bluuebunny/crossref_metadata_2025_split huggingface dataset:
PASylation Enhances the Stability, Potency, and Plasma Half‐Life of Interferon α‐2a: A Molecular Dynamics Simulation
Authors: Shamloo Amir , Rostami Peyman , Mahmoudi Ashkan 
Published: April 2020

AbstractIn this study, the effectiveness of PASylation in enhancing the potency and plasma half‐life of pharmaceutical proteins has been accredited as an alternative technique to the conventional methods such as PEGylation. Proline, alanine, and serine (PAS) chain has shown some advantages including biodegradability improvement and plasma half‐life enhancement while lacking immunogenicity or toxicity. Although some experimental studies have been performed to find the mechanism behind PASylation, the detailed mechanism of PAS effects on the pharmaceutical proteins has remained obscure, especially at the molecular level. In this study, the interaction of interferon α‐2a (IFN) and PAS chain is investigated using molecular dynamics simulation method. Several important parameters including secondary structure, root‐mean‐square distance, and solvent accessible surface area to investigate the stability, bioavailability, and bioactivity of the PASylated protein are studied. The results demonstrate that IFN conformation is not affected critically through PASylation while it results in improvement of the protein stability and bioactivity. Therefore, PASylation can be considered as a proper biological alternative technique to increase the plasma half‐life of the biopharmaceutical proteins through enlarging apparent volume. The proposed simulation represents a computational approach that would provide a basis for the study of PASylated pharmaceutical proteins for different future applications.
Fluorescent indicators for continuous and lineage‐specific reporting of cell‐cycle phases in human pluripotent stem cells
Authors: Chang Yun , Hellwarth Peter B. , Randolph Lauren N. , Sun Yufei , Xing Yuxian , Zhu Wuqiang , Lian Xiaojun Lance , Bao Xiaoping 
Published: April 2020

AbstractProper cell‐cycle progression is essential for the self‐renewal and differentiation of human pluripotent stem cells (hPSCs). The fluorescent ubiquitination‐based cell‐cycle indicator (FUCCI) has allowed the dual‐color visualization of the G1 and S/G2/M phases in various dynamic models, but its application in hPSCs is not widely reported. In addition, lineage‐specific FUCCI reporters have not yet been developed to analyze complex tissue‐specific cell‐cycle progression during hPSC differentiation. Desiring a robust tool for spatiotemporal reporting of cell‐cycle events in hPSCs, we employed the CRISPR/Cas9 genome editing tool and successfully knocked the FUCCI reporter into the AAVS1 safe harbor locus of hPSCs for stable and constitutive FUCCI expression, exhibiting reliable cell‐cycle‐dependent fluorescence in both hPSCs and their differentiated progeny. We also established a cardiac‐specific TNNT2‐FUCCI reporter for lineage‐specific cell‐cycle monitoring of cardiomyocyte differentiation from hPSCs. This powerful and modular FUCCI system should provide numerous opportunities for studying human cell‐cycle activity, and enable the identification and investigation of novel regulators for adult tissue regeneration.
Treatment of PERItoneal disease in Stomach Cancer with cytOreductive surgery and hyperthermic intraPEritoneal chemotherapy: PERISCOPE I initial results
Authors: Kaaij R T , Wassenaar E C E , Koemans W J , Sikorska K , Grootscholten C , Los M , Huitema A , Schellens J H M , Veenhof A A F A , Hartemink K J , Aalbers A G J , Ramshorst B , Boerma D , Boot H , Sandick J W 
Published: April 2020

Abstract

Background
The role of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer is unknown. This non-randomized dose-finding phase I–II study was designed to assess the safety and feasibility of HIPEC, following systemic chemotherapy, in patients with gastric cancer and limited peritoneal dissemination. The maximum tolerated dose of normothermic intraperitoneal docetaxel in combination with a fixed dose of intraperitoneal oxaliplatin was also explored.

Methods
Patients with resectable cT3–cT4a gastric adenocarcinoma with limited peritoneal metastases and/or tumour-positive peritoneal cytology were included. An open HIPEC technique was used with 460 mg/m2 hyperthermic oxaliplatin for 30 min followed by normothermic docetaxel for 90 min in escalating doses (0, 50, 75 mg/m2).

