bluuebunny/crossref_metadata_2025_split huggingface dataset:
LUBAC accelerates B-cell lymphomagenesis by conferring resistance to genotoxic stress on B cells
Authors: Jo Tomoyasu , Nishikori Momoko , Kogure Yasunori , Arima Hiroshi , Sasaki Katsuhiro , Sasaki Yoshiteru , Nakagawa Tomoko , Iwai Fumie , Momose Shuji , Shiraishi Aki , Kiyonari Hiroshi , Kagaya Noritaka , Onuki Tetsuo , Shin-ya Kazuo , Yoshida Minoru , Kataoka Keisuke , Ogawa Seishi , Iwai Kazuhiro , Takaori-Kondo Akifumi 
Published: April 2020

Abstract
The linear ubiquitin chain assembly complex (LUBAC) is a key regulator of NF-κB signaling. Activating single-nucleotide polymorphisms of HOIP, the catalytic subunit of LUBAC, are enriched in patients with activated B-cell–like (ABC) diffuse large B-cell lymphoma (DLBCL), and expression of HOIP, which parallels LUBAC activity, is elevated in ABC-DLBCL samples. Thus, to clarify the precise roles of LUBAC in lymphomagenesis, we generated a mouse model with augmented expression of HOIP in B cells. Interestingly, augmented HOIP expression facilitated DLBCL-like B-cell lymphomagenesis driven by MYD88-activating mutation. The developed lymphoma cells partly shared somatic gene mutations with human DLBCLs, with increased frequency of a typical AID mutation pattern. In vitro analysis revealed that HOIP overexpression protected B cells from DNA damage-induced cell death through NF-κB activation, and analysis of the human DLBCL database showed that expression of HOIP positively correlated with gene signatures representing regulation of apoptosis signaling, as well as NF-κB signaling. These results indicate that HOIP facilitates lymphomagenesis by preventing cell death and augmenting NF-κB signaling, leading to accumulation of AID-mediated mutations. Furthermore, a natural compound that specifically inhibits LUBAC was shown to suppress the tumor growth in a mouse transplantation model. Collectively, our data indicate that LUBAC is crucially involved in B-cell lymphomagenesis through protection against DNA damage–induced cell death and is a suitable therapeutic target for B-cell lymphomas.
Immunogenomic identification and characterization of granulocytic myeloid-derived suppressor cells in multiple myeloma
Authors: Perez Cristina , Botta Cirino , Zabaleta Aintzane , Puig Noemi , Cedena Maria-Teresa , Goicoechea Ibai , Alameda Daniel , San José-Eneriz Edurne , Merino Juana , Rodríguez-Otero Paula , Maia Catarina , Alignani Diego , Maiso Patricia , Manrique Irene , Lara-Astiaso David , Vilas-Zornoza Amaia , Sarvide Sarai , Riillo Caterina , Rossi Marco , Rosiñol Laura , Oriol Albert , Blanchard María-Jesús , Rios Rafael , Sureda Anna , Martin Jesus , Martinez Rafael , Bargay Joan , de la Rubia Javier , Hernandez Miguel-Teodoro , Martinez-Lopez Joaquin , Orfao Alberto , Agirre Xabier , Prosper Felipe , Mateos Maria-Victoria , Lahuerta Juan-José , Blade Joan , San-Miguel Jesús F. , Paiva Bruno 
Published: April 2020

