bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contriving a chimeric polyvalent vaccine to prevent infections caused by Herpes Simplex Virus (Type-1 and Type-2): an exploratory immunoinformatic approach
Authors: Hasan Mahmudul , Islam Md Shiful , Chakraborty Sourav , Mustafa Abu Hasnat , Azim Kazi Faizul , Joy Ziaul Faruque , Hossain Md Nazmul , Foysal Shakhawat Hossain , Hasan Md Nazmul 
Published: June 2019

ABSTRACTHerpes simplex virus type 1 (HSV-1) and 2 (HSV-2) cause a variety of infections including oral-facial infections, genital herpes, herpes keratitis, cutaneous infection and so on. To date, FDA-approved licensed HSV vaccine is not available yet. Hence, the study was conducted to identify and characterize an effective epitope based polyvalent vaccine against both types of Herpes Simplex Virus through targeting six viral proteins. The selected proteins were retrieved from viralzone and assessed to design highly antigenic epitopes by binding analyses of the peptides with MHC class-I and class-II molecules, antigenicity screening, transmembrane topology screening, allergenicity and toxicity assessment, population coverage analysis and molecular docking approach. The final vaccine was constructed by the combination of top CTL, HTL and BCL epitopes from each protein along with suitable adjuvant and linkers. Physicochemical and secondary structure analysis, disulfide engineering, molecular dynamic simulation and codon adaptation were further employed to develop a unique multi-epitope peptide vaccine. Docking analysis of the refined vaccine structure with different MHC molecules and human immune TLR-2 receptor demonstrated higher interaction. Complexed structure of the modeled vaccine and TLR-2 showed minimal deformability at molecular level. Moreover, translational potency and microbial expression of the modeled vaccine was analyzed with pET28a(+) vector forE. colistrain strain K12. The study enabled design of a novel chimeric polyvalent vaccine to confer broad range immunity against both HSV serotypes. However, further wet lab based research using model animals are highly recommended to experimentally validate our findings.
Mycobacterium tuberculosisinfection boosts B cell responses to unrelated pathogens
Authors: Kimuda Simon G. , Andia-Biraro Irene , Sebina Ismail , Egesa Moses , Nalwoga Angela , Smith Steven G. , Bagaya Bernard S. , Levin Jonathan , Elliott Alison M. , Raynes John G. , Cose Stephen 
Published: June 2019

AbstractAntigens fromMycobacterium tuberculosis(M.tb), have been shown to stimulate human B cell responses to unrelated recall antigensin vitro. However, it is not known whether naturalM.tbinfection or whether vaccination with the related species,Mycobacterium bovisBCG, has a similar effect. This study investigated the effects ofM.tbinfection and BCG vaccination on B cell responses to heterologous pathogen recall antigens. Antibodies against several bacterial and viral pathogens were quantified by ELISA in 68 uninfected controls, 62 individuals with latent TB infection (LTBI) and 107 active pulmonary TB (APTB) cases, and 24 recently BCG-vaccinated adolescents and naive controls. Antibody avidity was investigated using surface plasmon resonance and B cell ELISPOT assays were used to measure plasmablast and memory B cell responses (MBC) in APTB cases and healthy donor controls. APTB was associated with higher levels of antibodies to tetanus toxoid (TT), diphtheria toxoid, respiratory syncytial virus, measles virus and Kaposi’s sarcoma herpesvirus, compared to uninfected controls. Vaccination with BCG did not alter levels of antibodies against heterologous pathogens. TT-specific antibody avidity was increased in APTB and the ratio of TT-specific plasmablasts to MBCs in the APTB cases was 7:1.M.tbinfection boosts serological memory to heterologous pathogens in human subjects and this process may be driven by polyclonal activation of memory B cells.SignificanceMycobacterium tuberculosis (M.tb)has potent immunostimulatory properties and has been used in adjuvant preparations to improve vaccine responses in animals. This study shows that naturalM.tbinfection in humans is associated with increased antibody and B cell recall responses to heterologous pathogens. This data suggests a potential role forM.tbantigens in immunotherapies designed to maintain antibody immunity to diverse infections.
A novel decellularization method to produce brain scaffolds
Authors: Granato Alessandro E.C. , da Cruz Edgar Ferreira , Rodrigues-Junior Dorival Mendes , Mosini Amanda Cristina , Ulrich Henning , Cheffer Arquimedes , Porcionatto Marimelia 
Published: June 2019

