bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patterns of ‘Analytical Irreproducibility’ in Multimodal Diseases
Authors: Basson Abigail R , Cominelli Fabio , Rodriguez-Palacios Alex 
Published: March 2020

AbstractMultimodal diseases are those in which affected individuals can be divided into subtypes (or ‘data modes’); for instance, ‘mild’ vs. ‘severe’, based on (unknown) modifiers of disease severity. Studies have shown that despite the inclusion of a large number of subjects, the causal role of the microbiome in human diseases remains uncertain. The role of the microbiome in multimodal diseases has been studied in animals; however, findings are often deemed irreproducible, or unreasonably biased, with pathogenic roles in 95% of reports. As a solution to repeatability, investigators have been told to seek funds to increase the number of human-microbiome donors (N) to increase the reproducibility of animal studies (doi:10.1016/j.cell.2019.12.025). Herein, through simulations, we illustrate that increasing N will not uniformly/universally enable the identification of consistent statistical differences (patterns of analytical irreproducibility), due to random sampling from a population with ample variability in disease and the presence of ‘disease data subtypes’ (or modes). We also found that studies do not use cluster statistics when needed (97.4%, 37/38, 95%CI=86.5,99.5), and that scientists who increased N, concurrently reduced the number of mice/donor (y=-0.21x, R2=0.24; and vice versa), indicating that statistically, scientists replace the disease variance in mice by the variance of human disease. Instead of assuming that increasing N will solve reproducibility and identify clinically-predictive findings on causality, we propose the visualization of data distribution using kernel-density-violin plots (rarely used in rodent studies; 0%, 0/38, 95%CI=6.9e-18,9.1) to identify ‘disease data subtypes’ to self-correct, guide and promote the personalized investigation of disease subtype mechanisms.HighlightsMultimodal diseases are those in which affected individuals can be divided into subtypes (or ‘data modes’); for instance, ‘mild’ vs. ‘severe’, based on (unknown) modifiers of disease severity.The role of the microbiome in multimodal diseases has been studied in animals; however, findings are often deemed irreproducible, or unreasonably biased, with pathogenic roles in 95% of reports.As a solution to repeatably, investigators have been told to seek funds to increase the number of human-microbiome donors (N) to increase the reproducibility of animal studies.Herein, we illustrate that although increasing N could help identify statistical effects (patterns of analytical irreproducibility), clinically-relevant information will not always be identified.Depending on which diseases need to be compared, ‘random sampling’ alone leads to reproducible ‘patterns of analytical irreproducibility’ in multimodal disease simulations.Instead of solely increasing N, we illustrate how disease multimodality could be understood, visualized and used to guide the study of diseases by selecting and focusing on ‘disease modes’.
Recapitulating evolutionary divergence in a singlecis-regulatory element is sufficient to cause expression changes of the lens geneTdrd7
Authors: Roscito Juliana G. , Subramanian Kaushikaram , Naumann Ronald , Sarov Mihail , Shevchenko Anna , Bogdanova Aliona , Kurth Thomas , Foerster Leo , Kreysing Moritz , Hiller Michael 
Published: March 2020

ABSTRACTMutations incis-regulatory elements play important roles for phenotypic changes during evolution. Eye degeneration in the blind mole rat (BMR) and other subterranean mammals is significantly associated with widespread divergence of eye regulatory elements, but the effect of these regulatory mutations on eye development and function has not been explored. Here, we investigate the effect of mutations observed in the BMR sequence of a conserved non-coding element upstream ofTdrd7, a pleiotropic gene required for lens development and spermatogenesis. We first show that this conserved element is a transcriptional repressor in lens cells and that the BMR sequence partially lost repressor activity. Next, we recapitulated the evolutionary changes by precisely replacing the endogenous regulatory element in a mouse line by the orthologous BMR sequence with CRISPR-Cas9. Strikingly, this repressor element has a large effect, causing a more than two-fold up-regulation ofTdrd7in developing lens. Interestingly, the increased mRNA level does not result in a corresponding increase in TDRD7 protein nor an obvious lens phenotype, likely explained by buffering at the posttranscriptional level. Our results are consistent with eye degeneration in subterranean mammals having a polygenic basis where many small-effect mutations in different eye-regulatory elements collectively contribute to phenotypic differences.
FcRn, but not FcγRs, drives maternal-fetal transplacental transport of human IgG antibodies
Authors: Borghi Sara , Bournazos Stylianos , Thulin Natalie K. , Li Chao , Gajewski Anna , Sherwood Robert , Zheng Sheng , Harris Eva , Jagannathan Prasanna , Wang Lai-Xi , Ravetch Jeffrey V. , Wang Taia T. 
Published: March 2020