Abstract
Granulocytic myeloid-derived suppressor cells (G-MDSCs) promote tumor growth and immunosuppression in multiple myeloma (MM). However, their phenotype is not well established for accurate monitoring or clinical translation. We aimed to provide the phenotypic profile of G-MDSCs based on their prognostic significance in MM, immunosuppressive potential, and molecular program. The preestablished phenotype of G-MDSCs was evaluated in bone marrow samples from controls and MM patients using multidimensional flow cytometry; surprisingly, we found that CD11b+CD14−CD15+CD33+HLADR− cells overlapped with common eosinophils and neutrophils, which were not expanded in MM patients. Therefore, we relied on automated clustering to unbiasedly identify all granulocytic subsets in the tumor microenvironment: basophils, eosinophils, and immature, intermediate, and mature neutrophils. In a series of 267 newly diagnosed MM patients (GEM2012MENOS65 trial), only the frequency of mature neutrophils at diagnosis was significantly associated with patient outcome, and a high mature neutrophil/T-cell ratio resulted in inferior progression-free survival (P &lt; .001). Upon fluorescence-activated cell sorting of each neutrophil subset, T-cell proliferation decreased in the presence of mature neutrophils (0.5-fold; P = .016), and the cytotoxic potential of T cells engaged by a BCMA×CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P = .0007). Most interestingly, RNA sequencing of the 3 subsets revealed that G-MDSC–related genes were specifically upregulated in mature neutrophils from MM patients vs controls because of differential chromatin accessibility. Taken together, our results establish a correlation between the clinical significance, immunosuppressive potential, and transcriptional network of well-defined neutrophil subsets, providing for the first time a set of optimal markers (CD11b/CD13/CD16) for accurate monitoring of G-MDSCs in MM.
Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial
Authors: Voorhees Peter M. , Kaufman Jonathan L. , Laubach Jacob , Sborov Douglas W. , Reeves Brandi , Rodriguez Cesar , Chari Ajai , Silbermann Rebecca , Costa Luciano J. , Anderson Larry D. , Nathwani Nitya , Shah Nina , Efebera Yvonne A. , Holstein Sarah A. , Costello Caitlin , Jakubowiak Andrzej , Wildes Tanya M. , Orlowski Robert Z. , Shain Kenneth H. , Cowan Andrew J. , Murphy Sean , Lutska Yana , Pei Huiling , Ukropec Jon , Vermeulen Jessica , de Boer Carla , Hoehn Daniela , Lin Thomas S. , Richardson Paul G. 
Published: April 2020

Abstract
Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab (D) to RVd (D-RVd) in transplant-eligible NDMM patients was evaluated. Patients (N = 207) were randomized 1:1 to D-RVd or RVd induction (4 cycles), ASCT, D-RVd or RVd consolidation (2 cycles), and lenalidomide or lenalidomide plus D maintenance (26 cycles). The primary end point, stringent complete response (sCR) rate by the end of post-ASCT consolidation, favored D-RVd vs RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval, 0.87-2.82; 1-sided P = .068) and met the prespecified 1-sided α of 0.10. With longer follow-up (median, 22.1 months), responses deepened; sCR rates improved for D-RVd vs RVd (62.6% vs 45.4%; P = .0177), as did minimal residual disease (MRD) negativity (10−5 threshold) rates in the intent-to-treat population (51.0% vs 20.4%; P &lt; .0001). Four patients (3.8%) in the D-RVd group and 7 patients (6.8%) in the RVd group progressed; respective 24-month progression-free survival rates were 95.8% and 89.8%. Grade 3/4 hematologic adverse events were more common with D-RVd. More infections occurred with D-RVd, but grade 3/4 infection rates were similar. Median CD34+ cell yield was 8.2 × 106/kg for D-RVd and 9.4 × 106/kg for RVd, although plerixafor use was more common with D-RVd. Median times to neutrophil and platelet engraftment were comparable. Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT02874742.
Interplay of erythropoietin, fibroblast growth factor 23, and erythroferrone in patients with hereditary hemolytic anemia
Authors: van Vuren Annelies. J. , Eisenga Michele F. , van Straaten Stephanie , Glenthøj Andreas , Gaillard Carlo A. J. M. , Bakker Stephan J. L. , de Borst Martin H. , van Wijk Richard , van Beers Eduard J. 
Published: April 2020

