bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting of EGFR by a combination of antibodies mediates unconventional EGFR trafficking and degradation
Authors: Jones Sylwia , King Peter J. , Antonescu Costin N. , Sugiyama Michael G. , Bhamra Amandeep , Surinova Silvia , Angelopoulos Nicos , Kragh Michael , Pedersen Mikkel W. , Hartley John A. , Futter Clare E. , Hochhauser Daniel 
Published: January 2020

AbstractAntibody combinations targeting cell surface receptors are a new modality of cancer therapy. The trafficking and signalling mechanisms regulated by such therapeutics are not fully understood but could underlie differential tumour responses. We explored EGFR trafficking upon treatment with the antibody combination Sym004 which has shown promise clinically. Sym004 promoted EGFR endocytosis distinctly from EGF: it was asynchronous, not accompanied by canonical signalling events and involved EGFR clustering within detergent-insoluble plasma mebrane-associated tubules. Sym004 induced lysosomal degradation independently of EGFR ubiquitylation but dependent upon Hrs/Tsg101 that are required for the formation of intraluminal vesicles (ILVs) within late endosomes. We propose Sym004 cross-links EGFR physically triggering EGFR endocytosis and incorporation onto ILVs and so Sym004 sensitivity correlates with EGFR numbers available for binding, rather than specific signalling events. Consistently Sym004 efficacy and potentiation of cisplatin responses correlated with EGFR surface expression in head and neck cancer cells. These findings will have implications in understanding the mode of action of this new class of cancer therapeutics.
Digging deeper - A new data mining workflow for improved processing and interpretation of high resolution GC-Q-TOF MS data in archaeological research
Authors: Korf Ansgar , Hammann Simon , Schmid Robin , Froning Matti , Hayen Heiko , Cramp Lucy J. E. 
Published: January 2020

AbstractGas chromatography-mass spectrometry profiling is the most established method for the analysis of organic residues, particularly lipids, from archaeological contexts. This technique allows the decryption of hidden chemical information associated with archaeological artefacts, such as ceramic pottery fragments. The molecular and isotopic compositions of such residues can be used to reconstruct past resource use, and hence address major questions relating to patterns of subsistence, diet and ritual practices in the past. A targeted data analysis approach, based on previous findings reported in the literature is common but greatly depends on the investigator’s prior knowledge of specific compound classes and their mass spectrometric behaviour, and poses the risk of missing unknown, potentially diagnostic compounds. Organic residues from post-prehistoric archaeological samples often lead to highly complex chromatograms, which makes manual chromatogram inspection very tedious and time consuming, especially for large datasets. This poses a significant limitation regarding the scale and interpretative scopes of such projects. Therefore, we have developed a non-targeted data mining workflow to extract a higher number of known and unknown compounds from the raw data to reduce investigator’s bias and to vastly accelerate overall analysis time. The workflow covers all steps from raw data handling, feature selection, and compound identification up to statistical interpretation.
Anthranilamide-based Short Peptides Self-Assembled Hydrogels as Antibacterial Agents
Authors: Aldilla Vina R. , Chen Renxun , Martin Adam D. , Marjo Christopher E. , Rich Anne M. , Black David StC. , Thordarson Pall , Kumar Naresh 
Published: January 2020

AbstractIn this study, we describe the synthesis and molecular properties of anthranilamide-based short peptides which were synthesised via ring opening of isatoic anhydride in excellent yields. These short peptides were incorporated as low molecular weight gelators (LMWG), bola amphiphile, and C3-symmetric molecules to form hydrogels in low concentrations (0.07–0.30% (w/v)). The critical gel concentration (CGC), viscoelastic properties, secondary structure, and fibre morphology of these short peptides were influenced by the aromaticity of the capping group or by the presence of electronegative substituent (namely fluoro) and hydrophobic substituent (such as methyl) in the short peptides. In addition, the hydrogels showed antibacterial activity against S. aureus 38 and moderate toxicity against HEK cells in vitro.
Head motion predictability explains activity-dependent suppression of vestibular balance control
Authors: Dietrich H. , Heidger F. , Schniepp R. , MacNeilage P. R. , Glasauer S. , Wuehr M. 
Published: January 2020

