bluuebunny/crossref_metadata_2025_split huggingface dataset:
Compartmentalization of enhanced biomolecular interactions for high-throughput drug screening in test tubes
Authors: Zhou Min , Li Weiping , Li Jian , Xie Leiming , Wu Rongbo , Wang Liang , Fu Shuai , Su Wei , Hu Jianyang , Wang Jing , Li Pilong 
Published: January 2020

AbstractModification-dependent and -independent biomolecular interactions (BIs), including protein-protein, protein-DNA/RNA and protein-lipid, play crucial roles in all cellular processes. Dysregulation of BIs or malfunction of the associated enzymes results in various diseases, thus they are attractive targets for therapies. High-throughput screening (HTS) can greatly facilitate the discovery of drugs for these targets. Here we describe a HTS drug discovery method, calledcompartmentalization ofenhancedbiomolecular interactions in test tubes (CEBIT). CEBIT uses selective recruitment of biomolecules into phase separated compartments harboring their cognate binding partners as readouts. CEBIT were tailored to detect various BIs and associated modifying enzymes. Using CEBIT-based HTS assays, we successfully identified known inhibitors of the p53/MDM2 interaction and of SUV39H1 from a compound library. CEBIT is simple and versatile, and is likely to become a powerful tool for drug discovery and basic biomedical research.
Neutralizing PD-L1 and PD-L2 Enhances the Efficacy of Immune Checkpoint Inhibitors in Ovarian Cancer
Authors: Miao Yu Rebecca , Thakkar Kaushik N. , Qian Jin , Kariolis Mihalis S. , Wei Huang , Nandagopal Saravanan , Yang Teddy , Diep Anh N. , Cherf Gerald Maxwell , Xu Yu , Moon Eui Jung , Xiao Yiren , Alemany Haizea , Li Tianer , Yu Wenhua , Wei Bo , Rankin Erinn B. , Giaccia Amato J. 
Published: January 2020

AbstractImmune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have improved for a number of solid tumors. Unfortunately, ovarian cancer represents a major clinical hurdle for immune checkpoint blockade (ICB) with reported low patient response rates. Using IHC staining, we find that PD-L2 is highly expressed in ovarian cancers and other malignancies with sub-optimal response to ICB, and is expressed at low levels in cancers responsive to ICB. Based on this observation, we hypothesized that the elevated expression of PD-L2 produced by both tumor and surrounding stromal cells contributes to immune-suppression. Since PD-L2 has been reported to have a 6- to10-fold higher native binding affinity to PD-1 compared with PD-L1, we hypothesized that high levels of PD-L2 can lead to insufficient blockade of the PD-1 signaling pathway. To overcome the immune repressive activity of PD-L2, we engineered a soluble PD-1 decoy molecule (sPD-1 mutant) that binds and neutralizes both PD-L1 and PD-L2 with a 10,000- and 200- fold improvement in binding affinity, respectively, when compared to wild-type binding to these same molecules. Such enhancement in binding affinity is facilitated by amino acid mutations both within and outside of the binding interface. Furthermore, this high affinity sPD-1 mutant molecule demonstrates superiorin vivoefficacy in multiple cancer models including ovarian cancer where PD-L2 is highly expressed on the cell surface.One Sentence SummaryDual Inhibition of PD-L1 and PD-L2 using an affinity enhanced sPD-1 decoy molecule delivers superior antitumor activity when compared with αPD-1 and αPD-L1 antibodies in ovarian cancer.
Selective germline genome edited pigs and their long immune tolerance in Non Human Primates
Authors: Zou Lijin , Zhang Youlai , He Ying , Yu Hui , Chen Jun , Liu Delong , Lin Sixiong , Gao Manman , Zhong Gang , Lei Weicheng , Zhou Guangqian , Zou Xuenong , Li Kai , Yu Yin , Zha Gaofeng , Li Linxian , Zeng Yuanlin , Wang Jianfei , Wang Gang 
Published: January 2020

