bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early impact of donor CYP3A5 genotype and Graft-to-Recipient Weight Ratio on tacrolimus pharmacokinetics in pediatric liver transplant patients
Authors: Pinon Michele , De Nicolò Amedeo , Pizzol Antonio , Antonucci Miriam , D’Avolio Antonio , Serpe Loredana , Dell’Olio Dominic , Catalano Silvia , Tandoi Francesco , Romagnoli Renato , Canaparo Roberto , Calvo Pier Luigi 
Published: January 2021

AbstractTacrolimus (TAC) pharmacokinetics is influenced by the donorCYP3A5genotype and the age of pediatric liver recipients. However, an optimization of a genotype-based algorithm for determining TAC starting is needed to earlier achieve stable target levels. As the graft itself is responsible for its metabolism, the Graft-to-Recipient Weight Ratio (GRWR) might play a role in TAC dose requirements. A single-center study was carried out in a cohort of 49 pediatric recipients to analyse the impact of patient and graft characteristics on TAC pharmacokinetics during the first 15 post-transplant days. Children < 2 years received grafts with a significantly higher GRWR (4.2%) than children between 2–8 (2.6%) and over 8 (2.7%). TAC concentration/weight-adjusted dose ratio was significantly lower in recipients fromCYP3A5*1/*3donors or with extra-large (GRWR > 5%) or large (GRWR 3–5%) grafts. The donorCYP3A5genotype and GRWR were the only significant predictors of the TAC weight adjusted doses. Patients with a GRWR > 4% had a higher risk of acute rejection, observed in 20/49 (41%) patients. In conclusion, TAC starting dose could be guided according to the donorCYP3A5genotype and GRWR, allowing for a quicker achievement of target concentrations and eventually reducing the risk of rejection.
Long-term follow-up study on surgical outcomes of the Faden operation in consecutive esotropia
Authors: Ha Suk-Gyu , Kim Seung-Hyun 
Published: January 2021

AbstractWe evaluated the long-term surgical outcomes of medial rectus (MR) recession with the Faden operation in consecutive esotropia (CET). We retrospectively analyzed patients who underwent MR recession with the Faden operation for CET between 2013 and 2018, and compared surgical outcomes between patients who underwent MR recession with the Faden operation (Faden group) and MR recession only (control group). We followed up the patients at 24 months postoperatively. Postoperative success was defined as final deviation of less than distant 5 prism diopters (PD) of eso- or exodeviation at the final visit. We compared postoperative alignment and stereoacuity between the two groups. Stereoacuity was classified as good (60 or better seconds of arc), fair (80–3000 s of arc) or nil. The Faden and control group included 11 and 13 patients, respectively. All patients in the Faden group showed orthophoria and eight patients (72.7%) showed good stereoacuity at the final visit. One patient (9.1%) in the Faden group showed adduction limitation at the final visit. Eight patients (61.5%) in the control group had successful outcomes at the final visit. Six patients (46.2%) in the control group showed good stereoacuity at the final visit. One patient (7.7%) in the control group underwent reoperation for recurrent esotropia at 18 months postoperatively. The surgical outcomes after MR recession with the Faden operation for CET were excellent in long-term follow- up. The Faden operation could be a good surgical option for CET.
Maternal high-fat-diet exposure is associated with elevated blood pressure and sustained increased leptin levels through epigenetic memory in offspring
Authors: Lin Xian-Hua , Gao Ling , Tian Shen , Klausen Christian , Guo Meng-Xi , Gao Qian , Liu Miao-E. , Wang Hui , Wu Dan-Dan , Zhou Cheng-Liang , Yang Jing , Meng Ye , Liu Ye , Xu Gu-Feng , Tan Ya-Jing , Ullah Kamran , Zhu Yi-Min , Fraser William D. , Sheng Jian-Zhong , Leung Peter C. K. , Muglia Louis J. , Wu Yan-Ting , Huang He-Feng 
Published: January 2021