Abstract
Recently, erythropoietin (EPO) was identified as regulator of fibroblast growth factor 23 (FGF23). Proteolytic cleavage of biologically active intact FGF23 (iFGF23) results in the formation of C-terminal fragments (cFGF23). An increase in cFGF23 relative to iFGF23 suppresses FGF receptor signaling by competitive inhibition. EPO lowers the i:cFGF23 ratio, thereby overcoming iFGF23-mediated suppression of erythropoiesis. We investigated EPO-FGF23 signaling and levels of erythroferrone (ERFE) in 90 patients with hereditary hemolytic anemia (www.trialregister.nl [NL5189]). We show, for the first time, the importance of EPO-FGF23 signaling in hereditary hemolytic anemia: there was a clear correlation between total FGF23 and EPO levels (r = +0.64; 95% confidence interval [CI], 0.09-0.89), which persisted after adjustment for iron load, inflammation, and kidney function. There was no correlation between iFGF23 and EPO. Data are consistent with a low i:cFGF23 ratio. Therefore, as expected, we report a correlation between EPO and ERFE in a diverse set of hereditary hemolytic anemias (r = +0.47; 95% CI, 0.14-0.69). There was no association between ERFE and total FGF23 or iFGF23, which suggests that ERFE does not contribute to the connection between FGF23 and EPO. These findings open a new area of research and might provide potentially new druggable targets with the opportunity to ameliorate ineffective erythropoiesis and the development of disease complications in hereditary hemolytic anemias.
Associations of bedtime, sleep duration, and sleep quality with semen quality in males seeking fertility treatment: a preliminary study
Authors: Hvidt Julius Edward Miller , Knudsen Ulla Breth , Zachariae Robert , Ingerslev Hans Jakob , Philipsen Marie Tholstrup , Frederiksen Yoon 
Published: April 2020

AbstractBackgroundPoor sleep has been linked to a number of adverse health outcomes. Recent studies suggest that late bedtimes, short or long sleep durations, and poor sleep quality may impair semen quality. No study has previously explored all three factors in relation to semen quality.ResultsOne hundred and four men and their partners treated at three fertility clinics in Denmark between 2010 and 2012 completed an online-version of the Pittsburgh Sleep Quality Index (PSQI). The results of the semen analyses conducted at the fertility clinics were self-reported and categorised as normal or reduced.Early bedtime (< 10:30 PM) was more often associated with normal semen quality compared with both regular (10:30 PM-11:29 PM) and late (≥11:30 PM) bedtime (OR: 2.75, 95%CI: 1.1–7.1,p = 0.04 and OR: 3.97, 95%CI: 1.2–13.5,p = 0.03). Conventional sleep duration (7.5–7.99 h) was more often associated with normal semen quality than both short (7.0–7.49 h) and very short (< 7.0 h) sleep duration (OR: 1.36, 95% CI: 1.2–12.9,p = 0.03 and OR: 6.18, 95%CI: 1.6–24.2,p = 0.01). Although poor sleep quality was associated with reduced semen quality in the descriptive statistics (p = 0.04), no differences were found between optimal (PSQI ≤6) and either borderline (PSQI 7–8) or poor (PSQI ≥9) sleep quality (OR: 1.19, 95%CI: 0.4–3.4,p = 0.75 and OR: 2.43, 95%CI: 0.8–7.1,p = 0.11) in multivariate regression models.ConclusionEarly bedtimes (< 10:30 PM) and conventional sleep duration (7.5–7.99 h) were associated with self-reported normal semen quality. The role of subjective sleep quality remains uncertain.
Dual graph convolutional neural network for predicting chemical networks
Authors: Harada Shonosuke , Akita Hirotaka , Tsubaki Masashi , Baba Yukino , Takigawa Ichigaku , Yamanishi Yoshihiro , Kashima Hisashi 
Published: April 2020

Abstract
Background
Predicting of chemical compounds is one of the fundamental tasks in bioinformatics and chemoinformatics, because it contributes to various applications in metabolic engineering and drug discovery. The recent rapid growth of the amount of available data has enabled applications of computational approaches such as statistical modeling and machine learning method. Both a set of chemical interactions and chemical compound structures are represented as graphs, and various graph-based approaches including graph convolutional neural networks have been successfully applied to chemical network prediction. However, there was no efficient method that can consider the two different types of graphs in an end-to-end manner.

Results
We give a new formulation of the chemical network prediction problem as a link prediction problem in a graph of graphs (GoG) which can represent the hierarchical structure consisting of compound graphs and an inter-compound graph. We propose a new graph convolutional neural network architecture called dual graph convolutional network that learns compound representations from both the compound graphs and the inter-compound network in an end-to-end manner.

