Zika virus (ZIKV) infection is primarily transmitted by mosquitoes and often asymptomatic in most individuals. Infection during pregnancy can lead to severe birth defects such as congenital microcephaly, and currently, there is no approved vaccine for ZIKV. Several studies are investigating the development of ZIKV vaccine using DNA and RNA as well as recombinant protein technologies; however, the outcomes thus far have not been consistently noteworthy. In this study, we designed an mRNA vaccine for ZIKV and evaluated its immunogenicity using a mouse model. Our vaccine, termed 3xEIII, encodes a triple repeat of domain III from the ZIKV E protein. We effectively encapsulated the mRNA within lipid nanoparticles (LNPs), administered 3xEIII to mice via two intramuscular injections, and assessed the induced humoral and cellular immune responses. Specifically, the vaccine elicited neutralizing antibodies that effectively eliminated ZIKV from the organs of challenged mice. Notably, 3xEIII conferred both protective effects and long-term immunity. In subsequent challenges conducted 40 weeks after boosting, immunized mice experienced temporary weight loss but showed significantly reduced viral titers in target organs by the 9th day post-infection. Conclusively from these findings, 3xEIII stands out as a promising noteworthy mRNA vaccine candidate for Zika virus.

Supplementary Tables S1-S3 and Supplementary Figures S1-S6. Table S1 - EC50 values for B-cell malignancies treated with HDAC inhibitors of varying isoform selectivity Table S2 - EC50 values for B-ALL cell line treated with a panel of HDAC inhibitors Table S3 - statistics for cell growth assay in Figure 3 Figure S1 - In vitro survival and PD for B-ALL cells treated with LAQ824 Figure S2 - Western analyses of B-ALL cells treated with MS275 Figure S3 - Western blots, cell growth and cell cycle analysis for B-ALL cells transduced with HDAC1,2, or 3 specific shRNA Figure S4 - Western analyses, cell growth and survival of B-ALL cell treated with Merck60 Figure S5 - Survival and western blots for B-ALL cells treated with HDACi with an apoptosis inhibitor. Figure S6 - Western blots to show DNA damage caused by HDACi or doxorubicin in Merck60 insensitive multiple myeloma cell lines.

Rearrangments in Histone-lysine-N-methyltransferase 2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis with an event-free-survival of 38%. Herein we evaluate 1116 FDA approved compounds in primary KMT2Ar infant ALL specimens and identify a sensitivity to proteasome inhibition. Upon exposure to this class of agents, cells demonstrate a depletion of histone H2B monoubiquitination (H2Bub1) and histone H3 lysine 79 dimethylation (H3K79me2) at KMT2A target genes in addition to a downregulation of the KMT2A gene expression signature, providing evidence that it targets the KMT2A transcriptional complex and alters the epigenome. A cohort of relapsed/refractory KMT2Ar patients treated with this approach on a compassionate basis had an overall response rate of 90%. In conclusion, we report on a high throughput drug screen in primary pediatric leukemia specimens whose results translate into clinically meaningful responses. This innovative treatment approach is now being evaluated in a multi-institutional upfront trial for infants with newly diagnosed ALL.

SARS-CoV-2 is the third pathogenic coronavirus to emerge since 2000. Experience from prior outbreaks of SARS-CoV and MERS-CoV has demonstrated the importance of both humoral and cellular immunity to clinical outcome, precepts that have been recapitulated for SARS-CoV-2. Despite the unprecedented rapid development and deployment of vaccines against SARS-CoV-2, more vaccines are needed to meet global demand and to guard against immune evasion by newly emerging SARS-CoV-2 variants. Here we describe the development of pGO-1002, a novel bi-cistronic synthetic DNA vaccine that encodes consensus sequences of two SARS-CoV-2 antigens, Spike and ORF3a. Mice immunized with pGO-1002 developed humoral and cellular responses to both antigens, including antibodies and capable of neutralizing infection by a clinical SARS-CoV-2 isolate. Rats immunized with pGO-1002 by intradermal (ID) injection followed by application of suction with our GeneDerm device also developed humoral responses that included neutralizing antibodies and RBD-ACE2 blocking antibodies as well as robust cellular responses to both antigens. Significantly, in a Syrian hamster vaccination and challenge model, ID+GeneDerm-assisted vaccination prevented viral replication in the lungs and significantly reduced viral replication in the nares of hamsters challenged with either an ancestral SARS-CoV-2 strain or the B.1.351 (Beta) variant of concern. Furthermore, vaccinated immune sera inhibited virus-mediated cytopathic effects in vitro. These data establish the immunogenicity of the SARS-CoV-2 vaccine candidate pGO-1002 which induces potent humoral and cellular responses to the Spike and ORF3a antigens and may provide greater protection against emerging variants.

