Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8(+) T-cell proliferation and survival

The authors thank Dr Esteban Celis and Dr Rhea-Beth Markowitz for reviewing the manuscript and for their valuable suggestions and also thank Dr Lei Huang for his suggestions.Peer reviewedPublisher PD

Vaccination with DNA plasmids expressing Gn coupled to C3d or alphavirus replicons expressing Gn protects mice against rift valley fever virus

Background: Rift Valley fever (RVF) is an arthropod-borne viral zoonosis. Rift Valley fever virus (RVFV) is an important biological threat with the potential to spread to new susceptible areas. In addition, it is a potential biowarfare agent. Methodology/Principal Findings: We developed two potential vaccines, DNA plasmids and alphavirus replicons, expressing the Gn glycoprotein of RVFV alone or fused to three copies of complement protein, C3d. Each vaccine was administered to mice in an all DNA, all replicon, or a DNA prime/replicon boost strategy and both the humoral and cellular responses were assessed. DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn elicited high titer neutralizing antibodies that were similar to titers elicited by the live-attenuated MP12 virus. Mice vaccinated with an inactivated form of MP12 did elicit high titer antibodies, but these antibodies were unable to neutralize RVFV infection. However, only vaccine strategies incorporating alphavirus replicons elicited cellular responses to Gn. Both vaccines strategies completely prevented weight loss and morbidity and protected against lethal RVFV challenge. Passive transfer of antisera from vaccinated mice into naïve mice showed that both DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn elicited antibodies that protected mice as well as sera from mice immunized with MP12. Conclusion/Significance: These results show that both DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn administered alone or in a DNA prime/replicon boost strategy are effective RVFV vaccines. These vaccine strategies provide safer alternatives to using live-attenuated RVFV vaccines for human use. © 2010 Bhardwaj et al

Detection of the 128 day radial velocity variations in the supergiant {\alpha} Persei. Rotational modulations, pulsations, or a planet?

Aims. In order to search for and study the nature of the low-amplitude and long-periodic radial velocity (RV) variations of massive stars, we have been carrying out a precise RV survey for supergiants that lie near or inside the Cepheid instability strip. Methods. We have obtained high-resolution spectra of {\alpha} Per (F5 Ib) from November 2005 to September 2011 using the fiber-fed Bohyunsan Observatory Echelle Spectrograph (BOES) at Bohyunsan Optical Astronomy Observatory (BOAO). Results. Our measurements reveal that {\alpha} Per shows a periodic RV variation of 128 days and a semi-amplitude of 70 m/s. We find no strong correlation between RV variations and bisector velocity span (BVS), but the 128-d peak is indeed present in the BVS variations among several other significant peaks in periodogram. Conclusions. {\alpha} Per may have an exoplanet, but the combined data spanning over 20 years seem to suggest that the 128-d RV variations have not been stable on long-term scale, which is somewhat difficult to reconcile with the exoplanet explanation. We do not exclude the pulsational nature of the 128-d variations in {\alpha} Per. Although we do not find clear evidence for surface activity or rotational modulations by spots, coupled with the fact that the expected rotation period is ~ 130 days the rotational modulation seems to be the most likely cause of the RV variations. More observational data and research are needed to clearly determine the origin of RV the variations in {\alpha} Per.Comment: 7 pages, 10 figures, 4 table

Reducing AD-Like Pathology in 3xTg-AD Mouse Model by DNA Epitope Vaccine — A Novel Immunotherapeutic Strategy

BACKGROUND: The development of a safe and effective AD vaccine requires a delicate balance between providing an adequate anti-Abeta antibody response sufficient to provide therapeutic benefit, while eliminating an adverse T cell-mediated proinflammatory autoimmune response. To achieve this goal we have designed a prototype chemokine-based DNA epitope vaccine expressing a fusion protein that consists of 3 copies of the self-B cell epitope of Abeta(42) (Abeta(1-11)) , a non-self T helper cell epitope (PADRE), and macrophage-derived chemokine (MDC/CCL22) as a molecular adjuvant to promote a strong anti-inflammatory Th2 phenotype. METHODS AND FINDINGS: We generated pMDC-3Abeta(1-11)-PADRE construct and immunized 3xTg-AD mouse model starting at age of 3-4 months old. We demonstrated that prophylactic immunizations with the DNA epitope vaccine generated a robust Th2 immune response that induced high titers of anti-Abeta antibody, which in turn inhibited accumulation of Abeta pathology in the brains of older mice. Importantly, vaccination reduced glial activation and prevented the development of behavioral deficits in aged animals without increasing the incidence of microhemorrhages. CONCLUSIONS: Data from this transitional pre-clinical study suggest that our DNA epitope vaccine could be used as a safe and effective strategy for AD therapy. Future safety and immunology studies in large animals with the goal to achieve effective humoral immunity without adverse effects should help to translate this study to human clinical trials

Future perspectives in melanoma research: meeting report from the "Melanoma Bridge";: Napoli, December 3rd-6th 2014.

