bluuebunny/crossref_metadata_2025_split huggingface dataset:
5-AZA-dC induces epigenetic changes associated with modified glycosylation of secreted glycoproteins and increased EMT and migration in chemo-sensitive cancer cells
Authors: Greville Gordon , Llop Esther , Howard Jane , Madden Stephen F. , Perry Antoinette S. , Peracaula Rosa , Rudd Pauline M. , McCann Amanda , Saldova Radka 
Published: February 2021

Abstract
Background
Glycosylation, one of the most fundamental post-translational modifications, is altered in cancer and is subject in part, to epigenetic regulation. As there are many epigenetic-targeted therapies currently in clinical trials for the treatment of a variety of cancers, it is important to understand the impact epi-therapeutics have on glycosylation.

Results
Ovarian and triple negative breast cancer cells were treated with the DNA methyltransferase inhibitor, 5-AZA-2-deoxycytidine (5-AZA-dC). Branching and sialylation were increased on secreted N-glycans from chemo-sensitive/non-metastatic cell lines following treatment with 5-AZA-dC. These changes correlated with increased mRNA expression levels in MGAT5 and ST3GAL4 transcripts in ovarian cancer cell lines. Using siRNA transient knock down of GATA2 and GATA3 transcription factors, we show that these regulate the glycosyltransferases ST3GAL4 and MGAT5, respectively. Moreover, 5-AZA-dC-treated cells displayed an increase in migration, with a greater effect seen in chemo-sensitive cell lines. Western blots showed an increase in apoptotic and senescence (p21) markers in all 5-AZA-dC-treated cells. The alterations seen in N-glycans from secreted glycoproteins in 5-AZA-dC-treated breast and ovarian cancer cells were similar to the N-glycans previously known to potentiate tumour cell survival.

Conclusions
While the FDA has approved epi-therapeutics for some cancer treatments, their global effect is still not fully understood. This study gives insight into the effects that epigenetic alterations have on cancer cell glycosylation, and how this potentially impacts on the overall fate of those cells.

Graphic abstract
A stochastic modeling approach for traffic analysis of a tramway system with virtual tags and local positioning
Authors: da Silva Leandro Dias , Lollini Paolo , Mongelli Diamantea , Bondavalli Andrea , Mandò Gianluca 
Published: February 2021

AbstractTraditional solutions for tramway interlocking systems are based on physical sensors (balizes) distributed along the infrastructure which detect passing of the trams and trigger different actions, like the communications with the ground infrastructure and the interlocking system. This approach is not easily scalable and maintainable, and it is costly. The SISTER project designed new architectural solutions for addressing the previous problems based on the virtualization of the sensors and on the local positioning of each tram. The key idea is to trigger actions when the computed local position corresponds to a virtual tag. However, the computed position can be affected by errors, compared to the real one. Therefore, it is important to understand the impact of these new solutions on the traffic that can be supported by the tramway network. This paper presents a stochastic modeling approach for analysing the performability of a tramway system based on the SISTER architectural solutions, aiming to identify the parts of the tramway network that are more critical and sensible to the variation of the traffic conditions and to the setting of the key architectural parameters. We build a model using Stochastic Activity Networks and run sensitivity analyses on (i) the accuracy of the positioning, (ii) the different SISTER parameters, and (iii) considering possible outages temporarily blocking the journey of a tram. This analysis allows to properly set and fine-tune the key architectural parameters, to understand the impact of the accuracy on the positioning, to understand the impact of the outages.
Bridging the divide between medical school and clinical practice: identification of six key learning outcomes for an undergraduate preparatory course in radiology
Authors: Simelane Thabisile , Ryan David J. , Stoyanov Slavi , Bennett Deirdre , McEntee Mark , Maher Michael M. , O’Tuathaigh Colm M. P. , O’Connor Owen J. 
Published: February 2021

Abstract
Background
There exists a significant divide between what is learnt in medical school and subsequently what is required to practice medicine effectively. Despite multiple strategies to remedy this discordance, the problem persists. Here, we describe the identification of a comprehensive set of learning outcomes for a preparation for practice course in radiology.

Methods
Assessment of interns’ readiness to interact with the radiology department was conducted using a national survey of both interns and radiologists. In parallel, group concept mapping (GCM) which involves a combination of qualitative and quantitative techniques was used to identify the shared understanding of participants from a diverse range of medical specialties regarding what topics should be included in an intern preparatory course for interacting with the radiology department.

