bluuebunny/crossref_metadata_2025_split huggingface dataset:
Opportunities and challenges of speed breeding: A review
Authors: Wanga Maliata Athon , Shimelis Hussein , Mashilo Jacob , Laing Mark D. 
Published: March 2021

AbstractBreeding new and high performing cultivars with market‐preferred traits take more than 10 years in the absence of an integrated pre‐breeding programme. During the early phases of breeding a significant amount of time, space and resources are invested in the selection and genetic advancement stages after initial crosses are performed with parental genotypes. Speed breeding has the potential to reduce the time required for cultivar development, release and commercialization. The objective of this review was to present the key opportunities and challenges of speed breeding to guide pre‐breeding and breeding programmes. Key challenges of speed breeding include: (a) access to suitable facilities, (c) staff trained in the protocol, (b) adopting major changes to breeding programme design and operations, and (d) the need for long‐term funding. The current review highlights the potential advantages of speed breeding for the successful development and release of pure line cultivars in self‐pollinated crops in ~5 years versus 8 to 10 years when using traditional methods.
Identification of quantitative trait loci (QTL) controlling fibre content of sugarcane (Saccharum hybrids spp.)
Authors: Islam Md S. , Pan Yong‐Bao , Lomax Lionel , Grisham Michael P. 
Published: March 2021

AbstractThe fibre content (FC) of sugarcane millable stalks is important for both sugar and bioenergy production. Higher FC favours the energy producer while lower FC facilitates the efficient sugar extraction. A molecular marker for FC helps select improved sugarcane cultivars with favourable partitioning of FC for both sugar and energy production industries. A quantitative trait loci (QTL) study was conducted using an enriched linkage map of LCP 85‐384 and FC data from two crop cycles (plant cane and first ratoon) of its self‐progeny population. A total of five unique QTL were identified across both crop cycles and combined, of which three QTL (qFC020, qFC044 and qFC053) were common explained a total of 22.46%, 23.93% and 25.14% of the phenotypic variances for plant cane, first ratoon and combined data, respectively. As FC values increased gradually, the QTL allele combination effect also increased. Using markers linked to these putative common QTL alleles would benefit the breeders to select sugarcane lines for sugar and bioenergy production.
Trade policy uncertainty: Evidence from the Arab League countries
Authors: Benaddi Atika , Silva Peri 
Published: March 2021

AbstractWe investigate the effects of trade policy uncertainty on the entry decisions of exporters into Arab League markets. Using a product‐level dataset on World Trade Organization members exporting to Arab League countries for the years 1998–2015, we provide empirical evidence that trade policy uncertainty, a result of significant gaps between tariff bindings and applied tariffs (“tariff water”), led to the reduced entry of exporters into Arab League markets. We then extend our analysis to investigate the effects of policy uncertainty combined with additional uncertainty related to falling incomes associated with the 2007–2010 worldwide economic downturn. Our results suggest that this macroeconomic shock contributed to a considerably more uncertain economic environment, thereby affecting the decision to enter these markets. We also analyze exporters’ decisions to enter new markets, while controlling for the level of market power displayed by the Arab League importing country. We find empirical evidence confirming that the effects of uncertainty on entry magnify in the presence of high levels of market power.
Risk of hepatitis‐E virus infections among blood donors in a regional blood transfusion centre in western India
Authors: Mishra Kanchan K. , Patel Krima , Trivedi Apeksha , Patel Parizad , Ghosh Kanjaksha , Bharadva Sumit 
Published: March 2021