Compared with dehydrogenation in conventional petroleum refinery processes, relatively pure hydrogen can be produced by propane dehydrogenation (PDH) without innate contaminants like sulfur and metals. Among the existing catalysts for PDH, Pt catalysts are popular and are often used in conjunction with Sn as a co-catalyst. Coke formation is a major concern in PDH, where catalyst regeneration is typically achieved by periodic coke burning to achieve sustainable operation. In this study, Pt-Sn/Al(2)O(3)catalysts were regenerated after coke burning in three stages: mixing the catalyst with liquid hydrochloric acid, drying, and calcining under air atmosphere. In this process, the optimum concentration of hydrochloric acid was found to be 35%w/w. HCl treatment was effective for enhancing redispersion of the metal catalysts and aiding the formation of the Pt3Sn alloy, which is considered to be effective for PDH reaction. HCl treatment may provide oxychlorination-like conditions under the calcination atmosphere. The characteristics of the catalysts were examined by X-ray diffraction (XRD), transmission electron microscopy (TEM), temperature-programmed reduction (TPR), X-ray photoelectron spectroscopy (XPS), and CO chemisorption.

Infants diagnosed with KMT2A-rearranged (KMT2Ar) acute lymphoblastic leukemia (ALL) have a poor prognosis with an event free survival of 23-44%. To identify new treatment approaches we previously performed in vitro and in vivo assays to evaluate the activity of FDA approved compounds in 15 primary KMT2Ar infant leukemia samples. Three classes of agents were found to be active in these assays: proteasome inhibitors, anthracyclines, and histone deacetylase inhibitors (HDACi). KMT2Ar infant leukemia samples were exquisitely sensitive to the proteasome inhibitor bortezomib, requiring 10-100 fold less drug to achieve 50% toxicity when compared to non-KMT2Ar childhood ALL. Bortezomib is FDA approved for multiple myeloma and laboratory studies using this model system have previously demonstrated responses to be mediated through several mechanisms including NFKB inhibition, stabilization of cell cycle regulatory proteins, and perhaps most importantly the induction of an unfolded protein response (UPR) and endoplasmic reticulum (ER)-stress-induced apoptosis. To evaluate global protein dynamics in KMT2Ar ALL cells treated with bortezomib, we performed tandem mass tag (TMT) quantitative mass spectrometry on synchronized SEM cells exposed to either 50nM of bortezomib or DMSO at 0 hours (hr), 6hr, 12hr, 16hr, and 20hr. Applying pairwise comparison for 9232 unique proteins measured over the time course compared to untreated controls, we identified 1593 proteins with a log2 fold change >1.5 in bortezomib treated cells compared to 101 proteins in the DMSO control (FDR<0.01). Several proteins associated with ER-stress-induced apoptosis including ATF4, DDIT4, ATF3, TSC22D3 (GILZ), and PMAIP1 (NOXA) were upregulated more than 3-fold between 6 and 20hr, suggesting this pathway may play a role in bortezomib induced apoptosis of KMT2Ar cells (p<0.05 and log2 fold change of +/- 0.58). To validate this finding and further understand the role of the UPR and ER-stress-induced apoptosis, we evaluated seven key mediators of this pathway by western blot following bortezomib exposure on synchronized SEM cells over a 12 hour time course including ATF4, ATF6, CHOP, PERK, GADD34, CReP, and eIF2α as well as phosphorylated PERK (p-PERK) and eIF2α (p-eIF2α). This demonstrated a critical time point at 6hr where an increase in ATF4 (3.5 fold), CHOP (1.6 fold), and CReP (2.9 fold) protein levels was accompanied by a decrease in p-PERK (0.7 fold), and p-eIF2α (0.8 fold) whereas GADD34 levels remained constant. Although full-sized ATF6 (ATF6a) protein showed a considerable increase (1.9 fold), the levels of cleaved ATF6 (ATF6f) were only slightly increased (1.2 fold) consistent with ATF4-mediated upregulation of CHOP leading to increased protein synthesis along with ATP depletion, oxidative stress, and cell death. While GADD34 has been shown to be the main phosphatase that functions in a negative feedback loop to resolve cell stress, recent data suggests that stabilization of CReP mRNA by ER stress is able to reverse eIF2α phosphorylation at later stages of UPR leading to re-expression of key UPR proteins. Further, p-eIF2α-attenuated protein synthesis, and not ATF4 mRNA translation has been shown to promote cell survival. Our data support a model whereby the UPR and ER-stress in KMT2Ar ALL cells is induced upon exposure to bortezomib leading to increased levels of ATF4 and CHOP. Attenuation of p-eIF2α by CReP further contributes to cell death through the recovery of protein synthesis in a setting of limited protein folding capacity. These results support the use of proteasome inhibitors in KMT2Ar leukemia which is currently being formally evaluated in a Phase II clinical trial for newly diagnosed patients with infant ALL (NCT02553460). Disclosures Gruber: Bristol-Myers Squibb: Consultancy.