Results
The survey demonstrated that most interns and radiologists felt that undergraduate medical training did not prepare interns to interact with the radiology department. GCM identified six learning outcomes that should be targeted when designing a preparatory module: requesting investigations; clinical decision support; radiology department IT and communication; adverse reactions and risks; interpretation of radiology results and urgent imaging. The thematic clusters from the group concept mapping corroborated the deficiencies identified in the national survey.

Conclusion
We have identified six key learning outcomes that should be included in a preparation for practice module in radiology. Future courses targeting these thematic clusters may facilitate a smoother transition from theory to practice for newly graduated doctors.
Umbilical mesenchymal stem cell-derived exosomes facilitate spinal cord functional recovery through the miR-199a-3p/145-5p-mediated NGF/TrkA signaling pathway in rats
Authors: Wang Yang , Lai Xunwei , Wu Depeng , Liu Bin , Wang Nanxiang , Rong Limin 
Published: February 2021

Abstract
Background
Although exosomes, as byproducts of human umbilical cord mesenchymal stem cells (hUC-MSCs), have been demonstrated to be an effective therapy for traumatic spinal cord injury (SCI), their mechanism of action remains unclear.

Methods
We designed and performed this study to determine whether exosomes attenuate the lesion size of SCI by ameliorating neuronal injury induced by a secondary inflammatory storm and promoting neurite outgrowth. We determined the absolute levels of all exosomal miRNAs and investigated the potential mechanisms of action of miR-199a-3p/145-5p in inducing neurite outgrowth in vivo and in vitro.

Results
miR-199a-3p/145-5p, which are relatively highly expressed miRNAs in exosomes, promoted PC12 cell differentiation suppressed by lipopolysaccharide (LPS) in vitro through modulation of the NGF/TrkA pathway. We also demonstrated that Cblb was a direct target of miR-199a-3p and that Cbl was a direct target of miR-145-5p. Cblb and Cbl gene knockdown resulted in significantly decreased TrkA ubiquitination levels, subsequently activating the NGF/TrkA downstream pathways Akt and Erk. Conversely, overexpression of Cblb and Cbl was associated with significantly increased TrkA ubiquitination level, subsequently inactivating the NGF/TrkA downstream pathways Akt and Erk. Western blot and coimmunoprecipitation assays confirmed the direct interaction between TrkA and Cblb and TrkA and Cbl. In an in vivo experiment, exosomal miR-199a-3p/145-5p was found to upregulate TrkA expression at the lesion site and also promote locomotor function in SCI rats.

Conclusions
In summary, our study showed that exosomes transferring miR-199a-3p/145-5p into neurons in SCI rats affected TrkA ubiquitination and promoted the NGF/TrkA signaling pathway, indicating that hUC-MSC-derived exosomes may be a promising treatment strategy for SCI.
Conditioned medium-preconditioned EPCs enhanced the ability in oligovascular repair in cerebral ischemia neonatal rats
Authors: Zhou Ning , Wang Lei , Fu Ping , Cui Zihao , Ge Yuhang , Jiang Feiyu , Liu Jing , Ren Chao , Luan Zuo , Fan Hongbin , Yao Ruiqin 
Published: February 2021

Abstract
Background
Oligovascular niche mediates interactions between cerebral endothelial cells and oligodendrocyte precursor cells (OPCs). Disruption of OPC-endothelium trophic coupling may aggravate the progress of cerebral white matter injury (WMI) because endothelial cells could not provide sufficient support under diseased conditions. Endothelial progenitor cells (EPCs) have been reported to ameliorate WMI in the adult brain by boosting oligovascular remodeling. It is necessary to clarify the role of the conditioned medium from hypoxic endothelial cells preconditioned EPCs (EC-pEPCs) in WMI since EPCs usually were recruited and play important roles under blood-brain barrier disruption. Here, we investigated the effects of EC-pEPCs on oligovascular remodeling in a neonatal rat model of WMI.

Methods
In vitro, OPC apoptosis induced by the conditioned medium from oxygen-glucose deprivation-injured brain microvascular endothelial cells (OGD-EC-CM) was analyzed by TUNEL and FACS. The effects of EPCs on EC damage and the expression of cytomokine C-X-C motif ligand 12 (CXCL12) were examined by western blot and FACS. The effect of the CM from EC-pEPCs against OPC apoptosis was also verified by western blot and silencing RNA. In vivo, P3 rat pups were subjected to right common carotid artery ligation and hypoxia and treated with EPCs or EC-pEPCs at P7, and then angiogenesis and myelination together with cognitive outcome were evaluated at the 6th week.

