bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tissue-specific multiOMICs analysis of atrial fibrillation
Authors: Assum Ines , Krause Julia , Scheinhardt Markus O. , Müller Christian , Hammer Elke , Börschel Christin S. , Völker Uwe , Conradi Lenard , Geelhoed Bastiaan , Zeller Tanja , Schnabel Renate B. , Heinig Matthias 
Published: April 2020

AbstractGenome-wide association studies (GWAS) for atrial fibrillation (AF) have uncovered numerous disease-associated variants. Their underlying molecular mechanisms, especially consequences for mRNA and protein expression remain largely elusive. Thus, novel multiOMICs approaches are needed for deciphering the underlying molecular networks. Here, we integrated genomics, transcriptomics, and proteomics of human atrial tissue which allowed for identifying widespread effects of genetic variants on both transcript (cis eQTL) and protein (cis pQTL) abundance. We further established a novel targeted trans QTL approach based on polygenic risk scores to identify candidates for AF core genes. Using this approach, we identified two trans eQTLs and four trans pQTLs for AF GWAS hits, and elucidated the role of the transcription factor NKX2-5 as a link between the GWAS SNP rs9481842 and AF. Altogether, we present an integrative multiOMICs method to uncover trans-acting networks in small datasets and provide a rich resource of atrial tissue-specific regulatory variants for transcript and protein levels for cardiovascular disease gene prioritization.
SARS-COV-2 RBD Oral Vaccine Boosted by Mucosal Immune Adjuvant LTB26 via DCs and B Cells Activation in Mice
Authors: Ma Yongping , Shi Qinlin , Wang Qiujuan , Chen Sijing , Gan Sijie , Fang Changyin , Shen Yanxi , Jiang Min , Lin Tao , Song Fangzhou 
Published: April 2020

AbstractAlthough several SARS-COV-2 vaccines have been approved, no one oral live vaccine is available. Here, an oral SARS-COV-2 RBD live vaccine containing LTB26 adjuvant has been developed. BALB/c mice are oral vaccinated with attenuatedSalmonella typhimuriumSL7207 containing pcDNA3.1-LTB26RBD or pcDNA3.1-RBD plasmids. The result shows that the high level of RBD specific antibody is produced in pcDNA3.1- LTB26RBD treatment. The mechanism indicates that LTB26 enhances RBD antibody production by significantly upregulating the activity of MHC II+DCs and CD19+CD45+B cells. LTB26 mutant is derived from heat-labile enterotoxin B subunit (LTB) wild type ofEscherichia coliwith enhanced immune adjuvanticity. Based on the pre-experiment result that SL7207 interferes the function of LTB26, the purified LTB26 was mixed with purified human rotavirus VP8 antigen to explore the mechanism of adjuvant. The results suggests that LTB26 enhances mucosal immune responses via increased of BCR and MHC II+expression. Furthermore, LTB26 promotes both Th1 and Th2 cell mediated immunity. Therefore, LTB26 maybe a potent adjuvant for mucosal vaccine development in view of the safety of LTB26 than LT toxin.
Inhibition of nonsense-mediated decay rescues functional p53β/γ isoforms in MDM2-amplified cancers
Authors: Gudikote Jayanthi P. , Cascone Tina , Poteete Alissa , Sitthideatphaiboon Piyada , Wu Qiuyu , Morikawa Naoto , Zhang Fahao , Peng Shaohua , Tong Pan , Li Lerong , Shen Li , Nilsson Monique , Jones Phillip , Sulman Erik P. , Wang Jing , Bourdon Jean-Christophe , Johnson Faye M. , Heymach John V. 
Published: April 2020

ABSTRACTCommon mechanisms for p53 loss in cancer include expression of MDM2 or the human papilloma virus (HPV)-encoded E6 protein which both mediate degradation of wild-type (WT) p53 (p53α). Here, we show that two alternatively-spliced, functional, truncated isoforms of p53 (p53β and p53γ, containing exons 1-9 of the p53 gene) can be markedly upregulated by pharmacologic or genetic inhibition of nonsense mediated decay (NMD), a regulator of aberrant mRNA stability. These isoforms lack the MDM2 binding domain and hence have reduced susceptibility to MDM2-mediated degradation. In MDM2-overexpressing cells bearing wildtypeTP53gene, NMD blockade increased p53β/γ expression and p53 pathway activation, enhanced radiosensitivity, and inhibited tumor growth. A similar pattern was observed in HPV+cancer cells and in cancer cells with p53 mutations downstream of exon 9. These results identify a novel therapeutic strategy for restoration of p53 function in tumors rendered p53 deficient through MDM2 overexpression, HPV infection, or certain p53 mutations.
Invasion and maintenance of meiotic drivers in populations of ascomycete fungi
Authors: Martinossi-Allibert Ivain , Veller Carl , Ament-Velásquez S. Lorena , Vogan Aaron A. , Rueffler Claus , Johannesson Hanna 
Published: April 2020