Pt–Sn/Al2O3 catalysts were prepared by the direct reduction method at temperatures from 450 to 900 °C, denoted as an SR series (SR450 to SR900 according to reduction temperature). Direct reduction was performed immediately after catalyst drying without a calcination step. The activity of SR catalysts and a conventionally prepared (Cal600) catalyst were compared to evaluate its effect on direct reduction. Among the SR catalysts, SR550 showed overall higher conversion of propane and propylene selectivity than Cal600. The nano-sized dispersion of metals on SR550 was verified by transmission electron microscopy (TEM) observation. The phases of the bimetallic Pt–Sn alloys were examined by X-ray diffraction, TEM, and energy dispersive X-ray spectroscopy (EDS). Two characteristic peaks of Pt3Sn and PtSn alloys were observed in the XRD patterns, and these phases affected the catalytic performance. Moreover, EDS confirmed the formation of Pt3Sn and PtSn alloys on the catalyst surface. In terms of catalytic activity, the Pt3Sn alloy showed better performance than the PtSn alloy. Relationships between the intermetallic interactions and catalytic activity were investigated using X-ray photoelectron spectroscopy. Furthermore, qualitative analysis of coke formation was conducted after propane dehydrogenation using differential thermal analysis.

Mobile Ad-hoc network is widely used as emerging technology in many applications. It is also

We investigated the effects of different Cu weight ratio on θ or γ-Al2O3 which were impregnated with platinum in terms of catalytic activity for propane dehydrogenation and physicochemical properties. 1.5 wt% Pt, 0-10 wt% Cu catalyst supported on θ-Al2O3 or γ-Al2O3 was prepared by incipient wetness co-impregnation. Enhanced Pt dispersion by increasing Cu contents in γ-Al2O3 supported catalyst was confirmed via XRD and XPS. Pt and CuO was separated in Pt-Cu/θ-Al2O3, but Pt-Cu alloy was identified after reduction treatment. Also, adding Cu in Pt/Al2O3 makes catalyst’s acidity lower and this property led to increased propylene yield in propane dehydrogenation. However, Pt3Cu was not good for yield of PDH, which was confirmed in Pt-10Cu/θ-Al2O3 through XRD.