ABSTRACTScaffolds composed of extracellular matrix (ECM) can assist tissue remodeling and repair following injury. The ECM is a complex biomaterial composed of proteins, glycoproteins, proteoglycans, and glycosaminoglycans, secreted by cells. The ECM contains fundamental biological cues that modulate cell behavior and serves as a structural scaffold for cell adhesion and growth. For clinical applications, where immune rejection is a constraint, ECM can be processed using decellularization methods intended to remove cells and donor antigens from tissue or organs, while preserving native biological cues essential for cell growth and differentiation. Recent studies show bioengineered organs composed by a combination of a diversity of materials and stem cells as a possibility of new therapeutic strategies to treat diseases that affect different tissues and organs, including the central nervous system (CNS). Nevertheless, the methodologies currently described for brain decellularization involve the use of several chemical reagents with many steps that ultimately limit the process of organ or tissue recellularization. Here, we describe for the first time a fast and straightforward method for complete decellularization of mice brain by the combination of rapid freezing and thawing following the use of only one detergent (Sodium dodecyl sulfate (SDS)). Our data show that using the protocol we describe here the brain can be entirely decellularized, while still maintaining ECM components that are essential for cell survival and repopulation of the scaffold. Our results also show the repopulation of the decellularized brain matrix with Neuro2a cells, that were identified by immunohistochemistry in their undifferentiated form. We conclude that this novel and simple method for brain decellularization can be used as a biocompatible scaffold for cell repopulation.Impact StatementFor the first time we describe an easy, effective and low cost method for complete decellularization of murine brain by the use of only one detergent (SDS) combined with rapid freezing and thawing, that can be used as a 3D scaffold for cell culture of neuronal cells. The results show that the decellularized brains still maintain ECM components essential for cell survival and repopulation of the scaffold. Moreover, we found that the decellularized brain matrix can be repopulated with neural cells, showing its biocompatibility.GRAFICAL ABSTRACT
TLR3 Deficiency Leads to Altered Immune Responses toChlamydia trachomatisInfection in Human Oviduct Epithelial Cells
Authors: Xu Jerry Z. , Kumar Ramesh , Gong Haoli , Liu Luyao , Ramos-Solis Nicole , Li Yujing , Derbigny Wilbert A. 
Published: June 2019

ABSTRACTReproductive tract pathology caused byChlamydia trachomatisinfection is an important global cause of human infertility. To better understand the mechanisms associated withChlamydia-induced genital tract pathogenesis in humans, we used CRISPR genome editing to disrupt TLR3 function in the human oviduct epithelial (hOE) cell-line OE-E6/E7, in order to investigate the possible role(s) of TLR3 signaling in the immune response toChlamydia. Disruption of TLR3 function in these cells significantly diminished theChlamydia-induced synthesis of several inflammation biomarkers including IFN-β, IL-6, IL-6Ra, sIL-6Rβ (gp130), IL-8, IL-20, IL-26, IL-34, sTNF-R1, TNFSF13B, MMP-1, MMP-2, and MMP-3. In contrast, theChlamydia-induced synthesis of CCL-5, IL-29 (IFNλ1) and IL-28A (IFNλ2) were significantlyincreasedin the TLR3-deficient hOE cells when compared to their wild-type counterparts. Our results propose a role for TLR3 signaling in limiting the genital tract fibrosis, scarring, and chronic inflammation often associated with human chlamydial disease. Interestingly, we saw thatChlamydiainfection induced the production of biomarkers associated with persistence, tumor metastasis, and autoimmunity such as soluble CD163 (sCD163), chitinase-3-like protein 1, osteopontin, and pentraxin-3 in the hOE cells; however, their expression levels were significantly dysregulated in the TLR3-deficient hOE cells. Finally, we demonstrate using the hOE cells that TLR3 deficiency resulted in an increased amount of chlamydial LPS within theChlamydiainclusion, which is suggestive that TLR3 deficiency leads to enhanced chlamydial replication and possibly increased genital tract pathogenesis during human infection.AbbreviationshOE, human OE-E6/E7 cells; TLR3 KO, TLR3 knockout cell line; poly (I:C), Polyinosinic–polycytidylic acid sodium salt.
p63 sets the threshold for induction of apoptosis using a kinetically encoded ‘doorbell-like’ mechanism
Authors: Gebel Jakob , Tuppi Marcel , Chaikuad Apirat , Hötte Katharina , Schulz Laura , Löhr Frank , Gutfreund Niklas , Finke Franziska , Schröder Martin , Henrich Erik , Mezhyrova Julija , Lehnert Ralf , Pampaloni Francesco , Hummer Gerhard , Stelzer Ernst H.K. , Knapp Stefan , Dötsch Volker 
Published: June 2019

