bluuebunny/crossref_metadata_2025_split huggingface dataset:
Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma
Authors: van Hooren Luuk , Vaccaro Alessandra , Ramachandran Mohanraj , Vazaios Konstantinos , Libard Sylwia , van de Walle Tiarne , Georganaki Maria , Huang Hua , Pietilä Ilkka , Lau Joey , Ulvmar Maria H. , Karlsson Mikael C. I. , Zetterling Maria , Mangsbo Sara M. , Jakola Asgeir S. , Olsson Bontell Thomas , Smits Anja , Essand Magnus , Dimberg Anna 
Published: July 2021

AbstractGliomas are brain tumors characterized by an immunosuppressive microenvironment. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors, but are yet to be evaluated for glioma. Here, we demonstrate that systemic delivery of αCD40 in preclinical glioma models induces the formation of tertiary lymphoid structures (TLS) in proximity of meningeal tissue. In treatment-naïve glioma patients, the presence of TLS correlates with increased T cell infiltration. However, systemic delivery of αCD40 induces hypofunctional T cells and impairs the response to immune checkpoint inhibitors in pre-clinical glioma models. This is associated with a systemic induction of suppressive CD11b+ B cells post-αCD40 treatment, which accumulate in the tumor microenvironment. Our work unveils the pleiotropic effects of αCD40 therapy in glioma and reveals that immunotherapies can modulate TLS formation in the brain, opening up for future opportunities to regulate the immune response.
Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity
Authors: Vanderbeke L. , Van Mol P. , Van Herck Y. , De Smet F. , Humblet-Baron S. , Martinod K. , Antoranz A. , Arijs I. , Boeckx B. , Bosisio F. M. , Casaer M. , Dauwe D. , De Wever W. , Dooms C. , Dreesen E. , Emmaneel A. , Filtjens J. , Gouwy M. , Gunst J. , Hermans G. , Jansen S. , Lagrou K. , Liston A. , Lorent N. , Meersseman P. , Mercier T. , Neyts J. , Odent J. , Panovska D. , Penttila P. A. , Pollet E. , Proost P. , Qian J. , Quintelier K. , Raes J. , Rex S. , Saeys Y. , Sprooten J. , Tejpar S. , Testelmans D. , Thevissen K. , Van Buyten T. , Vandenhaute J. , Van Gassen S. , Velásquez Pereira L. C. , Vos R. , Weynand B. , Wilmer A. , Yserbyt J. , Garg A. D. , Matthys P. , Wouters C. , Lambrechts D. , Wauters E. , Wauters J. 
Published: July 2021

AbstractEpidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.
Purkinje cell axonal swellings enhance action potential fidelity and cerebellar function
Authors: Lang-Ouellette Daneck , Gruver Kim M. , Smith-Dijak Amy , Blot François G. C. , Stewart Chloe A. , de Vanssay de Blavous Pauline , Li Connie H. , Van Eitrem Carter , Rosen Charlotte , Faust Phyllis L. , Schonewille Martijn , Watt Alanna J. 
Published: July 2021

AbstractAxonal plasticity allows neurons to control their output, which critically determines the flow of information in the brain. Axon diameter can be regulated by activity, yet how morphological changes in an axon impact its function remains poorly understood. Axonal swellings have been found on Purkinje cell axons in the cerebellum both in healthy development and in neurodegenerative diseases, and computational models predicts that axonal swellings impair axonal function. Here we report that in young Purkinje cells, axons with swellings propagated action potentials with higher fidelity than those without, and that axonal swellings form when axonal failures are high. Furthermore, we observed that healthy young adult mice with more axonal swellings learn better on cerebellar-related tasks than mice with fewer swellings. Our findings suggest that axonal swellings underlie a form of axonal plasticity that optimizes the fidelity of action potential propagation in axons, resulting in enhanced learning.
DNA repair glycosylase hNEIL1 triages damaged bases via competing interaction modes
Authors: Liu Menghao , Zhang Jun , Zhu Chenxu , Zhang Xiaoxue , Xiao Weide , Yan Yongchang , Liu Lulu , Zeng Hu , Gao Yi Qin , Yi Chengqi 
Published: July 2021

