bluuebunny/crossref_metadata_2025_split huggingface dataset:
The influence of peptide context on signalling and trafficking of glucagon-like peptide-1 receptor biased agonists
Authors: Fang Zijian , Chen Shiqian , Pickford Philip , Broichhagen Johannes , Hodson David J , Corrêa Ivan R , Kumar Sunil , Görlitz Frederik , Dunsby Christopher , French Paul , Rutter Guy A , Tan Tricia , Bloom Stephen R , Tomas Alejandra , Jones Ben 
Published: February 2020

AbstractSignal bias and membrane trafficking have recently emerged as important considerations in the therapeutic targeting of the glucagon-like peptide-1 receptor (GLP-1R) in type 2 diabetes and obesity. In the present study, we have evaluated a peptide series with varying sequence homology between native GLP-1 and exendin-4, the archetypal ligands on which approved GLP-1R agonists are based. We find notable differences in agonist-mediated signalling, endocytosis and recycling, dependent both on the introduction of a His → Phe switch at position 1 and the specific mid-peptide helical regions and C-termini of the two agonists. These observations were linked to insulin secretion in a beta cell model and provide insights into how ligand factors influence GLP-1R function at the cellular level.Graphical abstract
Single-Cell Mass Cytometry on Peripheral Blood Identifies Immune Cell Subsets Associated with Primary Biliary Cholangitis
Authors: Jang Jin Sung , Juran Brian , Cunningham Kevin Y. , Gupta Vinod K. , Son YoungMin , Yang Ju Dong , Ali Ahmad H. , Enninga Elizabeth Ann L. , Sung Jaeyun , Lazaridis Konstantinos N. 
Published: February 2020

AbstractThe relationship between Primary Biliary Cholangitis (PBC), a chronic cholestatic autoimmune liver disease, and the peripheral immune system remains to be fully understood. Herein, we performed the first mass cytometry (CyTOF)-based, immunophenotyping analysis of the peripheral immune system in PBC at single-cell resolution. CyTOF was performed on peripheral blood mononuclear cells (PBMCs) from PBC patients (n=33) and age-/sex-matched healthy controls (n=33) to obtain immune cell abundance and marker expression profiles. Hiearchical clustering methods were applied to identify immune cell types and subsets significantly associated with PBC. Subsets of gamma-delta T cells (CD3+TCRgd+), CD8+T cells (CD3+CD8+CD161+PD1+), and memory B cells (CD3-CD19+CD20+CD24+CD27+) were found to have lower abundance in PBC than in control. In contrast, higher abundance of subsets of monocytes and naïve B cells were observed in PBC compared to control. Furthermore, several naïve B cell (CD3-CD19+CD20+CD24-CD27-) subsets were significantly higher in PBC patients with cirrhosis (indicative of late-stage disease) than in those without cirrhosis. Alternatively, subsets of CD8+CD161+T cells and memory B cells were lower in abundance in cirrhotic relative to non-cirrhotic PBC patients. Future immunophenotyping investigations could lead to better understanding of PBC pathogenesis and progression, and also to the discovery of novel biomarkers and treatment strategies.
Projections of non-invasive human recordings into state space show unfolding of spontaneous and over-trained choice
Authors: Takagi Yu , Hunt Laurence , Woolrich Mark W , Behrens Timothy EJ , Klein-Flügge Miriam C 
Published: February 2020

AbstractChoices rely on a transformation of sensory inputs into motor responses. Using invasive single neuron recordings, the evolution of a choice process has been tracked by projecting population neural responses into state spaces. Here we develop an approach that allows us to recover state space trajectories on a millisecond timescale in non-invasive human recordings. We selectively suppress activity related to relevant and irrelevant sensory inputs and response direction in magnetoencephalography data acquired during context-dependent choices. Recordings from premotor cortex show a smooth progression from sensory input encoding to response encoding. In contrast to previous macaque recordings, information related to choice-irrelevant features is represented more weakly than choice-relevant sensory information. To test whether this mechanistic difference between species is caused by extensive overtraining common in non-human primate studies, we trained humans on >20,000 trials of the task. Choice-irrelevant features were still weaker than relevant features in premotor cortex after overtraining.
Duchenne Muscular Dystrophy Cell Culture Models Created By CRISPR/Cas 9 Gene Editing And Their Application To Drug Screening
Authors: Soblechero-Martín P. , Albiasu-Arteta E. , Anton-Martinez A. , de la Puente-Ovejero L. , Garcia-Jimenez I. , González-Iglesias G. , Larrañaga-Aiestaran I. , López-Martinez A. , Poyatos-García J. , Ruiz-Del-Yerro E. , Gonzalez F. , Arechavala-Gomeza V. 
Published: February 2020

