bluuebunny/crossref_metadata_2025_split huggingface dataset:
CMR Diffusion Tensor Imaging Provides Novel Imaging Markers of Adverse Myocardial Remodeling in Aortic Stenosis
Authors: Gotschy Alexander , von Deuster Constantin , Weber Lucas , Gastl Mareike , Schmiady Martin O. , van Gorkum Robbert J. H. , Stimm Johanna , von Spiczak Jochen , Manka Robert , Kozerke Sebastian , Stoeck Christian T. 
Published: August 2020

AbstractObjectivesThis study sought to determine microstructural cardiac remodeling in aortic stenosis (AS) and its reversibility following valve replacement using cardiovascular magnetic resonance (CMR) diffusion tensor imaging (DTI).BackgroundMyocardial involvement in AS, such as focal and diffuse fibrosis is associated with worse outcome, even after timely aortic valve replacement (AVR). Alterations of myofiber architecture and myocardial diffusion may precede fibrosis, but its extent and reversibility after AVR are unknown.MethodsPatients with isolated severe AS (n = 21, 62% male; mean age 75 years) and sex-matched senior control subjects underwent prospective CMR DTI. Changes in the DTI parameters: mean diffusivity (MD), fractional anisotropy (FA) as well as helix angle (HA) and absolute E2A sheet angle (E2A) were quantified and compared with native T1 and extracellular volume (ECV) as standard CMR markers of myocardial fibrosis. Six months after AVR eleven patients were scheduled for a follow-up CMR.ResultsIn AS patients, significantly elevated MD (p = 0.002) and reduced FA (p< 0.001) were measured when compared to controls. Myocyte aggregate orientation exhibited a steeper transmural HA slope (p< 0.001) and increased absolute E2A sheet angle (p< 0.001) in AS. Six months post AVR, the HA slope (p< 0.001) was reduced to the level of healthy controls and MD (p = 0.014), FA (p = 0.011) and E2A (p = 0.003) showed a significant regression towards normal values. In contrast, native T1 was similar in AS and controls and did not change significantly after AVR. ECV showed a non-significant trend (p = 0.16) to higher values after AVR.ConclusionIn patients with severe aortic stenosis, CMR DTI provides a set of parameters that identifies structural and diffusion abnormalities, which are largely reversible after AVR. DTI parameters showed proportionally greater changes in response to AS and AVR compared to metrics of myocardial fibrosis and may, therefore, aid risk stratification in earlier stages of severe AS.Condensed AbstractCMR diffusion tensor imaging (DTI) is a novel, noninvasive technique that allows for the assessment of myocardial microstructure in diseased hearts. We used CMR DTI to investigate myocardial involvement in patients with aortic stenosis (AS) before and after aortic valve replacement (AVR). Measures of tissue diffusion as well as parameters of myocyte orientation were significantly altered by AS and showed a clear trend towards normalization after AVR. Conventional markers of myocardial fibrosis (native T1 & extracellular volume) did not change significantly after AVR. Therefore, CMR DTI may unlock a new level of detail for phenotyping myocardial involvement in AS with potential value for improved risk stratification by visualizing earlier stages of adverse remodeling.
The necessary cooperation between governments and public in the fight against COVID-19: why non-pharmaceutical interventions may be ineffective
Authors: Borges Christielly Mendonça , Coelho Marco Túlio Pacheco , Diniz-Filho José Alexandre Felizola , Rangel Thiago Fernando 
Published: August 2020

AbstractThe coronavirus disease (COVID-19) outbreak is the biggest public health challenge in the last 100 years. No successful pharmaceutical treatment is yet available, thus effective public health interventions to contain COVID-19 include social distancing, isolation and quarantine measures, however the efficiency of these containment measures varied among countries and even within states in the same country. Despite Brazil being deeply affected by coronavirus, the federal government never proposed a coordinated action to control COVID-19 and Brazilian states, which are autonomous, each imposed different containment measures. The state of Goiás declared strict social distancing measures in March 13, but gradually relaxed many of its first measures due specially to public pressure. Here we use a Susceptible-Infected-Recovered (SIR) model combined with Bayesian inference and a time-dependent spreading rate to assess how past state-level interventions affected the spread of COVID-19 in Goiás. The interventions succeeded in decreasing the transmission rate in the state, however, after the third intervention the rate remained positive and exponential. Thus, other stricter interventions were made necessary to avoid the growth of new cases and a collapse in the health system. Governmental interventions need to be taken seriously by the population in order for them have the proposed outcome. Our results reflect the population’s disregard with the measures imposed and the need for cooperation between governments and its citizens in the fight against COVID-19.
Suboptimal SARS-CoV-2-specific CD8+ T-cell response associated with the prominent HLA-A*02:01 phenotype
Authors: Habel Jennifer R , Nguyen Thi H O , van de Sandt Carolien E , Juno Jennifer A , Chaurasia Priyanka , Wragg Kathleen , Koutsakos Marios , Hensen Luca , Jia Xiaoxiao , Chua Brendon , Zhang Wuji , Tan Hyon-Xhi , Flanagan Katie L , Doolan Denise L , Torresi Joseph , Chen Weisan , Wakim Linda M , Cheng Allen C , Doherty Peter C , Petersen Jan , Rossjohn Jamie , Wheatley Adam K , Kent Stephen J , Rowntree Louise C , Kedzierska Katherine 
Published: August 2020