AbstractBackgroundHepatitis‐E virus (HEV) is an emerging infectious threat to blood safety. The enormity of the transmission of HEV and its clinical consequence are issues currently under debate. This study aimed to evaluate the prevalence of HEV‐RNA in blood donors in western India.Materials and MethodsWe screened 13 050 blood donors for HEV using HEV‐RNA screening of 10 mini‐pools using RealStar HEV RT‐PCR Kit (95% limit of detection (LOD): 4.7 IU/ml). Furthermore, all HEV‐RNA‐positive donors were investigated for the presence of IgM/IgG antibody along with liver function tests.ResultsOf the 13 050 blood donations, 7 (0.53%) were found to be HEV‐RNA positive, and the prevalence of HEV nucleic acid testing yield cases among blood donors was 1 in 1864. All seven HEV‐RNA‐positive samples were tested with anti‐HEV IgM and anti‐HEV IgG antibodies; this resulted in two (28.5%) positive anti‐HEV IgM and two (28.5%) positive anti‐HEV IgG antibodies. Hepatic activity was measured, with two of seven HEV‐RNA‐positive donors demonstrating abnormal serum glutamic oxaloacetic transaminase (SGOT) andserum glutamic pyruvic transaminase (SGPT). Two HEV‐RNA‐positive blood donors who had abnormal SGOT and SGPT were found to have a high HEV viral load. Furthermore, we were able to follow up two HEV‐RNA donors, and both were HEV‐RNA positive and had anti‐HEV IgM and anti‐HEV IgG antibodies; moreover, their liver function tests were also abnormal. One of the HEV‐RNA donors with high viral load did show hepatitis‐E‐like virus on electron microscopy.ConclusionOur studies indicate that there is a significant risk of blood‐borne transmission of HEV. This finding may help to provide a direction towards the safety of blood transfusions in clinical settings in countries like India, which fall under the endemic category for HEV infection.
Evidence Theory Representations for Properties Associated With Weak Link/Strong Link Systems, Part 1: Loss of Assured Safety
Authors: Helton Jon C. , Brooks Dusty M. , Darby John L. 
Published: March 2021

AbstractThe use of evidence theory in the analysis of loss of assured safety (LOAS) for weak link (WL)/strong link (SL) systems is introduced and illustrated. Article content includes (i) an introduction to evidence theory, (ii) definition of two WLs and two SLs used for illustration, (iii) belief and plausibility for the occurrence of LOAS for a one WL/two SL system, and (iv) a sampling-based procedure for the verification of belief and plausibility calculations. The presented results can be generalized to systems with more than one WL and two SLs.
Evidence Theory Representations for Properties Associated With Weak Link/Strong Link Systems, Part 3: Margins for Failure Time and Failure Temperature
Authors: Helton Jon C. , Brooks Dusty M. , Darby John L. 
Published: March 2021

Abstract
The use of evidence theory and associated cumulative plausibility functions (CPFs), cumulative belief functions (CBFs), cumulative distribution functions (CDFs), complementary cumulative plausibility functions (CCPFs), complementary cumulative belief functions (CCBFs), and complementary cumulative distribution functions (CCDFs) in the analysis of time and temperature margins associated with loss of assured safety (LOAS) for one weak link (WL)/two strong link (SL) systems is illustrated. Article content includes cumulative and complementary cumulative belief, plausibility, and probability for (i) SL/WL failure time margins defined by (time at which SL failure potentially causes LOAS) − (time at which WL failure potentially prevents LOAS), (ii) SL/WL failure temperature margins defined by (the temperature at which SL failure potentially causes LOAS) − (the temperature at which WL failure potentially prevents LOAS), and (iii) SL/SL failure temperature margins defined by (the temperature at which SL failure potentially causes LOAS) − (the temperature of SL whose failure potentially causes LOAS at the time at which WL failure potentially prevents LOAS).
A Hybrid Contact Model With Experimental Validation
Authors: Liu Qian , Cheng Jing , Li Delun , Wei Qingqing 
Published: March 2021

Abstract
This brief paper emphasizes on the experimental study of a hybrid contact model combining a traditional physical-based contact model and a data-driven error model in order to provide a more accurate description of a contact dynamics phenomenon. The physical-based contact model is employed to describe the known contact physics of a complex contact case, while the data-driven error model, which is an artificial neural network model trained from experimental data using a machine learning technique, is used to represent the inherent unmodeled factors of the contact case. A bouncing ball experiment is designed and performed to validate the model. The hybrid contact model can duplicate experimental results well, which demonstrates the feasibility and accuracy of the presented approach.
Effects of Turning Angle and Turning Internal Radius on Channel Impingement Cooling for a Novel Internal Cooling Structure
Authors: He Wei , Deng Qinghua , Yang Guoying , Feng Zhenping 
Published: March 2021

