bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clipper: p-value-free FDR control on high-throughput data from two conditions
Authors: Ge Xinzhou , Chen Yiling Elaine , Song Dongyuan , McDermott MeiLu , Woyshner Kyla , Manousopoulou Antigoni , Wang Ning , Li Wei , Wang Leo D. , Li Jingyi Jessica 
Published: November 2020

AbstractHigh-throughput biological data analysis commonly involves identifying features such as genes, genomic regions, and proteins, whose values differ between two conditions, from numerous features measured simultaneously. The most widely-used criterion to ensure the analysis reliability is the false discovery rate (FDR), which is primarily controlled based on p-values. However, obtaining valid p-values relies on either reasonable assumptions of data distribution or large numbers of replicates under both conditions. Clipper is a general statistical framework for FDR control without relying on p-values or specific data distributions. Clipper outperforms existing methods for a broad range of applications in high-throughput data analysis.
A newly identified prophage-encoded gene,ymfM, causes SOS-inducible filamentation inEscherichia coli
Authors: Ansari Shirin , Walsh James C. , Bottomley Amy L. , Duggin Iain G. , Burke Catherine , Harry Elizabeth J. 
Published: November 2020

AbstractRod-shaped bacteria such asEscherichia colican regulate cell division in response to stress, leading to filamentation, a process where cell growth and DNA replication continues in the absence of division, resulting in elongated cells. The classic example of stress is DNA damage which results in the activation of the SOS response. While the inhibition of cell division during SOS has traditionally been attributed to SulA inE. coli, a previous report suggests that the e14 prophage may also encode an SOS-inducible cell division inhibitor, previously named SfiC. However, the exact gene responsible for this division inhibition has remained unknown for over 35 years. A recent high-throughput over-expression screen inE. coliidentified the e14 prophage gene,ymfM, as a potential cell division inhibitor. In this study, we show that the inducible expression ofymfMfrom a plasmid causes filamentation. We show that this expression ofymfMresults in the inhibition of Z ring formation and is independent of the well characterised inhibitors of FtsZ ring assembly inE. coli, SulA, SlmA and MinC. We confirm thatymfMis the gene responsible for the SfiC+phenotype as it contributes to the filamentation observed during the SOS response. This function is independent of SulA, highlighting that multiple division inhibition pathways exist during the stress-induced SOS response. Our data also highlight that our current understanding of cell division regulation during the SOS response is incomplete and raises many questions regarding how many inhibitors there actually are and their purpose for the survival of the organism.ImportanceFilamentation is an important biological mechanism which aids in the survival, pathogenesis and antibiotic resistance of bacteria within different environments, including pathogenic bacteria such as uropathogenicEscherichia coli. Here we have identified a bacteriophage-encoded cell division inhibitor which contributes to the filamentation that occurs during the SOS response. Our work highlights that there are multiple pathways that inhibit cell division during stress. Identifying and characterising these pathways is a critical step in understanding survival tactics of bacteria which become important when combating the development of bacterial resistance to antibiotics and their pathogenicity.
Comparative genomics of Exiguobacterium reveals what makes a cosmopolitan bacterium
Authors: Zhang De-Chao , Zhu Zhaolu , Li Xudong , Guan Ziyu , Zheng Jinshui 
Published: November 2020

