bluuebunny/crossref_metadata_2025_split huggingface dataset:
GSK3β suppression inhibits MCL1 protein synthesis in human acute myeloid leukemia cells
Authors: Lee Yuan‐Chin , Shi Yi‐Jun , Wang Liang‐Jun , Chiou Jing‐Ting , Huang Chia‐Hui , Chang Long‐Sen 
Published: June 2020

AbstractPrevious studies have shown that glycogen synthase kinase 3β (GSK3β) suppression is a potential strategy for human acute myeloid leukemia (AML) therapy. However, the cytotoxic mechanism associated with GSK3β suppression remains unresolved. Thus, the underlying mechanism of N‐(4‐methoxybenzyl)‐N′‐(5‐nitro‐1,3‐thiazol‐2‐yl)urea (AR‐A014418)‐elicited GSK3β suppression in the induction of AML U937 and HL‐60 cell death was investigated in this study. Our study revealed that AR‐A014418‐induced MCL1 downregulation remarkably elicited apoptosis of U937 cells. Furthermore, the AR‐A014418 treatment increased p38 MAPK phosphorylation and decreased the phosphorylated Akt and ERK levels. Activation of p38 MAPK subsequently evoked autophagic degradation of 4EBP1, while Akt inactivation suppressed mTOR‐mediated 4EBP1 phosphorylation. Furthermore, AR‐A014418‐elicited ERK inactivation inhibited Mnk1‐mediated eIF4E phosphorylation, which inhibited MCL1 mRNA translation in U937 cells. In contrast to GSK3α, GSK3β downregulation recapitulated the effect of AR‐A014418 in U937 cells. Transfection of constitutively active GSK3β or cotransfection of constitutively activated MEK1 and Akt suppressed AR‐A014418‐induced MCL1 downregulation. Moreover, AR‐A014418 sensitized U937 cells to ABT‐263 (BCL2/BCL2L1 inhibitor) cytotoxicity owing to MCL1 suppression. Collectively, these results indicate that AR‐A014418‐induced GSK3β suppression inhibits ERK–Mnk1–eIF4E axis‐modulated de novo MCL1 protein synthesis and thereby results in U937 cell apoptosis. Our findings also indicate a similar pathway underlying AR‐A014418‐induced death in human AML HL‐60 cells.
Molecular structure and function of microfibrillar‐associated proteins in skeletal and metabolic disorders and cancers
Authors: Zhu Sipin , Ye Lin , Bennett Samuel , Xu Huazi , He Dengwei , Xu Jiake 
Published: June 2020

AbstractMicrofibrillar‐associated proteins (MFAPs) are extracellular matrix glycoproteins, which play a role in microfibril assembly, elastinogenesis, and tissue homeostasis. MFAPs consist of five subfamily members, including MFAP1, MFAP2, MFAP3, MFAP4, and MFAP5. Among these, MFAP2 and MFAP5 are most closely related, and exhibit very limited amino acid sequence homology with MFAP1, MFAP3, and MFAP4. Gene expression profiling analysis reveals that MFAP2, MFAP5, and MFAP4 are specifically expressed in osteoblastic like cells, whereas MFAP1 and MFAP3 are more ubiquitously expressed, indicative of their diverse role in the tropism of tissues. Molecular structural analysis shows that each MFAP family member has distinct features, and functional evidence reveals discrete purposes of individual MFAPs. Animal studies indicate that MFAP2‐deficient mice exhibit progressive osteopenia with elevated receptor activator of NF‐κB ligand (RANKL) expression, whereas MFAP5‐deficient mice are neutropenic, and MFAP4‐deficient mice displayed emphysema‐like pathology and the impaired formation of neointimal hyperplasia. Emerging data also suggest that MFAPs are involved in cancer progression and fat metabolism. Further understanding of tissue‐specific pathophysiology of MFAPs might offer potential novel therapeutic targets for related diseases, such as skeletal and metabolic disorders, and cancers.
Irisin deficiency disturbs bone metabolism
Authors: Zhu Xiaofang , Li Xiangfen , Wang Xiaoxuan , Chen Ting , Tao Fengjuan , Liu Chuanju , Tu Qisheng , Shen Guofang , Chen Jake J. 
Published: June 2020

