Research Agreement Research Articles

Mapping experiences and perspectives of equity in international health collaborations: a scoping review

BackgroundWhilst global health research often involves international collaborations, achieving or promoting equity within collaborations remains a key challenge, despite established conceptual approaches and the development of frameworks and guidelines to promote equity. There have also been several empirical studies documenting researchers’ experiences of inequity and views on what is required to advance equity in global health collaborations. While these empirical studies provide critical insights, there has been no attempt to systematically synthetize what constitutes equity and how it can be achieved. To address this gap, we conducted a scoping review of qualitative studies, opinion and editorial pieces about what equity is and how it can be promoted in international collaborations.MethodsWe conducted a scoping review to explore domains of equity in international health collaborations. This review included qualitative studies and opinion pieces or editorial pieces on equity in international health collaborations. We mapped the data and identified common themes using a thematic analysis approach.ResultsThis initial search retrieved a total of 7611 papers after removing duplicates. A total of 11 papers were included in this review, 10 empirical studies and 1 editorial piece. We conducted our search between October – November 2019. We identified 10 key domains which are important for promoting equity in international collaborations: funding; capacity building; authorship; sample ownership and export; trust; research agreement; acknowledging inequality; recognition and communication.DiscussionOur findings suggest that for international collaborations to be considered more equitable, it must at least consider the 10 domains we highlighted. The 10 domains map onto five key aspects of social justice theory, namely avoiding unequal power relations like subordination, group recognition and affirmation, promoting the well-being of all, inclusion in decision-making and ensuring self-development.

A <i>Trans</i>-Complementation System for SARS-CoV-2

The biosafety level-3 (BSL-3) requirement to culture severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a bottleneck for research and countermeasure development. Here we report a trans-complementation system that produces single-round infectious SARS-CoV-2 that recapitulates authentic viral replication. We demonstrate that the single-round infectious SARS-CoV-2 can be used at BSL-2 laboratories for high-throughput neutralization and antiviral testing. The trans-complementation system consists of two components: a genomic viral RNA containing a deletion of ORF3 and envelope gene, and a producer cell line expressing the two deleted genes. Trans-complementation of the two components generates virions that can infect naive cells for only one round, but does not produce wild-type SARS-CoV-2. Hamsters and K18-hACE2 transgenic mice inoculated with the complementation-derived virions exhibited no detectable disease, even after intracranial inoculation with the highest possible dose. The results suggest that the trans-complementation platform can be safely used at BSL-2 laboratories for research and countermeasure development.Funding: P.-Y.S. was supported by NIH grants AI142759, AI134907, AI145617, and UL1TR001439; awards from the Sealy & Smith Foundation, Kleberg Foundation, John S. Dunn Foundation, Amon G. Carter Foundation, Gilson Longenbaugh Foundation, and Summerfield Robert Foundation; and fund in sponsored research agreement from Q2 Solutions. M.S.D. was supported by R01 AI157155. V.D.M. was supported by NIH grants U19AI100625, R00AG049092, R24AI120942, and a STARs Award from the University of Texas System. S.C.W. was supported by NIH grant R24 AI120942. J.L. is supported by the postdoctoral fellowship from the McLaughlin Fellowship Endowment at UTMB. P.R. and X.X. were partially supported by the Sealy & Smith Foundation.Conflict of Interest: X.Z., X.X., and P.-Y.S. have filed a patent on the trans-complementation system of SARS CoV-2. M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, and Carnival Corporation, and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions.Ethical Approval: Animal studies were carried out in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocols were approved by the Institutional Animal Care and Use Committee at the Washington University School of Medicine (assurance number A3381–01). The research protocol for use of human serum specimens was approved by the University of Texas Medical Branch (UTMB) Institutional Review Board (IRB protocol number 20-0070). All human serum specimens were obtained at the UTMB with patient information de-identified. All aspects of this study were approved by the Institutional Biosafety Committee of the University of Texas Medical Branch at Galveston before the initiation of this study.

SARS-CoV-2 Ferritin Nanoparticle Vaccines Elicit Broad SARS Coronavirus Immunogenicity