AbstractMeiotic drivers are selfish genetic elements that are able to become over-represented among the products of meiosis. This transmission advantage makes it possible for them to spread in a population even when they impose fitness costs on their host organisms. Whether a meiotic driver can invade a population, and subsequently reach fixation or coexist in a stable polymorphism, depends on the one hand on the biology of the host organism, including its life-cycle, mating system, and population structure, and on the other hand on the specific fitness effects of the driving allele on the host. Here, we present a population genetic model for spore killing, a type of drive specific to fungi. We show how ploidy level, rate of selfing, and efficiency of spore killing affect the invasion probability of a driving allele and the conditions for its stable coexistence with the non-driving allele. Our model can be adapted to different fungal life-cycles, and is applied here to two well-studied genera of filamentous ascomycetes known to harbor spore killing elements,NeurosporaandPodospora. We discuss our results in the light of recent empirical findings for these two systems.
Influence of historical and human factors on genetic structure and diversity patterns in peripheral populations: implications for the conservation of Moroccan trout
Authors: Perea S , Al Amouri M , Gonzalez EG , Alcaraz L , Yahyaoui A , Doadrio I 
Published: April 2020

AbstractThe brown trouts.l.has been the focus of numerous phylogeographic and conservation studies due to its socioeconomic importance, its marked genetic and phenotypic differentiation and its broad distribution range. Especially interesting evolutionary patterns are observed for populations occupying peripheral areas of a distribution range, such as in the case of the highly isolated trout populations in Morocco.Continuous stocking programs may conceal natural genetic patterns, making it challenging to discern evolutionary patterns. In Morocco, trout stocking programs have been implemented to increase the genetic diversity of native populations by pooling fish of different origins in the Ras el Ma hatchery (Azrou region) and then stocking them in the different basins. In this study, phylogenetic and phylogeographic patterns, as well as genetic structure and diversity, of Moroccan trout populations were analyzed to evaluate the impact of continuous fish stocking on evolutionary processes in order to better distinguish between natural and human-mediated patterns.Two mitochondrial and nine microsatellite markers were analyzed for all populations along the entire distribution range of brown trout in Morocco. Phylogenetic and phylogeographic analyses rendered two highly divergent evolutionary lineages, one comprising populations in the Drâa Basin and a second grouping the remaining Moroccan populations. Divergence of the Drâa lineage occurred during the Upper Pliocene, whilst differentiation within the second lineage coincided with the onset of the Pleistocene.Genetic structuring among populations was evident. Nevertheless, populations exhibiting higher levels of genetic diversity were those affected by human-mediated processes, making it difficult to associate this diversity with natural processes. In fact, highly geographically isolated, not stocked populations showed the lowest values of genetic diversity. Although stocking management may increase the genetic diversity of these populations, it could also lead to the loss of local adaptive genotypes. Hence, current trout conservation programs should be revised.
Developing snakebite risk model using venomous snake habitat suitability as an indicating factor: An application of species distribution models in public health research
Authors: Yousefi Masoud , Kafash Anooshe , Khani Ali , Nabati Nima 
Published: April 2020

