Viral Takeover of the Host Ubiquitin System

Like the other more well-characterized post-translational modifications (phosphorylation, methylation, acetylation, acylation, etc.), the attachment of the 76 amino acid ubiquitin (Ub) protein to substrates has been shown to govern countless cellular processes. As obligate intracellular parasites, viruses have evolved the capability to commandeer many host processes in order to maximize their own survival, whether it be to increase viral production or to ensure the long-term survival of latently infected host cells. The first evidence that viruses could usurp the Ub system came from the DNA tumor viruses and Adenoviruses, each of which use Ub to dysregulate the host cell cycle (Scheffner et al., 1990; Querido et al., 2001). Today, the list of viruses that utilize Ub includes members from almost every viral class, encompassing both RNA and DNA viruses. Among these, there are examples of Ub usage at every stage of the viral life cycle, involving both ubiquitination and de-ubiquitination. In addition to viruses that merely modify the host Ub system, many of the large DNA viruses encode their own Ub modifying machinery. In this review, we highlight the latest discoveries regarding the myriad ways that viruses utilize Ub to their advantage

The urban land use in the COSMO-CLM model: A comparison of three parameterizations for Berlin

The regional non-hydrostatic climate model COSMO-CLM is increasingly being used on fine spatial scales of 1–5 km. Such applications require a detailed differentiation between the parameterization for natural and urban land uses. Since 2010, three parameterizations for urban land use have been incorporated into COSMO-CLM. These parameterizations vary in their complexity, required city parameters and their computational cost. We perform model simulations with the COSMO-CLM coupled to these three parameterizations for urban land in the same model domain of Berlin on a 1-km grid and compare results with available temperature observations. While all models capture the urban heat island, they differ in spatial detail, magnitude and the diurnal variation

The Great Escape: Viral Strategies to Counter BST-2/Tetherin

The interferon-induced BST-2 protein has the unique ability to restrict the egress of HIV-1, Kaposi's sarcoma–associated herpesvirus (KSHV), Ebola virus, and other enveloped viruses. The observation that virions remain attached to the surface of BST-2-expressing cells led to the renaming of BST-2 as “tetherin”. However, viral proteins such as HIV-1 Vpu, simian immunodeficiency virus Nef, and KSHV K5 counteract BST-2, thereby allowing mature virions to readily escape from infected cells. Since the anti-viral function of BST-2 was discovered, there has been an explosion of research into several aspects of this intriguing interplay between host and virus. This review focuses on recent work addressing the molecular mechanisms involved in BST-2 restriction of viral egress and the species-specific countermeasures employed by various viruses

Addition of cetuximab to first-line chemotherapy in patients with advanced non-small-cell lung cancer: a cost-utility analysis

Background: Adding cetuximab to standard chemotherapy results in a moderate increase of overall survival in patients with advanced non-small-cell lung cancer (NSCLC), but the cost-effectiveness is unknown. Materials and methods: A Markov model was constructed based on the results of the First-Line ErbituX in lung cancer randomized trial, adding cetuximab to cisplatin-vinorelbine first-line chemotherapy in patients with advanced NSCLC. The primary outcome was the incremental cost-effectiveness ratio (ICER) of adding cetuximab, expressed as cost per quality-adjusted life year (QALY) gained, and relative to a willingness-to-pay threshold of €60 000/QALY. The impact of cetuximab intermittent dosing schedules on the ICER was also evaluated. Results: Adding cetuximab to standard chemotherapy leads to a gain of 0.07 QALYs per patient at an additional cost of €26 088. The ICER for adding cetuximab to chemotherapy was €376 205 per QALY gained. Intermittent cetuximab dosing schedules resulted in ICERs per QALY gained between €31 300 and €83 100, under the assumption of equal efficacy. Conclusions: From a health economic perspective, the addition of cetuximab to standard first-line chemotherapy in patients with epidermal growth factor receptor-expressing advanced NSCLC cannot be recommended to date, due to a high ICER compared with other health care interventions. Treatment schedules resulting in more favorable cost-utility ratios should be evaluate

Entwicklung, Erprobung, Umsetzung und Evaluation von Strategien in den Bereichen Tiergesundheit, Haltung, Fütterung, Management in der ökologischen Ferkelerzeugung