The fourth "Melanoma Bridge Meeting" took place in Naples, December 3-6th, 2014. The four topics discussed at this meeting were: Molecular and Immunological Advances, Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent advances in tumor biology and immunology have led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors as well as other signaling pathway inhibitors, are being tested in patients with metastatic melanoma either as monotherapy or in combination, and all have yielded promising results. These include inhibitors of receptor tyrosine kinases (BRAF, MEK, and VEGFR), the phosphatidylinositol 3 kinase (PI3K) pathway [PI3K, AKT, mammalian target of rapamycin (mTOR)], activators of apoptotic pathway, and the cell cycle inhibitors (CDK4/6). Various locoregional interventions including radiotherapy and surgery are still valid approaches in treatment of advanced melanoma that can be integrated with novel therapies. Intrinsic, adaptive and acquired resistance occur with targeted therapy such as BRAF inhibitors, where most responses are short-lived. Given that the reactivation of the MAPK pathway through several distinct mechanisms is responsible for the majority of acquired resistance, it is logical to combine BRAF inhibitors with inhibitors of targets downstream in the MAPK pathway. For example, combination of BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) have been demonstrated to improve survival compared to monotherapy. Application of novel technologies such sequencing have proven useful as a tool for identification of MAPK pathway-alternative resistance mechanism and designing other combinatorial therapies such as those between BRAF and AKT inhibitors. Improved survival rates have also been observed with immune-targeted therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with melanoma as well. These agents are being studied in combination with targeted therapies in attempt to produce longer-term responses than those more typically seen with targeted therapy. Other combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for this patient population. This meeting's specific focus was on advances in combination of targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma

Influence of intermediaries on the efficiency of export of small and medium business production in developing countries

Small and medium business plays an important role in the national economies of developing countries. From this perspective, to create an effective system for exports is of key importance for these countries. The article provides the basis for the implementation of intermediary export organizations and systems for their interaction with small and medium business entities. On the example of Armenia, the authors proved that the introduction of intermediary organizations to enhance the participation of small and medium business in export operations is expedient. These organizations may be implemented in other developing countries. We used methods of analysis, synthesis, induction, deduction, comparative method, statistical analysis and others. The authors proposed three possible options for establishing intermediary export organizations in developing countries. Firstly, we considered the intermediary export organizations, established and managed directly by the state. Secondly, intermediary export organizations may be created by uniting of small and medium enterprises (SMEs) of a particular industry in association. And the final option is the commercial intermediary organizations for export. By applying a comparative cost analysis of direct and indirect exports, the authors have developed a method for assessing the effectiveness of interaction of intermediary export organizations with small and medium-sized businesses. We defined the following components of the total exports costs: The costs of warehousing, packaging, transportation, information collection, contracts, search for the shadow broker and interaction with him/her, marketing, export documentation, broker services, banking and insurance services, personnel costs, operation of the structure, tax and customs payments. We have analysed possible changes in these costs and defined the value of the cost changes total indicator that shows more effective indirect exports. The study defines the possible risks faced by the exporter when entering the foreign market. These are the risk of interaction with unscrupulous buyers, the risk associated with the application of penalties and the inability to quickly ship the exported goods, and the long waiting times for loaded wagons. The research results can be applied to the implement or improve state policy in the sphere of small and medium enterprises, to develop medium-and long-term plans to optimize the activities of small and medium enterprises and their export strategy. © 2018 Institute of Economics, Ural Branch of the Russian Academy of Sciences. All rights reserved.Разработана основа формирования посреднических экспортных организаций и систем их взаимодействия с субъектами малого и среднего бизнеса. Предложены варианты создания посреднических организаций по экспорту в развивающихся странах, особое внимание уделено Армении. Выделены компоненты совокупных затрат на экспорт. Представлены возможные риски, с которыми сталкивается экспортер при выходе на внешний рынок.This work has been supported by the Ministry of Education and Science of the Russian Federation in the framework of the research project The issues of small and medium enterprises products and services export in Republic of Armenia and the Russian Federa