TLR4) and TIR-domain-containing adapter-inducing interferon-β (TRIF). Our studies reveal that TNFR1 signaling additionally acts to promote Yersinia-induced cell death, via caspase-8 and RIPK1. Importantly, cell-extrinsic TNF, produced by cells that escape the effects of YopJ inhibition, is necessary for promoting this response. Thus, innate immune cytokine signaling acts to potentiate the apoptotic response to pathogen inhibition and perhaps reflects a coordinated response by heterogeneous cell populations to counter infection. We further demonstrate an in vivo function for RIPK1 kinase activity in promoting host protection and inflammatory cytokine responses to Yersinia infection that is consistent with a function of Yersinia-induced apoptosis in promoting host protective anti-bacterial immunity. Together, these data demonstrate that the apoptotic response induced during infection with pathogens that inhibit host signaling is promoted by cytokine signaling and plays an important role in potentiating host protection. Understanding the regulation of these responses to infection provides novel mechanistic insight into the pathways that may regulate cell death and inflammation in diverse pathologic states and could be targeted to treat disease

Lidar User’s Manual

This is intended to be a user’s manual for the upgraded USU Rayleigh lidar. As such, it begins with a discussion of the purpose of a lidar. This is followed by a brief explanation of the fundamentals of Rayleigh scatter lidar. Next the reasons for and benefits of upgrading the lidar are discussed and as well as how the upgrade was accomplished. After establishing this basis, instructions are provided for operating the lidar, performing basic maintenance, and aligning various components

Effectiveness of Solution-Focused Brief Therapy: A Systematic Qualitative Review of Controlled Outcome Studies

Objective: We review all available controlled outcome studies of solution-focused brief therapy (SFBT) to evaluate evidence of its effectiveness. Method: Forty-three studies were located and key data abstracted on problem, setting, SFBT intervention, design characteristics, and outcomes. Results: Thirty-two (74%) of the studies reported significant positive benefit from SFBT; 10 (23%) reported positive trends. The strongest evidence of effectiveness came in the treatment of depression in adults where four separate studies found SFBT to be comparable to well-established alternative treatments. Three studies examined length of treatment and all found SFBT used fewer sessions than alternative therapies. Conclusion: The studies reviewed provide strong evidence that SFBT is an effective treatment for a wide variety of behavioral and psychological outcomes and, in addition, it may be briefer and therefore less costly than alternative approaches

Facing an Uncertain Future: An Investigation of the Preparation and Readiness of First-Time Superintendents to Lead in a Democratic Society

The preparation of superintendents is a critical component, an essential element, of systemic education reform, although as (Cooper, Fusarelli, Jackson, & Poster, 2002) observed, “the process is rife with difficulties,” including synchronization of preparation and actual practice, the theory-practice disconnect, the need for life-long learning, and development of an adequate knowledge base (Cooper et al., 2002, p. 242). The vast majority of research on the efficacy of administrator preparation programs focuses on principals. Most doctoral programs in educational administration serve as de facto preparation programs for superintendents, even though some contain little coursework specifically tailored for the position (Andrews & Grogan, 2002). A number of scathing reports critical of university-based preparation programs for school administrators, coupled with increasingly conservative state legislatures, have produced some significant changes in licensure for school administrators. Licensing requirements for superintendents have been eliminated or lowered in a growing number of states. For example, 9 states no longer require a license; among the remaining 41 states, 54% grant waivers or emergency licenses and 37% allow or sanction alternative routes to licensure (Feistritzer, 2003). In addition, recommendations to make administrative licensing voluntary across all states (Broad Foundation and Thomas B. Fordham Institute, 2003; Hess, 2003) and to discontinue doctoral programs for practitioners (Levine, 2005) have received an inordinate amount of national media attention. Recognizing that efforts to lower the qualifications and stature of school superintendents are gaining momentum, Kowalski (2004) has recommended a concerted effort to improve the professional knowledge base on practice in this position. One purpose of this endeavor is to ensure that policymakers will at least have an opportunity to examine empirical evidence as they evaluate anti-professionist contentions and intentions. This study focuses on arguably the most relevant consideration in relation to preparation and licensure—the experiences of first-time superintendents. Subjects included novice public school superintendents employed at the beginning of the 2004-05 school year in four states: California, Missouri, North Carolina, and Ohio. The overarching objectives 3 were to (a) produce profiles of the novice superintendents, (b) produce profiles of the employing school districts, (c) identify the dispositions of novices toward their academic preparation, and (d) compare outcomes across the four states

