bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impaired Humoral Immunity to SARS-CoV-2 Vaccination in Non-Hodgkin Lymphoma and CLL Patients
Authors: Diefenbach Catherine , Caro Jessica , Koide Akiko , Grossbard Michael , Goldberg Judith D. , Raphael Bruce , Hymes Kenneth , Moskovits Tibor , Kreditor Maxim , Kaminetzky David , Fleur-Lominy Shella Saint , Choi Jun , Thannickal Sara A. , Stapleford Kenneth A. , Koide Shohei 
Published: June 2021

AbstractPatients with hematologic malignancies are a high priority for SARS-CoV-2 vaccination, yet the benefit they will derive is uncertain. We investigated the humoral response to vaccination in 53 non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or CLL patients. Peripheral blood was obtained 2 weeks after first vaccination and 6 weeks after second vaccination for antibody profiling using the multiplex bead-binding assay. Serum IgG, IgA, and IgM antibody levels to the spike specific receptor binding domain (RBD) were evaluated as a measure of response. Subsequently, antibody-positive serum were assayed for neutralization capacity against authentic SARS-CoV-2. Histology was 68% lymphoma and 32% CLL; groups were: patients receiving anti-CD20-based therapy (45%), monitored with disease (28%), receiving BTK inhibitors (19%), or chemotherapy (all HL) (8%). SARS-CoV-2 specific RBD IgG antibody response was decreased across all NHL and CLL groups: 25%, 73%, and 40%, respectively. Antibody IgG titers were significantly reduced (p < 0.001) for CD20 treated and targeted therapy patients, and (p = 0.003) for monitored patients. In 94% of patients evaluated after first and second vaccination, antibody titers did not significantly boost after second vaccination. Only 13% of CD20 treated and 13% of monitored patients generated neutralizing antibodies to SARS-CoV-2 with ICD50s 135 to 1767, and 445 and > 10240. This data has profound implications given the current guidance relaxing masking restrictions and for timing of vaccinations. Unless immunity is confirmed with laboratory testing, these patients should continue to mask, socially distance, and to avoid close contact with non-vaccinated individuals.Statement of Translational RelevanceNon Hodgkin lymphoma (NHL) and Chronic Lymphocytic leukemia (CLL) patients who are treated with anti-CD20 antibody therapy, BTK inhibitor therapy, or who are monitored with active disease, have decreased antibody response to SARS-CoV-2 vaccination and decreased antibody titers compared to healthy controls. Antibody titers do not boost following second vaccination, and very few patients generate neutralizing antibodies against SARS-CoV-2. This data is of particular importance, given the recent guidance from the CDC that vaccinated patients no longer need to be masked indoors as well as outdoors. Patients with NHL or CLL who fall into these categories should not consider their immunity from vaccination to be assured. If infected with SARS-CoV-2, they should be a high priority for monoclonal antibody directed therapy. Unless immune response to vaccination is confirmed with laboratory testing, they should continue to mask, socially distance, and to avoid close contact with non-vaccinated individuals.
Vitamin D receptor polymorphisms in overweight/obese chronic kidney disease patients undergoing hemodialysis
Authors: Bagci Gokhan , Huzmeli Can , Candan Ferhan 
Published: June 2021

AbstractBackgroundMany studies were carried out to investigate the relationship between single nucleotide polymorphisms (SNPs) in vitamin D receptor (VDR) gene with obesity. However, little is known about the role of VDR gene polymorphism with obesity in hemodialysis (HD) patients. Therefore, we aimed to investigate VDR gene TaqI, ApaI and FokI SNPs in overweight/obese HD patients.MethodsSeventy one normal weight and 68 overweight/obese HD patients were included in study. PCR-RFLP method was used for genotyping. Demographic and laboratory data obtained from medical records of patients.ResultsFor all three SNPs, no significant association was found between normal and overweight/obese patients (P>0.05). Lower HDL concentrations and higher levels of triglyceride (TG) and glucose were detected in the obese/overweight patients compared to normal weight (p<0.001 for HDL, and TG and p=0.023 for glucose). In obese/overweight patients, subjects with CC genotype of TaqI showed higher PTH level (717.1±616.4 pg/ml) than those TC genotype (342.7±360.8 pg/ml) and TT genotype (310.2±323.4 pg/ml) (p=0.028); higher TG level was found in patients with CC genotype of ApaI (627.3±653.0 mg/dl) compared to AA (223.3±156.6) and AC genotypes (193.1±85.4) (p<0.001). Obese/overweight patients carrying FokI TT genotype had higher glucose concentration compared to those carrying CC and CT genotypes (CC=183.4±128.4 mg/dl; TT=151.9±66.1 mg/dl; CT=107.6±41.9 mg/dl, p=0.008).ConclusionsOur study suggest that VDR TaqI, ApaI and FokI polymorphisms are not associated with obesity in HD patients. However, they might be increase the risk of secondary hyperparathyroidism, dyslipidemia, and hyperglycemia, which are among the most common obesity related comorbidities of chronic kidney disease.
Efficacy of ancestral receptor-binding domain, S1 and trimeric spike protein vaccines against SARS-CoV-2 variants B.1.1.7, B.1.351, and B.1.617.1
Authors: Yang Yong , Zang Jinkai , Xu Shiqi , Zhang Xueyang , Yuan Sule , Lavillette Dimitri , Zhang Chao , Huang Zhong 
Published: June 2021