AbstractDNA glycosylases must distinguish the sparse damaged sites from the vast expanse of normal DNA bases. However, our understanding of the nature of nucleobase interrogation is still limited. Here, we show that hNEIL1 (human endonuclease VIII-like 1) captures base lesions via two competing states of interaction: an activated state that commits catalysis and base excision repair, and a quarantine state that temporarily separates and protects the flipped base via auto-inhibition. The relative dominance of the two states depends on key residues of hNEIL1 and chemical properties (e.g. aromaticity and hydrophilicity) of flipped bases. Such a DNA repair mechanism allows hNEIL1 to recognize a broad spectrum of DNA damage while keeps potential gratuitous repair in check. We further reveal the molecular basis of hNEIL1 activity regulation mediated by post-transcriptional modifications and provide an example of how exquisite structural dynamics serves for orchestrated enzyme functions.
Chromatin states shaped by an epigenetic code confer regenerative potential to the mouse liver
Authors: Zhang Chi , Macchi Filippo , Magnani Elena , Sadler Kirsten C. 
Published: July 2021

AbstractWe hypothesized that the highly controlled pattern of gene expression that is essential for liver regeneration is encoded by an epigenetic code set in quiescent hepatocytes. Here we report that epigenetic and transcriptomic profiling of quiescent and regenerating mouse livers define chromatin states that dictate gene expression and transposon repression. We integrate ATACseq and DNA methylation profiling with ChIPseq for the histone marks H3K4me3, H3K27me3 and H3K9me3 and the histone variant H2AZ to identify 6 chromatin states with distinct functional characteristics. We show that genes involved in proliferation reside in active states, but are marked with H3K27me3 and silenced in quiescent livers. We find that during regeneration, H3K27me3 is depleted from their promoters, facilitating their dynamic expression. These findings demonstrate that hepatic chromatin states in quiescent livers predict gene expression and that pro-regenerative genes are maintained in active chromatin states, but are restrained by H3K27me3, permitting a rapid and synchronized response during regeneration.
Neurodevelopment regulators miR-137 and miR-34 family as biomarkers for early and adult onset schizophrenia
Authors: Chen Bao-Yu , Lin Jin-Jia , Lu Ming-Kun , Tan Hung-Pin , Jang Fong-Lin , Lin Sheng-Hsiang 
Published: July 2021

AbstractEarly-onset schizophrenia (EOS) may have stronger familial aggregation and a more severe outcome than adult-onset schizophrenia (AOS). MicroRNA (miRNA) takes on dual roles as a genetic and epigenetic modulator, which may mediate the influence of genetic risk. Neurological soft signs (NSS) are neurological abnormalities that may be intermediate phenotypes or endophenotypes for schizophrenia. Our previous study found poorer performance on NSS tests from patients with EOS and their unaffected first-degree relatives. Thus, we aimed to identify a set of aberrant neurodevelopmental-related miRNAs that could serve as potential biomarkers for EOS or schizophrenia with NSS. This study included 215 schizophrenia patients (104 EOS and 111 AOS), 72 unaffected first-degree relatives, 31 patients with bipolar disorder, and 100 healthy controls. Differential expression analysis revealed that miR-137, miR-34b, and miR-34c were significantly up-regulated in patients with schizophrenia and their unaffected first-degree relatives compared to healthy controls. Receiver operating characteristic (ROC) analysis showed that the miR-137 expression signature could be used to discriminate between patients with EOS and healthy controls (AUC = 0.911). Additionally, miR-34b had the highest ability to discriminate between EOS and AOS (AUC = 0.810), which may indicate different aetiological pathways to disease onset. Moreover, miR-137 dysregulation was correlated with almost all NSS subscales (i.e., sensory integration, motor sequencing, etc.) and, when EOS patients with NSS, miR-137 expression discriminated these patients from healthy controls to a greater extent (AUC = 0.957). These findings support the potential for neurodevelopmental-related miRNAs to be used as indicators of vulnerability to EOS.
Holocene life and microbiome profiling in ancient tropical Lake Chalco, Mexico
Authors: Moguel Bárbara , Pérez Liseth , Alcaraz Luis D. , Blaz Jazmín , Caballero Margarita , Muñoz-Velasco Israel , Becerra Arturo , Laclette Juan P. , Ortega-Guerrero Beatriz , Romero-Oliva Claudia S. , Herrera-Estrella Luis , Lozano-García Socorro 
Published: July 2021

