bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathogenic, but not non-pathogenic,Rickettsiaevade inflammasome-dependent IL-1 responses to establish an intracytosolic replication niche
Authors: Voss Oliver H. , Cobb Jennifer , Gaytan Hodalis , Díaz Natalia Rivera , Sanchez Rigoberto , DeTolla Louis , Rahman M. Sayeedur , Azad Abdu F. 
Published: September 2021

ABSTRACTRickettsiaspecies (spp.) are strict obligate intracellular bacteria, with some being pathogenic in their mammalian host, including humans. One critical feature of these stealthy group of pathogens is their ability to manipulate hostile cytosolic environments to their benefits. Although our understanding ofRickettsiacell biology and pathogenesis are evolving, the mechanisms by which pathogenicRickettsiaspp. evade host innate immune detection remains elusive. Here, we showed that disease severity in wild-type (WT) C57BL/6J mice infected withR. typhi(etiologic agent of murinetyphus) andR. rickettsii(etiologic agent of Rocky Mountain Spotted Fever), but not with non-pathogenicR. montanensis, correlated with levels of bacterial burden as detected in the spleens, as well as the serum concentrations of pro-inflammatory cytokine IL-1α and to a lesser extent IL- 1β. Antibody-mediated neutralization of IL-1α confirmed a key role in controlling mortality rates and bacterial burdens of rickettsiae-infectedWTmice. As macrophages are a primary source of both IL-1α and IL-1β cytokines, we determined the mechanism of the anti-rickettsial activities using bone-marrow-derived macrophages. We found that pathogenicR. typhiandR. rickettsii, but not non-pathogenicR. montanensis, eluded pro- IL-1α induction and benefited pre-dominantly from the reduced IL-1α secretion, via a Caspase-11-Gsdmd-dependent pathway, to facilitate intracytosolic replication. Adoptative transfer experiments identified that IL-1α secretion by macrophages was critical for controlling rickettsiosis inWTmice. In sum, we identified a previously unappreciated pathway by which pathogenic, unlike non-pathogenic, rickettsiae preferentially target the Caspase-11-Gsdmd-IL-1α signaling axis in macrophages thus supporting their replication within the host.IMPORTANCECurrently, no vaccines are available to prevent rickettsioses, while vector-borne rickettsial infections in humans are on the rise globally. In fact, the insufficient understanding of how pathogenicRickettsiaspecies circumvent host immune defense mechanisms has significantly hindered the development of more effective therapeutics. Here, we identified a previously unappreciated role for the Caspase-11-Gsdmd-IL-1α signaling axis, to limiting the replication of pathogenicR. rickettsiaandR. typhispecies in murine macrophages and wild-type (WT) C57BL/6J mice. Adoptative transfer studies further identified IL-1α-secreting macrophages as critical mediators in controlling rickettsial infection inWTmice. Collectively, these findings provide insight into the potential mechanism of how pathogenic, but not non-pathogenicRickettsiaspp., benefit from a reduction in the Caspase-11-Gsdmd-mediated release of IL-1α to support host colonization.
A redox cycle with complex II promotes sulfide quinone oxidoreductase dependent H2S oxidation
Authors: Kumar Roshan , Landry Aaron P. , Guha Arkajit , Vitvitsky Victor , Lee Ho Joon , Seike Keisuke , Reddy Pavan , Lyssiotis Costas A. , Banerjee Ruma 
Published: September 2021

The dueling roles of H2S as an endogenously synthesized respiratory substrate and as a toxin, raise questions as to how it is cleared when the electron transport chain is inhibited. Sulfide quinone oxidoreductase (SQOR) is a mitochondrial inner membrane flavoprotein that catalyzes the first step in the H2S oxidation pathway and uses coenzyme Q (CoQ) as an electron acceptor. However, complex IV poisoning by H2S inhibits complex III-dependent recycling of CoQH2, which is needed to sustain H2S oxidation. We have discovered that under these conditions, reversal of complex II activity using fumarate as an electron acceptor, establishes a new redox cycle with SQOR. The purine nucleotide cycle and the malate aspartate shuttle are sources of fumarate in H2S treated cells, which accumulate succinate. Complex II knockdown decreases the efficiency of H2S clearance and increases recovery time to the basal respiration rate in H2S treated cells. In contrast, attenuation of complex I, which is a major competitor for the mitochondrial CoQ pool, has the opposite effects. Targeted knockout of complex II in murine intestinal epithelial cells that are routinely exposed to microbiota derived H2S, decreases serum, urine, and fecal thiosulfate, a product of H2S oxidation. Our study identifies a metabolic reprogramming response to H2S that furnishes fumarate as an alternate electron acceptor and supports H2S oxidation independent of complex IV activity. Complex II-linked redox cycling of SQOR has important implications for gut H2S metabolism as colonocytes are routinely exposed to high concentrations of this gas derived from the microbiota.One Sentence SummaryReversal of complex II sustains and prioritizes H2S oxidation when respiration is poisoned.
Angiotensin-converting enzyme governs endogenous opioid signaling and synaptic plasticity in nucleus accumbens
Authors: Trieu Brian H. , Remmers Bailey C. , Toddes Carlee , Brandner Dieter D. , Xie Wei , More Swati S. , Rothwell Patrick E. 
Published: September 2021

AbstractAngiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is expressed at uniquely high levels in the striatonigral pathway, but its central function remains poorly understood. We find that ACE degrades an unconventional enkephalin heptapeptide, Met-enkephalin-Arg-Phe, in the nucleus accumbens of mice. ACE inhibition enhanced mu opioid receptor activation by Met-enkephalin-Arg-Phe, causing a cell type-specific long-term depression of glutamate release onto medium spiny projection neurons expressing the Drd1 dopamine receptor. Systemic ACE inhibition was not intrinsically rewarding, but decreased the conditioned place preference caused by fentanyl administration, and enhanced reciprocal social interaction. Our results raise the enticing prospect that central ACE inhibition can boost endogenous opioid signaling for clinical benefit, while mitigating risk of addiction.
Charged sequence motifs increase affinity towards liquid-liquid phase separation
Authors: Szabó András László , Sánta Anna , Pancsa Rita , Gáspári Zoltán 
Published: September 2021

AbstractProtein phase separation is a major governing factor in multiple cellular processes, such as those concerning RNA metabolism and RNA-binding proteins. Despite many key observations, the exact structural characteristics of proteins involved in the process are still not fully deciphered. In this work we show that proteins harbouring sequence regions with specific charged residue patterns are significantly associated with liquid-liquid phase separation. In particular, regions with repetitive arrays of alternating charges show the strongest association, whereas segments with generally high charge density and single α-helices also show detectable but weaker connections.
Gut microbiota and age shape susceptibility to clostridial enteritis in lorikeets under human care
Authors: Minich David , Madden Christopher , Navarro Mauricio A. , Glowacki Leo , French-Kim Kristen , Chan Willow , Evans Morgan V. , Soares Kilmer , Mrofchak Ryan , Madan Rushil , Ballash Gregory A. , LaPerle Krista , Paul Subhadeep , Vodovotz Yael , Uzal Francisco A. , Martinez Margaret , Hausmann Jennifer , Junge Randall E. , Hale Vanessa L. 
Published: September 2021

