bluuebunny/crossref_metadata_2025_split huggingface dataset:
Programmable downsizing of CRISPR-Cas9 activity for precise and safe genome editing
Authors: Kawamata Masaki , Suzuki Hiroshi I. , Kimura Ryota , Suzuki Atsushi 
Published: November 2020

AbstractCRSIPR-Cas9 system has opened up the avenue to efficient genome editing1–4. However, together with known off-target effects, several concerns of current CRISPR-Cas9 platform, including severe DNA damage, cytotoxicity, and large genomic alteration, have emerged in recent reports5–7and establish a formidable obstacle to precisely model allele dosage effects of disease mutations and risk variants, especially mono-allelic effects, and correct them. Here, by developing an allele-specific indel monitor system (AIMS), we demonstrate that small and simple modification of conventional single-guide RNAs (sgRNAs) enable programmable tuning of CRISPR-Cas9 activities and alleviate such adverse effects. AIMS, which visualizes various indel events in two alleles separately in living cells, is convenient and accurate to determine thein vitroediting efficiency and revealed frequent mosaicism during genome editing. Using AIMS, we show that adding cytosine stretches to the 5’ end of conventional sgRNA efficiently reduced Cas9 activity in a length dependent manner. By combining systematic experiments and computational modeling, we established the quantitative relationships between the length of cytosine extension and multiple aspects of CRISPR-Cas9 system. In general, short cytosine extension dramatically relieves p53-dependent cytotoxicity and suppression of homology-directed repair (HDR) while relatively maintaining on-target activity. Long cytosine extension further decreases on-target activity, thereby maximizing mono-allelic editing, while conventional system typically induces bi-allelic editing. Furthermore, such downregulation of on-target activity contributes to downregulation of relative off-target activity and protection of HDR-allele from second off-target editing. Therefore, cytosine extension method finally enables both single-step generation of heterozygous single-nucleotide disease mutations from homozygous states in mouse ES cells and correction of heterozygous disease mutations in human iPS cells. Taken together, our study proposes updates of standard CRISPR-Cas9 platform in mammalian cells toward precise and safe genome editing in diverse applications.
Photosynthetic activity triggers pH and NAD redox signatures across different plant cell compartments
Authors: Elsässer Marlene , Feitosa-Araujo Elias , Lichtenauer Sophie , Wagner Stephan , Fuchs Philippe , Giese Jonas , Kotnik Florian , Hippler Michael , Meyer Andreas J. , Maurino Veronica G. , Finkemeier Iris , Schallenberg-Rüdinger Mareike , Schwarzländer Markus 
Published: November 2020

AbstractA characteristic feature of most plants is their ability to perform photosynthesis, which ultimately provides energy and organic substrates to most life. Photosynthesis dominates chloroplast physiology but represents only a fraction of the tightly interconnected metabolic network that spans the entire cell. Here, we explore how photosynthetic activity affects the energy physiological status in cell compartments beyond the chloroplast. We develop precision live monitoring of subcellular energy physiology under illumination to investigate pH, MgATP2−and NADH/NAD+dynamics at dark-light transitions by confocal imaging of genetically encoded fluorescent protein biosensors in Arabidopsis leaf mesophyll. We resolve thein vivosignature of stromal alkalinisation resulting from photosynthetic proton pumping and observe a similar pH signature also in the cytosol and the mitochondria suggesting that photosynthesis triggers an ‘alkalinisation wave’ that affects the pH landscape of large parts of the cell. MgATP2−increases in the stroma at illumination, but no major effects on MgATP2−concentrations in the cytosol were resolved. Photosynthetic activity triggers a signature of substantial NAD reduction in the cytosol that is driven by photosynthesis-derived electron export. Strikingly, cytosolic NAD redox status was deregulated in mutants of chloroplastic NADP- and mitochondrial NAD-dependent malate dehydrogenases even at darkness, pinpointing the participation of the chloroplasts and mitochondria in shaping cytosolic redox metabolismin vivowith a dominant function of malate metabolism. Our data illustrate how profoundly and rapidly changes in photosynthetic activity affect the physiological and metabolic landscape throughout green plant cells.One-sentence summary:Dark-light transitions trigger profound re-orchestration of subcellular pH and NAD redox physiology not only in the chloroplast but also beyond, in the cytosol and the mitochondria, as revealed by precision live-monitoring using fluorescent protein biosensors.
Study on H3K9 acetylation modification and TLR9 immune regulation mechanism in patients with anti-HBV treatment using thymosin a1 combined with entecavir
Authors: Zhu Hai-Peng , Wang Ke , Du Wei , Cao Huan-Huan , Zhong Qing-Yang , Yin Si-Chun , Zhong Jian-Bo , Li Fa-Wu 
Published: November 2020

