bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Brassica napus Wall-Associated Kinase-Like (WAKL) gene Rlm9 provides race-specific blackleg resistance
Authors: Larkan Nicholas J. , Ma Lisong , Haddadi Parham , Buchwaldt Miles , Parkin Isobel A. P. , Djavaheri Mohammad , Borhan M. Hossein 
Published: October 2019

AbstractIn plants, race-specific defense against microbial pathogens is facilitated by resistance (R) genes which correspond to specific pathogen avirulence (Avr) genes. This study reports the cloning of a blackleg R gene from Brassica napus (canola); Rlm9, which encodes a wall-associated kinase-like (WAKL) protein, a newly-discovered class of race-specific plant RLK resistance genes. Rlm9 provides race-specific resistance against isolates of Leptosphaeria maculans carrying the corresponding avirulence gene AvrLm5-9, representing only the second WAKL-type R gene described to date. The Rlm9 protein is predicted to be cell membrane-bound yet appears to have no direct interaction with AvrLm5-9. Rlm9 forms part of a distinct evolutionary family of RLK proteins in B. napus, and while little is yet known about WAKL function, the Brassica-Leptosphaeria pathosystem may prove to be a model system by which the mechanism of fungal avirulence protein recognition by WAKL-type R genes can be determined.
Host relatedness and landscape connectivity shape pathogen spread in a large secretive carnivore
Authors: Fountain-Jones Nicholas M. , Kraberger Simona , Gagne Roderick , Trumbo Daryl R. , Salerno Patricia , Funk W. Chris , Crooks Kevin , Biek Roman , Alldredge Mathew , Logan Ken , Baele Guy , Dellicour Simon , Ernest Holly B , VandeWoude Sue , Carver Scott , Craft Meggan E. 
Published: October 2019

AbstractUrban expansion can fundamentally alter wildlife movement and gene flow, but how urbanization alterspathogenspread is poorly understood. Here we combine high resolution host and viral genomic data with landscape variables to examine the context of viral spread in puma from two contrasting regions: one bounded by the wildland urban interface (WUI) and one unbounded with minimal anthropogenic development. We found landscape variables and host gene flow explained significant amounts of variation of feline immunodeficiency virus (FIV) spread in the WUI, but not in the unbounded region. The most important predictors of viral spread also differed; host spatial proximity, host relatedness, and mountain ranges played a role in FIV spread in the WUI, whereas unpaved roads were more important in the unbounded region. Our research demonstrates how anthropogenic landscapes can alter pathogen spread, providing a more nuanced understanding of host-pathogen relationships to inform disease ecology in free-ranging species.
Broad-Spectrum Antifungal Activities and Mechanism of Drimane Sesquiterpenoids
Authors: Edouarzin Edruce , Horn Connor , Paduyal Anuja , Zhang Cunli , Lu Jianyu , Tong Zongbo , Giaever Guri , Nislow Corey , Veerapandian Raja , Hua Duy H. , Vediyappan Govindsamy 
Published: October 2019

ABSTRACTEight drimane sesquiterpenoids including (-)-drimenol and (+)-albicanol were synthesized from (+)-sclareolide and evaluated for their antifungal activities. Three compounds, (-)-drimenol, (+)-albicanol, and (1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalene-1-carbaldehyde (4) showed strong activity against C. albicans. (-)-Drimenol, the strongest inhibitor of the three, (at concentrations of 8 – 64 μg/ml, causing 100% death of fungi), acts not only against C. albicans as a fungicidal manner, but also inhibits other fungi such as Aspergillus, Cryptococcus, Pneumocystis, Blastomyces, Fusarium, Rhizopus, Saksenaea and FLU resistant strains of C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. auris. These observations suggest drimenol is a broad-spectrum antifungal agent. At high concentration (100 μg/ml), drimenol caused a rupture of the fungal cell wall/membrane. In a nematode model of C. albicans infection, drimenol rescued the worms from C. albicans-mediated death, indicating drimenol is tolerable and bioactive in a metazoan. Genome-wide fitness profiling assays of both S. cerevisiae (nonessential homozygous and essential heterozygous) and C. albicans (Tn-insertion mutants) collections revealed putative genes and pathways affected by drimenol. Using a C. albicans mutants spot assay, the Crk1 kinase associated gene products, Ret2, Cdc37, and novel putative targets orf19.759, orf19.1672, and orf19.4382 were revealed to be the potential targets of drimenol. Further, computational modeling results suggest possible modification of the structure of drimenol including the A ring for improving antifungal activity.
A framework for effective application of machine learning to microbiome-based classification problems
Authors: Topçuoğlu Begüm D. , Lesniak Nicholas A. , Ruffin Mack , Wiens Jenna , Schloss Patrick D. 
Published: October 2019