AbstractBalancing the process of bone formation and resorption is important in the maintenance of healthy bone. Therefore, the discovery of novel factors that can regulate bone metabolism remains needed. Irisin is a newly identified hormone‐like peptide. Recent studies have reported the involvement of irisin in many physiological and pathological conditions with bone mineral density changes, including osteopenia and osteoporotic fractures. In this study, we generated the first line of Osx‐Cre:FNDC5/irisin KO mice, in which FNDC5/irisin was specifically deleted in the osteoblast lineage. Gene and protein expressions of irisin were remarkably decreased in bones but no significant differences in other tissues were observed in knockout mice. FNDC5/irisin deficient mice showed a lower bone density and significantly delayed bone development and mineralization from early‐stage to adulthood. Our phenotypical analysis exhibited decreased osteoblast‐related gene expression and increased osteoclast‐related gene expression in bone tissues, and reduced adipose tissue browning due to bone‐born irisin deletion. By harvesting and culturing MSCs from the knockout mice, we found that osteoblastogenesis was inhibited and osteoclastogenesis was increased. By using irisin stimulated wildtype primary cells as a gain‐of‐function model, we further revealed the effects and mechanisms of irisin on promoting osteogenesis and inhibiting osteoclastogenesis in vitro. In addition, positive effects of exercise, including bone strength enhancement and body weight loss were remarkably weakened due to irisin deficiency. Interestingly, these changes can be rescued by supplemental administration of recombinant irisin during exercise. Our study indicates that irisin plays an important role in bone metabolism and the crosstalk between bone and adipose tissue. Irisin represents a potential molecule for the prevention and treatment of bone metabolic diseases.
Efficacy of daratumumab combination regimen in patients with multiple myeloma: A combined analysis of phase III randomized controlled trials
Authors: Htut Thura W. , Thein Kyaw Z. , Lawrie Alastair , Tighe Jane , Preston Gavin 
Published: June 2020

AbstractThe use of the CD38 monoclonal antibody daratumumab in combination with standard myeloma chemotherapy regimens has been studied extensively in recent years. We undertook an updated meta‐analysis of phase III randomized controlled trials (RCT) to determine the efficacy of daratumumab combination regimens. The relative risk for progression was significantly lower in daratumumab‐treated cohorts (HR 0.46, 95% CI 0.38‐0.55) and this was consistent across newly diagnosed and relapsed cases. No statistically significant improvement was identified in newly diagnosed patients with high‐risk cytogenetics and this group remains a therapeutic challenge.
An efficient synthesis of designed 4‐thiazolidinone fused pyrimidine derivatives as potent antimicrobial agents
Authors: Patel Janki J. , Morja Mayur I. , Chikhalia Kishor H. 
Published: June 2020

AbstractA novel series of hybrid 2‐substituted ((pyrimidin‐2‐yl)hydrazinyl)thiazolidin‐4‐one derivatives were synthesized by means of aromatic nucleophilic displacement of chlorine atoms of 2,4,6‐trichloro pyrimidine. Synthesis of some novel 2‐(2‐(6‐morpholino‐4‐substituted(phenyl amino)pyrimidin‐2‐yl)hydrazinyl)thiazol‐4(5H)‐one derivatives have been carried out by the displacement of chlorine atoms on the basis of functionality concept on varying conditions. The synthesized hydrazinyl thiazolidin‐4‐one pyrimidine derivatives were evaluated for their expected antimicrobialactivity; where, the majority of these compounds showed potent antibacterial and antifungal activities against the tested strains of bacteria and fungi. Afforded title analogs were subsequently characterized by elemental analysis, IR, 1H NMR, 13C NMR, Mass spectroscopy. SAR and HOMO‐LUMO studies were also carried out for confirming the structure biological activity. Thus, these studies suggested that hydrazinyl pyrimidine derivatives bearing thiazolidinone moiety are interesting scaffolds for the development of novel antimicrobial agents.
LPS-mediated neutrophil VEGF-A release is modulated by cannabinoid receptor activation
Authors: Braile Mariantonia , Cristinziano Leonardo , Marcella Simone , Varricchi Gilda , Marone Giancarlo , Modestino Luca , Ferrara Anne Lise , De Ciuceis Agnese , Scala Sara , Galdiero Maria Rosaria , Loffredo Stefania 
Published: June 2020