The need for SARS-CoV-2 next-generation vaccines has been highlighted by the rise of variants of concern (VoC) and the long-term threat of emerging coronaviruses. Here, we designed and characterized four categories of engineered nanoparticle immunogens that recapitulate the structural and antigenic properties of prefusion SARS-CoV-2 Spike (S), S1 and RBD. These immunogens induced robust S-binding, ACE2-inhibition, and authentic and pseudovirus neutralizing antibodies against SARS-CoV-2. A Spike-ferritin nanoparticle (SpFN) vaccine elicited neutralizing titers (ID50 > 10,000), 20-fold greater than convalescent donor serum titers following a single immunization, while RBD-Ferritin nanoparticle (RFN) immunogens elicited similar responses after two immunizations, that also showed potent neutralization against circulating variants of concern. Passive transfer of IgG purified from SpFN- or RFN-immunized mice protected K18-hACE2 transgenic mice from a lethal SARS-CoV-2 challenge. Furthermore, S-domain nanoparticle immunization elicited ACE2 blocking activity and ID50 neutralizing antibody titers >2,000 against SARS-CoV-1 highlighting the broad response elicited by these immunogens.Funding: We acknowledge support from the U.S. Department of Defense, Defense Health Agency (Restoral FY20). This work was also partially executed through a cooperative agreement between the U.S. Department of Defense and the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (W81XWH-18-2- 0040).Declaration of Interest: M.G.J. and K.M. are named as inventors on International Patent Application No. WO/2021/21405 entitled “Vaccines against SARS-CoV-2 and other coronaviruses.” M.G.J. is named as an inventor on International Patent Application No. WO/2018/081318 and U.S. patent 10,960,070 entitled “Prefusion Coronavirus Spike Proteins and Their Use.” Z.B. is named as an inventor on U.S. patent 10,434,167 entitled “Non-toxic adjuvant formulation comprising a monophosphoryl lipid A (MPLA)-containing liposome composition and a saponin.” Z.B. and G.R.M are named inventors on “Compositions And Methods For Vaccine Delivery”, US Patent Application: 16/607,917. M.S.D. is a consultant for Inbios, Vir Biotechnology, Fortress Biotech and Carnival Corporation and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, Kaleido, and Emergent BioSolutions. S.R., P.M.M., and M.T.E. are employees of AstraZeneca and currently hold AstraZeneca stock or stock options. Zoltan Beck is currently employed at Pfizer.Ethical Approval: All research in this study involving animals was conducted in compliance with the Animal Welfare Act, and other federal statutes and regulations relating to animals and experiments involving animals and adhered to the principles stated in the Guide for the Care and Use of Laboratory Animals, NRC Publication, 1996 edition. The research protocol was approved by the Institutional Animal Care and Use Committee of WRAIR. BALB/c and C57BL/6 mice were obtained from Jackson Laboratories (Bar Harbor, ME).

Levels of SARS-CoV-2 Lineage P.1 Neutralization by Antibodies Elicited after Natural Infection and Vaccination

Background: A new SARS-CoV-2 lineage, named P.1 (20J/501Y.V3), has recently been detected in Brazil. Mutations accrued by the P.1 lineage include amino acid changes in the receptor-binding domain of the spike protein that also are reported in variants of concern in the United Kingdom (B.1.1.7) and South Africa (B.1.325).Methods: We isolated two P.1-containing specimens from nasopharyngeal and bronchoalveolar lavage samples of patients of Manaus, Brazil. We measured neutralization of the P.1 virus after incubation with the plasma of 19 COVID-19 convalescent blood donors and recipients of the chemically-inactivated CoronaVac vaccine and compared these results to neutralization of a SARS-CoV-2 B-lineage previously circulating in Brazil.Findings: The immune plasma of COVID-19 convalescent blood donors had 6-fold less neutralizing capacity against the P.1 than against the B-lineage. Moreover, five months after booster immunization with CoronaVac, plasma from vaccinated individuals failed to efficiently neutralize P.1 lineage isolates.Interpretation: These data indicate that the P.1 lineage may escape from neutralizing antibodies generated in response to polyclonal stimulation against previously circulating variants of SARS-CoV-2.Funding: São Paulo Research Foundation, MCTI/FINEP, Medical Research Council, National Council for Scientific and Technological Development, National Institutes of Health.Conflict of Interest: M.S.D. is a consultant for Inbios, Vir Biotechnology, NGMBiopharmaceuticals, and Carnival Corporation, and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions.Ethical Approval: All procedures followed the ethical standards of the responsible committee on humanexperimentation and approved by the ethics committees from the University of Campinas, Brazil (Approval number CONEP 4.021.484 for plasma collection of blood donors, CAEE32078620.4.0000.5404 and 30227920.9.0000.5404 for the sampling of vaccinated and viral genome sequencing, respectively). All patient data were anonymized before study inclusion.Informed consent was obtained from all subjects for being included in the study.