AbstractGene edition methods are an attractive putative therapeutic option for Duchenne muscular dystrophy and they have an immediate application in the generation of research models. To generate two new edited myoblast cultures that could be usefulin vitrodrug screening, we have optimised a CRISPR/Cas9 gene edition protocol. We have successfully used it in wild type immortalised myoblasts to delete exon 52 of the dystrophin gene: DMDΔ52-Model, modelling a common Duchenne muscular dystrophy mutation; and in patient’s immortalised cultures we have deleted an inhibitory microRNA target region of the utrophin UTR, leading to utrophin upregulation. We have characterised these cultures and, to show their use in the assessment of DMD treatments, we have performed exon skipping in the DMDΔ52-Model and have used the unedited cultures/ DMD-UTRN-Model combo to assess utrophin overexpression after drug treatment. While the practical use of DMDΔ52-Model is limited to the validation to our gene edition protocol, DMD-UTRN-Model offers a possible therapeutic gene edition target as well as a useful positive control in the screening of utrophin overexpression drugs.
Intra-abdominal resection of the umbilical vein and urachus of bovine fetuses using videolaparoscopy and celiotomy: surgical time and feasibility (cadaveric study)
Authors: Monteiro Francisco Décio de Oliveira , Gurgel Heytor Jales , de Sousa Simon Silva , Barroso João Pedro Monteiro , Vasconcelos Gabrielle Patrizi Braga , dos Santos Daniele Lira , Araújo Luiz Henrique Vilela , de Sousa Loise Araújo , dos Santos Gabriela Melo Alves , Rossy Kayan da Cunha , da Silva Verena Siqueira , Fernandes Camila do Espirito Santo , Guilherme Barbara da Conceição , Miranda Helaine Freitas , Silva Carla Rozilene Guimarães , Albuquerque Rodrigo dos Santos , Borges Luisa Pucci Bueno , de Araújo Gilson Ferreira , Teixeira Pedro Paulo Maia 
Published: February 2020

AbstractSurgical intervention for umbilical diseases in calves, when indicated, is a complementary and indispensable therapeutic resource for the treatment of umbilical conditions and is commonly performed using celiotomy. However, videolaparoscopy has demonstrated feasibility in many diagnostic and therapeutic procedures. The aim of this study was to assess the feasibility of the techniques and the surgical time of videolaparoscopy and celiotomy used in intra-abdominal resection of the umbilical vein and urachus of bovine fetuses (cadavers). Resection of the umbilical vein and urachus using videolaparoscopy and celiotomy was performed in 26 anatomical specimens (bovine fetuses obtained from an official slaughterhouse). Resection of umbilical structures was feasible with both techniques, but shorter surgical time and minimal tissue damage were achieved using videolaparoscopy. Laparoscopy requires specialized training and appropriate instruments and is an important tool for diagnostic and therapeutic exploration of the umbilical structures, liver, bladder, and associated/adjacent structures.
Coevolution of retroviruses withSERINCs following whole-genome duplication divergence
Authors: Ramdas Pavitra , Bhardwaj Vipin , Singh Aman , Vijay Nagarjun , Chande Ajit 
Published: February 2020