Western corn rootworm pyrethroid resistance confirmed by aerial application simulations of commercial insecticides

The western corn rootworm (Diabrotica virgifera virgifera LeConte) (WCR) is a major insect pest of corn (Zea mays L.) in the United States (US) and is highly adaptable to multiple management tactics. A low level of WCR field-evolved resistance to pyrethroid insecticides has been confirmed in the US western Corn Belt by laboratory dose-response bioassays. Further investigation has identified detoxification enzymes as a potential part of the WCR resistance mechanism, which could affect the performance of insecticides that are structurally related to pyrethroids, such as organophosphates. Thus, the responses of pyrethroid-resistant and -susceptible WCR populations to the commonly used pyrethroid bifenthrin and organophosphate dimethoate were compared in active ingredient bioassays. Results revealed a relatively low level of WCR resistance to both active ingredients. Therefore, a simulated aerial application bioassay technique was developed to evaluate how the estimated resistance levels would affect performance of registered rates of formulated products. The simulated aerial application technique confirmed pyrethroid resistance to formulated rates of bifenthrin whereas formulated dimethoate provided optimal control. Results suggest that the relationship between levels of resistance observed in dose-response bioassays and actual efficacy of formulated product needs to be further explored to understand the practical implications of resistance

Crystal structure of the cowpox virus-encoded NKG2D ligand OMCP

The NKG2D receptor is expressed on the surface of NK, T, and macrophage lineage cells and plays an important role in antiviral and antitumor immunity. To evade NKG2D recognition, herpesviruses block the expression of NKG2D ligands on the surface of infected cells using a diverse repertoire of sabotage methods. Cowpox and monkeypox viruses have taken an alternate approach by encoding a soluble NKG2D ligand, the orthopoxvirus major histocompatibility complex (MHC) class I-like protein (OMCP), which can block NKG2D-mediated cytotoxicity. This approach has the advantage of targeting a single conserved receptor instead of numerous host ligands that exhibit significant sequence diversity. Here, we show that OMCP binds the NKG2D homodimer as a monomer and competitively blocks host ligand engagement. We have also determined the 2.25-Å-resolution crystal structure of OMCP from the cowpox virus Brighton Red strain, revealing a truncated MHC class I-like platform domain consisting of a beta sheet flanked with two antiparallel alpha helices. OMCP is generally similar in structure to known host NKG2D ligands but has notable variations in regions typically used to engage NKG2D. Additionally, the determinants responsible for the 14-fold-higher affinity of OMCP for human than for murine NKG2D were mapped to a single loop in the NKG2D ligand-binding pocket

Laboratory Diagnosis of \u3cem\u3eClostridium difficile \u3c/em\u3eInfection: Can Molecular Amplification Methods Move Us Out of Uncertainty?

The laboratory diagnosis of Clostridium difficile infection (CDI) continues to be challenging. Recent guidelines from professional societies in the United States note that enzyme immunoassays for toxins A and B do not have adequate sensitivity to be used alone for detecting CDI, yet the optimal method for diagnosing this infection remains unclear. Nucleic acid amplification tests (NAATs) that target chromosomal toxin genes (usually the toxin B gene, tcdB) show high sensitivity and specificity, provide rapid results, and are amenable to both batch and on-demand testing, but these tests were not universally recommended for routine use in the recent guidelines. Rather, two-step algorithms that use glutamate dehydrogenase (GDH) assays to screen for C. difficile in stool specimens, followed by either direct cytotoxin testing or culture to identify toxin-producing C. difficile isolates, were recommended in one guideline and either GDH algorithms or NAATs were recommended in another guideline. Unfortunately, neither culture nor direct cytotoxin testing is widely available. In addition, this two-step approach requires 48 to 92 hours to complete, which may delay the initiation of therapy and critical infection control measures. Recent studies also show the sensitivity of several GDH assays to be \u3c90%. This review considers the role of NAATs for diagnosing CDI and explores their potential advantages over two-step algorithms, including shorter time to results, while providing comparable, if not superior, accuracy