AbstractThe IgG Fc domain has the capacity to interact with diverse types of receptors, including FcRn and FcγRs, which confer pleiotropic biological activities. Whereas FcRn regulates IgG epithelial transport and recycling, Fc effector activities, such as ADCC and phagocytosis are mediated by FcγRs, which upon crosslinking transduce signals that modulate the function of effector leukocytes. Despite the well-defined and non-overlapping functional properties of FcRn and FcγRs, recent studies have suggested that FcγRs mediate transplacental IgG transport, as certain Fc glycoforms were reported to be enriched in fetal circulation. To determine the contribution of FcγRs and FcRn to the maternal-fetal transport of IgG, we characterized the IgG Fc glycosylation in paired maternal-fetal samples from patient cohorts from Uganda and Nicaragua. No differences in IgG1 Fc glycan profiles and minimal differences in IgG2 Fc glycans were noted, whereas the presence or absence of galactose on the Fc glycan of IgG1 did not alter FcγRIIIA or FcRn binding, half-life, or their ability to deplete target cells in FcγR/FcRn humanized mice. Modeling maternal/fetal transport in FcγR/FcRn humanized mice confirmed that only FcRn contributed to transplacental transport of IgG; IgG selectively enhanced for FcRn binding resulted in enhanced accumulation of maternal antibody in the fetus. In contrast, enhancing FcγRIIIA binding did not result in enhanced maternal/fetal transport. These results argue against a role for FcγRs in IgG transplacental transport, suggesting Fc engineering of maternally administered antibody to only enhance FcRn binding as a means to improve maternal/fetal transport of IgG.Significance StatementTransport of IgG antibodies from the maternal to the fetal circulation is a key process for neonatal immunity, as neonates cannot sufficiently generate IgG antibodies to reach protective levels during the first months after birth. In humans and other primates, maternal to fetal transport of IgG antibodies is largely mediated through the placental tissue. FcRn has been previously identified as the major driver of IgG transplacental transport. Here we examined whether other receptors, such as FcγRs, also contribute to the maternal-fetal IgG transfer. By characterizing the Fc domain structure of paired maternal-fetal IgG samples and modeling transplacental IgG transport in genetically engineered mouse strains, we determined that FcRn, but not FcγRs, is the major receptor that mediates transplacental IgG transport.
Click-chemistry enabled directed evolution of glycosynthases for bespoke glycans synthesis
Authors: Agrawal Ayushi , Bandi Chandra Kanth , Burgin Tucker , Woo Youngwoo , Mayes Heather B. , Chundawat Shishir P. S. 
Published: March 2020

AbstractEngineering of carbohydrate-active enzymes like glycosynthases for chemoenzymatic synthesis of bespoke oligosaccharides has been limited by the lack of suitable directed evolution based protein engineering methods. Currently there are no ultrahigh-throughput screening methods available for rapid and highly sensitive single cell-based screening of evolved glycosynthase enzymes employing azido sugars as substrates. Here, we report a fluorescence-based approach employing click-chemistry for the selective detection of glycosyl azides (versus free inorganic azides) that facilitated ultrahigh-throughputin-vivosingle cell-based assay of glycosynthase activity. This discovery has led to the development of a directed evolution methodology for screening and sorting glycosynthase mutants for synthesis of desired fucosylated oligosaccharides. Our screening technique facilitated rapid fluorescence activated cell sorting of a large library of glycosynthase variants (>106mutants) expressed inE. colito identify several novel mutants with increased activity for β-fucosyl-azide activated donor sugars towards desired acceptor sugars, demonstrating the broader applicability of this methodology.
Clonal propagation ofOsyris lanceolatathrough air layering at Bazawit Hill, Northern Ethiopia. An Endangered Medicinal and sandal wood Plant in East Africa
Authors: Admas Adugnaw , Melese Smegnew , Genetu Amare , Kidane Berhane , Yilma Zewdu , Admasu Melaku , Misga Tesaka 
Published: March 2020

