Kaposi's sarcoma-associated herpesvirus oncoprotein K13 protects against B cell receptor induced growth arrest and apoptosis through NF-κB activation

Kaposi's sarcoma-associated herpesvirus (KSHV) has been linked to the development of Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease (MCD). We have characterized the role of KSHV-encoded viral FLICE inhibitory protein K13 in the modulation of anti-IgM induced growth arrest and apoptosis in B cells. We demonstrate that K13 protects WEHI 231, an immature B cell line, against anti-IgM induced growth arrest and apoptosis. The protective effect of K13 was associated with the activation of the NF-κB pathway and was deficient in its mutant, K13-58AAA, and a structural homolog, vFLIP E8, which lack NF-κB activity. K13 upregulated the expression of NF-κB subunit RelB and blocked the anti-IgM induced decline in c-Myc and rise in p27(Kip1) that have been associated with growth arrest and apoptosis. K13 also upregulated the expression of Mcl-1, an anti-apoptotic member of the Bcl2 family. Finally, K13 protected the mature B cell line Ramos against anti-IgM induced apoptosis through NF-κB activation. Inhibition of anti-IgM induced apoptosis by K13 may contribute to the development of KSHV-associated lymphoproliferative disorders

Dedicated versus mainstreaming approaches in local climate plans in Europe

Cities are gaining prominence committing to respond to the threat of climate change, e.g., by developing local climate plans or strategies. However, little is known regarding the approaches and processes of plan development and implementation, or the success and effectiveness of proposed measures. Mainstreaming is regarded as one approach associated with (implementation) success, but the extent of integration of local climate policies and plans in ongoing sectoral and/or development planning is unclear. This paper analyses 885 cities across the 28 European countries to create a first reference baseline on the degree of climate mainstreaming in local climate plans. This will help to compare the benefits of mainstreaming versus dedicated climate plans, looking at policy effectiveness and ultimately delivery of much needed climate change efforts at the city level. All core cities of the European Urban Audit sample were analyzed, and their local climate plans classified as dedicated or mainstreamed in other local policy initiatives. It was found that the degree of mainstreaming is low for mitigation (9% of reviewed cities; 12% of the identified plans) and somewhat higher for adaptation (10% of cities; 29% of plans). In particular horizontal mainstreaming is a major effort for local authorities; an effort that does not necessarily pay off in terms of success of action implementation. This study concludes that climate change issues in local municipalities are best tackled by either, developing a dedicated local climate plan in parallel to a mainstreamed plan or by subsequently developing first the dedicated and later a mainstreaming plan (joint or subsequent “dual track approach”). Cities that currently provide dedicated local climate plans (66% of cities for mitigation; 26% of cities for adaptation) may follow-up with a mainstreaming approach. This promises effective implementation of tangible climate actions as well as subsequent diffusion of climate issues into other local sector policies. The development of only broad sustainability or resilience strategies is seen as critical.We thank the many council representatives that supported the datacollection. Special thanks to Birgit Georgi who helped in setting up this large net work of researchers across the EU-28. We also thank the EU COST Action TU 0902 (ledbyRichardDawson) that established the core research network and the positive engagement and interaction of th emembers of this group. OH is Fellow of the Tyndall Centre for Climate Change Research and was funded by the UK EPSRC LC Transforms: Low Carbon Transitions of Fleet Operations in Metropolitan Sites Project (grant number EP/N010612/1). EKL was supported by the Ministry of Education, Youth and Sports, Czechia, within the National Sustainability Program I (NPU I) (grant number LO1415). DG ac-knowledges support by the Ministry of Education, University and Research (MIUR), Italy ("Departments of Excellence" grant L. 232/2016). HO was supported by the Ministry of Education and Research, Estonia (grantnumberIUT34-17). MO acknowledges funding from the Ministry of Economy and Competitiveness (MINECO), Spain (grant number IJCI-2016-28835). SS acknowledges that CENSE's research is partially funded by the Science Foundation, Portugal (grant number UID/AMB/04085/2019). The paper reflects only the views of the authors. The European Union, the European Environment Agency or other supporting bodies are not liable for any use that may be made of the information that is provided in this manuscript

Low intensity pulsed ultrasound (LIPUS) for bone healing: A clinical practice guideline

Does low intensity pulsed ultrasound (LIPUS) accelerate recovery in adults and children who have experienced bone fractures or osteotomy (cutting of a bone)? An expert panel rapidly produced these recommendations based on a linked systematic review triggered by a large multi-centre randomised trial in adults with tibial fracture

Probing Tectonic Topography in the Aftermath of Continental Convergence in Central Europe