ABSTRACTAlthough the adaptation strategies of bacteria to specific environmental conditions are widely reported, fewer studies have addressed how microbe with cosmopolitan distribution adapted to diverse habitats. Exiguobacterium is a versatile genus whose members have been commonly found in great variety of habitats. To understand the mechanism behind the universally of Exiguobacterium, we isolated 103 strains from diverse environments, and performed large-scale metabolic and adaptive ability tests. We found that the capacities of survival in a wide range of temperature, salinity and pH are common for most Exiguobacterium members. According to the core genome based phylogeny and ANI analysis, 26 putative species including 13 putative new ones were identified and two genetic groups were classified as Group I and II. Comparative genomic analysis revealed that Exiguobacterium members can not only utilize a variety of complex polysaccharides and proteins that are ubiquitous in both terrestrial and marine environments, but also have a number of chaperonins and transporters which could support them to survive in different extreme environments. In addition, we found that the species from Group I can be found in more diverse environments with larger genome size compared to those of Group II. Twenty-five transporter families involved in transport of organic or inorganic substrates and environments stresses resistance were predicted to be enriched in Group I strains. This study provided the comprehensive insight into general genetic basis of the cosmopolitan distribution of a bacteria genus and deciphered putative determinants behind the ecological difference of different groups belonging to the same genus.IMPORTANCEThe wide distribution characteristics make Exiguobacterium a valuable model for studying adaptive strategy of bacteria adapted to multiple habitats. In this study, we found that comprehensive capacity of diverse polysaccharides utilization and environmental stress resistance is the important basis for survival, and selective expansion of transporters is an evolution and adaptation strategy for extensive distribution. Our findings are significant for understanding the adaptation and evolution mechanisms of cosmopolitan bacteria and explaining the vital genomic traits that facilitate niches adaptation.
Spatio-temporal Control of ERK Pulse Frequency Coordinates Fate Decisions during Mammary Acinar Morphogenesis
Authors: Ender Pascal , Gagliardi Paolo Armando , Dobrzyński Maciej , Frismantiene Agne , Dessauges Coralie , Höhener Thomas , Jacques Marc-Antoine , Cohen Andrew R. , Pertz Olivier 
Published: November 2020

AbstractThe signaling events controlling proliferation, survival, and apoptosis during mammary epithelial acinar morphogenesis remain poorly characterized. By imaging single-cell ERK activity dynamics in MCF10A acini, we find that these fates depend on the average frequency of non-periodic ERK pulses. High pulse frequency is observed during initial acinus growth, correlating with rapid cell motility. Subsequent decrease in motility correlates with lower ERK pulse frequency and quiescence. Later, during lumen formation, coordinated ERK waves emerge across multiple cells of an acinus, correlating with high and low ERK pulse frequency in outer surviving and inner dying cells respectively. Optogenetic entrainment of ERK pulses causally connects high ERK pulse frequency with inner cell survival. Acini harboring the PIK3CA H1047R mutation, commonly observed in breast cancer, display increased ERK pulse frequency, inner cell survival and loss of lumen formation. Thus, fate decisions during acinar morphogenesis are fine-tuned by different spatio-temporal coordination modalities of ERK pulse frequency.
How a Hemicarcerand Incarcerates Guests at Room Temperature Decoded with Modular Simulations
Authors: McFerrin Katherine G. , Pang Yuan-Ping 
Published: November 2020

AbstractHemicarcerands are host molecules created to study constrictive binding with guest molecules for insights into the rules of molecular complexation. However, the molecular dynamics simulations that facilitate such studies have been limited because three-dimensional models of hemicarcerands are tedious to build and their atomic charges are complicated to derive. There have been no molecular dynamics simulations of the reported water-soluble hemicarcerand (Octacid4) that explain how it uniquely encapsulates its guests at 298 K and keeps them encapsulated at 298 K in NMR experiments. Herein we report a modular approach to hemicarcerand simulations that simplifies the model building and charge derivation in a manner reminiscent of the approach to protein simulations with truncated amino acids as building blocks. We also report thatapoOctacid4 in water adopts two clusters of conformations, one of which has an equatorial portal open thus allowing guests to enter the cavity of Octacid4, in microsecond molecular dynamics simulations performed using the modular approach at 298 K. Under the same simulation conditions, the guest-bound Octacid4 adopts one cluster of conformations with all equatorial portals closed thus keeping the guests incarcerated. These results explain the unique constrictive binding of Octacid4 and suggest that the guest-induced host conformational change that impedes decomplexation is a previously unrecognized conformational characteristic that promotes strong molecular complexation.
IBEX – A versatile multi-plex optical imaging approach for deep phenotyping and spatial analysis of cells in complex tissues
Authors: Radtke Andrea J. , Kandov Evelyn , Lowekamp Bradley , Speranza Emily , Chu Colin J. , Gola Anita , Thakur Nishant , Shih Rochelle , Yao Li , Yaniv Ziv Rafael , Beuschel Rebecca T. , Kabat Juraj , Croteau Joshua , Davis Jeremy , Hernandez Jonathan M. , Germain Ronald N. 
Published: November 2020