AbstractVestibular balance control is dynamically weighted during locomotion. This might result from a selective suppression of vestibular inputs in favor of a feed-forward balance regulation based on locomotor efference copies. The feasibility of such a feed-forward mechanism should however critically depend on the predictability of head movements (HMP) during locomotion. To test this, we studied in 10 healthy subjects the differential impact of a stochastic vestibular stimulation (SVS) on body sway (center-of-pressure, COP) during standing and walking at different speeds and compared it to activity-dependent changes in HMP. SVS-COP coupling was determined by correlation analysis in frequency and time domains. HMP was quantified as the proportion of head motion variance that can be explained by the average head trajectory across the locomotor cycle. SVS-COP coupling decreased from standing to walking and further dropped with faster locomotion. Correspondingly, HMP increased with faster locomotion. Furthermore, SVS-COP coupling depended on the gait-cycle-phase with peaks corresponding to periods of least HMP. These findings support the assumption that during stereotyped human self-motion, locomotor efference copies selectively replace vestibular cues, similar to what was previously observed in animal models.
A Mathematical Theory of Cortex-Receptor Artificial Extension
Authors: Xing You-Lu 
Published: January 2020

AbstractMany physiology experiments demonstrate that an organism’s cortex and receptor system can be artificially extended, giving the organism new types of perceptual capabilities. To examine artificial extension of the cortex-receptor system, I propose a computational model that allows new types of sensory pathways to be added directly to the computational model itself in an online manner. A synapse expandable artificial neuron model that can grow new synapses, forming a bridge between the novel perceptual information and the existing neural network is introduced to absorb the novel sensory pathway. The experimental results show that the computational model can effectively integrate sudden emerged sensory channels and the neural circuits in the computational model can be reused for novel modalities without influencing the original modality.
Functional mechanism and pathogenic potential of MYRF ICA domain mutations implicated in birth defects
Authors: An Hongjoo , Fan Chuandong , Sharif Mohamed , Kim Dongkyeong , Poitelon Yannick , Park Yungki 
Published: January 2020

AbstractMyrf is a membrane-bound transcription factor that plays a key role in various biological processes. The Intramolecular Chaperone Auto-processing (ICA) domain of Myrf forms a homo-trimer, which carries out the auto-cleavage of Myrf. The ICA homo-trimer-mediated auto-cleavage of Myrf is a prerequisite for its transcription factor function in the nucleus. Recent exome sequencing studies have implicated two MYRF ICA domain mutations (V679A and R695H) in a novel syndromic form of birth defects. It remains unknown whether and how the two mutations impact the transcription factor function of Myrf and, more importantly, how they are pathogenic for congenital anomalies. Here, we show that V679A and R695H cripple the ICA domain, blocking the auto-cleavage of Myrf. Consequently, Myrf-V679A and Myrf-R695H do not exhibit any transcriptional activity. Molecular modeling suggests that V679A and R695H abrogate the auto-cleavage function of the ICA homo-trimer by destabilizing its homo-trimeric assembly. We also found that the ICA homo-trimer can tolerate one copy of Myrf-V679A or Myrf-R695H for its auto-cleavage function, indicating that V679A and R695H are not dominant negatives. Thus, if V679A and R695H in a heterozygous state caused birth defects, it would be via haploinsufficiency of MYRF.
Potential osteomyelitis biomarkers identified by plasma metabolome analysis in mice
Authors: Isogai Norihiro , Shiono Yuta , Kuramoto Tetsuya , Yoshioka Kenji , Ishihama Hiroko , Funao Haruki , Nakamura Masaya , Matsumoto Morio , Ishii Ken 
Published: January 2020

AbstractOsteomyelitis, which often arises from a surgical-site infection, is a serious problem in orthopaedic surgery. However, there are no specific biomarkers for osteomyelitis. Here, to identify specific plasma biomarkers for osteomyelitis, we conducted metabolome analyses using a mouse osteomyelitis model and bioluminescence imaging. We divided adult male pathogen-free BALB/C mice into control, sham-control, and infected groups. In the infected group, a bioluminescent Staphylococcus aureus strain was inoculated into the femur, and osteomyelitis was detected by bioluminescence imaging. We next analysed the metabolome, by comprehensively measuring all of the small molecules. This analysis identified 279 metabolites, 12 of which were significantly higher and 45 were significantly lower in the infected group than in the sham-control and control groups. Principal component analysis identified sphingosine as the highest loading factor. Several acyl carnitines and fatty acids, particularly ω-3 and ω-6 polyunsaturated fatty acids, were significantly lower in the infected group. Several metabolites in the tricarboxylic acid cycle were lower in the infected group than in the other groups. Thus, we identified two sphingolipids, sphinganine and sphingosine, as positive biomarkers for mouse osteomyelitis, and two components in the tricarboxylic acid cycle, two-oxoglutarate and succinic acid, as negative biomarkers.
Effects of microbial inoculants on the fermentation characteristics and microbial communities of sweet sorghum bagasse silage
Authors: Dong Miaoyin , Li Qiaoqiao , Xu Fuqiang , Wang Shuyang , Chen Jihong , Li Wenjian 
Published: January 2020

