CENDARI Archival Research Guide

This Archival Research Guide (ARG) aims to provide the user with a broad overview of the Archival Directory, a key component of the CENDARI Virtual Research Environment. The CENDARI Archival Directory consists of all available data in the AtoM application (“Access to Memory”) and data in the main repository, which is derived from international or national aggregators as well as national archives or other data providers. All data, whether manually inputted via the AtoM application or collected from institutions, form together the Archival Directory. In this guide the term “Archival Directory” refers only to the application AtoM and it hence will be used in this narrow sense. The term “Archival Directory AtoM” reinforces this definition. Unlike most of the other ARGs in CENDARI, this is not a thematic overview of a historical subject but instead a practical guide to the Archival Directory AtoM’s aims and how it was created and organised. This guide will present the methodology used by researchers associated with the CENDARI project when creating archival description and archival institution entries in CENDARI. It explains how material was selected to be entered into the Archival Directory AtoM, which institutions were considered as ‘hidden archives’ by the CENDARI team, what material was not included, the limitations of the project and the future of the Archival Directory AtoM. The CENDARI Archival Directory AtoM can be accessed both directly from the website and indirectly via the link provided in the Note-Taking Environment (NTE)

Comparative susceptibility of mosquito populations in North Queensland, Australia to oral infection with dengue virus.

Dengue is the most prevalent arthropod-borne virus, with at least 40% of the world's population at risk of infection each year. In Australia, dengue is not endemic, but viremic travelers trigger outbreaks involving hundreds of cases. We compared the susceptibility of Aedes aegypti mosquitoes from two geographically isolated populations to two strains of dengue virus serotype 2. We found, interestingly, that mosquitoes from a city with no history of dengue were more susceptible to virus than mosquitoes from an outbreak-prone region, particularly with respect to one dengue strain. These findings suggest recent evolution of population-based differences in vector competence or different historical origins. Future genomic comparisons of these populations could reveal the genetic basis of vector competence and the relative role of selection and stochastic processes in shaping their differences. Lastly, we show the novel finding of a correlation between midgut dengue titer and titer in tissues colonized after dissemination

Single transit candidates from K2 : detection and period estimation

Photometric surveys such as Kepler have the precision to identify exoplanet and eclipsing binary candidates from only a single transit. K2, with its 75 d campaign duration, is ideally suited to detect significant numbers of single-eclipsing objects. Here we develop a Bayesian transit-fitting tool (‘Namaste: An Mcmc Analysis of Single Transit Exoplanets’) to extract orbital information from single transit events. We achieve favourable results testing this technique on known Kepler planets, and apply the technique to seven candidates identified from a targeted search of K2 campaigns 1, 2 and 3. We find EPIC203311200 to host an excellent exoplanet candidate with a period, assuming zero eccentricity, of 540+410 −230 d and a radius of 0.51 ± 0.05RJup. We also find six further transit candidates for which more follow-up is required to determine a planetary origin. Such a technique could be used in the future with TESS, PLATO and ground-based photometric surveys such as NGTS, potentially allowing the detection of planets in reach of confirmation by Gaia

Constructing AMR: an ethnographic account of AMR research at a British University