Results
Between 2014 and 2017, 37 patients were included. Of 25 patients who completed the full study protocol, four were treated at dose level 1 (0 mg/m2 docetaxel), six at dose level 2 (50 mg/m2) and four at dose level 3 (75 mg/m2). At dose level 3, two dose-limiting toxicities occurred, both associated with postoperative ileus. Thereafter, another 11 patients were treated at dose level 2, with no more dose-limiting toxicities. Based on this, the maximum tolerated dose was 50 mg/m2 intraperitoneal docetaxel. Serious adverse events were scored in 17 of 25 patients. The reoperation rate was 16 per cent (4 of 25) and the treatment-related mortality rate was 8 per cent (2 patients, both in dose level 3).

Conclusion
Gastrectomy combined with cytoreductive surgery and HIPEC was feasible using 460 mg/m2 oxaliplatin and 50 mg/m2 normothermic docetaxel.
Total tumour volume as a prognostic factor in patients with resectable colorectal cancer liver metastases
Authors: Tai K , Komatsu S , Sofue K , Kido M , Tanaka M , Kuramitsu K , Awazu M , Gon H , Tsugawa D , Yanagimoto H , Toyama H , Murakami S , Murakami T , Fukumoto T 
Published: April 2020

Abstract

Background
Although total tumour volume (TTV) may have prognostic value for hepatic resection in certain solid cancers, its importance in colorectal liver metastases (CRLM) remains unexplored. This study investigated its prognostic value in patients with resectable CRLM.

Method
This was a retrospective review of patients who underwent hepatic resection for CRLM between 2008 and 2017 in a single institution. TTV was measured from CT images using three-dimensional construction software; cut-off values were determined using receiver operating characteristic (ROC) curve analyses. Potential prognostic factors, overall survival (OS) and recurrence-free survival (RFS) were determined using multivariable and Kaplan–Meier analyses.

Results
Some 94 patients were included. TTV cut-off values for OS and RFS were 100 and 10 ml respectively. Right colonic primary tumours, primary lymph node metastasis and bilobar liver metastasis were included in the multivariable analysis of OS; a TTV of 100 ml or above was independently associated with poorer OS (hazard ratio (HR) 6·34, 95 per cent c.i. 2·08 to 17·90; P = 0·002). Right colonic primary tumours and primary lymph node metastasis were included in the RFS analysis; a TTV of 10 ml or more independently predicted poorer RFS (HR 1·90, 1·12 to 3·57; P = 0·017). The 5-year OS rate for a TTV of 100 ml or more was 41 per cent, compared with 67 per cent for a TTV below 100 ml (P = 0·006). Corresponding RFS rates with TTV of 10 ml or more, or less than 10 ml, were 14 and 58 per cent respectively (P = 0·009). A TTV of at least 100 ml conferred a higher rate of unresectable initial recurrences (12 of 15, 80 per cent) after initial hepatic resection.

Conclusion
TTV was associated with RFS and OS after initial hepatic resection for CRLM; TTV of 100 ml or above was associated with a higher rate of unresectable recurrence.
Generation and characterization of Six2 conditional mice
Authors: Li Chaochang , Liu Han , Hu Yueh‐Chiang , Lan Yu , Jiang Rulang 
Published: April 2020

SummaryHeterozygous deletion of Six2, which encodes a member of sine oculis homeobox family transcription factors, has recently been associated with the frontonasal dysplasia syndrome FND4. Previous studies showed that Six2 is expressed in multiple tissues during craniofacial development in mice, including embryonic head mesoderm, postmigratory frontonasal neural crest cells, and epithelial and mesenchymal cells of the developing palate and nasal structures. Whereas Six2
−/− mice exhibited cranial base defects but did not recapitulate frontonasal phenotypes of FND4 patients, Six1
−/‐Six2
−/− double mutant mice showed severe craniofacial defects including midline facial clefting. The complex phenotypes of FND4 patients and of Six1
−/‐Six2
−/− mutant mice indicate that Six2 plays crucial roles in distinct cell types at multiple stages of craniofacial morphogenesis. Here we report generation of mice carrying insertions of a pair of loxP sites flanking exon‐1 of the Six2 gene (Six2
f allele) using CRISPR/Cas9‐mediated genome editing. We show that the Six2
f allele functions normally and is effectively inactivated by Cre‐mediated recombination in vivo. Furthermore, we show that Six2
f/f;Wnt1‐Cre mice recapitulated cranial base defects but not neonatal lethality of Six2
−/− mice. These results indicate that Six2
f/f mice enable systematic investigation of cell type‐ and stage‐specific Six2 function in development and disease.
Simple embryo injection of long single‐stranded donor templates with the CRISPR/Cas9 system leads to homology‐directed repair in Xenopus tropicalis and Xenopus laevis
Authors: Nakayama Takuya , Grainger Robert M. , Cha Sang‐Wook 
Published: April 2020