Die ökologische Ferkelerzeugung weist hinsichtlich Tiergesundheit, Leistungsfähigkeit und Wirtschaftlichkeit große Defizite auf. Die Ursachen sind komplex und betreffen u.a. Fütterung, Haltung und Hygiene. Für diese Bereiche sollten durch Exakt- und Praxisversuche Lösungsansätze entwickelt werden. Teilprojekte umfassten folgende Themen: Der Einfluss unterschiedlicher Raufutter in der Fütterung tragender Sauen, die Wirkung einer Inulinzugabe sowie vom Extrudieren von Ackerbohnen in Sauen- und Ferkelfutter, die Bewertung alternativer Desinfektionsverfahren, ein Vergleich von Einzelhaltung versus kombinierte Einzel- und Gruppenhaltung säugender Sauen sowie die Optimierung des Ferkelliegebereichs in der Ferkelaufzucht. Zentrale Ergebnisse: - Die verschiedenen Raufuttervarianten (Kleegrassilage, Heu, Maissilage, Topinamburknollen) hatten keine negativen Effekte auf Körperkonstitution und Reproduktionsleistungen der Sauen. - Die Saugferkel der mit Inulin versorgten Sauen entwickelten sich gegenüber der Kontrollgruppe während der Säugezeit leistungsmäßig besser, während der Ferkelaufzucht gab es keine Leistungssteigerungen. Der Einsatz von getoasteten Ackerbohnen führte zu signifikant besseren Ferkelzunahmen gegenüber dem Einsatz von extrudierten Ackerbohnen. - Keines der getesteten alternativen Desinfektionsverfahren (Heißwasserdampf, elektroaktiviertes Wasser, Abflammen) ist eine Alternative zur chemischen Desinfektion bezüglich Keimreduktion, Arbeitsaufwand und Kosten. - Gruppensäugen führt bei Sauen zu erhöhter Aktivität sowie zu spezifischen Verhaltensanpassungen. Leistungseinbußen konnten weder für Sauen noch für Ferkel dokumentiert werden. „Gruppensäugen“ führt zu einem höheren Arbeitszeitbedarf und steigenden Baukosten. - Der Liegebereich für Aufzuchtferkel ist in vielen Betrieben nicht optimal und durch z. T. einfache Maßnahmen (Abdichten des Liegenestes, Wärmedämmung des Bodens, Bodenheizung, Anbringen einer weiteren Wärmequelle) für die Tiere zu verbessern

La production biologique de porcs en Europe - Gestion de la santé des porcs dans les élevages de production

Les éleveurs de porcs biologiques ont développé en Europe différents systèmes de logement qui dépendent de la disponibilité des terres, des caractéristiques du sol et du climat, des traditions et des schémas de certification. Ce guide décrit les principaux systèmes de logement des porcs biologiques. Il compare les avantages et les inconvénients de chacun et donne des recommandations aux éleveurs pour mieux agir sur la santé des animaux

The secreted protein Cowpox Virus 14 contributes to viral virulence and immune evasion by engaging Fc-gamma-receptors

The genome of cowpoxvirus (CPXV) could be considered prototypical for orthopoxviridae (OXPV) since it contains many open reading frames (ORFs) absent or lost in other OPXV, including vaccinia virus (VACV). These additional ORFs are non-essential for growth in vitro but are expected to contribute to the broad host range, virulence and immune evasion characteristics of CPXV. For instance, unlike VACV, CPXV encodes proteins that interfere with T cell stimulation, either directly or by preventing antigen presentation or co-stimulation. When studying the priming of naïve T cells, we discovered that CPXV, but not VACV, encodes a secreted factor that interferes with activation and proliferation of naïve CD8+ and CD4+ T cells, respectively, in response to anti-CD3 antibodies, but not to other stimuli. Deletion mapping revealed that the inhibitory protein is encoded by CPXV14, a small secreted glycoprotein belonging to the poxvirus immune evasion (PIE) family and containing a smallpoxvirus encoded chemokine receptor (SECRET) domain that mediates binding to chemokines. We demonstrate that CPXV14 inhibition of antibody-mediated T cell activation depends on the presence of Fc-gamma receptors (FcγRs) on bystander cells. In vitro, CPXV14 inhibits FcγR-activation by antigen/antibody complexes by binding to FcγRs with high affinity and immobilized CPXV14 can trigger signaling through FcγRs, particularly the inhibitory FcγRIIB. In vivo, CPXV14-deleted virus showed reduced viremia and virulence resulting in reduced weight loss and death compared to wildtype virus whereas both antibody and CD8+ T cell responses were increased in the absence of CPXV14. Furthermore, no impact of CPXV14-deletion on virulence was observed in mice lacking the inhibitory FcγRIIB. Taken together our results suggest that CPXV14 contributes to virulence and immune evasion by binding to host FcγRs