This thesis explores relationship between the problem of antimicrobial resistance and scientific academic AMR research at a British research-intensive university I call the University of Cityford. To do this, I conducted 18 months of discontinuous, largely online ethnographic fieldwork with scientists and researchers studying AMR at the University of Cityford during the height of the Covid-19 pandemic in the UK between October 2020 and June 2023.Antimicrobial resistance (AMR) refers to the ability of microbes to resist antimicrobial substances like antibiotics which are used to treat and prevent infection in biomedicine and agriculture by killing microbes. AMR has been identified as a threat to health and food security with serious economic and social consequences. AMR can also be understood as a symptom of existing problems within these spheres including industrial agriculture, extractive economic policies, inadequate health and social infrastructures and waste management among others. Resistance genes are conferred in multiple ways, blurring the boundaries between self and other, body and environment. This makes AMR a complex challenge to locate, overcome and intervene in. Therefore, AMR is often referred to as a ‘wicked problem’ not only due to its scale and complexity but also because its entanglements entail no clearly defined boundaries, single fixes and lack of unified consensus around potential solutions. The identification of AMR as a national and global priority by the UK government resulted in the first 2013 National Action Plan (NAP) and subsequent commitment to “contain and control” AMR by 2040. The University of Cityford like many other research-intensive universities in the UK have responded to the challenge of AMR and increased support for AMR related research by developing ‘AMR strategies’. AMR research encompasses a wide diversity of disciplines and expertise, with cross disciplinary collaboration increasingly encouraged and funded in the UK. As such, AMR researchers are forming, participating in, and seeking new modes of collaboration, investigation, and formulations of research projects to support their work and in doing so, they shape how AMR emerges as an object of research as the problem of antimicrobial resistance necessitates shifts in academic research. At Cityford, researchers are encouraged to contribute to AMR research through increased funding opportunities for early career researchers, participation in key ‘research themes’ within AMR and through interdisciplinary collaborations such as the Cityford AMR Collective. To structure my analysis, I draw on Joan Fujimura’s model for constructing doable problems. How problems are formulated, constructed, and understood shape and limit the possibilities for action, opening up some possibilities or foreclosing others. Fujimura’s model shows that how research becomes ‘doable’ when a problem can be successfully articulated across three levels of work organisation: the experiment, the laboratory, and the social world. Applying Fujimura’s model to my own context, level one: ‘experiment’, refers to the everyday labour of research scientists to produce data for their AMR research projects. Level two: the ‘laboratory’ refers to the research groups, ‘lab groups’ or ‘labs’ which are headed by a Principal Investigator and form the basic unit to which researchers generally belong within the IRC. Here, individual experiments coalesce into collective laboratory projects. Level three in Fujimura’s context is the ‘social world’, the largest and most complex of the three levels. In my thesis the third level and refers to the AMR community at the University of Cityford as well national and international AMR stakeholders, funders, and organisations. Here, the work generated by researchers and their laboratories comes together to create a larger, cohesive and emergent ‘social world’ of ideas, facts, experts, funders, methods, problems, networks, communities, agendas and strategies oriented towards solving the AMR problem. By paying conscious attention to the nature of AMR as a research object, it is possible to situate the construction of AMR research within its particular relational, affective, historical and imaginative context. The thesis makes three contributions, the first concerns AMR as an emergent academic research object, the second elaborates on this to account for how academic research is constructed for such an emergent object, and the third concerns how AMR necessitates relational understandings of human-microbe relationships and health within a global ecology. To the first, AMR is part of a growing number of scientific problems and research objects considered 'wicked problems. These comprise an emergent kind of research object, one that is necessarily complex, entangled, materially situated, implicating, amorphous, relational, and emergent - requiring different modes of engagement and inquiry from researchers in academia. In my ethnography I show that AMR is not a self-evident object but as a way of making sense of relations with the goal of promoting (human) health and wellbeing (microbiome development and infection resilience); as an intensifier or catalyst for other problems (vaccine efficacy, RTIs); a mode of pursuing wider questions of academic interest (evolution, systems modelling). AMR then becomes an articulation in and of itself, a way of making other concerns, questions, and obligations doable: contingent on strategic, practical, or affective motivations of researchers as they build academic research careers within the particular research ecology of the University of Cityford. To the second, AMR is flexible enough as a conceptual framing to encompass a wide variety of projects and questions, making it an appealing choice for a diverse cohort of researchers motivated by different research interests and affects. The experimental level is supported by the availability and accessibility of the tools, techniques and protocols required to generate data about microbial life, at the University of Cityford. At the level of the laboratory, researchers, and research groups from a wide variety of disciplinary backgrounds are encouraged to articulate their work through 'AMR' on the basis of the availability of research funding and connection to a growing community of potential collaborators. Mutual engagement and relationships were vital to the process of conducting research. Relational work was essential to the construction of research from experimental data to growing a research community. This was challenged and underscored by the Covid-19 pandemic and lockdown restrictions. AMR researchers at Cityford, are intentionally building new forms of academic community in order to construct future AMR research. Practices of care, the development of trust, respect and strong interpersonal relationships were understood as vital to achieve this. To the third, AMR is a problem often defined in terms of regaining human control over the non-human world. My research shows that scientists are engaging with an understanding of the human is "relational, uncertain, complex and hybrid" (Haraway, 2003: 14) and increasingly required to pursue lines of investigation which reimagine human-microbe relationships away from antagonistic frames. Working closely with AMR researchers working on the immune system, inflammation and the microbiome revealed that AMR research could lead to new configurations, constructions, and imaginaries of human microbe relationships in the course of conducting experimental work. Health here emerged as ecologically dependent, about maintaining 'balance' between host and microbiome, as well as between host and wider 'ecological' context. Il health therefore meant that this balance had surpassed an essential 'tipping point'. Taken together, during fieldwork I found understandings of infection which moved away from linear transmission and 'breach points' of pathological microbes and towards a wider ecological context which includes commensal microbes, societal relationships, land use, political structures, immune responses, and temporal scales, thus shaping the direction of research and the composition of research communities. However, scientists highlighted the difficulties some scientists have articulating these relationships in journal articles, funding applications and presentation of data, indicating that more work is required to craft new narratives and modes of presenting human-microbe relationships in line with this complexity