AbstractIn the recent years medicinal and other economical important plants are getting attention due to the presence of therapeutically important active contents; however over exploitation and propagation problems are the major concern for conservation of several econmically important plant species. Among economical imprortant plants an attempt has been made to develop a propagation method for African sandalwood (Osyris lanceolata) by air layering approach aiming at providing an alternative propagation technique to the use of seeds or cuttings that germinate or root poorly. Air layers were applied root hormone to the stem branches ofOsyris lanceolata(still attached to the plant) during Novmbere 2019, at Bazawit Hill, Nothern Ethiopia at edge of Blue-Nile River from its source at Lake Tana. Root initiation were starts after 12 weeks of the experments.The factors assessed in this experiment were the effect IBA as rooting promoter at three concentrations (0,50, 100 and 150 ppm). From the data collected it was observed 88.8% rooting were achieved from air layers in the mother plants it selef those treated by IBA hormone and the controls not responding root.Making this propagation technique is a viable alternative to the use of seed or cutting propagation. Rooting response success were influenced by application of rooting hormone of IBA, soil composition and the seasons. At a rate of 150 ppm 100% all expermented plants were intiated and primarly other than other treatmeants responded root. The significance enhancing of root making onOsyris lanceolataplants stem via air layers is linked to the advantage of more rooting hormone concentartion.
Elucidating another level of epigenetic regulation in osteoarthritis by identifying functionalcis-acting long non-coding RNAs and their targets in articular cartilage
Authors: van Hoolwerff Marcella , Metselaar Paula I. , Tuerlings Margo , Suchiman H. Eka D. , Lakenberg Nico , Ramos Yolande F.M. , Cats Davy , Nelissen Rob G.H.H. , Broekhuis Demiën , Mei Hailiang , de Almeida Rodrigo Coutinho , Meulenbelt Ingrid 
Published: March 2020

ABSTRACTObjectiveTo identify robustly differentially expressed long non-coding RNAs (lncRNAs) with osteoarthritis (OA) pathophysiology in cartilage. Moreover to explore potential target mRNAs by establishing co-expression networks, followed by functional validation.MethodsRNA sequencing was performed on macroscopically lesioned and preserved OA cartilage of patients who underwent a joint replacement surgery due to OA (N=98). Differential expression (DE) analysis was performed on lncRNAs that were annotated in GENCODE and Ensembl. To identify potential interactions, correlations were calculated between the identified DE lncRNAs and previously reported DE protein-coding genes in the same samples. Modulation of chondrocyte lncRNA expression was achieved using LNA GapmeRs.ResultsBy applying our in-house pipeline we identified 5,053 lncRNAs to be robustly expressed, of which 191 were FDR significant differentially expressed between lesioned and preserved OA cartilage. Upon integrating mRNA sequencing data, we showed that intergenic and antisense DE lncRNAs show high, positive correlations with their flanking, respectively, sense genes. To functionally validate this observation we selectedP3H2-AS1, which was downregulated in primary chondrocytes, resulting in downregulation ofP3H2gene expression levels. As such, we can confirm thatP3H2-AS1regulates its sense geneP3H2.ConclusionBy applying an improved detection strategy, robustly differentially expressed lncRNAs in OA cartilage were detected. Integration of these lncRNAs with differential mRNA expression levels in the same samples showed insight into their regulatory networks. Our data signifies that intergenic, as well as antisense lncRNAs play an important role in regulating the pathophysiology of OA.
Noise ceiling on the crossvalidated performance of reweighted models of representational dissimilarity: Addendum to Khaligh-Razavi & Kriegeskorte (2014)
Authors: Storrs Katherine R. , Khaligh-Razavi Seyed-Mahdi , Kriegeskorte Nikolaus 
Published: March 2020