AbstractBackgroundEnteritis is a common cause of morbidity and mortality in lorikeets that can be challenging to diagnose and treat. In this study, we examine gut microbiota in two lorikeet flocks with enteritis (Columbus Zoo and Aquarium – CZA; Denver Zoo - DZ). Since 2012, the CZA flock has experienced repeated outbreaks of enteritis despite extensive diet, husbandry, and clinical modifications. In 2018, both CZA and DZ observed a spike in enteritis. Recent research has revealed that the gut microbiota can influence susceptibility to enteropathogens. We hypothesized that a dysbiosis, or alteration in the gut microbial community, was making some lorikeets more susceptible to enteritis, and our goal was to characterize this dysbiosis and determine the features that predicted susceptibility.ResultsWe employed 16S rRNA sequencing to characterize the cloacal microbiota in lorikeets (CZA n = 67, DZ n = 24) over time. We compared the microbiota of healthy lorikeets, to lorikeets with enteritis, and lorikeets susceptible to enteritis, with “susceptible” being defined as healthy birds that subsequently developed enteritis. Based on sequencing data, culture, and toxin gene detection in intestinal contents, we identified Clostridium perfringens type A (CZA and DZ) and C. colinum (CZA only) at increased relative abundances in birds with enteritis. Histopathology and immunohistochemistry further identified the presence of gram-positive bacilli and C. perfringens, respectively, in the necrotizing intestinal lesions. Finally, using Random Forests and LASSO models, we identified several features (young age and the presence of Rhodococcus fascians and Pseudomonas umsongensis) associated with susceptibility to clostridial enteritis.ConclusionsWe identified C. perfringens type A and C. colinum associated with lorikeet necrohemorrhagic enteritis at CZA and DZ. Susceptibility testing of isolates lead to an updated clinical treatment plan which ultimately resolved the outbreaks at both institutions. This work provides a foundation for understanding gut microbiota features that are permissive to clostridial colonization and host factors (e.g. age, prior infection) that shape responses to infection.
SARS-CoV-2 mRNA vaccination elicits robust and persistent T follicular helper cell response in humans
Authors: Mudd Philip A. , Minervina Anastasia A. , Pogorelyy Mikhail V. , Turner Jackson S. , Kim Wooseob , Kalaidina Elizaveta , Petersen Jan , Schmitz Aaron J. , Lei Tingting , Haile Alem , Kirk Allison M. , Mettelman Robert C. , Crawford Jeremy Chase , Nguyen Thi H.O. , Rowntree Louise C. , Rosati Elisa , Klebert Michael K. , Suessen Teresa , Middleton William D. ,   the SJTRC Study Team, Wolf Joshua , Teefey Sharlene A. , O’Halloran Jane A. , Presti Rachel M. , Kedzierska Katherine , Rossjohn Jamie , Thomas Paul G. , Ellebedy Ali H. 
Published: September 2021

SummarySARS-CoV-2 mRNA vaccines induce robust anti-spike (S) antibody and CD4+ T cell responses. It is not yet clear whether vaccine-induced follicular helper CD4+ T (TFH) cell responses contribute to this outstanding immunogenicity. Using fine needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we show that frequency of TFH correlates with that of S-binding germinal center B cells. Mining of the responding TFH T cell receptor repertoire revealed a strikingly immunodominant HLADPB1* 04-restricted response to S167-180 in individuals with this allele, which is among the most common HLA alleles in humans. Paired blood and lymph node specimens show that while circulating S-specific TFH cells peak one week after the second immunization, S-specific TFH persist at nearly constant frequencies for at least six months. Collectively, our results underscore the key role that robust TFH cell responses play in establishing long-term immunity by this efficacious human vaccine.
Heat efficiently inactivates coronaviruses inside vehicles
Authors: Karthigeyan Krithika P. , Flanigan Chloe , Machado Denis Jacob , Kiziltas Alper A. , Janies Daniel A. , Chen Jay , Cooke David , Lee Marcia V. , Saif Linda J. , Henegar Sonny , Jahnes Jeff , Mielewski Deborah F. , Kwiek Jesse J. 
Published: September 2021

AbstractHeat is an established method to inactivate coronaviruses, and there is utility in using heat to reduce viral load on common touch points in vehicles exposed to a person shedding SARS-CoV-2. As SARS-CoV-2 is a Biosafety level (BSL)-3 pathogen, real world testing of heat as a sanitation method for public and private vehicles becomes a challenge, requiring a surrogate coronavirus that can be handled safely outside of a BSL-3 facility. In this study, we used Bovine Coronavirus (BCoV) as a surrogate for SARS-CoV-2 to test the efficacy of heat-based betacoronavirus inactivation. In vitro, a 30-minute exposure to 56°C completely inactivated BCoV in solution, and a 15-minute exposure reduced recovery of BCoV >1000-fold. When heated to 56°C for 15 minutes, the infectivity of BCoV spotted and dried on typical porous and non-porous automobile interior materials was reduced by 99 - 99.99%. When BCoV was spotted and dried on hard plastic (seat) material placed inside an out of service transit bus, 56°C heat for 30 minutes reduced BCoV infectivity 85 - 99.5%. Thus, 56°C is an accessible, rapid, and effective method to inactivate coronaviruses inside motor vehicles.
An ultrasensitive microfluidic approach reveals correlations between the physico-chemical and biological activity of experimental peptide antibiotics
Authors: Cama Jehangir , Al Nahas Kareem , Fletcher Marcus , Hammond Katharine , Ryadnov Maxim G. , Keyser Ulrich F. , Pagliara Stefano 
Published: September 2021