AbstractSweet sorghum bagasse (SSB) is a promising raw material for silage fermentation due to its high residual nutritive, but the efficient fermentation strategy of SSB has not been reported yet. This study evaluated the effects of microbial inoculant on the fermentation quality, chemical composition and microbial community of SSB silage. The silage inoculated with isolated lactic acid bacteria (LpE) achieved better fermentation than that of commercial inoculant A, B (CIA, CIB) and untreatment, including low pH value, high levels of lactic acid and water soluble carbohydrates (WSC) content, which demonstrated that the LpE inoculant could contribute to the preservation of nutrition and the manipulation of fermentation process of SSB. In addition, the results of microbial community analysis indicated that the LpE inoculant significantly changed the composition and diversity of bacteria in SSB silage. After ensiling, the LpE inoculated silage were dominated by Lactobacillus(95.71%), Weissella(0.19%). These results were of great guiding significance aiming for high-quality silage production using SSB materials on the basis of target-based regulation methods.
Comparing the rates of methane production in patients with and without appendectomy: results from a large-scale cohort
Authors: Takakura Will , Oh Sun Jung , Singer-Englar Tahli , Mirocha James , Leite Gabriela , Fridman Adie , Pimentel Mark , Mathur Ruchi , Pichetshote Nipaporn , Rezaie Ali 
Published: January 2020

AbstractThere is no clear study identifying the microbiome of the appendix. However, in other diverticular conditions, such as diverticulosis, methanogens appear important. We investigated whether patients who had undergone appendectomies had decreased levels of exhaled methane (CH4). Consecutive patients who underwent breath testing (BT) from November 2005 to October 2013 were deterministically linked to electronic health records. The numbers of patients with CH4 ≥ 1 ppm (detectable) and ≥ 3 and ≥ 10 ppm (excess) were compared between patients who did and did not undergo appendectomy using a multivariable model adjusted for age and sex. Of the 4977 included patients (48.0 ± 18.4 years, 30.1% male), 1303 (26.2%) had CH4 ≥ 10 ppm, and 193 (3.9%) had undergone appendectomy. Appendectomy was associated with decreased odds of CH4 ≥ 1, ≥ 3, and ≥ 10 ppm (ORs (95% CI) = 0.67 (0.47–0.93), p = 0.02; 0.65 (0.46–0.92), p = 0.01; and 0.66 (0.46–0.93), p = 0.02, respectively). Additionally, the percentage of CH4 producers increased 4-fold from the first to ninth decade of life. This is the first study to report that appendectomy is associated with decreased exhaled CH4. The appendix may play an active physiologic role as a reservoir of methanogens.
CR6-interacting factor 1 deficiency reduces endothelial nitric oxide synthase activity by inhibiting biosynthesis of tetrahydrobiopterin
Authors: Lee Ikjun , Kim Seonhee , Nagar Harsha , Choi Su-jeong , Jeon Byeong Hwa , Piao Shuyu , Kim Cuk-Seong 
Published: January 2020

AbstractDownregulation of CR6 interacting factor 1 (CRIF1) has been reported to induce mitochondrial dysfunction, resulting in reduced activity of endothelial nitric oxide synthase (eNOS) and NO production in endothelial cells. Tetrahydrobiopterin (BH4) is an important cofactor in regulating the balance between NO (eNOS coupling) and superoxide production (eNOS uncoupling). However, whether the decreased eNOS and NO production in CRIF1-deficient cells is associated with relative BH4 deficiency-induced eNOS uncoupling remains completely unknown. Our results showed that CRIF1 deficiency increased eNOS uncoupling and depleted levels of total biopterin and BH4 by reducing the enzymes of BH4 biosynthesis (GCH-1, PTS, SPR, and DHFR) in vivo and vitro, respectively. Supplementation of CRIF1-deficient cells with BH4 significantly increased the recovery of Akt and eNOS phosphorylation and NO synthesis. In addition, scavenging ROS with MitoTEMPO treatment replenished BH4 levels by elevating levels of GCH-1, PTS, and SPR, but with no effect on the level of DHFR. Downregulation of DHFR synthesis regulators p16 or p21 in CRIF1-deficient cells partially recovered the DHFR expression. In summary, CRIF1 deficiency inhibited BH4 biosynthesis and exacerbated eNOS uncoupling. This resulted in reduced NO production and increased oxidative stress, which contributes to endothelial dysfunction and is involved in the pathogenesis of cardiovascular diseases.
Profiling of human lymphocytes reveals a specific network of protein kinases modulated by endurance training status
Authors: Alack Katharina , Weiss Astrid , Krüger Karsten , Höret Mona , Schermuly Ralph , Frech Torsten , Eggert Martin , Mooren Frank-Christoph 
Published: January 2020