AbstractCell fate decisions such as apoptosis require cells to translate signaling input into a binary yes/no response. A tight control of the process is required to avoid loss of cells by accidental activation of cell death pathways. One particularly critical situation exists in primary oocytes because their finite number determines the reproductive capacity of females. On the one hand a stringent genetic quality control is necessary to maintain the genetic integrity of the entire species; on the other hand an overly stringent mechanism that kills oocytes with even minor DNA damage can deplete the whole primary oocyte pool leading to infertility. The p53 homolog TAp63α is the key regulator of genome integrity in oocytes. After DNA damage TAp63α is activated by multistep phosphorylation involving multiple phosphorylation events by the kinase CK1, which triggers the transition from a dimeric and inactive conformation to an open and active tetramer. By measuring activation kinetics in ovaries and single site phosphorylation kineticsin vitrowith peptides and full length protein we show that TAp63α phosphorylation follows a biphasic behavior. While the first two CK1 phosphorylation events are fast, the third one that constitutes the decisive step to form the active conformation is slow. We reveal the structural mechanism for the difference in the kinetic behavior based on an unusual CK1/TAp63α substrate interaction and demonstrate by quantitative simulation that the slow phosphorylation phase determines the threshold of DNA damage required for induction of apoptosis.
Plant mixed lineage kinase domain-like proteins limit biotrophic pathogen growth
Authors: Mahdi Lisa , Huang Menghang , Zhang Xiaoxiao , Nakano Ryohei Thomas , Kopp Leïla Brulé , Saur Isabel M.L. , Jacob Florence , Kovacova Viera , Lapin Dmitry , Parker Jane E. , Murphy James M. , Hofmann Kay , Schulze-Lefert Paul , Chai Jijie , Maekawa Takaki 
Published: June 2019

AbstractMixed lineage kinase domain-like (MLKL) protein mediates necroptotic cell death in vertebrates. We report here the discovery of a conserved protein family across seed plants that is structurally homologous to vertebrate MLKL. TheArabidopsis thalianagenome encodes three MLKLs with overlapping functions in limiting growth of obligate biotrophic fungal and oomycete pathogens. Although displaying a cell death activity mediated by N-terminal helical bundles, termed HeLo domain,AtMLKL-dependent immunity can be separated from host cell death. Cryo-electron microscopy structures ofAtMLKLs reveal a tetrameric configuration, in which the pseudokinase domain and brace region bury the HeLo-domains, indicative of an auto-repressed complex. We also show the association of twoAtMLKLs with microtubules. These findings, coupled with resistance-enhancing activity and altered microtubule association of a phosphomimetic mutation in the pseudokinase domain ofAtMLKL1, point to a cell death-independent immunity mechanism.One Sentence SummaryPlants have a protein family that is structurally homologous to vertebrate mixed lineage kinase domain-like protein, which induces necroptotic cell death, but these plant proteins can confer immunity without host cell death.
Neurocomputational mechanisms underlying emotional awareness: insights afforded by deep active inference and their potential clinical relevance
Authors: Smith Ryan , Lane Richard D. , Parr Thomas , Friston Karl J. 
Published: June 2019