AbstractAntimicrobial resistance challenges the ability of modern medicine to contain infections. Given the dire need for new antimicrobials, peptide antibiotics hold particular promise. These agents hit multiple targets in bacteria starting with their most exposed regions – their membranes. However, suitable assays to quantify the efficacy of peptide antibiotics at the membrane and cellular level have been lacking. Here, we employ two complementary microfluidic platforms to probe the structure-activity relationships of two experimental series of peptide antibiotics. We reveal strong correlations between each peptide’s physicochemical activity at the membrane level and biological activity at the cellular level by assaying the membranolytic activities of the antibiotics on hundreds of individual giant lipid vesicles, and quantifying phenotypic responses within clonal bacterial populations with single-cell resolution. Our strategy proved capable of detecting differential responses for peptides with single amino acid substitutions between them, and can accelerate the rational design and development of peptide antimicrobials.
The function of α-Catenin mechanosensing in tissue morphogenesis
Authors: Sheppard Luka , Tepass Ulrich 
Published: September 2021

Abstractα-catenin couples the cadherin-catenin complex to the actin cytoskeleton. The mechanosensitive α-catenin M region undergoes conformational changes upon application of force to recruit binding partners. Here, we took advantage to the tension landscape in the Drosophila embryo to define three different states of α-catenin mechanosensing in support of cell adhesion. Low, medium, and high tension contacts showed α-catenin M region-dependent low, medium, and high levels of Vinculin and Ajuba recruitment. In contrast, Afadin/Canoe acts in parallel to α-catenin at bicellular low and medium tension junctions, but requires an interaction with α-catenin for its tension-sensitive enrichment at high-tension tricellular junctions. Individual M region domains make complex contributions to cell adhesion through their impact on binding partner recruitment, and redundancies with the function of Afadin/Canoe. Our data argue that α-catenin and its interaction partners are part of a cooperative and partially redundant, mechanoresponsive network that supports AJs remodelling during morphogenesis.
Semisynthesis of functional transmembrane proteins in GUVs
Authors: Podolsky K. A. , Masubuchi T. , Debelouchina G. T. , Hui E. , Devaraj N. K. 
Published: September 2021

AbstractCellular transmembrane (TM) proteins are essential sentries of the cell facilitating cell-cell communication, internal signaling, and solute transport. Reconstituting functional TM proteins into model membranes remains a challenge due to the difficulty of expressing hydrophobic TM domains and the required use of detergents. Herein, we use a intein-mediated ligation strategy to semisynthesize bitopic TM proteins in synthetic membranes. We have adapted the trans splicing capabilities of split inteins for a native peptide ligation between a synthetic TM peptide embedded in the membrane of giant unilamellar vesicles (GUVs) and an expressed soluble protein. We demonstrate that the extracellular domain of programmed cell death protein 1 (PD-1), a mammalian transmembrane immune checkpoint receptor, retains its function for binding its ligand PD-L1 at a reconstituted membrane interface after ligation to a synthetic TM peptide in GUV membranes. We envision that the construction of full-length TM proteins using orthogonal split intein-mediated semisynthetic protein ligations will expand applications of membrane protein reconstitution in pharmacology, biochemistry, biophysics, and artificial cell development.
Distal regulation, silencers and a shared combinatorial syntax are hallmarks of animal embryogenesis
Authors: Cornejo-Páramo Paola , Roper Kathrein , Degnan Sandie M , Degnan Bernard M , Wong Emily S 
Published: September 2021

AbstractThe chromatin environment plays a central role in regulating developmental gene expression in metazoans. Yet, the basal regulatory landscape of metazoan embryogenesis is unknown. Here, we generate chromatin accessibility profiles for six embryonic, plus larval and adult stages in the sponge Amphimedon queenslandica. These profiles are reproducible within stages, reflect histone modifications, and identify transcription factor (TF) binding sequence motifs predictive of cis-regulatory elements during embryogenesis in other metazoans, but not the unicellular relative Capsaspora. Motif analysis of chromatin accessibility profiles across Amphimedon embryogenesis identifies three major developmental periods. As in bilaterian embryogenesis, early development in Amphimedon involves activating and repressive chromatin in regions both proximal and distal to transcription start sites. Transcriptionally repressive elements (‘silencers’) are prominent during late embryogenesis. They coincide with an increase in cis-regulatory regions harbouring metazoan TF binding motifs, and an increase in the expression of metazoan-specific genes. Changes in chromatin state and gene expression in Amphimedon suggest the conservation of distal enhancers, dynamically silenced chromatin, and TF-DNA binding specificity in animal embryogenesis.
The pseudobranch of jawed vertebrates is a mandibular arch-derived gill
Authors: Hirschberger Christine , Gillis J. Andrew 
Published: September 2021

