bluuebunny/crossref_metadata_2025_split huggingface dataset:
Larazotide Acetate for Treatment of Celiac Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Abu-Zaid Ahmed , Alhaddab Noor Tariq , Alnujaidi Razan Abdulkarim , Alharbi Hadeel Abdulaziz , Alangari Fulwah , Alyahyawi Naseem , Kamal Aminah , Altowairqi Abdulaziz Khalaf , Alhabeeb Habeeb , Almustanyir Sami , Alyoubi Reem Abdullah 
Published: September 2020

ABSTRACTPurposeThe standard of care for treatment of celiac disease (CD) is a stringent lifetime glutenfree diet (GFD), which is very challenging. Larazotide acetate (AT-1001) is an anti-zonulin which functions as a gut permeability regulator for treatment of CD. We endeavored to conduct a systematic review and meta-analysis of all randomized controlled trials (RCTs) which studied the efficacy and safety of larazotide acetate in patients with CD.MethodsWe examined four databases from inception to 20-August-2020 using related keywords. We identified all relevant RCTs and judged their risk of bias. We pooled continuous outcomes as mean difference and dichotomous outcomes as risk ratio with 95% confidence interval under fixed-effects meta-analysis model.ResultsFour RCTs met our eligibility criteria, comprising 626 patients (larazotide acetate, n = 465, placebo, n = 161). Three and two studies reported outcomes of patients undergoing gluten challenge and GFD, respectively. For change in lactulose-to-mannitol ratio, the overall effect estimate did not reveal a significant difference between larazotide acetate and placebo groups. For change in total gastrointestinal symptom rating scale (GSRS), subgroup analysis showed that larazotide acetate significantly yielded better symptomatic improvement in the gluten challenge but not gluten free subgroup. Similar finding was found for change in celiac-disease GSRS (CD-GSRS) favoring the gluten challenge over gluten free subgroup. When compared to placebo, larazotide acetate favorably reduced the adverse event (AE) of gluten-related diarrhea in patients who underwent gluten challenge. Other AEs were comparable between both treatment groups.ConclusionsLarazotide acetate is well-endured and superior to placebo in alleviating gastrointestinal symptoms.
NLRC5 regulates expression of MHC-I and provides a target for anti-tumor immunity in transmissible cancers
Authors: Ong Chrissie E. B. , Patchett Amanda L. , Darby Jocelyn M. , Chen Jinying , Liu Guei-Sheung , Lyons A. Bruce , Woods Gregory M. , Flies Andrew S. 
Published: September 2020

ABSTRACTDownregulation of major histocompatibility complex I (MHC-I) on tumor cells is a primary means of immune evasion by many types of cancer. Additionally, MHC-I proteins are a primary target of immune-mediated transplant rejection. Transmissible tumors that overcome allograft rejection mechanisms and evade anti-tumor immunity have killed thousands of wild Tasmanian devils (Sarcophilus harrisii). Interferon gamma (IFNG) upregulates surface MHC-I expression on devil facial tumor (DFT) cells but is not sufficient to induce tumor regressions. Transcriptome analysis of IFNG-treated DFT cells revealed strong upregulation ofNLRC5, a master regulator of MHC-I in humans and mice. To explore the role of NLRC5 in transmissible cancers, we developed DFT cell lines that constitutively overexpress NLRC5. Transcriptomic results suggest that the role of NLRC5 as a master regulator of MHC-I is conserved in devils. Furthermore, NLRC5 was shown to drive the expression of many components of the antigen presentation pathway. To determine if MHC-I is a target of allogeneic immune responses, we tested serum from devils with anti-DFT responses including natural DFT regressions against DFT cells. Antibody binding occurred with cells treated with IFNG and overexpressed NLRC5. However, CRISPR/Cas9-mediated knockout of MHC-I subunit beta-2-microglobulin (B2M) eliminated antibody binding to DFT cells. Consequently, MHC-I could be identified as a target for anti-tumor and allogeneic immunity and provides mechanistic insight into MHC-I expression and antigen presentation in marsupials. NLRC5 could be a promising target for immunotherapy and vaccines to protect devils from transmissible cancers and inform development of transplant and cancer therapies for humans.
A negative feedback loop of the TOR signaling moderates growth and enables rapid sensing of stress signals in plants
Authors: Jamsheer K Muhammed , Jindal Sunita , Sharma Mohan , Sharma Manvi , Sivaj Sreejath , Mannully Chanchal Thomas , Laxmi Ashverya 
Published: September 2020

