bluuebunny/crossref_metadata_2025_split huggingface dataset:
Substrate-induced conformational dynamics of the dopamine transporter
Authors: Nielsen Anne Kathrine , Möller Ingvar R. , Wang Yong , Rasmussen Søren G. F. , Lindorff-Larsen Kresten , Rand Kasper D. , Loland Claus J. 
Published: June 2019

AbstractThe dopamine transporter is a member of the neurotransmitter:sodium symporters (NSSs), which are responsible for termination of neurotransmission through Na+-driven reuptake of neurotransmitter from the extracellular space. Experimental evidence elucidating the coordinated conformational rearrangements related to the transport mechanism has so far been limited. Here we probe the global Na+- and dopamine-induced conformational dynamics of the wild-typeDrosophila melanogasterdopamine transporter using hydrogen-deuterium exchange mass spectrometry. We identify Na+- and dopamine-induced changes in specific regions of the transporter, suggesting their involvement in protein conformational transitions. Furthermore, we detect ligand-dependent slow cooperative fluctuations of helical stretches in several domains of the transporter, which could be a molecular mechanism that assists in the transporter function. Our results provide a framework for understanding the molecular mechanism underlying the function of NSSs by revealing detailed insight into the state-dependent conformational changes associated with the alternating access model of the dopamine transporter.
Conformational manipulation of scale-up prepared single-chain polymeric nanogels for multiscale regulation of cells
Authors: Chen Xiaoyu , Li Rui , Wong Siu Hong Dexter , Wei Kongchang , Cui Miao , Chen Huaijun , Jiang Yuanzhang , Yang Boguang , Zhao Pengchao , Xu Jianbin , Chen Heng , Yin Chao , Lin Sien , Lee Wayne Yuk-Wai , Jing Yihan , Li Zhen , Yang Zhengmeng , Xia Jiang , Chen Guosong , Li Gang , Bian Liming 
Published: June 2019

AbstractFolded single chain polymeric nano-objects are the molecular level soft material with ultra-small size. Here, we report an easy and scalable method for preparing single-chain nanogels (SCNGs) with improved efficiency. We further investigate the impact of the dynamic molecular conformational change of SCNGs on cellular interactions from molecular to bulk scale. First, the supramolecular unfoldable SCNGs efficiently deliver siRNAs into stem cells as a molecular drug carrier in a conformation-dependent manner. Furthermore, the conformation changes of SCNGs enable dynamic and precise manipulation of ligand tether structure on 2D biomaterial interfaces to regulate the ligand–receptor ligation and mechanosensing of cells. Lastly, the dynamic SCNGs as the building blocks provide effective energy dissipation to bulk biomaterials such as hydrogels, thereby protecting the encapsulated stem cells from deleterious mechanical shocks in 3D matrix. Such a bottom-up molecular tailoring strategy will inspire further applications of single-chain nano-objects in the biomedical area.
Establishing microbial composition measurement standards with reference frames
Authors: Morton James T. , Marotz Clarisse , Washburne Alex , Silverman Justin , Zaramela Livia S. , Edlund Anna , Zengler Karsten , Knight Rob 
Published: June 2019

AbstractDifferential abundance analysis is controversial throughout microbiome research. Gold standard approaches require laborious measurements of total microbial load, or absolute number of microorganisms, to accurately determine taxonomic shifts. Therefore, most studies rely on relative abundance data. Here, we demonstrate common pitfalls in comparing relative abundance across samples and identify two solutions that reveal microbial changes without the need to estimate total microbial load. We define the notion of “reference frames”, which provide deep intuition about the compositional nature of microbiome data. In an oral time series experiment, reference frames alleviate false positives and produce consistent results on both raw and cell-count normalized data. Furthermore, reference frames identify consistent, differentially abundant microbes previously undetected in two independent published datasets from subjects with atopic dermatitis. These methods allow reassessment of published relative abundance data to reveal reproducible microbial changes from standard sequencing output without the need for new assays.
Brain leptin reduces liver lipids by increasing hepatic triglyceride secretion and lowering lipogenesis
Authors: Hackl Martina Theresa , Fürnsinn Clemens , Schuh Christina Maria , Krssak Martin , Carli Fabrizia , Guerra Sara , Freudenthaler Angelika , Baumgartner-Parzer Sabina , Helbich Thomas H. , Luger Anton , Zeyda Maximilian , Gastaldelli Amalia , Buettner Christoph , Scherer Thomas 
Published: June 2019