Standardized Two-Step Testing of Antibody Activity in COVID-19 Convalescent Plasma

The COVID-19 pandemic revealed an urgent need for rapid profiling of neutralizing antibody responses and development of antibody therapeutics. The current Food and Drug Administration-approved serological tests do not measure antibody-mediated viral neutralization, and there is a need for standardized quantitative neutralization assays. We report a high-throughput two-step profiling approach for identifying neutralizing convalescent plasma. Screening and down-selection for serum antibody binding to the receptor-binding domain are followed by quantitative neutralization testing using a chimeric vesicular stomatitis virus expressing spike protein of SARS-CoV-2 in a real-time cell analysis assay. This approach enables a predictive screening process for identifying plasma units that neutralize SARS-CoV-2. To calibrate antibody neutralizing activity in serum from convalescent plasma donors, we introduce a neutralizing antibody standard reagent composed of two human antibodies that neutralize SARS-CoV strains, including SARS-CoV-2 variants of concern. Our results provide a framework for establishing a standardized assessment of antibody-based interventions against COVID-19. Funding Information: This work was supported by the National Institute of Health (NIH) National Center for Advancing Translational Sciences (NCATS) grant 3UL1TR002243-04S4, Vanderbilt Institute for Infection, Immunology, and Inflammation (VI4), the Hays Foundation COVID-19 Research Fund (to I.T.), Defense Advanced Research Projects Agency (DARPA) grant HR0011-18-2-0001, U.S. N.I.H. contract 75N93019C00074, the Dolly Parton COVID-19 Research Fund at Vanderbilt, and a grant from Fast Grants, Mercatus Center, George Mason University. Declaration of Interests: I.T. reports grants from NIH/NIAID, during the conduct of the study, and has served as a consultant for Nashville Biosciences and Horizon Therapeutics. J. D. C., L.J.S., and M.R.D. report grants from NIH/NCATS, during the conduct of the study. T.W.R. reports grants from NIH/NCATS, during the conduct of the study; personal fees from Cumberland Pharmaceuticals, Inc, personal fees from Sanofi Pharma, and personal fees from Cytovale, outside the submitted work. T.G.S. reports grants from NIH, during the conduct of the study. W.H.S. reports grants from NCATS of the NIH, during the conduct of the study. M.S.D. is a consultant for Inbios, Vir Biotechnology, Fortress Biotech, and Carnival Corporation and on the Scientific Advisory Boards of Moderna an Immunome. The Diamond laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology and Emergent BioSolutions. J.E.C. has served as a consultant for Luna Biologics, is a member of the Scientific Advisory Board of Meissa Vaccines and is Founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from Takeda Vaccines, IDBiologics and AstraZeneca and grants from NIH, and DARPA during the conduct of the study. Vanderbilt University has applied for patents related to antibodies described in this paper. All other authors declare no competing interests. Ethics Approval Statement: The studies were approved by the Vanderbilt University Medical Center Institutional Review Board, and samples were collected after written informed consent was obtained by research personnel.

Research Agreements for National R&D Projects and Contracts under Public Law – Focusing on the Practical Problems –

Contracts under public law in Germany are also based on a number of laws in Korea. In this paper, the legal nature of the contract was studied, focusing on the research agreement for the national R&D project, which is the representative of the contract under the public law. The selection of a research and development project in the national R&D project is a profitable administrative act performed by the administrative agency to one of the applicants on the premise of two or more applicants. Research agreements govern detailed contents related to R&D projects. Since national R&D projects are related to public law, research agreements should be viewed as contracts under public law. Under the public law, contracts are divided into a contract to determine the details of an administrative act and a contract that replaces an administrative act . Usually, when a contract is concluded after an administrative act, it corresponds to the former, and a research agreement is an example. Regarding legal relations derived from research agreements, such as termination of the agreement or sanctions under the agreement, the Supreme Court generally regards it as an administrative disposition in accordance with the existing position that has been viewed as an administrative disposition if there is a legal basis. However, if the research agreement is viewed as a contract under public law, it is logical to view the legal relationship derived from it as a contract act. However, considering that sanctions under the Convention can be enforced on their own, beyond the legal basis, it is more appropriate to view this as an administrative disposition.

Подмосковные Фили в 1920-е годы.

The author examines socio-economic and cultural provisions of the Fili, located in the Western suburb of Moscow of during the nep. Topic for the study area in scientific and local history the literature was practically not studied. The source base was documents extracted from archives Moscow and newly introduced in scientific - research agreements, protocol, statements, resolutions and instructions to deputies. Sources allow you to determine features of peasant occupations agriculture, small scale artisanal fisheries, trade. Special attention is paid to on the establishment of industrial production, its industry focus. Documents reflecting the activities at Fili concession of enterprise the firm Junkers, let us find out the forms and methods governance and relationships foreign companies with Soviet power. The article also explains the state of improvement, life and leisure local population. The conclusion of the article emphasizes the temporary the nature of the nep and its collapse by the late 1920s.