AbstractMaternal metabolism dysregulation during pregnancy predisposes offspring to major diseases, including hypertension, in later life, but the mechanism involved remains to be fully elucidated. A high-fat-diet (HFD) pregnant rat model was used to investigate whether excessive intrauterine lipid exposure was associated with elevated blood pressure in offspring and increased levels of leptin, an important biomarker and mediator of vascular dysfunction and hypertension. We found that gestational hyperlipidemia predisposed offspring to blood pressure elevation and sustained increases in leptin levels with no difference in body weight in the rat model. Increased leptin expression and leptin promoter hypomethylation were found in adipose tissues of HFD-exposed offspring. The treatment of mesenchymal stem cells with free fatty acids during adipogenic differentiation resulted in increased leptin expression, accompanied by leptin promoter hypomethylation. In addition, we also followed up 121 children to evaluate the association between maternal triglyceride levels and offspring blood pressure. Consistent with the animal study results, we observed elevated serum leptin levels and blood pressure in the offspring born to women with gestational hypertriglyceridemia. Our findings provide new insights that maternal hyperlipidemia is associated with elevated blood pressure in offspring and is associated with increases in leptin levels through epigenetic memory.
Movement detection thresholds reveal proprioceptive impairments in developmental dyslexia
Authors: Laprevotte Julie , Papaxanthis Charalambos , Saltarelli Sophie , Quercia Patrick , Gaveau Jeremie 
Published: January 2021

AbstractDevelopmental dyslexia is associated with vision and hearing impairments. Whether these impairments are causes or comorbidities is controversial. Because both senses are heavily involved in reading, cognitive theories argue that sensory impairments are comorbidities that result from a lack of reading practice. Sensory theories instead argue that this is sensory impairments that cause reading disabilities. Here we test a discriminant prediction: whether sensory impairments in developmental dyslexia are restrained to reading-related senses or encompass other senses. Sensory theories predict that all senses are affected, whereas, according to the lack of reading practice argument, cognitive theories predict that only reading-related senses are affected. Using a robotic ergometer and fully automatized analyses, we tested proprioceptive acuity in seventeen dyslexic children and seventeen age-matched controls on a movement detection task. Compared to controls, dyslexics had higher and more variable detection thresholds. For the weakest proprioceptive stimuli, dyslexics were twice as long and twice as variable as controls. More, proprioceptive acuity strongly correlated with reading abilities, as measured by blind cognitive evaluations. These results unravel a new sensory impairment that cannot be attributed to a lack of reading practice, providing clear support to sensory theories of developmental dyslexia. Protocol registration: This protocol is part of the following registration, ClinicalTrials.gov Identifier: NCT03364010; December 6, 2017.
Ascending dorsal column sensory neurons respond to spinal cord injury and downregulate genes related to lipid metabolism
Authors: Ewan Eric E. , Avraham Oshri , Carlin Dan , Gonçalves Tassia Mangetti , Zhao Guoyan , Cavalli Valeria 
Published: January 2021

AbstractRegeneration failure after spinal cord injury (SCI) results in part from the lack of a pro-regenerative response in injured neurons, but the response to SCI has not been examined specifically in injured sensory neurons. Using RNA sequencing of dorsal root ganglion, we determined that thoracic SCI elicits a transcriptional response distinct from sciatic nerve injury (SNI). Both SNI and SCI induced upregulation of ATF3 and Jun, yet this response failed to promote growth in sensory neurons after SCI. RNA sequencing of purified sensory neurons one and three days after injury revealed that unlike SNI, the SCI response is not sustained. Both SCI and SNI elicited the expression of ATF3 target genes, with very little overlap between conditions. Pathway analysis of differentially expressed ATF3 target genes revealed that fatty acid biosynthesis and terpenoid backbone synthesis were downregulated after SCI but not SNI. Pharmacologic inhibition of fatty acid synthase, the enzyme generating palmitic acid, decreased axon growth and regeneration in vitro. These results support the notion that decreased expression of lipid metabolism-related genes after SCI, including fatty acid synthase, may restrict axon regenerative capacity after SCI.
epihet for intra-tumoral epigenetic heterogeneity analysis and visualization
Authors: Chen Xiaowen , Ashoor Haitham , Musich Ryan , Wang Jiahui , Zhang Mingsheng , Zhang Chao , Lu Mingyang , Li Sheng 
Published: January 2021

AbstractIntra-tumoral epigenetic heterogeneity is an indicator of tumor population fitness and is linked to the deregulation of transcription. However, there is no published computational tool to automate the measurement of intra-tumoral epigenetic allelic heterogeneity. We developed an R/Bioconductor package, epihet, to calculate the intra-tumoral epigenetic heterogeneity and to perform differential epigenetic heterogeneity analysis. Furthermore, epihet can implement a biological network analysis workflow for transforming cancer-specific differential epigenetic heterogeneity loci into cancer-related biological function and clinical biomarkers. Finally, we demonstrated epihet utility on acute myeloid leukemia. We found statistically significant differential epigenetic heterogeneity (DEH) loci compared to normal controls and constructed co-epigenetic heterogeneity network and modules. epihet is available at https://bioconductor.org/packages/release/bioc/html/epihet.html.
Increased planting density combined with reduced nitrogen rate to achieve high yield in maize
Authors: Du Xiangbei , Wang Zhi , Lei Weixia , Kong Lingcong 
Published: January 2021