AbstractOrgan transplantation is the only curative treatment for patients with terminal organ failure, however, there is a worldwide organ shortage. Genetically modified pig organs and tissues have become an attractive and practical alternative solution for the severe organ shortage, which has been made possible by significant progress in xenotransplantation in recent years. The past several decades witnessed an expanding list of genetically engineered pigs due to technology advancements, however, the necessary combination of genetic modifications in pig for human organ xenotransplantation has not been determined. In the current study, we created a selective germline genome edited pig (SGGEP). The first triple xenoantigens (GGTA, B4GAL, and CAMH) knockout somatic cells were generated to serve as a prototype cells and then human proteins were expressed in the xenoantigen knockout cells, which include human complement system negative regulatory proteins (CD46, CD55, and CD59); human coagulation system negative regulatory proteins thrombomodulin (THBD); tissue factor pathway inhibitor (TFPI); CD39; macrophage negative regulatory proteins (human CD47); and natural killer cell negative regulatory human HLA-E. After the successful establishment of SGGEP by the nuclear tranfer, we engrafted SGGEP skin to NHP, up to 25 days graft survival without immunosuppressive drugs was observed. Because a pig skin graft does not impact the success of a subsequent allograft or autograft or vice versa, thus our SGGEP could have a great potential for clinical value to save severe and large area burn patients and the other human organ failure. Therefore, this combination of specific gene modifications is a major milestone and provides proof of concept to initiate investigator-initiated clinical trials (IITs) in severe burn patients with defined processes and governance measures in place and the other clinical application.
Inhibitory effects of Akt on neuronal FoxO4 activation after subarachnoid hemorrhagein vivoandin vitro
Authors: Qi Min , Gao Sheng-qing , Liu Jia-qiang , Han Yan-ling , Yuan Bin , Zhou Xiao-ming , Liu Xi-lin , Zhou Meng-liang , Zheng Lan-rong 
Published: January 2020

AbstractSecondary brain injury following subarachnoid hemorrhage (SAH) is the critical contributor to the mortality of SAH patients. The underlying mechanisms are poorly understood. In this study, we utilized a mice model of SAH to investigate whether FoxO4 is related to the brain injury after SAH and identified its upstream regulator Akt. Experimental SAH was induced in adult male mice by prechiasmatic cistern injection. Brain FoxO4 protein levels in cytoplasm and nucleaus were examined in the sham-operated controls, and in mice 1h, 6h, 12h, 24h, 3d, and 5d after SAH induction. The Akt inhibitor LY294002 was administered by intracerebroventricular infusion to determine its effects on FoxO4. Moreover, the expression of FoxO4 was also investigated in neurons incubated with hemoglobinin vitro, which was also dertermined after inhibition of Akt. FoxO4 protein expression in the nuclei increased remarkably after SAH. The Akt inhibitor LY294002 induced more FoxO4 nuclear localization after SAHin vivoandin vitro. Our results suggest the activation of FoxO4 after SAH and which was inhibited by the increased phosphorylated Akt (p-Akt).
Bacillus subtilisspore induces efficient generation of memory T cells via ICAM-1 expression on dendritic cells
Authors: Huang Lulu , Lin Jian , Li Yuchen , Zhang Penghao , Yu Qinghua , Yang Qian 
Published: January 2020

AbstractThe intestinal mucosa is the primary exposure and entry site of infectious organisms. Tissue-resident memory T cells (Trms) is an important first line of defense against infection in mucosal tissues, their function in intestinal immunization remains to be investigated. Here, we reported that the levels of local mucosal and systemic immune responses were enhanced through oral immunization with H9N2 whole inactivated virus (H9N2 WIV) plus spore. Subsequently, H9N2 WIV plus spore led to the generation of CD103+CD69+Trms, which was independent of circulating T cells during the immune period. Meanwhile, we also found thatBacillus subtilisspore can stimulate Acrp30 expression in 3T3-L1 adipocytes. Moreover, adipocyte supernatant or spore also upregulated intercellular adhesion molecule-1 (ICAM-1) expression on dendritic cells (DCs) (P<0.01). Furthermore, the proportion of HA-tetramer+cells was severely curtailed when ICAM-1 expression was suppressed, which was also dependent on HA-loaded DCs. Taken together, our data demonstrated that spore promoted the immune response by stimulating Trms, which were associated with activation of ICAM-1 in DCs.Author summaryTaken together, Bacillus subtilis spore combined with H9N2 WIV enhanced the mucosal antibody response and induced efficient intestinal-resident memory T cells. Then we demonstrated that spore can induce memory T cell formation through an ICAM-1-mediated contact of a dendritic cell (DC)-derived mechanism. Further, our findings indicated that Acrp30 from adipocytes induced by spore might increase ICAM-1 expression on DCs, which might provide new insight into the significance of adipocyte metabolism related molecules in regulating immunological memory T cells.
Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits
Authors: Palacios-Filardo Jon , Udakis Matt , Brown Giles A. , Tehan Benjamin G. , Congreve Miles S. , Nathan Pradeep J. , Brown Alastair J.H. , Mellor Jack R. 
Published: January 2020