Characteristics and outcome of patients with newly diagnosed advanced or metastatic lung cancer admitted to intensive care units (ICUs)

BACKGROUND: Although patients with advanced or metastatic lung cancer have poor prognosis, admission to the ICU for management of life-threatening complications has increased over the years. Patients with newly diagnosed lung cancer appear as good candidates for ICU admission, but more robust information to assist decisions is lacking. The aim of our study was to evaluate the prognosis of newly diagnosed unresectable lung cancer patients. METHODS: A retrospective multicentric study analyzed the outcome of patients admitted to the ICU with a newly diagnosed lung cancer (diagnosis within the month) between 2010 and 2013. RESULTS: Out of the 100 patients, 30 had small cell lung cancer (SCLC) and 70 had non-small cell lung cancer. (Thirty patients had already been treated with oncologic treatments.) Mechanical ventilation (MV) was performed for 81 patients. Seventeen patients received emergency chemotherapy during their ICU stay. ICU, hospital, 3- and 6-month mortality were, respectively, 47, 60, 67 and 71%. Hospital mortality was 60% when invasive MV was used alone, 71% when MV and vasopressors were needed and 83% when MV, vasopressors and hemodialysis were required. In multivariate analysis, hospital mortality was associated with metastatic disease (OR 4.22 [1.4-12.4]; p = 0.008), need for invasive MV (OR 4.20 [1.11-16.2]; p = 0.030), while chemotherapy in ICU was associated with survival (OR 0.23, [0.07-0.81]; p = 0.020). CONCLUSION: This study shows that ICU management can be appropriate for selected newly diagnosed patients with advanced lung cancer, and chemotherapy might improve outcome for patients with SCLC admitted for cancer-related complications. Nevertheless, tumors' characteristics, numbers and types of organ dysfunction should be taken into account in the decisional process before admitting these patients in ICU.Peer reviewe

IRF-3, IRF-5, and IRF-7 Coordinately Regulate the Type I IFN Response in Myeloid Dendritic Cells Downstream of MAVS Signaling

Although the transcription factors IRF-3 and IRF-7 are considered master regulators of type I interferon (IFN) induction and IFN stimulated gene (ISG) expression, Irf3-/-×Irf7-/- double knockout (DKO) myeloid dendritic cells (mDC) produce relatively normal levels of IFN-β after viral infection. We generated Irf3-/-×Irf5-/-×Irf7-/- triple knockout (TKO) mice to test whether IRF-5 was the source of the residual induction of IFN-β and ISGs in mDCs. In pathogenesis studies with two unrelated positive-sense RNA viruses (West Nile virus (WNV) and murine norovirus), TKO mice succumbed at rates greater than DKO mice and equal to or approaching those of mice lacking the type I IFN receptor (Ifnar-/-). In ex vivo studies, after WNV infection or exposure to Toll-like receptor agonists, TKO mDCs failed to produce IFN-β or express ISGs. In contrast, this response was sustained in TKO macrophages following WNV infection. To define IRF-regulated gene signatures, we performed microarray analysis on WNV-infected mDC from wild type (WT), DKO, TKO, or Ifnar-/- mice, as well as from mice lacking the RIG-I like receptor adaptor protein MAVS. Whereas the gene induction pattern in DKO mDC was similar to WT cells, remarkably, almost no ISG induction was detected in TKO or Mavs-/- mDC. The relative equivalence of TKO and Mavs-/- responses suggested that MAVS dominantly regulates ISG induction in mDC. Moreover, we showed that MAVS-dependent induction of ISGs can occur through an IRF-5-dependent yet IRF-3 and IRF-7-independent pathway. Our results establish IRF-3, -5, and -7 as the key transcription factors responsible for mediating the type I IFN and ISG response in mDC during WNV infection and suggest a novel signaling link between MAVS and IRF-5