Results
In vitro, EPCs enhanced endothelial function and decreased OPC apoptosis. Meanwhile, it was confirmed that OGD-EC-CM induced an increase of CXCL12 in EPCs, and CXCL12-CXCR4 axis is a key signaling since CXCR4 knockdown alleviated the anti-apoptosis effect of EPCs on OPCs. In vivo, the number of EPCs and CXCL12 protein level markedly increased in the WMI rats. Compared to the EPCs, EC-pEPCs significantly decreased OPC apoptosis, increased vascular density and myelination in the corpus callosum, and improved learning and memory deficits in the neonatal rat WMI model.

Conclusions
EC-pEPCs more effectively promote oligovascular remodeling and myelination via CXCL12-CXCR4 axis in the neonatal rat WMI model.
Intrapancreatic MSC transplantation facilitates pancreatic islet regeneration
Authors: Khatri Rahul , Petry Sebastian Friedrich , Linn Thomas 
Published: February 2021

Abstract
Background
Type 1 diabetes mellitus (T1D) is characterized by the autoimmune destruction of the pancreatic β cells. The transplantation of mesenchymal stromal/stem cells (MSC) was reported to rescue the damaged pancreatic niche. However, there is an ongoing discussion on whether direct physical contact between MSC and pancreatic islets results in a superior outcome as opposed to indirect effects of soluble factors released from the MSC entrapped in the lung microvasculature after systemic administration. Hence, MSC were studied in direct contact (DC) and indirect contact (IDC) with murine pancreatic β cell line MIN6-cells damaged by nitrosourea derivative streptozotocin (STZ) in vitro. Further, the protective and antidiabetic outcome of MSC transplantation was evaluated through the intrapancreatic route (IPR) and intravenous route (IVR) in STZ-induced diabetic NMRI nude mice.

Methods
MSC were investigated in culture with STZ-damaged MIN6-cells, either under direct contact (DC) or separated through a semi-permeable membrane (IDC). Moreover, multiple low doses of STZ were administered to NMRI nude mice for the induction of hyperglycemia. 0.5 × 106 adipose-derived mesenchymal stem cells (ADMSC) were transferred through direct injection into the pancreas (IPR) or the tail vein (IVR), respectively. Bromodeoxyuridine (BrdU) was injected for the detection of proliferating islet cells in vivo, and real-time polymerase chain reaction (RT-PCR) was employed for the measurement of the expression of growth factor and immunomodulatory genes in the murine pancreas and human MSC. Phosphorylation of AKT and ERK was analyzed with Western blotting.

Results
The administration of MSC through IPR ameliorated hyperglycemia in contrast to IVR, STZ, and non-diabetic control in a 30-day window. IPR resulted in a higher number of replicating islet cells, number of islets, islet area, growth factor (EGF), and balancing of the Th1/Th2 response in vivo. Physical contact also provided a superior protection to MIN6-cells from STZ through the AKT and ERK pathway in vitro in comparison with IDC.

Conclusion
Our study suggests that the physical contact between MSC and pancreatic islet cells is required to fully unfold their protective potential.
Pluripotent stem cell-induced skeletal muscle progenitor cells with givinostat promote myoangiogenesis and restore dystrophin in injured Duchenne dystrophic muscle
Authors: Xuan Wanling , Khan Mahmood , Ashraf Muhammad 
Published: February 2021

Abstract
Background
Duchenne muscular dystrophy (DMD) is caused by mutations of the gene that encodes the protein dystrophin. A loss of dystrophin leads to severe and progressive muscle wasting in both skeletal and heart muscles. Human induced pluripotent stem cells (hiPSCs) and their derivatives offer important opportunities to treat a number of diseases. Here, we investigated whether givinostat (Givi), a histone deacetylase inhibitor, with muscle differentiation properties could reprogram hiPSCs into muscle progenitor cells (MPC) for DMD treatment.

Methods
MPC were generated from hiPSCs by treatment with CHIR99021 and givinostat called Givi-MPC or with CHIR99021 and fibroblast growth factor as control-MPC. The proliferation and migration capacity were investigated by CCK-8, colony, and migration assays. Engraftment, pathological changes, and restoration of dystrophin were evaluated by in vivo transplantation of MPC. Conditioned medium from cultured MPC was collected and analyzed for extracellular vesicles (EVs).