AbstractAcetylcholine release in the hippocampus plays a central role in the formation of new memory representations by facilitating synaptic plasticity. It is also proposed that memory formation requires acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3, but this influential theory has not been directly tested. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, greater depression of feedforward inhibition from entorhinal cortex results in an overall enhancement of excitatory-inhibitory balance and CA1 activation. Underpinning the prioritisation of entorhinal inputs, entorhinal and CA3 pathways engage distinct feedforward interneuron subpopulations and depression is mediated differentially by presynaptic muscarinic M3and M4receptors respectively. These mechanisms enable acetylcholine to prioritise novel information inputs to CA1 during memory formation and suggest selective muscarinic targets for therapeutic intervention.
Analyzing kinetic signaling data for G-protein-coupled receptors
Authors: Hoare Sam R.J. , Tewson Paul H. , Quinn Anne Marie , Hughes Thomas E. , Bridge Lloyd J. 
Published: January 2020

AbstractIn classical pharmacology, bioassay data are fit to general equations (e.g. the dose response equation) to determine empirical drug parameters (e.g. EC50and Emax), which are then used to calculate chemical parameters such as affinity and efficacy. Here we used a similar approach for kinetic, time course signaling data, to allow empirical and chemical definition of signaling by G-protein-coupled receptors in kinetic terms. Experimental data are analyzed using general time course equations (model-free approach) and mechanistic model equations (mechanistic approach) in the commonly-used curve-fitting program, GraphPad Prism. A literature survey indicated signaling time course data usually conform to one of four curve shapes: the straight line, association exponential curve, rise-and-fall to zero curve, and rise-and-fall to steady-state curve. In the model-free approach, the initial rate of signaling is quantified and this is done by curve-fitting to the whole time course, avoiding the need to select the linear part of the curve. It is shown that the four shapes are consistent with a mechanistic model of signaling, based on enzyme kinetics, with the shape defined by the regulation of signaling mechanisms (e.g. receptor desensitization, signal degradation). Signaling efficacy is the initial rate of signaling by agonist-occupied receptor (kτ), simply the rate of signal generation before it becomes affected by regulation mechanisms, measurable using the model-free analysis. Regulation of signaling parameters such as the receptor desensitization rate can be estimated if the mechanism is known. This study extends the empirical and mechanistic approach used in classical pharmacology to kinetic signaling data, facilitating optimization of new therapeutics in kinetic terms.
Short and long-run impacts of climate change on agriculture: an empirical evidence from China
Authors: Chandio Abbas Ali , Jiang Yuansheng , Rehman Abdul , Rauf Abdul 
Published: January 2020