AbstractSnakebite envenoming is an important public health problem in Iran, despite its risk not being quantified. This study aims to use venomous snakes’ habitat suitability as an indicator of snakebite risk, to identify high-priority areas for snakebite management across the country. Thus, an ensemble approach using five distribution modeling methods: Generalized Boosted Models, Generalized Additive Models, Maximum Entropy Modeling Generalized Linear Models, and Random Forest was applied to produce a spatial snakebite risk model for Iran. To achieve this, four venomous snakes’ habitat suitability (Macrovipera lebetina, Echis carinatus, Pseudocerastes persicusandNaja oxiana) were modeled and then multiplied. These medically important snakes are responsible for the most snakebite incidents in Iran. Multiplying habitat suitability models of the four snakes showed that the northeast of Iran (west of Khorasan-e-Razavi province) has the highest snakebite risk in the country. In addition, villages that were at risk of envenoming from the four snakes were identified. Results revealed that 51,112 villages are at risk of envenoming fromM. lebetina, 30,339 fromE. carinatus, 51,657 fromP. persicusand 12,124 fromN. oxiana. This paper demonstrates application of species distribution modeling in public health research and identified potential snakebite risk areas in Iran by using venomous snakes’ habitat suitability models as an indicating factor. Results of this study can be used in snakebite and human–snake conflict management in Iran. We recommend increasing public awareness of snakebite envenoming and education of local people in areas which identified with the highest snakebite risk.
Ectodomain shedding of L-selectin by ADAM17 in canine neutrophils
Authors: Snyder Kristin M. , McAloney Camille , Montel Joshua S. , Modiano Jaime F. , Walcheck Bruce 
Published: April 2020

AbstractThe adhesion protein L-selectin (CD62L) is expressed at high levels by circulating neutrophils and has a critical role in initiating their recruitment at sites of inflammation. L-selectin expression is rapidly downregulated upon neutrophil activation by various stimuli through a proteolytic process referred to as ectodomain shedding, which regulates L-selectin’s binding avidity and neutrophil recruitment. In humans and mice, L-selectin shedding is primarily mediated by ADAM17 (a disintegrin and metalloproteinase 17). L-selectin expression is also rapidly downregulated by canine neutrophils upon their activation; however, the role of ADAM17 in this process has not been previously investigated. We show that a highly selective inhibitor of ADAM17, but not an inhibitor of its most closely related family member ADAM10, effectively blocked L-selectin downregulation from the surface of canine neutrophils following their activation. The ADAM17 inhibitors did not block the rapid upregulation of the CD18 integrin Mac-1 (CD11b/CD18), showing that they did not broadly impair neutrophil activation. To directly examine the expression of ADAM17, we used several anti-human ADAM17 mAbs. Many did not stain canine neutrophils; however, the ADAM17 function-blocking mAbs MEDI3622 and D1(A12) did stain and also blocked L-selectin downregulation. Taken together, our findings provide the first direct evidence that ADAM17 is a primary sheddase of canine L-selectin, which may serve as an important therapeutic target to prevent neutrophil dysfunction during conditions of excessive inflammation, such as sepsis.
First Detection of PathogenicEscherichia coliIsolates Associated With Donkey Foals’ Diarrhea in Northern China
Authors: Wen-qiang Liu , Nan Xia , Jing-wen Zhang , Ren-hu Wang , Gui-miao Jiang 
Published: April 2020

ABSTRACTObjectiveThe aim of this study was to identify the biological features, influence factor and Genome-wide properties of pathogenic donkeyEscherichia coli(DEC) isolates associated with severe diarrhea in Northern China.MethodsThe isolation and identification of DEC isolates were carried out by the conventional isolation、automatic biochemical analysis system、serotype identification、16S rRNA test、animal challenge and antibiotics sensitivity examination. The main virulence factors were identified by PCR. The complete genomic re-sequence and frame-sequence were analyzed.Results216 strains of DEC were isolated from diarrhea samples, conforming to the bacterial morphology and biochemical characteristics ofE.coli. The average size of the pure culture was 329.4 nm×223.5 nm. Agglutination test showed that O78 (117/179, 65.4%) was the dominant serotype and ETEC(130/216, 60.1%) was the dominant pathogenic type. Noticeable pathogenic were observed in 9 of 10 (90%) randomly selected DEC isolates caused the death of test mice (100%, 5/5) within 6h∼48h, 1 of 10 (10%) isolates caused the death of test mice (40%, 2/5) within 72h. Our data confirmed that DEC plays an etiology role in dirarrea/death case of donkey foal. Antibiotics sensitivity test showed significant susceptibility to DEC isolates were concentrated in Nor、EFT、ENR、CIP and AMK,while the isolates with severe antibiotic resistance was AM、TE、APR、FFC、RL and CN. Multi-drug resistance was also observed. A total of 15 virulence gene fragments were determined from DEC(n=30) including OMPA (73%), safD (77%), traTa (73%), STa(67%), EAST1 (67%), astA (63%), kspII (60%), irp2 (73%), iucD (57%), eaeA (57%), VAT (47%), iss (33%), cva (27%), ETT2 (73%) and K88 (60%) respectively. More than 10 virulence genes from 9 of 30(30%) DEC strains were detected, while 6 of 30(20%) DEC strains detected 6 virulence factors. phylogenetic evolutionary tree of 16S rRNA gene from different isolates shows some variability. The original data volume obtained from the genome re-sequencing of DEC La18 was 2.55G and Genome framework sequencing was carried out to demonstrate the predicted functions and evolutionary direction and genetic relationships with other animalE.coli.ConclusionsThese findings provide firstly fundamental data that might be useful in further study of the role of DEC and provide a new understanding of the hazards of traditionalcolibacillosisdue to the appear of new production models.
Combined single-cell gene and isoform expression analysis in haematopoietic stem and progenitor cells
Authors: Mincarelli Laura , Uzun Vladimir , Rushworth Stuart A. , Haerty Wilfried , Macaulay Iain C. 
Published: April 2020