AbstractTo date, the effects of endurance exercise training on lymphocyte physiology at the kinome level are largely unknown. Therefore, the present study used a highly sensitive peptide-based kinase activity profiling approach to investigate if the basal activity of tyrosine (Tyr) and serine/threonine (Ser/Thr) kinases of human lymphocytes is affected by the aerobic endurance training status. Results revealed that the activity of various tyrosine kinases of the FGFR family and ZAP70 was increased, whereas the activity of multiple Ser/Thr kinases such as IKKα, CaMK4, PKAα, PKCα+δ (among others) was decreased in lymphocytes of endurance trained athletes (ET). Moreover, functional associations between several differentially regulated kinases in ET-derived lymphocytes were demonstrated by phylogenetic mapping and network analysis. Especially, Ser/Thr kinases of the AGC-kinase (protein kinase A, G, and C) family represent exercise-sensitive key components within the lymphocytes kinase network that may mediate the long-term effects of endurance training. Furthermore, KEGG (Kyoto Encyclopedia of Genes and Genomes) and Reactome pathway analysis indicate that Ras as well as intracellular signaling by second messengers were found to be enriched in the ET individuals. Overall, our data suggest that endurance exercise training improves the adaptive immune competence by modulating the activity of multiple protein kinases in human lymphocytes.
The ubiquitin ligase HERC1 regulates cell migration via RAF-dependent regulation of MKK3/p38 signaling
Authors: Pedrazza Leonardo , Schneider Taiane , Bartrons Ramon , Ventura Francesc , Rosa Jose Luis 
Published: January 2020

AbstractProtein modifications by phosphorylation or ubiquitylation have been selected throughout evolution as efficient regulatory mechanisms of cellular processes. Cell migration is a complex, highly coordinated process where these mechanisms must participate in an integrated manner to transmit signaling during migration. In this study, we show that the ubiquitin ligase HERC1 regulates the p38 signaling pathway, and that this regulation is mediated by the MAPK kinase MKK3. Moreover, we demonstrate a crosstalk between RAF and MKK3/p38 pathways where RAF acts upstream of MKK3. Mechanistically, HERC1 regulates the protein levels of C-RAF and MKK3. Thus, HERC1 ubiquitylates C-RAF, targeting it for proteasomal degradation, and RAF proteins regulate MKK3 mRNA levels. Accordingly, HERC1 knockdown induces C-RAF stabilization and activation of RAF proteins; in turn, this activation increases MKK3, which phosphorylates and activates p38. The importance of these observations is demonstrated by HERC1 regulation of cell migration through regulation of p38 signaling via a RAF-dependent mechanism. Thus, HERC1 plays an essential role as a regulator of crosstalk between RAF/MKK3/p38 signaling pathways during cell migration.
An innovative automated active compound screening system allows high-throughput optimization of somatic embryogenesis in Coffea arabica
Authors: Awada Rayan , Verdier Dorothée , Froger Solène , Brulard Eric , de Faria Maraschin Simone , Etienne Hervé , Breton David 
Published: January 2020