­­­The Antigenic Anatomy of SARS-CoV-2 Receptor Binding Domain

Antibodies are crucial to immune protection against SARS-CoV-2 with some in emergency use as therapeutics. Here we identified 377 human monoclonal antibodies (mAbs) recognizing the viral spike, and focused on 80 which bind the receptor binding domain (RBD). By mapping antigenic sites using a unique computational methodology and comparing with inhibitory activity, we show that binding sites are widely dispersed, but neutralizing epitopes highly focused. Nearly all highly potent neutralizing mAbs (IC50< 0.1mg/ml) block receptor interaction, although one binds a unique epitope in the N-terminal domain. Many mAbs use public V-genes and are close to germline, boding well for vaccine responses. 19 Fab-antigen structures, some as RBD complexed with two Fabs, reveal two novel modes of engagement for potently inhibitory mAbs. Several Fabs are glycosylated, enhancing neutralisation for three, for two of which the sugar contacts the antigen. The most potent mAbs protect, prophylactically or therapeutically, in animal models. Ethical Approval: Patients were recruited into the Sepsis Immunomics project [Oxford REC C, reference:19/SC/0296] ISARIC/WHO Clinical Characterisation Protocol for Severe Emerging Infections [Oxford REC C, reference 13/SC/0149]. Animal studies were carried out in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocols were approved by the Institutional Animal Care and Use Committee at the Washington University School of Medicine (assurance number A3381–01). Funding: The Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (ID: 2018-I2M-2-002); Medical Research Council, UK. National Institute for Health Research Biomedical Research Centre Funding Scheme (to G.R.S.), the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (grant number: 2018-I2M-2-002) to D.I.S. and G.R.S., and G.R.S. is supported as a Wellcome Trust Senior Investigator (grant 095541/A/11/Z). H.M.E.D. and J.Ren are supported by the Wellcome Trust (101122/Z/13/Z), Y.Z. by Cancer Research UK (C375/A17721) and D.I.S. by the UK Medical Research Council (MR/N00065X/1). D.I.S. and GRS are Jenner Investigators. N.M.K is supported by T32AI007172. The National Institute for Health Research Biomedical Research Centre Funding Scheme supports G.R.S. We are also grateful for a Fast Grant from Fast Grants, Mercatus Center to support the isolation of human monoclonal antibodies to SARS-2 and Schmidt Futures for support of this work. G.R.S. is also supported as a Wellcome Trust Senior Investigator (grant 095541/A/11/Z). This is a contribution from the UK Instruct-ERIC Centre. The Wellcome Centre for Human Genetics is supported by the Wellcome Trust (grant 090532/Z/09/Z). We acknowledge Diamond Light Source for time on Beamline I03 under Proposal lb27009 and for electron microscope time at the UK national electron bio-imaging centre (eBIC), Proposal BI26983. Computational aspects were supported by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z and the NIHR Oxford BRC. This study was supported by grants from NIH (R01 AI157155) and the Defense Advanced Research Project Agency (HR001117S0019). J.B.C. is supported by a Helen Hay Whitney Foundation postdoctoral fellowship. Competing Interest: M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, Carnival Corporation and on the Scientific Advisory Boards of Moderna and Immunome. The M.S.D. laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. GRS sits on the GSK Vaccines Scientific Advisory Board.

A Single Intranasal or Intramuscular Immunization with Chimpanzee Adenovirus Vectored SARS-CoV-2 Vaccine Protects Against Pneumonia in Hamsters

The development of an effective vaccine against SARS-CoV-2, the etiologic agent of COVID-19, is a global priority. Here, we compared the protective capacity of intranasal and intramuscular delivery of a chimpanzee adenovirus-vectored vaccine encoding a pre-fusion stabilized spike protein (ChAd-SARS-CoV-2-S) in Golden Syrian hamsters. While immunization with ChAd-SARS-CoV-2-S induced robust spike protein specific antibodies capable or neutralizing the virus, antibody levels in serum were higher in hamsters immunized by an intranasal compared to intramuscular route. Accordingly, ChAd-SARS-CoV-2-S immunized hamsters were protected against a challenge with a high dose of SARS-CoV-2. After challenge, ChAd-SARS-CoV-2-S-immunized hamsters had less weight loss and showed reductions in viral RNA and infectious virus titer in both nasal swabs and lungs, and reduced pathology and inflammatory gene expression in the lungs, compared to ChAd-Control immunized hamsters. Intranasal immunization with ChAd-SARS-CoV-2-S provided superior protection against SARS-CoV-2 infection and inflammation in the upper respiratory tract. These findings support intranasal administration of the ChAd-SARS-CoV-2-S candidate vaccine to prevent SARS-CoV-2 infection, disease, and possibly transmission.Funding: This study was funded by NIH contracts and grants (R01 AI157155, 75N93019C00062, U01 AI151810, HHSN272201400018C, and HHSN272201700060C). J.B.C. is supported by a Helen Hay Whitney Foundation postdoctoral fellowship.Conflict of Interest: M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, andCarnival Corporation and on the Scientific Advisory Board of Moderna and Immunome. TheDiamond laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. The Boon laboratory has received unrelated funding support in sponsored research agreements from AI Therapeutics, 548 GreenLight Biosciences Inc., AbbVie Inc., and Nano targeting & Therapy Biopharma Inc. M.S.D. and A.O.H.have filed a disclosure with Washington University for possible commercial development of ChAd SARS-CoV-2.

