bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stat2 loss disrupts damage signalling and is protective in acute pancreatitis
Authors: Heath Helen , Britton Gary , Kudo Hiromi , Renney George , Ward Malcolm , Hutchins Robert , Foster Graham R. , Goldin Robert , Alazawi William 
Published: September 2019

ABSTRACTSeverity of sterile inflammation, as seen in acute pancreatitis, is determined by damage-sensing receptors, signalling cascades and cytokine production. Stat2 is a type I interferon signalling mediator that also has interferon-independent roles in murine lipopolysaccharide-induced NF-κB-mediated sepsis. However its role in sterile inflammation is unknown. We hypothesised that Stat2 determines severity of non-infective inflammation in the pancreas.Wild type (WT) and Stat2−/− mice were injected intraperitoneally with cerulein or L-arginine. Specific cytokine-blocking antibodies were used in some experiments. Pancreata and blood were harvested 1h and 24h after the final dose of cerulein and up to 96h post L-arginine. Whole-tissue phosphoproteomic changes were assessed using label-free mass spectrometry. Tissue-specific Stat2 effects were studied in WT/Stat2−/− bone-marrow chimera and using Cre-lox recombination to delete Stat2 in pancreatic and duodenal homeobox 1(Pdx1)-expressing cells.Stat2−/− mice were protected from cerulein- and L-arginine-induced pancreatitis. Protection was independent of type I interferon signalling. Stat2−/− mice had lower cytokine levels including TNFα and IL-10 and reduced NF-kB nuclear localisation in pancreatic tissue compared to WT. Inhibition of TNFα improved (inhibition of IL-10 worsened) cerulein-induced pancreatitis in WT but not Stat2−/− mice. Phosphoproteomics showed down-regulation of mitogen-activated protein kinase (MAPK) mediators but accumulation of Ser412-phosphorylated Tak1. Stat2 deletion in Pdx1-expressing acinar cells (Stat2flox/Pdx1-cre) reduced pancreatic TNFα expression, but not histological injury or serum amylase. WT/Stat2−/− bone-marrow chimera were protected from pancreatitis irrespective of host or recipient genotype.Stat2 loss results in disrupted signalling in pancreatitis, upstream of NF-κB in non-acinar and/or bone marrow derived cells.
Functional connectivity between the entorhinal and posterior cingulate cortices associated with navigation impairment following path integration in at-genetic-risk Alzheimer’s disease
Authors: Coughlan Gillian , Zhukovsky Peter , Puthusseryppady Vaisakh , Gillings Rachel , Minihane Anne-Marie , Cameron Donnie , Hornberger Michael 
Published: September 2019

ABSTRACTNavigation processes mediated selectively by the entorhinal cortex (EC) may be impaired in individuals with suspected preclinical Alzheimer’s disease (AD), but the clinical utility of navigation tests to detect such impairments remains to be established. In a sample of 64 individuals (32 e3e3 and 32 e3e4), we tested whether an existing paradigm, the Virtual Supermarket Test (VST), can reliably detect the presence or absence of the APOE e4 allele which accelerates amyloid plaque deposition in the brain. The present study assessed four major navigational processes that are subserved by functionally specialised cell groups located in AD vulnerable regions including the EC and examined the relationship between navigation process and regional functional connectivity (FC) given FC is a marker early AD-related tau seeding. While heading direction and spatial memory were unaffected by at-risk AD, clear altered navigational strategies following path integration were found on the VST in the e3e4 group. The APOE-sensitive VST measure correctly classified 77% of the APOE cohort. Including resting-state FC between the EC and the posterior cingulate cortex, a correlate of the path integration deficit in the APOE e4 group, the classification model increased the accuracy to 85%. Our findings show that at-genetic-risk AD selectively impairs path integration and biases self-reported spatial locations away from the centre and towards the boundary of a virtual environment. Importantly, this impairment is associated with reduced FC between the EC and the posterior cingulate cortex, which in turn informs the neurobiological mechanisms of at-genetic-risk of AD.
Modulation of peptidoglycan synthesis by recycled cell wall tetrapeptides
Authors: Hernández Sara B. , Dörr Tobias , Waldor Matthew K. , Cava Felipe 
Published: September 2019