SummaryWe report model experiments in which simple microinjection of fertilized eggs has been used to effectively perform homology‐directed repair (HDR)‐mediated gene editing in the two Xenopus species used most frequently for research: X. tropicalis and X. laevis. We have used long single‐stranded DNAs having phosphorothioate modifications as donor templates for HDR at targeted genomic sites using the Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR‐associated protein 9 (CRISPR/Cas9) system. First, X. tropicalis tyr mutant (i.e., albino) embryos were successfully rescued: partially pigmented tadpoles were seen in up to 35% of injected embryos, demonstrating the potential for efficient insertion of targeted point mutations. Second, in order to demonstrate the ability to tag genes with fluorescent proteins (FPs), we targeted the melanocyte‐specific gene slc45a2.L of X. laevis to label it with the Superfolder green FP (sfGFP), seeing mosaic expression of sfGFP in melanophores in up to 20% of injected tadpoles. Tadpoles generated by these two approaches were raised to sexual maturity, and shown to successfully transmit HDR constructs through the germline with precise targeting and seamless recombination. F1 embryos showed rescue of the tyr mutation (X. tropicalis) and tagging in the appropriate pigment cell‐specific manner of slc45a2.L with sfGFP (X. laevis).
Improving emotion recognition in anorexia nervosa: An experimental proof‐of‐concept study
Authors: Preis Mira A. , Schlegel Katja , Stoll Linda , Blomberg Maximilian , Schmidt Hagen , Wünsch‐Leiteritz Wally , Leiteritz Andreas , Brockmeyer Timo 
Published: April 2020

AbstractObjectivePrevious research has found increasing evidence for difficulties in emotion recognition ability (ERA) and social cognition in anorexia nervosa (AN), and recent models consider these factors to contribute to the development and maintenance of the disorder. However, there is a lack of experimental studies testing this hypothesis. Therefore, the present proof‐of‐concept study examined whether ERA can be improved by a single session of a computerized training in AN, and whether this has short‐term effects on eating disorder symptoms.MethodForty inpatients (22.20 ± 7.15 years) with AN were randomly assigned to receive a single session of computerized training of ERA (TERA) or a sham training (training the recognition of different types of clouds). ERA, self‐reported eating disorder symptoms, and body mass index (BMI) were assessed within 3 days before and after training.ResultsAfter training, both groups showed improved ERA, reduced self‐reported eating disorder symptoms, and an increased BMI. As compared to patients in the control group, patients who received TERA showed greater improvements in ERA and self‐reported eating disorder symptoms.DiscussionERA can be effectively trained in patients with AN. Moreover, short‐term improvements in self‐reported eating disorder symptoms provide tentative support for the hypothesis that difficulties in ERA contribute to the maintenance of AN, and that specific trainings of ERA hold promise as an additional component in AN treatment. Future studies are needed to replicate these findings in larger samples, and to investigate long‐term effects and transfer into real‐world settings.
Magnitude and direction of stream–forest community interactions change with timescale
Authors: Marcarelli Amy M. , Baxter Colden V. , Benjamin Joseph R. , Miyake Yo , Murakami Masashi , Fausch Kurt D. , Nakano Shigeru 
Published: April 2020