ABSTRACTTOR kinase is a central coordinator of nutrient-dependent growth in eukaryotes. Maintaining optimal TOR signaling is critical for the normal development of organisms. However, the mechanisms involved in the maintenance of optimal TOR signaling are currently unknown in plants. In this study, we describe a negative feedback loop of TOR signaling helping in the adaptability of plants in changing environmental conditions. Using an interdisciplinary approach, we identified a plant-specific zinc finger protein FLZ8, as a regulator of TOR signaling in Arabidopsis. In sugar sufficiency, FLZ8 is upregulated by TOR-dependent and –independent histone modifications. FLZ8 negatively regulates TOR signaling by promoting antagonistic SnRK1α1 signaling and bridging the interaction of SnRK1α1 with RAPTOR, a crucial accessory protein of TOR. This negative feedback loop moderates the TOR-growth signaling axis in the favorable condition and helps in the rapid activation of stress signaling in unfavorable conditions establishing its importance in the adaptability of plants.
Secreted and cell surface proteome analysis of pathogenicCorynebacterium diphtheriaereveals proteins relevant to virulence
Authors: Goring Andrew K. , Chen Yu , Clubb Robert T. , Loo Joseph A. 
Published: September 2020

AbstractCorynebacterium diphtheriaeis responsible for the severe upper respiratory tract disease, diphtheria, which can be fatal in healthy individuals without proper treatment. Its interaction with the infected host is crucial to its virulence, secreting diphtheria toxin and a variety of machinery to acquire nutrients for further import into the cell. Additionally, it shares a conserved iron import mechanism with related pathogenic actinobacteria such asMycobacterium tuberculosis, and contains sortase-mediated anchored cell wall proteins similar to other gram-positive bacteria. Information obtained from secreted and cell-surface proteomes are relevant for the study of diphtheria and related bacterial infections. Mass spectrometry-based proteomics measurements on samples of pathogenicCorynebacterium diphtheriaeculture supernatant and cell-surface digested proteins identified greater than 3 times more proteins than a previous similar study. The diphtheria toxin was identified, as well as pathologically relevant proteins involved in iron-uptake and cell adhesion. For instance, 17 proteins predicted to be on the iron-regulated DtxR promoter were identified in cells grown under different iron concentrations, opening the door to performing comparative quantitative proteomics studies on samples where iron sources are modulated. Results of this study serve as a repository for future studies on pathogenicC. diphtheriaeuptake.
A heterologous in-cell assay for investigating intermicrovillar adhesion complex interactions and function
Authors: Weck Meredith L. , Crawley Scott W. , Tyska Matthew J. 
Published: September 2020

ABSTRACTSolute transporting epithelial cells build arrays of microvilli on their apical surface to increase membrane scaffolding capacity and enhance function potential. In epithelial tissues such as the kidney and gut, microvilli are length-matched and assembled into tightly packed ‘brush borders’, which are organized by ∼50 nm thread-like links that form between the distal tips of adjacent protrusions. Composed of protocadherins CDHR2 and CDHR5, adhesion links are stabilized at the tips by a cytoplasmic tripartite module containing the scaffolds USH1C and ANKS4B, and the actin-based motor, MYO7B. As several questions about the formation and function of this ‘intermicrovillar adhesion complex’ remain open, we devised a system that allows one to study individual binary interactions between specific complex components and MYO7B. Our approach employs a chimeric myosin consisting of the motor domain of MYO10 fused to the cargo-binding tail domain of MYO7B. When expressed in HeLa cells, which do not normally produce adhesion complex proteins, this motor exhibited robust trafficking to the tips of filopodia and was also able to transport individual components to these sites. Unexpectedly, the MYO10/MYO7B chimera was able to deliver CDHR2 and CDHR5 to distal tips in the absence USH1C or ANKS4B. Cells engineered to localize high levels of CDHR2 at filopodial tips acquired inter-filopodial adhesion and exhibited a striking dynamic length matching activity that aligned distal tips over time. These observations reveal a robust adhesion-dependent mechanism for matching the lengths of adjacent surface protrusions, and may offer insight on how epithelial cells minimize microvillar length variability.
EPH Receptor Tyrosine Kinases Regulate Epithelial Morphogenesis and Phosphorylate the PAR-3 Scaffold Protein to Modulate Downstream Signaling Networks
Authors: Banerjee Sara L. , Lavoie Noémie , Jacquet Kévin , Lessard Frédéric , Osornio-Hernandez Ana , Lavoie Josée N. , Elowe Sabine , Lambert Jean-Philippe , Laprise Patrick , Bisson Nicolas 
Published: September 2020