AbstractSingle-cell RNA sequencing (scRNA-seq) enables gene expression profiling and characterization of novel cell types within heterogeneous cell populations. However, most approaches cannot detect alternatively spliced transcripts, which can profoundly shape cell phenotype by generating functionally distinct proteins from the same gene. Here, we integrate short- and long-read scRNA-seq of hematopoietic stem and progenitor cells to characterize changes in cell type abundance, gene and isoform expression during differentiation and ageing.
Protein manipulation using single copies of short peptide tags in cultured cells and inDrosophila melanogaster
Authors: Vigano M. Alessandra , Ell Clara-Maria , Kustermann Manuela MM , Aguilar Gustavo , Matsuda Shinya , Zhao Ning , Stasevich Timothy J , Pyrowolakis George , Affolter Markus 
Published: April 2020

AbstractCellular development and specialized cellular functions are regulated processes which rely on highly dynamic molecular interactions among proteins, distributed in all cell compartments. Analysis of these interactions and their mechanisms of action has been one of the main topics in cellular and developmental research over the last fifty years. Studying and understanding the functions of proteins of interest (POIs) has been mostly achieved by their alteration at the genetic level and the analysis of the phenotypic changes generated by these alterations. Although genetic and reverse genetic technologies contributed to the vast majority of information and knowledge we have gathered so far, targeting specific interactions of POIs in a time- and space-controlled manner or analyzing the role of POIs in dynamic cellular processes such as cell migration or cell division would require more direct approaches. The recent development of specific protein binders, which can be expressed and function intracellularly, together with several improvements in synthetic biology techniques, have contributed to the creation of a new toolbox for direct protein manipulations. We selected a number of short tag epitopes for which protein binders from different scaffolds have been developed and tested whether these tags can be bound by the corresponding protein binders in living cells when they are inserted in a single copy in a POI. We indeed find that in all cases, a single copy of a short tag allows protein binding and manipulation. UsingDrosophila, we also find that single short tags can be recognized and allow degradation and relocalization of POIsin vivo.
Trade-Offs between Speed, Accuracy, and Dissipation in tRNAIleAminoacylation
Authors: Yu Qiwei , Mallory Joel D. , Kolomeisky Anatoly B. , Ling Jiqiang , Igoshin Oleg A. 
Published: April 2020

AbstractLiving systems maintain a high fidelity in information processing through kinetic proofreading, a mechanism to preferentially remove incorrect substrates at the cost of energy dissipation and slower speed. Proofreading mechanisms must balance their demand for higher speed, fewer errors, and lower dissipation, but it is unclear how rates of individual reaction steps are evolutionary tuned to balance these needs, especially when multiple proofreading mechanisms are present. Here, using a discrete-state stochastic model, we analyze the optimization strategies inEscherichia coliisoleucyl-tRNA synthetase. Surprisingly, this enzyme adopts an economic proofreading strategy and improves speed and dissipation as long as the error is tolerable. Through global parameter sampling, we reveal a fundamental dissipation-error relation that bounds the enzyme’s optimal performance and explains the importance of the post-transfer editing mechanism. The proximity of native system parameters to this bound demonstrates the importance of energy dissipation as an evolutionary force affecting fitness.Graphical TOC Entry
Impact of Advanced Maternal Age on Physiologic Adaptations to Pregnancy in Vervet Monkeys
Authors: Plant Maren , Armstrong Cecilia , Ruggiero Alistaire , Sherrill Chrissy , Uberseder Beth , Jeffries Rachel , Nevarez Justin , Jorgensen Matthew J. , Kavanagh Kylie , Quinn Matthew A. 
Published: April 2020