The convergence of minerals and life: Reply to comments on "Mineral self-organization on a lifeless planet".

We want to thank again our commentators for their stimulating ideas and insightful comments that we are sure helped to clarify and develop our ideas. Authors acknowledge funding from the European Research Council (ERC) under the European Union's Seven Framework Program grant agreement n∘ 340863 (JMG-R) and under the Horizon 2020 research and innovation program grant agreement n∘ 646894 (MvZ). JMG-R also acknowledges the Ministerio de Economia y Competitividad of Spain for funding the project CGL2016-78971-P . This is IPGP contribution n∘ 4161 .

Meeting Indigenous youth where they are at: knowing and doing with 2SLGBTTQQIA and gender non-conforming Indigenous youth: a qualitative case study

BackgroundResearch carried out in partnership with Indigenous youth at The Native Youth Sexual Health Network (NYSHN) demonstrates that Indigenous youth can (and do) develop and implement public health interventions amongst their peers and within their communities, when supported by non-youth allies and mentors.MethodsTogether, NYSHN and Well Living House researchers co-designed a qualitative case study to demonstrate and document how Indigenous youth can and do practice their own form of public health implementation research (PHIR) in the realm of mental health promotion for 2SLGBTTQQIA and Gender Non-Conforming Indigenous youth. Academic and Indigenous youth researchers were: participant observers; conducted a focus group; and designed and implemented an online survey with Indigenous youth project participants. Governance, intellectual property, financial terms and respective academic and NYSHN roles and responsibilities were negotiated using a customized community research agreement. The data were thematically analyzed using a critical decolonizing lens that recognizes the historic and ongoing marginalization of Indigenous peoples while also highlighting the unique and diverse strengths of Indigenous communities’ knowledge and practice in maintaining their health and wellbeing.ResultsAnalysis revealed how colonialism and intergenerational trauma have impacted Indigenous youth identity and the value of self-determination as it relates to their identity, their relationships, health and wellbeing. We also learned how knowing and doing about and for Indigenous youth needs to be youth determined – ‘nothing about us, without us’ -- yet also supported by allies. Finally, our analysis shares some promising practices in knowing and doing for and with Indigenous youth.ConclusionsThis study provides a reminder of the need to centre Indigenous youth throughout PHIR in order to realize sustainable benefit from research, services and programming. It emphasizes the need to recognize Indigenous youth as leaders and partners in these initiatives, support their efforts to self-determine, compensate them as partners, and prioritize Indigenous youth-determined frameworks and accountability mechanisms.

Interfacial Potentials in a Thin Film All-Solid-State Li-Ion Battery Probed By in Operando KPFM

Designing smaller, safer, cheaper, and more stable batteries necessitates thorough understanding of the electrochemical processes governing their operation at multiple length scales. In all-solid-state power sources the electrolyte is no-flammable and can be made ultimately thin, making them safer and more compact. Yet, experimental evidence suggests that the multiple internal interfaces in their layered structure give rise to high impedances, limiting their performance. Studying these nanoscopic interfaces requires microscopic tools. Here, we employ in operando Kelvin Probe Force Microscopy (KPFM) to quantitatively measure the potential distribution in a solid-state Li-ion battery as a function of its state of charge. The battery was fabricated by sequentially depositing thin layers of Pt (110-130 nm), LiCoO2 (280-420 nm), LIPON (1100-1200 nm), Si (50-240 nm) Cu or Pt (150-200 nm) onto a Si/SiO2 wafer (oxide thickness 100 nm). The fabricated battery was cleaved in an Ar atmosphere to expose the stacked layers, mounted on a holder, wired, and safely transferred without exposing to air into a dual-beam instrument that combines a scanning electron microscope (SEM), a Ga-ion focused ion beam (FIB) and an atomic force microscope (AFM) in one vacuum chamber (residual pressure of 10-4 Pa). The stacked battery was milled to expose a cross-section of the layers, and imaged using SEM and KPFM, while cycling the battery. The acquired potential maps reveal a highly non-uniform interelectrode potential distribution, with most of the potential drop occurring at the electrolyte-Si anode interface in the pristine battery. During the first charge, the potential distribution gradually changes, revealing complex polarization within the LIPON layer due to Li-ion redistribution. Cycling the battery at high rate significantly decreased its capacity, although the capacity loss can be recovered. KPFM imaging allowed the detection of the interface responsible for this capacity loss. Li distribution in the battery was also measured using Neutron Depth Profiling as a function of the state of charge. The acquired data was compared to first principles calculations shedding light onto the interfacial Li-ion transport in the battery and its reversibility.ES acknowledges support under the Cooperative Research Agreement between the University of Maryland and the National Institute of Standards and Technology Center for Nanoscale Science and Technology, Award 70NANB14H209, through the University of Maryland.