AbstractThe diverse composition of mammalian tissues poses challenges for understanding the cell-cell interactions required for organ homeostasis and how spatial relationships are perturbed during disease. Existing methods such as single-cell genomics, lacking a spatial context, and traditional immunofluorescence, capturing only 2-6 molecular features, cannot resolve these issues. Imaging technologies have been developed to address these problems, but each possesses limitations that constrain widespread use. Here we report a new method that overcomes major impediments to highly multi-plex tissue imaging.IterativeBleachingExtends multi-pleXity (IBEX) uses an iterative staining and chemical bleaching method to enable high resolution imaging of >65 parameters in the same tissue section without physical degradation. IBEX can be employed with various types of conventional microscopes and permits use of both commercially available and user-generated antibodies in an ‘open’ system to allow easy adjustment of staining panels based on ongoing marker discovery efforts. We show how IBEX can also be used with amplified staining methods for imaging strongly fixed tissues with limited epitope retention and with oligonucleotide-based staining, allowing potential cross-referencing between flow cytometry, Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-Seq), and IBEX analysis of the same tissue. To facilitate data processing, we provide an open source platform for automated registration of iterative images. IBEX thus represents a technology that can be rapidly integrated into most current laboratory workflows to achieve high content imaging to reveal the complex cellular landscape of diverse organs and tissues.Significance StatementSingle cell flow cytometry and genomic methods are rapidly increasing our knowledge of the diversity of cell types in metazoan tissues. However, suitably robust methods for placing these cells in a spatial context that reveal how their localization and putative interactions contribute to tissue physiology and pathology are still lacking. Here we provide a readily accessible pipeline (IBEX) for highly multi-plex immunofluorescent imaging that enables a fine-grained analysis of cells in their tissue context. Additionally, we describe extensions of the IBEX workflow to handle hard to image tissue preparations and a method to facilitate direct integration of the imaging data with flow cytometry and sequencing technologies.
Genome-wide screen of genomic imprinting in endosperm and population-level analysis reveal allelic variation for imprinting in flax
Authors: Jiang Haixia , Guo Dongliang , Ye Jiali , Gao Yanfang , Liu Huiqing , Wang Yue , Xue Min , Yan Qingcheng , Chen Jiaxun , Duan Lepeng , Li Gongzhe , Li Xiao , Xie Liqiong 
Published: November 2020

AbstractGenomic imprinting is an epigenetic phenomenon caused by the biased expression of maternally and paternally inherited alleles. In flowering plants, genomic imprinting predominantly occurs in triploid endosperm and plays a vital role in seed development. In this study, we identified 241 candidate imprinted genes including 143 maternally expressed imprinted genes (MEGs) and 98 paternally expressed imprinted genes (PEGs) in flax (Linum usitatissimumL.) endosperm using deep RNA sequencing. The conservation of imprinting in plants is very limited and imprinting clustering is not a general feature. MEGs tends to be endosperm expression specific, while PEGs are non-tissue specific. Imprinted SNPs differentiated 200 flax cultivars into oil flax, oil-fiber dual purpose flax (OF) and fiber flax subgroups, suggesting that genomic imprinting contributes to intraspecific variation in flax. The nucleotide diversity (π) of imprinted genes in oil flax subgroup is significantly higher than that in fiber flax subgroup, indicating that some imprinted genes undergo positive selection during flax domestication from oil flax to fiber flax. Imprinted genes undergo positive selection is related to the functions. Eleven imprinted genes related to seed size and weight were identified using the candidate gene-based association study. Our study provides information for further exploring the function and genomic variation of imprinted genes in flax population.
Bioinformatic Analysis Linking Genomic Defects to Chemosensitivity and Mechanism of Action
Authors: Covell David G. 
Published: November 2020