Abstract
Neutrophils (PMNs) are innate immune cells with primary roles in inflammation and in host defense against infections. Both inflammatory and tumor angiogenesis are modulated by a sequential, coordinated production of angiogenic factors such as vascular endothelial growth factors (VEGFs), angiopoietins, hepatocyte growth factor (HGF), and chemokines. These factors are produced by several immune cells, including PMNs. Activation of cannabinoid receptor type-1 (CB1) and -2 (CB2) has been suggested as a new strategy to modulate in vitro and in vivo angiogenesis. We sought to investigate whether activation of CB1 and CB2 by CB agonists modulate LPS-mediated angiogenic activity of human PMNs. Highly purified PMNs were isolated from buffy coats of healthy donors. Cells were stimulated with CB1 and CB2 agonists/antagonists alone and/or in combination with LPS. Angiogenic factors in cell-free supernatants were measured by ELISA. The modulation of activation markers of PMNs by CB agonists was evaluated by flow cytometry. Angiogenesis in vitro was measured as tube formation by optical microscopy. Endothelial cell permeability was assessed by an in vitro vascular permeability assay. LPS-activated PMNs released VEGF-A, CXCL8, and HGF. Preincubation of PMNs with low concentrations of CB1 and CB2 agonists inhibited VEGF-A release induced by LPS, but did not affect CXCL8 and HGF production. The effects of CB agonists on VEGF-A release induced by LPS were reversed by preincubation with CB antagonists. CB agonists modulated in vitro angiogenesis and endothelial permeability induced by supernatants of LPS-activated PMNs through the reduction of VEGF-A. Neutrophils play a central role in the control of bacterial infections and in the outcome of sepsis. The latter condition is associated with an increase in circulating levels of VEGF-A. We demonstrated that low concentrations of CB agonists inhibit VEGF-A release from LPS-activated PMNs. These results suggest that CB agonists might represent a novel therapeutic strategy in patients with sepsis.
TLR3 expression by maternal and fetal cells at the maternal-fetal interface in normal and preeclamptic pregnancies
Authors: Gierman Lobke M , Silva Gabriela B , Pervaiz Zahra , Rakner Johanne J , Mundal Siv B , Thaning Astrid J , Nervik Ingunn , Elschot Mattijs , Mathew Seema , Thomsen Liv Cecilie V , Bjørge Line , Iversen Ann-Charlotte 
Published: June 2020

Abstract
Inflammation and oxidative stress at the maternal-fetal interface characterize the placental dysfunction that underlies the pregnancy disorder preeclampsia. Specialized fetal trophoblasts directly interact with leukocytes at both sites of the maternal-fetal interface; the uterine wall decidua; and the placenta. TLR3 has been implicated in the harmful inflammation at the maternal-fetal interface in preeclampsia, but the cellular involvement in the decidua and placenta has not been determined. This study aimed to characterize and quantify cell-specific TLR3 expression and function at the maternal-fetal interface in normal and preeclamptic pregnancies. TLR3 expression was assessed by immunohistochemistry and quantified by a novel image-based and cell-specific quantitation method. TLR3 was expressed at the maternal-fetal interface by all decidual and placental trophoblast types and by maternal and fetal leukocytes. Placental, but not decidual, TLR3 expression was significantly higher in preeclampsia compared to normal pregnancies. This increase was attributed to placental intravillous tissue and associated with both moderate and severe placental dysfunction. TLR3 pathway functionality in the decidua and placenta was confirmed by TLR3 ligand-induced cytokine response, but the TLR3 expression levels did not correlate between the two sites. In conclusion, functional TLR3 was broadly expressed by maternal and fetal cells at both sites of the maternal-fetal interface and the placental intravillous expression was increased in preeclampsia. This suggests TLR3-mediated inflammatory involvement with local regulation at both sites of the maternal-fetal interface in normal and preeclamptic pregnancies.
Spinal microglia-neuron interactions in chronic pain
Authors: Ho Idy H T , Chan Matthew T V , Wu William K K , Liu Xiaodong 
Published: June 2020