AbstractMachine learning (ML) modeling of the human microbiome has the potential to identify microbial biomarkers and aid in the diagnosis of many diseases such as inflammatory bowel disease, diabetes, and colorectal cancer. Progress has been made towards developing ML models that predict health outcomes using bacterial abundances, but inconsistent adoption of training and evaluation methods call the validity of these models into question. Furthermore, there appears to be a preference by many researchers to favor increased model complexity over interpretability. To overcome these challenges, we trained seven models that used fecal 16S rRNA sequence data to predict the presence of colonic screen relevant neoplasias (SRNs; n=490 patients, 261 controls and 229 cases). We developed a reusable open-source pipeline to train, validate, and interpret ML models. To show the effect of model selection, we assessed the predictive performance, interpretability, and training time of L2-regularized logistic regression, L1 and L2-regularized support vector machines (SVM) with linear and radial basis function kernels, decision trees, random forest, and gradient boosted trees (XGBoost). The random forest model performed best at detecting SRNs with an AUROC of 0.695 [IQR 0.651-0.739] but was slow to train (83.2 h) and not inherently interpretable. Despite its simplicity, L2-regularized logistic regression followed random forest in predictive performance with an AUROC of 0.680 [IQR 0.625-0.735], trained faster (12 min), and was inherently interpretable. Our analysis highlights the importance of choosing an ML approach based on the goal of the study, as the choice will inform expectations of performance and interpretability.ImportanceDiagnosing diseases using machine learning (ML) is rapidly being adopted in microbiome studies. However, the estimated performance associated with these models is likely over-optimistic. Moreover, there is a trend towards using black box models without a discussion of the difficulty of interpreting such models when trying to identify microbial biomarkers of disease. This work represents a step towards developing more reproducible ML practices in applying ML to microbiome research. We implement a rigorous pipeline and emphasize the importance of selecting ML models that reflect the goal of the study. These concepts are not particular to the study of human health but can also be applied to environmental microbiology studies.
Syncytins enable novel possibilities to transduce human or mouse primary B cells and to achieve well-toleratedin vivogene transfer
Authors: Coquin Y. , Ferrand M. , Seye A. , Menu L. , Galy A. 
Published: October 2019

AbstractSyncytins are cellular transmembrane glycoproteins with fusogenic and immunosuppressive properties that are encoded by endogenous retroviral envelope sequences in mammalian genomes. Based on their properties, syncytins may be useful to pseudotype lentiviral gene transfer vectors (LV) and to obtain well-toleratedin vivogene delivery but their cellular targets are unknown in this context. We pseudotyped LV with human or murine syncytins. Such LV-Syn particles were infectiousin vitrobut required a transduction additive, as do other retroviral envelope LV pseudotypes. In these conditions, LV-Syn remarkably transduced quiescent human or murine primary B cells at high levelin vitroincluding naïve blood B cells or B cell precursors from murine bone marrow. Transduced human B cells could be expanded in culture and were functional. Human or murine T cells were transduced less efficiently than B cells, in agreement with lower levels of syncytin receptors on T cells compared to B cells. Well-toleratedin vivogene transfer was possible without additive, as demonstrated with murine syncytin A-mediated gene delivery in C57BL/6 mice. A single intravenous injection of LV-SynA vector to mice led to stable gene transfer into spleen germinal center B cells. LV-SynA were also intrinsically less immunogenic than LV-VSVG, leading to low antibody responses against the vector capsid. This is the first evidence of interactions between syncytins and B cells, providing novel opportunities for B cell genetic engineering and for well-tolerated gene transferin vivo. The findings also suggest that some immunosuppressive properties of syncytins could be mediated by B cells.One Sentence SummarySyncytins are fusogenic cellular proteins that can pseudotype lentiviral gene transfer vector particles, achieving efficient gene transfer into primary quiescent B cells and reducing thein vivoimmunogenicity of the particles following systemic administration.
MNase profiling of promoter chromatin inS. typhimurium-stimulated GM12878 cells reveals dynamic and response-specific nucleosome architecture
Authors: Cole Lauren , Dennis Jonathan 
Published: October 2019