AbstractHepatic steatosis develops when lipid influx and production exceed the liver’s ability to utilize/export triglycerides. Obesity promotes steatosis and is characterized by leptin resistance. A role of leptin in hepatic lipid handling is highlighted by the observation that recombinant leptin reverses steatosis of hypoleptinemic patients with lipodystrophy by an unknown mechanism. Since leptin mainly functions via CNS signaling, we here examine in rats whether leptin regulates hepatic lipid flux via the brain in a series of stereotaxic infusion experiments. We demonstrate that brain leptin protects from steatosis by promoting hepatic triglyceride export and decreasing de novo lipogenesis independently of caloric intake. Leptin’s anti-steatotic effects are generated in the dorsal vagal complex, require hepatic vagal innervation, and are preserved in high-fat-diet-fed rats when the blood brain barrier is bypassed. Thus, CNS leptin protects from ectopic lipid accumulation via a brain-vagus-liver axis and may be a therapeutic strategy to ameliorate obesity-related steatosis.
IL-33 drives group 2 innate lymphoid cell-mediated protection during Clostridium difficile infection
Authors: Frisbee Alyse L. , Saleh Mahmoud M. , Young Mary K. , Leslie Jhansi L. , Simpson Morgan E. , Abhyankar Mayuresh M. , Cowardin Carrie A. , Ma Jennie Z. , Pramoonjago Patcharin , Turner Stephen D. , Liou Alice P. , Buonomo Erica L. , Petri William A. 
Published: June 2019

AbstractClostridium difficile (C. difficile) incidence has tripled over the past 15 years and is attributed to the emergence of hypervirulent strains. While it is clear that C. difficile toxins cause damaging colonic inflammation, the immune mechanisms protecting from tissue damage require further investigation. Through a transcriptome analysis, we identify IL-33 as an immune target upregulated in response to hypervirulent C. difficile. We demonstrate that IL-33 prevents C. difficile-associated mortality and epithelial disruption independently of bacterial burden or toxin expression. IL-33 drives colonic group 2 innate lymphoid cell (ILC2) activation during infection and IL-33 activated ILC2s are sufficient to prevent disease. Furthermore, intestinal IL-33 expression is regulated by the microbiota as fecal microbiota transplantation (FMT) rescues antibiotic-associated depletion of IL-33. Lastly, dysregulated IL-33 signaling via the decoy receptor, sST2, predicts C. difficile-associated mortality in human patients. Thus, IL-33 signaling to ILC2s is an important mechanism of defense from C. difficile colitis.
Methylation and transcription patterns are distinct in IDH mutant gliomas compared to other IDH mutant cancers
Authors: Unruh Dusten , Zewde Makda , Buss Adam , Drumm Michael R. , Tran Anh N. , Scholtens Denise M. , Horbinski Craig 
Published: June 2019

AbstractMutations in isocitrate dehydrogenases 1 and 2 (IDHmut) are present in a variety of cancers, including glioma, acute myeloid leukemia (AML), melanoma, and cholangiocarcinoma. These mutations promote hypermethylation, yet it is only a favorable prognostic marker in glioma, for reasons that are unclear. We hypothesized that the patterns of DNA methylation, and transcriptome profiles, would vary among IDHmut cancers, especially gliomas. Using Illumina 450K and RNA-Seq data from The Cancer Genome Atlas, we show that of 365,092 analyzed CpG sites, 70,591 (19%) were hypermethylated in IDHmut gliomas compared to wild-type (IDHwt) gliomas, and only 3%, 2%, and 4% of CpG sites were hypermethylated in IDHmut AML, melanoma, and cholangiocarcinoma, relative to each of their IDHwt counterparts. Transcriptome differences showed pro-malignant genes that appear to be unique to IDHmut gliomas. However, genes involved in differentiation and immune response were suppressed in all IDHmut cancers. Additionally, IDHmut caused a greater degree of hypermethylation in undifferentiated neural progenitor cells than in mature astrocytes. These data suggest that the extent and targets of IDHmut-induced genomic hypermethylation vary greatly according to the cellular context and may help explain why IDHmut is only a favorable prognostic marker in gliomas.
Analysing the evolutional and functional differentiation of four types of Daphnia magna cryptochrome in Drosophila circadian clock
Authors: Nitta Yohei , Matsui Sayaka , Kato Yukine , Kaga Yosuke , Sugimoto Kenkichi , Sugie Atsushi 
Published: June 2019