Continental topography is at the interface of processes taking place at depth in the Earth,at its surface,and above it.Topography influences society, not only in terms of slow processes of landscape change and earthquakes,but also in terms of how it affects climate.The Pannonian Basin–Carpathian Orogen System in Central and Eastern Europe represents a key natural laboratory for the development of a new generation of models for ongoing orogeny and its effect on continental topography development (Figure 1).This system comprises some of the best documented sedimentary basins in the world,located within the Alpine orogenic belt, at the transition between the western European lithosphere and the East European Craton. It includes one of the most active seismic zones in Europe,with intermediate depth (50–220 km) mantle earthquakes of significant magnitude occurring in a geographically restricted area in the Vrancea zone of southeastern Romania

Primary effusion lymphoma associated with Human Herpes Virus-8 and Epstein Barr virus in an HIV-infected woman from Kampala, Uganda: a case report

<p>Abstract</p> <p>Introduction</p> <p>Primary effusion lymphoma is a recently recognized entity of AIDS related non-Hodgkin lymphomas. Despite Africa being greatly affected by the HIV/AIDS pandemic, an extensive MEDLINE/PubMed search failed to find any report of primary effusion lymphoma in sub-Saharan Africa. To our knowledge this is the first report of primary effusion lymphoma in sub-Saharan Africa. We report the clinical, cytomorphologic and immunohistochemical findings of a patient with primary effusion lymphoma.</p> <p>Case presentation</p> <p>A 70-year-old newly diagnosed HIV-positive Ugandan African woman presented with a three-month history of cough, fever, weight loss and drenching night sweats. Three weeks prior to admission she developed right sided chest pain and difficulty in breathing. On examination she had bilateral pleural effusions.</p> <p>Haematoxylin and eosin stained cytologic sections of the formalin-fixed paraffin-embedded cell block made from the pleural fluid were processed in the Department of Pathology, Makerere University, College of Health Sciences, Kampala, Uganda. Immunohistochemistry was done at the Institute of Haematology and Oncology "L and A Seragnoli", Bologna University School of Medicine, Bologna, Italy, using alkaline phosphatase anti-alkaline phosphatase method. <it>In situ </it>hybridization was used for detection of Epstein-Barr virus.</p> <p>The tumor cells were CD45+, CD30+, CD38+, HHV-8 LANA-1+; but were negative for CD3-, CD20-, CD19-, and CD79a- and EBV RNA+ on <it>in situ </it>hybridization. CD138 and Ki-67 were not evaluable. Our patient tested HIV positive and her CD4 cell count was 127/μL.</p> <p>Conclusions</p> <p>A definitive diagnosis of primary effusion lymphoma rests on finding a proliferation of large immunoblastic, plasmacytoid and anaplastic cells; HHV-8 in the tumor cells, an immunophenotype that is CD45+, pan B-cell marker negative and lymphocyte activated marker positive. It is essential for clinicians and pathologists to have a high index of suspicion of primary effusion lymphoma when handling HIV positive patients who have effusions without palpable tumor masses. Basic immunohistochemistry is essential for definitive diagnosis.</p

Kaposi's Sarcoma-Associated Herpesvirus K7 Induces Viral G Protein-Coupled Receptor Degradation and Reduces Its Tumorigenicity

The Kaposi's sarcoma-associated herpesvirus (KSHV) genome encodes a G protein-coupled receptor (vGPCR). vGPCR is a ligand-independent, constitutively active signaling molecule that promotes cell growth and proliferation; however, it is not clear how vGPCR is negatively regulated. We report here that the KSHV K7 small membrane protein interacts with vGPCR and induces its degradation, thereby dampening vGPCR signaling. K7 interaction with vGPCR is readily detected in transiently transfected human cells. Mutational analyses reveal that the K7 transmembrane domain is necessary and sufficient for this interaction. Biochemical and confocal microscopy studies indicate that K7 retains vGPCR in the endoplasmic reticulum (ER) and induces vGPCR proteasomeal degradation. Indeed, the knockdown of K7 by shRNA-mediated silencing increases vGPCR protein expression in BCBL-1 cells that are induced for KSHV lytic replication. Interestingly, K7 expression significantly reduces vGPCR tumorigenicity in nude mice. These findings define a viral factor that negatively regulates vGPCR protein expression and reveal a post-translational event that modulates GPCR-dependent transformation and tumorigenicity

Primary Effusion Lymphoma Cell Death Induced by Bortezomib and AG 490 Activates Dendritic Cells through CD91

To understand how cytotoxic agent-induced cancer cell death affects the immune system is of fundamental importance to stimulate immune response to counteract the high mortality due to cancer. Here we compared the immunogenicity of Primary Effusion Lymphoma (PEL) cell death induced by anticancer drug Bortezomib (Velcade) and Tyrphostin AG 490, a Janus Activated Kinase 2/signal trasducer and activator of transcription-3 (JAK2/STAT3) inhibitor. We show that both treatments were able to induce PEL apoptosis with similar kinetics and promote dendritic cells (DC) maturation. The surface expression of molecules involved in immune activation, namely calreticulin (CRT), heat shock proteins (HSP) 90 and 70 increased in dying cells. This was correlated with DC activation. We found that PEL cell death induced by Bortezomib was more effective in inducing uptake by DC compared to AG 490 or combination of both drugs. However the DC activation induced by all treatments was completely inhibited when these cells were pretreated with a neutralizing antiboby directed against the HSP90/70 and CRT common receptor, CD91. The activation of DC by Bortezomib and AG 490 treated PEL cells, as seen in the present study, might have important implications for a combined chemo and immunotherapy in such patients