AbstractThe combination effects of nitrogen (N) fertilizer and planting density on maize yield, N use efficiency and the characteristics of canopy radiation capture and radiation use efficiency are not well documented in the Huanghuaihai Plain region in China. A 2-year field experiment was conducted from 2017 to 2018 in a split plot design with two N levels (240 and 204 kg N ha−1) applied to main plots and three plant densities (67,500, 77,625 and 87,750 plants ha−1) allocated to sub plots. Our results show that a 30% greater plant density combined with a 15% lower N rate (basal N) enhanced N partial factor productivity (NPFP) by 24.7% and maize grain yield by 6.6% compared with those of the conventional high N rate combined with a low density planting management practice. The yield increase was mainly attributed to significantly increased kernel numbers and biomass. The increased intercepted photosynthetically active radiation (IPAR) was the primary factor responsible for the high productivity of maize at increased planting density under reduced N conditions. The results indicate that increase planting density with reduced basal N application might benefit maize cropping for achieving high yields and sustainable development of agriculture.
Individual-oocyte transcriptomic analysis shows that genotoxic chemotherapy depletes human primordial follicle reserve in vivo by triggering proapoptotic pathways without growth activation
Authors: Titus S. , Szymanska K. J. , Musul B. , Turan V. , Taylan E. , Garcia- Milian R. , Mehta S. , Oktay K. 
Published: January 2021

AbstractGonadotoxic chemotherapeutics, such as cyclophosphamide, can cause early menopause and infertility in women. Earlier histological studies showed ovarian reserve depletion via severe DNA damage and apoptosis, but others suggested activation of PI3K/PTEN/Akt pathway and follicle ‘burn-out’ as a cause. Using a human ovarian xenograft model, we performed single-cell RNA-sequencing on laser-captured individual primordial follicle oocytes 12 h after a single cyclophosphamide injection to determine the mechanisms of acute follicle loss after gonadotoxic chemotherapy. RNA-sequencing showed 190 differentially expressed genes between the cyclophosphamide- and vehicle-exposed oocytes. Ingenuity Pathway Analysis predicted a significant decrease in the expression of anti-apoptotic pro-AktPECAM1(p = 2.13E-09),IKBKE(p = 0.0001), andANGPT1(p = 0.003), and reduced activation of PI3K/PTEN/Akt after cyclophosphamide. The qRT-PCR and immunostaining confirmed that in primordial follicle oocytes, cyclophosphamide did not change the expressions ofAkt(p = 0.9),rpS6(p = 0.3),Foxo3a(p = 0.12) and anti-apoptoticBcl2(p = 0.17), nor affect their phosphorylation status. There was significantly increased DNA damage by γH2AX (p = 0.0002) and apoptosis by active-caspase-3 (p = 0.0001) staining in the primordial follicles and no change in the growing follicles 12 h after chemotherapy. These data support that the mechanism of acute follicle loss by cyclophosphamide is via apoptosis, rather than growth activation of primordial follicle oocytes in the human ovary.
HERC2 inactivation abrogates nucleolar localization of RecQ helicases BLM and WRN
Authors: Zhu Mingzhang , Wu Wenwen , Togashi Yukiko , Liang Weixin , Miyoshi Yasuo , Ohta Tomohiko 
Published: January 2021

AbstractThe nucleolus is a nuclear structure composed of ribosomal DNA (rDNA), and functions as a site for rRNA synthesis and processing. The rDNA is guanine-rich and prone to form G-quadruplex (G4), a secondary structure of DNA. We have recently found that HERC2, an HECT ubiquitin ligase, promotes BLM and WRN RecQ DNA helicases to resolve the G4 structure. Here, we report the role of HERC2 in the regulation of nucleolar localization of the helicases. Furthermore, HERC2 inactivation enhances the effects of CX-5461, an inhibitor of RNA polymerase I (Pol I)-mediated transcription of rRNA with an intrinsic G4-stabilizing activity. HERC2 depletion or homozygous deletion of the C-terminal HECT domain of HERC2 prevented the nucleolar localization of BLM and WRN, and inhibited relocalization of BLM to replication stress-induced nuclear RPA foci. HERC2 colocalized with fibrillarin and Pol I subunit RPA194, both of which are required for rRNA transcription. The HERC2 dysfunction enhanced the suppression of pre-rRNA transcription by CX-5461. These results suggest the effect of HERC2 status on the functions of BLM and WRN on rRNA transcription in the nucleolus. Since HERC2 is downregulated in numerous cancers, this effect may be clinically relevant considering the beneficial effects of CX-5461 in cancer treatments.
Bidirectional causal control in the dynamics of handstand balance
Authors: Wyatt Hannah E. , Vicinanza Domenico , Newell Karl M. , Irwin Gareth , Williams Genevieve K. R. 
Published: January 2021