AbstractThe pseudobranch is a gill-like epithelial elaboration that sits behind the jaw of most fishes. This structure was classically regarded as a vestige of the ancestral gill-arch like condition of the gnathostome jaw. However, more recently, hypotheses of jaw evolution by transformation of a gill arch have been challenged, and the pseudobranch has alternatively been considered a specialised derivative of the second (hyoid) pharyngeal arch. Here, we demonstrate by cell lineage tracing in a cartilaginous fish, the skate (Leucoraja erinacea), that the pseudobranch does, in fact, derive from the mandibular arch, and that it shares gene expression features and cell types with gills. We also show that the mandibular arch pseudobranch is supported by a spiracular cartilage that is patterned by ashh-expressing epithelial signalling centre. This closely parallels the condition seen in the gill arches, where cartilaginous appendages called branchial rays supporting the respiratory lamellae of the gills are patterned by ashh-expressing gill arch epithelial ridge (GAER). Taken together, these findings support serial homology of the pseudobranch and gills, and an ancestral origin of gill arch-like anatomical features from the gnathostome mandibular arch.
Attitude toward organic agribusiness: an approach to developing sustainable business
Authors: Shiri Nematollah 
Published: September 2021

PurposeToday due to the use of chemical fertilizers in Iran's agricultural sector, the human health has been in danger. While the literature has increasingly focused on investigating farmers' attitude toward organic agriculture, few studies have been conducted on the attitude of experts toward organic farming. To address this research gap, the current study was performed to investigate the determinants of the attitude of agricultural extension workers (AEW) toward organic agribusiness in Ilam province, Iran.Design/methodology/approachThe statistical sample of this study comprises 394 AEW in Ilam province (located in the west of Iran) selected through random simple sampling method. The instrument in this study was a questionnaire. Data were analyzed by using SPSSWin26 software.FindingsResults showed that the AEW's attitude toward organic agribusiness was at the moderate level. Findings of multiple regression analysis indicated that about 42.6% of AEW's attitude toward organic agribusiness is explained by the variables of “reading research articles”, “use of social networks” and “number of information sources”.Originality/valueThe results of this study have practical implications for promoting sustainable agribusinesses in order to produce environmentally friendly products. In this regard, they can encourage agricultural extension experts to study the findings of research in the field of organic agriculture, launching educational channels and groups on organic farming on social networks such as Telegram and WhatsApp, and encourage agricultural extension experts to join these groups. Finally, it is suggested that programs and films in mass media such as TV, radio and satellite programs be designed and implemented to raise people's awareness about organic agribusiness.
Food-related lifestyles across generations
Authors: Arenas-Gaitán Jorge , Peral-Peral Begoña , Reina-Arroyo Jesús 
Published: September 2021

PurposeThere is a strong relationship between the changes that society faces and food. The aim of this work is to analyse the differences between generations related to their behaviour towards food.Design/methodology/approachTo characterise people's behaviour towards their food, the authors will use a tool, food-related lifestyles (FRL), which has been widely employed in the literature. To achieve this general objective, the authors are going to break this down into two operational goals. Firstly, the authors will analyse if there exist differences in generations regarding the characteristics which make up their FRL. Secondly, the authors will determine if there is an association between generations and specific FRL. The authors have developed a study of 1,200 consumers.FindingsThe results have enabled is to achieve the proposed aims and to describe the behaviour of each generation towards its FRL. There are significant differences in 15 of the 22 dimensions of the LRF analysed according to generations. The authors noted six consumer segments with regard to the FRL and the authors have found a relation between the characteristics which define the generations and their FRL. The findings enable offering implications for the food sector and for society.Originality/valueFirstly, this research spans the five generations present in the current society. Secondly, most works are centred on how FRL correspond with the consumption of specific products. This paper is dedicated to going thoroughly into the intergenerational similarities and differences regarding their FRL. Thirdly, the FRL tool has been especially applied in the context of Central European and Nordic countries, the USA and South-East Asia. In this work, the authors apply the FRL to a Mediterranean cultural context, Spain, characterised by a Mediterranean diet and by a significant family and social component in the diet.