Results
Givi-MPC exhibited superior proliferation and migration capacity compared to control-MPC. Givi-MPC produced less reactive oxygen species (ROS) after oxidative stress and insignificant expression of IL6 after TNF-α stimulation. Upon transplantation in cardiotoxin (CTX)-injured hind limb of Mdx/SCID mice, the Givi-MPC showed robust engraftment and restored dystrophin in the treated muscle than in those treated with control-MPC or human myoblasts. Givi-MPC significantly limited infiltration of inflammatory cells and reduced muscle necrosis and fibrosis. Additionally, Givi-MPC seeded the stem cell pool in the treated muscle. Moreover, EVs released from Givi-MPC were enriched in several miRNAs related to myoangiogenesis including miR-181a, miR-17, miR-210 and miR-107, and miR-19b compared with EVs from human myoblasts.

Conclusions
It is concluded that hiPSCs reprogrammed into MPC by givinostat possessing anti-oxidative, anti-inflammatory, and muscle gene-promoting properties effectively repaired injured muscle and restored dystrophin in the injured muscle.
Generation of inner ear sensory neurons using blastocyst complementation in a Neurog1+/−−deficient mouse
Authors: Steevens Aleta R. , Griesbach Matthew W. , You Yun , Dutton James R. , Low Walter C. , Santi Peter A. 
Published: February 2021

AbstractThis research is the first to produce induced pluripotent stem cell-derived inner ear sensory neurons in the Neurog1+/− heterozygote mouse using blastocyst complementation. Additionally, this approach corrected non-sensory deficits associated with Neurog1 heterozygosity, indicating that complementation is specific to endogenous Neurog1 function. This work validates the use of blastocyst complementation as a tool to create novel insight into the function of developmental genes and highlights blastocyst complementation as a potential platform for generating chimeric inner ear cell types that can be transplanted into damaged inner ears to improve hearing.
Induced neural stem cell grafts exert neuroprotection through an interaction between Crry and Akt in a mouse model of closed head injury
Authors: Gao Mou , Dong Qin , Wang Wenjia , Yang Zhijun , Guo Lili , Lu Yingzhou , Ding Boyun , Chen Lihua , Zhang Jianning , Xu Ruxiang 
Published: February 2021

Abstract
Background
Recently, growing evidence has indicated an important role of the complement system, a crucial component of immunity, in mediating neuroinflammation and promoting neuronal apoptosis following closed head injury (CHI). We previously reported that transplanted induced neural stem cells (iNSCs) pre-treated with CHI mouse serum could enhance complement receptor type 1-related protein y (Crry) expression and ameliorate complement-mediated damage in mouse CHI models. However, the mechanism underlying the elevated levels of Crry expression remains elusive.

Methods
CHI models were established using a standardized weight-drop device. We collected CHI mouse serum at 12 h post-trauma. RT-QPCR assay, western blot analysis, complement deposition assay, Akt inhibition assay, flow cytometry, cell transplantation, and functional assay were utilized to clarify the mechanism of Crry expression in iNSCs receiving CHI mouse serum treatment.

Results
We observed dramatic increases in the levels of Crry expression and Akt activation in iNSCs receiving CHI mouse serum treatment. Remarkably, Akt inhibition led to the reduction of Crry expression in iNSCs. Intriguingly, the treatment of iNSC-derived neurons with recombinant complement receptor 2-conjugated Crry (CR2-Crry), which inhibits all complement pathways, substantially enhanced Crry expression and Akt activation in neurons after CHI mouse serum treatment. In subsequent in vitro experiments of pre-treatment of iNSCs with CR2-Crry, we observed significant increases in the levels of Crry expression and Akt activation in iNSCs and iNSC-derived astrocytes and neurons post-treatment with CHI mouse serum. Additionally, an in vivo study showed that intracerebral-transplanted iNSCs pre-treated with CR2-Crry markedly enhanced Crry expression in neurons and protected neurons from complement-dependent damage in the brains of CHI mice.

Conclusion
INSCs receiving CR2-Crry pre-treatment increased the levels of Crry expression in iNSCs and iNSC-derived astrocytes and neurons and attenuated complement-mediated injury following CHI.
Endometrial regeneration with endometrial epithelium: homologous orchestration with endometrial stroma as a feeder
Authors: Yokomizo Ryo , Fujiki Yukiko , Kishigami Harue , Kishi Hiroshi , Kiyono Tohru , Nakayama Sanae , Sago Haruhiko , Okamoto Aikou , Umezawa Akihiro 
Published: February 2021

Abstract
Background
Thin endometrium adversely affects reproductive success rates with fertility treatment. Autologous transplantation of exogenously prepared endometrium can be a promising therapeutic option for thin endometrium; however, endometrial epithelial cells have limited expansion potential, which needs to be overcome in order to make regenerative medicine a therapeutic strategy for refractory thin endometrium. Here, we aimed to perform long-term culture of endometrial epithelial cells in vitro.