AbstractEmotional awareness (EA) is recognized as clinically relevant to the vulnerability to, and maintenance of, psychiatric disorders. However, the neurocomputational processes that underwrite individual variations remain unclear. In this paper, we describe a deep (active) inference model that reproduces the cognitive-emotional processes and self-report behaviors associated with EA. We then present simulations to illustrate (seven) distinct mechanisms that (either alone or in combination) can produce phenomena – such as somatic misattribution, coarse-grained emotion conceptualization, and constrained reflective capacity – characteristic of low EA. Our simulations suggest that the clinical phenotype of impoverished EA can be reproduced by dissociable computational processes. The possibility that different processes are at work in different individuals suggests that they may benefit from distinct clinical interventions. As active inference makes particular predictions about the underlying neurobiology of such aberrant inference, we also discuss how this type of modelling could be used to design neuroimaging tasks to test predictions and identify which processes operate in different individuals – and provide a principled basis for personalized precision medicine.
A bacterial assay for rapid screening of IAA catabolic enzymes
Authors: Federica Brunoni , Silvio Collani , Jan Šimura , Markus Schmid , Catherine Bellini , Karin Ljung 
Published: June 2019

AbstractBackgroundPlants rely on concentration gradients of the native auxin, indole-3-acetic acid (IAA), to modulate plant growth and development. Both metabolic and transport processes participate in the dynamic regulation of IAA homeostasis. Free IAA levels can be reduced by inactivation mechanisms, such as conjugation and degradation. IAA can be conjugated via ester linkage to glucose, or via amide linkage to amino acids, and degraded via oxidation. Members of the UDP glucosyl transferase (UGT) family catalyze the conversion of IAA to indole-3-acetyl-1-glucosyl ester (IAGlc); by contrast, IAA is irreversibly converted to indole-3-acetyl-L-aspartic acid (IAAsp) and indole-3-acetyl glutamic acid (IAGlu) by Group II of the GRETCHEN HAGEN3 (GH3) family of acyl amido synthetases. DIOXYGENASE OF AUXIN OXIDATION (DAO) irreversibly oxidizes IAA to oxindole-3-acetic acid (oxIAA) and, in turn, oxIAA can be further glucosylated to oxindole-3-acetyl-1-glucosyl ester (oxIAGlc) by UGTs. These metabolic pathways have been identified based on mutant analyses, in vitro activity measurements, and in planta feeding assays. In vitro assays for studying protein activity are based on expressing Arabidopsis enzymes in a recombinant form in bacteria or yeast followed by recombinant protein purification. However, the need to extract and purify the recombinant proteins represents a major obstacle when performing in vitro assays.ResultsIn this work we report a rapid, reproducible and cheap method to screen the enzymatic activity of recombinant proteins that are known to inactivate IAA. The enzymatic reactions are carried out directly in bacteria that express the recombinant protein. The enzymatic products can be measured by direct injection of a small supernatant fraction from the bacterial culture on ultrahigh-performance liquid chromatography coupled to electrospray ionization tandem spectrometry (UHPLC-ESI-MS/MS). Experimental procedures were optimized for testing the activity of different classes of IAA-modifying enzymes without the need to purify recombinant protein.ConclusionsThis new method represents an alternative to existing in vitro assays. It can be applied to the analysis of IAA metabolites that are produced upon supplementation of substrate to engineered bacterial cultures and can be used for a rapid screening of orthologous candidate genes from non-model species.
Bacterial protein interaction networks: connectivity is ruled by gene conservation, essentiality and function
Authors: Dilucca Maddalena , Cimini Giulio , Giansanti Andrea 
Published: June 2019