ABSTRACTA joint analysis of NCI60 small molecule screening data, their genetically defective genes and mechanisms of action (MOA) of FDA approved cancer drugs screened in the NCI60 is proposed for identifying links between chemosensitivity, genomic defects and MOA. Self-organizing-maps (SOMs) are used to organize the chemosensitivity data. Student’s t-tests are used to identify SOM clusters with chemosensitivity for tumor cells harboring genetically defective genes. Fisher’s exact tests are used to reveal instances where defective gene to chemosensitivity associations have enriched MOAs. The results of this analysis find a relatively small set of defective genes, inclusive of ABL1, AXL, BRAF, CDC25A, CDKN2A, IGF1R, KRAS, MECOM, MMP1, MYC, NOTCH1, NRAS, PIK3CG, PTK2, RPTOR, SPTBN1, STAT2, TNKS and ZHX2, as possible candidates for roles in chemosensitivity for compound MOAs that target primarily, but not exclusively, kinases, nucleic acid synthesis, protein synthesis, apoptosis and tubulin. This analysis may contribute towards the goals of cancer drug discovery, development decision making, and explanation of mechanisms.
Evaluation of Genomic and Proteomic Expression of Surfactant Protein D in the Mouse Retina
Authors: Vieira Frederico , Kung Johannes W. , Bhatti Faizah 
Published: November 2020

AbstractSurfactant Protein D (SP-D), an essential protein related to innate immunity, is expressed in multiple tissue types throughout the body. A closely-related protein, Surfactant Protein A (SP-A), is present in the mouse retina and is associated with neovascularization (NV) in the Oxygen-Induced Retinopathy (OIR) mouse model, mimicking retinopathy of prematurity (ROP). We hypothesized that SP-D would be present in the retina and is also associated with OIR and ROP, which is one of the leading causes of pediatric blindness due to increasing survival rates of extremely preterm newborns. In our study, we did not detect SP-D in the mouse retina through proteomic and genomic investigation at baseline and in pathways known to up-regulate SP-D in other mammal tissues. It is therefore unlikely that SP-D participates in neovascularization in the mouse retina.
Structural dynamics of the functional nonameric Type III translocase export gate
Authors: Yuan Biao , Portaliou Athina G. , Parakra Rinky , Smit Jochem H. , Wald Jiri , Li Yichen , Srinivasu Bindu , Loos Maria S. , Dhupar Harveer Singh , Fahrenkamp Dirk , Kalodimos Charalampos G. , Duong van Hoa Franck , Cordes Thorben , Karamanou Spyridoula , Marlovits Thomas C. , Economou Anastassios 
Published: November 2020

AbstractType III protein secretion is widespread in Gram-negative pathogens. It comprises the injectisome with a surface-exposed needle and an inner membrane translocase. The translocase contains the SctRSTU export channel enveloped by the export gate subunit SctV that binds chaperone/exported clients and forms a putative ante- chamber. We probed the assembly, function, structure and dynamics of SctV from enteropathogenicE.coli(EPEC). In both EPEC andE.colilab strains, SctV forms peripheral oligomeric clusters that are detergent-extracted as homo-nonamers. Membrane-embedded SctV9is necessary and sufficient to act as a receptor for different chaperone/exported protein pairs with distinct C-domain binding sites that are essential for secretion. Negative staining electron microscopy revealed that peptidisc-reconstituted His-SctV9forms a tripartite particle of ∼22 nm with a N- terminal domain connected by a short linker to a C-domain ring structure with a ∼5 nm-wide inner opening. The isolated C-domain ring was resolved with cryo-EM at 3.1 Å and structurally compared to other SctV homologues. Its four sub-domains undergo a three-stage “pinching” motion. Hydrogen-deuterium exchange mass spectrometry revealed this to involve dynamic and rigid hinges and a hyper-flexible sub-domain that flips out of the ring periphery and binds chaperones on and between adjacent protomers. These motions are coincident with pore surface and ring entry mouth local conformational changes that are also modulated by the ATPase inner stalk. We propose a model that the intrinsic dynamics of the SctV protomer are modulated by chaperones and the ATPase and could affect allosterically the other subunits of the nonameric ring during secretion.
Molecular signatures of resource competition: clonal interference favors ecological diversification and can lead to incipient speciation
Authors: Amicone Massimo , Gordo Isabel 
Published: November 2020