ABSTRACTThe bacterial cell wall is made of peptidoglycan (PG), a polymer that is essential for maintenance of cell shape and survival. During growth, bacteria remodel their PG, releasing fragments that are predominantly re-internalized by the cell, where they are recycled for synthesis of new PG. Although the PG recycling pathway is widely conserved, its components are not essential and its roles in cell wall homeostasis are not well-understood. Here, we identified LdcV, aVibrio choleraeL,D-carboxypeptidase that cleaves the terminal D-Alanine from recycled murotetrapeptides. In the absence ofldcV, recycled tetrapeptides accumulated in the cytosol, leading to two toxic consequences for the cell wall. First, incorporation of tetrapeptide-containing PG precursors into the cell wall led to reduction in D,D-cross-linkage between stem peptides, diminishing PG integrity. Second, tetrapeptide accumulation led to a decrease in canonical UDP-pentapeptide precursors, reducing PG synthesis. Thus, LdcV and the recycling pathway promote optimal cell wall assembly and composition. Furthermore, Ldc substrate preference for murotetrapeptides containing canonical (D-Alanine) vs. non-canonical (D-Methionine) D-amino acids is conserved, suggesting that accumulation of tetrapeptide recycling intermediates may modulate PG homeostasis in environments enriched in non-canonical-muropeptides via substrate competition.
Muntjac chromosome evolution and architecture
Authors: Mudd Austin B. , Bredeson Jessen V. , Baum Rachel , Hockemeyer Dirk , Rokhsar Daniel S. 
Published: September 2019

AbstractDespite their recent divergence, muntjac deer show striking karyotype differences. Here we describe new chromosome-scale genome assemblies for the Chinese and Indian muntjacs,Muntiacus reevesi(2n=46) andMuntiacus muntjak(2n=6/7), and analyze their evolution and architecture. We identified six fusion events shared by both species relative to the cervid ancestor and therefore present in the muntjac common ancestor, six fusion events unique to theM. reevesilineage, and twenty-six fusion events unique to theM. muntjaklineage. One of theseM. muntjakfusions reverses an earlier fission in the cervid lineage. Although comparative Hi-C analysis revealed differences in long-range genome contacts and A/B compartment structures, we discovered widespread conservation of local chromatin contacts between the muntjacs, even near the fusion sites. A small number of genes involved in chromosome maintenance show evidence for rapid evolution, possibly associated with the dramatic changes in karyotype. Analysis of muntjac genomes reveals new insights into this unique case of rapid karyotype evolution and the resulting biological variation.
Clinical severity in Fanconi anemia correlates with residual function of FANCB missense variants
Authors: Jung Moonjung , Ramanagoudr-Bhojappa Ramanagouda , van Twest Sylvie , Rosti Rasim Ozgur , Murphy Vincent , Tan Winnie , Donovan Frank X. , Lach Francis P. , Kimble Danielle C. , Jiang Caroline S. , Vaughan Roger , Mehta Parinda , Pierri Filomena , Doufour Carlo , Auerbach Arleen D. , Deans Andrew J. , Smogorzewska Agata , Chandrasekharappa Settara C. 
Published: September 2019

ABSTRACTFanconi anemia (FA) is the most common genetic cause of bone marrow failure, and is caused by inherited pathogenic variants in any of 22 genes. Of these, onlyFANCBis X-linked. We describe a cohort of 19 children withFANCBvariants, from 16 families of the International Fanconi Anemia Registry (IFAR). Those withFANCBdeletion or truncation demonstrate earlier than average onset of bone marrow failure, and more severe congenital abnormalities compared to a large series of FA individuals in the published reports. This reflects the indispensable role of FANCB protein in the enzymatic activation of FANCD2 monoubiquitination, an essential step in the repair of DNA interstrand crosslinks. ForFANCBmissense variants, more variable severity is associated with the extent of residual FANCD2 monoubiquitination activity. We used transcript analysis, genetic complementation, and biochemical reconstitution of FANCD2 monoubiquitination to determine the pathogenicity of each variant. Aberrant splicing and transcript destabilization was associated with two missence variants. Individuals carrying missense variants with drastically reduced FANCD2 monoubiquitination in biochemical and/or cell-based assays showed earlier onset of hematologic disease and shorter survival. Conversely, variants with near-normal FANCD2 monoubiquitination were associated with more favorable outcome. Our study reveals a genotype-phenotype correlation within the FA-B complementation group of FA, where severity is linked to the extent of residual FANCD2 monoubiquitination.KEY POINTSX-linkedFANCBpathogenic variants predominantly cause acute, early onset bone marrow failure and severe congenital abnormalitiesBiochemical and cell-based assays with patient variants reveal functional properties of FANCB that associate with clinical severity
Golgi-localized PAQR4 mediates Anti-apoptotic Ceramidase Activity in Breast Cancer
Authors: Pedersen Line , Panahandeh Pouda , Siraji Muntequa Ishtiaq , Knappskog Stian , Lønning Per Eystein , Zhu Qingzhang , Gordillo Ruth , Scherer Philipp E. , Molven Anders , Teigen Knut , Halberg Nils 
Published: September 2019