AbstractContextThe trend to delay pregnancy in the United States has resulted in the number of advanced maternal age (AMA) pregnancies to also increase. In humans, AMA is associated with a variety of pregnancy-related pathologies such as preeclampsia (PE). While AMA is known to be a factor which contributes to the development of pregnancy-induced diseases, the molecular and cellular mechanisms giving rise to this phenomenon are still very limited. This is due in part to lack of a pre-clinical model which has physiologic relevance to human pregnancy while also allowing control of environmental and genetic variability inherent in human studies.ObjectiveTo determine potential physiologic relevance of the vervet/African green monkey (Chlorocebus aethiops sabaeus)as a pre-clinical model to study the effects of AMA on adaptations to pregnancy.DesignThirteen age-diverse pregnant vervet monkeys (3-16 y.o.) were utilized to measure third trimester blood pressure (BP), complete blood count, iron measurements and hormone levels.ResultsSignificant associations were observed between third trimester diastolic BP and maternal age. Furthermore, the presence of leukocytosis with enhanced circulating neutrophils was observed in AMA mothers compared to younger mothers. Moreover, we observed a negative relationship between maternal age and estradiol, progesterone and cortisol levels. Finally, offspring born to AMA mothers displayed a postnatal growth retardation phenotype.ConclusionsThese studies demonstrate physiologic impairment in the adaptation to pregnancy in AMA vervet/African green monkeys. Our data indicate the vervet/African green monkey may serve as a useful pre-clinical model and tool for deciphering pathological mediators of maternal disease in AMA pregnancy.
MicroRNA arm switching regulated by uridylation
Authors: Kim Haedong , Kim Jimi , Yu Sha , Lee Young-Yoon , Park Junseong , Choi Ran Joo , Yoon Seon-Jin , Kang Seok-Gu , Kim V. Narry 
Published: April 2020

SUMMARYStrand selection is a critical step in microRNA (miRNA) biogenesis. Although the dominant strand may alter depending on cellular contexts, the molecular mechanism and physiological significance of such alternative strand selection (or “arm switching”) remain elusive. Here we find mir-324 as one of the strongly regulated miRNAs by arm switching, and identify terminal uridylyl transferases TUT4 and TUT7 as the key regulators. Uridylation of pre-mir-324 by TUT4/7 re-positions DICER on the pre-miRNA and shifts the cleavage site. This alternative processing produces a duplex with a different terminus, from which the 3′ strand (3p) is selected instead of the 5′ strand (5p). In glioblastoma, the TUT4/7 and 3p levels are upregulated while the 5p level is reduced. Manipulation of the strand ratio is sufficient to impair glioblastoma cell proliferation. This study uncovers a role of uridylation as a molecular switch in alternative strand selection and implicates its therapeutic potential.
Gamete-specific expression of TALE class HD genes activates the diploid sporophyte program inMarchantia polymorpha
Authors: Dierschke Tom , Flores-Sandoval Eduardo , Rast-Somssich Madlen I. , Althoff Felix , Zachgo Sabine , Bowman John L. 
Published: April 2020

AbstractEukaryotic life cycles alternate between haploid and diploid phases and in phylogenetically diverse unicellular eukaryotes, expression of paralogous homeodomain genes in the two gametes directs the haploid-to-diploid transition. In the unicellular Chlorophyte algaChlamydomonasKNOX and BELL TALE-homeodomain genes mediate the transition. Here we demonstrate that in the liverwortMarchantia polymorphapaternal (sperm) expression three of the five phylogenetically diverse BELL genes, MpBELL234, and maternal (egg) expression of MpKNOX1mediate the haploid-to-diploid transition. Loss-of-function alleles of either result in zygotic or early embryonic arrest. In land plants both the haploid gametophyte and diploid sporophyte are complex multicellular organisms. Expression of MpKNOX1and two other paralogs, MpBELL1and MpKNOX2, during sporophyte development is consistent with a later role in patterning the sporophyte. These results indicate that the ancestral mechanism to activate diploid gene expression was retained in early diverging land plants and subsequently co-opted during evolution of the diploid sporophyte body.