bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced HbF reactivation by multiplex mutagenesis of thalassemic CD34+ cells in vitro and in vivo
Authors: Psatha Nikoletta , Georgakopoulou Aphrodite , Li Chang , Nandakumar Vivek , Georgolopoulos Grigorios , Acosta Reyes , Paschoudi Kiriaki , Nelson Jemma , Chee Daniel , Athanasiadou Anastasia , Kouvatsi Anastasia , Funnell Alister Peter William , Lieber André , Yannaki Evangelia , Papayannopoulou Thalia 
Published: June 2021

Abstract
Thalassemia or sickle cell patients with hereditary persistence of fetal hemoglobin (HbF) have an ameliorated clinical phenotype and, in some cases, can achieve transfusion independence. Inactivation via genome editing of γ-globin developmental suppressors, such as BCL11A or LRF/ZBTB7A, or of their binding sites, have been shown to significantly increase expression of endogenous HbF. To broaden the therapeutic window beyond a single-editing approach, we have explored combinations of cis- and trans-editing targets to enhance HbF reactivation. Multiplex mutagenesis in adult CD34+ cells was well tolerated and did not lead to any detectable defect in the cells’ proliferation and differentiation, either in vitro or in vivo. The combination of 1 trans and 1 cis mutation resulted in high editing retention in vivo, coupled with almost pancellular HbF expression in NBSGW mice. The greater in vivo performance of this combination was also recapitulated using a novel helper-dependent adenoviral-CRISPR vector (HD-Ad-dualCRISPR) in CD34+ cells from β-thalassemia patients transplanted to NBSGW mice. A pronounced increase in HbF expression was observed in human red blood cells in mice with established predominant β0/β0-thalassemic hemopoiesis after in vivo injection of the HD-Ad-dualCRISPR vector. Collectively, our data suggest that the combination of cis and trans fetal globin reactivation mutations has the potential to significantly increase HbF both totally and on a per cell basis over single editing and could thus provide significant clinical benefit to patients with severe β-globin phenotype.
GPR34 activation potentially bridges lymphoepithelial lesions to genesis of salivary gland MALT lymphoma
Authors: Korona Boguslawa , Korona Dagmara , Zhao Wanfeng , Wotherspoon Andrew C. , Du Ming-Qing 
Published: June 2021

Abstract
GPR34 translocation and mutation are specifically associated with salivary gland MALT lymphoma (SG-MALT-lymphoma). The majority of GPR34 mutations are clustered in its C-terminus, resulting in truncated proteins lacking the phosphorylation motif important for receptor desensitization. It is unclear why GPR34 genetic changes associate with SG-MALT-lymphoma and how these mutations contribute to the development of lymphoma. We generated isogenic Flp-InTRex293 cell lines that stably expressed a single copy of GPR34 or its various mutants and performed a range of in vitro assays. We found that the GPR34 Q340X truncation, but not the R84H and D151A mutants, conferred a significantly increased resistance to apoptosis and greater transforming potential than the GPR34 wild type. The GPR34 truncation mutant had a significantly delayed internalization compared with the wild type after ligand (lysophosphatidylserine) stimulation. Among the 9 signaling pathways examined, the GPR34 Q340X truncation, and to a lesser extent the D151A mutant, significantly activated CRE, NF-κB, and AP1 reporter activities, particularly in the presence of ligand stimulation. We further described the enhanced activities of phospholipase-A1/2 in the culture supernatant of Flp-InTRex293 cells that expressed the GPR34 Q340X mutant, as well as their potential to catalyze the synthesis of lysophosphatidylserine from phosphatidylserine. Importantly, phospholipase-A1 was abundantly expressed in the duct epithelium of salivary glands and those involved in lymphoepithelial lesions (LELs). Our findings advocate a model of paracrine stimulation of malignant B cells via GPR34, in which phospholipase A is released by LELs and hydrolyzes the phosphatidylserine exposed on apoptotic cells, generating lysophosphatidylserine, the ligand for GPR34. Thus, GPR34 activation potentially bridges LELs to genesis of SG-MALT-lymphoma.
The contact activation inhibitor AB023 in heparin-free hemodialysis: results of a randomized phase 2 clinical trial
Authors: Lorentz Christina U. , Tucker Erik I. , Verbout Norah G. , Shatzel Joseph J. , Olson Sven R. , Markway Brandon D. , Wallisch Michael , Ralle Martina , Hinds Monica T. , McCarty Owen J. T. , Gailani David , Weitz Jeffrey I. , Gruber András 
Published: June 2021