AbstractMetagenomic and traditional paleolimnological approaches are suitable to infer past biological and environmental changes, however, they are often applied independently, especially in tropical regions. We combined both approaches to investigate Holocene Prokaryote and Eukaryote diversity and microbial metabolic pathways in ancient Lake Chalco, Mexico. Here, we report on diversity among a large number of lineages (36,722 OTUs) and functional diversity (27,636,243 non-clustered predicted proteins, and 6,144 annotated protein-family genes). The most abundant domain is Bacteria (81%), followed by Archaea (15%) and Eukarya (3%). We also determined the diversity of protein families and their relationship to metabolic pathways. The early Holocene (> 11,000 cal years BP) lake was characterized by cool, freshwater conditions, which later became warmer and hyposaline (11,000–6,000 cal years BP). We found high abundances of cyanobacteria, and fungi groups associated with mature forests in these sediments. Bacteria and Archaea include mainly anaerobes and extremophiles that are involved in the sulfur, nitrogen, and carbon cycles. We found evidence for early human impacts, including landscape modifications and lake eutrophication, which began ~ 6,000 cal years BP. Subsaline, temperate conditions were inferred for the past 5,000 years. Finally, we found nitrogen-fixing bacteria and protein-family genes that are linked to contaminated environments, as well as several fungal pathogens of crops in near-surface sediments.
Experimental infection of Asian house geckos with Enterococcus lacertideformus demonstrates multiple disease transmission routes and the in-vivo efficacy of antibiotics
Authors: Agius Jessica E. , Rose Karrie , Emery Jon-Paul , Phalen David N. 
Published: July 2021

AbstractThe disease caused by Enterococcus lacertideformus is multisystemic and ultimately fatal. Since its emergence, the bacterium has significantly impacted the captive breeding programs of the extinct in the wild Christmas Island Lister’s gecko (Lepidodactylus listeri) and blue-tailed skink (Cryptoblepharus egeriae). The bacterium’s pathogenicity, inability to grow in-vitro, and occurrence beyond the confines of Christmas Island necessitated the development of an experimental infection and treatment model. Asian house geckos (Hemidactylus frenatus) were challenged with a single dose of E. lacertideformus inoculum either by mouth, application to mucosal abrasion or skin laceration, subcutaneous injection, coelomic injection, or via co-housing with an infected gecko. Five healthy geckos acted as controls. Each transmission route resulted in disease in at least 40% (n = 2) geckos, expanding to 100% (n = 5) when E. lacertideformus was applied to skin laceration and mucosal abrasion groups. Incubation periods post-infection ranged between 54 and 102 days. To determine the efficacy of antibiotic treatment, infected geckos were divided into six groups (enrofloxacin 10 mg/kg, per os (PO), every 24 h (q24), amoxicillin-clavulanic acid 10 mg/kg, PO, q24, enrofloxacin 10 mg/kg combined with amoxicillin-clavulanic acid 10 mg/kg, PO, q24, rifampicin 15 mg/kg, PO, q24, clarithromycin 15 mg/kg, PO, q24, and untreated controls) for 21 days. Response to treatment was assessed by the change in lesion size, bacterial dissemination, and histological evidence of a host immune response. Irrespective of the antibiotic given, histology revealed that geckos inoculated by skin laceration were observed to have more extensive disease spread throughout the animal’s body compared to other inoculation routes. The reduction in the average surface area of gross lesions was 83.6% for geckos treated with enrofloxacin, followed by the combination therapy amoxicillin-clavulanic acid and enrofloxacin (62.4%), amoxicillin-clavulanic acid (58.2%), rifampicin (45.5%), and clarithromycin (26.5%). Lesions in geckos untreated with antibiotics increased in size between 100 and 300%. In summary, enrofloxacin and amoxicillin-clavulanic acid show promising properties for the treatment of E. lacertideformus infection in geckos. The Asian house gecko E. lacertideformus infection model therefore provides foundational findings for the development of effective therapeutic treatment protocols aimed at conserving the health of infected and at-risk reptiles.
UV-induced Zn:Cd/S quantum dots in-situ formed in the presence of thiols for sensitive and selective fluorescence detection of thiols
Authors: Assi Navid , Nejdl Lukas , Zemankova Kristyna , Pavelicova Kristyna , Bezdekova Jaroslava , Macka Mirek , Adam Vojtech , Vaculovicova Marketa 
Published: July 2021