AbstractThe ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The current SARS-CoV-2 vaccines are based on spike (S) protein, S1 subunit, or receptor-binding domain (RBD) of prototype strain. Emergence of several novel SARS-CoV-2 variants has raised concern about potential immune escape. In this study, we performed an immunogenicity comparison of ancestral RBD, S1, and S ectodomain trimer (S-trimer) antigens and tested the efficacy of these prototype vaccines against the circulating variants, especially B.1.617 that has been linked to India’s current COVID-19 surge. We found that RBD and S-trimer proteins could induce significantly higher neutralizing antibody titers than S1 protein. For the three vaccines, the neutralizing titers decreased over time, but still remained high for at least five months after immunization. Importantly, the three prototype vaccines were still effective in neutralizing the variants of concern, although B.1.351 and B.1.617.1 lineages showed varying degrees of reduction in neutralization by the immune sera. The vaccines-induced sera were shown to block receptor binding and inhibit S protein-mediated membrane fusion. In addition, the immune sera did not promote antibody-dependent enhancement (ADE) in vitro. Our work provides valuable information for development of SARS-CoV-2 subunit vaccines and also supports the continued use of ancestral RBD or S-based vaccines to fight the COVID-19 epidemic.
Cardiac and respiratory muscle responses to dietary N-acetylcysteine in rats consuming a high-saturated fat, high-sucrose diet
Authors: Kelley Rachel C. , Muscato Derek R. , Hahn Dongwoo , Christou Demetra D. , Ferreira Leonardo F. 
Published: June 2021

AbstractBACKGROUNDExertional dyspnea is a significant clinical concern in individuals with overweight or obesity. The pathophysiology of dyspnea is multifactorial and complex. Previous data suggest that diaphragm and cardiac abnormalities should be considered as likely contributors to obesity-related exertional dyspnea. Additionally, oxidative stress is a causative factor in the general etiology of obesity as well as skeletal and cardiac muscle pathology. Thus, this preclinical study aimed to define diaphragm and cardiac morphological and functional alterations following an obesogenic diet in rats and the therapeutic potential of an antioxidant supplement, N-acetylcysteine (NAC).METHODSMale Wistar rats (∼7 weeks old) consumed ad libitum either lean (20% protein, 70% carbohydrate, 10% fat) or high-saturated fat, high-sucrose (HFHS, 20% protein, 35% carbohydrate, 45% fat) diets for ∼22 weeks. Rats receiving HFHS diet were randomized to drink control water or water with NAC (2 mg/ml) for the last eight weeks of the dietary intervention: Lean, HFHS, and HFHS+NAC (n = 8 per group). We evaluated diaphragm bundles (in vitro function and histology) and hearts (weights and echocardiography) for all groups.RESULTSFinal body weights of HFHS rats, but not HFHS+NAC rats, were significantly higher than Lean controls. Neither HFHS diet nor NAC supplementation affected diaphragm specific force (N/cm2), peak power (W/kg), or morphology. In cardiac muscle, right and left ventricle weights (normalized to tibia length) of HFHS rats were greater than those of Lean controls and HFHS+NAC rats. Cardiac functional abnormalities were also present in HFHS rats, with left ventricular fractional shortening (%) and posterior wall maximal shortening velocity (cm/s) increasing compared to Lean controls, but HFHS+NAC rats did not demonstrate these markers of hypercontractility. HFHS rats showed an elevated deceleration rate of early transmitral diastolic velocity (E/DT) consistent with diastolic dysfunction, but NAC eliminated this effect.CONCLUSIONOur data suggest that an HFHS diet does not compromise diaphragm muscle morphology or in vitro function, suggesting other possible contributors to breathing abnormalities in obesity (e.g., neuromuscular transmission abnormalities). However, an HFHS diet resulted in cardiac hypertrophy, hypercontractility, and diastolic dysfunction. Supplementation with NAC did not affect diaphragm morphology or function but attenuated cardiac abnormalities in the HFHS diet. Our findings support future studies testing NAC supplementation in clinical trials of humans with obesity.
High activity and high functional connectivity are mutually exclusive in resting state zebrafish and human brains
Authors: Zarei Mahdi , Xie Dan , Jiang Fei , Abigrove Adil , Huang Bo , Raj Ashish , Nagarajan Srikantan , Guo Su 
Published: June 2021