AbstractCryptochrome (CRY) plays an important role in the input of circadian clocks in various species, but gene copies in each species are evolutionarily divergent. Type I CRYs function as a photoreceptor molecule in the central clock, whereas type II CRYs directly regulate the transcriptional activity of clock proteins. Functions of other types of animal CRYs in the molecular clock remain unknown. The water flea Daphnia magna contains four Cry genes. However, it is still difficult to analyse these four genes. In this study, we took advantage of powerful genetic resources available from Drosophila to investigate evolutionary and functional differentiation of CRY proteins between the two species. We report differences in subcellular localisation of each D. magna CRY protein when expressed in the Drosophila clock neuron. Circadian rhythm behavioural experiments revealed that D. magna CRYs are not functionally conserved in the Drosophila molecular clock. These findings provide a new perspective on the evolutionary conservation of CRY, as functions of the four D. magna CRY proteins have diverse subcellular localisation levels. Furthermore, molecular clocks of D. magna have been evolutionarily differentiated from those of Drosophila. This study highlights the extensive functional diversity existing among species in their complement of Cry genes.
Mechanical characterization of squid giant axon membrane sheath and influence of the collagenous endoneurium on its properties
Authors: Montanino Annaclaudia , Deryckere Astrid , Famaey Nele , Seuntjens Eve , Kleiven Svein 
Published: June 2019

AbstractTo understand traumas to the nervous system, the relation between mechanical load and functional impairment needs to be explained. Cellular-level computational models are being used to capture the mechanism behind mechanically-induced injuries and possibly predict these events. However, uncertainties in the material properties used in computational models undermine the validity of their predictions. For this reason, in this study the squid giant axon was used as a model to provide a description of the axonal mechanical behavior in a large strain and high strain rate regime $$({\boldsymbol{\varepsilon }}={\bf{10}}{\boldsymbol{ \% }},\,\mathop{{\boldsymbol{\varepsilon }}}\limits^{\cdot }={\bf{1}}{{\boldsymbol{s}}}^{-{\bf{1}}})$$
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, which is relevant for injury investigations. More importantly, squid giant axon membrane sheaths were isolated and tested under dynamic uniaxial tension and relaxation. From the lumen outward, the membrane sheath presents: an axolemma, a layer of Schwann cells followed by the basement membrane and a prominent layer of loose connective tissue consisting of fibroblasts and collagen. Our results highlight the load-bearing role of this enwrapping structure and provide a constitutive description that could in turn be used in computational models. Furthermore, tests performed on collagen-depleted membrane sheaths reveal both the substantial contribution of the endoneurium to the total sheath’s response and an interesting increase in material nonlinearity when the collagen in this connective layer is digested. All in all, our results provide useful insights for modelling the axonal mechanical response and in turn will lead to a better understanding of the relationship between mechanical insult and electrophysiological outcome.
Predictive Value of Pretherapeutic Maximum Standardized Uptake Value (Suvmax) In Laryngeal and Hypopharyngeal Cancer
Authors: Werner Jonas , Hüllner Martin W. , Rupp Niels J. , Huber Alexander M. , Broglie Martina A. , Huber Gerhard F. , Morand Grégoire B. 
Published: June 2019