AbstractTheSERINCgene family comprises of five paralogs in humans of whichSERINC3andSERINC5inhibit HIV-1 infectivity and are counteracted by Nef. The origin of this anti-retroviral activity, its prevalence among the remaining paralogs, and its ability to target retroviruses remain largely unknown. Here we show that despite their early divergence, the anti-retroviral activity is functionally conserved among four humanSERINCparalogs withSERINC2 being an exception. The lack of activity in humanSERINC2 is associated with its post-whole genome duplication (WGD) divergence, as evidenced by the ability of pre-WGD orthologs from yeast, fly, and a post-WGD-proximateSERINC2 from coelacanth to inhibit nef-defective HIV-1. Intriguingly, potent retroviral factors from HIV-1 and MLV are not able to relieve theSERINC2-mediated particle infectivity inhibition, indicating that such activity was directed towards other retroviruses that are found in coelacanth (like foamy viruses). However, foamy-derived vectors are intrinsically resistant to the action ofSERINC2, and we show that a foamy virus envelope confers this resistance. Despite the presence of weak arms-race signatures, the functional reciprocal adaptation amongSERINC2 andSERINC5 and, in response, the emergence of antagonizing ability in foamy virus appears to have resulted from a long-term conflict with the host.
Correlation of pathogenic factors with antimicrobial resistance of clinicalProteus mirabilisstrains
Authors: Filipiak Aneta , Chrapek Magdalena , Literacka Elżbieta , Wawszczak Monika , Głuszek Stanisław , Majchrzak Michał , Wróbel Grzegorz , Gniadkowski Marek , Adamus-Białek Wioletta 
Published: February 2020

AbstractProteus mirabilisis the third most common etiological factor of the urinary tract infection (UTI). It produces urease, which contributes to the formation of crystalline biofilm, considered to be one of the most important virulence factors ofP. mirabilisstrains, along with their ability to swarm on a solid surface. The aim of this study was to analyze the pathogenic properties of two selected groups of clinicalP. mirabilisisolates, antimicrobial-susceptible and multidrug-resistant (MDR), collected from hospitals in different regions in Poland. The strains were examined based on virulence gene profiles, urease and hemolysin production, biofilm formation, and swarming properties. Additionally, the strains were differentiated based on the Dienes test and antibiotic susceptibility patterns. It turned out that the MDR strains exhibited kinship more often than susceptible ones. The strains which were able to form stronger biofilm had broader antimicrobial resistance profiles. It was also found that the strongest swarming motility correlated with susceptibility to most antibiotics. The correlations described in this work encourage further investigation of the mechanisms of pathogenicity ofP. mirabilis.Author summaryProteus mirabilisis widely widespread in environment but also it is responsible for mostProteusinfections, especially in human urinary tracts. They cause complicated, persistent infections especially due to the ability to form urinary stones. The clinical importance ofP. mirabilishave been described in the literature many times. However, the role of pathogenic features with correlation to drug resistance require further investigation. In this research we analyzed thee virulence factors in relation to drug resistance of clinicalP. mirabilisstrains isolated from urine. The virulence genes, ureolytic and hemolytic activity, biofilm formation, swarming growth and strains kindship were analyzed. The most important observation was that the strains exhibited a stronger territorialism were kindred to a lower number of other strains, formed weaker biofilm and exhibited a lower resistance to antibiotics. Furthermore, we proved that the strains which were more likely to mutual growth, they were also less similar in the drug resistance profile but exhibited a higher resistance to antibiotics, which can be beneficial for different bacteria living together. We believe thatP. mirabiliswith strong territorialism can represent a wild group of strains with poor experience of antibiotic pressure. The environmental influence (toxins, antibiotics, bacterial neighbors) stimulates the development of a less dispersed community with stronger biofilm, exchange of genes and increase of resistance to antibiotics.
Reducing 14-3-3ζ expression influences adipocyte maturity and impairs function
Authors: Oppong Abel K. , Diallo Kadidia , Frayne Isabelle Robillard , Rosiers Christine Des , Lim Gareth E. 
Published: February 2020

AbstractOne of the primary metabolic functions of a mature adipocyte is to supply energy via lipolysis, or the catabolism of stored lipids. Hormone-sensitive lipase (HSL) is a critical lipolytic enzyme, and its phosphorylation and subsequent activation by PKA generates phospho-binding sites for 14-3-3 proteins, a ubiquitously expressed family of molecular scaffolds. While we previously identified essential roles of the 14-3-3ζ isoform in murine adipogenesis, the presence of 14-3-3 protein binding sites on HSL suggests that 14-3-3ζ could also influence mature adipocyte processes like lipolysis. Herein, we demonstrate that 14-3-3ζ is necessary for lipolysis in male mice and fully differentiated 3T3-L1 adipocytes, as depletion of 14-3-3ζ significantly impaired glycerol and FFA release. Unexpectedly, this was not due to impairments in signaling events underlying lipolysis; instead, reducing 14-3-3ζ expression was found to significantly impact adipocyte maturity, as observed by reduced abundance of PPARγ2 protein and expression of mature adipocytes genes and those associated withde novotriglyceride synthesis and lipolysis. The impact of 14-3-3ζ depletion on adipocyte maturity was further examined with untargeted lipidomics, which revealed that reductions in 14-3-3ζ abundance promoted the acquisition of a lipidomic signature that resembled undifferentiated, pre-adipocytes. Collectively, these findings reveal a novel aspect of 14-3-3ζ in adipocytes, as reducing 14-3-3ζ was found to have a negative effect on adipocyte maturity and adipocyte-specific processes like lipolysis.
The metabolite receptor SUCNR1 in oxidative stress-induced age-related macular degeneration
Authors: Louer Elja M.M. , Deen Peter M.T. , den Hollander Anneke I. 
Published: February 2020