AbstractProtein-protein interaction (PPI) networks are the backbone of all processes in living cells. In this work we study how conservation, essentiality and functional repertoire of a gene relate to the connectivitykof the corresponding protein in the PPI networks. Focusing on a set of 42 mostly distantly related bacterial species, we investigate three issues: i) whether the distribution of connectivity values changes between PPI subnetworks of essential and nonessential genes; ii) how gene conservation, measured both by the evolutionary retention index (ERI) and by evolutionary pressure (as represented by the ratioKa/Ks) is related to the the connectivity of the corresponding protein; iii) how PPI connectivities are modulated by evolutionary and functionaly relationships, as represented by the Clusters of Orthologous Proteins (COGs). We show that conservation, essentiality and functional specialization of genes control in a universal way the topology of the emerging bacterial PPI networks. Noteworthy, a structural transition in the network is observed such that, for connectivitiesk≥ 40, bacterial PPI networks are mostly populated by genes that are conserved, essential and which, in most cases, belong to the COG cluster J, related to ribosomal functions and to the processing of genetic information.
Translatomic database of cortical astroglia across male and female mouse development reveals two distinct developmental phenotypes
Authors: Rurak Gareth M. , Simard Stephanie , Charih François , Van Geel Amanda , Stead John , Woodside Barbara , Green James R. , Coppola Gianfilippo , Salmaso Natalina 
Published: June 2019

AbstractAstroglial cells are emerging as key players in the development and homeostatic maintenance of neurons and neuronal networks. Astroglial cell functions are critical to neuronal migration and maturation, myelination, and synapse dynamics, however little is known about astroglial phenotypic changes over development. Furthermore, astroglial cells express steroid hormone receptors and show rapid responses to hormonal manipulations, however, despite important sex differences in telencephalic regions such as the cortex and hippocampus few studies have examined sex differences in astroglial cells in development and outside of the hypothalamus and amygdala. To phenotype cortical astroglial cells across postnatal development while considering potential sex differences, we used translating ribosome affinity purification together with RNA sequencing (TRAPseq) and immunohistochemistry to phenotype the entire astroglial translatome in males and females at key developmental time points: P1, P4, P7, P14, P35 and in adulthood. Overall, we found two distinct astroglial phenotypes between early (P1-P7) and late development (P14-Adult). We also noted that although astroglia show few basal sex differences in adulthood, they show significant sex differences in developmental gene expression patterns, with peak sex differences observed at P7. At least part of the sex differences observed at P7 appear to be due to males reaching a more mature astroglial phenotype earlier than females. Together, these data clearly delineate and phenotype astroglia across development and identify sex differences in astroglial developmental programs. Importantly, these developmental sex differences could have an impact on the construction and maintenance of neuronal networks and potential developmental windows of vulnerability to neurologic and psychiatric disease.
Potential antigenic mismatch of the H3N2 component of the 2019 Southern Hemisphere influenza vaccine
Authors: Gouma Sigrid , Weirick Madison , Hensley Scott E. 
Published: June 2019

AbstractHere, we find that the egg-adapted H3N2 component of the 2019 Southern Hemisphere influenza vaccine elicits an antibody response in ferrets that is highly focused on antigenic site A of hemagglutinin. This is potentially problematic since most H3N2 viruses currently circulating in the Southern Hemisphere possess antigenic site A substitutions.
Mutational processes of distinct POLE exonuclease domain mutants drive an enrichment of a specific TP53 mutation in colorectal cancer
Authors: Fang Hu , Barbour Jayne A. , Poulos Rebecca C. , Katainen Riku , Aaltonen Lauri A. , Wong Jason W. H. 
Published: June 2019

AbstractCancer genomes with mutations in the exonuclease domain of Polymerase Epsilon (POLE) present with an extraordinarily high somatic mutation burden. In vitro studies have shown that distinct POLE mutants exhibit different polymerase activity and yet, how these POLE mutants generate mutations across cancer genomes and influence driver events remains poorly understood. Here we analyzed 7,345 colorectal cancer samples, including nine whole genome sequenced samples harboring POLE mutations. Our analysis identified differential mutation spectra across the mutants including methylation-independent enrichment of C>T mutations in POLE V411L. In contrast, analysis of other genomic regions showed similar mutation profiles across the different POLE mutants. Notably, we found that POLE mutants with the TP53 R213* mutation, caused by a TT[C>T]GA substitution, have significantly higher relative frequency of this mutational context compared with samples without this mutation. This finding demonstrates that variations in underlying mutation spectra can increase the likelihood of specific driver mutation formation.