PurposeThe climate change effects on agricultural output in different regions of the world and have been debated in the literature of emerging economies. Recently, the agriculture sector has influenced globally through climate change and also hurts all sectors of economies. This study aims to examine and explore the impact of global climate change on agricultural output in China over the period of 1982-2014.Design/methodology/approachDifferent unit root tests including augmented Dickey–Fuller, Phillips–Perron and Kwiatkowski, Phillips, Schmidt and Shin are used to check the order of integration among the study variables. The autoregressive distributed lag (ARDL) bounds testing approach to cointegration and the Johansen cointegration test are applied to assess the association among the study variables with the evidence of long-run and short-run analysis.FindingsUnit root test estimations confirm that all variables are stationary at the combination of I(0) and I(1). The results show that CO2emissions have a significant effect on agricultural output in both long-run and short-run analyses, while temperature and rainfall have a negative effect on agricultural output in the long-run. Among other determinants, the land area under cereal crops, fertilizer consumption, and energy consumption have a positive and significant association with agricultural output in both long-run and short-run analysis. The estimated coefficient of the error correction term is also highly significant.Research limitations/implicationsChina’s population is multiplying, and in the coming decades, the country will face food safety and security challenges. Possible initiatives are needed to configure the Chinese Government to cope with the adverse effects of climate change on agriculture and ensure adequate food for the growing population. In concise, the analysis specifies that legislators and policy experts should spot that the climate change would transmute the total output factors, accordingly a county or regional specific and crop-specific total factor of production pattern adaptation is indorsed.Originality/valueThe present empirical study is the first, to the best of the authors’ knowledge, to investigate the impact of global climate change on agricultural output in China by using ARDL bounds testing approach to cointegration and Johansen cointegration test.
Effects of implementation of International Public Sector Accounting Standards on Nigeria’s financial reporting quality
Authors: Muraina Saheed Adekunle , Dandago Kabiru Isa 
Published: January 2020

Purpose
The purpose of this paper is to examine the effects of the implementation of the International Public Sector Accounting Standards (IPSAS) on Nigeria’s financial reporting quality.

Design/methodology/approach
The study employed a survey research design to determine the effects of the implementation of the IPSAS on Nigeria’s financial reporting quality. Partial Least Square 3(SmartPLS 3) technique of analysis was applied to achieve the research objective.

Findings
The study found that accountability positively and significantly affects the quality of financial reporting in Nigeria. Specifically, IPSAS has improved the level of accountability, which in turn improved Nigeria’s financial reporting quality.

Research limitations
The study only explored two explanatory variables whereas other variables such as transparency, corruption minimization, comparability and faithful representation were not considered in this study. It is, therefore, recommended that further studies could expand the scope to cover some other variables not included in this paper.

Practical implications
IPSAS-Accrual has engendered the Nigerian Government to launch the Asset Tracking and Management Project (ATMProject) in order to easily track its assets for the purpose of accountability. Thus, accountability was discovered in this study to be the most essential factor to enhance the quality of financial reporting using accrual-based IPSAS in Nigeria.

Social implications
Accountability will impact positively on the lives of Nigerians in relation to the application of public funds to impact on the lives of the masses.

Originality/value
The statistical significance of accountability found in this study, using partial least square technique of data analysis, will further enhance financial integrity in the country.
Observed effectiveness of the COSO 2013 framework
Authors: Udeh Ifeoma 
Published: January 2020

Purpose
This paper aims to examine the effectiveness of the Committee of Sponsoring Organization’s 2013 Framework, by investigating how the number of auditor-reported material weaknesses compares for Early-, Timely- and Late-adopters of the framework, and how the number of auditor-reported material weaknesses changed for Early- and Timely-adopters following their adoption of the framework.

Design/methodology/approach
The paper uses regression analyses based on a sample of US firms subject to Sarbanes-Oxley Act Section 404(b).

Findings
Timely-adopters of the 2013 Framework continued to exhibit fewer instances of auditor-reported material weaknesses than Late-adopters, even though they had a marginal increase in the number of auditor-reported material weaknesses, in the post-2013 Framework period.

Practical implications
The findings suggest that the effectiveness of the 2013 Framework may lie in the iterative nature of the internal control process, and as firms remedy deficiencies they or their auditors identify, they will continuously improve the effectiveness of their internal control systems.