Abstract
Leading-edge multi-channel double-wall design, a novel internal cooling structure, has been presented recently to enable higher overall cooling effectiveness with less penalty of coolant and pressure loss. Our previous work has proved the advantages of the design under operating condition relative to conventional internal cooling methods, including impingement cooling and swirl cooling. Channel impingement cooling structure, which is utilized at the turning region of the leading edge, is the critical factor to realize the high cooling performance of the design. Hence, the turning angle and turning internal radius of the cooling channel are two key parameters for the novel design, and this paper focuses on the effects of these two parameters on the flow and heat transfer characteristics of the design. Nine simplified single-channel models with different turning angles (45 deg, 60 deg, and 75 deg) and radii (0.6 mm, 0.9 mm, and 1.2 mm) were adopted to conduct the study, and the jet Reynolds number ranges from 10,000 to 40,000. The results show that the turning angle and turning internal radius affect the jet form significantly for the same mechanism. Small turning angle means large impingement, which leads to stream-wise counter-rotational vortices and high turbulence intensity, but increasing turning internal radius transfers the jet form from impingement jet to laminar layer attaching the target surface with low heat transfer. The turning internal radius has stronger effect than turning angle. With higher jet Reynolds number, both the heat transfer and total pressure loss increase dramatically, and the effects of geometrical parameters are clearer.
Reovirus-induced cell-mediated immunity for the treatment of multiple myeloma within the resistant bone marrow niche
Authors: Müller Louise M E , Migneco Gemma , Scott Gina B , Down Jenny , King Sancha , Askar Basem , Jennings Victoria , Oyajobi Babatunde , Scott Karen , West Emma , Ralph Christy , Samson Adel , Ilett Elizabeth J , Muthana Munitta , Coffey Matt , Melcher Alan , Parrish Christopher , Cook Gordon , Lawson Michelle , Errington-Mais Fiona 
Published: March 2021

BackgroundMultiple myeloma (MM) remains an incurable disease and oncolytic viruses offer a well-tolerated addition to the therapeutic arsenal. Oncolytic reovirus has progressed to phase I clinical trials and its direct lytic potential has been extensively studied. However, to date, the role for reovirus-induced immunotherapy against MM, and the impact of the bone marrow (BM) niche, have not been reported.MethodsThis study used human peripheral blood mononuclear cells from healthy donors and in vitro co-culture of MM cells and BM stromal cells to recapitulate the resistant BM niche. Additionally, the 5TGM1-Kalw/RijHSD immunocompetent in vivo model was used to examine reovirus efficacy and characterize reovirus-induced immune responses in the BM and spleen following intravenous administration. Collectively, these in vitro and in vivo models were used to characterize the development of innate and adaptive antimyeloma immunity following reovirus treatment.ResultsUsing the 5TGM1-Kalw/RijHSD immunocompetent in vivo model we have demonstrated that reovirus reduces both MM tumor burden and myeloma-induced bone disease. Furthermore, detailed immune characterization revealed that reovirus: (i) increased natural killer (NK) cell and CD8+T cell numbers; (ii) activated NK cells and CD8+T cells and (iii) upregulated effector-memory CD8+T cells. Moreover, increased effector-memory CD8+T cells correlated with decreased tumor burden. Next, we explored the potential for reovirus-induced immunotherapy using human co-culture models to mimic the myeloma-supportive BM niche. MM cells co-cultured with BM stromal cells displayed resistance to reovirus-induced oncolysis and bystander cytokine-killing but remained susceptible to killing by reovirus-activated NK cells and MM-specific cytotoxic T lymphocytes.ConclusionThese data highlight the importance of reovirus-induced immunotherapy for targeting MM cells within the BM niche and suggest that combination with agents which boost antitumor immune responses should be a priority.
Camrelizumab in combination with apatinib in second-line or above therapy for advanced primary liver cancer: cohort A report in a multicenter phase Ib/II trial
Authors: Mei Kuimin , Qin Shukui , Chen Zhendong , Liu Ying , Wang Linna , Zou Jianjun 
Published: March 2021