SUMMARYThe EPH family is the largest among receptor tyrosine kinases (RTKs) in humans. In contrast to other RTKs, EPH receptors (EPHRs) cognate ligands, ephrins, are tethered to the cell surface. This results in EPHR-ephrin signaling being mainly involved in short-range cell-cell communication events that regulate cell adhesion, migration and tissue boundary formation. Although EPHRs functions have been broadly studied, the molecular mechanisms by which they control these processes are far from being understood. To address this, we sought to identify new effector proteins acting downstream of EPHRs and determine their role in EPHR-regulated functions. To unravel EPHR-associated signaling complexes under native conditions, we applied a mass spectrometry-based approach, namely BioID proximity labeling. We obtained a composite proximity network from EPHA4, -B2, -B3 and -B4 receptors that comprises 395 proteins, most of which were not previously linked to EPH signaling. A gene ontology and pathway term analysis of the most common candidates highlighted cell polarity as a novel function associated with EPHR activity. We found that EPHA1 and EPHB4 expression is restricted to the basal and lateral membrane domains in polarized Caco-2 3D spheroidal cell cultures. We further discovered that their depletion impairs the compartmentalized distribution of polarity proteins as well as overall spheroid morphogenesis. Moreover, we examined the contribution of a number of candidates, selected from EPHR proximity networks, via loss-of-function in an EPHR-dependent cell segregation assay. We found that depletion of the signaling scaffold PAR-3 blocks cell sorting. We also delineated a signalling complex involving the C-terminal SRC kinase (CSK), whose recruitment to PAR-3 complexes is dependent on EPHR signals. Our work sheds a new light on EPHR signaling networks and describes conceptually novel the mechanisms by which EPHRs signal at the membrane to contribute to the regulation of cellular phenotypes.
Comparative mapping of crawling-cell morphodynamics in deep learning-based feature space
Authors: Imoto Daisuke , Saito Nen , Nakajima Akihiko , Honda Gen , Ishida Motohiko , Sugita Toyoko , Ishihara Sayaka , Katagiri Koko , Okimura Chika , Iwadate Yoshiaki , Sawai Satoshi 
Published: September 2020

AbstractNavigation of fast migrating cells such as amoebaDictyosteliumand immune cells are tightly associated with their morphologies that range from steady polarized forms that support high directionality to those more complex and variable when making frequent turns. Model simulations are essential for quantitative understanding of these features and their origins, however systematic comparisons with real data are underdeveloped. Here, by employing deep-learning-based feature extraction combined with phase-field modeling framework, we show that a low dimensional feature space for 2D migrating cell morphologies obtained from the shape stereotype of keratocytes,Dictyosteliumand neutrophils can be fully mapped by interlinked signaling network of cell-polarization and protrusion dynamics. Our analysis links the data-driven shape analysis to the underlying causalities by identifying key parameters critical for migratory morphologies both normal and aberrant under genetic and pharmacological perturbations. The results underscore the importance of deciphering self-organizing states and their interplay when characterizing morphological phenotypes.
Early alphavirus replication dynamics in single cells reveal a passive basis for superinfection exclusion
Authors: Singer Zakary S. , Ambrose Pradeep M. , Danino Tal , Rice Charles M. 
Published: September 2020