AbstractAge-related macular degeneration (AMD) is the leading cause of vision impairment in elderly people. AMD is a multifactorial disease which is characterised by complex interactions between metabolic and environmental factors as well as multiple genetic susceptibility factors. The exact mechanism of the most prominent environmental factors, age and smoking, in combination with genetic susceptibility factors is little studied. Here, we set out to study the influence of age, smoking induced oxidative stress and the role of succinate receptor 1 (SUCNR1) in AMD development in mice.Sucnr1wild-type (WT), heterozygous (HT) and knock-out (KO) mice were exposed to smoking related oxidative stress by the addition of hydroquinone (HQ), the most abundant oxidant in cigarette smoke, to the drinking water of the mice. Using immunohistochemical staining, accumulation of oxidized LDL (oxLDL) in the mouse retina was assessed at 40 and 48 weeks of age.At 40 weeks of age, a significant increase in oxLDL in theSucnr1KO mice treated with HQ was observed when compared to the WT and HT mice treated with HQ (p<0.01). However, at 48 weeks, no significant difference was observed between any of the groups. A second experiment analyzing the mice at 40 weeks of age was unable to confirm the observed results of the first experiment.We identified oxLDL accumulations inSucnr1KO retinas exposed to HQ, but were unable to repeat this finding. Therefore, under the present conditions, theSucnr1KO mouse model is not a suitable model to study AMD development.
Structure and conformational cycle of a bacteriophage-encoded chaperonin
Authors: Bracher Andreas , Paul Simanta S. , Wang Huping , Wischnewski Nadine , Hartl F. Ulrich , Hayer-Hartl Manajit 
Published: February 2020

AbstractChaperonins are ubiquitous molecular chaperones found in all domains of life. They form ring-shaped complexes that assist in the folding of substrate proteins in an ATP-dependent reaction cycle. Key to the folding cycle is the transient encapsulation of substrate proteins by the chaperonin. Here we present a structural and functional characterization of the chaperonin gp146 (ɸEL) from the phage EL ofPseudomonas aeruginosa. ɸEL, an evolutionary distant homolog of bacterial GroEL, is active in ATP hydrolysis and prevents the aggregation of denatured protein in a nucleotide-dependent manner. However, ɸEL failed to refold the encapsulation-dependent model substrate rhodanese and did not interact withE. coliGroES, the lid-shaped co-chaperone of GroEL. ɸEL forms tetradecameric double-ring complexes, which dissociate into single rings in the presence of ATP. Crystal structures of ɸEL (at 3.54 and 4.03 Å) in presence of ATP•BeFxrevealed two distinct single-ring conformational states, both with open access to the ring cavity. One state showed uniform ATP-bound subunit conformations (symmetric state), whereas the second combined distinct ATP- and ADP-bound subunit conformations (asymmetric state). Cryo-electron microscopy of apo-ɸEL revealed a double-ring structure composed of rings in the asymmetric state (3.45 Å resolution). We propose that the phage chaperonin undergoes nucleotide-dependent conformational switching between double- and single rings and functions in aggregation prevention without substrate protein encapsulation. Thus, ɸEL may represent an evolutionary more ancient chaperonin prior to acquisition of the encapsulation mechanism.
RNF40-dependent epigenetic regulation of actin cytoskeletal dynamics is required for HER2-driven mammary tumorigenesis
Authors: Wegwitz Florian , Prokakis Evangelos , Pejkovska Anastasija , Kosinsky Robyn Laura , Glatzel Markus , Pantel Klaus , Wikman Harriet , Johnsen Steven A. 
Published: February 2020