AbstractMicrobial ecosystems harbor an astonishing diversity that can persist for long times. To understand how such diversity is structured and maintained, ecological and evolutionary processes need to be integrated at similar timescales. Here, we study a model of resource competition that allows for evolutionvia de novomutation, and focus on rapidly adapting asexual populations with large mutational inputs, as typical of many bacteria species. We characterize the adaptation and diversification of an initially maladapted population and show how the eco-evolutionary dynamics are shaped by the interaction between simultaneously emerging lineages – clonal interference. We find that in large populations, more intense clonal interference fosters diversification under sympatry, increasing the probability that phenotypically and genetically distinct clusters stably coexist. In smaller populations, the accumulation of deleterious and compensatory mutations can push further the diversification process and kick-start speciation. Our findings have implications beyond microbial populations, providing novel insights about the interplay between ecology and evolution in clonal populations.
Improved prediction of femoral fracture toughness in mice by combining standard medical imaging with Raman spectroscopy
Authors: Massie Christine , Knapp Emma , Chen Keren , Berger Andrew J , Awad Hani A 
Published: November 2020

AbstractBone fragility and fracture risk are assessed by measuring the areal bone mineral density (aBMD) using dual-energy X-ray absorptiometry (DXA). While aBMD correlates with bone strength, it is a poor predictor of fragility fracture risk. Alternatively, fracture toughness assesses the bone’s resistance to crack propagation and fracture, making it a suitable bone quality metric. Here, we explored how femoral midshaft measurements from DXA, micro-computed tomography (μCT), and Raman spectroscopy could predict fracture toughness. We hypothesized that ovariectomy (OVX) decreases aBMD and fracture toughness compared to controls and we can optimize a multivariate assessment of bone quality by combining results from X-ray and Raman spectroscopy. Female mice underwent an OVX (n=5) or sham (n=5) surgery at 3 months of age. Femurs were excised 3 months after ovariectomy and assessed with Raman spectroscopy, μCT, and DXA. Subsequently, a notch was created on the anterior side of the mid-diaphysis of the femurs. Three-point bending induced a controlled fracture that initiated at the notch. The OVX mice had a significantly lower aBMD, cortical thickness, and fracture toughness when compared to controls (p<0.05). A leave one out cross-validated (LOOCV) partial least squares regression (PLSR) model based only on the combination of aBMD and cortical thickness showed no significant predictive correlations with fracture toughness, whereas a PLSR model based on principal components derived from the full Raman spectra yielded significant prediction (r2=0.71, p<0.05). Further, the PLSR model was improved by incorporating aBMD, cortical thickness, and principal components from Raman spectra (r2=0.92, p<0.001). This exploratory study demonstrates combining X-ray with Raman spectroscopy leads to a more accurate assessment of bone fracture toughness and could be a useful diagnostic tool for the assessment of fragility fracture risk.
A causal analysis of the effect of age and sex differences on brain atrophy in the elderly brain
Authors: Gómez-Ramírez Jaime , Fernández-Blázquez Miguel A. , González-Rosa Javier 
Published: November 2020

AbstractWe study how brain volume loss at old age is affected by factors such as age, APOE gene, sex, and school level. The quantitative characterization of brain volume loss at old age relative to young age requires at least in principle two MRI scans performed at both young and old age. There is, however, a way to address the problem by having only one MRI scan at old age. We compute the total brain loss of elderly subjects as the ratio between the estimated brain volume and the estimated total intracranial volume. Magnetic resonance imaging (MRI) scans of 890 healthy subjects aged 70 to 85 were assessed. The causal analysis of factors affecting brain atrophy was performed using Probabilistic Bayesian Modeling and the Mathematics of Causal Inference. We find that healthy subjects get into their seventies with an average brain volume loss of 30% from their maximum brain volume at a young age. Both age and the sexes are causally related to brain atrophy, with women getting to elderly age with 1% larger brain volume relative to intracranial volume than men. How the brain ages and what are the reasons for sex differences in adult lifespan are causal questions that need to be addressed with causal inference and empirical data. The graphical causal modeling presented here can be instrumental in understanding a puzzling scientific inquiry -the biological age of the brain.