Originality/value
Unlike existing literature, this paper uses data from the pre-2013 Framework, transition and post-2013 Framework periods to examine changes in the number of auditor-reported material weaknesses, thus differentiating between Early-, Timely- and Late-adopters of the 2013 Framework. It also shows the effect of adopting the 2013 Framework on the number of auditor-reported material weaknesses.
Money-laundering and terrorism-financing compliance – unsolved issues
Authors: Teichmann Fabian Maximilian Johannes 
Published: January 2020

PurposeThis paper aims to focus on developing prevention mechanisms for banks, this paper shows the ongoing feasibility of laundering money and financing terrorism undetected. It, thereby highlights that the current anti-money-laundering and anti-terrorism-financing mechanisms can be easily circumvented.Design/methodology/approachA three-step research process, including both qualitative and quantitative methods, was used. The empirical findings are based on qualitative content analysis of 35 informal interviews with illegal financial services providers and 35 formal interviews with compliance experts and law enforcement officers.FindingsDuring those interviews, concrete and specific methods of financing terrorism and limiting the risks of being prosecuted were discussed. To assess compliance officers’ awareness of those methods, a quantitative survey of 190 compliance officers was subsequently conducted to determine what leads to investigations.Research limitations/implicationsThe findings only convey the perspectives of the 70 interviewees and 190 survey participants.Practical implicationsThe practical implications include suggestions for financial regulators, financial institutions and compliance officers on how to more effectively combat money laundering and terrorism financing.Originality/valueWhile the empirical findings are based in Europe, the results could be applied globally.
Ownership structure and the cost of equity in the European context
Authors: La Rosa Fabio , Bernini Francesca , Verona Roberto 
Published: January 2020

Purpose
Based on the institutionalized agency theory, this paper aims to analyses the role of earnings management (EM) in mediating the relationship between ownership structure (OS) and the cost of equity capital (COE).

Design/methodology/approach
The authors test the above relationship by investigating a sample of 249 European non-financial listed companies during 2005-2012. The authors adopt different measures for both EM and COE and identify three main types of ownership by the majority share of the ultimate owners. Path analysis is used to explore the role of direct, mediated (i.e. EM) and total effects of OS on COE.

Findings
While OS directly affects COE, the results support the idea that an EM-mediating effect contributes to further explain this relationship in some ownership structures. Particularly European listed family-owned firms experience lower COE owing to the prevailing direct and negative effect of OS, despite the fact that both accrual and real EM mediate and have a positive effect on COE. In financial institutions-owned firms, only a direct and positive effect can be observed on COE while state-owned firms do not have a direct influence on the COE, although they do reduce real EM, which, in turn, decreases the COE in a mediated effect. Further analysis comparing the Anglo-Saxon context with Continental Europe shows more detailed results.

Practical implications
The study marks its entry into the international debate on the evolution in the value relevance of accounting information by arguing that the COE implications of EM depend on institutional factors such as OS and the context investigated.

Originality/value
The paper contributes to extant finance, accounting and corporate governance literature by providing new, robust evidence on the mediating role of EM in defining COE for different ownership types and their diverse risk-taking propensities in Continental Europe, which differs from the Anglo-Saxon context both institutionally and legally.
Risk management in facility management for data centres: status and deficits
Authors: Bieser Juergen , Kurzrock Björn-Martin , Batra Ritika 
Published: January 2020

Purpose
Data centres (DC) serve as critical infrastructure and require a sustainable and uninterrupted building operation. Effective risk management (RM), as a component of enterprise RM (ERM), is the basis for secure DC operations. The purpose of this paper is to determine, whether holistic and integrated RM solutions already exist or what they might look like.

Design/methodology/approach
A literature review of laws, norms, standards, methods and certifications combined with transcribed paper and pencil expert interviews with DC, facility service companies and consulting firms has been conducted. The study also investigates RM practices of 23 large international DC and facility service companies.

Findings
Results of literature research and intensive interviews with experienced DC experts, covering the entire life cycle of buildings, indicate that there are no holistic and integrated RM practice applications for DC on a sound academic basis.

Practical implications
Findings suggest that there is a need for developing a holistic and integrated RM framework for DC. This paper is a contribution to the expansion of ERM research and can be very valuable for builders and operators. The results of this research form the basis for the development of a structured RM framework for DC that improves performance.

Originality/value
The study allows professionals to understand the operational state-of-the-art of RM in critical environments and shed light on the wide spectrum of conceptualities and definitions.