AbstractNetworks of direct and indirect biotic interactions underpin the complex dynamics and stability of ecological systems, yet experimental and theoretical studies often yield conflicting evidence regarding the direction (positive or negative) or magnitude of these interactions. We revisited pioneering data sets collected at the deciduous forested Horonai Stream and conducted ecosystem‐level syntheses to demonstrate that the direction of direct and indirect interactions can change depending on the timescale of observation. Prior experimental studies showed that terrestrial prey that enter the stream from the adjacent forest caused positive indirect effects on aquatic invertebrates during summer by diverting fish consumption. Seasonal and annual estimates of secondary production and organic matter flows along food web pathways demonstrate that this seasonal input of terrestrial invertebrate prey increases production of certain fish species, reversing the indirect effect on aquatic invertebrates from positive at the seasonal timescale to negative at the annual timescale. Even though terrestrial invertebrate prey contributed 54% of the annual organic matter flux to fishes, primarily during summer, fish still consumed 98% of the aquatic invertebrate annual production, leading to top‐down control that is not revealed in short‐term experiments and demonstrating that aquatic prey may be a limiting resource for fishes. Changes in the direction or magnitude of interactions may be a key factor creating nonlinear or stabilizing feedbacks in complex systems, and these dynamics can be revealed by merging experimental and comparative approaches at different scales.
Prussian Blue Nanocubes‐SnO2 Quantum Dots‐Reduced Graphene Oxide Ternary Nanocomposite: An Efficient Non‐noble‐metal Electrocatalyst for Non‐enzymatic Detection of H2O2
Authors: Chauhan Seema , Sahoo Srikant , Satpati Ashis Kumar , Sharma Chhaya , Sahoo Prasanta Kumar 
Published: April 2020

AbstractDeveloping non‐noble‐metal electrocatalyst for non‐enzymatic H2O2 sensing is highly attractive. A facile, two‐step approach has been utilized for the synthesis of PBNCs/SnO2 QDs/RGO ternary nanocomposite. TEM, SEM, XPS, and XRD techniques were used to the characterize the structural and morphological properties of synthesized ternary nanocomposite. The synthesized ternary nanocomposite has been examined as an electrode material for the electrochemical detection of H2O2 using the Amperometry technique. Under optimum conditions, PBNCs/SnO2 QDs/RGO ternary nanocomposite performed very well in the electrocatalytic reduction of H2O2 with a linear dynamic range from 25–225 μM (R2=0.996) with a low detection limit of 71 nM (S/N=3). Compared to the recent literature, PBNCs/SnO2QDs/RGO ternary nanocomposite based modified electrode exhibit a wider linear dynamic range with a low detection limit. Furthermore, PBNCs/SnO2 QDs/RGO ternary nanocomposite based modified electrode showed an excellent anti‐interference ability against various common interfering agents. The practical applicability of this ternary nanocomposite based modified electrode was further extended to determine the H2O2 in tap water with acceptable recovery. The present performance of PBNCs/SnO2 QDs/RGO ternary nanocomposite material towards H2O2 sensing might widen its application for developing a new type of non‐noble metal‐based non‐enzymatic electrochemical biosensors.
The metabolic response to inflammation in astrocytes is regulated by nuclear factor‐kappa B signaling
Authors: Robb Josephine L. , Hammad Nadia A. , Weightman Potter Paul G. , Chilton John K. , Beall Craig , Ellacott Kate L. J. 
Published: April 2020

AbstractInflammation and metabolism are intrinsically linked with inflammatory stimuli inducing metabolic changes in cells and, in turn, metabolic capacity determining cellular inflammatory responses. Although well characterized in peripheral immune cells there is comparatively less known about these “immunometabolic” responses in astrocytes. In this study, we tested the hypothesis that the astrocytic inflammatory response driven by nuclear factor‐kappa B (NF‐κB) signaling is dependent on glycolytic metabolism. Using mouse primary cortical astrocyte cultures, we assessed changes in cellular metabolism after exposure to lipopolysaccharide (LPS), with cytokine ELISAs and immunoblotting being used to measure inflammatory responses. Results indicate temporally distinct metabolic adaptations to pro‐inflammatory stimulation in astrocytes: 3 hr LPS treatment increased glycolysis but did not alter mitochondrial metabolism, while following 24 hr of LPS treatment we observed increased oxidative phosphorylation, and decreased glycolytic capacity and glucose uptake, partly due to reduced glucose transporter 1 expression. Inhibition of NF‐κB signaling with the IKK‐beta inhibitor TPCA‐1 prevented the LPS induced changes to glycolysis and oxidative phosphorylation. Furthermore, TPCA‐1 treatment altered both glycolysis and oxidative phosphorylation independently from inflammatory stimulation, indicating a role for NF‐κB signaling in regulation of basal metabolism in astrocytes. Inhibition of glycolysis with 2‐deoxyglucose significantly attenuated LPS‐induced cytokine release and NF‐κB phosphorylation, indicating that intact glycolysis is required for the full inflammatory response to LPS. Together our data indicate that astrocytes display immunometabolic responses to acute LPS stimulation which may represent a potential therapeutic target for neuroinflammatory disorders.
Hepatic Choline Transport Is Inhibited During Fatty Acid–Induced Lipotoxicity and Obesity
Authors: O’Dwyer Conor , Yaworski Rebecca , Katsumura Sakie , Ghorbani Peyman , Gobeil Odai Kaelan , Nunes Julia R.C. , LeBlond Nicholas D. , Sanjana Sabrin , Smith Tyler T.K. , Han Shauna , Margison Kaitlyn D. , Alain Tommy , Morita Masahiro , Fullerton Morgan D. 
Published: April 2020