SummaryThe metabolic network of sphingolipids plays important roles in cancer biology. Prominent sphingolipids include ceramides and sphingosine-1-phosphate that regulate multiple aspects of growth, apoptosis and cellular signaling. Although many significant enzymatic regulators of the sphingolipid pathway have been described in detail, the list is currently incomplete. Here, we applied a systemic approach to identify and molecularly define progestin and adipoQ receptor family member IV (PAQR4) as a Golgi-localized ceramidase. We find PAQR4 to be ∼5 fold upregulated in breast cancer compared to matched control tissue and that its overexpression correlate with disease-specific survival rates in breast cancer. PAQR4 is a seven transmembrane protein, and depletion of PAQR4 leads to cellular apoptosis through accumulation of ceramides. Our findings establish PAQR4 as Golgi-localized ceramidase required for cellular growth in breast cancer.
Naturally Occurring Shorter and Tumor-associated Mutant RNF167 Variants Facilitates Lysosomal Exocytosis and Plasma Membrane Resealing
Authors: Nair Sreeja V. , Narendradev Nikhil Dev , Nambiar Rithwik P. , Kumar Rakesh , Srinivasula Srinivasa M. 
Published: September 2019

AbstractLysosomal exocytosis and resealing of damaged plasma membrane play critical roles in physiological and pathological processes, including, restoration of cellular homeostasis and tumor invasion. However, to-date, only a few regulatory molecules of these biological processes have been identified. Moreover, no mutations in any of the known regulators of lysosomal exocytosis in primary tumors of patients have been characterized. Here we demonstrate that RNF167, a lysosomal associated ubiquitin ligase, negatively regulates lysosomal exocytosis by inducing perinuclear clustering of lysosomes. Importantly, we also characterized a set of novel natural mutations in RNF167, which are commonly found in diverse tumor types. We found that RNF167-K97N mutant, unlike the wild-type, localizes in the cytoplasm and does not promote perinuclear lysosomal clustering and that cells expressing RNF167-K97N exhibit dispersed lysosomes, increased exocytosis, and enhanced plasma membrane repair. Interestingly, these functional features of RNF167-K97N were shared with a naturally occurring short version of RNF167, i.e. isoform b. In brief, the results presented here reveal a novel role of RNF167 as well as its natural variants, RNF167-K97N and RNF167-b as an upstream regulator of lysosomal exocytosis and plasma membrane resealing which might play an important role in organelle dynamics or tumor progression or both.
Fluctuation-Based Super-Resolution Traction Force Microscopy
Authors: Stubb Aki , Laine Romain F. , Guzmán Camilo , Henriques Ricardo , Jacquemet Guillaume , Ivaska Johanna 
Published: September 2019

AbstractCellular mechanics play a crucial role in tissue morphogenesis and homeostasis and are often misregulated in disease. Traction force microscopy (TFM) is one of the key methods that has enabled researchers to study fundamental aspects of mechanobiology; however, the power of TFM is limited by poor resolution and low throughput. Here, we propose a simplified protocol and imaging strategy, relying on super-resolution microscopy enabled by fluorophore fluctuation analysis, to enhance the output of TFM, by increasing both bead density as well as the accuracy of bead tracking in TFM gels. Our analysis pipeline can be used on either camera-based confocal or widefield microscopes and is fully compatible with available TFM analysis software. In addition, we demonstrate that our workflow can be used to gain biologically relevant information and is suitable for long-term live measurement of traction forces even in light-sensitive cells. Finally, we propose that our strategy could be used to considerably simplify the implementation of TFM screens. Our streamlined protocol can be performed with minimal hardware and software investment, and has the potential to standardize high-resolution TFM.
SCAR FORMATION AND DECREASED CARDIAC FUNCTION FOLLOWING ISCHEMIA/REPERFUSION INJURY IN 1-MONTH-OLD SWINE
Authors: Agnew Emma J , Velayutham Nivedhitha , Ortiz Gabriela Matos , Alfieri Christina M , Moore Victoria , Riggs Kyle W , Baker R. Scott , Gibson Aaron M , Ponny Sithara Raju , Alsaied Tarek , Zafar Farhan , Yutzey Katherine E 
Published: September 2019