AbstractIn this work, we explored a new approach to a simple and sensitive fluorescence detection of thiols. The approach takes advantage of an in-situ formation of UV light-induced fluorescent nanoparticles (ZnCd/S quantum dots), while utilizing the thiol group of the analyte as a capping agent. The selectivity is ensured by the selective isolation of the thiol analyte by a polydopamine molecularly imprinted polymeric (MIP) layer. Based on this approach, a method for determination of thiols was designed. Key experimental parameters were optimized, including those of molecular imprinting and of effective model thiol molecule (l-cysteine) isolation. The relationship between the fluorescence intensity of ZnCd/S quantum dots and the concentration of l-cysteine in the range of 12–150 µg/mL was linear with a detection limit of 3.6 µg/mL. The molecularly imprinted polymer showed high absorption mass capacity (1.73 mg/g) and an excellent selectivity factor for l-cysteine compared to N-acetyl-l-cysteine and l-homocysteine of 63.56 and 87.48, respectively. The proposed method was applied for l-cysteine determination in human urine with satisfactory results. Due to a high variability of molecular imprinting technology and versatility of in-situ probe formation, methods based on this approach can be easily adopted for analysis of any thiol of interest.
Observation of exceptional point in a PT broken non-Hermitian system simulated using a quantum circuit
Authors: Zhang Geng-Li , Liu Di , Yung Man-Hong 
Published: July 2021

AbstractExceptional points (EPs), the degeneracy points of non-Hermitian systems, have recently attracted great attention because of their potential of enhancing the sensitivity of quantum sensors. Unlike the usual degeneracies in Hermitian systems, at EPs, both the eigenenergies and eigenvectors coalesce. Although EPs have been widely explored, the range of EPs studied is largely limited by the underlying systems, for instance, higher-order EPs are hard to achieve. Here we propose an extendable method to simulate non-Hermitian systems and study EPs with quantum circuits. The system is inherently parity-time (PT) broken due to the non-symmetric controlling effects of the circuit. Inspired by the quantum Zeno effect, the circuit structure guarantees the success rate of the post-selection. A sample circuit is implemented in a quantum programming framework, and the phase transition at EP is demonstrated. Considering the scalable and flexible nature of quantum circuits, our model is capable of simulating large-scale systems with higher-order EPs.
Understanding protection from SARS-CoV-2 using metabolomics
Authors: Barberis Elettra , Amede Elia , Tavecchia Matteo , Marengo Emilio , Cittone Micol G. , Rizzi Eleonora , Pedrinelli Anita R. , Tonello Stelvio , Minisini Rosalba , Pirisi Mario , Manfredi Marcello , Sainaghi Pier Paolo 
Published: July 2021