SummaryWhile decades of research have elucidated many steps in the alphavirus lifecycle, the earliest replication dynamics have remained unclear. This missing time window has obscured early replicase strand synthesis behavior and prevented elucidation of how the resulting activity gives rise to a superinfection exclusion environment, one of the fastest competitive phenotypes among viruses. Using quantitative live-cell and single-molecule imaging, we characterize the strand preferences of the viral replicasein situ, and measure protein kinetics in single cells over time. In this framework, we evaluate competition between alphaviruses, and uncover that early superinfection exclusion is actually not a binary and unidirectional process, but rather a graded and bidirectional viral interaction. In contrast to competition between other viruses, alphaviruses demonstrate a passive basis for superinfection exclusion, emphasizing the utility of analyzing viral kinetics within single cells.
Decapping complex is essential for functional P-body formation and is buffered by nuclear localization
Authors: Tishinov Kiril , Spang Anne 
Published: September 2020

AbstractmRNA decay is a key step in regulating the cellular proteome. Cytoplasmic mRNA is largely turned over in processing bodies (P-bodies). P-body units assemble to form P-body granules under stress conditions. How this assembly is regulated, however, remains still poorly understood. Here, we show that the translational repressor Scd6 and the decapping stimulator Edc3 act partially redundantly in P-body assembly by capturing the Dcp1/2 decapping complex and preventing it from becoming imported into the nucleus by the karyopherin ß Kap95. Nuclear Dcp1/2 does not drive mRNA decay and might be stored there as a ready releasable pool, indicating a dynamic equilibrium between cytoplasmic and nuclear Dcp1/2. Cytoplasmic Dcp1/2 is linked to Dhh1 via Edc3 and Scd6. Functional P-bodies are present at the endoplasmic reticulum where Dcp2 potentially acts to increase the local concentration of Dhh1 through interaction with Scd6 and Edc3 to drive phase separation and hence P-body formation.
Bioinformatics evaluation of the homologues ofSchistosoma mansonibiomarker proteins of bladder cancer in otherSchistosomaspecies
Authors: Folayowon JO , Adebayo AS , Isokpehi RD , Anumudu CI 
Published: September 2020

AbstractSchistosomiasis remains a public health problem in developing countries. An ideal diagnostic test capable of detecting parasites as early as possible after the onset of infection is therefore highly desired. The identification of biomarker proteins associated with active infection and immune response may constitute the basis for the development of a successful diagnostic test. The aim of this study is to contribute to the development of protein biomarkers for schistosomiasis using a bioinformatics approach. The homologues of 36 previously identified urine biomarker proteins from aSchistosoma mansonidatabase, were identified in otherSchistosomaspecies using SMARTBLAST and analyzed for similarities and differences using multiple sequence alignment. Of the 36S. mansonibiomarker proteins, 29 had homologues with bothS. haematobiumandS. japonicumor either ofS. haematobiumandS. japonicum. Most of the 29S. mansonibiomarker proteins aligned with their homologues with many conserved regions. However, some vital biomarker proteins like venom allergen-like proteins, which had been proposed as a putative drug and vaccine target, showed more semi conserved regions in which the amino acids had similar shape but weakly similar properties. The predictions of 12 markers found in all three species also show that treatment of infections may possibly benefit from the investigational drug Artenimol and specific nutraceuticals or supplements. Experimental evaluation is needed to confirm the potential of the proteins as biomarkers for early diagnosis of schistosomiasis and associated bladder cancer.
RNA polymerases in strict endosymbiont bacteria with extreme genome reduction show distinct erosions that could result in limited and differential promoters’ recognition
Authors: Rangel-Chávez Cynthia Paola , Galán-Vásquez Edgardo , Pescador-Tapia Azucena , Delaye Luis , Martínez-Antonio Agustino 
Published: September 2020