ABSTRACTStudies in mice show a brief neonatal period of cardiac regeneration with minimal scar formation. Less is known about reparative mechanisms in large mammals. A transient cardiac injury approach (ischemia/reperfusion, IR) was used in weaned postnatal day (P)30 pigs, to assess regenerative repair in young large mammals. Female and male P30 pigs were subjected to cardiac ischemia (1 hour) by occlusion of the left anterior descending artery followed by reperfusion, or to sham operation. Following IR, myocardial damage occurred, with cardiac ejection fraction significantly decreased 2 hours post-ischemia. No improvement or worsening of cardiac function to the 4 week study end-point was observed. Histology demonstrated cardiomyocyte (CM) cell cycling at 2-months-of-age in multinucleated CMs in both sham-operated and IR pigs. Regional scar formation and inflammation in the epicardial region proximal to injury were observed 4 weeks post-IR. Sex differences were found, suggestive of females creating a greater fibrotic response with worse cardiac function, highlighting the importance of representing both sexes in cardiac injury studies. Together, our results describe an effective novel cardiac injury model in P30 swine, at a time when CMs are still cycling. Pigs subjected to IR show myocardial damage with a prolonged decrease in cardiac function, formation of a small, regional scar with increased inflammation. These data demonstrate that P30 pigs do not regenerate myocardium, even in the presence of CM mitotic activity, but form a scar after transient IR injury.NEW & NOTEWORTHYHere, we report for the first time ischemia/reperfusion (IR) cardiac injury in 1-month-old (P30) pigs. This model of IR injury highlights lack of cardiac regeneration, even in the presence of cardiomyocyte (CM) cell cycling in young swine. An effective injury approach is described for use in large mammals to investigate cardiac function, CM cell cycling, extracellular matrix (ECM) remodeling, and gene expression changes, while highlighting the importance of studying both sexes.
Neural Mechanisms for Executive Control of Speed-Accuracy Tradeoff
Authors: Reppert Thomas R. , Heitz Richard P. , Schall Jeffrey D. 
Published: September 2019

SUMMARYThe balance of speed with accuracy requires error detection and performance adaptation. To date, neural concomitants of these processes have been investigated only with noninvasive measures. To provide the first neurophysiological description, macaque monkeys performed visual search under cued speed accuracy tradeoff (SAT). Monkeys changed SAT emphasis immediately after a cued switch while neuron discharges were sampled in medial frontal cortex area supplementary eye field (SEF). A multiplicity of SEF neurons signaled production of choice errors and timing errors. Modulation of SEF activity after choice errors predicted production of un-rewarded corrective saccades. Modulation of activity after timing errors signaled reward prediction error. Adaptation of performance during SAT of visual search was accomplished through pronounced changes in neural state from before search array presentation until after reward delivery. These results contextualize previous findings using noninvasive measures, complement neurophysiological findings in visuomotor structures, endorse the role of medial frontal cortex as a critic relative to the actor instantiated in visuomotor structures, and extend our understanding of the distributed neural mechanisms of SAT.HIGHLIGHTSMedial frontal cortex enables post-error adjustment during SATChoice and timing errors were signaled by partially overlapping neural poolsMedial frontal cortex can proactively modulate visuomotor processesMedial frontal cortex is to visuomotor circuits as critic to actor
Food-borne mycotoxin hazards in the Kenyan market-a retrospective study
Authors: Kibugu James Karuku , Mburu David , Munga Leonard Karongo , Kurgat Richard , Mukasa Bernard , Lusweti Fransisca Naliaka , Grace Delia , Lindahl Johanna 
Published: September 2019