AbstractThe nucleosome is the primary unit of chromatin structure and commonly imputed as a regulator of nuclear events, although the exact mechanisms remain unclear. Recent studies have shown that certain nucleosomes can have different sensitivities to micrococcal nuclease (MNase) digestion, resulting in the release of populations of nucleosomes dependent on the concentration of MNase. Mapping MNase sensitivity of nucleosomes at transcription start sites genome-wide reveals an important functional nucleosome organization that correlates with gene expression levels and transcription factor binding. In order to understand nucleosome distribution and sensitivity dynamics during a robust genome response, we mapped nucleosome position and sensitivity using multiple concentrations of MNase. We use the innate immune response as a model system to understand chromatin-mediated regulation. Herein we demonstrate that stimulation of a human lymphoblastoid cell line (GM12878) with heat-killedSalmonella typhimurium(HKST) results in widespread nucleosome remodeling of response-specific loci. We further show that the response alters the sensitivity of promoter nucleosomes. Finally, we correlate the increased sensitivity with response-specific transcription factor binding. These results indicate that nucleosome distribution and sensitivity dynamics are integral to appropriate cellular response and pave the way for further studies that will deepen our understanding of the specificity of genome response.
Characterization of splice isoform switching during human kidney development
Authors: Wineberg Yishay , Kanter Itamar , Ben-Haim Nissim , Pode-Shakked Naomi , Bucris Efrat , Bar-Lev Tali Hana , Oriel Sarit , Yehuda Yishai , Gershon Rotem , Shukrun Rachel , Bar-Lev Dekel Dov , Urbach Achia , Dekel Benjamin , Kalisky Tomer 
Published: October 2019

ABSTRACTNephrons are the functional units of the kidney. During kidney development, cells from the cap mesenchyme – a transient kidney-specific progenitor state – undergo a mesenchymal to epithelial transition (MET) and subsequently differentiate into the various epithelial cell types that create the tubular structures of the nephron. Faults in this transition can lead to a pediatric malignancy of the kidney called Wilms’ tumor that mimics normal kidney development. While kidney development has been characterized at the gene expression level, a comprehensive characterization of alternative splicing is lacking. We therefore performed RNA sequencing on cell populations representing early, intermediate, and late developmental stages of the human fetal kidney, as well as three blastemal-predominant Wilms’ tumor patient-derived xenografts. We identified a set of transcripts that are alternatively spliced between the different developmental stages. Moreover, we found that cells from the earliest developmental stage have a mesenchymal splice-isoform profile that is similar to that of blastemal-predominant Wilms’ tumors. RNA binding motif enrichment analysis suggests that the mRNA binding proteins ESRP1, ESRP2, RBFOX2, and QKI regulate mRNA splice isoform switching during human kidney development. These findings illuminate new molecular mechanisms involved in kidney development and pediatric kidney tumors.HIGHLIGHTSDuring fetal kidney development, kidney progenitor cells undergo a mesenchymal to epithelial transition (MET) and subsequently differentiate into the various epithelial cell types that create the tubular structures of the nephron.RNA sequencing identifies a set of transcripts that undergo splice isoform switching during the mesenchymal to epithelial transition (MET) that occurs in the course of human fetal kidney development.Cells in the early stages of kidney development have a mesenchymal splice-isoform profile that is similar to that observed in blastemal-predominant Wilms’ tumor patient-derived xenografts (WT-PDX) that represent an aggressive subtype of Wilms’ tumors.RNA binding motif enrichment analysis indicates that the mRNA binding proteins ESRP1, ESRP2, RBFOX2, and QKI regulate splice isoform switching during human kidney development.
Temporal models using environmental variables to predict Aedes aegypti oviposition activity in a temperate region of Argentina
Authors: Benitez Elisabet M. , Estallo Elizabet L. , Grech Marta , Frías-Céspedes Maria , Almirón Walter R. , Ludueña-Almeida Francisco F. 
Published: October 2019