Choline is an essential nutrient and a critical component of the membrane phospholipid phosphatidylcholine (PC), the neurotransmitter acetylcholine, while also contributing to the methylation pathway. In the liver specifically, PC is the major membrane constituent and can be synthesized by the cytidine diphosphate–choline or the phosphatidylethanolamine N‐methyltransferase pathway. With the continuing global rise in the rates of obesity and nonalcoholic fatty liver disease, we sought to explore how excess fatty acids on primary hepatocytes and diet‐induced obesity affect choline uptake and metabolism. Our results demonstrate that hepatocytes chronically treated with palmitate, but not oleate or a mixture, had decreased choline uptake, which was associated with lower choline incorporation into PC and lower expression of choline transport proteins. Interestingly, a reduction in the rate of degradation spared PC levels in response to palmitate when compared with control. The effects of palmitate treatment were independent of endoplasmic reticulum stress, which counterintuitively augmented choline transport and transporter expression. In a model of obesity‐induced hepatic steatosis, male mice fed a 60% high‐fat diet for 10 weeks had significantly diminished hepatic choline uptake compared with lean mice fed a control diet. Although the transcript and protein expression of various choline metabolic enzymes fluctuated slightly, we observed reduced protein expression of choline transporter‐like 1 (CTL1) in the liver of mice fed a high‐fat diet. Polysome profile analyses revealed that in livers of obese mice, the CTL1 transcript, despite being more abundant, was translated to a lesser extent compared with lean controls. Finally, human liver cells demonstrated a similar response to palmitate treatment. Conclusion: Our results suggest that the altered fatty acid milieu seen in obesity‐induced fatty liver disease progression may adversely affect choline metabolism, potentially through CTL1, but that compensatory mechanisms work to maintain phospholipid homeostasis.
Tidal regime shift in Lingdingyang Bay, the Pearl River Delta: An identification and assessment of driving factors
Authors: Wang Heng , Zhang Ping , Hu Shuai , Cai Huayang , Fu Linxi , Liu Feng , Yang Qingshu 
Published: April 2020

AbstractBoth natural changes (e.g., tidal forcing from the ocean and global sea level rise) and human‐induced changes (e.g., dredging for navigation, sand excavation, and land reclamation) exert considerable influences on the long‐term evolution of tidal regimes in estuaries. Evaluating the impacts of these factors on tidal‐regime shifts is particularly important for the protection and management of estuarine environments. In this study, an analytical approach is developed to investigate the impacts of estuarine morphological alterations (mean water depth and width convergence length) on tidal hydrodynamics in Lingdingyang Bay, Southeast China. Based on the observed tidal levels from two tidal gauging stations along the channel, tidal wave celerity and tidal damping/amplification rate of different tidal constituents are computed using tidal amplitude and phase of tidal constituents extracted from a standard harmonic analysis. We show that the minimum mean water depth for the whole estuary occurred in 2006, whereas a shift in tidal wave celerity for the M2 tide component occurred in 2009. As such, the study period (1990–2016) could be separated into pre‐human (1990–2009) and post‐human (2010–2016) phases. Our results show that the damping/amplification rate and celerity of the M2 tide have increased by 31% (from 7 to 9.2 m−1) and 28% (from 7 to 9 m·s−1) respectively, as a consequence of the substantial impacts of human interventions. The proposed analytical method is subsequently applied to analyse the historical development of tidal hydrodynamics and regime shifts induced by human interventions, thus linking the evolution of estuarine morphology to the dominant tidal hydrodynamics along the channel. The observed tidal regime shift is primarily caused by channel deepening, which substantially enlarged the estuary and reduced effective bottom friction resulting in faster celerity and stronger wave amplification. Our proposed method for quantifying the impacts of human interventions on tidal regime shifts can inform evidence‐based guidelines for evaluating hydraulic responses to future engineering activities.