Variation in Results of Three Biology‐Focused Search Engines: A Case Study Using North American Tree Species

Variation in Results of Three Biology‐Focused Search Engines: A Case Study Using North American Tree Species

Targeting 1q21 Amplification with APG2575 and Lenalidomide to Sensitize BCL-2 Inhibition with the Decrease of MCL-1 Protein in High Risk MM Models

Background Multiple myeloma (MM) is a heterogenous plasma cell malignancy. About 30-40% of newly diagnosed and 20-60% of relapsed/refractory MM patients carry 1q21 amplification worldwide, a high-risk indicator for poor prognosis in RRMM. Different BCL-2 family anti-death proteins play important roles in MM survival and drug resistance. High expression of BCL-2 due to t (11;14) renders cell vulnerability to BCL-2 antagonist, however, patients carrying other genetic abnormality including 1q21 amplification have limited response to the newly emerged treatment choice. With MCL-1 upregulation accompanied with 1q21 amplification, we tested whether BCL-2 antagonist combined with IMiDs (immunomodulatory imide drugs), improves cell killing in high-risk MM patient models, including those resistant to bortezomib and lenalidomide. For that aim, we studied APG-2575, a novel and potent BCL-2 inhibitor developed by Ascentage Pharma Group and it is currently in clinical trials for hematologic malignances, including MM. Methods 1. Cells were treated with APG-2575 single agent or in combination with lenalidomide; 2. Cell line viability was assessed by CellTiter-Glo (CTG) assay; 3. Flow cytometry analysis was used to detect CD138+ cell surface marker in primary cells derived from MM patients; 4. Western blot analysis for BCL-2 family and IMiD signaling proteins. Results We first determined the cell sensitivity of APG-2575 as a single agent in a panel of MM cell lines, and as expected, those carrying t (11;14) were very sensitive to APG-2575, with low IC50 values ranging 7-23 nM. The IC50 values for cells carrying other genetic markers were greater than 5-10 μM. We then evaluated cell-death inducing activity of APG-2575 in MM patient-derived primary cells ex vivo, which were freshly prepared from patients' bone marrow aspirates. Primary cells were treated with APG-2575 or ABT-199 (venetoclax) for 18-24 hours, and the loss of CD138 surface marker was used to quantify cell death. As shown in Figure 1a, APG-2575 induced cell death (CD138+ loss) in a dose-dependent manner, and significant cell death was observed at 0.37-3.3 μM of APG-2575, indicating primary cells more sensitive than MM cell lines. Interestingly, the sensitivity to APG-2575 is similar in primary MM cells with or without 1q21 amplification. Since moderate cell death inducing activity was observed in MM cells when APG-2575 used as a single agent, we combined APG-2575 with lenalidomide. Cell death was increased in the combination groups compared with single agent, and it was dose-dependent (Figure 1b).Similar enhanced antiproliferative activity was confirmed in RPMI 8226 cell line, which carries 1q21 amplification (Figure 1c). We furthered to understand the mechanism of action (MoA) of this combination. In Figure 1d, Western blot analysis of RPMI 8226 cell line revealed that IKZF1 and IKZF3 proteins from the NF-KB pathway were downregulated by lenalidomide. And the decrease of MCL-1 protein and the strong induction of pro-death protein BAK were evident in the combination group of APG-2575 and lenalidomide, which helps to illustrate MoA underlying the synergistic effect of APG-2575 and lenalidomide in MM models. Conclusions In both cell lines and primary samples derived from MM patients, APG-2575 demonstrates cell death inducing activity as a single agent, and enhanced/synergistic effects when it combines with lenalidomide in RRMM resistant to lenalidomide and bortezomib. The combination decreases IKZF1, IKZF3 and MCL-1 proteins, and upregulates pro-death protein BAK, thus providing a strong rationale to combine BCL-2 inhibitor and lenalidomide to treat high-risk patient populations carrying 1q21 amplification. Disclosures FU: Ascentage Pharma (SuZhou) Co., Ltd: Other: research agreement contract . Yin:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment. Mao:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment. Deng:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment. Fang:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment. Yang:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests. Zhai:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests.

Immediate &lt;i&gt;Versus&lt;/i&gt; Delayed Stenting in Patients with Acute ST-Elevation Myocardial Infarction: A Randomized Open-Label Bayesian Trial