AbstractMycotoxin contamination data (n=1818) in feed and food from major laboratories were categorized into hazardous and non-hazardous using contaminants regulatory limits, analyzed by logistic regression and chi-square test to identify potential health hazards. Feeds were most contaminated, with 64% and 39% having total aflatoxin (AFT) levels above Kenyan and American standards respectively. Peanuts, the most contaminated food, had 61% and 47% of samples failing Kenyan and American AFT standards respectively. By European standards, wheat had highest AFT contamination rate of 84%. Half of baby foods sampled had AFT level above Kenyan and European standards. Maize had failure rates of 20% (Kenyan standard), 14% (American standard) and 25% (European standard) for AFT. We observed high frequency of mycotoxins (AFT, aflatoxin M1, zearalenone, T-2 toxin, ochratoxin A, fumonisins, deoxynivalenol) and AFT hazards with significantly (p<0.001) higher failure rates in wheat, peanuts, mycotoxin hazards in dairy products in that order (European standard). Failure rates were significantly (p<0.001) higher in feed ingredients (p<0.01), baby foods (p<0.05), maize (p<0.001), fodder (p<0.05) for mycotoxins, and compound feeds, peanuts, wheat (p<0.001), feed ingredients, baby foods (p<0.01), maize (p<0.001), fodder (0.01), in that order, for AFT (American standard). Fail rates were significantly higher for mycotoxins in compound feeds, feed ingredients, peanuts, wheat, baby foods, maize (p<0.001), herbal health drink (p<0.01), and for AFT in compound feeds, feed ingredients, peanuts, wheat (p<0.001), baby foods (p<0.01), herbal health drink (p<0.05), maize (p<0.001) in that order (Kenyan standard). High frequency of mycotoxin and AFT hazards in maize, baby foods, herbal health drink and aflatoxin M1 in dairy products was noted. Detection by different laboratories varied significantly (p<0.001). Health and economic implications of this and limitations of current food safety standards are discussed. Humans and animals in Kenya are chronically exposed to mycotoxin hazards that require constant surveillance and strict regulation.
Unpacking the Allee effect: determining individual-level mechanisms that drive global population dynamics
Authors: Fadai Nabil T. , Johnston Stuart T. , Simpson Matthew J. 
Published: September 2019

AbstractWe present a solid theoretical foundation for interpreting the origin of Allee effects by providing the missing link in understanding how local individual-based mechanisms translate to global population dynamics. Allee effects were originally proposed to describe population dynamics that cannot be explained by exponential and logistic growth models. However, standard methods often calibrate Allee effect models to match observed global population dynamics without providing any mechanistic insight. By introducing a stochastic individual-based model, with proliferation, death, and motility rates that depend on local density, we present a modelling framework that translates particular global Allee effects to specific individual-based mechanisms. Using data from ecology and cell biology, we unpack individual-level mechanisms implicit in an Allee effect model and provide simulation tools for others to repeat this analysis.
AKrüppel-like factor 1(KLF1) mutation associated with severe congenital dyserythropoietic anemia alters its DNA-binding specificity
Authors: Kulczynska Klaudia , Bieker James J , Siatecka Miroslawa 
Published: September 2019

AbstractKrüppel-like factor 1 (KLF1/EKLF) is a transcription factor that globally activates genes involved in erythroid cell development. Various mutations are identified in the human KLF1 gene. The E325K mutation causes congenital dyserythropoietic anemia (CDA) type IV, characterized by severe anemia and non-erythroid-related symptoms. The CDA mutation is in the second zinc finger of KLF1 at a position functionally involved in its interactions with DNA. The molecular parameters of how CDA-KLF1 exerts its biological effects have not been addressed. Here, using an in vitro selection strategy we determined the preferred DNA-binding site for CDA-KLF1. Binding to the deduced consensus sequence is supported by in vitro gel shifts and by in vivo functional reporter gene studies. Two significant changes compared to WT binding are observed: G is selected as the middle nucleotide and the 3’-portion of the consensus sequence is more degenerate. As a consequence CDA-KLF1 did not bind the WT consensus sequence. However, activation of ectopic sites is promoted. Continuous activation of WT target genes occurs if they fortuitously contain the novel CDA site nearby. Our findings provide a molecular understanding of how a single mutation in the KLF1 zinc finger exerts an effects on erythroid physiology in CDA type IV.