The routing misbehavior is one of the most serious threats to wireless ad hoc networks where nodes are not forwarding messages correctly. Once the attack has been launched, nodes in the network are not able to send messages anymore. Thus it could be a kind of DoS (denial of service) attack. So far, in order to detect the attack, most researches employ a watchdog method although it is not efficient and has a high false positive ratio. In this paper, we propose a novel approach to detect the attacks based on routing misbehavior. It can detect attacks in a more effective way as well as solve problems in existing watchdog. In the proposed method a node in the network cooperates with its neighbor nodes to collect statistics on packets. According to the statistical information, the method determines each nodes misbehavior. The simulation results shows that the proposed method is practical and effective to apply to real domain.

1 Division of Hematology/Oncology, Boston Children’s Hospital, Department of Pediatric Oncology, Dana-Farber-Cancer Institute, and Harvard Medical School, Boston, MA, USA 2 Department of Medical Oncology, Dana-Farber-Cancer Institute and Harvard Medical School, Boston, MA, USA 3 Harvard Stem Cell Institute, Boston, MA, USA 4 Current affiliation – Incyte Corporation, Wilmington, DE 5 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY Corresponding Author: Matthew C. Stubbs Phone: 302-498-5716 Fax : 302-425-2759 Email: mstubbs@incyte.com Address: Incyte Corporation 1801 Augustine Cut-off Wilmington, DE 19803

Abstract Purpose: Histone deacetylase inhibitors (HDACi) have recently emerged as efficacious therapies that target epigenetic mechanisms in hematologic malignancies. One such hematologic malignancy, B-cell acute lymphoblastic leukemia (B-ALL), may be highly dependent on epigenetic regulation for leukemia development and maintenance, and thus sensitive to small-molecule inhibitors that target epigenetic mechanisms. Experimental Design: A panel of B-ALL cell lines was tested for sensitivity to HDACi with varying isoform sensitivity. Isoform-specific shRNAs were used as further validation of HDACs as relevant therapeutic targets in B-ALL. Mouse xenografts of B-cell malignancy–derived cell lines and a pediatric B-ALL were used to demonstrate pharmacologic efficacy. Results: Nonselective HDAC inhibitors were cytotoxic to a panel of B-ALL cell lines as well as to xenografted human leukemia patient samples. Assessment of isoform-specific HDACi indicated that targeting HDAC1-3 with class I HDAC-specific inhibitors was sufficient to inhibit growth of B-ALL cell lines. Furthermore, shRNA-mediated knockdown of HDAC1 or HDAC2 resulted in growth inhibition in these cells. We then assessed a compound that specifically inhibits only HDAC1 and HDAC2. This compound suppressed growth and induced apoptosis in B-ALL cell lines in vitro and in vivo, whereas it was far less effective against other B-cell–derived malignancies. Conclusions: Here, we show that HDAC inhibitors are a potential therapeutic option for B-ALL, and that a more specific inhibitor of HDAC1 and HDAC2 could be therapeutically useful for patients with B-ALL. Clin Cancer Res; 21(10); 2348–58. ©2015 AACR.

Propane dehydrogenation and regeneration of Pt–Sn/θ-Al2O3 catalysts was evaluated with oxychlorination treatment. It was observed that the catalytic activity was not fully recovered after coke burning followed by hydrogen reduction process because of the unsatisfying recovery of Pt sintering. In this study, oxychlorination treatment was additionally employed between coke burning and hydrogen reduction. Oxychlorination used diluted HCl at the range of 625–7000 ppm. The best recovery of catalytic activity was achieved at the HCl concentration of 5000 ppm. The effective redispersion of Pt was also examined by CO chemisorption, XRD, XPS, CHSN analysis, and STEM.