AbstractCurrent deficiency in our understanding of acute-to-chronic pain transition remains a hurdle for developing effective treatments against chronic pain. Whereas neurocentric mechanisms alone are insufficient to provide satisfactory explanation for such transition, neuro-immune crosstalk has attracted attention in recent pain research. In contrast to brain microglia, spinal microglia are activated immediately in various pain states. The fast-responsive enrichment and activation of spinal microglia among different pain conditions have highlighted the crucial role of neuroinflammation caused by microglia-neuron crosstalk in pain initiation. Recent studies have revealed spinal microglia-neuron interactions are also involved in chronic pain maintenance, albeit, with different anatomic distribution, cellular and molecular mechanisms, and biologic functions. Delineating the exact temporal discrepancies of spinal microglia distribution and functions along acute-to-chronic pain transition may provide additional mechanistic insights for drug development to prevent deterioration of acute pain into the chronic state. This narrative review summerizes the longitudinal alterations of spinal microglia-neuron interactions in the initiation of pain hypersensitivity, acute-to-chronic pain progression, and chronic pain maintenance, followed by an overview of current clinical translation of preclinical studies on spinal microglia. This review highlights the crucial role of the interaction between spinal microglia and neighboring neurons in the initiation and maintenance of pain hypersensitivity, in relation to the release of cytokines, chemokines, and neuroactive substances, as well as the modulation of synaptic plasticity. Further exploration of the uncharted functions of spinal microglia-neuron crosstalk may lead to the design of novel drugs for preventing acute-to-chronic pain transition.
The Controversial Effect of Age on Divergent Thinking Abilities: A Systematic Review
Authors: Fusi Giulia , Lavolpe Sara , Crepaldi Maura , Rusconi Maria Luisa 
Published: June 2020

AbstractDivergent thinking (DT) is considered as an indicator of creative potential and a predictor of creative achievement. Furthermore, it is also conceptualized as an indicator of cognitive reserve (CR) in healthy elderly. CR refers to a functional benefit that can potentially offer protection against brain pathologies and is thereby considered a protective factor against cognitive decline. Creativity researchers have therefore attempted to understand the impact of the aging processes on DT abilities; however, it is difficult to draw a coherent picture from these studies. The aim of our systematic review was to more consistently summarize and interpret evidence about this topic. We selected 16 studies using the Preferred Reporting Items for Systematic reviews and Meta‐Analyses (PRISMA) guidelines. Our findings highlight a complex and multidimensional, rather than a simple linear relationship between the aging processes and DT performances, especially if the different DT indexes are considered separately. We also found that findings from more recent studies suggest that older subjects are able to think as divergently as younger people, particularly in the verbal domain, if no time constraints are imposed and if the workload is not too high. We conclude by discussing theoretical and methodological issues and implications for future research.
Pharmacists subject to complaints: a national study of pharmacists reported to health regulators in Australia
Authors: Taouk Yamna , Bismark Marie , Hattingh Hendrika Laetitia 
Published: June 2020

AbstractBackgroundComplaints against pharmacists provide an opportunity for learning and improvement within the profession. The aim of the present study was to describe the nature and prevalence of complaints about pharmacists in Australia and to identify factors associated with an increased risk of complaints.MethodDe‐identified data on all pharmacists registered to practise in Australia between 1 January 2011 and 31 December 2016 was linked with complaints about pharmacists lodged with health regulators during the same period. Descriptive statistics describe the source, nature, outcome, and clustering of complaints. Regression analyses identify factors associated with complaints.ResultsAround 6% of pharmacists who were registered over the six‐year study period were subject to at least one complaint to a regulator. Over half of these complaints resulted in regulatory action. Four‐fifths of complaints related to five issues: accuracy and appropriateness of dispensing, lawfulness of supply, communication and interpersonal behaviour, records and information, and the health of the pharmacist. Fewer than 1% of pharmacists were the subject of two or more complaints: this group accounted for nearly a third of all complaints. Male pharmacists and those aged 36 to 44 years were at increased risk of complaints compared with their peers.ConclusionA small group of pharmacists in Australia receive a disproportionate share of complaints. Complaints against pharmacists provide an opportunity for learning and improvement within the profession. Improved understanding of complaint patterns may assist in the development of programs to reduce risk to patients and support safe practice by pharmacists.
Recent advances of ambient ionization mass spectrometry imaging in clinical research
Authors: Li Na , Nie Honggang , Jiang Liping , Ruan Guihua , Du Fuyou , Liu Huwei 
Published: June 2020