AbstractStrict endosymbiont bacteria with high degree of genome reduction retain smaller proteins and, in certain cases, lack complete functional domains compared to their free-living counterparts. Until now, the mechanisms underlying these genetic reductions are not well understood. However, it is thought that, in order to compensate for gene reduction, somehow hosts take over those vital functions that endosymbionts cannot perform. In the present study, the conservation of RNA polymerases, the essential machinery for gene expression, is analysed in bacteria with extreme genome reductions. For this purpose, comparative genomics, phylogenetic analysis and three-dimensional models of RNA polymerase subunits were done over four lineages of endosymbiotic proteobacteria with the smallest genomes known to date. Amino acids under positive selection in the α subunit and loss of motifs in other subunits of RNA polymerase were observed. According to three-dimensional models, sites under positive selection might compensate the loss of motifs in α subunit. In addition, variations in the σ subunit were identified, some of them already studied inE. colias a result of random mutagenesis. Amino acid changes in RNA polymerase suggest a possible modification in the binding specificity of the canonical −10 box (TATAAT) in some of these organisms. Furthermore, the β-flap helix domain is absent in someHodgkiniastrains, as observed in RNA pol II of Archaea, thus lacking the capacity to bind to the −35 box. Here, we propose several RNA polymerases models for endosymbiont bacteria with extremely reduced genomes. Evidence suggests that RNA polymerases of each endosymbiont bacteria follow a unique evolutionary path, without necessarily following the same path as a lineage, this is probably influenced by the intimate interactions sustained with other endosymbionts and its hosts.
Effects of gypenosides on enteroendocrine L-cell function and GLP-1 secretion
Authors: Patibandla Chinmai , Campbell Erin , Shu Xinhua , Shaw Angus M , Dolan Sharron , Patterson Steven 
Published: September 2020

AbstractGlucagon-like peptide 1 (GLP-1) is an incretin hormone produced in gut L-cells, which regulates postprandial glucose-dependent insulin secretion, also known as the incretin effect. GLP-1 secretion may be reduced in type 2 diabetes mellitus, impacting on glycaemic regulation. Thus, methods to enhance endogenous GLP-1 secretion by use of natural GLP-1 secretagogues may improve glucose control in diabetes. Gypenosides (GYP) extracted from the plantGynostemma Pentaphyllum(Jiaogulan) are known for their glucose-lowering effects bothin vitroandin vivo, although their effect on GLP-1 secretion is unknown. Our results showed that GYP enhanced cell viability and significantly upregulated antioxidant gene Nrf2, Cat and Ho-1 expression. GYP did not affect glucokinase expression but downregulated proglucagon gene expression over 24h, although, cellular GLP-1 content was unchanged. Prohormone convertase 1 (Pcsk1) gene expression was unchanged by GYP over 24h, although protein levels were significantly downregulated, while prohormone convertase 2 (Pcsk2) mRNA and protein levels were significantly upregulated. Acute exposure to gypenosides enhanced calcium uptake and GLP-1 release from GLUTag cells both at low and high glucose concentrations. These results suggest that anti-diabetic properties of gypenosides are partly linked to their ability to stimulate GLP-1 secretion. Gypenosides enhance antioxidant gene expression and may protect L-cells from excess oxidative stress.
An fMRI study of initiation and inhibition of manual responses in people who stutter
Authors: Wiltshire Charlotte E. E. , Chesters Jennifer , Krishnan Saloni , Healy Máiréad P. , Watkins Kate E. 
Published: September 2020

AbstractDevelopmental stuttering is a speech motor disorder characterised by difficulties initiating speech and frequent interruptions to the speech flow. Previous work suggests that people who stutter (PWS) have an overactive response suppression mechanism. Imaging studies of speech production in PWS consistently reveal greater activity of the right inferior frontal cortex, an area robustly implicated in inhibitory control of both manual and spoken responses. Here, we used a manual response version of the stop-signal task during fMRI to investigate neural differences related to response initiation and inhibition in PWS. Behaviourally, PWS were slower to respond to ‘go’ stimuli than people who are typically fluent (PWTF), but there was no difference in stop-signal reaction time. Our fMRI results were consistent with these behavioural results. The fMRI analysis revealed the expected networks associated with manual response initiation and inhibition in both groups. However, all contrasts between the two groups were characterised by overactivity in PWS relative to PWTF. This overactivity was significantly different for the initiation of responses (i.e. the ‘go’ trials) but not for response inhibition (i.e. the ‘stop’ trials). One explanation of these results is that PWS are consistently in a heightened inhibition state, i.e. areas of the inhibition network are more active, generally. This interpretation is consistent with predictions from the global response suppression hypothesis.