AbstractThe aim of the study was to evaluate whether pretherapeutic metabolic tumor parameters from 18-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging could predict larynx preservation in laryngeal and hypopharyngeal cancer patients prior to primary chemoradiation. Tumor metabolic parameters [maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG)] were retrospectively assessed in a consecutive cohort of laryngeal and hypopharyngeal cancer patients undergoing primary (chemo-)radiation. Main outcome measures were larynx preservation and survival. The study included 97 patients with a median follow-up of 32 months (IQR 20–54.5). For hypopharyngeal cancer, multivariable analysis showed that patients with a primary tumor’s SUVmax > 9.5 entailed a higher risk of undergoing salvage pharyngolaryngectomy after chemoradiation (HR = 8.64, 95% CI = 1.1–67.3, P = 0.040). In laryngeal cancer, SUVmax did not predict the need for salvage laryngectomy. The only predictor for larynx preservation in laryngeal cancer patients was T-classification at initial diagnosis (HR = 6.67, 95% CI = 0.82–53.9, P = 0.039). In conclusion, SUVmax of primary tumor could be used as a predictor of larynx preservation prior to primary chemoradiation in hypopharyngeal cancer patients. This information may be important for patient counseling, as high SUVmax was correlated with reduced probability of larynx preservation. However, in laryngeal cancer patients, SUVmax does not seem to be predictive of outcome.
Midterm prognosis of type B aortic dissection with and without dissecting aneurysm of descending thoracic aorta after endovascular repair
Authors: Wang Jian , Zhao Jichun , Ma Yukui , Huang Bin , Yuan Ding , Yang Yi 
Published: June 2019

AbstractFew studies support guidelines for the use of thoracic endovascular aortic repair (TEVAR) to address type B aortic dissection (TBAD) coexisting with descending thoracic aortic dissection and aneurysm (dTADA). This cohort study investigated midterm outcomes of TBAD with dTADA (dTADA group, n = 31) and without dTADA (non-dTADA group, n = 98) after TEVAR. Compared with the non-dTADA group, the dTADA group exhibited higher incidences of type Ia endoleak (29.0% vs. 3.1%, P < 0.001) and reintervention (16.1% vs. 5.1%, P = 0.045). The completely thrombosed rate of the thoracic false lumen was significantly lower in the dTADA group than in the non-dTADA group (45.2% vs. 80.6%, P < 0.001). Although the two groups exhibited similar mortality rates, TBAD coexisting with no regressive dTADA after TEVAR was an independent predictor of mortality (HR: 15.52, 95% CI: 1.614–149.233, P = 0.018). Moreover, the change percentages of false lumen retraction and true lumen re-expansion in the dTADA group were significantly inferior to those of the non-dTADA group at levels of 4th, 6th, 8th and 10th thoracic vertebra throughout follow-up. In conclusion, in the presence of preexisting dTADA, the failure of the dTADA to regress after TEVAR is associated with lower survival and a higher risk of reintervention.
Mechanism of gut microbiota and Axl/SOCS3 in experimental autoimmune encephalomyelitis
Authors: Li Xiao-Ling , Zhang Bo , Sun Meng-Jiao , Bao Cai-Cai , Yuan Bo-Yao , Xie Qin-Fang , Wang Li-Juan , Wang Man-Xia 
Published: June 2019

AbstractMultiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS). The present study explored the role of intestinal microbiota in the initiation and propagation of mice induced by experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. 48 C57BL/6 were randomly divided into control group and EAE group. The changes of body weight and the scores of neurological function were recorded. The mRNA expression of the receptor tyrosine kinase subfamily (AXL) was detected by real-time quantitative PCR. The levels of IL-17 and IFN-γ in blood samples were examined by ELISA. The intestinal microbial composition of mice at different time points during the EAE induction was analyzed by 16S rRNA gene-based sequencing. In EAE group, the body weight began to reduce at day 3 and neurological symptoms began to appear at day 7 after EAE induction. The levels of IL-17 and IFN-γ in EAE group reached the peak at day 21 and then decreased gradually. However, the expression of Axl and SOCS3 reached the lowest level at day 21 and then increased gradually. The microbiome analyses revealed that the abundances of Alistipes, Blautia, and Lachnospiraceae_NK4A136_group were significantly changed at day 14, whereas the abundances of Allobaculum, Eubacterium and Helicobacter were significantly changed at day 30 of EAE induction. The prevotellaceae_NK3B31_group may be key bacteria that contribute to the development of MS. Regulation of intestinal microbiota composition can become a new therapeutic target for the treatment of MS.
CaMKII/proteasome/cytosolic calcium/cathepsin B axis was present in tryspin activation induced by nicardipine
Authors: Xiao Juan , Lin Houmin , Liu Binggang , Jin Junfei 
Published: June 2019