AbstractThe aim of this study was to identify motor control solutions associated with the ability to maintain handstand balance. Using a novel approach, we investigated the dynamical interactions between centre of pressure (CoP) and centre of mass (CoM) motion. A gymnastics cohort was divided into a ‘less skilled’ group, who held handstands for 4–6 s, and a ‘more skilled’ group, who held handstands in excess of 10 s. CoP–CoM causality was investigated in anterior–posterior (AP) and medio-lateral (ML) directions, in addition to time–space, time–frequency and Hurst Exponent (H) analyses. Lower AP CoP to CoM causal drive and lowerHvalues (> 0.6) indicated the more skilled gymnasts were less reliant on CoP mechanics to drive CoM motion. More skilled performance demonstrated greater adaptability through use of reactive, as opposed to anticipatory, control strategies. Skilled performers additionally exploited mechanical advantages in ML (e.g. a wider base of support), compared to the less skilled athletes. A multiple regression analysis revealedHand frequency domain measures to be better predictors of handstand balance duration than time–space domain measures. The study findings highlight the advantage of an adaptable motor control system with a directional profile, and provide new insight into the clear, measurable footprint of CoP on the dynamics of CoM.
BIRC5 is a prognostic biomarker associated with tumor immune cell infiltration
Authors: Xu Linlong , Yu Wenpeng , Xiao Han , Lin Kang 
Published: January 2021

AbstractBIRC5 is an immune-related gene that inhibits apoptosis and promotes cell proliferation. It is highly expressed in most tumors and leads to poor prognosis in cancer patients. This study aimed to analyze the relationship between the expression level of BIRC5 in different tumors and patient prognosis, clinical parameters, and its role in tumor immunity. Genes co-expressed with BIRC5 were analyzed, and functional enrichment analysis was performed. The relationship between BIRC5 expression and the immune and stromal scores of tumors in pan-cancer patients and the infiltration level of 22 tumor-infiltrating lymphocytes (TILs) was analyzed. The correlation of BIRC5 with immune checkpoints was conducted. Functional enrichment analysis showed that genes co-expressed with BIRC5 were significantly associated with the mitotic cell cycle, APC/C-mediated degradation of cell cycle proteins, mitotic metaphase, and anaphase pathways. Besides, the high expression of BIRC5 was significantly correlated with the expression levels of various DNA methyltransferases, indicating that BIRC5 regulates DNA methylation. We also found that BIRC5 was significantly correlated with multiple immune cells infiltrates in a variety of tumors. This study lays the foundation for future research on how BIRC5 modulates tumor immune cells, which may lead to the development of more effective targeted tumor immunotherapies.
Defining a therapeutic range for regeneration of ischemic myocardium via shock waves
Authors: Pölzl Leo , Nägele Felix , Hirsch Jakob , Graber Michael , Lobenwein Daniela , Kirchmair Elke , Huber Rosalie , Dorfmüller Christian , Lechner Sophia , Schäfer Georg , Hermann Martin , Fritsch Helga , Tancevski Ivan , Grimm Michael , Holfeld Johannes , Gollmann-Tepeköylü Can 
Published: January 2021

AbstractShockwave therapy (SWT) represents a promising regenerative treatment option for patients with ischemic cardiomyopathy. Although no side-effects have been described upon SWT, potential cellular damage at therapeutic energies has not been addressed so far. In this work, we aimed to define a therapeutic range for shock wave application for myocardial regeneration. We could demonstrate that SWT does not induce cellular damage beneath energy levels of 0.27 mJ/mm2 total flux density. Endothelial cell proliferation, angiogenic gene expression and phosphorylation of AKT and ERK are enhanced in a dose dependent manner until 0.15 mJ/mm2 energy flux density. SWT induces regeneration of ischemic muscle in vivo via expression of angiogenic gene expression, enhanced neovascularization and improved limb perfusion in a dose-dependent manner. Therefore, we provide evidence for a dose-dependent induction of angiogenesis after SWT, as well as the absence of cellular damage upon SWT within the therapeutic range. These data define for the first time a therapeutic range of SWT, a promising regenerative treatment option for ischemic cardiomyopathy.
A functional interaction between GRP78 and Zika virus E protein
Authors: Khongwichit Sarawut , Sornjai Wannapa , Jitobaom Kunlakanya , Greenwood Mingkwan , Greenwood Michael P. , Hitakarun Atitaya , Wikan Nitwara , Murphy David , Smith Duncan R. 
Published: January 2021