Conclusions
Experiments using four chemical networks with different sparsity levels and degree distributions shows that our dual graph convolution approach achieves high prediction performance in relatively dense networks, while the performance becomes inferior on extremely-sparse networks.
Maladaptive plasticity facilitates evolution of thermal tolerance during an experimental range shift
Authors: Leonard Aoife M. , Lancaster Lesley T. 
Published: April 2020

Abstract
Background
Many organisms are responding to climate change with dramatic range shifts, involving plastic and genetic changes to cope with novel climate regimes found at higher latitudes. Using experimental lineages of the seed beetle Callosobruchus maculatus, we simulated the initial phase of colonisation to progressively cooler and/or more variable conditions, to investigate how adaptation and phenotypic plasticity contribute to shifts in thermal tolerance during colonisation of novel climates.

Results
We show that heat and cold tolerance rapidly evolve during the initial stages of adaptation to progressively cooler and more variable climates. The evolved shift in cold tolerance is, however, associated with maladaptive plasticity under the novel conditions, resulting in a pattern of countergradient variation between the ancestral and novel, fluctuating thermal environment. In contrast, lineages exposed to progressively cooler, but constant, temperatures over several generations expressed only beneficial plasticity in cold tolerances and no evolved response.

Conclusions
We propose that thermal adaptation during a range expansion to novel, more variable climates found at high latitudes and elevations may typically involve genetic compensation arising from maladaptive plasticity in the initial stages of adaptation, and that this form of (countergradient) thermal adaptation may represent an opportunity for more rapid and labile evolutionary change in thermal tolerances than via classic genetic assimilation models for thermal tolerance evolution (i.e., selection on existing reaction norms). Moreover, countergradient variation in thermal tolerances may typically mask cryptic genetic variability for these traits, resulting in apparent evolutionary stasis in thermal traits.
GWAS and co-expression network combination uncovers multigenes with close linkage effects on the oleic acid content accumulation in Brassica napus
Authors: Yao Min , Guan Mei , Zhang Zhenqian , Zhang Qiuping , Cui Yixin , Chen Hao , Liu Wei , Jan Habib U. , Voss-Fels Kai P. , Werner Christian R. , He Xin , Liu Zhongsong , Guan Chunyun , Snowdon Rod J. , Hua Wei , Qian Lunwen 
Published: April 2020

AbstractBackgroundStrong artificial and natural selection causes the formation of highly conserved haplotypes that harbor agronomically important genes. GWAS combination with haplotype analysis has evolved as an effective method to dissect the genetic architecture of complex traits in crop species.ResultsWe used the 60 KBrassicaInfinium SNP array to perform a genome-wide analysis of haplotype blocks associated with oleic acid (C18:1) in rapeseed. Six haplotype regions were identified as significantly associated with oleic acid (C18:1) that mapped to chromosomes A02, A07, A08, C01, C02, and C03. Additionally, whole-genome sequencing of 50 rapeseed accessions revealed three genes (BnmtACP2-A02, BnABCI13-A02 and BnECI1-A02) in theA02 chromosome haplotype region and twogenes(BnFAD8-C02 and BnSDP1-C02) in theC02 chromosome haplotype region that were closely linked to oleic acid content phenotypic variation. Moreover, the co-expression network analysis uncovered candidate genes from these two different haplotype regions with potential regulatory interrelationships with oleic acid content accumulation.ConclusionsOur results suggest that several candidate genes are closely linked, which provides us with an opportunity to develop functional haplotype markers for the improvement of the oleic acid content in rapeseed.
A chromosome-scale assembly of the smallest Dothideomycete genome reveals a unique genome compaction mechanism in filamentous fungi
Authors: Wang Bo , Liang Xiaofei , Gleason Mark L. , Hsiang Tom , Zhang Rong , Sun Guangyu 
Published: April 2020

Abstract
Background
The wide variation in the size of fungal genomes is well known, but the reasons for this size variation are less certain. Here, we present a chromosome-scale assembly of ectophytic Peltaster fructicola, a surface-dwelling extremophile, based on long-read DNA sequencing technology, to assess possible mechanisms associated with genome compaction.

Results
At 18.99 million bases (Mb), P. fructicola possesses one of the smallest known genomes sequence among filamentous fungi. The genome is highly compact relative to other fungi, with substantial reductions in repeat content, ribosomal DNA copies, tRNA gene quantity, and intron sizes, as well as intergenic lengths and the size of gene families. Transposons take up just 0.05% of the entire genome, and no full-length transposon was found. We concluded that reduced genome sizes in filamentous fungi such as P. fructicola, Taphrina deformans and Pneumocystis jirovecii occurred through reduction in ribosomal DNA copy number and reduced intron sizes. These dual mechanisms contrast with genome reduction in the yeast fungus Saccharomyces cerevisiae, whose small and compact genome is associated solely with intron loss.