Background: Stents immediately implanted in thrombus-laden arteries cause embolization, which paradoxically impairs myocardial reperfusion and function. Methods: We conducted a Bayesian open-label randomized trial across 15 centres in France and Canada. Patients with acute ST-elevation myocardial infarction (STEMI) and reperfused by thrombectomy or small-size balloon angioplasty were randomly assigned to immediate stenting or to a bridging anti-thrombin therapy and delayed stenting between 18h to 48h after reperfusion. Using a hierarchical Bayesian analysis, we borrowed data from exchangeable twin trials to form a posterior probability of the risk ratio (RR) for the combined occurrence of cardiovascular death, heart failure, non-fatal myocardial infarction (MI), or target-vessel revascularisation (TVR) over 9 months in the intent-to-treat populations. Findings: Between April 2014 and September 2017, 305 participants were randomly assigned to delayed (n = 152) or immediate stenting (n = 153). In parallel, four similar RCTs were reported that satisfied exchangeability requirements, leading to 1,873 participants, including 930 assigned to delayed and 943 assigned to immediate stenting. The primary endpoint occurred in 167 participants (18.1%) assigned to delayed stenting compared to 194 participants (20.6%) assigned to immediate stenting (RR, 0.91; 95% credible interval [95%CrI], 0.76 to 1.09; probability of superiority, 89%). Delayed stenting led to a meaningful increase in unplanned target revascularization acutely (RR, 1.54; 95% CrI, 0.98 to 2.41, probability of inferiority, 99%). At long term, delayed stenting reduced the combined occurrence of CV death or heart failure (RR, 0.83; 95% CrI, 0.67 to 1.02, probability of superiority, 99%). Interpretation: In patients with STEMI, delayed stenting did not reduce the occurrence of cardiovascular death, non-fatal MI, heart failure and unplanned TVR compared to the immediate stenting. There is a high probability that delayed stenting substantially reduces cardiovascular death and heart failure in the longer-term. Trial Registration: ClinicalTrials.gov identifier: NCT01542385. Funding Statement: The trial was supported by an operating grant from the peer-reviewed, publically funded Canadian Institute of Health Research (CIHR), through the Industry-Partnered Collaborative Research program (grant #298937), in collaboration with Boston Scientific and AstraZeneca (unrestricted grants support). The industry partners played no role in the conduct and oversight of the study. Declaration of Interests: The investigators disclose the following relationships: E. Marc Jolicoeur: Advisory Board: Institut National d’Excellence en Sante et Services Sociaux du Quebec, Servier, Imbria Pharmaceutical, Carre technology; Board of Directors, Societe de Sciences Vasculaires du Quebec; Data Safety Monitoring Board: XyloCor; Research grants; Boston Scientific, AstraZeneca; The University of Glasgow (employer, C Berry) holds research and/or consultancy agreements with AstraZeneca, Abbott Vascular, Boehringer Ingelheim, GSK, HeartFlow, Novartis and Siemens Healthcare; Francois Roubille: Advisory Board: Abbott, Air liquide, Research grants; Boston Scientific, AstraZeneca. Consultancy agreements with AstraZeneca, Abbott Vascular, Air liquide, Amgen, Boehringer Ingelheim, GSK, MSD, Novartis, Sanofi, Novartis, Novonordisk, Vifor; Geraud Souteyrand: Consultancy agreements; Medtronic, Abbott, and Terumo; Guillaume Cayla: Consultancy agreements; Astra Zeneca, Amgen, Abbot Vascular, BMS, Boston, Biotronik, Medtronic, Pfizer, and Sanofi; Nicolas Delarche: Advisory board: Novartis; Samer Mansour: Consultant/Advisory board/Speaker’s Bureau: Abbott vascular, Soundbite, Boehringer Ingelheim, AstraZeneca, Bayer, BMS-Pfizer Alliance, Medtronic, Amgen, Sanofi, Servier, Gilead and Novartis; Erick Schampaert: Consultant/Advisory board/Speaker’s Bureau: Abbott, AstraZeneca, Bayer, BMS-Pfizer Alliance, Medtronic, Philips-Volcano, Servier; Loic Belle: Research Grant: AstraZeneca, Medtronic, Biotronic, Boston Scientific, Abbott Vascular, Terumo Ethics Approval Statement: The protocol complied with the Declaration of Helsinki and was approved by IRB at each participating centers. The trial was coordinated by the Montreal Health Innovation Coordinating Centre under the direction of the executive committee, which was responsible for trial conduct, the integrity of the data analysis, and the reporting of results.

(Invited) Percolation Carbon Nanotube Thin Film Transistors

The decrease of the gate voltage swing switching a field effect transistor from on to off state and, consequently, the decrease of the power supply voltage is the key challenge of the transistor design. Gate voltage dependent tunneling has been used to achieve this goal by decreasing the slope of the exponential current decay in the subthreshold regime below 60 mV per decade. We describe a new Carbon Nanotube (CNT) Percolating Thin Film Transistor (PTFT) that should allow achieving a steep subthreshold slope. CNT TFTs use mats of CNTs deposited on a substrate and forming a random percolating network. The conduction contacts between the individual CNTs is determined by tunneling and, therefore, could be strongly affected by external agents, such as gases or biological fluids. The asymmetry of the contacts to each CNT enables the rectification of electromagnetic radiation impacted on the CNT mat changing the drain-to-source conduction, with giant relative changes near the percolation point. Our experimental data show that sub-THz radiation shifts the percolation point at high intensity, when the rectified radiation changes the shape of the potential barrier between the CNT in a proximity contact. The CNT PTFT operates near the percolation point. In this regime, the gate bias shifts the percolation point by (a) depleting the CNTs in the subthreshold regime and (b) changing the shape of the tunneling barrier. This ensures the metal-insulator transition resulting in a sharp decrease of the subthreshold current slope. We present a compact model of the percolated CNT PTFT based on our Unified SPICE/ADS model that shows that this effect could reduce the subthreshold slope of the CNT TFs from 340 meV per decade to about 190 meV per decade.AcknowledgmentsThis work at RPI was supported by the U.S. Army Research Laboratory under the Cooperative Research Agreement (Project Monitor Dr. Meredith Reed) and by the US ONR (Project Monitor Dr. Paul Maki).