Abstract
End-stage renal disease (ESRD) patients on chronic hemodialysis have repeated blood exposure to artificial surfaces that can trigger clot formation within the hemodialysis circuit. Dialyzer clotting can lead to anemia despite erythropoietin and iron supplementation. Unfractionated heparin prevents clotting during hemodialysis, but it is not tolerated by all patients. Although heparin-free dialysis is performed, intradialytic blood entrapment can be problematic. To address this issue, we performed a randomized, double-blind, phase 2 study comparing AB023, a unique antibody that binds factor XI (FXI) and blocks its activation by activated FXII, but not by thrombin, to placebo in 24 patients with ESRD undergoing heparin-free hemodialysis. Patients were randomized to receive a single predialysis dose of AB023 (0.25 or 0.5 mg/kg) or placebo in a 2:1 ratio, and safety and preliminary efficacy were compared with placebo and observations made prior to dosing within each treatment arm. AB023 administration was not associated with impaired hemostasis or other drug-related adverse events. Occlusive events requiring hemodialysis circuit exchange were less frequent and levels of thrombin-antithrombin complexes and C-reactive protein were lower after AB023 administration compared with data collected prior to dosing. AB023 also reduced potassium and iron entrapment in the dialyzers, consistent with less blood accumulation within the dialyzers. We conclude that despite the small sample size, inhibition of contact activation–induced coagulation with AB023 was well tolerated and reduced clotting within the dialyzer. This trial was registered at www.clinicaltrials.gov as #NCT03612856.
Multi-Scale Convolutional Gated Recurrent Unit Networks for Tool Wear Prediction in Smart Manufacturing
Authors: Xu Weixin , Miao Huihui , Zhao Zhibin , Liu Jinxin , Sun Chuang , Yan Ruqiang 
Published: June 2021

AbstractAs an integrated application of modern information technologies and artificial intelligence, Prognostic and Health Management (PHM) is important for machine health monitoring. Prediction of tool wear is one of the symbolic applications of PHM technology in modern manufacturing systems and industry. In this paper, a multi-scale Convolutional Gated Recurrent Unit network (MCGRU) is proposed to address raw sensory data for tool wear prediction. At the bottom of MCGRU, six parallel and independent branches with different kernel sizes are designed to form a multi-scale convolutional neural network, which augments the adaptability to features of different time scales. These features of different scales extracted from raw data are then fed into a Deep Gated Recurrent Unit network to capture long-term dependencies and learn significant representations. At the top of the MCGRU, a fully connected layer and a regression layer are built for cutting tool wear prediction. Two case studies are performed to verify the capability and effectiveness of the proposed MCGRU network and results show that MCGRU outperforms several state-of-the-art baseline models.
Associations between handgrip strength and hypertension in relation to circulating CD34-positive cell levels among Japanese older men: a cross-sectional study
Authors: Shimizu Yuji , Kawashiri Shin-Ya , Nobusue Kenichi , Yamanashi Hirotomo , Nagata Yasuhiro , Maeda Takahiro 
Published: June 2021

Abstract
Background
A positive association between handgrip strength and blood pressure has been reported. Since these factors are linked to the condition of the endothelium, the activity of endothelial repair might influence the association between handgrip strength and hypertension.

Methods
A cross-sectional study was conducted with 257 Japanese men aged 60–69 years who underwent an annual health checkup. As individuals with high level of circulating CD34-positive cells might show active endothelial repair, which plays an important role in vascular homeostasis, participants were stratified by circulating CD34-positive cell levels, using the median value of this population (0.96 cells/μL) as the cutoff.

Results
Independent of known cardiovascular risk factors, for participants with a high CD34-positive cell, handgrip strength is significantly positively associated with hypertension (odds ratio and 95% confidence interval of hypertension for 1 standard deviation increment of handgrip strength were 1.85 (1.19, 2.88) but not for participants with a low CD34-positive cell (0.91 (0.61, 1.37)).