AbstractFor hepatitis B antiviral treatment, there has been no comprehensive method yet. Interferon has poor antiviral efficacy, while nucleoside drugs have long course of treatment and high relapse rate. To improve the anti-HBV curative effect, treatment methods such as thymosin combined with entecavir have become a focus of clinical investigation. To explore potential mechanism of the combination therapy, based on previous studies, this paper explores the relationship between TLR9 expression in PBMCs, secretion of corresponding downstream inflammatory factors and HBV load in anti-HBV treatment with Thymosin a1 (Ta1) combined with entecavir. Chromatin immunoprecipitation combined with PCR method was adopted to detect H3K9 acetylation modification in patients. The relationship between TLR9 expression was explored using RT-QPCR, the relationship between secretion of inflammatory factors, efficacy and TLR9 mRNA expression was determined using Luminex technology. The results showed that during anti-HBV treatment with Ta1 combined with entecavir, histone acetylation increased in patients’ PBMCs, acetylated protein H3K9Ac had significant binding with promoter region of the TRL9 gene, thereby increasing the expression of TRL9 mRNA, activating the immune pathway under TRL9 regulation, promoting secretion of inflammation factors IL-6, IL-12, IFN-γ, and TNF-α, boosting the progress of antiviral therapy. H3K9 acetylation modification of TLR9 exists and plays an important role in patients with chronic hepatitis B. During the combination therapy with entecavir and Ta1, histone acetylation modification of TLR9 was significantly improved, which increased the expression of TLR9 at the mRNA and protein levels, and further regulated IL-6, IL-12 and other cytokines.
CovidSIMVL – Agent-Based Modeling of Localized Transmission within a Heterogeneous Array of Locations – Motivation, Configuration and Calibration
Authors: Moselle Kenneth A. , Chang Ernie 
Published: November 2020

ABSTRACTCovidSIMVL is an agent-based infectious disease modeling tool that is designed specifically to simulate localized spread of infectious disease. It is intended to support tactical decision-making around localized/staged re-institution of pre-pandemic levels and patterns of social/economic/health service delivery activity, following an initial stage of pan-societal closures of social/economic institutions and broad-based reductions in services.By design, CovidSIMVL supports the generation of dynamic models that reflect heterogeneity within and between a network of interacting localized contexts. This heterogeneity is embodied in a hierarchically organized set of rules. Primary rules reflect the pathophysiology of transmission. Secondary rules (“HazardRadius” and “Mingle Factor” in CovidSIMVL) relate transmission to proximity and movement within physically demarcated and relatively contained spaces (“Universes”). Tertiary rules (“Schedules”) relate probabilities of transmission to movement of people between a network of localized contexts (a CovidSIMVL “Multiverse”).This report focuses mainly on calibration of secondary rules. To calibrate the HazardRadius and MingleFactor parameters, growth curves were generated with CovidSIMVL by setting different configurations of values on those two proximal determinants of viral transmission. These were compared to the characteristic shapes of curves generated by equation-based compartmental models (e.g., SEIR models) that fit different real-world datasets embodying different reproduction numbers (R0).By operating with parameter values in CovidSIMVL that generate “real-world” growth curves, the tool can be used to produce plausible simulations of localized chains of transmission. These include transmission among different groups of persons (e.g., staff, patients) who are co-located within a single setting such as a long-term care facility. The Multiverse version of CovidSIMVL can be used to simulate localized cross-over transmission among arrays consisting of both unaffected and impacted contexts and associated sub-populations, via agents who interact within and across arrays of contexts such as schools, multigenerational families, recreational facilities, places of work, emergency shelters for homeless persons, or other settings in which people are in close physical proximity.
Photoacoustic 3D imaging detects potential microvascular injuries
Authors: Ishida Yoshihiro , Matsumoto Yoshiaki , Asao Yasufumi , Yoshikawa Aya , Kataoka Masako , Yagi Takayuki , Kabashima Kenji , Toi Masakazu 
Published: November 2020