TLR3 essentially promotes protective class I–restricted memory CD8+ T-cell responses to Aspergillus fumigatus in hematopoietic transplanted patients

Aspergillus fumigatus is a model fungal pathogen and a common cause of severe infections and diseases. CD8+ T cells are present in the human and murine T-cell repertoire to the fungus. However, CD8+ T-cell function in infection and the molecular mechanisms that control their priming and differentiation into effector and memory cells in vivo remain elusive. In the present study, we report that both CD4+ and CD8+ T cells mediate protective memory responses to the fungus contingent on the nature of the fungal vaccine. Mechanistically, class I MHC-restricted, CD8+ memory T cells were activated through TLR3 sensing of fungal RNA by cross-presenting dendritic cells. Genetic deficiency of TLR3 was associated with susceptibility to aspergillosis and concomitant failure to activate memory-protective CD8+ T cells both in mice and in patients receiving stem-cell transplantations. Therefore, TLR3 essentially promotes antifungal memory CD8+ T-cell responses and its deficiency is a novel susceptibility factor for aspergillosis in high-risk patients.These studies were supported by the Specific Targeted Research Project ALLFUN (FP7-HEALTH-2009 contract number 260338 to L.R.), by SYBARIS (FP7-HEALTH-2009 contract number 242220 to L.R.), and by the Italian Project AIDS 2010 by the Istituto Superiore di Sanita (contract number 40H40 to L.R.). A.C. and C.C. were supported by fellowships from Fundacao para a Ciencia e Tecnologia, Portugal (contracts SFRH/BPD/46292/2008 and SFRH/BD/65962/2009, respectively)

Allogeneic Stem Cell Transplantation for Relapsed/Refractory B Cell Lymphomas: Results of a Multicenter Phase II Prospective Trial including Rituximab in the Reduced-Intensity Conditioning Regimen.

The treatment of patients with refractory/relapsed B cell non-Hodgkin lymphoma (NHL) is evolving because of the availability of novel drugs. Allogeneic stem cell transplantation (alloSCT) can be curative, but its morbidity and mortality remain a matter of concern. We conducted a multicenter prospective phase II trial to evaluate the benefit of including only 1 dose of rituximab in the conditioning regimen before alloSCT. The primary endpoint was progression-free survival. The study enrolled 121 patients with relapsed/refractory B cell lymphomas. The conditioning regimen consisted of thiotepa, cyclophosphamide, fludarabine, and rituximab (500\u2009mg/m2). Rabbit antithymocyte globulin was administered only in case of unrelated donors. Sixty-seven (55%) and 54 (45%) patients received grafts from related and unrelated donors, respectively. The crude cumulative incidence (CCI) of nonrelapse mortality (NRM) was 21% at 3 years. The CCIs of chronic graft-verus-host disease (GVHD) at 3 years were 54% and 31% in recipients of matched sibling and unrelated grafts, respectively. At a median follow-up of 41 months, the estimated 3-year progression-free and overall survival were 50% and 61%, respectively. Long-term outcome was also evaluated with the composite endpoint of GVHD-free and relapse-free survival (GRFS). This is the first work evaluating the GRFS in a prospective trial of lymphoma patients: the 1-year and 3-year GRFS were 40% and 34%, respectively. AlloSCT can cure a fraction of patients with rather low NRM and an encouraging PFS and GRFS