Conclusion
The positive association between handgrip strength and hypertension is limited to high CD34-positive cells. This result may help clarify the role of vascular homeostasis in maintaining muscle strength.
The variability of urban safety performance functions for different road elements: an Italian case study
Authors: Intini Paolo , Berloco Nicola , Cavalluzzi Gabriele , Lord Dominique , Ranieri Vittorio , Colonna Pasquale 
Published: June 2021

Abstract
Background
Urban safety performance functions are used to predict crash frequencies, mostly based on Negative Binomial (NB) count models. They could be differentiated for considering homogeneous subsets of segments/intersections and different predictors.

Materials and methods
The main research questions concerned: a) finding the best possible subsets for segments and intersections for safety modelling, by discussing the related problems and inquiring into the variability of predictors within the subsets; b) comparing the modelling results with the existing literature to highlight common trends and/or main differences; c) assessing the importance of additional crash predictors, besides traditional variables. In the context of a National research project, traffic volumes, geometric, control and additional variables were collected for road segments and intersections in the City of Bari, Italy, with 1500 fatal+injury related crashes (2012–2016). Six NB models were developed for: one/two-way homogeneous segments, three/four-legged, signalized/unsignalized intersections.

Results
Crash predictors greatly vary within the different subsets considered. The effect of vertical signs on minor roads/driveways, critical sight distance, cycle crossings, pavement/markings maintenance was specifically discussed. Some common trends but also differences in both types and effect of crash predictors were found by comparing results with literature.

Conclusion
The disaggregation of urban crash prediction models by considering different subsets of segments and intersections helps in revealing the specific influence of some predictors. Local characteristics may influence the relationships between well-established crash predictors and crash frequencies. A significant part of the urban crash frequency variability remains unexplained, thus encouraging research on this topic.
A rat model for retinitis pigmentosa with rapid retinal degeneration enables drug evaluation in vivo
Authors: Inoue Chisato , Takeuchi Tamaki , Shiota Akira , Kondo Mineo , Nshizawa Yuji 
Published: June 2021

Abstract
Background
Although retinitis pigmentosa (RP) is most frequently studied in mouse models, rats, rabbits, and pigs are also used as animal models of RP. However, no studies have reported postnatal photoreceptor cell loss before complete development in these models. Here, we generated a transgenic rat strain, named the P347L rat, in which proline at position 347 in the rhodopsin protein was replaced with leucine.

Results
A pathological analysis of photoreceptor cells in the P347L rat model was performed, and drugs with potential use as therapeutic agents against RP were investigated. The data clearly showed rapid degeneration and elimination of the outer nuclear layer even before the photoreceptor cells were fully established in P347L rats. To test the usefulness of the P347L rat in the search for new therapeutic agents against RP, the effects of rapamycin on RP were investigated in this rat strain. The findings suggest that rapamycin promotes autophagy and autophagosomal uptake of the rhodopsin that has accumulated abnormally in the cytoplasm, thereby alleviating stress and delaying photoreceptor cell death.

Conclusions
In this RP model, the time to onset of retinal degeneration was less than that of previously reported RP models with other rhodopsin mutations, enabling quicker in vivo evaluation of drug efficacy. Administration of rapamycin delayed the photoreceptor cell degeneration by approximately 1 day.
Long non-coding RNA exploration for mesenchymal stem cell characterisation
Authors: Riquier Sébastien , Mathieu Marc , Bessiere Chloé , Boureux Anthony , Ruffle Florence , Lemaitre Jean-Marc , Djouad Farida , Gilbert Nicolas , Commes Thérèse 
Published: June 2021

Abstract
Background
The development of RNA sequencing (RNAseq) and the corresponding emergence of public datasets have created new avenues of transcriptional marker search. The long non-coding RNAs (lncRNAs) constitute an emerging class of transcripts with a potential for high tissue specificity and function. Therefore, we tested the biomarker potential of lncRNAs on Mesenchymal Stem Cells (MSCs), a complex type of adult multipotent stem cells of diverse tissue origins, that is frequently used in clinics but which is lacking extensive characterization.

Results
We developed a dedicated bioinformatics pipeline for the purpose of building a cell-specific catalogue of unannotated lncRNAs. The pipeline performs ab initio transcript identification, pseudoalignment and uses new methodologies such as a specific k-mer approach for naive quantification of expression in numerous RNAseq data. We next applied it on MSCs, and our pipeline was able to highlight novel lncRNAs with high cell specificity. Furthermore, with original and efficient approaches for functional prediction, we demonstrated that each candidate represents one specific state of MSCs biology.