AbstractThe structural information and spatial distribution of molecules in biological tissues are closely related to the potential molecular mechanisms of disease origin, transfer, and classification. Ambient ionization mass spectrometry imaging is an effective tool that provides molecular images while describing in situ information of biomolecules in complex samples, in which ionization occurs at atmospheric pressure with the samples being analyzed in the native state. Ambient ionization mass spectrometry imaging can directly analyze tissue samples at a fairly high resolution to obtain molecules in situ information on the tissue surface to identify pathological features associated with a disease, resulting in the wide applications in pharmacy, food science, botanical research, and especially clinical research. Herein, novel ambient ionization techniques, such as techniques based on spray and solid‐liquid extraction, techniques based on plasma desorption, techniques based on laser desorption ablation, and techniques based on acoustic desorption were introduced, and the data processing of ambient ionization mass spectrometry imaging was briefly reviewed. Besides, we also highlight recent applications of this imaging technology in clinical researches and discuss the challenges in this imaging technology and the perspectives on the future of the clinical research.
Longterm Outcomes of Patients Undergoing Liver Transplantation for Acute‐on‐Chronic Liver Failure
Authors: Sundaram Vinay , Mahmud Nadim , Perricone Giovanni , Katarey Dev , Wong Robert J. , Karvellas Constantine J. , Fortune Brett E. , Rahimi Robert S. , Maddur Harapriya , Jou Janice H. , Kriss Michael , Stein Lance L. , Lee Moses , Jalan Rajiv ,   for the Multi‐Organ Dysfunction, Evaluation for Liver Transplantation (MODEL) Consortium
Published: June 2020

Recent data have demonstrated >80% 1‐year survival probability after liver transplantation (LT) for patients with severe acute‐on‐chronic liver failure (ACLF). However, longterm outcomes and complications are still unknown for this population. Our aim was to compare longterm patient and graft survival among patients transplanted across all grades of ACLF. We analyzed the United Network for Organ Sharing database for the years 2004‐2017. Patients with ACLF were identified using the European Association for the Study of the Liver–Chronic Liver Failure criteria. Kaplan‐Meier and Cox regression methods were used to determine patient and graft survival and associated predictors of mortality in adjusted models. A total of 56,801 patients underwent transplantation of which 31,024 (54.6%) had no ACLF, 8757 (15.4%) had ACLF grade 1, 9039 (15.9%) had ACLF grade 2, and 7891 (14.1%) had ACLF grade 3. The 5‐year patient survival after LT was lower in the ACLF grade 3 patients compared with the other groups (67.7%; P < 0.001), although after year 1, the percentage decrease in survival was similar among all groups. Infection was the primary cause of death among all patient groups in the first year. Infection was the primary cause of death among all patient groups in the first year. After the first year, infection was the main cause of death in patients transplanted with ACLF grade 1 (32.1%), ACLF grade 2 (33.9%), and ACLF grade 3 (37.6%), whereas malignancy was the predominant cause of death in those transplanted with no ACLF (28.5%). In conclusion, patients transplanted with ACLF grade 3 had lower 5‐year survival as compared with patients with ACLF grades 0‐2, but mortality rates were not significantly different after the first year following LT. Graft survival was excellent across all ACLF groups.
Axiomatizing first order consequences in inclusion logic
Authors: Yang Fan 
Published: June 2020

AbstractInclusion logic is a variant of dependence logic that was shown to have the same expressive power as positive greatest fixed‐point logic. Inclusion logic is not axiomatisable in full, but its first order consequences can be axiomatized. In this paper, we provide such an explicit partial axiomatization by introducing a system of natural deduction for inclusion logic that is sound and complete for first order consequences in inclusion logic.
The choice property in tame expansions of o‐minimal structures
Authors: Eleftheriou Pantelis E. , Günaydın Ayhan , Hieronymi Philipp 
Published: June 2020

AbstractWe establish the choice property, a weak analogue of definable choice, for certain tame expansions of o‐minimal structures. Most noteworthily, this property holds for dense pairs of real closed fields, as well as for expansions of o‐minimal structures by a dense independent set.
The Cichoń diagram for degrees of relative constructibility
Authors: Switzer Corey Bacal 
Published: June 2020

AbstractFollowing a line of research initiated in [4], we describe a general framework for turning reduction concepts of relative computability into diagrams forming an analogy with the Cichoń diagram for cardinal characteristics of the continuum. We show that working from relatively modest assumptions about a notion of reduction, one can construct a robust version of such a diagram. As an application, we define and investigate the Cichoń diagram for degrees of constructibility relative to a fixed inner model W. Many analogies hold with the classical theory as well as some surprising differences. Along the way, we introduce a new axiom stating, roughly, that the constructibility diagram is as complex as possible.