Abstract
Premature trypsinogen activation is the early event of acute pancreatitis. Therefore, the studies on the processes of trypsinogen activation induced by compounds are important to understand mechanism underly acute pancreatitis under various conditions. Calcium overload in the early stage of acute pancreatitis was previously found to cause intracellular trypsinogen activation; however, treatment of acute pancreatitis using calcium channel blockers did not produced consistent results. Proteasome activity that could be inhibited by some calcium channel blocker has recently been reported to affect the development of acute pancreatitis; however, the associated mechanism were not fully understood. Here, the roles of nicardipine were investigated in trypsinogen activation in pancreatic acinar cells. The results showed that nicardipine could increase cathepsin B activity that caused trypsinogen activation, but higher concentration of nicardipine or prolonged treatment had an opposite effect. The effects of short time treatment of nicardipine at low concentration were studied here. Proteasome inhibition was observed under nicardipine treatment that contributed to the up-regulation in cytosolic calcium. Increased cytosolic calcium from ER induced by nicardipine resulted in the release and activation of cathepsin B. Meanwhile, calcium chelator inhibited cathepsin B as well as trypsinogen activation. Consistently, proteasome activator protected acinar cells from injury induced by nicardipine. Moreover, proteasome inhibition caused by nicardipine depended on CaMKII. In conclusion, CaMKII down-regulation/proteasome inhibition/cytosolic calcium up-regulation/cathepsin B activation/trypsinogen activation axis was present in pancreatic acinar cells injury under nicardipine treatment.
Endothelin receptor antagonism during preeclampsia: a matter of timing?
Authors: Hitzerd Emilie , Neuman Rugina I. , Mirabito Colafella Katrina M. , Reiss Irwin K.M. , van den Meiracker Anton H. , Danser A.H. Jan , Visser Willy , Versmissen Jorie , Saleh Langeza 
Published: June 2019

Abstract
Preeclampsia (PE) is a pregnancy complication, featuring elevated blood pressure and proteinuria, with no appropriate treatment. Activation of the endothelin system has emerged as an important pathway in PE pathophysiology based on experimental PE models where endothelin receptor antagonists (ERAs) prevented or attenuated hypertension and proteinuria. Hence, ERAs have been suggested as potential therapy for PE. However, developmental toxicity studies in animals have shown severe teratogenic effects of ERAs, particularly craniofacial malformations. Nonetheless, sporadic cases of pregnancy in women using ERAs to treat pulmonary hypertension have been described. In this review we give an overview of cases describing ERA use in pregnancy and critically address their possible teratogenic effects. A systematic search in literature yielded 18 articles describing 39 cases with ERA exposure during human pregnancy. In most cases there was only exposure in the first trimester, but exposure later or throughout pregnancy was reported in five cases. Elective termination of pregnancy was performed in 12 pregnancies (31%), two ended in a spontaneous miscarriage (5%) and no fetal congenital abnormalities have been described in the remaining cases. These preliminary findings support the idea that ERA treatment for severe, early onset PE might be an option if applied later in pregnancy, when organogenesis is completed to avoid teratogenic risks. However, third trimester toxicology studies are warranted to evaluate drug safety. Subsequently, it remains to be established whether ERA treatment is effective for alleviating maternal symptoms, as demonstrated in preclinical PE models, allowing pregnancy prolongation without leading to adverse neonatal outcomes.
Creep-resistant aeroengine shaft steels: Precipitates and consequences
Authors: Huang Zixin 
Published: June 2019

Creep resistant steels must be stable over long periods of time under severe operating conditions. This paper reviews precipitation in Cr–Mo steels and maraging steels destined for elevated temperature applications. It also covers aspects of structural evolution, strengthening and degradation, all of which are essential for alloy design. Two classes of steels are emphasised, those with origins in the power generation industries, and a novel approach based on intermetallic precipitates. This review was submitted as part of the 2019 Materials Literature Review Prize of the Institute of Materials, Minerals and Mining run by the Editorial Board of MST. Sponsorship of the prize by TWI Ltd is gratefully acknowledged.