AbstractThe photoacoustic imaging (PAI) system is an emerging imaging modality that can be useful in clinical diagnostic testing. Previous studies have shown utility of PAI in diagnosing breast cancer, visualizing vascular change in ageing, and planning flap reconstruction surgeries. In this study, we show that PAI can be used to non-invasively visualize microvascular injuries in smokers, and in a vasculitis patient.We used two prototype PAI systems, PAI-03, and PAI-04 in this study. These systems were equipped with hemisphere-detector arrays, and used lasers at wavelengths of 795 nm (PAI-03), 756 and 797nm (PAI-04). Healthy volunteers and a patient diagnosed with vasculitis were enrolled upon obtaining written informed consent. The whole hand of the volunteers was scanned.We noted there were unique circular structures that we coined “minute signals”. There were higher number of minute signals in smokers than in non-smokers. Enhanced minute signals were noted in the patient with vasculitis. In this patient, minute signals were suggested to have lower oxygenated hemoglobin content, likely suggesting blood clots or hemorrhage. Our study shows PAI systems can visualize unappreciated abnormalities in fine vasculatures non-invasively. Use of PAI can extend to other clinical entities with suspected vascular involvement.
Predicting progression to septic shock in the emergency department using an externally generalizable machine learning algorithm
Authors: Wardi Gabriel , Carlile Morgan , Holder Andre , Shashikumar Supreeth , Hayden Stephen R , Nemati Shamim 
Published: November 2020

ABSTRACTObjectiveMachine-learning (ML) algorithms allow for improved prediction of sepsis syndromes in the ED using data from electronic medical records. Transfer learning, a new subfield of ML, allows for generalizability of an algorithm across clinical sites. We aimed to validate the Artificial Intelligence Sepsis Expert (AISE) for the prediction of delayed septic shock in a cohort of patients treated in the ED and demonstrate the feasibility of transfer learning to improve external validity at a second site.MethodsObservational cohort study utilizing data from over 180,000 patients from two academic medical centers between 2014 and 2019 using multiple definitions of sepsis. The AISE algorithm was trained using 40 input variables at the development site to predict delayed septic shock (occurring greater than 4 hours after ED triage) at varying prediction windows. We then validated the AISE algorithm at a second site using transfer learning to demonstrate generalizability of the algorithm.ResultsWe identified 9354 patients with severe sepsis of which 723 developed septic shock at least 4 hours after triage. The AISE algorithm demonstrated excellent area under the receiver operating curve (>0.8) at 8 and 12 hours for the prediction of delayed septic shock. Transfer learning significantly improved the test characteristics of the AISE algorithm and yielded comparable performance at the validation site.ConclusionsThe AISE algorithm accurately predicted the development of delayed septic shock. The use of transfer learning allowed for significantly improved external validity and generalizability at a second site. Future prospective studies are indicated to evaluate the clinical utility of this model.
SARS-CoV-2 transmission during team-sport: Do players develop COVID-19 after participating in rugby league matches with SARS-CoV-2 positive players?
Authors: Jones Ben , Phillips Gemma , Kemp Simon PT , Payne Brendan , Hart Brian , Cross Matt , Stokes Keith A 
Published: November 2020