Conclusions
We showed that our approach can be employed to harness lncRNAs as cell markers. More specifically, our results suggest different candidates as potential actors in MSCs biology and propose promising directions for future experimental investigations.
Integrated metabolome and transcriptome analysis of the anthocyanin biosynthetic pathway in relation to color mutation in miniature roses
Authors: Lu Jiaojiao , Zhang Qing , Lang Lixin , Jiang Chuang , Wang Xiaofeng , Sun Hongmei 
Published: June 2021

Abstract
Background
Roses are famous ornamental plants worldwide. Floral coloration is one of the most prominent traits in roses and is mainly regulated through the anthocyanin biosynthetic pathway. In this study, we investigated the key genes and metabolites of the anthocyanin biosynthetic pathway involved in color mutation in miniature roses. A comparative metabolome and transcriptome analysis was carried out on the Neptune King rose and its color mutant, Queen rose, at the blooming stage. Neptune King rose has light pink colored petals while Queen rose has deep pink colored petals.

Result
A total of 190 flavonoid-related metabolites and 38,551 unique genes were identified. The contents of 45 flavonoid-related metabolites, and the expression of 15 genes participating in the flavonoid pathway, varied significantly between the two cultivars. Seven anthocyanins (cyanidin 3-O-glucosyl-malonylglucoside, cyanidin O-syringic acid, cyanidin 3-O-rutinoside, cyanidin 3-O-galactoside, cyanidin 3-O-glucoside, peonidin 3-O-glucoside chloride, and pelargonidin 3-O-glucoside) were found to be the major metabolites, with higher abundance in the Queen rose. Thirteen anthocyanin biosynthetic related genes showed an upregulation trend in the mutant flower, which may favor the higher levels of anthocyanins in the mutant. Besides, eight TRANSPARENT TESTA 12 genes were found upregulated in Queen rose, probably contributing to a high vacuolar sequestration of anthocyanins. Thirty transcription factors, including two MYB and one bHLH, were differentially expressed between the two cultivars.

Conclusions
This study provides important insights into major genes and metabolites of the anthocyanin biosynthetic pathway modulating flower coloration in miniature rose. The results will be conducive for manipulating the anthocyanin pathways in order to engineer novel miniature rose cultivars with specific colors.
A severe case of human coronavirus 229E pneumonia in an elderly man with diabetes mellitus: a case report
Authors: Sun Wen , Liao Ji-Ping , Yu Kun-Yao , Qiu Jian-Xing , Que Chen-Li , Wang Guang-Fa , Ma Jing 
Published: June 2021

Abstract
Background
With pandemic of coronavirus disease 2019 (COVID-19), human coronaviruses (HCoVs) have recently attached worldwide attention as essential pathogens in respiratory infection. HCoV-229E has been described as a rare cause of lower respiratory infection in immunocompetent adults.

Case presentation
We reported a 72-year-old man infected by HCoV-229E with rapid progression to acute respiratory distress syndrome, in conjunction with new onset atrial fibrillation, intensive care unit acquired weakness, and recurrent hospital acquired pneumonia. Clinical and radiological data were continuously collected. The absolute number of peripheral T cells and the level of complement components diminished initially and recovered after 2 months. The patient was successfully treated under intensive support care and discharged from the hospital after 3 months and followed.

Conclusion
HCoV-229E might an essential causative agent of pulmonary inflammation and extensive lung damage. Supportive treatment was essential to HCoVs infection on account of a long duration of immunological recovery in critical HCoV-229E infection.
Coronavirus disease (COVID-19) pandemic: an overview of systematic reviews
Authors: Borges do Nascimento Israel Júnior , O’Mathúna Dónal P. , von Groote Thilo Caspar , Abdulazeem Hebatullah Mohamed , Weerasekara Ishanka , Marusic Ana , Puljak Livia , Civile Vinicius Tassoni , Zakarija-Grkovic Irena , Pericic Tina Poklepovic , Atallah Alvaro Nagib , Filoso Santino , Bragazzi Nicola Luigi , Marcolino Milena Soriano ,   On behalf of the International Network of Coronavirus Disease 2019 (InterNetCOVID-19)
Published: June 2021

Abstract
Background
Navigating the rapidly growing body of scientific literature on the SARS-CoV-2 pandemic is challenging, and ongoing critical appraisal of this output is essential. We aimed to summarize and critically appraise systematic reviews of coronavirus disease (COVID-19) in humans that were available at the beginning of the pandemic.