AbstractThe COVID-19 pandemic is still raging in most countries. Although the recent mass vaccination campaign has opened a new chapter in the battle against SARS-CoV-2, the world is still far from herd immunity. There is an urgent need to identify healthy people at high risk of contracting COVID-19, as well as supplements and nutraceuticals that can reduce the risk of infection or mitigate symptoms. In the present study, a metabolic phenotype that could protect individuals from SARS-CoV-2 infection or predispose them to developing COVID-19 was investigated. Untargeted metabolomics was performed on serum samples collected from 51 healthcare workers who were in good health at the beginning of the COVID-19 outbreak in Italy, and who were later exposed to the same risk of developing COVID-19. Half of them developed COVID-19 within three weeks of the blood collection. Our results demonstrate the presence of a specific signature associated with protection from SARS-CoV-2. Circulating monolaurin, which has well-known antiviral and antibacterial properties, was higher in protected subjects, suggesting a potential defensive role against SARS-CoV-2 infection; thus, dietary supplements could boost the immune system against this infection. In addition, our data demonstrate that people with higher levels of cholesterol are at higher risk of developing COVID-19. The present study demonstrates that metabolomics can be of great help for developing personalized medicine and for supporting public healthcare strategies. Studies with larger cohorts of subjects are necessary to confirm our findings.
High glucose induces trafficking of prorenin receptor and stimulates profibrotic factors in the collecting duct
Authors: Gogulamudi Venkateswara R. , Arita Danielle Y. , Bourgeois Camille R. T. , Jorgensen Justine , He Jing , Wimley William C. , Satou Ryosuke , Gonzalez Alexis A. , Prieto Minolfa C. 
Published: July 2021

AbstractGrowing evidence indicates that prorenin receptor (PRR) is upregulated in collecting duct (CD) of diabetic kidney. Prorenin is secreted by the principal CD cells, and is the natural ligand of the PRR. PRR activation stimulates fibrotic factors, including fibronectin, collagen, and transforming growth factor-β (TGF-β) contributing to tubular fibrosis. However, whether high glucose (HG) contributes to this effect is unknown. We tested the hypothesis that HG increases the abundance of PRR at the plasma membrane of the CD cells, thus contributing to the stimulation of downstream fibrotic factors, including TGF-β, collagen I, and fibronectin. We used streptozotocin (STZ) male Sprague–Dawley rats to induce hyperglycemia for 7 days. At the end of the study, STZ-induced rats showed increased prorenin, renin, and angiotensin (Ang) II in the renal inner medulla and urine, along with augmented downstream fibrotic factors TGF-β, collagen I, and fibronectin. STZ rats showed upregulation of PRR in the renal medulla and preferential distribution of PRR on the apical aspect of the CD cells. Cultured CD M-1 cells treated with HG (25 mM for 1 h) showed increased PRR in plasma membrane fractions compared to cells treated with normal glucose (5 mM). Increased apical PRR was accompanied by upregulation of TGF-β, collagen I, and fibronectin, while PRR knockdown prevented these effects. Fluorescence resonance energy transfer experiments in M-1 cells demonstrated augmented prorenin activity during HG conditions. The data indicate HG stimulates profibrotic factors by inducing PRR translocation to the plasma membrane in CD cells, which in perspective, might be a novel mechanism underlying the development of tubulointerstitial fibrosis in diabetes mellitus.
Nutritional quality, nutrient uptake and biomass production of Pennisetum purpureum cv. King grass
Authors: Botero-Londoño Julián M. , Celis-Celis Erika M. , Botero-Londoño Mónica A. 
Published: July 2021

AbstractThe research was conducted to determine the effects of cutting interval and fertilization on the nutritional quality, nutrient uptake, and biomass production of King grass. The experimental design was a randomized complete block, using 4 blocks and 8 treatments per block; treatments consisted of 4 ages of cutting (30, 45, 60, and 90 days), with fertilization and without fertilization. The results showed increases of up to 72,000 kg ha−1 year−1of dry matter (DM) when fertilization was implemented. There was a significant reduction in with an increase in the cutting days (12.70–6.53% protein). Fiber increased (48.79–72.99% NDF) when fertilization treatments were included and cutting days increased. The elements that were included in fertilization (N, P, K) showed a higher foliar content and also presented a reduction in foliar content with growth of the plant. Treatments with fertilization showed a nutrient uptake increase for all the elements up to 60 days, where a reduction in uptake capacity was observed. King grass is a plant with a high nutrient uptake capacity and, therefore, with high biomass and nutrient production. This is an advantage since it can be used in multiple applications, such as animal feed, biofuel production, and as a substrate for biodigestion, among others.