AbstractActive neurons impact cell types with which they are functionally connected. Both activity and functional connectivity are heterogeneous across the brain, but the nature of their relationship is not known. Here we employ brain-wide calcium imaging at cellular resolution in larval zebrafish to record spontaneous activity of >12,000 neurons in the forebrain. By classifying their activity and functional connectivity into three levels (high, medium, low), we find that highly active neurons have low functional connections and highly connected neurons are of low activity. Intriguingly, deploying the same analytical methods on functional magnetic resonance imaging (fMRI) data from the resting state human brain, we uncover a similar relationship between activity and functional connectivity, that is, regions of high activity are non-overlapping with those of high connectivity. These findings reveal a previously unknown and evolutionarily conserved brain organizational principle that have implications for understanding disease states and designing artificial neuronal networks.
The VIL gene CRAWLING ELEPHANT controls maturation and differentiation in tomato via polycomb silencing
Authors: Shwartz Ido , Yahav Chen , Kovetz Neta , Israeli Alon , Bar Maya , Levy Matan , Duval Katherine L. , Jiménez-Gómez José M. , Deal Roger B. , Ori Naomi 
Published: June 2021

AbstractVERNALIZATION INSENSITIVE 3-LIKE (VIL) proteins are PHD-finger proteins that recruit the repressor complex Polycomb Repressive Complex 2 (PRC2) to the promoters of target genes. Most known VIL targets are flowering repressor genes. Here, we show that the tomato VIL gene CRAWLING ELEPHANT (CREL) promotes differentiation throughout plant development by facilitating the trimethylation of Histone H3 on lysine 27 (H3K27me3). We identified the crel mutant in a screen for suppressors of the simple-leaf phenotype of entire (e), a mutant in the AUX/IAA gene ENTIRE/SlIAA9, involved in compound-leaf development in tomato. crel mutants have increased leaf complexity, and suppress the ectopic blade growth of e mutants. In addition, crel mutants are late flowering, and have delayed and aberrant stem, root and flower development. Consistent with a role for CREL in recruiting PRC2, crel mutants present altered H3K27me3 modifications at a subset of PRC2 targets throughout the genome. Our results uncover a wide role for CREL in plant and organ differentiation in tomato and suggest that CREL is required for targeting PRC2 activity to, and thus silencing, a specific subset of polycomb targets.Author summaryPlants form organs continuously throughout their lives, and the number and shape of their organs is determined in a flexible manner according to the internal and external circumstances. Alongside this flexibility, plants maintain basic developmental programs to ensure proper functioning. Among the ways by which plants achieve flexible development is by tuning the pace of their maturation and differentiation, at both the plant and organ levels. One of the ways plants regulate the rate of maturation and differentiation is by changing gene expression. Here, we identified a gene that promotes plant and organ maturation and differentiation. This gene, CRAWLING ELEPHANT (CREL) acts by bringing a repressing complex to target genes. We show the importance of CREL in multiple developmental processes and in the expression of multiple genes throughout the tomato genome.
Brain mitochondrial diversity and network organization predict anxiety-like behavior in mice
Authors: Rosenberg Ayelet M , Saggar Manish , Monzel Anna S , Devine Jack , Rogu Peter , Limoges Aaron , Junker Alex , Sandi Carmen , Mosharov Eugene V , Dumitriu Dani , Anacker Christoph , Picard Martin 
Published: June 2021