Viral FLICE Inhibitory Protein of Rhesus Monkey Rhadinovirus Inhibits Apoptosis by Enhancing Autophagosome Formation

Rhesus monkey rhadinovirus (RRV) is a gamma-2 herpesvirus closely related to human herpesvirus 8 (HHV8). RRV encodes viral FLICE inhibitory protein (vFLIP), which has death effector domains. Little is known about RRV vFLIP. This study intended to examine its function in apoptosis. Here we found that RRV vFLIP inhibits apoptosis induced by tumor necrosis factor-α (TNF-α) and cycloheximide. In HeLa cells with vFLIP expression, the cleavage of poly [ADP-ribose] polymerase 1 (PARP-1) and activities of caspase 3, 7, and 9 were much lower than those in controls. Cell viability of HeLa cells with vFLIP expression was significantly higher than control cells after apoptosis induction. However, RRV vFLIP appears unable to induce NF-κB signaling when tested in NF-κB reporter assay. RRV vFLIP was able to enhance cell survival under starved conditions or apoptosis induction. At early time points after apoptosis induction, autophagosome formation was enhanced and LC3-II level was elevated in cells with vFLIP and, when autophagy was blocked with chemical inhibitors, these cells underwent apoptosis. Moreover, RRV latent infection of BJAB B-lymphoblastoid cells protects the cells against apoptosis by enhancing autophagy to maintain cell survival. Knockdown of vFLIP expression in the RRV-infected BJAB cells with siRNA abolished the protection against apoptosis. These results indicate that vFLIP protects cells against apoptosis by enhancing autophagosome formation to extend cell survival. The finding of vFLIP’s inhibition of apoptosis via the autophagy pathway provides insights of vFLIP in RRV pathogenesis

Types of Corruption in Small and Micro Enterprises (SMEs) in Ibadan, Nigeria

Corruption is a phenomenon that manifests in various types and forms especially among operators of Small and Micro Enterprises (SMEs). Many actions of the operators which constitute corrupt practices often tend to be overlooked in spite of their grave consequences for the success SMEs in Nigeria. The fight against corruption in Nigeria is more concentrated in the formal sector. This study was, therefore, designed to investigate various forms in which corrupt practices are carried out among Small and Micro Enterprises in Ibadan, Nigeria. Business owners, their employees, apprentices and consumers constituted the study population. Primary data were collected using questionnaire administered on 200 business owners, 150 employees and 150 apprentices randomly chosen in five business districts in Ibadan; and the conduct of 10 in-depth interviews with purposively selected participants. Quantitative data were analysed at uni-variate level using simple percentages and frequencies while qualitative data were content analysed. Findings from the study revealed that corrupt practices were rampant among actors in SMEs and the common types of corrupt practices included stealing (60%), deception of customers (78.4%), tax evasion (62%), sale of fake products (76%), sale of expired products (65.2%), tampering with measurement scales (69.6%), bribery (82.4%), and poor service delivery (73%). The study concludes that the level of corruption in SMEs calls for concern and government should extend the fight against corruption to the informal sector in Nigeria

Activation of Host Translational Control Pathways by a Viral Developmental Switch

In response to numerous signals, latent herpesvirus genomes abruptly switch their developmental program, aborting stable host–cell colonization in favor of productive viral replication that ultimately destroys the cell. To achieve a rapid gene expression transition, newly minted capped, polyadenylated viral mRNAs must engage and reprogram the cellular translational apparatus. While transcriptional responses of viral genomes undergoing lytic reactivation have been amply documented, roles for cellular translational control pathways in enabling the latent-lytic switch have not been described. Using PEL-derived B-cells naturally infected with KSHV as a model, we define efficient reactivation conditions and demonstrate that reactivation substantially changes the protein synthesis profile. New polypeptide synthesis correlates with 4E-BP1 translational repressor inactivation, nuclear PABP accumulation, eIF4F assembly, and phosphorylation of the cap-binding protein eIF4E by Mnk1. Significantly, inhibiting Mnk1 reduces accumulation of the critical viral transactivator RTA through a post-transcriptional mechanism, limiting downstream lytic protein production, and impairs reactivation efficiency. Thus, herpesvirus reactivation from latency activates the host cap-dependent translation machinery, illustrating the importance of translational regulation in implementing new developmental instructions that drastically alter cell fate