AbstractAn improved understanding of human T-cell-mediated immunity in COVID-19 is important if we are to optimize therapeutic and vaccine strategies. Experience with influenza shows that infection primes CD8+ T-cell memory to shared peptides presented by common HLA types like HLA-A2. Following re-infection, cross-reactive CD8+ T-cells enhance recovery and diminish clinical severity. Stimulating peripheral blood mononuclear cells from COVID-19 convalescent patients with overlapping peptides from SARS-CoV-2 Spike, Nucleocapsid and Membrane proteins led to the clonal expansion of SARS-CoV-2-specific CD8+ and CD4+ T-cells in vitro, with CD4+ sets being typically robust. For CD8+ T-cells taken directly ex vivo, we identified two HLA-A*02:01-restricted SARS-CoV-2 epitopes, A2/S269–277 and A2/Orf1ab3183–3191. Using peptide-HLA tetramer enrichment, direct ex vivo assessment of the A2/S269+CD8+ and A2/Orf1ab3183+CD8+ populations indicated that the more prominent A2/S269+CD8+ set was detected at comparable frequency (∼1.3×10−5) in acute and convalescent HLA-A*02:01+ patients. But, while the numbers were higher than those found in uninfected HLA-A*02:01+ donors (∼2.5×10−6), they were low when compared with frequencies for influenza-specific (A2/M158) and EBV-specific (A2/BMLF1280) (∼1.38×10−4) populations. Phenotypic analysis ex vivo of A2/S269+CD8+ T-cells from COVID-19 convalescents showed that A2/S269+CD8+ T-cells were predominantly negative for the CD38, HLA-DR, PD-1 and CD71 activation markers, although the majority of total CD8+ T-cells were granzyme and/or perforin-positive. Furthermore, the bias towards naïve, stem cell memory and central memory A2/S269+CD8+ T-cells rather than effector memory populations suggests that SARS-CoV2 infection may be compromising CD8+ T-cell activation. Priming with an appropriate vaccine may thus have great value for optimizing protective CD8+ T-cell immunity in COVID-19.
A Lymph Node Targeted Amphiphile Vaccine Induces Potent Cellular and Humoral Immunity to SARS-CoV-2
Authors: Steinbuck Martin P. , Seenappa Lochana M. , Jakubowski Aniela , McNeil Lisa K. , Haqq Christopher M. , DeMuth Peter C. 
Published: August 2020

AbstractThe SARS-CoV-2 pandemic has led to public health, economic, and social consequences that mandate urgent development of effective vaccines to contain or eradicate infection. To that end, we evaluated a novel amphiphile (AMP) vaccine adjuvant, AMP-CpG, composed of diacyl lipid-modified CpG, admixed with the SARS-CoV-2 Spike-2 receptor binding domain protein as a candidate vaccine (ELI-005) in mice. AMP immunogens are efficiently delivered to lymph nodes, where innate and adaptive immune responses are generated. Compared to alum, AMP immunization induced >25-fold higher antigen-specific T cells which produced multiple Th1 cytokines and trafficked into lung parenchyma and respiratory secretions. Antibody responses favored Th1 isotypes (IgG2bc, IgG3) and potently neutralized Spike-2-ACE2 receptor binding, with titers 265-fold higher than the natural immune response from convalescent COVID-19 patients; responses were maintained despite 10-fold dose-reduction in Spike antigen. Both cellular and humoral immune responses were preserved in aged mice. These advantages merit clinical translation to SARS-CoV-2 and other protein subunit vaccines.
Short duration splice promoting compound enables a tunable mouse model of spinal muscular atrophy
Authors: Rietz A , Hodgetts KJ , Lusic H , Quist KM , Osman EY , Lorson CL , Androphy EJ 
Published: August 2020