AbstractThe brain and behavior are under energetic constraints, limited by mitochondrial energy transformation capacity. However, the mitochondria-behavior relationship has not been systematically studied on a brain-wide scale. Here we examined the association between multiple features of mitochondrial respiratory chain capacity and stress-related behaviors in mice with diverse behavioral phenotypes. Miniaturized assays of mitochondrial respiratory chain enzyme activities and mitochondrial DNA (mtDNA) content were deployed on 571 samples across 17 brain areas, defining specific patterns of mito-behavior associations. By applying multi-slice network analysis to our brain-wide mitochondrial dataset, we identified three large-scale networks of brain areas with shared mitochondrial signatures. A major network composed of cortico-striatal areas exhibited the strongest mitochondria-behavior correlations, accounting for up to 50% of animal-to-animal behavioral differences, suggesting that this mito-based network is functionally significant. The mito-based brain networks also overlapped with regional gene expression and structural connectivity and quantitatively diverged in their molecular mitochondrial phenotype signatures. Therefore, this work provides convergent multimodal evidence anchored in enzyme activities, gene expression, and animal behavior that distinct, behaviorally-relevant mitochondrial phenotypes exist across the mouse brain.
In an “ecological-belonging” intervention to reduce inequities in STEM, context matters
Authors: Hammarlund Sarah P. , Scott Cheryl , Binning Kevin R. , Cotner Sehoya 
Published: June 2021

AbstractDoubts about belonging in the classroom are often shouldered disproportionately by students from historically marginalized groups, which can lead to underperformance. Ecological-belonging interventions use a classroom-based activity to instill norms that adversity is normal, temporary and surmountable. Building on prior studies, we sought to identify the conditions under which such interventions are effective. In a chemistry course (Study 1), students from underrepresented ethnic backgrounds underperformed relative to their peers in the absence of the intervention. This performance gap was eliminated by the intervention. In an introductory biology course (Study 2), there were no large performance gaps in the absence of the intervention, and the intervention had no effect. Study 2 also explored the role of the instructor that delivers the intervention. The intervention boosted scores in classrooms of instructors with a fixed (versus growth-oriented) intelligence mindset. Our results suggest that ecological-belonging interventions are more effective in more threatening classroom contexts.
GlyConnect: a glycan-based conjugation extension of the GlycoDelete technology
Authors: Van Breedam Wander , Thooft Karel , Santens Francis , Vanmarcke Sandrine , Wyseure Elise , Laukens Bram , Van Moer Berre , Nerinckx Wim , Devos Simon , Madder Annemieke , Callewaert Nico 
Published: June 2021

ABSTRACTRecently, our lab developed GlycoDelete, a technology suite that allows a radical simplification of eukaryotic N-glycosylation. The technology allows to produce glycoproteins that carry single GlcNAc, LacNAc, or LacNAc-Sia type glycans on their N-linked glycosylation sequons. GlycoDelete-type N-glycans are uniquely suited for glycan-based conjugation purposes, as these provide a short, homogeneous and hydrophilic link to the protein backbone. Targeting GlycoDelete-glycans allows for highly site-specific conjugation at sites in the protein which are normally occupied by bulky glycans, thus ensuring minimal interference with protein structure and function. The current manuscript describes the evaluation and optimization of both chemical and chemo-enzymatic conjugation of molecules onto the GlycoDelete-type glycans of a limited set of benchmark proteins.
Characterization of the interaction domains between the phosphoprotein and the nucleocapsid of human Metapneumovirus
Authors: Decool Hortense , Bardiaux Benjamin , Ruano Luis Checa , Sperandio Olivier , Fix Jenna , Gutsche Irina , Richard Charles-Adrien , Bajorek Monika , Eléouët Jean-François , Galloux Marie 
Published: June 2021