AbstractThe HER2-driven breast cancer subtype displays a particularly aggressive behavior. Alterations of the epigenome are common in cancers and represent attractive novel molecular therapeutic targets. Monoubiquitination of histone 2B (H2Bub1) by its obligate heterodimeric E3 ubiquitin ligase complex RNF20/RNF40 has been described to have tumor suppressor functions and loss of H2Bub1 has been associated with cancer progression. In this study, we utilized human tumor samples, cell culture models, and a mammary carcinoma mouse model with tissue-specificRnf40deletion and identified an unexpected tumor-supportive role of RNF40 in HER2-positive breast cancer. We demonstrate that RNF40-driven H2B monoubiquitination is essential for transcriptional activation of RHO/ROCK/LIMK pathway components and proper actin cytoskeleton dynamics through a trans-histone crosstalk with histone 3 lysine 4 trimethylation (H3K4me3). Collectively, this work demonstrates a previously unknown essential role of RNF40 in HER2-positive breast cancer, revealing the RNF20/RNF40/H2Bub1 axis as a possible tumor context-dependent therapeutic target in breast cancer.Statement of significanceHER2-positive breast cancer patients frequently develop resistance to anti-HER2 therapies. Here we demonstrate that RNF20/RNF40-mediated H2B monoubiquitination supports the oncogenic properties of cancer cells of this subtype by regulating actin dynamics. The RNF20/RNF40/H2Bub1 axis may therefore represent an attractive drug target for novel therapies.
Alterations of specific inhibitory circuits of the prefrontal cortex underlie abnormal network activity in a mouse model of Down syndrome
Authors: de San Martin Javier Zorrilla , Donato Cristina , Peixoto Jérémy , Aguirre Andrea , Choudhary Vikash , De Stasi Angela Michela , Lourenço Joana , Potier Marie-Claude , Bacci Alberto 
Published: February 2020

AbstractDown syndrome (DS) results in various degrees of cognitive deficits. In DS mouse models, recovery of behavioral and neurophysiological deficits using GABAAR antagonists led to hypothesize an excessive activity of inhibitory circuits in this condition. Nonetheless, whether over-inhibition is present in DS and whether this is due to specific alterations of distinct GABAergic circuits is unknown. In the prefrontal cortex of Ts65Dn mice (a well-established DS model), we found that the dendritic synaptic inhibitory loop formed by somatostatin-positive Martinotti cells (MCs) and pyramidal neurons (PNs) was strongly enhanced, with no alteration of their excitability. Conversely, perisomatic inhibition from parvalbumin-positive (PV) interneurons was unaltered, but PV cells of DS mice lost their classical fast-spiking phenotype and exhibited increased excitability. These microcircuit alterations resulted in reduced pyramidal-neuron firing and increased phase locking to cognitive-relevant network oscillationsin vivo. These results define important synaptic and circuit mechanisms underlying of cognitive dysfunctions in DS.
Ultrasound Mediated Delivery of Quantum Dots from a Capsule Endoscope to the Gastrointestinal Wall
Authors: Stewart Fraser , Cummins Gerard , Turcanu Mihnea V. , Cox Benjamin F. , Prescott Alan , Clutton Eddie , Newton Ian P. , Desmulliez Marc P.Y. , Thanou M. , Mulvana H. , Cochran Sandy , Näthke Inke 
Published: February 2020

AbstractBiologic drugs, defined as therapeutic agents produced from or containing components of a living organism, are of growing importance to the pharmaceutical industry. Though oral delivery of medicine is convenient, biologics require invasive injections because of their poor bioavailability via oral routes. Delivery of biologics to the small intestine using electronic delivery with devices that are similar to capsule endoscopes is a promising means of overcoming this limitation and does not require reformulation of the therapeutic agent. The efficacy of such capsule devices for drug delivery could be further improved by increasing the permeability of the intestinal tract lining with an integrated ultrasound transducer to increase uptake. This paper describes a novel proof of concept capsule device capable of electronic application of focused ultrasound and delivery of therapeutic agents. Fluorescent markers, which were chosen as a model drug, were used to demonstrate in-vivo delivery in the porcine small intestine with this capsule. We show that the fluorescent markers can penetrate the mucus layer of the small intestine at low acoustic powers when combining microbubbles with focussed ultrasound. These findings suggest that the use of focused ultrasound together with microbubbles could play a role in the oral delivery of biologic therapeutics.