AbstractSpinal muscular atrophy (SMA) is a motor neuron disease and the leading cause of infant mortality. SMA results from insufficient survival motor neuron protein (SMN) levels due to alternative splicing. Antisense oligonucleotides, gene therapy and splicing modifiers recently received FDA approval. However, early intervention is required for optimal outcomes, and even continuous treatment maybe insufficient to restore full motor function. Although severe SMA transgenic mouse models have been beneficial for testing therapeutic efficacy, models mimicking milder cases that manifest post-infancy have proven challenging to develop. We have established a titratable model of mild and moderate SMA using the splicing compound NVS-SM2. Administration for 30 days prevented development of the SMA phenotype in severe SMA mice, which typically show rapid weakness and succumb by postnatal day 11. Furthermore, administration at day eight resulted in phenotypic recovery. Remarkably, acute dosing limited to the first three days of life significantly enhanced survival in two severe SMA mice models, easing the burden on neonates and demonstrating the compound as suitable for evaluation of follow-on therapies without potential drug-drug interactions.
Potent neutralizing equine antibodies raised against recombinant SARS-CoV-2 spike protein for COVID-19 passive immunization therapy
Authors: Cunha Luis Eduardo R. , Stolet Adilson A. , Strauch Marcelo A. , Pereira Victor A. R. , Dumard Carlos H. , Gomes Andre M. O. , Souza Patrícia N. C. , Fonseca Juliana G. , Pontes Francisco E. , Meirelles Leonardo G. R. , Albuquerque José W. M. , Sacramento Carolina Q. , Fintelman-Rodrigues Natalia , Lima Tulio M. , Alvim Renata G. F. , Marsili Federico F. , Caldeira Marcella Moreira , Higa Luisa M. , Monteiro Fábio L. , Zingali Russolina B. , de Oliveira Guilherme A. P. , Souza Thiago M. L. , Tanuri Amilcar , Oliveira Andréa C. , Guedes Herbert L. M. , Castilho Leda R. , Silva Jerson L. 
Published: August 2020

AbstractWe used the trimeric spike (S) glycoprotein (residues 1-1208) in the prefusion conformation to immunize horses for production of hyperimmune globulins against SARS-CoV-2. Serum antibody titers measured by anti-spike ELISA were above 1:1,000,000, and neutralizing antibody titer was 1:14,604 (average PRNT90), which is 140-fold higher than the average neutralizing titer of plasma from three convalescent COVID-19 patients analyzed for comparison. Using the same technology routinely used for industrial production of other horse hyperimmune products, plasma from immunized animals was pepsin digested to remove the Fc portion and purified, yielding a F(ab’)2preparation with PRNT90titers 150-fold higher than the neutralizing titers in human convalescent plasma. Repeating the hyperimmunization in a second group of horses confirmed the very high neutralizing titers in serum and in a GMP clinical F(ab’)2lot. Virus-neutralizing activity in samples from mice that received the F(ab’)2preparation was detected even three days after injection, indicating an appropriate half-life for therapeutic intervention. These results supported the design of a clinical trial (identifierNCT04573855) to evaluate safety and efficacy of this horse F(ab’)2preparation.
Distinct roles of two RDL GABA-receptors in fipronil action in the diamondback moth (Plutella xylostella)
Authors: Li Benjie , Wang Kunkun , Chen Dongping , Yan Ying , Cai Xuling , Chen Huimin , Dong Ke , Lin Fei , Xu Hanhong 
Published: August 2020

AbstractThe phenylpyrazole insecticide, fipronil, blocks insect RDL γ-aminobutyric acid (GABA) receptors, thereby impairs inhibitory neurotransmission. Some insect species, such as the diamondback moth (Plutella xylostella), possess more than oneRdlgene. The involvement of multipleRdlsin fipronil toxicity and resistance remain largely unknown. In this study, we investigated the roles of twoRdlgenes,PxRdl1andPxRdl2, fromP. xylostellain the action of fipronil. Expressed inXenopusoocytes,PxRDL2 receptors were 40-times less sensitive to fipronil thanPxRDL1.PxRDL2 receptors were also less sensitive to GABA compared toPxRDL1. Knockout of the fipronil-sensitivePxRdl1gene reduced the potency of fipronil by 10 fold, whereas knockout of the fipronil-resistantPxRdl2gene enhanced the potency of fipronil by 4.4 fold. Furthermore, in two fipronil-resistant diamondback moth field populations, the expression ofPxRdl2was elevated by 3.7-fold and 4.1-fold, respectively compared to a susceptible strain, whereas the expression ofPxRdl1was comparable among the resistant and susceptible strains. Collectively, our results indicate antagonistic effects ofPxRDL1 andPxRDL2 on the fipronil actionin vivoand suggest enhanced expression of fipronil-resistantPxRdl2 potentially a new mechanism of fipronil resistance in insects.
A Newly Identified Role for IL-22 in Bladder Immunity
Authors: Honeycutt Jared , Le Loc , Hsieh Yi-Ju , Hsieh Michael H. 
Published: August 2020