AbstractAn error was made in including noise ceilings for human data in Khaligh-Razavi and Kriegeskorte (2014). For comparability with the macaque data, human data were averaged across participants before analysis. Therefore the noise ceilings indicating variability across human participants do not accurately depict the upper bounds of possible model performance and should not have been shown. Creating noise ceilings appropriate for the fitted models is not trivial. Below we present a method for doing this, and the results obtained with this new method. The corrected results differ from the original results in that the best-performing model (weighted combination of AlexNet layers and category readouts) does not reach the lower bound of the noise ceiling. However, the best-performing model is not significantly below the lower bound of the noise ceiling. The claim that the model “fully explains” the human IT data appears overstated. All other claims of the paper are unaffected.
Examining the molecular mechanisms contributing to the success of an invasive species across different ecosystems
Authors: Lamar Sarah K. , Beddows Ian , Partridge Charlyn G. 
Published: March 2020

ABSTRACTInvasive species provide an opportune system to investigate how populations respond to new environments. Baby’s breath (Gypsophila paniculata) was introduced to North America in the 1800’s and has since spread throughout the United States and western Canada. We used an RNA-seq approach to explore how molecular processes contribute to the success of invasive populations with similar genetic backgrounds across distinct habitats. Transcription profiles were constructed from seedlings collected from a sand dune ecosystem in Petoskey, MI (PSMI) and a sagebrush ecosystem in Chelan, WA (CHWA). We assessed differential gene expression and identified SNPs within differentially expressed genes. We identified 1,146 differentially expressed transcripts across all sampled tissues between the two populations. GO processes enriched in PSMI were associated with nutrient starvation, while enriched processes in CHWA were associated with abiotic stress. Only 7.4% of the differentially expressed transcripts contained SNPs differing in allele frequencies of at least 0.5 between populations. Common garden studies found the two populations differed in germination rate and seedling emergence success. Our results suggest the success ofG. paniculatain these two environments is likely due to plasticity in specific molecular processes responding to different environmental conditions, although some genetic divergence may be contributing to these differences.
FPfilter: A false-positive-specific filter for whole-genome sequencing variant calling from GATK
Authors: Tan Yuxiang , Zhang Yu , Yang Hengwen , Yin Zhinan 
Published: March 2020

1.AbstractMotivationAs whole genome sequencing (WGS) is becoming cost-effective progressivelly, it has been applied increasingly in medical and scientific fields. Although the traditional variant-calling pipeline (BWA+GATK) has very high accuracy, false positives (FPs) are still an unavoidable problem that might lead to unfavorable outcomes, especially in clinical applications. As a result, filtering out FPs is recommended after variant calling. However, loss of true positives (TPs) is inevitable in FP-filtering methods, such as GATK hard filtering (GATK-HF). Therefore, to minimize the loss of TPs and maximize the filtration of FPs, a comprehensive understanding of the features of TPs and FPs, and building an improved model of classification are necessary. To obtain information about TPs and FPs, we used Platinum Genome (PT) as the mutation reference and its 300× deep sequenced dataset NA12878 as the simulation template. Then random sampling across depth gradients from NA12878 was performed to study the depth effect.ResultsFPs among heterozygous mutations were found to have pattern distinct from that of FPs among homozygous mutations. FPfilter makes use of this model to filter out FPs specifically. We evaluated FPfilter on a training dataset with depth gradients from NA12878 and a test dataset from NA12877 and NA24385. Compared with GATK-HF, FPfilter showed a significantly higher FP/TP filtration ratio and F-measure score. Our results indicate that FPfilter provides an improved model for distinguishing FPs from TPs and filters FPs with high specificity.AvailabilityFPfilter is freely available for download on GitHub (https://github.com/yuxiangtan/FPfilter). Users can easily install it from anaconda.
The evolution of suppressed recombination between sex chromosomes by chromosomal inversions
Authors: Olito Colin , Abbott Jessica K. 
Published: March 2020