AbstractEnvironmental variables are some of the factors that more impact on Aedes aegypti, vector of Dengue, Chikungunya and Zika viruses. In this study, the Ae. aegypti oviposition activity was related to satellite and meteorological variables, in Córdoba City (Argentina). Eggs were collected using ovitraps placed throughout the city from 2009 to 2012, replaced them weekly. Generalized Linear Mixed Models were developed with negative binomial distributions of errors, modeling average number of eggs collected weekly as a function of satellite and meteorological variables with time lags. The best model included a vegetation index, vapor pressure of water, precipitation and photoperiod, lagged between 3 and 4 weeks. By each increment unit in vegetation index, vapor pressure (hPa) and light hour, the average number of eggs increases by 72%, 20% and 29%, respectively, in the following 3 or 4 weeks. In addition, the average number of eggs decreases a 50% in the following month by each millimeter of rain. The results evince the relevant importance of the vegetation, maybe due to the shade that provide to the containers as breeding habitat of this species and the shelter for adults. On the other hand, the negative effect of precipitation could be a consequence of abundant rainfalls that fulfill containers avoiding females to lay eggs in there. Although no significant effect of the photoperiod on the vector abundance has been detected in the north of the country, in Córdoba City an important effect is observed when it is presented together with other variables, producing different effects of these variables in different regions. Lastly, it is necessary to emphasize the importance of the minimum temperature in temperate zones, since it would be a limiting factor that prevents the Ae. aegypti oviposition activity.
Radiographic and clinical risk factors of total knee arthroplasty in asymptomatic knees; a 15-year follow-up study
Authors: Nielsen Flemming Kromann , Jurik Anne Grethe , Jørgensen Anette , Egund Niels 
Published: October 2019

AbstractBackgroundRadiographic signs of osteoarthritis (OA) are frequent in knees without symptoms. The long-term impact of these findings is not completely elucidated. We wanted to evaluate whether radiographic or clinical baseline findings are associated with the risk of total knee arthroplasty (TKA) in knees without symptomatic OA but with clinical OA of the other knee during a mean follow-up period of 15 years.MethodsA follow-up analysis was performed in 100 persons with unilateral, clinical knee OA according to the ACR (American College of Rheumatology) criteria, who participated in a clinical trial between 2000 and 2002. Baseline radiographs of the contralateral, non-symptomatic knee were available in 88 participants at follow-up. Data on TKA procedures were extracted from the Danish National Patient Register at follow-up. Radiographic and clinical findings were analyzed for associations with subsequent TKA.ResultsAt follow-up, 40% had received a TKA in their non-symptomatic knee. The risk of TKA was significantly associated with baseline joint space narrowing (risk ratio (RR) 1.6 (95% confidence interval (95% CI) 1.4 to 1.9)), osteophytes (RR 1.5 (95% CI 1.3 to 1.8)) and subchondral sclerosis (RR 2.4 (95% CI 1.6 to 3.7)). Among the clinical findings, only baseline body mass index (BMI) was significantly associated with the risk of TKA (RR 1.4 (95& CI 1.1 to 1.8)).ConclusionsRadiographic OA changes and BMI at baseline were significantly associated with the long-term risk of TKA in persons without symptomatic knee OA but with symptomatic OA in the contralateral knee, implying that radiographic OA findings are important prognostic factors regardless of symptoms.
An integrated platform for genome engineering and gene expression perturbation in Plasmodium falciparum
Authors: Nasamu Armiyaw S. , Falla Alejandra , Pasaje Charisse Flerida A. , Wall Bridget A. , Wagner Jeffrey C. , Ganesan Suresh M. , Goldfless Stephen J. , Niles Jacquin C. 
Published: October 2019