BackgroundEmerging clinical data suggest that an immune checkpoint inhibitor in combination with an antiangiogenic agent is a reasonable strategy for multiple malignancies. We assessed the combination of camrelizumab with apatinib in pretreated advanced primary liver cancer (PLC, cohort A) from a multicohort phase Ib/II trial.MethodsPatients with PLC after prior systemic treatment(s) were administered camrelizumab (3 mg/kg, once every 2 weeks) plus apatinib (125, 250, 375, or 500 mg; once per day) in a 3+3 dose-escalation stage and subsequent expansion stage. The primary endpoints were tolerability and safety of study treatment.ResultsFrom April 2017 to July 2019, 28 patients (21 with hepatocellular carcinoma and 7 with intrahepatic cholangiocarcinoma) received camrelizumab plus apatinib. Two dose-limiting toxicities (both grade 3 diarrhea) were reported in the 500 mg cohort. Therefore, the 375 mg cohort was expanded. Of the 19 patients in the 375 mg cohort, dose reduction to 250 mg occurred in 8 patients within 2 months after treatment initiation. Of the 28 patients with PLC, 26 had grade ≥3 treatment-related adverse events, with hypertension being the most common (9/28). One treatment-related death occurred. The objective response rate was 10.7% (95% CI 2.3% to 28.2%). Median progression-free survival and overall survival were 3.7 months (95% CI 2.0 to 5.8) and 13.2 months (95% CI 8.9 to not reached), respectively.ConclusionThe combination of camrelizumab with apatinib had a manageable toxicity and promising antitumor activity in patients with advanced PLC. Apatinib at a dose of 250 mg is recommended as a combination therapy for further studies of advanced PLC treatment.Trial registration numbersNCT03092895.
Evaluation of the prognostic value of GDF-15, ABC-AF-bleeding score and ABC-AF-death score in patients with atrial fibrillation across different geographical areas
Authors: Pol Tymon , Hijazi Ziad , Lindbäck Johan , Alexander John H , Bahit M Cecilia , De Caterina Raffaele , Eikelboom JW , Ezekowitz Michael D , Gersh Bernard J , Granger Christopher B , Hylek Elaine M , Lopes Renato , Siegbahn Agneta , Wallentin Lars 
Published: March 2021

ObjectivesGrowth differentiation factor 15 (GDF-15) is a biomarker independently associated with bleeding and death in anticoagulated patients with atrial fibrillation (AF). GDF-15 is also used as one component in the more precise biomarker-based ABC (age, biomarkers, clinical history)-AF-bleeding and ABC-AF-death risk scores. Data from large trials indicate a geographic variability in regard to overall outcomes, including bleeding and mortality risk. Our aim was to assess the consistency of the association between GDF-15, ABC-AF-bleeding score and ABC-AF-death score, with major bleeding and death, across world geographic regions.MethodsData were available from 14 767 patients with AF from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial and 8651 patients with AF from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial in this cohort study. GDF-15 was analysed from plasma samples obtained at randomisation. The geographical consistency of the associations between outcomes and GDF-15, ABC-AF-bleeding score and ABC-AF-death scores were assessed by Cox-regression models including interactions with predefined geographical region.ResultsGDF-15 and the ABC-AF-bleeding score were associated with major bleeding in both trials across regions (p<0.0001). Similarly, GDF-15 and the ABC-AF-death score were associated with all-cause mortality in both trials across regions (p<0.0001). Overall, the association between GDF-15, the ABC-AF-bleeding score and ABC-AF-death risk score with major bleeding and death was consistent across regions in both ARISTOTLE and the RE-LY trial cohorts. The ABC-AF-bleeding and ABC-AF-death risk scores were consistent regarding discriminative ability when comparing geographic regions in both trial cohorts. The C-indices ranged from 0.649 to 0.760 for the ABC-AF-bleeding and from 0.677 to 0.806 for the ABC-AF-death score by different geographic regions.ConclusionsIn patients with AF on anticoagulation, GDF-15 and the biomarker-based ABC-AF-bleeding and ABC-AF-death risk scores are consistently associated with respectively increased risk of major bleeding and death and have similar prognostic value across world geographic regions.Trial registration numberClinicalTrials.gov RegistryNCT00412984andNCT00262600.
EWS-FLI1 and Menin Converge to Regulate ATF4 Activity in Ewing Sarcoma
Authors: Jiménez Jennifer A. , Apfelbaum April A. , Hawkins Allegra G. , Svoboda Laurie K. , Kumar Abhijay , Ruiz Ramon Ocadiz , Garcia Alessandra X. , Haarer Elena , Nwosu Zeribe C. , Bradin Joshua , Purohit Trupta , Chen Dong , Cierpicki Tomasz , Grembecka Jolanta , Lyssiotis Costas A. , Lawlor Elizabeth R. 
Published: March 2021