AbstractBacterial and parasitic urinary tract infections(UTI) affect many, but our understanding of associated immunity remains poor. Prior work indicates interleukin-22(IL-22) is a key cytokine during infection of other epithelia. We hypothesized IL-22 is crucial during UTI.IL-22-null(KO) and wild-type(wt) mice underwent bladder wall injection withS. haematobiumeggs or transurethral infection with uropathogenicE. coliUTI89.IL-22 and its soluble binding protein, IL-22BP, were increased in the bladder afterS. haematobiumegg injection. Genes typically induced by IL-22(CXCL2, REG3G[antimicrobial defense protein]], S100A8, S100A9, and Areg) were expressed at higher levels followingS. haematobiumegg injection. IL-22 stimulation of bladder tissue induced REG3B expression. IL-22 receptor alpha-1 expression was detectable in the urothelium by immunofluorescence and qPCR.Injection ofS. haematobiumeggs into IL-22-KO vs wt mice triggered differential expression of genes related to transferase activity(transferring alkyl or aryl groups) and epithelial cell development. Numerous uroplakin genes were downregulated in egg-injected, IL-22-KO mice versus their wt counterparts. These decreases in uroplakin expression suggest that, as in the gut, IL-22 is important for replenishing the epithelium during infection-related injury.Following transurethral infection with UTI89, IL-22-KO mice had lower bacterial counts in their urine, bladder, and kidneys. Giving stabilized IL-22 cytokine (IL-22-Fc) to UTI89-infected mice led to higher kidney bacterial counts and increased morbidity.Our data suggest that IL-22 is indeed important in urinary tract immunity, and may interfere with clearance of bacteria from the urinary tract, potentially through its role in maintenance of mature urothelium.
GATA4 regulates epithelial morphogenesis in the developing mouse stomach to promote establishment of a glandular columnar epithelium
Authors: DeLaForest Ann , Kohlnhofer Bridget M. , Franklin Olivia D. , Stavniichuk Roman , Thompson Cayla A. , Pulakanti Kirthi , Rao Sridhar , Battle Michele A. 
Published: August 2020

AbstractThe transcription factor GATA4 is broadly expressed in nascent foregut endoderm. As development progresses, GATA4 is lost in the domain giving rise to the stratified squamous epithelium of the esophagus and forestomach (FS), while it is maintained in the domain giving rise to the simple columnar epithelium of the hindstomach (HS). Differential GATA4 expression within these domains coincides with the onset of distinct tissue morphogenetic events, suggesting a role for GATA4 in diversifying foregut endoderm into discrete esophageal/FS and HS tissues. By eliminating GATA4 in the developing HS or maintaining GATA4 in the developing FS, we identified GATA4 as an essential, principal regulator of simple columnar epithelium morphogenesis within the developing HS. GATA4- deficient HS epithelium adopted FS-like fate, and conversely, GATA4- expressing FS epithelium adopted HS-like fate. Underlying structural changes in these epithelia were broad changes in gene expression networks attributable to GATA4 directly activating or repressing expression of HS or FS defining transcripts. Our data implicate GATA4 as having a primary role in suppressing an esophageal/FS transcription factor network during HS development to promote a columnar epithelium. Moreover, GATA4-dependent phenotypes in developmental mutants reflected changes associated with Barrett’s esophagus, suggesting that developmental biology can provide insight into human disease mechanisms.
A mesoscopic simulator to uncover heterogeneity and evolutionary dynamics in tumors
Authors: Juan Jiménez-Sánchez , Álvaro Martínez-Rubio , Anton Popov , Julián Pérez-Beteta , Youness Azimzade , David Molina-García , Juan Belmonte-Beitia , Gabriel F Calvo , Víctor M Pérez-García 
Published: August 2020