ABSTRACTHuman metapneumovirus (HMPV) causes severe respiratory diseases in young children. The HMPV RNA genome is encapsidated by the viral nucleoprotein, forming an RNA-N complex (NNuc), which serves as template for genome replication and mRNA transcription by the RNA-dependent RNA polymerase (RdRp). The RdRp is formed by the association of the large polymerase subunit (L), which has RNA polymerase, capping and methyltransferase activities, and the tetrameric phosphoprotein (P). P plays a central role in the RdRp complex by binding to NNuc and L, allowing the attachment of the L polymerase to the nucleocapsid template. During infection these proteins concentrate in cytoplasmic inclusion bodies (IBs) where viral RNA synthesis occurs. By analogy to the closely related pneumovirus respiratory syncytial virus (RSV), it is likely that the formation of IBs depends on the interaction between P and NNuc. However, the HMPV P-NNuc interaction still remains to characterize. Here, we finely characterized the binding domains involved in HMPV P and NNuc interaction by studying binding between recombinant proteins, combined with the use of a functional assay of the polymerase complex activity and the study of the recruitment of these proteins to IBs by immunofluorescence. We show that the last 6 C-terminal residues of HMPV P are necessary and sufficient for binding to NNuc, that P binds the N-terminal domain of N (NNTD), and identified conserved N residues critical for the interaction. Our results allowed to propose a structural model of the HMPV P-NNuc interaction.IMPORTANCELike respiratory syncytial virus (RSV), human metapneumovirus (HMPV) is a leading cause of severe respiratory infections in children but also affects human populations of all ages worldwide. Nowadays, no vaccine or efficient antiviral treatments are available for these two pneumoviruses. A better understanding of the molecular mechanisms involved in viral replication could help the design or discovery of specific antiviral compounds. In this work we have investigated the interaction between two major viral proteins involved in HMPV RNA synthesis, the N and P proteins. We finely characterized their domains of interaction, in particular a pocket on the surface of the N protein that could be used as a template for the design of compounds interfering with N-P complexes and viral replication.
Predicting localized affinity of RNA binding proteins to transcripts with convolutional neural networks
Authors: Kitaygorodsky Alexander , Jin Emily , Shen Yufeng 
Published: June 2021

AbstractRNA binding proteins (RBPs) are important regulators of transcriptional and post-transcriptional processes. Computational prediction of localized RBP binding affinity with transcripts is important for interpretation of genetic variation, especially variants outside of protein coding region. Here we describe POLARIS (PredictionOfLocalizedAffinity forRBPsInSequence), a new deep-learning method for achieving fast, site-specific binding affinity predictions of RNA-binding proteins (RBPs) to the transcribed genome. POLARIS has two modules: 1. a convolutional neural network (CNN) to predict overall RBP binding within a region based on transcript sequence content and expression level; 2. a Gradient-weighted Class Activation Mapping (GradCAM) implementation for efficient signal backpropagation to individual sequence positions. We trained the model using enhanced crosslinking and immunoprecipitation (eCLIP) data from ENCODE. POLARIS has good performance with a median AUC ~ 0.96 for 160 RBPs across three different cell lines, substantially higher than selected popular published methods trained and tested on the same data sets. When tested on data from a different cell line with the same RBPs, the overall performance is maintained, supporting the ability of cell-type specific affinity prediction. Finally, the GradCAM module allows the model to identify the informative sites in a region that drive prediction. The localized prediction facilitates interpretation of the results and provides basis for inference of functional impact of noncoding variants.
Insights into cisplatin-induced neurotoxicity and mitochondrial dysfunction in Caenorhabditis elegans
Authors: Martínez-Fernández Carmen , Bergamino Milana , Brena David , Ventura Natascia , Honnen Sebastian , Villanueva Alberto , Nadal Ernest , Cerón Julián 
Published: June 2021

ABSTRACTCisplatin is the most common drug in first-line chemotherapy against solid tumors. We and others have previously used the nematode Caenorhabditis elegans to identify genetic factors influencing the sensitivity and resistance to cisplatin. In this study, we take advantage of C. elegans to explore cisplatin effects on mitochondrial functions and investigate cisplatin-induced neurotoxicity through a high-resolution semi-automated system for evaluating locomotion. Firstly, we report that a high-glucose diet sensitizes C. elegans to cisplatin at the physiological level and that mitochondrial CED-13 protects the cell from cisplatin-induced oxidative stress. Additionally, by assessing mitochondrial function with a Seahorse Analyzer, we observed a detrimental additive effect of cisplatin and glucose in mitochondrial respiration. Secondly, since we previously found that catechol-O-methyltransferases (involved in dopamine degradation) were upregulated upon cisplatin exposure, we studied the protective role of the FDA-approved drug dopamine against cisplatin-induced neurotoxicity. To implement the use of the Tierpsy Tracker system for measuring neurotoxicity in C. elegans, we showed that abnormal displacements and body postures in cat-2 mutants, which have the dopamine synthesis pathway disrupted, can be rescued by adding dopamine. Then, we used such a system to demonstrate that dopamine treatment protects from the dose-dependent neurotoxicity caused by cisplatin.