In this paper, we propose an e-Learning system that can accomplish the following two goals; personalization and interactivity. First of all, the system support personalized learning envir onment and allows learners to participate in their learning. This system can register and inquire for courses using personalized functio n and provide statistics on progress rate, by contents and learning type. Useful statistics and link registration can be retrieved in real time. Sec ond, the system implements real-time interactive video contents that are usable both teachers-learners and learners-learne rs in video lectures. These new bidirectional learning components are suitable for maximizing the learning effects. These interactive video conte nts are compatible with standard web-based learning system and maintain the information consistency. We accomplished this by expanding the standard for the sharable content object reference model (SCORM) currently used in building the learning management system (LMS) and the learning content management system (LCMS). This new components can be easily fit into the existing system. Mor eover in video-lectures, this system can attach various functions in real-time that learners can make a true interactive learning en vironment.

Growth factor independence 1 (Gfi-1) is a part of the transcriptional network that regulates the development of adult hematopoietic stem and progenitor cells. Gfi-1-null (Gfi-1(-/-)) mice have reduced numbers of hematopoietic stem cells (HSCs), impaired radioprotective function of hematopoietic progenitor cells (HPCs), and myeloid and erythroid hyperplasia. We found that the development of HPCs and erythropoiesis, but not HSC function, was rescued by reducing the expression of inhibitor of DNA-binding protein 2 (Id2) in Gfi-1(-/-) mice. Analysis of Gfi-1(-/-);Id2(+/-) mice revealed that short-term HSCs, common myeloid progenitors (CMPs), erythroid burst-forming units, colony-forming units in spleen, and more differentiated red cells were partially restored by reducing Id2 levels in Gfi-1(-/-) mice. Moreover, short-term reconstituting cells, and, to a greater extent, CMP and megakaryocyte-erythroid progenitor development, and red blood cell production (anemia) were rescued in mice transplanted with Gfi-1(-/-);Id2(+/-) bone marrow cells (BMCs) in comparison with Gfi-1(-/-) BMCs. Reduction of Id2 expression in Gfi-1(-/-) mice increased the expression of Gata1, Eklf, and EpoR, which are required for proper erythropoiesis. Reducing the levels of other Id family members (Id1 and Id3) in Gfi-1(-/-) mice did not rescue impaired HPC function or erythropoiesis. These data provide new evidence that Gfi-1 is linked to the erythroid gene regulatory network by repressing Id2 expression.

Case-based reasoning (CBR), a problem-solving method that effectively draws the proper solutions to new issues by appropriately altering the solutions based on similar past problem-solving cases when new issues are presented, is widely used in daily life as it is very similar to humans' problem-solving process. This research was conducted to design a system in which the most proper strategy will be used in the current battle situation based on similar past cases, by applying CBR to the combat strategy system. In such system, when the squad members gather to conduct a military operation on a squad scale, the squad members will act according to the designated plan, to achieve the final goal. This process should consist of military tactics for actions such as attack, ambush, and strategic maneuvers. In other words, new strategies are necessary according to the attendant circumstances, such as the location of the shelters and enemies, and such strategies can be generated based on the learning acquired by the squad or platoon commanders from military manuals, and on their accumulated experiences. In this paper, a combat strategy generation system using CBR is proposed, in which the most appropriate similar cases stored in a case database (DB) was retrieved and applied after proper modification to the current situation. Simulated is followed by implementing the proposed system.

Mixed reality (MR) systems provide an immersive virtual environment where the gap between real and virtual world is minimal. Current MR applications use fixed display to create this environment. However, the environment is never fixed in real world and it is difficult to achieve this non-static environment using traditional MR frameworks. Therefore, in this paper, an efficient multi-display MR system is proposed. The proposed system uses moveable displays to create dynamically changing immersive virtual environment. An agent-mediator based framework is used for communication in which a mediator is connected to several agents. Mediator administers the position of display and synchronizes the view across all agents. Agents gather interaction data from user which is passed to mediator. Moreover, distributed graphic contents rendering technique is used to efficiently render complex graphical contents. In this technique, mediator divides the contents and transmits these to each agent. This division of contents optimises the rendering process on agents, thus increasing the efficiency of the MR system.