ABSTRACTObjectivesEvaluate the interactions between SARS-CoV-2 positive players and other players during rugby league matches, to determine the risk of in-game SARS-CoV-2 transmission.DesignObservational.SettingSuper League rugby league during four matches in which SARS-CoV-2 positive players were retrospectively found to have participated (2nd August and 4th October 2020).Participants136 male elite rugby league players: eight SARS-CoV-2 positive participants, 28 identified close contacts and 100 other players who participated in any of the four matches.Main Outcome measuresClose contacts were defined by analysis of video footage for player interactions and microtechnology (GPS) data for proximity analysis. Close contacts and other players involved in the matches becoming positive for SARS-CoV-2 by RT-PCR within 14 days of the match were reported.ResultsThe eight SARS-CoV-2 positive players were involved in up to 14 tackles with other individual players. SARS-CoV-2 positive players were within a 2 m proximity of other players for up to 316 secs, from 60 interactions. One identified contact returned a positive SARS-CoV-2 result within 14 days of the match (subsequently linked to an outbreak within their club environment, rather than in-match transmission), whereas the other 27 identified contacts returned negative SARS-CoV-2 follow up tests and no one developed COVID-19 symptoms. Ninety-five players returned negative and five players returned positive SARS-CoV-2 RT-PCR routine tests within 14 days of the match. Sources of transmission in the five cases were linked to internal club COVID-19 outbreaks and wider-community transmission.ConclusionDespite a high number of tackle involvements and close proximity interactions between SARS-CoV-2 positive players and players on the same and opposition teams during a rugby league match, these data suggest that in-game SARS-CoV-2 transmission is limited during these types of team sport activities played outdoors.
The National Defense Education Act, the American Association of University Professors and the dilemma of academic freedom in the mid-twentieth century
Authors: Wang Huimin 
Published: November 2020

PurposeThis study asks how American institutions of higher education defended the principles of academic freedom (or intellectual autonomy) during the 1950s, even as they became increasingly dependent on the federal government's financial support, their eligibility for which required an oath of political loyalty under the terms of the National Defense Education Act of 1958. Universities whose students or professors resisted the oath faced a dilemma of institutional governance as well as intellectual integrity during the early years of the Cold War.Design/methodology/approachThe study draws on documentary and archival sources, including the Congressional Record, the AAUP Bulletin, student pamphlets, newspapers and other publications of the US federal government, and on secondary sources.FindingsThe author finds that the US federal government began to invest heavily in higher education during the 1950s, but financial support was often accompanied by political oversight. Higher education institutions and their professors struggled to reconcile a sense of responsibility for national service with a desire for academic freedom. The findings show how the federal government treated institutions of higher education and dealt with the issue of academic freedom during the Cold War.Originality/valueThis study draws on a large pool of primary sources and previous research to offer new insights into an enduring ideological tension between academic freedom, public service and financial patronage.
Supply chain structures for distributing surplus food
Authors: Sundgren Caroline 
Published: November 2020

PurposeNew actors have emerged in the food supply chain in response to the increased awareness of food waste and the need to distribute surplus food. The purpose of this study is to analyse the different supply chain structures that have emerged to make surplus food available to consumers.Design/methodology/approachThis study adopts a qualitative multiple-case study of three new surplus food actors: a surplus food platform, an online retailer and a surplus food terminal. Data sources included interviews, documentary evidence and participatory observations.FindingsThree different types of actor constellations in surplus food distribution have been identified: a triad, a tetrad and a chain. Both centralised (for ambient products) and decentralised supply chain structures (for chilled products) have emerged. The analysis identified weak links amongst new actors and surplus food suppliers. The new actors have adopted the roles of connector, service provider and logistics service provider and the sub-roles of mediator, auditor and consultant.Originality/valueThis paper contributes to research on closed-loop or circular supply chains for the reuse of products in the context of surplus food distribution.
Breastfeeding challenges among Thai adolescent mothers: hidden breastfeeding discontinuation experiences
Authors: Nuampa Sasitara , Chanprapaph Pharuhas , Tilokskulchai Fongcum , Sudphet Metpapha 
Published: November 2020