Conclusions
Our results reveal a unique genomic compaction architecture of filamentous fungi inhabiting plant surfaces, and broaden the understanding of the mechanisms associated with compaction of fungal genomes.
A modular cloning toolkit for genome editing in plants
Authors: Hahn Florian , Korolev Andrey , Sanjurjo Loures Laura , Nekrasov Vladimir 
Published: April 2020

Abstract
Background
CRISPR/Cas has recently become a widely used genome editing tool in various organisms, including plants. Applying CRISPR/Cas often requires delivering multiple expression units into plant and hence there is a need for a quick and easy cloning procedure. The modular cloning (MoClo), based on the Golden Gate (GG) method, has enabled development of cloning systems with standardised genetic parts, e.g. promoters, coding sequences or terminators, that can be easily interchanged and assembled into expression units, which in their own turn can be further assembled into higher order multigene constructs.

Results
Here we present an expanded cloning toolkit that contains 103 modules encoding a variety of CRISPR/Cas-based nucleases and their corresponding guide RNA backbones. Among other components, the toolkit includes a number of promoters that allow expression of CRISPR/Cas nucleases (or any other coding sequences) and their guide RNAs in monocots and dicots. As part of the toolkit, we present a set of modules that enable quick and facile assembly of tRNA-sgRNA polycistronic units without a PCR step involved. We also demonstrate that our tRNA-sgRNA system is functional in wheat protoplasts.

Conclusions
We believe the presented CRISPR/Cas toolkit is a great resource that will contribute towards wider adoption of the CRISPR/Cas genome editing technology and modular cloning by researchers across the plant science community.
Association between the tissue accumulation of advanced glycation end products and exercise capacity in cardiac rehabilitation patients
Authors: Kunimoto Mitsuhiro , Shimada Kazunori , Yokoyama Miho , Matsubara Tomomi , Aikawa Tatsuro , Ouchi Shohei , Shimizu Megumi , Fukao Kosuke , Miyazaki Tetsuro , Kadoguchi Tomoyasu , Fujiwara Kei , Abulimiti Abidan , Honzawa Akio , Yamada Miki , Shimada Akie , Yamamoto Taira , Asai Tohru , Amano Atsushi , Smit Andries J. , Daida Hiroyuki 
Published: April 2020

Abstract
Background
Advanced glycation end products (AGEs) are associated with aging, diabetes mellitus (DM), and other chronic diseases. Recently, the accumulation of AGEs can be evaluated by skin autofluorescence (SAF). However, the relationship between SAF levels and exercise capacity in patients with cardiovascular disease (CVD) remains unclear. This study aimed to investigate the association between the tissue accumulation of AGEs and clinical characteristics, including exercise capacity, in patients with CVD.

Methods
We enrolled 319 consecutive CVD patients aged ≥40 years who underwent early phase II cardiac rehabilitation (CR) at our university hospital between November 2015 and September 2017. Patient background, clinical data, and the accumulation of AGEs assessed by SAF were recorded at the beginning of CR. Characteristics were compared between two patient groups divided according to the median SAF level (High SAF and Low SAF).

Results
The High SAF group was significantly older and exhibited a higher prevalence of DM than the Low SAF group. The sex ratio did not differ between the two groups. AGE levels showed significant negative correlations with peak oxygen uptake and ventilator efficiency (both P <  0.0001). Exercise capacity was significantly lower in the high SAF group than in the low SAF group, regardless of the presence or absence of DM (P <  0.05). A multivariate logistic regression analysis showed that SAF level was an independent factor associated with reduced exercise capacity (odds ratio 2.10; 95% confidence interval 1.13–4.05; P = 0.02).

Conclusion
High levels of tissue accumulated AGEs, as assessed by SAF, were significantly and independently associated with reduced exercise capacity. These data suggest that measuring the tissue accumulation of AGEs may be useful in patients who have undergone CR, irrespective of whether they have DM.