AbstractIncreasingly complex in-silico modeling approaches offer a way to simultaneously access cancerous processes at different spatio-temporal scales. High-level models, such as those based on partial differential equations, are computationally affordable and allow large tumor sizes and long temporal windows to be studied, but miss the discrete nature of many key underlying cellular processes. Individual-based approaches provide a much more detailed description of tumors, but have difficulties when trying to handle full-sized real cancers. Thus, there exists a trade-off between the integration of macroscopic and microscopic information, now widely available, and the ability to attain clinical tumor sizes. In this paper we put forward a stochastic mesoscopic simulation framework that incorporates key cellular processes during tumor progression while keeping computational costs to a minimum. Our framework captures a physical scale that allows both the incorporation of microscopic information, tracking the spatio-temporal emergence of tumor heterogeneity and the underlying evolutionary dynamics, and the reconstruction of clinically sized tumors from high-resolution medical imaging data, with the additional benefit of low computational cost. We illustrate the functionality of our modeling approach for the case of glioblastoma, a paradigm of tumor heterogeneity that remains extremely challenging in the clinical setting.Author summaryComputer simulation based on mathematical models provides a way to improve the understanding of complex processes in oncology. In this paper we develop a stochastic mesoscopic simulation approach that incorporates key cellular processes while keeping computational costs to a minimum. Our methodology captures the development of tumor heterogeneity and the underlying evolutionary dynamics. The physical scale considered allows microscopic information to be included, tracking the spatio-temporal evolution of tumor heterogeneity and reconstructing clinically sized tumors from high-resolution medical imaging data, with a low computational cost. We illustrate the functionality of the modeling approach for the case of glioblastoma, an epitome of heterogeneity in tumors.
Ascorbate peroxidase neofunctionalization at the origin of APx-R and APx-L: evidences from basal Archaeplastida
Authors: Lazzarotto Fernanda , Menguer Paloma Koprovski , Del-Bem Luiz-Eduardo , Margis-Pinheiro Márcia 
Published: August 2020

AbstractAscorbate peroxidases (APx) are class I members of the non-animal peroxidases superfamily, a large group of evolutionarily related enzymes. Through mining in public databases, our group has previously identified two unusual subsets of APx homologs, disclosing the existence of two uncharacterized families of class I peroxidases, which were named ascorbate peroxidase-related (APx-R) and ascorbate peroxidase-like (APx-L). As APx, APx-R proteins possess all catalytic residues required for peroxidase activity. Nevertheless, these proteins do not contain residues known to be critical for ascorbate binding, implying that members of this family must use other substrates while reducing hydrogen peroxide. On the other hand, APx-L proteins not only lack ascorbate-binding residues, as do not contain any residue known to be essential for peroxidase activity, in contrast with every other member of the non-animal peroxidase superfamily, which is composed by over 10,000 proteins distributed among bacteria, archaea, fungi, algae, and plants. Through a molecular phylogenetic analysis performed with sequences derived from basal Archaeplastida, we now show the existence of hybrid proteins, which combine features of these three families. Analysis performed on public databases show that the prevalence of these proteins varies among distinct groups of organisms, accounting for up to 33% of total APx homologs in species of green algae. The analysis of this heterogeneous group of proteins sheds light on the origin of APx-R and APx-L, through a process characterized by the progressive deterioration of ascorbate-binding sites and catalytic sites towards neofunctionalization.
Loss of Fas-signaling in pro-fibrotic fibroblasts impairs homeostatic fibrosis resolution and promotes persistent pulmonary fibrosis
Authors: Redente Elizabeth F. , Chakraborty Sangeeta , Sajuthi Satria , Black Bart P. , Edelman Benjamin L. , Seibold Max A. , Riches David W.H. 
Published: August 2020

ABSTRACTIdiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic disease of the distal lung alveoli that culminates in respiratory failure and reduced lifespan. Unlike normal lung repair in response to injury, IPF is associated with the accumulation and persistence of fibroblasts and myofibroblasts and continued production of collagen and other extracellular matrix (ECM) components. Prior in vitro studies have led to the hypothesis that the development of resistance to Fas-induced apoptosis by lung fibroblasts and myofibroblasts contibributes to their accumulation in the distal lung tissues of IPF patients. Here, we test this hypothesis in vivo in the resolving model of bleomycin-induced pulmonary fibrosis in mice. Using genetic loss-of-function approaches to inhibit Fas signaling in fibroblasts, novel flow cytometry strategies to quantify lung fibroblast subsets and transcriptional profiling of lung fibroblasts by bulk and single cell RNA-sequencing, we show that Fas is necessary for lung fibroblast apoptosis during homeostatic resolution of bleomycin-induced pulmonary fibrosis in vivo. Furthermore, we show that loss of Fas signaling leads to the persistence and continued pro-fibrotic functions of lung fibroblasts. Our studies provide novel insights into the mechanisms that contribute to fibroblast survival, persistence and continued ECM deposition in the context of IPF and how failure to undergo Fas-induced apoptosis prevents fibrosis resolution.