Studying the breaches in a collaborative research project in mathematics education: Making sense of the adaptations

This paper presents a collaborative research project developed by a researcher in mathematics education and a grade 3 Inuit teacher from Northern Quebec. Four learning situations were created, but discrepancies occurred between what was planned and agreed upon by both collaborators, and what was enacted during the project. We studied these discrepancies, which we define as breaches in the research agreement created by both collaborators. We found breaches in three components of the agreement: in the discrepancies between what was planned and what happened during the enactment of the lesson in the resources used, in the pedagogies used, and in the tasks; in the initial roles agreed upon by both collaborators; and in the goals of the collaborators.

Monopoly Spotting: The Management of Openness in University-Industry Research Collaborations

Industry and universities engage in collaborative research often without a clear understanding of how open the research results should be. The contractual terms of the research project document agreed on openness. The terms also decide if access through licensing will be exclusive to a few, or available for the many in open innovation. However, collaborative research agreements are complicated with entangled terms. We applied a novel method for analysing such agreements on 484 publicly sponsored projects in different industries. Placing the projects in the method’s two-by-two matrix, we found that around 20 per cent of the projects, across all industries, have agreements that allow knowledge monopolies to form. We find a positive association between the openness of the research results and the projects that are climate and transport-related. For organisations, research managers and policymakers, the method can be used on a single project or a portfolio of collaborative projects to better align with research policy.

THE NOTION OF INTELLECTUAL PROPERTY RIGHTS OBJECTS, CREATED ON THE BASIS OF RESEARCH AGREEMENTS IN THE HIGHER EDUCATIONAL INSTITUTIONS OF UKRAINE

The article deals with the issue of determining the notion of intellectualproperty rights objects created on the basis of research agreements in higher educational institutions of Ukraine. To achieve the goal of research, the author provides answers, in particular, to the following questions: 1) what the subject-matter of basic and applied research, research and technological development (RTD) is; 2) what the results of these researches are and whatpossible forms of objectification of these results can be; and 3) what type of intellectual property rights objects can be created as a result of these researches.To solve those questions, the author has analyzed, in particular, such notions as: subject of the research agreement (Chapter 62 of the Civil Code of Ukraine); fundamental and applied scientific research; scientific (scientific-technical) work; scientific result; scientific and technical (applied) result; technology and object of technology.Based on this analysis, there have been determined the aims and subject-matters of the above-mentioned researches, their results and implementation of those results. Whereupon, the list of intellectual property rights objects, created on the basis research agreements, has been determined. Based on the obtained results, the author draws a conclusion about the types of intellectual property rights objects, created on the basis of research agreements in higher educational institutions of Ukraine. In particular, this category of objects should include intellectual property rights objects, created as a result of carrying out basic and applied researches, research and technological development (RTD) on the basis of research agreements, one of the parties to which is a higher educational institution of Ukraine. In addition, the list of this category of intellectual property rights objects should include: copyright, scientific discoveries, inventions, utility models, industrial designs, layout designs (topographies) of integrated circuits, plant varieties and animalbreeds, phonograms, videograms, performances and trade secret. However, trademarks, trade names, geographical indications, innovative proposals and broadcasts cannot result directly from basic and applied researches, research and technological development, so they are not included in the list of intellectual property rights objects, created on the basis of research agreements in higher educational institutionsof Ukraine.Also, suggestions to improve the legislation of Ukraine have been made.

Studying the Real-World Issue of Climate Change through the Extended Project Qualification

This article is about the process and outcome of carrying out the author's Extended Project Qualification (EPQ). The title of her EPQ was: 'Is It Politically Possible to Keep Global Temperature Rise "Well below 2 °C"?' – using the wording of the Paris Agreement to focus on the temperature threshold that scientists believe is safe for our planet. Detailing the international, national and local levels of politics combatting climate change, the EPQ led the author to research agreements, such as Paris, and national issues, such as the United Kingdom's electricity generation. She discusses the value of the EPQ. It allowed her to explore a real-world issue, which not only made her more engaged in learning, but gave her a greater understanding of the world we live in.