PurposeThe purpose of this study was to explore the experiences of adolescent mothers who wean their babies from breastfeeding before the first six months from the perspective of a psychosocial aspect in the Thai context.Design/methodology/approachA descriptive qualitative design was applied to this study to obtain meaningful data. The adolescent mothers for the primary study and nine supplementary participants were recruited from the largest university hospital in Bangkok, Thailand. Semi-structured in-depth interviews were conducted with 20 adolescent mothers. Descriptive statistics and content analysis were used for data analysis.FindingsThe average breastfeeding duration was 3.1 months while breastfeeding exclusively lasted 1.3 months. More than half of the adolescent mothers encountered breastfeeding problems at hospitalization including sore/cracked nipples (63.6%), one side breastfeeding (27.3%) and exhaustion (9.1%). According to the content analysis, (1) breastfeeding obstacles concealed by the adolescents' dependence and (2) repetitive emotional mistakes encountered were the two main themes that emerged.Originality/valueThe influence of key family members plays a vital role in breastfeeding and psychological outcomes. Therefore, family-adolescent support programs including support from the adolescents' mothers and grandmothers may improve breastfeeding outcomes, yield positive emotions and enhance maternal attachment. Moreover, healthcare professions are important mediators to convince adolescent mothers' key family members to reach an agreement and provide suitable support.
Optimizing competitive performance of service firms in data-rich environment
Authors: Rahman Muhammad Sabbir , Hossain Md Afnan , Abdel Fattah Fadi Abdel Muniem , Akter Shahriar 
Published: November 2020

PurposeThe marketing information system (MkIS) in the data-rich business environment receives all the attention these days, but as essential and perhaps even more essential is the marketing information system management capability (MkISMC). Although many service firms apprehend the return from MkIS, others clearly struggle. It seems that MkIS management capability dynamics and their direct/indirect holistic influence on service firm's competitive performance (SFCP) are unsolved in the current data-driven service economy. This study aims to conceptualize a model and test the antecedents on service firms' competitive performance.Design/methodology/approachThis study utilizes a survey of a sizeable sample of service firms’ managers at the firm level. A total of 250 useable responses were obtained and analyzed through structural equation modeling.FindingsResults reveal that variables under their respective direct influences are positively and significantly related. Interestingly, MkISMC has a relatively large magnitude of positive and direct effects on service firms' competitive performance. The other variables, such as the use of marketing analytics (UMAN), service innovation and management (SINM), partially mediate the effect of MkISMC on the competitive performance of service firms.Practical implicationsThe findings inform practitioners that MkISMC, UMAN and SINM play a vital role in attaining service firms' competitive performance in the data-rich environment. Overall, it deepens the understanding of the mediation effect of UMAN and SINM of service firms on competitive performance.Originality/valueThe study advances theoretical understanding of resource-based view (RBV), market orientation and dynamic capability that formulate the relationship of MkISMC, UMAN and SINM in attaining SFCP in the ever-changing data-driven business economy.
Global trends in a fragile context: public–nonpublic collaboration, service delivery and social innovation
Authors: Bozic Aleksandar 
Published: November 2020

PurposeThis study aims to enhance the understanding of the nature of collaboration between public and nonpublic actors in delivering social services and achieving social innovation in a fragile context, with an emphasis on the role of civil society organisations (CSOs). The paper focuses on Bosnia and Herzegovina, a Southeastern European country which has faced a turbulent post-conflict transition and experienced challenges in its social welfare policy and practice.Design/methodology/approachThis study uses institutional theory, particularly new institutionalism and institutional networking, as a lens through which to understand public and nonpublic collaboration and social innovation within a fragile context. This study adopts a sequential mixed-method approach. Data were derived from 15 semi-structured interviews with representatives from local CSOs, international donors and public institutions, as well as a survey of 120 CSO representatives.FindingsThe collaboration and social innovation in a fragile welfare context have been initiated primarily by nonpublic actors and developed within the triple context of relations between public, civil and foreign donors’ organisations. In such a context, coercive, normative and mimetic isomorphisms act as leading drivers, but also as potential barriers of public–nonpublic collaboration and social innovation. They are triggered by influences from multiple actors, challenging power relations and external pressures on local CSOs.Originality/valueThe paper contributes to the growing research interest in the role of nonpublic actors in the provision of public services and public social innovation, but examines these issues from the perspective of a fragile context, which has thus far been overlooked in the literature.