AbstractZika virus (ZIKV) is a mosquito-transmitted virus that has caused significant public health concerns around the world, partly because of an association with microcephaly in babies born to mothers who were infected with ZIKV during pregnancy. As a recently emerging virus, little is known as to how the virus interacts with the host cell machinery. A yeast-2-hybrid screen for proteins capable of interacting with the ZIKV E protein domain III, the domain responsible for receptor binding, identified 21 proteins, one of which was the predominantly ER resident chaperone protein GRP78. The interaction of GRP78 and ZIKV E was confirmed by co-immunoprecipitation and reciprocal co-immunoprecipitation, and indirect immunofluorescence staining showed intracellular and extracellular co-localization between GRP78 and ZIKV E. Antibodies directed against the N-terminus of GRP78 were able to inhibit ZIKV entry to host cells, resulting in significant reductions in the levels of ZIKV infection and viral production. Consistently, these reductions were also observed after down-regulation of GRP78 by siRNA. These results indicate that GRP78 can play a role mediating ZIKV binding, internalization and replication in cells. GRP78 is a main regulator of the unfolded protein response (UPR), and the study showed that expression of GRP78 was up-regulated, and the UPR was activated. Increases in CHOP expression, and activation of caspases 7 and 9 were also shown in response to ZIKV infection. Overall these results indicate that the interaction between GRP78 and ZIKV E protein plays an important role in ZIKV infection and replication, and may be a potential therapeutic target.
Cigarette smoke-induced impairment of autophagy in macrophages increases galectin-8 and inflammation
Authors: Kono Yuta , Colley Thomas , To Masako , Papaioannou Andriana I. , Mercado Nicolas , Baker Jonathan R. , To Yasuo , Abe Shinji , Haruki Kosuke , Ito Kazuhiro , Barnes Peter J. 
Published: January 2021

AbstractCigarette smoke impairs autophagy, an intracellular protein degradation system, but the consequences of this defect have not been fully elucidated, especially in macrophages. Dysfunctional alveolar macrophages play an important role in chronic obstructive pulmonary disease (COPD). Here we show that galectin-8, a danger receptor that identifies damaged intracellular host vesicles and initiates autophagosome engulfment, is elevated due to activation of autophagy by cigarette smoke extract (CSE) in macrophages. CSE impaired autophagic flux in PMA-differentiated U937 macrophage-like cells, resulting in intracellular accumulation of galectin-8 and the autophagic adaptor protein NDP52. COPD patients showed elevated levels of galectin-8 and NDP52 in the lung homogenates with significant increase in the serum galectin-8 levels in patients with frequent acute exacerbations. Soluble galectin-8 induced interleukin (IL)-6 release in bronchial epithelial cells via PI3Kα signalling. Thus, increased galectin-8 due to CSE-induced impaired autophagy may be involved in the pathogenesis of COPD and may be a biomarker of this disease.
Safe and effective aerosolization of in vitro transcribed mRNA to the respiratory tract epithelium of horses without a transfection agent
Authors: Legere Rebecca M. , Cohen Noah D. , Poveda Cristina , Bray Jocelyne M. , Barhoumi Rola , Szule Joseph A. , de la Concha-Bermejillo Andrés , Bordin Angela I. , Pollet Jeroen 
Published: January 2021

AbstractVaccines and therapeutics using in vitro transcribed mRNA hold enormous potential for human and veterinary medicine. Transfection agents are widely considered to be necessary to protect mRNA and enhance transfection, but they add expense and raise concerns regarding quality control and safety. We found that such complex mRNA delivery systems can be avoided when transfecting epithelial cells by aerosolizing the mRNA into micron-sized droplets. In an equine in vivo model, we demonstrated that the translation of mRNA into a functional protein did not depend on the addition of a polyethylenimine (PEI)-derived transfection agent. We were able to safely and effectively transfect the bronchial epithelium of foals using naked mRNA (i.e., mRNA formulated in a sodium citrate buffer without a delivery vehicle). Endoscopic examination of the bronchial tree and histology of mucosal biopsies indicated no gross or microscopic adverse effects of the transfection. Our data suggest that mRNA administered by an atomization device eliminates the need for chemical transfection agents, which can reduce the cost and the safety risks of delivering mRNA to the respiratory tract of animals and humans.