RESCUE OF HIPPO CO-ACTIVATOR YAP1 TRIGGERS DNA DAMAGE-INDUCED APOPTOSIS IN HEMATOLOGICAL CANCERS

Oncogene–induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53–independent, pro-apoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway co–activator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1–induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine–threonine kinase, STK4. Importantly, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a novel synthetic–lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels

Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity.

We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp- and oral glucose tolerance test-based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs per allele [95% CI], -0.03 [-0.04, -0.01]; P = 0.004). This score was associated with lower BMI (-0.01 [-0.01, -0.0]; P = 0.02) and gluteofemoral fat mass (-0.03 [-0.05, -0.02; P = 1.4 × 10(-6)) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and γ-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (Pinteraction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (Pinteraction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.The MRC-Ely Study was funded by the Medical Research Council (MC_U106179471) and Diabetes UK. We are grateful to all the volunteers, and to the staff of St. Mary’s Street Surgery, Ely and the study team. The Fenland Study is funded by the Medical Research Council (MC_U106179471) and Wellcome Trust. We are grateful to all the volunteers for their time and help, and to the General Practitioners and practice staff for assistance with recruitment. We thank the Fenland Study Investigators, Fenland Study Co-ordination team and the Epidemiology Field, Data and Laboratory teams. DBS and RKS are funded by the Wellcome Trust, the U.K. NIHR Cambridge Biomedical Research Centre and the MRC Centre for Obesity and Related Metabolic Disease. Genotyping in ULSAM was performed by the SNP&SEQ Technology Platform in Uppsala (www.genotyping.se), which is supported by Uppsala University, Uppsala University Hospital, Science for Life Laboratory - Uppsala and the Swedish Research Council (Contracts 80576801 and 70374401). The RISC Study was supported by European Union grant QLG1-CT-2001-01252 and AstraZeneca. The RISC Study Project Management Board: B Balkau, F Bonnet, SW Coppack, JM Dekker, E Ferrannini, A Golay, A Mari, A Natali, J Petrie, M Walker. We thank all EPIC participants and staff for their contribution to the study. We thank the lab team at the MRC Epidemiology Unit for sample management and Nicola Kerrison of the MRC Epidemiology Unit for data management. Funding for the EPIC-InterAct project was provided by the EU FP6 programme (grant number LSHM_CT_2006_037197).In addition, EPIC-InterAct investigators acknowledge funding from the following agencies: PWF: Swedish Research Council, Novo Nordisk, Swedish Diabetes Association, Swedish Heart-Lung Foundation; LCG: Swedish Research Council; NS: Health Research Fund (FIS) of the Spanish Ministry of Health; Murcia Regional Government (Nº 6236); LA: We thank the participants of the Spanish EPIC cohort for their contribution to the study as well as to the team of trained nurses who participated in the recruitment; RK: German Cancer Aid, German Ministry of Research (BMBF); TJK: Cancer Research UK; PMN: Swedish Research Council; KO: Danish Cancer Society; SP: Compagnia di San Paolo; JRQ: Asturias Regional Government; OR: The Västerboten County Council; AMWS and DLvdA: Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands; RT: AIRE-ONLUS Ragusa, AVIS-Ragusa, Sicilian Regional Government; IS: Verification of diabetes cases was additionally funded by NL Agency grant IGE05012 and an Incentive Grant from the Board of the UMC Utrecht; IB: Wellcome Trust grant 098051 and United Kingdom NIHR Cambridge Biomedical Research Centre; MIM: InterAct, Wellcome Trust (083270/Z/07/Z), MRC (G0601261); ER: Imperial College Biomedical Research.This is the author accepted manuscript. The final version is available from the American Diabetes Association via http://dx.doi.org/10.2337/db14-031