Abstract

Ewing sarcomas are driven by EWS–ETS fusions, most commonly EWS-FLI1, which promotes widespread metabolic reprogramming, including activation of serine biosynthesis. We previously reported that serine biosynthesis is also activated in Ewing sarcoma by the scaffolding protein menin through as yet undefined mechanisms. Here, we investigated whether EWS-FLI1 and/or menin orchestrate serine biosynthesis via modulation of ATF4, a stress-response gene that acts as a master transcriptional regulator of serine biosynthesis in other tumors. Our results show that in Ewing sarcoma, ATF4 levels are high and that ATF4 modulates transcription of core serine synthesis pathway (SSP) genes. Inhibition of either EWS-FLI1 or menin leads to loss of ATF4, and this is associated with diminished expression of SSP transcripts and proteins. We identified and validated an EWS–FLI1 binding site at the ATF4 promoter, indicating that the fusion can directly activate ATF4 transcription. In contrast, our results suggest that menin-dependent regulation of ATF4 is mediated by transcriptional and post-transcriptional mechanisms. Importantly, our data also reveal that the downregulation of SSP genes that occurs in the context of EWS-FLI1 or menin loss is indicative of broader inhibition of ATF4-dependent transcription. Moreover, we find that menin inhibition similarly leads to loss of ATF4 and the ATF4-dependent transcriptional signature in MLL-rearranged B-cell acute lymphoblastic leukemia, extending our findings to another cancer in which menin serves an oncogenic role.

Implications:
These studies provide new insights into metabolic reprogramming in Ewing sarcoma and also uncover a previously undescribed role for menin in the regulation of ATF4.
Dasatinib Stimulates Its Own Mechanism of Resistance by Activating a CRTC3/MITF/Bcl-2 Pathway in Melanoma with Mutant or Amplified c-Kit
Authors: Sabbah Malak , Krayem Mohammad , Najem Ahmad , Sales François , Miller Wilson , del Rincon Sonia , Awada Ahmad , Ghanem Ghanem E. , Journe Fabrice 
Published: March 2021

Abstract

Amplification or activating mutations of c-Kit are a frequent oncogenic alteration, which occurs commonly in acral and mucosal melanoma. Among c-Kit inhibitors, dasatinib is the most active due to its ability to bind both active and inactive conformations of the receptor. However, its use as a single agent in melanoma showed limited clinical benefit. We first found that sensitivity to dasatinib is restricted to melanoma cell lines harboring c-Kit alteration but, unexpectedly, we observed lower effect at higher concentrations that can readily be found in patient blood. We then investigated relevant pathway alterations and found complete inhibition of MAPK and PI3K/AKT pathways but an increase in MITF and its downstream target Bcl-2 through CRTC3 pathway, which turn on the CREB regulated transcription of MITF. More importantly, dasatinib upregulates MITF and Bcl-2 through SIK2 inhibition revealed by CRTC3 reduced phosphorylation, CREB transcription activation of MITF, MITF transcription activation of Bcl-2 as well as pigmentation. Furthermore, overexpression of MITF renders melanoma cells resistant to all dasatinib concentrations. Selective Bcl-2 inhibition by ABT-199 or Bcl-2 knockout restores the sensitivity of melanoma cells to dasatinib, validating the involvement of MITF and Bcl-2 axis in the resistance of melanoma to dasatinib. In conclusion, we showed for the first time that dasatinib in melanoma stimulates its proper mechanism of resistance, independently of MAPK and PI3K/AKT pathways reactivation commonly associated to secondary c-Kit mutations, but through CRTC3/MITF/Bcl-2 pathway activation at clinically relevant doses which may explain the weak clinical benefit of dasatinib in patients with melanoma.

Implications:
Dasatinib stimulates its proper mechanism of resistance through CRTC3/MITF/Bcl-2 pathway, which may explain its modest clinical efficiency in patients with melanoma.