Methods
We prepared primary human endometrial epithelial cells and endometrial stromal cells and investigated whether endometrial stromal cells and human embryonic stem cell-derived feeder cells could support proliferation of endometrial epithelial cells. We also investigated whether three-dimensional culture can be achieved using thawed endometrial epithelial cells and endometrial stromal cells.

Results
Co-cultivation with the feeder cells dramatically increased the proliferation rate of the endometrial epithelial cells. We serially passaged the endometrial epithelial cells on mouse embryonic fibroblasts up to passage 6 for 4 months. Among the human-derived feeder cells, endometrial stromal cells exhibited the best feeder activity for proliferation of the endometrial epithelial cells. We continued to propagate the endometrial epithelial cells on endometrial stromal cells up to passage 5 for 81 days. Furthermore, endometrial epithelium and stroma, after the freeze-thaw procedure and sequential culture, were able to establish an endometrial three-dimensional model.

Conclusions
We herein established a model of in vitro cultured endometrium as a potential therapeutic option for refractory thin endometrium. The three-dimensional culture model with endometrial epithelial and stromal cell orchestration via cytokines, membrane-bound molecules, extracellular matrices, and gap junction will provide a new framework for exploring the mechanisms underlying the phenomenon of implantation. Additionally, modified embryo culture, so-called “in vitro implantation”, will be possible therapeutic approaches in fertility treatment.
Human amniotic mesenchymal stem cells to promote/suppress cancer: two sides of the same coin
Authors: Jafari Ameneh , Rezaei-Tavirani Mostafa , Farhadihosseinabadi Behrouz , Zali Hakimeh , Niknejad Hassan 
Published: February 2021

AbstractCancer is a leading cause of death in both developed and developing countries, and because of population growth and aging, it is a growing medical burden worldwide. With robust development in medicine, the use of stem cells has opened new treatment modalities in cancer therapy. In adult stem cells, mesenchymal stem cells (MSCs) are showing rising promise in cancer treatment due to their unique properties. Among different sources of MSCs, human amniotic fluid/membrane is an attractive and suitable reservoir. There are conflicting opinions about the role of human amniotic membrane/fluid mesenchymal stem cells (hAMSCS/hAFMSCs) in cancer, as some studies demonstrating the anticancer effects of these cells and others suggesting their progressive effects on cancer. This review focuses on recent findings about the role of hAMSCs/hAFMSCs in cancer treatment and summarizes the suppressing as well as promoting effects of these cells on cancer progression and underling mechanisms.
RegioSQM20: improved prediction of the regioselectivity of electrophilic aromatic substitutions
Authors: Ree Nicolai , Göller Andreas H. , Jensen Jan H. 
Published: February 2021

AbstractWe present RegioSQM20, a new version of RegioSQM (Chem Sci 9:660, 2018), which predicts the regioselectivities of electrophilic aromatic substitution (EAS) reactions from the calculation of proton affinities. The following improvements have been made: The open source semiempirical tight binding program is used instead of the closed source program. Any low energy tautomeric forms of the input molecule are identified and regioselectivity predictions are made for each form. Finally, RegioSQM20 offers a qualitative prediction of the reactivity of each tautomer (low, medium, or high) based on the reaction center with the highest proton affinity. The inclusion of tautomers increases the success rate from 90.7 to 92.7%. RegioSQM20 is compared to two machine learning based models: one developed by Struble et al. (React Chem Eng 5:896, 2020) specifically for regioselectivity predictions of EAS reactions (WLN) and a more generally applicable reactivity predictor (IBM RXN) developed by Schwaller et al. (ACS Cent Sci 5:1572, 2019). RegioSQM20 and WLN offers roughly the same success rates for the entire data sets (without considering tautomers), while WLN is many orders of magnitude faster. The accuracy of the more general IBM RXN approach is somewhat lower: 76.3–85.0%, depending on the data set. The code is freely available under the MIT open source license and will be made available as a webservice (regiosqm.org) in the near future.