Methods
Nine databases (Medline, EMBASE, Cochrane Library, CINAHL, Web of Sciences, PDQ-Evidence, WHO’s Global Research, LILACS, and Epistemonikos) were searched from December 1, 2019, to March 24, 2020. Systematic reviews analyzing primary studies of COVID-19 were included. Two authors independently undertook screening, selection, extraction (data on clinical symptoms, prevalence, pharmacological and non-pharmacological interventions, diagnostic test assessment, laboratory, and radiological findings), and quality assessment (AMSTAR 2). A meta-analysis was performed of the prevalence of clinical outcomes.

Results
Eighteen systematic reviews were included; one was empty (did not identify any relevant study). Using AMSTAR 2, confidence in the results of all 18 reviews was rated as “critically low”. Identified symptoms of COVID-19 were (range values of point estimates): fever (82–95%), cough with or without sputum (58–72%), dyspnea (26–59%), myalgia or muscle fatigue (29–51%), sore throat (10–13%), headache (8–12%) and gastrointestinal complaints (5–9%). Severe symptoms were more common in men. Elevated C-reactive protein and lactate dehydrogenase, and slightly elevated aspartate and alanine aminotransferase, were commonly described. Thrombocytopenia and elevated levels of procalcitonin and cardiac troponin I were associated with severe disease. A frequent finding on chest imaging was uni- or bilateral multilobar ground-glass opacity. A single review investigated the impact of medication (chloroquine) but found no verifiable clinical data. All-cause mortality ranged from 0.3 to 13.9%.

Conclusions
In this overview of systematic reviews, we analyzed evidence from the first 18 systematic reviews that were published after the emergence of COVID-19. However, confidence in the results of all reviews was “critically low”. Thus, systematic reviews that were published early on in the pandemic were of questionable usefulness. Even during public health emergencies, studies and systematic reviews should adhere to established methodological standards.
A Malaysian Delphi consensus on managing knee osteoarthritis
Authors: Yeap Swan Sim , Abu Amin Syamsul Rizal , Baharuddin Hazlyna , Koh Kar Chai , Lee Joon Kiong , Lee Verna Kar Mun , Mohamad Yahaya Nor Hamdan , Tai Cheh Chin , Tan Maw Pin 
Published: June 2021

AbstractBackgroundThe 2013 Malaysian Clinical Practice Guidelines on the Management of Osteoarthritis (OA) recommend a linear step-up approach to manage knee OA. However, patients with knee OA often require a multimodal approach to address OA-related pain symptoms and functional limitations. This consensus aimed to provide doctors with an updated set of evidence-based, clinical experience-guided recommendations to manage knee OA.MethodsA multi-speciality expert panel consisting of nine Malaysian physicians from different healthcare settings who manage a diverse OA patient population was convened. Using a combination of the ADAPTE process and modified Delphi method, the panel reviewed current evidence on the management of knee OA and synthesised a set of nine recommendations on the management of knee OA, supported by an algorithm that summarises the consensus’ core messages.ResultsA multimodal intervention strategy is the mainstay of OA management and the choice of any single or multimodal intervention may vary over the course of the disease. Overall, a non-pharmacological core treatment set of patient education, weight loss and exercise is recommended for all patients. When pharmacotherapy is indicated, symptomatic slow-acting drugs for osteoarthritis are recommended at the early stage of disease, and they can be paired with physical therapy as background treatment. Concurrent advanced pharmacotherapy that includes non-steroidal anti-inflammatory drugs, intraarticular injections and short-term weak opioids can be considered if patients do not respond sufficiently to background treatment. Patients with severe symptomatic knee OA should be considered for knee replacement surgery. Management should begin with specific treatments with the least systemic exposure or toxicity, and the choice of treatment should be determined as a shared decision between patients and their team of healthcare providers.ConclusionsThis consensus presents nine recommendations that advocate an algorithmic approach in the management of patients living with knee OA. They are applicable to patients receiving treatment from primary to tertiary care providers in Malaysia as well as other countries.