ABSTRACTEstablishing robust genome engineering methods in the malarial parasite, Plasmodium falciparum, has the potential to substantially improve the efficiency with which we gain understanding of this pathogen’s biology to propel treatment and elimination efforts. Methods for manipulating gene expression and engineering the P. falciparum genome have been validated. However, a significant barrier to fully leveraging these advances is the difficulty associated with assembling the extremely high AT content DNA constructs required for modifying the P. falciparum genome. These are frequently unstable in commonly-used circular plasmids. We address this bottleneck by devising a DNA assembly framework leveraging the improved reliability with which large AT-rich regions can be efficiently manipulated in linear plasmids. This framework integrates several key functional genetics outcomes via CRISPR/Cas9 and other methods from a common, validated framework. Overall, this molecular toolkit enables P. falciparum genetics broadly and facilitates deeper interrogation of parasite genes involved in diverse biological processes.
Cohesin depleted cells rebuild functional nuclear compartments after endomitosis
Authors: Cremer Marion , Brandstetter Katharina , Maiser Andreas , Rao Suhas S P , Schmid Volker , Guirao-Ortiz Miguel , Mitra Namita , Mamberti Stefania , Klein Kyle N , Gilbert David M , Leonhardt Heinrich , Cardoso Maria Cristina , Aiden Erez Lieberman , Harz Hartmann , Cremer Thomas 
Published: October 2019

AbstractCohesin plays an essential role in chromatin loop extrusion, but its impact on a compartmentalized nuclear architecture, linked to nuclear functions, is debatable. Using live-cell and super-resolved 3D microscopy, we demonstrate that cohesin depleted cells pass through an endomitosis and rebuild a single multilobulated nucleus (MLN) with chromosome territories (CTs) pervaded by interchromatin channels. CTs contain chromatin domain clusters with a zonal organization of repressed chromatin domains in the interior and transcriptionally competent domains located at the periphery. Splicing speckles are located nearby within the lining channel system. These clusters form microscopically defined, active and inactive compartments, which correspond to A/B compartments, detected with ensemble Hi-C. Functionality of MLN despite continuous absence of cohesin was demonstrated by their ability to pass through S-phase with typical spatio-temporal patterns of replication domains. Evidence for structural changes of these domains compared to controls suggests that cohesin is required for their full integrity.
Genetic control of the human brain proteome
Authors: Robins Chloe , Wingo Aliza P. , Fan Wen , Duong Duc M. , Meigs Jacob , Gerasimov Ekaterina S. , Dammer Eric B. , Cutler David J. , Jager Philip L. De , Bennett David A. , Lah James J. , Levey Allan I. , Seyfried Nicholas T. , Wingo Thomas S. 
Published: October 2019

AbstractAlteration of protein abundance and conformation are widely believed to be the hallmark of neurodegenerative diseases. Yet relatively little is known about the genetic variation that controls protein abundance in the healthy human brain. The genetic control of protein abundance is generally thought to parallel that of RNA expression, but there is little direct evidence to support this view. Here, we performed a large-scale protein quantitative trait locus (pQTL) analysis using single nucleotide variants (SNVs) from whole-genome sequencing and tandem mass spectrometry-based proteomic quantification of 12,691 unique proteins (7,901 after quality control) from the dorsolateral prefrontal cortex (dPFC) in 144 cognitively normal individuals. We identified 28,211 pQTLs that were significantly associated with the abundance of 864 proteins. These pQTLs were compared to dPFC expression quantitative trait loci (eQTL) in cognitive normal individuals (n=169; 81 had protein data) and a meta-analysis of dPFC eQTLs (n=1,433). We found that strong pQTLs are generally only weak eQTLs, and that the majority of strong eQTLs are not detectable pQTLs. These results suggest that the genetic control of mRNA and protein abundance may be substantially distinct and suggests inference concerning protein abundance made from mRNA in human brain should be treated with caution.