AbstractSomatic embryogenesis (SE) faces many challenges in fulfilling the growing demand for elite materials. A high-throughput approach is required to accelerate the optimization of SE protocols by multiplying experimental conditions within a limited time period. For the first time in plant micropropagation, we have developed a miniaturized and automated screening system to meet high-throughput standards. Coffea arabica embryo regeneration, classically achieved in 250-ml Erlenmeyer flasks, was successfully miniaturized in 24-well plates, allowing a volume downscaling factor of 100 and a space saving of 53 cm2/well. Cell clusters were ground and filtered to fit the automated pipetting platform, leading to fast, reproducible and uniform cluster distribution (23.0 ± 5.5 cell clusters/well) and successful regeneration (6.5 ± 2.2 embryos/well). Pilot screening of active compounds on SE was carried out. Compounds belonging to the histone deacetylase inhibitor family were tested for embryo regeneration efficiency. Cells treated with 1 µM Trichostatin A showed a marked 3-fold increase in the number of regenerated embryos. When re-tested in 250-ml flasks, the same enhancement was obtained, thereby validating the miniaturized and automated screening method. These results showed that our screening system is reliable and well suited to screening hundreds of compounds, offering unprecedented perspectives in plant micropropagation.
Clinical and epidemiological factors associated with spontaneous preterm birth: a multicentre cohort of low risk nulliparous women
Authors: Souza Renato T. , Costa Maria L. , Mayrink Jussara , Feitosa Francisco E. , Filho Edilberto A. Rocha , Leite Débora F. , Vettorazzi Janete , Calderon Iracema M. , Sousa Maria H. , Passini Renato , Baker Philip N. , Kenny Louise , Cecatti Jose G. ,   The Preterm SAMBA study group, Parpinelli Mary A. , Fernandes Karayna G. , Galvão Rafael B. , Guida José Paulo , Santana Danielly S. , Franchini Kleber G. , Cassettari Bianca F. , Pfitscher Lucia , Brust Luiza , Melo Elias F. , Anacleto Danilo , de Lucena Daisy , Sousa Benedita 
Published: January 2020

AbstractThe objective of this study was to determine incidence and risk factors associated with spontaneous preterm birth (sPTB). It was a prospective multicentre cohort study performed in five Brazilian referral maternity hospitals and enrolling nulliparous women at 19–21 weeks. Comprehensive maternal data collected during three study visits were addressed as potentially associated factors for sPTB. Bivariate and multivariate analysis estimated risk ratios. The main outcomes measures were birth before 37 weeks due to spontaneous preterm labour or premature rupture of membranes (sPTB). The comparison group was comprised of women with term births (≥37weeks). Outcome data was available for 1,165 women, 6.7% of whom had sPTB, 16% had consumed alcohol and 5% had used other illicit drugs during the first half of pregnancy. Current drinking at 19–21 weeks (RR 3.96 95% CI [1.04–15.05]) and a short cervix from 18–24 weeks (RR 4.52 95% CI [1.08–19.01]) correlated with sPTB on bivariate analysis. Increased incidence of sPTB occurred in underweight women gaining weight below quartile 1 (14.8%), obese women gaining weight above quartile 3 (14.3%), women with a short cervix (<25 mm) at 18–24 weeks (31.2%) and those with a short cervix and vaginal bleeding in the first half of pregnancy (40%). Cervical length (RRadj 4.52 95% CI [1.08–19.01]) was independently associated with sPTB. In conclusion, the incidence of sPTB increased in some maternal phenotypes, representing potential groups of interest, the focus of preventive strategies. Similarly, nulliparous women with a short cervix in the second trimester require further exploration.
Chromosome segregation error during early cleavage in mouse pre-implantation embryo does not necessarily cause developmental failure after blastocyst stage
Authors: Mashiko Daisuke , Ikeda Zenki , Yao Tatsuma , Tokoro Mikiko , Fukunaga Noritaka , Asada Yoshimasa , Yamagata Kazuo 
Published: January 2020

AbstractIn the pre-implantation embryo, aneuploidy resulting from chromosome segregation error is considered responsible for pregnancy loss. However, only a few studies have examined the relationship between chromosome segregation errors during early cleavage and development. Here, we evaluated this relationship by live-cell imaging using the histone H2B-mCherry probe and subsequent single blastocyst transfer using mouse embryos obtained by in vitro fertilization. We showed that some embryos exhibiting early chromosomal segregation error and formation of micronuclei retained their developmental potential; however, the error affected the blastocyst/arrest ratio. Further, single-cell sequencing after live-cell imaging revealed that all embryos exhibiting micronuclei formation during 1st mitosis showed aneuploidy at the 2-cell stage. These results suggest that early chromosome segregation error causing micronuclei formation affects ploidy and development to blastocyst but does not necessarily cause developmental failure after the blastocyst stage. Our result suggests the importance of the selection of embryos that have reached blastocysts.