AbstractThe idea that sex-differences in selection drive the evolution of suppressed recombination between sex chromosomes is well-developed in population genetics. Yet, despite a now classic body of theory, empirical evidence that sexual antagonism drives the evolution of recombination suppression remains meagre and alternative hypotheses underdeveloped. We investigate whether the length of ‘evolutionary strata’ formed by chromosomal inversions that expand the non-recombining sex determining region (SDR) on recombining sex chromosomes can offer an informative signature of whether, and how, selection influenced their fixation. We develop population genetic models that determine how the length of a chromosomal inversion that expands the SDR affects its fixation probability for three categories of inversions: (i) neutral, (ii) directly beneficial (i.e., due to breakpoint or position effects), and (iii) indirectly beneficial (especially those capturing sexually antagonistic loci). Our models predict that neutral inversions should leave behind a unique signature of large evolutionary strata, and that it will often be difficult or impossible to distinguish between smaller strata created by directly or indirectly beneficial inversions. An interesting and unexpected prediction of our models is that the physical location of the ancestral SDR on the sex chromosomes is the most important factor influencing the relation between inversion size and the probability of expanding the SDR. Our findings raise a suite of new questions about how physical as well as selective processes influence the evolution of recombination suppression between sex chromosomes.
WOX9 functions antagonistic to STF and LAM1 to regulate leaf blade expansion inMedicago truncatulaandNicotiana sylvestris
Authors: Wolabu Tezera W. , Wang Hui , Tadesse Dimiru , Zhang Fei , Behzadirad Marjan , Tvorogova Varvara E. , Abdelmageed Haggagi , Liu Ye , Chen Naichong , Chen Jianghua , Allen Randy D. , Tadege Million 
Published: March 2020

AbstractPlant specific WOX family transcription factors are known to regulate embryogenesis, meristem maintenance and lateral organ development. Modern clade WOX genes function through a transcriptional repression mechanism, and the intermediate clade transcriptional activator WOX9 functions with the repressor WOX genes in embryogenesis and meristems maintenance, but the mechanism of this interaction is unclear.WOX1homologuesSTFandLAM1are required for leaf blade outgrowth inMedicago truncatulaandNicotiana Sylvestris, respectively. Here we show thatWOX9negatively regulates leaf blade outgrowth and functions antagonistically toSTFandLAM1. WhileNsWOX9ectopic expression enhances thelam1mutant phenotype, and antisense expression partially rescues thelam1mutant, both overexpression ofNsWOX9and knockout by CRISPR/Cas9 genome editing inN. sylvestrisresulted in a range of severe leaf blade distortions, indicating that controlled negative regulation by NsWOX9 is required for proper blade development. Our results indicate that direct repression of WOX9 transcriptional activation activity by the transcriptional repressor STF/LAM1 is required for correct blade architecture and patterning inM. truncatulaandN. sylvestris. These findings suggest that a balance between transcriptional activation and repression mechanisms by direct interaction of activator and repressor WOX genes may be required for cell proliferation and differentiation homeostasis, and could be an evolutionarily conserved mechanism for the development of complex and diverse morphology in higher plants.One sentence summaryWOX9 negatively regulates blade outgrowth antagonizing STF function but directly repressed by STF indicating WOX-mediated homeostasis in cell proliferation and differentiation during leaf morphogenesis.
Systemic characterization of pppGpp, ppGpp and pGpp targets inBacillusreveals NahA converts (p)ppGpp to pGpp to regulate alarmone composition and signaling
Authors: Yang Jin , Anderson Brent W. , Turdiev Asan , Turdiev Husan , Stevenson David M. , Amador-Noguez Daniel , Lee Vincent T. , Wang Jue D. 
Published: March 2020

AbstractThe alarmones pppGpp and ppGpp (collectively (p)ppGpp) protect bacterial cells from nutritional and other stresses. Here we demonstrate the physiological presence of pGpp as a third closely related alarmone in bacterial cells and also characterize and compare the proteomic targets of pGpp, ppGpp and pppGpp in Gram-positiveBacillusspecies. We revealed two regulatory pathways for ppGpp and pppGpp that are highly conserved across bacterial species: inhibition of purine nucleotide biosynthesis and control of ribosome assembly/activity through GTPases. Strikingly, pGpp potently regulates the purine biosynthesis pathway but does not interact with the GTPases. Importantly, we identified a key enzyme NahA that efficiently produces pGpp by hydrolyzing (p)ppGpp, thus tuning alarmone composition to uncouple the regulatory modules of the alarmones. Correspondingly, anahAmutant displays significantly reduced pGpp levels and elevated (p)ppGpp levels, slower growth recovery from nutrient downshift, and loss of competitive fitness. These cellular consequences for regulating alarmone composition strongly implicate an expanded repertoire of alarmones in a new strategy of stress response inBacillusand its relatives.